PQ Continum

REVIEW ARTICLE

Behavioral and Cognitive
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Aspects of Concussion
By Russell M. Bauer, PhD; Michael S. Jaffee, MD, FAAN
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ABSTRACT
PURPOSE OF REVIEW: This review provides the reader with an overview of
concussion and mild traumatic brain injury (TBI). Key aspects of the
pathophysiology, signs, and symptoms, treatment and rehabilitation, and
recovery from concussion/mild TBI are reviewed with an emphasis on the
variety of factors that may contribute to cognitive concerns following injury.
CITE AS:
CONTINUUM (MINNEAP MINN)
2021;27(6, BEHAVIORAL NEUROLOGY RECENT FINDINGS: Concussion remains a clinical diagnosis based on
AND PSYCHIATRY):1646–1669. symptoms that occur in the immediate aftermath of an applied force and in
the hours, days, and weeks thereafter. Although advances have been made
Address correspondence to
Dr Russel M. Bauer, Department
in advanced diagnostics, including neuroimaging and fluid biomarkers in
of Clinical & Health Psychology, hopes of developing objective indicators of injury, such markers currently
University of Florida, PO Box lack sufficient specificity to be used in clinical diagnostics. The symptoms
100165 HSC, Gainesville, FL
32610-0165, rbauer@phhp.ufl. of concussion are heterogeneous and may be seen to form subtypes, each
edu. of which suggests a targeted rehabilitation by the interdisciplinary team.
Although the majority of patients with concussion recover within the first
RELATIONSHIP DISCLOSURE:
Dr Bauer has received personal 30 to 90 days after injury, some have persistent disabling symptoms. The
compensation for serving as an concept of postconcussion syndrome, implying a chronic syndrome of
oral examiner for the American
Board of Clinical
injury-specific symptoms, is replaced by a broader concept of persistent
Neuropsychology and a symptoms after concussion. This concept emphasizes the fact that most
conference speaker for the persistent symptoms have their basis in complex somatic, cognitive,
American Academy of Clinical
Neuropsychology and has psychiatric, and psychosocial factors related to risk and resilience. This
received grant support from the framework leads to the important conclusion that concussion is a treatable
National Institute of Mental injury from which nearly all patients can be expected to recover.
Health (1R01 MH118514-01A1).
Dr Jaffee has received personal
compensation for serving on the SUMMARY: Concussion/mild TBI is a significant public health problem in civilian,
scientific advisory board for
Novo Nordisk A/S and as a
military, and organized athletic settings. Recent advances have led to a better
subject matter expert for understanding of underlying pathophysiology and symptom presentation
McDermott Will & Emery on and efficacious treatment and rehabilitation of the resulting symptoms. An
behalf of the NCAA and has
received research support from
interdisciplinary team is well-positioned to provide problem-oriented,
the University of Florida and a integrated care to facilitate recovery and to advance the evidence base
grant from the National supporting effective practice in diagnosis, treatment, and prevention.
Institutes of Health
(R01NS058487).
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL INTRODUCTION
F
USE DISCLOSURE:
Drs Bauer and Jaffee report no
ew entities in clinical neurology have received the degree of scientific,
disclosures. clinical, and lay attention as has concussion/mild traumatic brain injury
(TBI). Widely recognized as imposing a significant public health
© 2021 American Academy burden, with nearly 1.7 million mild TBIs per year in the United States,
of Neurology. concussion/mild TBI has emerged as a significant area of clinical
1646 DECEMBER 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

specialty care and scientific inquiry. This article provides an overview of the KEY POINTS
current knowledge base in concussion, focusing on (1) the definition, signs,
● Both the American
symptoms, and pathophysiologic basis of concussion; (2) factors that facilitate Congress of Rehabilitation
and impede recovery; and (3) key principles of concussion management. Medicine and Concussion in
Sport Group definitions
CONCUSSION BASICS make clear the idea that
concussion represents a
Definitions of concussion have historically been broad to capture injury severities
functional, not a structural,
across the spectrum. According to the American Congress of Rehabilitation disturbance.
Medicine, concussion is a “traumatically induced physiological disruption of
brain function” where the Glasgow Coma Scale score range is 13 to 15 and the ● Concussion remains a
injury results in at least one of the following manifestations: (1) an alteration in clinical diagnosis that is
based on observed
mental status at the time of the accident (eg, disorientation, confusion); (2) alterations of
pretraumatic or posttraumatic memory loss (amnesia) spanning less than consciousness, reported
24 hours; (3) loss of consciousness (if any) less than 30 minutes; and (4) focal symptoms, and/or results of
neurologic deficits that may or may not be transient.1 Focusing on sport-related neurologic, cognitive,
balance, and ocular motor
concussion, the Concussion in Sport Group defined concussion as a “traumatic assessments.
brain injury induced by biomechanical forces.”2 Both the American Congress of
Rehabilitation Medicine and Concussion in Sport Group definitions make clear
the idea that concussion represents a functional, not a structural, disturbance.
Many experts use the term mild traumatic brain injury (TBI) and concussion
interchangeably.
Concussion may be caused by a direct blow to the head, face, neck, or
elsewhere on the body with an impulsive force transmitted to the head causing
acceleration/deceleration of the brain. Concussion results in a range of clinical
signs and symptoms that may or may not involve loss of consciousness.
Resolution of the clinical and cognitive features typically follows a sequential
course, and, in most cases, is complete within 1 month. However, in some cases,
symptoms may be prolonged. Concussion signs and symptoms cannot be solely
explained by drug, alcohol, or medication use, other injuries (eg, cervical injuries
or peripheral vestibular dysfunction), or other comorbidities (eg, coexisting
psychiatric or medical conditions). However, the presence of comorbidities can
prolong or complicate presentation and recovery (discussed later in this article).
The key concept here is that concussion remains a clinical diagnosis that is based
on observed alterations of consciousness, reported symptoms, and/or results of
neurologic, cognitive, balance, and ocular motor assessments.3 The
nonspecificity of concussionlike symptoms can lead to clinical uncertainty and
has sparked interest in more objective measures, particularly in light of research
suggesting that physiologic abnormalities to cognitive or physical challenges may
remain after the clinical manifestations of concussion have resolved.4,5
A multilevel pathophysiologic response occurs in the minutes, hours, and days
after concussion, which has been referred to as a neurometabolic cascade.6 The
linear and rotational forces associated with concussion result in shearing and
straining of white matter and cause mechanical axon deformation. These
deformations open membrane channels, resulting in an indiscriminate release of
the excitatory transmitter glutamate, as well as a large-scale efflux of potassium
and influx of calcium and sodium. Increased energy demands ensue to activate
ion pumps so that neuronal homeostasis can be restored. However, increased
energy demands occur in the context of decreased cerebral blood flow, causing a
supply and demand mismatch. This resulting cerebral energy crisis presumably
contributes to the acute symptoms following concussion.6 Mechanical injury to
CONTINUUMJOURNAL.COM 1647

BEHAVIORAL AND COGNITIVE ASPECTS OF CONCUSSION
axons and cytoskeletal components, as well as altered neurotransmission, may

occur downstream and be responsible for subacute or postacute symptoms,
particularly in cognition and motor performance. Inflammatory processes,
excitotoxicity, and oxidative stress, due in part to glutamate release and
activation of immune receptors, have been cited as a possible basis for more
chronic effects. However, the full extent to which unresolved physiologic
dysfunction contributes to persisting symptoms is largely unknown.
THE SYMPTOM LANDSCAPE OF CONCUSSION

Despite recent advances in neuroimaging and biomarker research, no definitive
“gold standard” diagnostic test for concussion exists. Concussion remains a
clinical diagnosis dependent on connecting the dots between a traumatic event
TABLE 7-1 Presentation, Evaluation, and Treatment of Concussion-Related Symptoms
Symptom
domain Symptomsa Objective evaluation techniquesb Treatment
Cognitive Fogginess, concentration Computerized or paper-and-pencil Cognitive rehabilitation,

difficulties, memory problems neuropsychological evaluation; cognitive-behavioral treatment,
symptom checklists (eg, Sports treatment of disruptive
Concussion Assessment Tool-Fifth symptoms in other domains
Edition [SCAT-5])
Ocular Headache, blurred vision, light Neurologic evaluation of eye Ocular motor physical therapy,
motor sensitivity, pressure behind the movements, convergence occupational therapy
eyes, sensitivity to activities
involving computer screens, eye
fatigue
Vestibular Dizziness, “fogginess,” nausea, Vestibular/ocular motor screening, Vestibular physical therapy;
disequilibrium dynamic visual acuity test Epley maneuver or related
interventions (if appropriate)
Headache Nausea, vomiting, light and noise Diagnostic interview, Migraine Medications, environmental
sensitivity, head pain Disability Assessment (MIDAS), manipulations
Headache Impact Test (HIT-6)
Anxiety Anxiety: nervousness, feeling Generalized Anxiety Disorder 7-Item Cognitive-behavior therapy,
and mood overwhelmed, hypervigilance; Scale (GAD-7), Patient Health medication
depression: sadness, irritability, Questionnaire 9-item depression scale
loss of energy, fatigue, poor (PHQ-9), Beck Depression Inventory,
motivation Beck Anxiety Inventory, State-Trait
Anxiety Inventory
Concussion-related conditions
Sleep Delayed initiation and poor Pittsburgh Sleep Quality Index (PSQI), Medication, environmental
maintenance of sleep, middle-of- Epworth Sleepiness Scale, STOP- manipulations, cognitive-
the-night awakenings, excessive BANG questionnaire behavioral therapy for insomnia
daytime sleepiness
Cervical Neck pain, neck stiffness, occipital Clinical examination, range of motion, Physical therapy, medications
strain or suboccipital headache pain assessment
a
Symptoms may be exacerbated by physical or mental activity.
b
Objective evaluation techniques should be used in conjunction with a thorough clinical examination.
1648 DECEMBER 2021

and a variable set of symptoms that, in the judgment of the clinician, are linked in KEY POINTS
time to the injury. Two key challenges to diagnosis and management are the
● Concussion can produce
marked heterogeneity of symptom presentations and the striking degree to concerns and problems in
which such symptoms overlap with other prevalent conditions. For example, cognitive function, including
posttraumatic headaches are common after mild TBI, but some patients do not reductions in attention,
have them, and headaches are seen in a large number of other neurologic and reaction time, processing
speed, working memory,
medical conditions besides concussion. A summary of symptom domains,
memory, and executive
associated concerns, and objective clinical evaluation tools is presented in functioning.
TABLE 7-1.
In the clinic, symptoms are assessed through structured clinical interviews or ● Assessment of cognitive
symptom checklists7,8 that ask the respondent to indicate whether they have had dysfunction should include
interview-based questions
each symptom and, if so, to rate it along a scale of severity. The Sports focused on the daily course
Concussion Assessment Tool-Fifth Edition (SCAT-5) is a widely used and factors that precipitate
consensus-based assessment tool that yields a symptom score (how many of the the onset of cognitive
22 symptoms are present) and an overall severity score (a summed severity symptoms, as well as
objective measurement of
rating of all present symptoms, with scores ranging from 0 to 132). When the cognitive function.
SCAT-5 and its predecessors (eg, SCAT-3) are subject to factor analysis, what
emerges is a general severity factor (on which all items load) and six specific
factors (vestibulo-ocular, headache, sensory, fatigue, cognitive, and
emotional/psychiatric)9 that reflect the primary symptom pattern. The idea that
clinical symptoms of concussion group themselves into distinct factors has
implications for specialty concussion care that are discussed after a basic review
of symptoms in each of the major domains is described. Currently, the key idea is
that, if different “subtypes” or “profiles” are identified early in the
postconcussive period, then rehabilitative pathways can be more readily tailored
to the patient’s presentation.10,11
Cognitive Dysfunction
Concussion can produce symptoms and problems in cognitive function,
including reductions in attention, reaction time, processing speed, working
memory, memory, and executive functioning.12 On symptom report measures,
patients report difficulty remembering, difficulty concentrating, feeling slowed
down, or feeling “in a fog.”
A 2020 study showed that cognitive disturbance is reported in 32% of patients
in the first 2 days after injury, 40% within the first 3 to 10 days, 47% in the first
month, and 39% in the first 3 months.12 Slightly lower rates of subjective memory
and concentration difficulties have been reported at 3 months (25% and 26%,
respectively)13 and 1 year after injury (26% and 25%, respectively).14 Additional
findings indicate that symptom reports of cognitive dysfunction across TBI
severities increased as a function of lower education, coexisting substance use,
and premorbid psychiatric diagnosis.14
Assessment of cognitive dysfunction should include interview-based
questions focused on the daily course and factors that precipitate the onset of
cognitive symptoms, as well as objective measurement of cognitive function.15
Although a comprehensive neuropsychological examination is preferred, it is not
feasible in the context of a multimodal TBI assessment. Therefore, clinicians have
adopted the use of computerized neurocognitive tests to screen for cognitive
disturbance. Some computerized neurocognitive tests have demonstrated
psychometric characteristics similar to those of the conventional
neuropsychological tests on which they are based.16,17 In a population-based

study, a proportion of participants with mild TBI demonstrated deficits in

domains of executive ability (21.5%), complex attention (26%), and cognitive
flexibility (27.4%) within 2 weeks of injury.18 Deficits in executive ability and
cognitive flexibility largely resolved by 1 and 6 months, respectively, but greater
than 20% remained in the very low range of complex attention at both time
points. Given the discrepancy between rates of subjective and objective cognitive
disturbance19 and that the majority of patients do not report debilitating
cognitive disturbance after concussion, it may be important to consider the fact
that cognition can suffer not only as a primary deficit but also when the patient
experiences significant associated emotional/psychiatric or somatic symptoms in
the aftermath of a concussion. Therefore, it is important to be aware of the other
associated symptoms of concussion because identifying and treating these
aspects may also be part of an overall approach to targeting cognitive dysfunction
following concussion.
Ocular Motor Dysfunction

Ocular motor symptoms can lead to difficulty obtaining, understanding, and
processing visual stimuli. Symptoms include frontal headache, blurred vision,
sensitivity to light, pressure behind the eyes, difficulty with visually based
activities, and eye fatigue.15 Specifically assessing these symptoms is necessary
because commonly used symptom checklists do not specify the location of the
headache or pressure in the head and do not query about difficulty with visually
based activities.
Ocular motor deficits occur in between 18% and 34% of patients within the
first 3 months after concussion.12 Dikmen and colleagues14 reported that blurred
vision and sensitivity to light were more common in patients with TBI compared
with trauma controls at 1 month. Although nonsignificant at 1 year after injury,
participants with mild TBI had slightly higher rates of blurred vision (16%) and
sensitivity to light (15%) compared with trauma controls (10% and 5%,
respectively).
Convergence insufficiency, a binocular visual dysfunction that results in eye
coordination and alignment dysfunction, is a common marker of ocular motor
dysfunction and has been reported in up to 42% of participants following mild
TBI.20 Convergence insufficiency can result in an increase in symptoms when
engaged in near-point activities, such as reading.21 Concentration difficulties
often accompany ocular motor deficits because of the disruption of the visual
system, which can mimic cognitive dysfunction. Pearce and colleagues22
demonstrated that athletes with convergence insufficiency (of greater than 5 cm)
reported higher symptom total scores and performed worse on computerized
memory and speed measures. When engaged in visual testing of smooth pursuit
and vertical or horizontal saccades, symptoms may be exacerbated. In a study of
adolescent athletes evaluated within 2 weeks of injury, 36.8%, 48.5%, and 53.6%
reported symptom exacerbation following smooth pursuits, horizontal saccades,
and vertical saccades, respectively.23 Failure to diagnose and treat these problems
may prolong symptoms in other domains.
Vestibular Dysfunction
Vestibular dysfunction is common after concussion and is manifested in
abnormalities on tests that involve movement and orientation of the body to
space and time. Symptoms include dizziness, fogginess, nausea, and
1650 DECEMBER 2021

disequilibrium.15 Patients with vestibular dysfunction report symptom KEY POINTS
exacerbation in highly stimulating environments or following rapid head or
● Given the discrepancy
body movements. between rates of subjective
Vestibular disturbance is common, with 24% to 51% of patients with and objective cognitive
concussion reporting symptoms in the first 3 months after injury.12 Evidence disturbance in patients with
suggests that the presence of vestibular symptoms predisposes the individual to a concussion and that the
majority of patients do not
prolonged recovery (beyond 1 month).24,25
report debilitating cognitive
Vestibular dysfunction can be assessed by using the vestibular/ocular motor disturbance after
screening and dynamic visual acuity test. The vestibular portion of concussion, it may be
vestibular/ocular motor screening consists of assessing symptom provocation important to consider the
fact that cognition can
following administration of horizontal and vertical movements of the eyes
suffer not only as a primary
(smooth pursuit and saccades) and then horizontal and vertical movements of deficit but also when the
the head. In a study of athletes with concussions, 61% (versus 9% in controls)26 patient experiences
reported symptom provocation following testing of horizontal gaze, and significant associated
symptom provocation or clinical abnormality on any vestibular/ocular domain emotional/psychiatric or
somatic symptoms in the
was associated with prolonged recovery in youth athletes (those younger than aftermath of a concussion.
18 years [13.9 ± 2.5 years old]). The dynamic visual acuity test objectively
measures visual acuity in dynamic and static positions. Research has revealed ● Ocular motor symptoms
abnormal dynamic visual acuity test scores in adults and youth following mild after concussion can lead to
difficulty obtaining,
TBI.27,28 However, the relationship between abnormal dynamic visual acuity test understanding, and
and recovery from concussion is relatively unknown. Vestibular symptoms that processing visual stimuli.
do not acutely resolve may persist in the absence of intervention.
● Vestibular dysfunction is
common after concussion
Headache
and is manifested in
Posttraumatic headache is a common symptom that may affect cognition and abnormalities on tests that
emotional status after concussion. The pattern of recurrent headaches can be involve movement and
moderate to severe in intensity. Symptoms accompanying the headache typically orientation of the body to
include nausea, vomiting, and sensitivity to light and noise that may be space and time.
exacerbated by physical activity.15 Depending on the severity, headaches can be ● Posttraumatic headache
present intermittently or may be chronic and frequent. is a common symptom that
In a prospective study of prevalence and characterization of headache may affect cognition and
following concussion, Lucas and colleagues29 reported 54% of participants emotional status after
concussion.
reported new or worsened headache immediately following the injury. Rates of
reported headache increased to 62%, 69%, and 58% at 3 months, 6 months, and ● After concussion, many
1 year, respectively. However, only 36% of participants reported headache at all patients report increases in
follow-up time points. Other studies have reported lower rates (15% to 44% anxiety or depressive
symptoms, attributable to
overall) of posttraumatic headaches at 3 months (15% to 21%),13,30 6 months
both the effects of injury on
(44%), and 1 year after injury (25%).31 History of premorbid headaches and neuronal function and the
female sex predict headache reporting across time points. Non–injury-related injured person’s reaction
factors including increased stress, sleep dysregulation, psychiatric comorbidities, to it.
and dietary changes may exacerbate migraine symptoms.
Diagnostic interviews together with validated headache scales32-34 are the gold
standard when measuring headache severity. However, when unavailable,
headache severity on traditional symptom scales is suitable. Including studies
that utilized both approaches, moderate-to-severe headaches are seen in 45% to
64% of participants within the first 3 months after concussion.12
Anxiety or Mood
After concussion, many patients report increases in anxiety or depressive
symptoms, attributable to both the effects of injury on neuronal function and the

injured person’s reaction to it. Anxiety symptoms can include nervousness, an

increase in reactivity, hypervigilance, ruminative thoughts, and feelings of being
overwhelmed. Depressive symptoms can include sadness, emotional instability,
anger, irritability, loss of energy, fatigue, and feelings of hopelessness.
Sleep-onset insomnia is also common in patients with symptoms of anxiety or
depression or both.15 Anxiety and depressive disorders commonly co-occur;
comorbid anxiety has been reported in 72% to 77% of participants with a brain
injury who have major depressive disorder.35,36
Anxiety and depressive symptoms can be quickly assessed by using
self-report questionnaires, such as the Generalized Anxiety Disorder 7-item
scale (GAD-7)37 and Patient Health Questionnaire 9-item depression scale
(PHQ-9).38 A prospective study using the PHQ-9 reported that 53.1% of
participants met criteria for major depressive disorder during the first
postinjury year.39 The prevalence of major depressive disorder at 1 and
6 months was 31% and 21%, respectively. Regarding anxiety disorders,
prevalence rates range up to 70%.40 A 2016 systematic review revealed that
prevalence rates of anxiety disorders ranged from 10% to 34%, with a pooled
prevalence rate of 21%, in the first year after injury.36 Higher rates of anxiety and
mood disturbance are seen within the first 2 days (28%), 3 to 10 days (52%),
11 days to 1 month (27%), and 1 to 3 months (23%) after injury.12 Predictors of
anxiety and depression after injury included current or past psychiatric
diagnosis, female sex, older age, being unemployed, and lifetime
alcohol dependence.36,39
CONCUSSION-ASSOCIATED CONDITIONS
In addition to the main associated subtypes or symptoms of concussion described
earlier, analyses have identified two concussion-associated conditions that may
also have effects on cognition and other symptoms of concussion.
Sleep Dysfunction
Sleep disturbance is quite common after concussion, and its presence can
modify the degree to which symptoms in other domains are expressed. Sleep
disturbance does not occur in isolation and is best thought of as an associated
condition rather than a separate subtype. The sleep-modifier–associated
condition is characterized by difficulty initiating or maintaining good-quality
sleep. Specific sleep disturbances may include insomnia or excessive daytime
sleepiness. Sleep disturbance can be primarily due to the injury itself or can be a
secondary consequence of other concussion-related impairments.41,42
Sleep disturbance has been reported in approximately 50% of individuals
following TBI of all severities.43 Concussion is associated with higher rates of
sleep disturbance compared with severe TBI.44 When specific aspects of sleep
disturbance are examined, patients with concussions report greater reductions in
sleep quality and sleep-related daytime impairment, but not sleep duration or
timing, when compared with controls.45
The Pittsburgh Sleep Quality Index (PSQI) is a simple outcome measure to
assess sleep quality after concussion/mild TBI.46 A score greater than eight on the
PSQI has been identified as a reliable indicator of insomnia in patients who have
had concussions.47 By using this cutoff, Theadom and colleagues48 reported
insomnia-level sleep difficulties in patients with concussions in approximately
36%, 30%, 23%, and 21% within 2 weeks, 1 month, 6 months, and 1 year,
1652 DECEMBER 2021

respectively. Similar rates of daytime sleepiness, as measured by the Epworth KEY POINTS
Sleepiness Scale, were reported across time points. Other studies have noted
● Sleep disturbance is quite
similar rates of sleep disturbance in the first 10 days (28%), but higher rates at common after concussion,
11 days to 1 month (59%) and 1 to 3 months (42%).12 and its presence can modify
After concussion, sleep disturbance can exacerbate other symptoms, the degree to which
contributing to functional disturbance.41 In fact, poor sleep quality is associated symptoms in other domains
are expressed.
with poorer cognition, reduced productivity, lower social integration, higher
levels of anxiety and depression, daytime sleepiness, and higher symptom ● Many patients who have
burden.48 Preinjury sleep quality, initial postinjury sleep quality, and baseline had a concussion present
cognitive ability predicted sleep quality at 12 months.48 Sleep provides a with neck pain, muscle
restorative function; that and the glymphatic clearance of toxic waste during stiffness, and headache,
typically localized to the
sleep49,50 may be critical factors in the understanding of how TBI-related sleep occipital/suboccipital
dysfunction may be not only a symptom but also a catalyst of brain dysfunction region.
after concussion/mild TBI.
Cervical Strain/Sprain
Many patients who have had a concussion present with neck pain, muscle
stiffness, and headache, typically localized to the occipital/suboccipital region.
Together with sleep dysfunction, cervical injuries are classified as an associated
condition because of the primary involvement of extracranial structures. Strain
to the soft tissue, most commonly in the upper cervical spine, causes disruption
to the afferent pathways that relay information from the neck to the brain.51
Damaged cervical afferents projecting to the thalamus and the primary
somatosensory area contribute to headache, dizziness, nausea, photophobia,
tinnitus, and memory dysfunction.52-54 Thus, multimodal assessment techniques
are required to isolate the cause of symptoms. Few studies have examined the
prevalence of cervical strain at multiple time points after concussion. A recent
study reported that 35% of patients who have had a concussion reported
symptoms of cervical strain at 1 to 3 months.12 Rates may significantly vary by
sample, as the mechanism of injury is likely a significant predictor of subsequent
cervical strain.
CASE 7-1 is an illustration of a patient who has several associated symptoms
following a concussion, as well as at least one concussion-associated condition.
CONCUSSION CLINICAL SUBTYPES

Having reviewed the landscape of concussion-related symptoms, the question
that arises is whether patients tend to form clinical profiles along these primary
symptom dimensions. Several research groups have presented preliminary
evidence of such profiles and have developed assessment tools for identifying
these profiles in the clinic. Collins and colleagues15 were among the first to
suggest the idea of clinical subtypes and proposed grouping patients on the basis
of their most severe symptoms. Their subtypes included primary dysfunction in
cognitive/fatigue, vestibular, ocular motor, posttraumatic migraine, affective, or
cervical domains that could be identified through a multidisciplinary assessment
approach. The subtypes were not thought to be mutually exclusive; for example,
a patient may have a predominately posttraumatic headache subtype but also
have elements of the vestibular subtype. The dominant symptom pattern may
evolve over time, such that early in the postinjury course, the patient may display
elements of one profile but develop characteristic symptoms of another profile
later in their recovery.

The Concussion Subtype Workgroup12 further refined the model proposed by

Collins and colleagues.15 Specifically, the workgroup conceptualized five distinct
clinical subtypes (headache/migraine, vestibular, ocular motor, cognitive, and
anxiety/mood) and two associated conditions (sleep disturbance and cervical
strain).12 The Concussion Subtype Workgroup also performed a meta-analysis of
existing literature to determine the prevalence of concussion subtypes and
associated conditions within the first 3 months after injury. Results indicated that
headache/migraine was the most prevalent subtype and ocular motor was the
least prevalent subtype during this time period. Regarding concussion-associated
conditions, sleep disturbance was more prevalent than cervical strain. Recently,
refinements of symptom checklists have been offered that provide clinicians
with a simple method of identifying symptom profiles in patients after a
CASE 7-1 A 23-year-old man sustained a concussion due to a multivehicle accident

in which he was rear-ended. He had a prior history of migraines, which
had been in remission with daily amitriptyline. He was evaluated in an
emergency department, had a normal noncontrast head CT, and was sent
home. He had no medical management until he was seen for a neurology
consultation 8 weeks after his injury.
At that time, he described cognitive “fogginess” that was more severe
during the first week after the accident. He described that he was having
more difficulty paying attention and keeping up with his graduate degree
program. A cognitive assessment showed psychometrically defined
deficits in attention and executive function. He described having severe
headaches at least 2 times a week, visual blurring when reading for an
extended period of time, and difficulty falling and staying asleep. He had
a reluctance to drive at night since the injury, and he had subsequently
limited his activity.
COMMENT This case shows objective cognitive impairment as a result of the patient’s
injury. In addition to the direct cognitive features of concussion, he has
several other factors that may be contributing to his cognitive symptoms.
The concussion appears to have exacerbated his headache syndrome from
remission. The anticholinergic aspect of the amitriptyline may have
contributed to the increased foggy sensation during the first week.
Untreated migraines may be contributing to his current cognitive
symptoms. The visual blurring with reading may be an associated feature of
migraines but may also represent convergence insufficiency as an ocular
motor feature of concussion. His associated sleep dysfunction may also be
contributing to his cognitive features. His new reluctance to drive at night
may suggest an anxiety component that should be further explored to see
if this may also be affecting his cognition. His limited activity may
contribute to delayed recovery. A full treatment plan would include not just
targeting the cognitive component but would also include treatments
targeting his headaches, sleep dysfunction, possible ocular motor
dysfunction, and possible anxiety.
1654 DECEMBER 2021

concussion. For example, the Concussion Clinical Profiles Screening tool55 is a
29-item self-report, clinical profile–based symptom inventory that measures the
following five concussion clinical profiles: (1) anxiety/mood, (2) cognitive/
fatigue, (3) migraine, (4) ocular, and (5) vestibular; and the following two
modifying factors: (1) sleep and (2) neck. Why is subtype identification
important? At this point in time, the concept of “concussion profiles” or
“concussion subtypes” is merely heuristic. However, in the short term, quick
identification of key symptoms enables rehabilitation pathways focusing on
alleviating the patient’s most debilitating symptoms. In the long term, subtype
identification is critical to harnessing variability in clinical research, suggesting
the possibility of distinct patterns of underlying pathophysiology as reflected in
neurologic, neuroimaging, or biomarker abnormalities.
ADVANCED DIAGNOSTICS FOR TRAUMATIC BRAIN INJURY

The diagnosis of concussion/mild TBI remains a clinical, symptom-driven
diagnosis with no firm gold standard test or indicator providing objective,
independent evidence of the occurrence or extent of injury. Because of this,
interest in developing objective biomarkers for mild TBI is ongoing. This section
reviews current knowledge in advanced neuroimaging and fluid biomarkers
of injury.
Neuroimaging
Neuroimaging data have figured prominently in prognostic models of moderate
to severe injury. Head CT scans are routinely ordered in the acute period to
identify structural brain abnormalities and determine the need for immediate
surgical intervention (eg, evacuation of a mass lesion). The IMPACT
(International Mission for Prognosis and Analysis of Clinical Trials in TBI)
extended model characterizes admission CT findings by using the Marshall CT
classification system, a robust predictor of TBI outcome.56,57 The Marshall CT
classification system categorizes patients into one of six categories (I through VI)
based on the extent of intracranial pathology seen on head CT scan.58 Limitations
of the Marshall CT classification system have led to newer approaches that
provide additional information about the location of a specific mass lesion (eg,
subdural, intracerebral, or epidural hematoma) and the extent of intraventricular
blood product or traumatic subarachnoid hemorrhage.59,60 This includes the
IMPACT model in which the presence of traumatic subarachnoid hemorrhage
increases the risk of unfavorable outcome.57,61
The situation with mild TBI is quite different from moderate to severe TBI.
Diagnostic criteria for mild TBI stipulate the absence of neuroimaging
abnormalities by using standard clinical imaging protocols. Nonetheless,
evidence has been mounting that mild TBI can produce abnormalities on
diffusion tensor and other high-resolution neuroimaging methods, particularly if
imaging is conducted in the postacute or chronic period.
In the past few years, many advanced neuroimaging techniques have been
developed or refined that may hold promise for harnessing variability in mild TBI
outcomes, including measures of cerebral blood flow (dynamic susceptibility-
weighted contrast-enhanced perfusion MRI, magnetic resonance arterial spin
labeling, and perfusion CT), structural damage (diffusion tensor imaging,
magnetic resonance elastography), neurochemical abnormalities (magnetic
resonance spectroscopy), and changes in activation and neural dynamics

(functional MRI [fMRI], convolutional neural networks).62 Several

reviews have shown that measures of white matter integrity derived from
diffusion tensor imaging can distinguish between mild TBI and controls,
including fractional anisotropy, mean diffusivity, and free water fraction or a
relatively new technique called neurite orientation dispersion and density
imaging.63-66 Although these results are promising, diffusion tensor
imaging–derived abnormalities are not specific to mild TBI and can be seen in
several comorbid disorders, limiting the diagnostic usefulness of these metrics in
individual cases.
Fluid Biomarkers
Fluid biomarkers offer a potential means of characterizing brain injury
physiology. Blood biomarkers of brain injury expressed peripherally within
serum and plasma are well studied and validated in the moderate to severe TBI
literature and are increasingly popular in mild TBI and sport-related concussion
research. It is overly simplistic to think that a valid, one-size-fits-all biomarker of
TBI will be forthcoming; instead, it is more useful to consider the multiple ways
in which measures of the brain’s neurometabolic response to traumatic injury can
be used in research and clinical management. Fluid biomarkers can (1) indicate
the presence/nature of injury, (2) provide prognostic information, or, in some
cases, (3) index risk for developing postinjury complications such as epilepsy or
memory dysfunction.67 Brain tissue proteins, cytokines, and coagulation markers
have been studied most commonly.68 The use of biomarkers has been most
extensively studied in moderate to severe TBI, although their use in mild TBI and
concussion has received significant recent attention.69,70
Proteomic markers can index acute and subacute damage including neuronal
cell body injury (ubiquitin C-terminal hydroxylase), gliosis/glial injury (glial
fibrillary acidic protein [GFAP]), axonal injury (neurofilament light chain), or
dendritic (microtubule-associated protein 2) injury or more chronic
neurodegenerative changes (phosphorylated tau, total tau, amyloid-β,
transactive response DNA-binding protein 43).71 Recently, attention has been
given to the potential utility of measuring differential microRNA expression in
the diagnosis of TBI, particularly in its role as a protein regulator.72
Regarding diagnosis of TBI itself, none of these biomarkers has been
sufficiently validated to justify its use as a diagnostic tool in the individual case.
Key limitations to the individual diagnostic application include (1) a lack of
“normative” values of these biomarker candidates in healthy (uninjured) people,
(2) the fact that injuries outside the brain/central nervous system (eg, orthopedic
trauma) can contribute to circulating plasma or serum concentrations, (3) a lack
of standardization or availability of assays timed to expected biomarker
elevations, and (4) variability in the definition of TBI.68,71,73
Regarding the prognostic value of biomarkers, S100B, GFAP, ubiquitin
C-terminal hydroxylase, and neurofilament light chain have all been shown in
some studies to predict outcome and recovery by using the Glasgow Outcome
Scale,71,74 although results have not been universally positive, and use in the
individual case is not indicated.75 The use of a multivariate panel of several
biomarkers simultaneously may hold more promise.76 Recently, the US Food and
Drug Administration (FDA) approved the use of a blood test in patients with
suspected mild TBI. This test combines ubiquitin C-terminal hydroxylase and
GFAP, at predetermined cutoff values, to predict traumatic intracranial injuries
1656 DECEMBER 2021

on head CT acutely after TBI, thus providing clinicians with a sensitive marker of KEY POINTS
the likelihood that CT scanning will have incremental diagnostic value.77 It is
● Regarding diagnosis of TBI
important to note that this is not a marker of mild TBI per se, but it provides itself, no biomarker has
information on whether CT is indicated in the individual patient. been sufficiently validated
Finally, several genetic marker candidates have shown promise as risk to justify its use as a
indicators for specific TBI-related outcomes, including posttraumatic epilepsy78 diagnostic tool in the
individual case.
and memory disorder.79
● The nature of concussion
RECOVERING FROM CONCUSSION as a transient disturbance of
The nature of concussion as a transient disturbance of brain function leads to the brain function leads to the
general expectation that most, if not all, concussed individuals have a good general expectation that the
large majority of concussed
prognosis for full recovery. At the same time, clinicians who work with these individuals have a good
patients know that the course and rapidity with which recovery occurs can be prognosis for full recovery.
quite variable. The key management principle is to address postconcussion At the same time, clinicians
symptoms and problems as actively and as quickly as feasible to prevent acute who work with these
patients know that the
symptoms from becoming chronic. course and rapidity with
which recovery occurs can
Neuropsychological Recovery be quite variable. The key
The extent to which concussion is associated with long-term cognitive deficits management principle is to
address postconcussion
has drawn considerable research interest. Several prospective and meta-analytic symptoms and problems as
studies have provided substantial insight into the expected cognitive recovery actively and as quickly as
from concussion. In an early prospective study, Dikmen and colleagues80 feasible to prevent acute
reported that the magnitude of cognitive impairments at 1 year after TBI was symptoms from becoming
chronic.
dependent on initial injury severity. In their landmark study, no significant
cognitive differences were found between a sample of patients with
concussion/mild TBI and controls on neuropsychological performance at 1 year
after injury; the authors concluded that, similar to earlier studies,81,82 concussion
was not associated with long-term neuropsychological impairments. Clinical
folklore evolved that took this conclusion one step further: not only were
long-term cognitive symptoms highly unlikely, they were also thought to be the
product of preexisting emotional or psychiatric risk factors that predisposed
these patients toward somatization.83
Since that time, several meta-analytic studies further added to the
understanding of cognitive recovery following concussion. Early meta-analytic
studies reported a small effect size of concussion on neuropsychological
performance, often smaller than the measurement error of neuropsychological
tests.84,85 Schretlen and Shapiro,86 in a meta-analysis of mostly cross-sectional
studies, reported the effect of moderate to severe TBI was more than 3 times the
effect of mild injuries on neuropsychological performance across all follow-up
periods; in concussion/mild TBI, they reported a trivial effect on cognitive
functioning at 1 to 3 months after injury compared with controls. Belanger and
colleagues87 conducted a meta-analysis of 39 studies involving concussion
participants and controls and reported no residual neuropsychological deficits by
90 days in unselected or prospective studies. Frencham and colleagues88 also
conducted a meta-analytic review of concussion studies and found that the effect
size of injury on neuropsychological performance approaches zero as the time
since the injury increases.
In an innovative approach, Iverson89 converted effect sizes from previous
meta-analytic studies to a standard metric that is more easily understood by
clinicians. Additionally, Iverson89 compared the neuropsychological effects of

other conditions to the neuropsychological effects of concussion, and the results

indicated that concussion has no effect on neuropsychological performance after
the acute recovery period. It was concluded that the effects of concussion,
following the acute period, are considerably smaller than the effects of
depression, bipolar disorder, attention deficit hyperactivity disorder,
benzodiazepine use/withdrawal, litigation, and malingering. These results
suggest that the effect of concussion on cognitive functioning is trivial by
3 months after injury. Furthermore, cognitive deficits at protracted time points
should be considered within the context of neurobiopsychosocial factors.
Symptomatic Recovery
Patients frequently ask about the time course of symptom recovery, and many
become concerned when they continue to experience symptoms over the weeks
and months after concussion. What is the normal course of symptomatic
recovery? The answer to this question has proven quite elusive and is dependent
on several factors. Findings from athlete studies consistently indicate resolution
of symptoms within 2 weeks.90-93 However, this special population has access to
immediate medical care, supportive rehabilitation, and academic environments
and may have special incentives that hasten recovery. These athlete data stand in
contrast to other studies suggesting that some patients experience longer
recovery times or persisting symptoms.
In a well-conducted prospective study, Rutherford and colleagues94 reported
that 14.5% of participants had at least one symptom at 1 year after injury.
However, fewer than 5% of participants reported more than one symptom.
Similarly, Alves and colleagues95 found that single symptoms were commonly
reported at 1 year after injury but multiple symptoms occurred in fewer than 6%
of participants. A prospective study conducted since then reported a higher rate
of multiple symptoms (44%) in participants with a concussion at 1 year after
injury14; however, the rate was not significantly different from that seen in
trauma controls (24%). In a longitudinal study examining the relationship
between financial compensation and symptom reporting after concussion,
Paniak and colleagues96 found that compensation-seeking participants remained
symptomatic over time, but those not seeking compensation performed as well
as noninjured controls at 3 months after injury.
Findings from methodologically sound studies that use appropriate control
groups and control for confounding factors suggest that symptoms resolve
within the first 1 to 3 months after concussion in the vast majority of individuals.
A minority of patients, discussed in the next section, continue to experience
persisting symptoms for up to 1 year or more after concussion. In understanding
this problem, it is important to remember that concussion-related symptoms are
not specific to brain injury; they can be seen in the context of many medical and
psychiatric conditions, and individual symptoms such as headache, attentional
lapses, or low mood may have substantial prevalence in the healthy
(nonconcussed) adult population.97-99 One key question is whether persisting
symptoms reflect the residual effects of concussion, the presence of other
premorbid conditions, or both.
PERSISTING SYMPTOMS AFTER CONCUSSION

Persisting symptoms after concussion represent real and potentially disabling
problems that are frustrating for the patient and often vexing for the clinician. In
1658 DECEMBER 2021

this section, the term persisting symptoms after concussion, as opposed to persistent KEY POINTS
postconcussion syndrome, is used to make it clear that the discussion focuses on
● In this article, the term
clinical symptoms that remain well after full recovery from the physiologic and persisting symptoms after
functional neurologic effects of concussion has been achieved. This approach concussion, as opposed to
emphasizes that such symptoms may not be simply or directly related to a single persistent postconcussion
common cause (the concussion) but that they may arise independently, at syndrome, is used to make it
clear that the discussion
different points in the patient’s life, and may amplify or mutually reinforce each
focuses on clinical
other to produce a persisting “syndrome.”100 symptoms that remain well
The etiology of persisting symptoms after concussion is complex and likely after full recovery from the
reflects neurobiopsychosocial causative pathways that include (1) preinjury physiologic and functional
neurologic effects of
medical and psychiatric history, (2) personal characteristics such as age and sex,
concussion has been
(3) injury-related factors such as severity and symptom burden, and (4) achieved.
postinjury factors including interruption of activities, coping style, and other
psychosocial circumstances.101 Premorbid history of previous head injuries, ● The etiology of
lower cognitive abilities, poor sleep quality, migraines, psychological distress, persisting symptoms after
concussion is complex
female sex, as well as young (younger than 4 years old) and old (older than and likely reflects
65 years old) age have been associated with an increased risk of developing neurobiopsychosocial
persisting symptoms.102-104 Postinjury factors such as the presence of causative pathways that
posttraumatic migraine symptoms, vestibulo-ocular dysfunction, development include (1) preinjury medical
and psychiatric history, (2)
of psychological problems, expectation of poor outcome, prolonged inactivity, personal characteristics
and a decline in cognitive functioning relative to baseline have also been such as age and gender, (3)
identified as risk factors for protracted symptom recovery.105-108 injury-related factors such
as severity and symptom
burden, and (4) postinjury
Early Treatment
factors including
One potential contributor of persisting symptoms after concussion in the general interruption of activities,
population is the lack of early treatment. Following discharge from the coping style, and other
emergency department, patients are often encouraged to follow up with their psychosocial circumstance.
primary care physician, who then refers to other medical specialties if symptoms
● A key concussion
persist. Patients may be referred to several providers over the course of weeks to management goal is to avoid
months before targeted treatment is received. Therefore, a model that allows premature reentry while
front-line medical professionals (eg, primary care physicians) to identify specific simultaneously avoiding the
clinical trajectories and refer patients for appropriate, targeted treatments may deconditioning that often
accompanies extended rest
eliminate or mitigate the onset of persisting symptoms. periods.
Rest, Activity, and Exercise

As patients await referral for further treatment after acute discharge, many
curtail or stop engaging in normal vocational or leisure activity or exercise, and
others may stop adhering to health-promoting nutritional or sleep habits.
Prescribed rest after concussion has been one of the cornerstones of medical
management, based on the perceived need to avoid cognitive and physical stress
in light of the TBI neurometabolic cascade.109 In the experience of the authors of
this article, many patients are given instructions to avoid all stimulation and are
taken out of normal school or work routines, a practice known as cocooning.
Several studies have now indicated that prolonged periods of prescribed rest
offer no benefit or may even be detrimental, compared with 1 to 2 days of rest
followed by a gradual return to activity.110-112 However, the clinical utility of rest
in the individual patient may be greater for those who present with objective
injury signs than for those who do not, regardless of symptom burden.113 A key
management goal is to avoid premature reentry while simultaneously avoiding
the deconditioning that often accompanies extended rest periods. In school-age

patients (those 5 to 18 years old), recent data do not support the widespread
practice of extended rest or school removal in terms of reducing persisting
symptoms.114 Removing patients, particularly those in their school-age years,
from school and work routines for an excessive period of time may also be
detrimental because it reduces face-to-face social stimulation and may result in
reduced learning, falling behind in assignments, and loss of academic supports.
Medical and Psychiatric Conditions

A 2017 meta-analytic review showed that the severity of a person’s acute and
subacute symptoms, including headaches or depression, is likely a risk factor for
persisting symptoms lasting longer than 1 month.115 Those with a preinjury
history of mental health problems appear to be at greater risk for having
persisting symptoms, but those with preexisting attention deficit hyperactivity
disorder or learning disabilities do not.115 The predictive value of premorbid
mental health should alert clinicians to target such concerns early in the
postinjury course, as the severity of psychological distress after concussion
may prolong recovery from somatic, cognitive, and sleep-related
symptoms.116
Fear-Avoidance and Coping Style

How patients cope and respond to symptoms after concussion may help
determine whether they engage in behaviors and activities that promote
symptom resolution or adopt a more passive avoidant strategy designed to
prevent discomfort. The fact that symptom provocation can occur with physical
or cognitive exertion may encourage some patients to avoid such exertional
challenges, which then reduces symptom severity, thus engaging a
self-reinforcing cycle of avoidance and relief.117 As this cycle continues,
avoidance begets symptom relief but results in withdrawal from normal physical
and cognitive activities, promoting depression and deconditioning. The opposite
pattern, known as endurance, involves a maladaptive cycle of overdoing followed
by symptom exacerbation and exhaustion, resulting in withdrawal from
activities to recover.117 These maladaptive behavioral patterns promote chronic
pain in headache and musculoskeletal pain disorders118,119 and hold promise as
treatment targets to reduce persisting symptoms after concussion.120
Expectations for Recovery

Illness perceptions, or how patients conceptualize their injury and their
likelihood of recovering from it, are known to affect concussion symptom
reporting and outcome.121 The concept of “diagnosis threat” refers to a sort of
stereotyped behavior in which individuals with strong beliefs that, for example,
TBI results in cognitive impairment show reduced cognitive performance on
neuropsychological tests.122 Evidence exists that patients expect negative
consequences from concussion/mild TBI123 and that some may overestimate the
effects of injury by recalling their preinjury health or achievements in an overly
positive light (the so-called “good old days” bias).124 Patients who attribute
symptoms and problems to their head injury, as opposed to other causes, tend to
experience more severe symptoms after concussion.125 Mittenberg and
colleagues107 and Ferguson and colleagues126 suggested that expectations can
serve as an etiologic factor in the self-reported severity and persistence of
postinjury symptoms and argued that clinicians could reduce or prevent
1660 DECEMBER 2021

persisting symptoms after concussion by providing brief, early
cognitive-behavioral interventions designed to help patients adjust overly
negative expectations about their recoveries to conform more closely with actual
outcome data.
TREATMENT OF MILD TRAUMATIC BRAIN INJURY AND CONCUSSION

A treatment plan should be developed targeting the symptoms from each clinical
subtype that the patient currently has. The treatment plan should keep in mind
whether some of these symptoms are de novo from the injury or an exacerbation
of a preexisting condition. A clearer understanding of the direct cognitive
manifestations often requires first controlling other associated symptoms such as
headache or sleep disturbance. TABLE 7-1 outlines key multidisciplinary treatment
alternatives for concussion symptoms.
Neurologic Interventions
Treatments from a neurologist are most commonly pharmacologic management
targeting specific symptoms or office-based procedures. Given that no
medications carry an FDA indication for posttraumatic or postconcussive use,
the preferred strategy of the authors of this article is to adapt a target-symptom
approach focusing on alleviating particular symptoms. Treatment selection
includes consideration of avoiding interactions with other medications and
avoiding medications that may have an adverse effect on cognition. Most
office-based procedures include trigger-point injections and/or occipital nerve
blocks targeting pain. Botulinum toxin injections have been used for chronic
headaches either worsened by or triggered by a concussion.
Conceptualizing symptoms and outcomes after concussion/mild TBI from a
broad neurobiopsychosocial framework is useful in guiding treatment decisions
at the individual patient level.5 Some treatments may involve therapies
coordinated with the assistance of other multidisciplinary team members.
Neuropsychological and Psychological Interventions

Neuropsychologists adopt a neurobiopsychosocial approach in providing
cognitive, psychotherapeutic, and psychosocial interventions to address a variety
of emotional and behavioral symptom patterns following concussion/mild TBI.
Cognitive rehabilitation interventions, described in more detail in the section on
occupational therapy, seek to restore cognitive skills through relearning or to
help the patient develop alternative, compensatory strategies in performing
everyday cognitive tasks.
Other psychological therapies have been used to target maladaptive thinking
and behavior that may be affecting recovery following a mild TBI. Such therapies
include cognitive-behavioral therapy and mindfulness-based stress reduction.
Psychological interventions are aimed at psychosocial stressors and poor reaction
or coping strategies that may be affecting recovery.
Physical Therapy Interventions

In the aftermath of TBI, physical therapists use a variety of treatment strategies
to address common postinjury symptoms. These can include physical activity,
vestibular intervention, and targeting of neck pain. Physical therapists can help
develop a plan to return to physical activity. The Fifth International Conference
on Concussion in Sport2 recommended a brief rest period (24 to 48 hours)

followed by gradual reintroduction of normal activity, which was supported by a

2017 systematic review.127 After acute symptoms have begun to subside,
individuals may begin to gradually increase activity. Some studies indicate that
early physical activity is associated with a reduced incidence of disabling
symptoms at 28 days.128 Following concussion, moderate-intensity physical
activities have been shown to reduce symptom duration as compared to either
complete rest or high-intensity activity. Research is ongoing to determine the
most effective mode and protocol for titrating the intensity of such beneficial
physical activity.
Dizziness and vestibular symptoms are the second most common physical
symptoms after concussion, following headache as the most common
symptom. Dizziness can result from dysfunction of the peripheral vestibular
apparatus, central vestibular pathways, injury to the cervical spine, autonomic
dysfunction, or anxiety. Proper intervention requires a precise differential
diagnosis of these alternatives. An assessment can help localize the source and
inform the most appropriate therapy. This may include an Epley maneuver for
posttraumatic benign paroxysmal positional vertigo if evaluation is consistent
with this. For other forms of vestibular dysfunction, a course of vestibular
rehabilitation therapy has been incorporated into treatment plans. A 2017
systematic review concluded that the use of vestibular rehabilitation therapy
to treat dizziness and balance dysfunction shows promise without significant
risk of adverse effects.129
Neck pain can be an associated feature. Because of the acceleration/
deceleration forces involved in mild TBI, it can be anticipated that some
patients may sustain coincident cervical sprains or strains. Therefore, an
evaluation of the cervical spine should be conducted in most patients. Neck pain
and headaches complicate diagnosis and treatment for patients who have
sustained traumatic injuries, and if left untreated, could contribute to
prolonged recovery.
Occupational Therapy Interventions

Occupational therapists use a variety of modalities to return patients to their
baseline overall function. This can include optimizing function for return to
work, education, recreation, and life tasks. Although facilitating a gradual return
to activity is beneficial to recovery, safety considerations should be taken into
account in balancing graded activity with activity restriction. A common
question that emerges is a safe return to driving, and occupational therapists can
assist in this evaluation with objective driving performance tasks that simulate
on-road conditions.
An emerging domain for occupational therapists working with neurologic
patients is assisting with ocular motor impairments following TBI. Ocular motor
dysfunction can include convergence insufficiency, diplopia, fixation and
accommodation dysfunction, and photophobia.20 These issues are described as a
clinical subtype of concussion. Targeted ocular motor-based exercises can
improve these functions. Treatment can be sometimes combined with
compensatory therapies to include light filters and tinted lenses that may be
used in tandem with remediation-based treatments for patients with
persisting symptoms.130
Occupational therapists are often involved in cognitive rehabilitation. During
the early postacute phases, cognitive rehabilitation strategies used rely mostly on
1662 DECEMBER 2021

compensatory strategies. Evidence supports the use of external memory aids to KEY POINTS
compensate for functional memory problems.131 Evidence also exists for the use
● Following concussion,
of internal strategies to improve recall performance for people with mild moderate-intensity physical
impairments. Compensatory cognitive strategies can be used to buoy everyday activities have been shown
functioning as the symptoms of mild TBI continue to resolve. Remedial to reduce symptom duration
intervention programs targeting attention, memory, social communication skills, as compared to either
complete rest or
and executive function have demonstrated clinical validity in the treatment of
high-intensity activity.
patients with mild TBI.131 Attention Process Training (APT-3)132 and N-Back Research is ongoing to
Exercises133 are two remediation-focused interventions to address persisting determine the most
problems of attention. Systematic studies of remediation interventions in mild effective mode and
protocol for titrating the
TBI are more limited than those seen for moderate to severe TBI, likely because
intensity of such beneficial
of the high recovery rate in mild TBI. physical activity.
● During the early

CONCLUSION postacute phases, cognitive
rehabilitation strategies
Concussion, a change in neurologic function coincident with the imposition of used rely mostly on
mechanical forces on the brain, is among the most widely recognized and studied compensatory strategies.
public health problems today. The diagnosis of concussion remains rooted in
clinical presentation and symptomatology, with no definitive gold standard to ● Symptomatically,
concussion presents with a
confirm it. No neuroimaging or fluid biomarkers have yet been discovered with
heterogeneous admixture of
sufficient specificity for concussion to warrant application at the individual cognitive, vestibular, ocular
patient level. Symptomatically, concussion presents with a heterogeneous motor, headache, and
admixture of cognitive, vestibular, ocular motor, headache, and neuropsychiatric neuropsychiatric problems
that are frequently
problems that are frequently accompanied by sleep disturbances and cervical
accompanied by sleep
symptoms. Increasing attention is being given to the possibility that these disturbances and cervical
heterogeneous presentations may represent pathophysiologic subtypes, each in symptoms. Increasing
need of a separate targeted treatment approach. attention is being given to
The large majority of patients with concussion will display full resolution of the possibility that these
heterogeneous
symptoms in 1 or 2 months, although a significant minority of patients will show presentations may
symptoms that persist and remain interfering or disabling for longer time represent pathophysiologic
periods. In recent years, substantial progress has been made in understanding subtypes, each in need of a
persisting symptoms after concussion and their basis in factors not directly separate targeted treatment
approach.
related to the concussion itself. It is known, for example, that mismanagement of
acute concussion (eg, excessive rest or prolonged prescribed inactivity), ● Mismanagement of acute
preexisting medical or psychiatric problems (eg, migraine, anxiety), as well as concussion (eg, excessive
current comorbidities (eg, cervical pain, sleep problems) and psychosocial rest or prolonged
prescribed inactivity),
factors (eg, fear-avoidance as a coping strategy) may prolong or complicate
preexisting medical or
recovery well beyond the point that the acute neurometabolic effects of psychiatric problems (eg,
concussion have resolved. These data suggest that the notion of persistent migraine, anxiety), as well as
postconcussion syndrome is obsolete and potentially misleading in its implied current comorbidities (eg,
cervical pain, sleep
emphasis on an “unrecovered” concussion. The persistent postconcussion
problems) and psychosocial
syndrome concept should be replaced by the concept of persisting symptoms factors (eg, fear-avoidance
after concussion and its emphasis on problem-focused neurobiopsychosocial as a coping strategy), may
treatment. prolong or complicate
Treatment of concussion is best administered by an interdisciplinary team that recovery well beyond the
point that the acute
adopts a cooperative, integrated focus on alleviating symptoms and encouraging neurometabolic effects of
a return to functional capacity within the limits of the patient’s individual concussion have resolved.
circumstances. Treatment to promote effective symptom resolution and a graded
return to preinjury activities can prevent the development of persisting
symptoms into the chronic period. Treatment may include pharmacologic

intervention; behavioral therapy targeting cognitive functioning, mood

symptoms, and sleep dysfunction; specialized therapies to reduce dizziness,
orthopedic pain, and visual disturbances; and addressing barriers to carrying out
activities of daily living. When specialized interdisciplinary care is not available,
an attempt should be made to refer the patient to health care professionals with
experience in the treatment and rehabilitation of patients with concussion/mild
TBI who may be able to implement key aspects of the problem-focused
treatment approach described in this article.
ACKNOWLEDGMENT
Funding/Support: This article was supported in part by a grant from the
National Institute of Mental Health (1R01 MH118514-01A1; Dr Bauer).
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Clinical Approach to
CONTINUUM AUDIO
INTERVIEW AVAILABLE
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Cognitive and
Neurobehavioral
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Symptoms
By Meredith Wicklund, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article provides a framework for the approach to
patients with cognitive or neurobehavioral concerns.
RECENT FINDINGS:Recent advances in structural neuroimaging, functional

neuroimaging, and disease biomarkers have greatly expanded knowledge
of brain-behavior relationships, neural networks and functional
connectivity, and pathophysiologic processes leading to cognitive and
neurobehavioral disorders. However, any one of these studies is subject to
misinterpretation if not applied in the appropriate clinical context.
SUMMARY: A systematic approach to the history and examination in patients

CITE AS:
CONTINUUM (MINNEAP MINN) with cognitive and neurobehavioral symptoms is important in marrying
2021;27(6, BEHAVIORAL NEUROLOGY clinical assessments with contemporary diagnostic studies and
AND PSYCHIATRY):1518–1548.
treatments.
Dr Meredith Wicklund, Barrow
Neurological Institute, 240 W
Thomas Rd, Ste 301, Phoenix,
AZ 85013, meredith.wicklund@ INTRODUCTION
C
dignityhealth.org. ognitive and neurobehavioral symptoms are common presenting
RELATIONSHIP DISCLOSURE :
chief complaints to a neurologist, whether evaluating an acute
Dr Wicklund has received confusional state in a hospitalized patient, progressive cognitive
research/grant support from decline in an older adult in the outpatient clinic, a focal
Alector, Inc, Barrow Neurological
Foundation, Biogen, F. Hoffman-
neurobehavioral syndrome such as aphasia or apraxia, or the
La Roche Ltd, Functional complex cognitive and behavioral features of many neurologic disorders such as
Neuromodulation Ltd, Green epilepsy, stroke, multiple sclerosis, movement disorders, or traumatic brain
Valley Inc, Janssen Research &
Development, and the National injury (TBI). Recent advances in neuroimaging, including functional MRI
Institutes of Health (fMRI) and positron emission tomography (PET), have provided extraordinary
(5P30AG019610-21).
advances in the understanding of brain-behavior relationships. Likewise,
UNLABELED USE OF developments in structural neuroimaging, including quantitative volumetric
P R O D U C T S/ I N V E S T I G A T I O N A L assessments with MRI and diffusion tensor imaging of white matter tracts,
USE DISCLOSURE:
Dr Wicklund reports no
continue to greatly expand knowledge of neural networks and their functional
disclosure. connectivity.1 Advances in biomarkers of many neurodegenerative disorders,
such as PET imaging with amyloid and tau in Alzheimer disease, have led to
© 2021 American Academy greater understanding of pathophysiologic processes and in vivo diagnosis.
of Neurology. However, these studies are subject to limitations in availability, cost, and
1518 DECEMBER 2021

guidelines for appropriate clinical use. Appropriate clinical phenotyping is KEY POINTS
necessary for selection of applicable diagnostic studies. This article provides a
● History should be
practical approach to the clinical assessment of disturbances of cognition obtained from both the
and behaviors encountered in the general neurology practice. patient and a collateral
source who knows the
CLINICAL HISTORY patient well because
patients with cognitive and
Obtaining a good history is paramount in patients presenting with cognitive
behavioral symptoms may
and neurobehavioral concerns. This can be challenging as patients may have not be able to provide an
difficulty attending to the interview because of disorders of attention/ accurate history.
concentration, organizing thoughts effectively because of disorders of executive
function, communicating symptoms because of disorders of language, recalling ● Age at onset of the first
symptom aids in determining
symptoms because of disorders of memory, or recognizing deficits because of the differential diagnosis
anosognosia. It is thus critical to have a conceptual approach and obtain because of varying
additional history from a collateral source who knows the patient well and can prevalence of diseases in
inform on the relevant aspects of the history. different age groups.
● Education, occupational
PATIENT DEMOGRAPHICS history, native language, and
Age at onset of the first symptom aids in determining the differential diagnosis. cultural factors are critical
Although not exclusively so, neurodegenerative and cerebrovascular disorders variables to be obtained for
interpretation of the mental
are increasingly more likely with older age, whereas younger individuals are
status examination.
more likely to have neurometabolic disorders, leukodystrophies, genetic
disorders, or demyelinating, infectious, or inflammatory etiologies.
Furthermore, the neurodevelopmental history of a patient can inform on
phenotypic manifestations of neurodegenerative diseases in later life. For example,
nonlanguage mathematical and visuospatial learning disabilities are more common
in the atypical visual presentation of Alzheimer disease (posterior cortical atrophy),2
whereas dyslexia is more common in the atypical language presentation of
Alzheimer disease (logopenic variant primary progressive aphasia)3 than in the
typical amnestic form of Alzheimer disease.
Education and occupational history provide important information about a
patient’s premorbid intelligence and are critical variables in the interpretation of
the mental status examination. For example, highly educated individuals may be
expected to have average performance or above on assessments; scores in the low
to average range, although not impaired across the spectrum of cognitively intact
adults, may reflect a decline from premorbid abilities for that patient and
indicate a potential emerging cognitive disorder.4 Additionally, the native
language of the individual and cultural factors must be factored into
interpretation of cognitive assessments.5
Handedness provides important information about lateralization of specific
cognitive functions in the cerebral hemispheres. Language is left lateralized in
about 96% of right-handed people and 76% of left-handed people, with
approximately 14% of left-handed people showing bilateral representation and
only 10% of left-handed people showing full lateralization to the right
hemisphere.6 It is important to keep in mind that many older individuals may
have experienced significant pressures to switch handedness because of cultural
and social stigma in their youth. In addition, many environmental constraints
for left-handed people living in a world dominated by those who are right
handed may affect a person’s hand preference.7
Furthermore, it is imperative to inquire about a patient’s lifestyle and daily
routine to understand how they might affect the patient’s health. Important

CLINICAL APPROACH TO COGNITIVE AND NEUROBEHAVIORAL SYMPTOMS
CASE 1-1 A 60-year-old right-handed woman presented with a chief complaint of

memory loss that had been slowly progressing over the previous year.
Upon clarification of what was meant by memory loss, her spouse noted
that she had difficulty recalling coworkers, specifically not recognizing
the faces of coworkers that she had worked with daily for many years.
She additionally had difficulty recognizing faces of famous people she
saw on billboards. Her spouse further noted that the patient commented
that her local neighborhood did not seem familiar to her and she had not
recognized familiar objects, such as not recognizing a flamingo lawn
ornament as a flamingo. Her spouse noted more recently that the patient
had seemed less empathetic and had developed compulsive behaviors.
On examination, she scored 28/30 on the Montreal Cognitive
Assessment (MoCA) with one point deducted each for delayed recall and
orientation to date. In a more detailed bedside mental status
examination, attention, memory, and executive functions were intact.
Conversational language, fluency,
repetition, verbal comprehension,
reading, and writing were normal.
She displayed difficulties with visual
but not auditory confrontation naming.
She had difficulty recognizing famous
faces but was able to discriminate
colors. Her performance on a line
bisection task, overlapping figures
task, and copy of a complex figure
was normal. Her general neurologic
examination was normal.
Brain MRI demonstrated focal right
temporal lobar atrophy (FIGURE 1-1).
Brain fludeoxyglucose positron
emission tomography (FDG-PET)
demonstrated right more than left FIGURE 1-1
Axial fluid-attenuated inversion
anterior hypometabolism. A diagnosis recovery (FLAIR) MRI of the patient in
of right temporal variant CASE 1-1 demonstrating right temporal
frontotemporal dementia was made. atrophy.
COMMENT This case highlights that many patients may describe any cognitive
disturbance as memory loss, but the nature of the presenting chief
complaint can be clarified by asking informants to provide examples.
Additionally, although this patient scored well on the screening
neurocognitive test, this test did not adequately assess her presenting
symptoms, and more detailed examination was needed. The cognitive
profile revealed findings of visual agnosia localizing to the right temporal
lobe, which was confirmed with neuroimaging.
1520 DECEMBER 2021

features to inquire about include with whom the patient resides and who lives KEY POINTS
nearby, access to transportation, physical activity, and social network. Of
● To develop realistic and
particular importance is inquiring about the physical, financial, and appropriate interventions
psychological impact of the patient’s illness on family and caregivers and the for both the patient and
capacity of those involved to provide practical and psychological support.1 By caregiver, the clinician
being aware of these features, more realistic and appropriate interventions can be should inquire about the
physical, financial, and
devised for both the patient and caregiver.
psychological impact of the
patient’s illness on family
GENERAL MEDICAL HISTORY and caregivers and the
When obtaining the history, it is also imperative to review the general medical capacity of those involved
to provide practical and
history, with particular attention to any medical disorders that may impact
psychological support.
cognition, such as liver and renal failure, endocrinopathies, or chronic
obstructive pulmonary disease. History of any major psychiatric illnesses is ● The clinician should query
likewise relevant. A detailed description of any neurologic disorders, such as about history of other
stroke, multiple sclerosis, or epilepsy is needed. Movement disorders are neurologic disorders (eg,
epilepsy, multiple sclerosis,
particularly common in many cognitive and neurobehavioral disorders, and their stroke), abnormal
presence should be specifically assessed. A screening question about TBI movements, traumatic brain
should be routine, with follow-up questions regarding the mechanism of injury, injury, and cerebrovascular
severity, and associated amnesia as needed.1 Medical history pertaining to risk factors (eg, diabetes,
hypertension, heart disease)
cerebrovascular risk factors such as hypertension, diabetes, coronary artery and supplement with review
disease, dyslipidemia, obesity, and smoking is important. When possible, of the electronic medical
it is helpful to supplement the history obtained from the patient and informant record, when possible.
with review of the general medical record because many patients are
● Many patients are
often unaware of important aspects of the medical history, such as results
unaware of the deleterious
of prior diagnostic studies or specific dosages of medications.8 cognitive effects of many
over-the-counter
FAMILY AND SOCIAL HISTORY medications, particularly
Family history, including history of and age at onset of cognitive and sleep aids, and do not report
use of these medications
neurobehavioral symptoms in relatives, is needed. A detailed pedigree is often unless directly asked.
needed for presentation of any cognitive or neurobehavioral disorders in young
patients (younger than 65). As many genetic disorders can have a wide spectrum
of phenotypes, a broad family history that asks about cerebrovascular diseases,
motor neuron diseases, epilepsy, psychiatric diseases, or any movement
disorders such as parkinsonism, ataxia, or chorea, is important. Social history
should include a review of alcohol, tobacco, and illicit substance use.
MEDICATIONS
A list of prescription and over-the-counter medications and supplements
should be obtained. Many patients are unaware of the deleterious cognitive
effects of many over-the-counter medications, particularly sleep aids, and do not
report use of these medications unless directly queried. Furthermore, patients
should be encouraged to bring pill bottles to the clinic for review. The clinician
should attempt to match the prescribing date on the bottles and the number of
pills in each bottle, as discrepancies may indicate patient noncompliance due
to forgetfulness.
PRESENTING SYMPTOMS
It is often necessary to clarify with patients and informants about the
presenting symptoms, as illustrated in CASE 1-1. Many patients and informants
report any cognitive disturbance as “memory loss.” For example, an

informant may report “memory loss for words” in the patient with an aphasic
disorder, or the informant may report memory loss when describing slips of
everyday actions (eg, forgetting the filter in the coffee pot) in the patient with
primary impairment in attention/working memory. Thus, it is helpful to
obtain specific examples from the informant about the presenting symptoms,
and it is up to the clinician to determine the reason based on the history and
examination. In addition, it is essential to be mindful of subtle, early changes
that may be dismissed by the informant as part of normal aging or due
to “stress.”9
TEMPO OF ILLNESS
Knowledge about the onset, pace, and sequences of events aids in localization
and informs the differential diagnosis, as highlighted in CASE 1-2. The important
aspects to inquire about include the following:
1 First symptom noted. Many cognitive and neurobehavioral disorders, particularly those
due to neurodegenerative diseases, have similar phenotypes in the end stages.10 By knowing
this key feature of the illness, a clearer understanding of localization can be ascertained.
2 Mode of onset (acute, subacute, or chronic) and pace of change (transient, static,
progressive, or fluctuating). This information assists in forming a differential diagnosis and
guiding further investigations, as noted in TABLE 1-1.
REVIEW OF SYMPTOMS PERTAINING TO COGNITIVE DOMAINS

Akin to a general medical review of systems, questions should be posed to query
the functioning of all cognitive domains and behaviors (TABLE 1-2). This is
important because many patients and informants report any cognitive disturbance
as “memory loss,” as noted earlier, and the presence or absence of reported
impairment in different domains provides information about the potential
localization and directs more detailed examination in those domains.9
REVIEW OF NEUROPSYCHIATRIC SYMPTOMS

Neuropsychiatric symptoms are common in cognitive disorders and are a
defining feature of behavioral disorders; they play a large role in the effect on the
patient and burden to the caregiver but yet are potentially amenable to many
nonpharmacologic and pharmacologic interventions.
Neuropsychiatric symptoms can be divided into behavioral domains as shown
in TABLE 1-3.9 A thorough review of each domain, similar to the review of each
cognitive domain, is an important aspect of the clinical history. This can be
accomplished through patient and informant interviews, but the use of
standardized measures allows for greater precision, assessment of severity, and a
means of monitoring evolution and response to treatment. A widely used
measure suitable for clinical practice is the Neuropsychiatric Inventory-Questionnaire
(NPI-Q),11 which can be supplemented with measures for particular neuropsychiatric
symptoms, such as for depression, if more detailed ascertainment of a particular
behavioral domain is needed.
REVIEW OF SLEEP-RELATED SYMPTOMS

Sleep disturbance is a common symptom in many cognitive and neurobehavioral
disorders and represents an important therapeutic target.12 Additionally, the
presence of certain sleep disturbances can aid in the differential diagnosis; rapid
1522 DECEMBER 2021

eye movement (REM) sleep disorder, in particular, is increasingly recognized as KEY POINTS
an important prodromal symptom in disorders of α-synuclein pathology.13
● It is helpful to obtain
When asking about sleep history, it is important to inquire about a patient’s specific examples from the
sleep schedule, including bedtime routine, sleep-onset latency, awakenings at informant about the
night, and daytime naps, to assess for sufficient sleep. Obtaining collateral presenting symptoms
history from a bedtime partner on snoring, noisy breathing, or apnea during because patients and
caregivers may describe any
sleep informs on the risk of obstructive sleep apnea, and asking about abnormal
cognitive symptom as
movements at night can indicate REM and non-REM parasomnias.14 “memory loss” or ascribe
subtle, early changes to
REVIEW OF FUNCTIONAL CAPACITY normal aging or
psychosocial stressors.
Determining a patient’s functional capacity aids in determining the stage of
illness from mild cognitive impairment, in which functional capacity is ● The clinician should
preserved, to mild, moderate, or severe dementia, in which functional capacity obtain history regarding the
is affected in increasing severity. Additionally, this aids in identifying specific first symptom noted, mode
areas for neurorehabilitation, addressing safety concerns such as driving, of onset (acute, subacute, or
chronic), and pace of
medication management, and fall risk, and assessing caregiver burden and change (transient, static,
mitigation strategies. progressive, or fluctuating).
Patients and caregivers should be asked about both instrumental and basic
activities of daily living (ADLs). Instrumental ADLs are the complex skills ● The presence of
symptoms in each cognitive
needed to live independently, such as driving, medication and financial
and neuropsychiatric and
management, preparing meals, shopping, and using devices. Basic ADLs are skills behavioral domain helps
needed for basic daily functioning such as dressing, toileting, bathing, or eating. It define the cognitive profile
is helpful to provide descriptors of the assistance an individual needs for each and aid in the differential
diagnosis.
instrumental and basic ADL, from doing so fully independently, needing
prompting but can do independently, needing some assistance, or fully dependent. ● Obtaining functional
Several standardized scales are available for assessment of ADLs. Some capacity of the patient aids
examples include the Functional Activities Questionnaire (FAQ)15 or the Lawton in defining the stage of
Instrumental Activities of Daily Living (IADL) Scale16 for assessment of illness, identifying needs for
neurorehabilitation,
instrumental ADLs and the Barthel Index17 or Katz Index18 for assessment of addressing safety concerns,
basic ADLs. Although an interview with an informant suffices in many and assessing caregiver
circumstances, the use of standardized scales structures the interview and burden.
provides helpful benchmarks to track changes over time.
EXAMINATION
After obtaining a complete history, the next step in evaluation of cognitive and
neurobehavioral symptoms is general medical and neurologic examinations.
General Medical Examination

A general medical examination can provide important diagnostic clues in
evaluation of cognitive and neurobehavioral disorders. General observations may
include assessment for signs of developmental anomalies, trauma, or physical
signs of substance abuse or withdrawal.1 Auscultation of the carotids and a
cardiac examination are important when considering cerebrovascular diseases.
An eye examination can show signs of retinitis pigmentosa seen in some
spinocerebellar ataxias and mitochondrial disorders, Kayser-Fleischer rings seen
in Wilson disease, or relative afferent pupillary defect seen in disorders affecting
the optic nerves (eg, demyelinating or mitochondrial disorders). An abdominal
examination should evaluate for organomegaly that may indicate liver
dysfunction that can be seen with alcohol use disorder, mitochondrial disorders,
Wilson disease, or neurometabolic disorders such as Gaucher disease.

CASE 1-2 A 65-year-old right-handed man presented for a 1-month history of

rapidly progressive confusion. His wife noted that he was having
difficulty with word finding and comprehending others. He had no other
associated neuropsychiatric symptoms. Two months ago, the patient was
successfully managing his own business; he was currently unable to
manage medications or finances but was able to prepare meals, operate
appliances, and complete all basic activities of daily living without
prompting or assistance. His medical history was notable for
hypertension and hyperlipidemia, and he had no family history of any
neurologic disorder.
On examination, he scored 5/30 on the Montreal Cognitive Assessment
(MoCA). His verbal output was characterized by normal grammar, syntax,
and phrase length but with frequent breaks for word retrieval and use of
numerous nonspecific words, such as “thing,” and occasional phonemic
paraphasias. Visual confrontation naming was markedly impaired, but he
was able to correctly match semantically related pictures, match words
with definitions, and answer yes/no questions appropriately.
Comprehension of simple, single-step verbal instructions was intact, but
comprehension for verbal instructions of increasing complexity was
impaired.
Brain MRI with and without contrast demonstrated advanced
subcortical white matter disease, multifocal acute infarcts, superficial
siderosis, and leptomeningeal enhancement of the left greater than right
cerebral hemisphere, most notable in the left temporoparietal and
occipital regions (FIGURE 1-2). CSF analysis showed mildly elevated protein
at 60 mg/dL but normal glucose and cell count and absence of
oligoclonal bands. CSF culture and studies for infectious organisms were
negative. Serum and CSF testing for neuronal antibodies was negative.
Catheter cerebral angiogram was normal. Brain biopsy demonstrated
abundant amyloid-β deposition in blood vessels with surrounding
granulomatous inflammation, diagnostic of amyloid-β related angiitis.
COMMENT The subacute onset and rapid progression of cognitive symptoms aids in
narrowing the differential diagnosis to an infectious, demyelinating,
inflammatory, autoimmune, paraneoplastic, or high-grade malignant
process. The screening neurocognitive test demonstrated severe, global
impairment that was disproportionately affected compared with the
patient’s functional capacity. That, combined with the patient’s presenting
symptoms of predominantly language-based difficulties, warranted more
in-depth assessment of language functions, which showed language
impairment localizing mainly to the temporoparietal region, corresponding
with the area of greatest abnormality on the brain MRI. A precise diagnosis
was made possible only with the combination of history, detailed
examination, and comprehensive diagnostic testing warranted by the rapid
onset.
1524 DECEMBER 2021

FIGURE 1-2
Representative MRI sequences of the patient in CASE 1-2. A, Axial diffusion-weighted images
demonstrating punctate acute infarcts in the left temporoparietal region (arrows). B, Axial
T2-weighted image showing hyperintensities of the white matter, which are advanced for
the age of 65 years. C, Axial susceptibility-weighted image showing diffuse hemosiderin
deposition of the cortical surface, consistent with superficial siderosis, most prominent in
the left temporoparietal region (arrow). D, Coronal postcontrast T1-weighted image showing
leptomeningeal contrast enhancement, most notable in the left temporoparietal region
(arrow).

Neurologic Examination
The neurologic examination helps determine the presence of a neurologic
abnormality and its localization, which may later be confirmed with
investigations. All neurologic systems should be screened, but as the presenting
symptom is a cognitive or neurobehavioral one, the focus is on a detailed
mental status examination.
MENTAL STATUS EXAMINATION. The mental status examination begins with

observation of the patient’s appearance and behavior during the interview with
the patient and caregiver. This includes assessment of arousal, motivation, mood
and affect, thought content and processes, judgment, and insight.
The mental status examination should provide a description of the degree of
arousal; it is more useful to describe arousal in terms of the degree of stimulus
needed to provoke a particular motor response (eg, the patient briefly opened his
eyes with light tactile stimulation) rather than terms such as alert, lethargic, or
obtunded. Assessment of appearance should also include a description of apparent
age, hygiene and grooming, eye contact, demeanor and interpersonal interactions,
and any noteworthy physical characteristics (eg, craniotomy scar, dysmorphic
features).1 Motivation is further noted through the extent to which the patient
expresses goal-directed thoughts and feelings while participating in the interview
and examination. Mood, affect, thought content, insight, and judgment are
TABLE 1-1 Selected Differential Diagnosis of Cognitive and Neurobehavioral

Symptoms Aided by Tempo of Presenting Symptom
Mode of onset
Pace of
change Acute (seconds to days) Subacute (weeks to months) Chronic (years)
Transient Transient ischemic attack Not applicable Not applicable
Migraine
Seizure
Static Stroke Metabolic Not applicable

Traumatic brain injury
Metabolic
Progressive Infection (viral, bacterial) Infection (spirochetal, fungal, prion) Cerebrovascular disease
(chronic small vessel ischemic
Inflammatory and demyelinating Endocrine
disease, multi-infarct dementia)
disorders
Demyelinating disorders
Neurodegenerative
Inflammatory
Genetic
Autoimmune
Tumors
Paraneoplastic
High-grade tumor
Fluctuating Not applicable Metabolic Epilepsy

Autoimmune
Paraneoplastic
1526 DECEMBER 2021

assessed as part of the review of neuropsychiatric symptoms in the history. KEY POINTS
Thought process is observed throughout the history with note of any deviation
● The mental status
from normal, logical, and goal-directed processes, such as tangential, circumstantial, examination begins with
perseverative, or bradyphrenic responses.1 observation of the patient’s
The bulk of the mental status examination centers on cognitive assessment, appearance and behavior,
which can be time-consuming. Thus, standardized screening evaluations, such as including assessment of
arousal, motivation, mood
the Mini-Mental Status Examination (MMSE)19 or Montreal Cognitive
and affect, thought content
Assessment (MoCA),20 are often used to obtain a basic understanding of the and processes, judgment,
patient’s cognitive functioning in a short amount of time. However, these and insight.
screening evaluations have inherent weaknesses, and they should not be used as
the sole basis for assessing cognitive dysfunction. For example, many of these ● Screening neurocognitive
tests are helpful in obtaining
screening tests were developed for assessing cognitive functions in older adults, a basic understanding of the
and they may not be generalizable to other cognitive and neurobehavioral patient’s cognitive
disorders. Many scales also focus largely on memory and orientation and may not functioning in a short
assess some cognitive domains altogether. However, by starting an examination amount of time, but they
have inherent weaknesses
with one of these standardized screening measures, the examiner can detect key and should not be used as
deficits and expand on them and supplement with additional tests for cognitive the sole basis for assessing
domains highlighted by the presenting symptom or that may be lacking in the cognitive dysfunction.
screening measure, as noted in CASE 1-1. The screening measures can also be
● Attention is a necessary
helpful for tracking changes over time.
substrate for intact
A mental status examination often, therefore, needs to be expanded with performance in all other
additional single-domain cognitive tests. These tests typically include assessment cognitive domains; thus,
of attention, memory, language, visual-perceptual-spatial, executive, and praxis interpretation of
performance in other
functions. The American Academy of Neurology Behavioral Neurology Section
cognitive domains is limited
Workgroup reviewed select single-domain tests that are useful in clinical if attention is impaired.
practice, with attention to being standardized, are easy/free to access, and have
short administration time.21 A detailed description of evaluation of each
cognitive domain is provided below with a summary of bedside cognitive tests
and pearls and pitfalls of these tests shown in TABLE 1-4.22-35 Assessment of praxis
is discussed separately in the article “Upper Limb Apraxia” by Kenneth L.
Heilman, MD, FAAN,36 in this issue of Continuum.
ATTENTION. It is helpful to begin assessment of cognitive function by first

assessing attention, as attention is a necessary substrate for intact performance in
all other cognitive domains. If attention is impaired, the examiner may consider
curtailing the remainder of the cognitive examination as interpretation of
performance in the remaining cognitive domains will be severely limited.
Additionally, impaired attention has little localizing value, although it is
classically associated with frontal and right parietal lesions.
Tests of attention can be divided into tests of “basic” and “complex” attention,
where basic attention reflects the ability to sustain focus to perform a certain task
and complex attention reflects the ability to control, shift, and divide attentional
focus.21 Basic attention can be assessed through forward digit span,31 in which the
examiner asks the patient to repeat a string of numbers of increasing length; intact
performance for an adult is 7 ± 2. Trail Making Test Part A22 is another common test
of basic attention (specifically, processing speed) in which the patient is asked to
draw connecting lines between numbers 1 through 25 randomly distributed on a
sheet of paper, sequencing in ascending order. If the paper template is not readily
available, Trail Making Test A can be completed orally as well by asking the patient
to verbally count 1 through 25. Vigilance can further be assessed with letter

cancellation tasks31 in which the patient is asked to signal when a specific letter is
found among other letters distributed on a piece of paper or presented orally.
Complex attention can be assessed through measures such as backward digit
span, in which the patient recites the backward order of digits read aloud; the
average adult can obtain a backward span of 5 ± 2. Alternatively, the examiner
can ask the patient to recite overlearned pieces of information, such as months,
days of the week, or the alphabet in reverse order. Note that subtraction of
serial 7s is a common test of complex attention, but many healthy older adults
TABLE 1-2 Sample Questions to Probe Function of Cognitive Domainsa
Cognitive domain Probing questions
Attention/working memory Does the patient have difficulty with:

Concentrating when reading a book?
Following the plot of a movie?
Maintaining train of thought?
Recalling why they entered a room?
Making frequent slips of everyday action such as forgetting a filter in the coffee pot?
Language Does the patient:

Sound as articulate as before?
Use words with incorrect or distorted sounds?
Have difficulty with correct grammar?
Have word-finding difficulty?
Substitute wrong words?
Have a decline in vocabulary?
Have difficulty understanding the meaning of words?
Have a change in ability to spell?
Read for pleasure?
Follow instructions (oral or written)?
Memory Does the patient:

Use lists or notes more than in the past?
Ask or make repetitive statements?
Forget recent conversations and events?
Frequently misplace objects?
Forget past personal events such as previous surgeries, jobs, or places of residence?
CONTINUED ON PAGE 1529
1528 DECEMBER 2021

make errors on this task, and this should not be interpreted as impairment in
attention when assessed in isolation.
Working memory is the ability to hold pieces of information in mind
for a brief period of time after presentation. Working memory is a function of
the attentional matrix and not the memory systems.25 It is assessed through
tasks mentioned earlier, such as digit span and citing months of the year in
reverse. Note that a patient with severe amnesia can have intact working
memory.
CONTINUED FROM PAGE 1528
Cognitive domain Probing questions
Visual-perceptual-spatial Is the patient able to:

Find places within and outside the immediate neighborhood?
Find objects on a counter/shelf directly in front of them?
Recognize familiar faces?
Recognize everyday objects?
Recognize landmarks?
Drive without acquiring new dents and scratches?
Walk without bumping into walls/doorways (in absence of motor deficit)?
Praxis Does the patient have:

Difficulty with manual skills such as opening a can, drawing the blinds?
Clumsiness, or do they move a limb in a coordinated manner?
Ability to use utensils or tools?
Difficulty knowing how to put on clothes?
Difficulty getting in/out of bed or the car?
Executive Is the patient capable of:

Resisting scams/advertisements?
Using appliances and gadgets?
Planning an outing/errand?
Balancing the checkbook?
Maintaining hobbies and activities (eg, card games, crafts, woodworking)?
Social Does the patient:

Take other people’s feelings into account?
Make inappropriate comments?
Have loss of manners/social decorum?
Show empathy/interpersonal warmth?
Show interest and initiative in activities?
Have compulsive, stereotyped, or ritualistic behaviors?
a
Reprinted with permission from Tang-Wai DF and Freedman M, Continuum (Minneap Minn).4 © 2018 American Academy of Neurology.

LANGUAGE. Bedside assessment of language begins with evaluation of

spontaneous language features during conversation. The examiner should listen
for articulation and note if words are well formed or if the words sound laborious
and distorted. The examiner should also be listening for paraphasias, grammar
and syntax, fluency, and prosody. Paraphasias can be phonemic or semantic,
with the phonemic form consisting of the patient selecting an incorrect sound
(or phoneme) of a syllable of the intended word and creating a nonword (eg, “laise”
for raise) and the semantic form consisting of the patient selecting an incorrect word
for the intended word (eg, “orange” for apple). Agrammatism is noted by simplified
syntax with shorter phrase length, lack of grammatical words such as pronouns or
prepositions, and errors of tense. Patients with agrammatism often sound
telegraphic, which means to be concise and omitting inessential words.
Fluency is a measure of phrase length and not necessarily the number of
breaks to produce verbal output. Thus, assessment of fluency must be separated
from difficulties with word-finding, as this may produce breaks in output.
However, patients with word-finding difficulties may be capable of occasionally
producing longer phrases and thus are not nonfluent.10
When assessing spontaneous verbal output, the examiner should note the
prosody (the melodic tone of the patient). This can be more formally assessed by
asking the patient to mimic the examiner’s affect or inflections. Aprosodia
is seen most often in nondominant hemisphere lesions.
Some patients produce little spontaneous verbal output but do better when
given context. Thus, language function should additionally be assessed by
providing the patient with a complex picture and asking the patient to describe
the picture. A picture from a magazine can serve this purpose.
Evaluation of language should also include assessment of naming, repetition,
comprehension, reading, and writing. Naming can be assessed informally by
TABLE 1-3 Behavioral Domains of Neuropsychiatric Symptomsa
Domain Examples
Disorders of volition and Apathy, impulsions, compulsions (including simple and complex rituals, hoarding)
self-control
Affective states Depression, anxiety, euphoria/jocularity, mania, irritability/agitation
Aggression Impulsive, reactive, premeditated
Abnormal precepts Illusions and pareidolias (imposing meaningful interpretation on nebulous stimuli), hallucinations
Abnormal ideation Preoccupations and ruminations, misinterpretations, delusions
Motor disturbances Restless/fidgeting, rummaging, roaming
Feeding disorders Anorexia, hyperphagia, foraging, pica
Abnormal sexual Asexuality/hyposexuality, misdirected intimacy, hypersexuality (which may include impulsive
behaviors propositions and intrusions)
Disorders of sleep Hyposomnia/insomnia, hypersomnia, sleep-cycle disruptions, rapid eye movement (REM) parasomnias
a
Reprinted with permission from Miller BL, Boeve BF, Cambridge University Press.9 © 2017 Cambridge University Press.
1530 DECEMBER 2021

asking the patient to name various objects on the examiner or within the KEY POINTS
examination room. However, deficits in naming show a marked frequency
● Working memory is a
effect, with even patients who have severe anomia able to name familiar, function of the attentional
high-frequency objects such as a pen. The frequency effect can be overcome by matrix and not the memory
asking the patient to name individual pieces of objects, such as the lapel on a shirt systems. A patient with
or the crystal of a watch. The examiner can also ask the patient to name line severe amnesia can have
intact working memory.
drawings of objects. Several standardized instruments are available, such as the
Boston Naming Test,37 that can be used for tracking changes over time. For ● Assessment of fluency
patients with visual deficits, naming can be assessed by asking the patient to should be distinguished
name objects from verbal, semantic cues provided by the examiner (eg, asking from difficulties with word
the patient to name an animal that roars). finding.
Assessment of repetition should begin with asking the patient to first repeat ● Deficits in naming show
single words and then a string of words of increasing phrase length. Patients with a marked frequency
apraxia of speech or phonologic processing deficits will be unable to repeat single effect; even patients who
multisyllabic words, particularly when asked to repeat the word multiple times have severe anomia are
able to name familiar,
successively. Note that errors of substitution and omission in repeating longer high-frequency objects
phrases can be due to deficits in working memory and not necessarily language such as a pen.
deficits. Additionally, errors can result from social and cultural factors or from
assessing repetition in the non-native language of the patient.1 ● Errors of substitution and
omission in repeating longer
Assessment of comprehension is divided into assessment of semantic and
phrases can be due to
syntactic comprehension. Semantic comprehension can be evaluated by asking deficits in working memory
yes/no questions (eg, “Is the sky blue?” or “Do pigs fly?”), asking the patient and not necessarily
to point to objects in the room of medium to low frequency (which can then language deficits. Errors can
later be used to assess spatial memory; see the following “Memory” section), also result from social and
cultural factors or from
or word-definition matching in which the patient is asked to provide a definition assessing repetition in the
of a word supplied by the examiner. Next, syntactic comprehension is assessed non-native language of the
by asking the patient to complete tasks of increasing syntactic complexity, patient.
such as “Point to your nose after you touch the desk.” Note that errors can be
caused by impaired working memory and not necessarily deficits in
comprehension.
Reading and writing are often neglected in bedside assessment of language
functions but provide important information as to localization, pathology, and
rehabilitation needs. Assessment of reading and writing should begin with
assessment of single letters and then single words, including regular, irregular,
and nonwords, and lastly sentences and paragraphs. Regular words are words
that are pronounced or spelled according to the phonic “rules” of the language,
whereas irregular words do not follow such rules and must be decoded by sight.
Reading errors can include errors in letter identification (as seen in pure alexia),
letter-by-letter reading, neglect, or deep or surface central linguistic errors.10
Deep dyslexia is characterized by semantic errors and the inability to read
nonwords, whereas surface dyslexia is characterized by regularization errors of
irregular words (eg, pronouncing “yatchet” when reading “yacht”).
Writing should be similarly assessed, including writing spontaneously and to
dictation of single words, phrases, and sentences. If a patient has deficits in
spelling, this can be further assessed with assessment of oral spelling, which
should include assessment of regular, irregular, and nonwords.
MEMORY. Assessment of memory focuses on testing of explicit (ie, declarative)

memory and refers to recollection of facts or events. Examination of explicit
memory includes assessment of orientation, awareness of current news, recall

TABLE 1-4 Bedside Assessment of Select Cognitive Domains
Cognitive domain Bedside tests Pearls and pitfalls
Attention/working Digit span (forward and reverse) These tasks are dependent on intact language;
memory consider tests of spatially mediated attention
Months, days of the week, or alphabet in
such as Corsi Block-Tapping Test23 or Spatial
reverse
Span subtest of Wechsler Memory Scale, Third
Spelling backward Edition24 if the patient is aphasic
Serial subtraction
Trail Making Test Parts A and B22
Language
Spontaneous Assess articulation, paraphasias, grammar and Separate word-finding difficulties from fluency;
syntax, fluency, and prosody during normal patients capable of producing longer phrases
conversation (~5 words or longer) are fluent, regardless of
pauses for word retrieval
Picture description Assess articulation, paraphasias, grammar and Subtle deficits in articulation, grammar and
syntax, fluency, and prosody with a narrative syntax, fluency, and prosody may be more
context, such as description of a complex notable within a narrative context
picture from a magazine
Naming Ask the patient to name objects present on Avoid frequency effect by asking the patient to
the examiner (eg, watch, lapel) or within the name objects with lower frequency in everyday
examination room life; provide verbal semantic cues for naming
objects in patients who are visually impaired;
watch for vague superordinate responses in
patients with semantic deficits
Repetition Ask the patient to repeat single words and Deficits of repetition of single, multisyllabic words
phrases of increasing complexity may be due to apraxia of speech or phonologic
processing deficits; deficits of repetition of longer
phrases may be due to deficits of working
memory, or social, cultural, or native language
features in addition to deficits in language function
Comprehension
Semantic Ask the patient to answer simple yes/no Errors can also arise from auditory or visual
questions and to match words and definitions perceptual deficits
Grammatical Ask the patient to perform tasks of increasing Errors can also be seen with deficits in working
syntactic complexity memory in addition to deficits in language function
Reading Ask the patient to read regular and irregular Consider neglect or dyslexia/dysgraphia if other
words, nonwords, and short paragraphs aspects of spoken language are normal
Writing Ask the patient to write spontaneously and to Acutely confused patients may write with
dictation, regular and irregular words, perseverative repetition of letters and careless
nonwords, and sentences penmanship25; deficits in grammar and syntax
may be more notable in the written than verbal
domain
Memory
Orientation Ask the patient for the current date, month, Orientation is also impaired in patients with
year, and location and reason for visit attentional disorders; assess with multiple-
choice in anomic/aphasic patients
1532 DECEMBER 2021

Retrograde memory Query patient about details of life in chronologic Look for a temporal gradient in retrograde
order and knowledge of major news events memory
Anterograde verbal Query patient about a recent holiday, journey Anterograde amnesia will have intact acquisition
memory to the clinic, or recent viewing of a television of a word list or story due to spared working
program; assess acquisition, recall, and memory, with impaired delayed free and
recognition of a word list or story recognition memory; impaired free delayed recall
with intact recognition implies deficit of memory
retrieval from frontal-subcortical dysfunction
Anterograde Walk the patient around clinic and ask to

nonverbal memory repeat the route alone; show the patient 3
objects in the room and later ask the patient to
point to the objects; ad hoc face recognition
from magazine pictures; copy and recall of
complex figures or shapes such as
Rey-Osterrieth Complex Figure Test26,27 or
Three Words–Three Shapes Test25
Visual-perceptual-spatial
Construction Cube copy Watch for stimulus-bound behavior of drawing

on top of or connected to the original, often seen
Copy of interlocking pentagons
in frontal lobe dysfunction
Clock drawing
Rey-Osterrieth Complex Figure Test
Visuoperception Judgment of Line Orientation28

Hooper Visual Organization Test29
Navon figure30
Overlapping figures31
Face Recognition Ask the patient to identify pictures in a

magazine or facial features of the examiner
Benton Facial Recognition Test32
Object Recognition Ask the patient to name objects by sight, and if

unable then ask the patient to name by sound
or touch
Spatial attention Double simultaneous stimulation

Line bisection33,34
Letter or shape cancellation tasks25,31
Executive function
Abstraction/reasoning Similarities Use unfamiliar similarities and proverbs, as some

can be overlearned
Proverbs
Motor sequencing Luria fist-edge-palm35
Set-shifting Tail Making Test Part B22 Use the oral version for patients who are visually
impaired

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35
Response inhibition Go/no-go test These tests are insensitive, but abnormalities are
25
pathologic
Alternating sequences
Verbal initiation/ Letter and semantic category fluency tasks Look for poor retrieval strategies, perseverative
planning responses, and difficulty switching between
tasks; category fluency is often better than letter
fluency unless there is a semantic memory deficit
Visual initiation/ Clock drawing

planning
Rey-Osterrieth Complex Figure Test
of past events, and ability to learn and retain new verbal and nonverbal
information.
Assessment of orientation includes person, place, time, and situation. Note
that even in severe amnestic disorders, it is unusual for patients to not be oriented
to name, except in functional cognitive impairment. Additionally, orientation to
place and orientation to the exact date are not very sensitive measures of
memory. Likewise, orientation requires intact attention, and patients with acute
confusional states are typically disoriented.
Retrograde memory is next assessed through inquiring with the patient about
culturally sensitive knowledge of public events, popular television shows, and
autobiographical information. An informant is needed to corroborate this
information. Individuals with a typical amnestic syndrome display retrograde
memory loss with a temporal gradient; that is, events that occurred closer in time
to the onset of the memory loss are recalled least well, whereas more remote
events are better recalled, presumably to the less extensive consolidation of more
recent memories.25 For example, an individual with an amnestic disorder is less
likely to recall events of September 11, 2001, than the assassination of President
John F. Kennedy or less likely to recall faces and names of grandchildren
than children.
The bulk of the bedside assessment of memory focuses on anterograde
memory, which refers to the learning, retention, and retrieval of newly presented
information. This should be assessed in both verbal and nonverbal domains
because of differing localizing values, as selective verbal memory deficits are
seen with unilateral left hippocampal lesions, and selective nonverbal memory
deficits are seen in unilateral right hippocampal lesions.
Anterograde verbal memory is routinely assessed with word lists in which the
patient is asked to learn a list of words over one or more trials and then recall
those words after a delay. Most screening cognitive tests incorporate lists of 3 to 5
words, but more robust lists of 10 to 15 words in length may be needed to fully
assess verbal memory function. In assessing delayed recall, it is helpful to assess
both freely recalled words as well as recognition or cued recall. Individuals who
are truly amnestic are impaired on both free and recognition recall, whereas
individuals with disorders of memory retrieval, which is classically seen in
1534 DECEMBER 2021

individuals with frontal-subcortical dysfunction, have impairment with free KEY POINTS
recall but no impairment with recognition or cued recall. Note also that the initial
● Individuals with a typical
portion of the task assesses learning, or acquisition, of the word list, and is a amnestic syndrome display
function of working memory. An individual with a pure anterograde amnesia has retrograde memory loss with
intact initial learning but impaired delayed recall. a temporal gradient; events
Anterograde verbal memory can also be assessed with learning and delayed that occurred closer in time
to the onset of the memory
recall of stories, also referred to as logical memory. A discrepancy between more
loss are recalled least well,
severely impaired word-list learning and relatively intact logical memory can be whereas more remote
seen in individuals with executive dysfunction, in which the context and events are better recalled.
organization of the story aid in recall.
Nonverbal domains of anterograde memory, such as spatial and face memory, ● In assessing delayed
recall, the clinician should
should also be examined. Nonverbal anterograde memory can be casually assess both freely recalled
examined by walking the patient around a route in the clinic and asking the words as well as recognition
patient to repeat that route or by pointing out objects in the examination room to or cued recall. Individuals
the patient and later asking the patient to point to those same objects. More who are truly amnestic are
impaired on both free and
formal tests of nonverbal anterograde memory incorporate asking the patient to recognition recall, whereas
copy a complex design, such as the Rey-Osterrieth Complex Figure Test individuals with disorders of
(FIGURE 1-3),26,27 or shape(s) and later draw the same design or shape(s). memory retrieval have
impairment with free recall
VISUAL-PERCEPTUAL-SPATIAL FUNCTION. Bedside tests of visual-perceptual-spatial but no impairment with
recognition or cued recall.
function typically involve asking the patient to copy a complex figure, such as a
cube or interlocking pentagons, or to draw a clock. Attention should be given to a
disorganized approach, which may suggest executive dysfunction, or an
impoverished half of the design that may reflect neglect due to nondominant
FIGURE 1-3
The Rey-Osterrieth Complex Figure.

hemispheric lesions. Standardized assessment can include the use of the

Rey-Osterrieth Complex Figure Test.
Visual-perceptual function can further be assessed through tasks such as
Judgment of Line Orientation,28 in which the patient is asked to match lines
drawn at specific angles, and the Hooper Visual Organization Task,29 in which
the patient is asked to conceptually rearrange fragments of line-drawing pictures
into unified objects. Part-whole discrimination, a feature of simultagnosia, can be
further assessed with the Navon figure,30 in which many small letters are used to
form a larger letter; an individual with simultagnosia can perceive the small
letters but not the larger one. Another common test of visual-perceptual function
involves the use of overlapping figures, in which a patient is asked to identify line
drawings of objects overlapping with one another.31
Visual agnosia is the most common of the agnosias and is, thus, discussed here.
Visual agnosia is the inability to recognize objects that are visually presented, despite
intact elementary visual processes. Visual agnosia is divided into apperceptive and
associative visual agnosia. Apperceptive visual agnosia is the inability to form a
complete percept of an object and can be assessed by asking the patient to copy a
complex figure, identify incomplete letters, or discriminate shapes. Associative
visual agnosia is the inability to access stored knowledge of the percept and can be
category specific (eg, faces, landmarks, objects), as noted in CASE 1-1. Recognition of
faces (prosopagnosia) can be assessed at the bedside by asking the patient to name
faces in a magazine or asking the patient to describe facial features (eg, hair or eye
color) of the examiner. Several standardized assessments of facial recognition exist,
such as the Benton Facial Recognition Test.32 Individuals can have the inability to
recognize written words despite preservation of other aspects of language function,
a condition known as pure word blindness or pure alexia. Furthermore, individuals
can have difficulty identifying and discriminating colors (achromatopsia), which
can be assessed by asking a patient to name and identify a color and asking to
match hues of colors. Visual object agnosia can be assessed with visual
confrontational naming tasks and then asking the patient to name the same
object by sound or touch. An individual with visual object agnosia will be unable
to identify an object when shown a picture of the object but may be able to do so
when the object is presented in other sensory modalities.
Spatial attention can be assessed through recognition of double simultaneous
stimulation in visual or tactile domains. Standardized assessment can include a
line bisection task33,34 or letter or shape cancellation tasks, in which the patient is
asked to cross out a specified letter or shape from a page full of random letters or
shapes.25,31 An individual with impaired spatial attention may selectively cross
out letters or shapes from a select portion of the full page.
EXECUTIVE FUNCTION. Often, the history obtained from the informant regarding
functional abilities to plan events and outings, operate appliances and gadgets,
multitask, etc, can be as informative, or more so, about the patient’s executive
function than a formal examination can be.10 Abstraction and reasoning can be
assessed at the bedside with use of similarities (eg, “How are an apple and a
banana similar?”) and proverbs (eg, “What does it mean, ‘Rome was not built in
a day’?”), although one should note the heavy influence of education and culture
on responses. Complex motor sequencing can be assessed with the Luria
fist-edge-palm test35 in which the patient is shown the sequence of three gestures
of the hand and then asked to demonstrate over six trials.
1536 DECEMBER 2021

Trail Making Test Part B consists of asking the patient to connect numbers KEY POINTS
and letters in alternating consecutive sequence, is a good assessment of
● Often, the history
set-shifting (as well as response inhibition), and can also be done orally for obtained from the informant
patients who have a visual impairment. Response inhibition can be further regarding functional abilities
assessed with the go/no-go task,35 in which the patient is asked to tap once in such as to plan events and
response to the examiner tapping once and asked to not tap when the outings, operate appliances
and gadgets, and multitask
examiner taps twice. Another bedside measure of response inhibition is the
can be as informative, or
alternating sequences task, in which the patient is asked to write or draw more so, about the patient’s
alternating sequences of letters (eg, alternating m-n-m-n) or shapes (eg, executive function than a
alternating triangle-square-triangle-square).25 formal examination can be.
Executive control of language functioning can be assessed with fluency tasks,
● Semantic fluency is often
in which the patient is asked to name words beginning with a target letter (eg, F) better than letter fluency
or belonging to a semantic category (eg, animals), with the total number of because of the contextual
responses calculated in 60 seconds. Often, in intact individuals a notable strategy organization offered by the
to a fluency task can be observed (eg, naming zoo animals then farm animals). semantic category that is
lacking in letter fluency, but
Individuals with poor executive function may show poor retrieval strategies, semantic fluency will be
perseverative responses, or difficulty switching between tasks. Note that disproportionately impaired
semantic fluency is often better than letter fluency because of the contextual in individuals with semantic
organization offered by the semantic category that is lacking in letter fluency, but naming deficits.
semantic fluency will be disproportionately impaired in individuals with
● The cognitive profile is
semantic naming deficits, as is often seen in early Alzheimer dementia. determined by contrasting
Executive control of visual functions can be assessed with the domains of primary
visual-construction tasks discussed earlier, such as the clock drawing, or the impairment with those in
which test failure is
Rey-Osterrieth Complex Figure Test.
secondary to another factor
A composite of frontal-executive bedside tests has been developed into and those in which
standardized batteries. One such common measure is the Frontal Assessment performance is normal.
Battery,38 comprising six tests of frontal executive function that can be calculated
into a total score up to 18, which can be tracked over time for change.
INTERPRETATION. After obtaining a complete mental status examination, one can

provide an interpretation of the elements into a cognitive profile, which aids in
localization and determination of potential etiology. The cognitive profile is
determined by contrasting domains of primary impairment with those in which
test failure is secondary to another factor and those in which performance is
normal.10 Performance may be affected by internal patient factors such as
education, occupation, age, native language, or culture or by external factors
such as poor sleep, anxiety/depression, or side effects of medications.39 In
interpreting the cognitive profile, it is important to keep in mind that no test is
perfectly selective for a single cognitive domain; thus the clinician must factor
in whether failure on a particular test was due to failure in the cognitive domain
for which the test was selected versus impairment in another cognitive domain.
For example, memory tests based on word lists also require attention,
motivation, and language processes for performance.25
In determining the primary cognitive domains of impairment, often one
domain is more impaired than others, and the profile is then labeled accordingly.
Common profiles are amnestic, language impairment, predominant
visual-perceptual-spatial impairment, or dysexecutive.4
The amnestic profile is characterized by intact learning of newly presented
verbal and visual material with rapid forgetting on delayed recall. Classic
amnestic syndromes localize to the limbic system or diencephalon or both.

Because much of the mental status examination relies on verbal presentation

of instructions and verbal responses, individuals with primary language
impairment tend to show widespread impairment across many cognitive
domains, with a discrepancy noted for relative preservation of tasks that are less
heavily influenced by verbal instructions and responses, such as tests of spatial
attention or visual memory tests. The heavy language influence is particularly
notable on screening measures such as MMSE or MoCA, in which patients who
are aphasic often score in severely impaired ranges, which is illustrated in
CASE 1-2. However, the examiner can be alerted that the patient may have
predominant language dysfunction by the discrepancy between the cognitive
screening measure and functional capacity of the patient, in which function is
typically more preserved than would be expected for the degree of impairment
on the screening measure. Language disorders classically localize to the
dominant hemisphere.
Individuals with a predominant visual-perceptual-spatial profile will show
impairment in tests of those domains as well as any tests of other cognitive
domains that are presented visually, such as Trail-Making Test Parts A and B,
spatial memory tests, or visual naming tests. Examining verbal memory,
auditory naming, and Trail Making Tests orally can help differentiate if
deficits are primarily due to visual-perceptual-spatial impairment and not
impairment in other cognitive domains. Visual-perceptual-spatial
impairment classically localizes to parieto-occipital and temporo-occipital
regions.
The dysexecutive cognitive profile classically localizes to prefrontal regions
and its subcortical basal ganglial-thalamic and cerebellar connections. In addition
to impairment on tests of executive function noted earlier, individuals with
dysexecutive impairment may show deficiency in the executive control of other
cognitive domains, as noted with impairment in lexical fluency and
visual-construction tests discussed earlier.
After interpreting the cognitive profile, the clinician can begin to refine the
differential diagnosis with the aid of the history already obtained. For example,
an amnestic profile but a reported abrupt onset with stable deficits suggests a
likely vascular etiology in the Papez circuit (eg, posterior cerebral artery
infarctions involving the hippocampus), whereas an insidious onset with
progression may suggest a neurodegenerative etiology involving mesial temporal
structures, such as Alzheimer disease.
COMPUTERIZED ASSESSMENTS. In an era of increasing demands on clinicians’ time

and poor reimbursement for detailed mental status testing, computerized
assessment of cognitive functioning is an increasingly attractive option. Indeed,
computerized assessments have potential advantages of improved efficiency,
cost, and accessibility; the ability to more precisely assess certain cognitive
features such as reaction times; ease of administration in different languages; and
automated interpretive algorithms.40
Although computerized assessments can be an additional tool to evaluate a
patient’s mental status, they cannot replace the clinician’s examination in its
entirety as computerized assessments lack the examiner’s observation of
behaviors and comportment; those observations, as well as the additional
information obtained from the history such as education and occupation, disease
course, comorbid illness, and functional capacity, are imperative for accurate
1538 DECEMBER 2021

interpretation of test results, regardless of any automated interpretation that may KEY POINTS
be provided.
● Individuals with primary
Additionally, increased anxiety can be associated with computer use, language impairment tend to
especially among older adults,41 as well as differing levels of familiarity with show widespread
computer interfaces,42 and changes in vision, hearing, and motor functions can impairment across many
confound results.43 Furthermore, it should be noted that although the landscape cognitive domains, with a
discrepancy noted for
of computerized assessments is rapidly evolving, normative data and
relative preservation of
psychometric properties of these assessments are limited. Careful attention must tasks that are less heavily
also be paid to the conditions in which the assessment is to be used (eg, for influenced by verbal
screening versus more detailed assessment of cognitive performance), age range, instructions and responses.
diagnoses, cultural and ethnic backgrounds, and ensuring that the platform is
● Although computerized
appropriately qualified for each unique patient encounter. assessments can be an
additional tool to evaluate a
GENERAL NEUROLOGIC EXAMINATION. Beyond the mental status examination, patient’s mental status, they
features of the general neurologic examination can provide important clues as to cannot replace the
clinician’s examination in its
the etiology of the presenting cognitive or neurobehavioral symptoms, as noted entirety.
in TABLE 1-544 and exemplified in CASE 1-3. In the cranial nerve examination,
assessment of smell is particularly helpful when considering TBI or ● Features of the general
neurodegenerative disorders involving mesial temporal structures neurologic examination can
provide important clues as
(eg, Alzheimer disease). Visual field assessment can provide important localizing
to the etiology of the
value to corroborate with the mental status examination; hemianopia indicates presenting cognitive or
contralateral occipital lobe dysfunction, whereas inferior quadrantanopia neurobehavioral symptoms.
signifies dysfunction of the contralateral parietal lobe and superior
quadrantanopia of the contralateral temporal lobe. Careful assessment of ● Parkinsonism is present in
many cognitive and
extraocular movements can provide signs of certain neurodegenerative, neurobehavioral disorders,
infectious, inflammatory, and inherited disorders. Many of these signs can be but the clinician should not
subtle, with greater sensitivity for detection of abnormal extraocular movements overinterpret subtle
when assessing saccades in addition to pursuits. Hearing loss can be indicative of findings, such as stooped
posture and general
certain disease processes (TABLE 1-5) but also is a risk factor for dementia.45 slowness of movement, that
The motor examination can provide many important clues to the diagnostic can be seen in aging
etiology. Upper motor neuron findings include pyramidal distribution weakness individuals.
(extensor greater than flexor weakness in the upper limbs, flexor greater than
extensor weakness in the lower limbs), spasticity, and hyperreflexia. Unilateral
upper motor neuron signs may signal space-occupying lesions whereas
asymmetric but not strictly unilateral upper motor neuron findings may indicate
cerebrovascular, demyelinating, or mitochondrial disorders; symmetric findings
are more typical of many inherited disorders. A combination of upper motor
neuron and lower motor neuron findings (flaccid tone, fasciculations,
hyporeflexia) on motor examination reflects motor neuron disease, indicative of
frontotemporal dementia with motor neuron disease.
Observation for involuntary movements including myoclonus, tremor, and
chorea also can narrow the differential diagnosis. Parkinsonism (tremor, rigidity,
bradykinesia, postural instability) is present in many cognitive and
neurobehavioral disorders and can be subtle, although clinicians should pay
careful attention to not overinterpret subtle findings, such as stooped posture
and general slowness of movement, that can be seen in aging individuals.
Likewise, mild parkinsonism is common in moderate to advanced stages of many
neurodegenerative disorders, including Alzheimer disease.
Many patients with cognitive and neurobehavioral disorders exhibit paratonia,
which is the inability to relax the muscles during muscle tone assessment.

TABLE 1-5 Selected Differential Diagnosis of Cognitive and Neurobehavioral

Symptoms Aided by Additional Neurologic Findingsa
Neurologic finding Differential diagnosis
Extraocular movements
Oculomasticatory myorhythmia Whipple disease
Oculomotor apraxia Corticobasal syndrome, posterior cortical atrophy
Supranuclear gaze palsy Vertical: Progressive supranuclear palsy, Niemann-Pick Type C

Horizontal: Gaucher disease
Dysconjugate gaze and/or nystagmus Mitochondrial disorders, spinocerebellar ataxias, paraneoplastic
Opsoclonus Paraneoplastic
Pyramidal signs Cerebrovascular disease

Leukodystrophies
Demyelinating disorders
Space-occupying lesions (abscess, tumor)
Frontotemporal dementia with motor neuron disease
Spinocerebellar ataxias
Autosomal dominant Alzheimer disease (some presenilin mutations)
Parkinsonism Lewy body diseases

Corticobasal syndrome
Progressive supranuclear palsy
Multiple system atrophy
Huntington disease
Frontotemporal lobar degeneration with parkinsonism-17
Cerebrovascular disease
Antipsychotic use
Chronic traumatic encephalopathy
Wilson disease
Fahr disease
Anoxic brain injury
Dystonia/chorea Huntington disease

Wilson disease
Neuroacanthocytosis
Neurodegeneration with brain iron accumulation
Neuroferritinopathy
Neuronal ceroid lipofuscinosis
Lesch-Nyhan syndrome
Dentatorubral-pallidoluysian atrophy
Anti–N-methyl-D-aspartate (NMDA)-receptor encephalitis
1540 DECEMBER 2021

Ataxia Alcohol use disorder

Thiamine deficiency
Anoxic brain injury
Paraneoplastic
Multiple system atrophy
Alexander disease
Fahr disease
Niemann-Pick type C disease
Neuronal ceroid lipofuscinosis
Fragile X tremor ataxia syndrome
Prion diseases
Superficial siderosis
Mitochondrial disorders
Myoclonus Prion diseases

Anoxic brain injury
Epileptic encephalopathies
Metabolic disturbances
Medications
Toxic disturbances (eg, bismuth toxicity)
Paraneoplastic
Subacute sclerosing panencephalitis
Systemic or central infection
Late stage of Alzheimer disease
Lewy body diseases
Huntington disease
Sialidosis

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Peripheral neuropathy Human immunodeficiency virus (HIV)

Alcohol
Leukodystrophies
Porphyria
Heavy metal toxicity
Fabry disease
Neuroacanthocytosis
Cerebrotendinous xanthomatosis
Sialidosis
Lafora body disease
Rheumatologic disorders
Myopathy Alcohol use disorder

Rheumatologic disorders
Hypothyroidism
Metabolic disturbances
Deafness Superficial siderosis

Sialidosis
a
Reprinted with permission from Rossor MN, et al, Lancet Neurol.44 © 2010 Elsevier Ltd.
Paratonia can suggest frontal-subcortical dysfunction but otherwise is of limited

diagnostic value. Paratonia occurs in two forms: (1) mitgehen, in which the
patient facilitates passive movements, and (2) gegenhalten, in which the patient
resists passive movements.1
Assessment of deep tendon reflexes is an important part of the motor
examination, largely to aid in assessment of upper and lower motor neuron
features. Frontal release signs, or primitive reflexes, are often performed as
part of the reflex examination in assessment of cognitive and neurobehavioral
disorders. Frontal release signs are reflexes that are present in a newborn
but become inhibited as the brain matures, causing the reflex to disappear.
Any brain disease that affects these inhibitory pathways can cause the
reflexes to be “released” and elicited on examination.46 Frontal release signs
include grasp, pout, snout, suck, palmomental, and glabellar tap responses.
Although traditionally thought to signify frontal lobe dysfunction, frontal
1542 DECEMBER 2021

release signs have little diagnostic value and can be seen in healthy older
adults.
Sensory examination should include examination of both large (vibration,
proprioception) and small (pain, temperature) fiber modalities. Abnormalities
may signify peripheral neuropathy, which is associated with several cognitive
and neurobehavioral disorders, including human immunodeficiency virus
(HIV), alcohol use disorder, and mitochondrial disorders, among others.
Reduced large fiber sensation in the toes should be recognized as a normal
feature of aging. If the basic large and small fiber sensations are intact, then the
sensory examination should also include assessment for cortical sensory loss. The
contralateral parietal cortex is largely responsible for discriminative sensation,
which can manifest with the inability to correctly discriminate two points,
identify traced fingers in the palm (graphesthesia), identify objects by touch
(stereognosis), or distinguish double simultaneous stimulation.
Examination of coordination should include tests of the limbs (eg, finger-nose
and heel-shin) and the trunk (posture and gait coordination), given their
separate localizing value (cerebellar hemispheres and vermis, respectively).
Many cognitive and neurobehavioral disorders are associated with ataxia,
including spinocerebellar ataxias, multiple system atrophy cerebellar type,
alcohol use disorder, paraneoplastic disorders, and mitochondrial disorders.
No neurologic examination is complete without watching a patient rise and walk.
Features of the gait can highlight dysfunction of many of the neurologic systems
described earlier. For example, individuals with parkinsonism may be noted to have
a stooped posture, lack of arm swing, and short, shuffling steps, whereas individuals
A 25-year-old left-handed man presented with insidious decline in CASE 1-3

cognitive, behavioral, and motoric functions over the preceding 7 years.
His family noted that he had difficulty making decisions and following
steps of instructions and was forgetful of recent events. He additionally
developed disinhibition, apathy, and compulsive behaviors. He also had
difficulty swallowing liquids, was slurring his words, and stumbled as he
walked. He had no family history of any neurologic disorders.
On examination, he was noted to be thin, had infrequent eye contact
with the examiner, and made inappropriate remarks. Cognitive testing
revealed impairment in attention, memory, and executive domains.
Neurologic examination showed a vertical supranuclear gaze palsy,
dysarthria, and ataxia. Brain MRI demonstrated generalized cerebral and
cerebellar atrophy. Cultured fibroblasts obtained from a skin biopsy
showed abnormal filipin staining, and molecular sequencing of the NPC1
gene revealed a pathologic mutation, confirming the diagnosis of
Niemann-Pick C1 disease.
Abnormalities of the neurologic examination aid in refining the differential COMMENT

diagnosis. In this case, Niemann-Pick C1 disease was suspected because of
the presence of vertical supranuclear gaze palsy and ataxia, which was
confirmed with biochemical testing and genetic sequencing.

with dystonia or chorea may have their abnormal movements become more
apparent during gait. Spasticity can often be seen with abnormal circumduction of
the lower limbs, and asking a patient to perform tandem (heel-toe) walking
provides a good opportunity for assessment of cerebellar vermis function.
INVESTIGATIONS
The history and examination mentioned earlier help determine further
investigations based on the localization and differential diagnosis formulated thus
far. For patients with a typical insidious onset and progression of a cognitive
syndrome suggesting a neurodegenerative dementia, often a minimal workup with
structural neuroimaging and a few serum laboratory tests is needed. However, with
CASE 1-4 A 67-year-old right-handed woman presented with a 1-year history of

progressive memory loss. Her family noted that she had been forgetful of
recent events and conversations. For example, she was unable to recall
many details of a recent family vacation and often forgot she had spoken
via telephone with family members when asked later the same day about
the conversations. In addition, her family noted that she was having
episodes of behavioral arrest, lasting minutes at a time. She also
developed bed-wetting at night, although she had no urinary
incontinence when awake. Instrumental and basic activities of daily living
(ADLs) were intact. She had no significant past medical history and did
not take any routine medications.
General neurologic examination was normal. She scored 26/30 on the
Montreal Cognitive Assessment (MoCA), with all points lost for delayed
recall. Neuropsychological examination revealed deficits in verbal but
not visual delayed recall and relative weakness in visual confrontation
naming and semantic fluency. Brain MRI was normal. EEG demonstrated
frequent left temporal sharp waves. CSF was normal, and no neuronal
antibodies were detected in serum or CSF.
Based on the clinical history, examination, and diagnostic studies, she
was diagnosed with transient epileptic amnesia. One month after
institution of levetiracetam, her family noted she was no longer forgetful,
she had no further episodes of behavioral arrest, and her
neuropsychological profile normalized.
COMMENT Insidious progression of memory loss with intact ADLs and

neuropsychological profile of impairment in delayed recall and relative
weakness in semantic fluency and visual confrontation naming is commonly
seen in mild cognitive impairment due to Alzheimer disease. In such cases,
limited diagnostic testing with serum laboratory tests and structural
neuroimaging is warranted. However, the reported behavioral arrests in
this patient are atypical of Alzheimer disease and merited further
diagnostic assessment with EEG, which revealed findings of left temporal
epileptogenicity. While EEG is not always abnormal in transient epileptic
amnesia, it was supportive in this case.
1544 DECEMBER 2021

a more acute-subacute onset, rapid course, atypical mental status or neurologic KEY POINTS
examination findings, or young age at onset, more detailed workup as discussed
● Although traditionally
may be needed. thought to signify frontal
lobe dysfunction, frontal
Neuropsychological Evaluation release signs have little
Neuropsychological evaluation represents an extension of the examiner’s mental diagnostic value and can be
seen in healthy older adults.
status examination. The goal is to support or refute the hypotheses generated by
the examiner thus far to aid in refining the differential diagnosis.47 ● Neuropsychological
Neuropsychological evaluation is particularly helpful in individuals with young- evaluation represents an
onset cognitive or behavioral impairment, in those with atypical features or extension of the examiner’s
significant confounding features in the mental status examination such as mental status examination.
The goal is to support, or
psychiatric disturbances, and when clarity is needed because of discrepancies refute, the hypotheses
among subjective concerns, functional capacity, and bedside mental status generated by the examiner
examination. The neuropsychological evaluation can also assess for performance thus far to aid in refining the
validity, that is, that the performance obtained during the course of evaluation is differential diagnosis.
a true indication of cognitive function. Performance can be invalid if the patient ● Structural brain imaging
is unable to effectively engage in the tasks, which can occur for a variety of with either head CT or MRI is
reasons, such as psychiatric illness or medicolegal reasons, but is not necessarily needed in evaluation of
an indicator of malingering, as impaired validity testing may occur in the cognitive and
neurobehavioral disorders.
presence of some health conditions (eg, untreated sleep apnea), dementia, low
Brain MRI is generally
intelligence, low education, or English as a second language. The preferred given the greater
neuropsychological evaluation can be helpful to elucidate areas of cognitive sensitivity for detection of
strength and weaknesses that are important for rehabilitation needs and atrophy patterns, white
matter diseases, lacunes,
providing resources and referrals to support patient and caregiver needs.
and microhemorrhages.
However, when the bedside mental status examination demonstrates severe or
global cognitive deficits, a neuropsychological evaluation may be taxing and
burdensome for the patient and may not provide any further diagnostic clarity.
Additional Testing
The American Academy of Neurology practice parameter recommends routine
testing of vitamin B12 and thyroid function in patients being evaluated for
dementia.48 Additionally, a basic metabolic panel, calcium, and liver and renal
function tests provide valuable information on factors that can cause or
worsen cognitive or neurobehavioral symptoms. In individuals with risk
factors, screening with HIV and syphilis serology is also needed.48
Structural brain imaging with either head CT or MRI is needed in evaluation of
cognitive and neurobehavioral disorders. Although structural brain imaging is often
unremarkable in routine evaluation of many cognitive and neurobehavioral disorders, it
is essential not to miss important structural changes that are potentially treatable, such
as subdural hematomas, tumors, or hydrocephalus. A brain MRI is generally preferred
given the greater sensitivity for detection of atrophy patterns, white matter diseases
(eg, small vessel ischemic disease, leukodystrophies), lacunes, and microhemorrhages.
In atypical cases, such as young onset or rapid progression of cognitive/
behavioral symptoms, further testing is guided by additional features in the
history regarding the tempo of onset (TABLE 1-1), neurologic examination
(TABLE 1-5), and structural imaging that aid in refining the differential diagnosis.
For example, an acute or subacute onset warrants additional serologic and CSF
testing for infectious, autoimmune, and paraneoplastic disorders. EEGs are
useful when considering prion diseases or when fluctuating symptoms
concerning for seizures are present (CASE 1-4). Advanced neuroimaging

techniques, such as brain FDG-PET or amyloid PET, or CSF analysis of amyloid-

β and tau can provide useful information in the evaluation of young-onset mild
cognitive impairment or dementia in which routine evaluations have not
suggested an etiology, but this is not routinely recommended because of a lack of
standard use criteria for biomarkers, limited standardization of biomarkers from
one locale to another, limited availability, and limited insurance coverage49,50;
however, a clinician may discuss with patients referral for biomarker research in
such instances.51 Imaging findings concerning for leukodystrophy warrant
neurometabolic screening such as serum very long chain fatty acids, arylsulfatase
A, hexosaminidase A, galactocerebrosidase, and β-galactosidase. Furthermore,
genetic testing may be considered in select cases where inherited etiologies are
being considered, but it is an individualized decision influenced by such factors
as the presence of other affected or at-risk family members and cost and
insurance coverage.
CONCLUSION
The clinical approach to cognitive and neurobehavioral symptoms involves first
obtaining a history from the patient and a collateral source that includes
demographic data, tempo of the presenting symptoms, associated cognitive and
behavioral impairments in other domains, functional capacity, and review of the
general medical, family, and social history and medications that may contribute
to the presenting symptoms. The history is then synthesized with the neurologic
examination, which focuses on the mental status examination. The mental status
examination encompasses selection of appropriate screening measures and
additional examination into attention, language, memory, visuospatial,
executive, and praxis functions as needed to expand on the presenting symptoms
and overcome weaknesses in the selected screening measure. A cognitive/
behavioral profile is then obtained, which aids in refining the localization. The
history and examination can then be combined to narrow the differential
diagnosis and select appropriate further diagnostic studies. In approaching
cognitive and behavioral symptoms in such a systematic manner, the clinician
can be confident in the diagnosis and develop a relevant therapeutic program
that can include disease-specific treatments, as well as neurorehabilitation of
cognitive and focal neurobehavioral symptoms, identification and management
of associated neuropsychiatric symptoms, and alleviation of caregiver burden.
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1548 DECEMBER 2021

REVIEW ARTICLE

Cognitive Rehabilitation
C O N T I N UU M A UD I O By Lindsey Kirsch-Darrow, PhD; Jack W. Tsao, MD, DPhil, FAAN
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article provides a definition of and introduction to

cognitive rehabilitation. It discusses different approaches to cognitive
rehabilitation (ie, restorative, compensatory, and metacognitive). It also
reviews types of memory impairment and how they can be distinguished to
improve treatment design and implementation.
Neural plasticity as a biological substrate for functional

RECENT FINDINGS:
changes from cognitive rehabilitation is an exciting new area of research.
SUMMARY: This article provides a high-level review of cognitive rehabilitation

and presents a complex case example.
INTRODUCTION
T
he word rehabilitation comes from the Latin roots re- (which
means “again”) and -habilitare (which means “to make fit”). Thus,
rehabilitation is the process of making patients more “fit” or suited for
their environment. For example, physical therapists teach motor
sequences to improve patients’ mobility and ability to navigate their
environment. Occupational therapists teach multistep activities to help patients
CITE AS:
with daily tasks, such as grooming and cooking. For the field of cognition, speech-
2021;27(6, BEHAVIORAL NEUROLOGY language pathologists and rehabilitation neuropsychologists teach patients
strategies to compensate for cognitive deficits in memory and attention. In some
systems, occupational therapists also take on the training of cognitive strategies.
Dr Jack W. Tsao, 855 Monroe Ave, Thus, rehabilitation is a way to make patients better fit to succeed in their
Ste 415, Memphis, TN 38163, environment—whether that be to climb stairs in the case of physical
jtsao@uthsc.edu.
rehabilitation or to remember tasks in the case of cognitive rehabilitation.
RELATIONSHIP DISCLOSURE: Rehabilitation of any type involves acquisition, mastery, maintenance, and
Dr Kirsch-Darrow reports no generalization of new learning. One particular challenge for cognitive
disclosure. Dr Tsao has received
research/grant support from the rehabilitation is that patients often have deficits in new learning.1 Therefore,
National Institutes of Health and cognitive rehabilitation must be tailored in ways to help those with learning
the US Army and publishing deficits. Examples of types of patients with learning deficits include those with
royalties from Springer Nature
Switzerland AG and holds stock acquired neurologic disorders, such as traumatic brain injury (TBI), stroke, and
in Illumina and Biogen. multiple sclerosis. Working with these patients requires professionals to design
UNLABELED USE OF PRODUCTS/
and deliver systematic instruction that takes into consideration patients’
INVESTIGATIONAL USE cognitive deficits.2 Systematic instruction’s main theory is that:
DISCLOSURE:
Drs Kirsch-Darrow and Tsao
report no disclosures. “…persons with learning challenges benefit most from structured
training that includes explicit models, a minimization of errors during
© 2021 American Academy initial acquisition (to prevent the learning of errors), strategies to
of Neurology. promote learning engagement, and carefully guided practice…”1
1670 DECEMBER 2021

In contrast to systematic instruction, other types of learning have been established, KEY POINTS
such as discovery learning (also called exploratory learning) and trial-and-error
● Rehabilitation is the
learning. Trial-and-error learning depends on patients drawing their own process of making patients
conclusions from experience.1 This assumes patients are able to recognize, more “fit” or suited for their
analyze, and remember the mistakes they make to learn from them. Patients environment.
with acquired brain injuries are often unable to perform all of the cognitive tasks
● Rehabilitation of any type
needed for discovery learning and trial-and-error learning. According to
involves acquisition,
Sohlberg and Turkstra,1 systematic instruction involves “structuring input in mastery, maintenance, and
deliberate ways while providing multiple opportunities for repetition.” This generalization of new
could involve stimulating an impaired cognitive process repetitively, training learning. A challenge for
steps of a functional activity, or practicing a strategy in a new context.1 cognitive rehabilitation is
that patients who need it,
With regard to research support, a review of the literature supports the such as those with traumatic
concept that the way information and procedures are introduced to people with brain injury, stroke, and
cognitive impairment can enhance the rate and quality of their learning.2 This other acquired brain injuries,
demonstrates the effectiveness of cognitive rehabilitation. Further, numerous typically have deficits in
new learning.
cognitive rehabilitation protocols with empirical research support are provided
in the Cognitive Rehabilitation Manual.3 This manual was developed based on ● Systematic instruction is a
the recommendations of the Cognitive Rehabilitation Task Force of the Brain form of cognitive
Injury Interdisciplinary Special Interest Group of the American Congress of rehabilitation that takes into
account patients’ deficits in
Rehabilitation Medicine (ACRM). It includes treatment protocols for executive
new learning by using
functioning, memory, attention, visual neglect, and social communication. It is structured training,
based on the comprehensive review articles published by a group at the JFK including explicit models,
Johnson Rehabilitation Institute.4,5,6 minimization of errors during
initial acquisition, and
carefully guided practice.
NEUROPSYCHOLOGICAL ASSESSMENT AND TYPES OF MEMORY
IMPAIRMENT ● Before the design and
Before the design and implementation of cognitive rehabilitation, it is important implementation of cognitive
to complete a thorough neuropsychological assessment. During this assessment, rehabilitation, it is important
to complete a thorough
patients are given a comprehensive set of tests evaluating cognitive abilities and
neuropsychological
emotional status. This allows the rehabilitation clinician to target specific assessment.
cognitive deficits and design treatments for those deficits. For example, patients
with memory impairments can have preservation of some types of memory and ● Neuropsychological
not others. If the rehabilitation clinician knows which types are preserved, they assessment can determine
which areas of cognition are
can be used to bolster the impaired type of memory. An important distinction is preserved and which are
between declarative memory, also called explicit memory, and nondeclarative impaired; preserved areas can
memory, also called implicit memory. Declarative memory is a type of memory help bolster impaired areas.
where the knowledge base is consciously known (eg, learning the capitals of US
● Declarative memory is a
states, remembering last year’s birthday celebration). In contrast, nondeclarative type of memory where the
memory does not require conscious awareness (eg, riding a bicycle, learning how knowledge base is
to hold a fork). TABLE 8-1 shows further details about types of declarative and consciously known (eg,
nondeclarative memory. learning capitals of US states).
In contrast, nondeclarative
For an example of how neuropsychological assessment can assess memory and
memory does not require
guide treatment, see CASE 8-1A. conscious awareness (eg,
riding a bicycle).
COGNITIVE TREATMENT
After completion of neuropsychological assessment, rehabilitation professionals
work together to provide feedback about test results, educate patients about their
deficits and how their brain injuries are causally related, and provide systematic
instruction to help patients improve on or compensate for the deficit. The
rehabilitation professionals on the team can include neurologists, physical

COGNITIVE REHABILITATION
medicine and rehabilitation specialists, occupational therapists, assistive

technologists, speech-language pathologists, and rehabilitation
neuropsychologists. Speech-language pathologists, occupational therapists,
assistive technologists, and sometimes rehabilitation neuropsychologists teach
compensatory strategies and coach patients through training drills as needed.
Rehabilitation neuropsychologists provide testing feedback and continuously
assess and treat patients’ emotional difficulties (CASE 8-1B).
COGNITIVE REHABILITATION TREATMENT APPROACHES

To delineate cognitive rehabilitation treatment approaches, an important
distinction is the classification of treatments as either restorative or
compensatory (TABLE 8-2). Restorative treatment approaches are designed to
reduce impairment in a basic cognitive function. For example, Attention
Process Training is designed to directly reduce attention impairment through
attention training drills. In contrast, compensatory treatment approaches are
designed to maximize functioning with or without changing the basic cognitive
function. CASE 8-1B illustrates improvement in a patient’s daily functioning via
compensatory techniques, while actual memory remains impaired.
An additional treatment category has been added to restorative and
compensatory ones: metacognitive approaches. Metacognition involves
monitoring one’s thinking and using it to evaluate and regulate one’s
behavior.1,9 It requires executive functioning skills to be intact (ie, at least the
ones involved in self-monitoring and regulation). In some cases, patients may
have anosognosia (lack of awareness of deficits). Approaches have been
developed to try to teach metacognitive strategies for patients with a lack of
awareness of their deficits. For more information on anosognosia, refer to the
article “Spatial Neglect and Anosognosia” by A. M. Barrett, MD, FAAN, FANA,
FASNR,10 in this issue of Continuum. Treating awareness problems involves the
rehabilitation professionals clearly pointing out an area of behavioral, emotional,
or cognitive concern to patients. Next, they provide psychoeducation to
TABLE 8-1 Definitions of Content-Dependent Forms of Memorya
Types of long-term memory Description
Declarative memory Explicit knowledge base, information held with conscious awareness
Episodic memory Storage of events that are tagged in time and place
Semantic memory Storage of facts and concepts
Metamemory Awareness of one’s own memory functioning
Prospective memory Remembering to initiate future intentions
Nondeclarative memory Implicit memory, does not require conscious awareness of learning
Procedural memory Acquisition of rules, sequences, and perceptual-motor skills
Emotional associations Associations of feelings with people and events
Priming Increased probability of producing a response because of having previously produced it
a
Reprinted with permission from Sohlberg MM, Turkstra LS.1 © 2011 The Guilford Press.
1672 DECEMBER 2021

A 64-year-old woman, with 18 years of education, who had no symptoms CASE 8-1A
and no significant prior neurologic or psychiatric history had an anterior
communicating artery aneurysm that was incidentally discovered. She
underwent surgery to repair the aneurysm and sustained an infarction in
the territory of the right recurrent artery of Heubner.
After the infarct, she experienced headaches and cognitive problems.
She was discharged to an acute rehabilitation hospital for 2 weeks and
then to home with home health for speech-language pathology, physical
therapy, and occupational therapy. After a gap in rehabilitation care in
which she returned to work and did not perform well, she was referred
for outpatient team-based rehabilitation care.
Neuropsychological testing was completed approximately 6 months
after the infarction, and results indicated she was within expected limits
for verbal fluency (ie, rapid production of words in a particular category),
mental manipulation of information (ie, working memory), sustained
attention, inhibition of overlearned responses, and fine motor control.
Her speed of processing was variable. She was impaired in recall of
information (ie, declarative memory). Initial learning was within expected
limits. However, free recall and recognition of both verbal and visual
material were impaired. She had a striking number of intrusive errors. For
example, she had an intrusion of the word “carrot” in a list of vegetables.
Then, she stated “carrot” as a word from the list across all future trials of
learning and at the 20-minute delay. Also, material from one memory test
intruded into another memory test when she was trying to freely recall
the information. Further, she learned two stories adequately at baseline,
but after a 30-minute delay, she could recall extremely little about the
stories: she freely recalled 0 of 25 pieces of information for the first
story, and for the second story, she recalled 3 of 25. Visual information
was slightly better retained than verbal information (borderline impaired
versus severely impaired). On self-report scales of emotional
functioning, she endorsed mild levels of depression and moderate levels
of anxiety. She exhibited no signs of posttraumatic stress disorder.
A thorough neuropsychological assessment is necessary for complex COMMENT

cognitive rehabilitation cases. Testing showed this patient had several
areas of preserved cognitive functioning. These were fluency, working
memory, ability to sustain attention, and ability to inhibit. Testing displayed
deficits in declarative memory. It also showed a tendency to insert
incorrect information, which led to miscommunication with her spouse and
others. The neuropsychological assessment also provided important
information about her emotional status (ie, depression and anxiety) that
affected her treatment progress.

CASE 8-1B For the 64-year-old woman with the recurrent artery of Heubner territory
stroke, the rehabilitation neuropsychologist provided feedback about
testing results to the patient and her spouse. She and her spouse
reported the feedback helped them understand the rationale for
treatment and increased the patient’s motivation to participate in
treatment. Initially, she had wanted to return to full-time employment
rather than spend time in treatment because she did not understand the
need. After receiving the feedback, she understood more about her
deficits and how they would lead to poor performance at work if she did
not receive treatment. The speech-language pathologist taught her
internal compensatory techniques of organizing information she needed
to remember into smaller “clusters” or chunks to reduce cognitive load
(ie, the amount of information to be remembered) and linking verbal
information to an image. The occupational therapist and assistive
technologist gave her an external compensatory technique of using a
smartpen (ie, a device that records audio while the patient writes to
specialized paper; that audio can be played back by touching the paper
or pressing play on the pen, and the information can also be uploaded to
the patient’s computer to be retrieved and edited as needed). She
rehearsed the same set of steps (ie, [1] press the power button on the
smartpen to turn it on; [2] open the notebook; [3] use the pen to tap on
the “Record” button on the bottom of the page; and [4] start writing a
note anywhere on the dot paper [the specialized paper meant for
recording]). Rehearsing these steps became routine such that she could
produce them on her own. When she practiced learning the steps for the
assistive smartpen device, the occupational therapist helped her perform
the steps without errors. She then used the smartpen to record
information she needed to remember, such as facts about her finances,
household tasks she needed to complete, and meetings she had as a
board member of an institution in her community.
COMMENT Treatment in rehabilitation is a team effort where many professionals work

in concert. It can include technology. Assistive technology involves external
aids that can be incorporated into rehabilitation. They can be low-tech (eg, a
paper planner, a carabiner to keep items attached to one another so they
aren’t lost) or high-tech (eg, smartphone application, smartpen).
From the perspective of cognitive rehabilitation of memory, it should be
noted that this patient was able to use her intact procedural memory (ie,
she could remember a rote procedure for using the smartpen such as
pushing a button, opening a page, tapping a dot) to compensate for her
declarative memory deficits (ie, she could not remember tasks she needed
to do or information from meetings). When the therapist taught her the
procedure, she sought to do it with as few errors as possible. Literature
suggests that if patients are prevented from making errors during initial
learning trials, they will learn faster and repeat fewer errors.7,8
1674 DECEMBER 2021

Treatment Approaches for Cognitive Rehabilitation TABLE 8-2
Treatment approach Goal Example(s)
Restorative Decrease Attention Processing Training (APT)

impairment in
Decreases impairment in attention by direct training
the basic
cognitive Five tracks of exercises arranged in a hierarchical order from elementary
function to complex
Tracks correspond to the five major types of attention: focused,
sustained, selective, alternating, and divided
APT-I used for more severe attention impairment, APT-II for less severe
attention impairment
Real-world generalization tasks are set up (eg, cooking for a sustained
attention task, cooking while monitoring the washer/dryer cycles for an
alternating attention task)
Compensatory Maximize Training patients to keep track of tasks by using external aids such as
functioning with memory notebooks, calendars (paper or electronic), and smartphone
or without applications
changing the
Teaching compensatory internal techniques such as using associating
basic cognitive
techniques (eg, mnemonics, associating verbal information with an image)
function
and organizing techniques (eg, arranging information in ways to assist with
memory such as chunking information into smaller groups)
Metacognitive Internalize Time Pressure Management

awareness
Helps patients cope with mental slowness by becoming more aware of,
and control
and regulating, information input
over behavior;
a type of Specific strategies taught involve asking for more specific information,
compensatory asking for more specific instructions, asking if the other person can briefly
approach stop talking when verbal instructions are being given, making a written plan
for how to perform a task, and restating the most important instructions
Self-talk
Helps patients “talk themselves through” tasks
Training begins with overt verbalization, then transitions to faded verbal
self-instruction (whispering), then internal verbal instruction (inner talk);
given the severity of the patient’s deficit, the therapist can assist the
patient in breaking down the task into steps and presenting it to the
patient to learn if they are unable to do it for themselves; overall, self-talk
is meant to allow a patient to transition an external strategy into an
internal strategy with practice
Formal problem-solving strategies
Helps patients follow a structure for problem solving
Some examples are slowing down, avoiding impulsive responses,
choosing among alternatives
Patients apply the strategy to each new problem starting with a written,
structured worksheet
With practice, it is internalized (if cognitive deficit level allows) and can be
applied more efficiently and consistently to new problems

patients about their brain injury/neurologic condition and the fact that it leads
to concrete problems with these areas. This can be done through discussion
and written material, as well as observing the patients’ pathology on brain
MRI in collaboration with their neurologist. When feedback is provided, it is
critical for rehabilitation professionals to be collaborative with patients (eg, by
saying “Let’s explore this together”) to reduce resistance or avoidance of
discussing their deficits. Understandably, starting to recognize one’s deficits
often comes with negative emotions and self-perceptions. Monitoring mistakes
or the problematic behavior in a supportive therapeutic context (ie, by the
patient, therapist, or trusted family member or friend) can be a concrete way to
raise awareness.
Sohlberg and Turkstra1 made the point that, although restorative,
compensatory, and metacognitive approaches are all based on different
theoretical models and practice standards, they still share the need to provide a
“structured environmental experience in order for the client to learn, maintain,
and transfer the skills to functional contexts.” The ACRM published a manual in
2012 for the practice of cognitive rehabilitation: Cognitive Rehabilitation Manual:
Translating Evidence-Based Recommendations Into Practice.3 It describes the
structured environmental experience needed for cognitive rehabilitation and
divides it into hierarchical stages. These are the (1) acquisition stage, (2)
application stage, and (3) adaptation stage (TABLE 8-3).
The acquisition stage involves patients being taught the purpose and
procedure of the treatment model and the therapist assessing their level
of awareness. Patients are taught how to use their memory notebooks,
worksheets, or other assistive tools (eg, calendar, smartpen). In this stage,
therapists may have patients monitor how they do with the strategy versus
without the strategy to demonstrate effectiveness. The application stage involves
patients applying the strategy to simple tasks inside the therapy session. It
begins with the therapist modeling and providing external cuing to help patients
use the strategy correctly. If patients are able (ie, depending on their level of
impairment, some patients will be able to and some will not), they may begin to
TABLE 8-3 Treatment Goals and Strategies Associated With Each Stage of Cognitive
Rehabilitationa
Stage of treatment Goals Types of strategies used
Acquisition Teach purpose and procedures of treatment model External

Help patients recognize and accept deficits and benefits of treatment
Application Improve effectiveness and independence in compensating for deficits External

Promote internalization of strategies Internal
Adaptation Promote transfer of training to tasks including those that are less External and internal
structured, more novel, complex, and/or distracting
Promote generalization of skills from the structured therapy setting to External and internal
less structured environments, such as home, community, and work
a
Reprinted with permission from Haskins HC, et al.3 © 2012 ACRM Publishing.
1676 DECEMBER 2021

internalize the strategy and rely less on the therapist. Finally, the adaptation KEY POINTS
stage involves patients applying the strategy to everyday tasks outside the clinic.
● After completion of
Everyday task examples include medication management, financial neuropsychological
management, and cooking. Strategies that were previously applied only in the assessment, the next steps
clinic can now be generalized to everyday functioning and activities of for cognitive rehabilitation
daily living.3 are to provide feedback
about test results, educate
Strategies chosen to address a cognitive problem can be external or internal.
patients about their injuries
External strategies are those that are external to the patient. These include and resulting cognitive
examples such as notebooks, calendars, electronic devices (eg, computers, deficits, and provide
smartpens, smartphones), and visual cuing such as sticky notes and cue cards. systematic instruction to
directly improve or
Internal strategies are self-generated processes to “enhance [the patient’s]
compensate for the deficit.
conscious control over their own thoughts, behaviors, or emotions.”3 Patients
are taught to cue themselves to use a trigger to take steps to address a problem ● In addition to
at hand. One example might be to cue themselves to slow down when doing neurologists, rehabilitation
detail-oriented work. Also, they may learn acronyms to remember a specific professionals on the
treatment team include
set of actions. For example, to pay better attention during conversations, physical medicine and
remember the acronym LEAP (Listen actively [turn body toward the speaker, rehabilitation specialists,
look at the speaker], Eliminate distractions [reduce environmental noise as able, occupational therapists,
turn off phone, move to a quiet place if possible], Ask questions [to allow for assistive technologists,
speech-language
active engagement and repetition], and Paraphrase the information [also allows pathologists, and
for active engagement and repetition]) (TABLE 8-3). rehabilitation
neuropsychologists.
OTHER ASPECTS OF TREATMENT ● An important distinction

Cognitive rehabilitation involves more than teaching strategies and techniques. in cognitive rehabilitation is
Patients also are adjusting to their injuries/illnesses and have emotional changes. the classification of
treatments as either
They can also have varying degrees of insight about their injury and resulting restorative or
cognitive deficits. Further, headaches, poor sleep, and fatigue are all common. compensatory.
They can all impede progress in cognitive rehabilitation (CASE 8-1C).
The case example in this article also illustrates two important points about ● Restorative treatment
approaches are designed to
memory. First, the fact that the patient was able to retain key information about
reduce impairment in a basic
her injury and cognitive deficits indicates that her declarative memory was not cognitive function, whereas
completely absent. It is notable that it took several repetitions and substantial compensatory treatment
time. Second, it illustrates that procedural memory (ie, a type of nondeclarative approaches are designed to
memory) is highly context dependent. Even though patients master a skill, they maximize functioning with or
without changing the basic
may still need cuing or prompts when it is in a different context or environment. cognitive function.
This is why it can be difficult to generalize behavior outside of the clinic. It also
speaks to the underlying importance of executive functioning skills in ● Metacognition is a type of
recognizing when to initiate a strategy. compensatory treatment
approach that involves
monitoring one’s thinking
COGNITIVE REHABILITATION APPLIED TO TRAUMATIC BRAIN INJURY and using it to evaluate and
regulate one’s behavior.
TBI is a significant cause of morbidity and mortality in the United States. From
the years 2006 to 2014, the number of emergency department visits,
hospitalizations, and deaths from TBIs increased by 53% to approximately
2.5 million, including more than 812,000 children. Falls, being struck by or
against an object, and motor vehicle accidents are the most common causes of
TBI (48%, 17%, and 13%, respectively). The highest risk groups for TBI were
older adults (people older than 74 years of age), young children up to the age of 4,
and people between the ages of 15 and 24. In 2014, an average of 155 individuals
died of injuries that included a TBI.11

Sequelae of TBI include cognitive impairments, personality changes, and

depression, which affect not only the injured person but also their family and
community. The cognitive and behavioral regulation issues can adversely affect
daily activities and cause significant challenges with school, work, and
interpersonal relationships. People who have sustained a TBI might benefit from
cognitive rehabilitation if they report impairment with complex activities of
daily living and moderate or severe cognitive symptoms disrupting activities of
specific items (relating to poor concentration, forgetfulness, difficulty making
CASE 8-1C Returning to the case of the 64-year-old woman who sustained an infarct
during aneurysmal surgery, although her scores on self-report measures
indicated mild depression and moderate anxiety, she presented as
moderately to severely depressed and moderately anxious. She had no
suicidal ideation, plan, or intent; however, she reported passive thoughts
about death (passive thoughts about death are a symptom of depression)
and that it might be better if she went to sleep and did not wake up. She
felt like a burden on her family even though they were highly supportive of
her. She had low frustration tolerance for her own mistakes. Her self-
esteem plummeted because she could no longer work effectively or
manage all the tasks at home like she used to (eg, the family finances). She
also experienced severe headaches, resulting in insomnia and fatigue.
During the initial stages of cognitive rehabilitation, she would cry during
the majority of the session because of headache pain and frustration. A
neurologist entered her treatment team to assist with diagnosis and
treatment of migraines. With improved control of pain from her
headaches, her sleep and frustration tolerance improved. Over time in
therapy, she began to regulate her emotions more easily and reduce some
of her self-disappointment and self-doubt.
Another important aspect of her presentation was that she had
limitations in awareness (ie, anosognosia) of her deficits. This improved
somewhat during her course of rehabilitation therapy through brain injury
education and repetition of this information about her deficit through
multiple sources including medical providers, her spouse, and her adult
children. She developed intellectual awareness of her deficits, which
means she could intellectually recognize she had a brain injury and,
therefore, had memory problems. However, by the end of her treatment,
she was not always able to anticipate situations when she might forget
information (ie, anticipatory awareness) or realize in the moment when
she was experiencing a problem (ie, emergent awareness). She needed to
be prompted by her therapists and family at times to use her memory aid
(ie, her smartpen). She had learned procedurally how to use it but did not
always recognize when she needed to use it.
COMMENT Considering other aspects that affect cognition such as emotional

symptoms, headaches, and poor sleep is key to making progress in
cognitive rehabilitation.
1678 DECEMBER 2021

decisions, slowed thinking, fatigue, irritability, and poor frustration tolerance) KEY POINTS
on the Neurobehavioral Symptom Inventory, a 22-item self-report of
● The structured
postconcussive symptoms (FIGURE 8-112). For individuals who sustained a TBI environmental experience
who have persistent cognitive symptoms lasting greater than 30 to 90 days that needed for cognitive
have been refractory to treatment for associated medical conditions (eg, sleep rehabilitation can be divided
disturbance, headache), cognitive rehabilitation may be beneficial as noted in the into hierarchical stages,
which are the (1) acquisition
VA/DoD Clinical Practice Guideline for Management of Concussion-Mild
stage, (2) application stage,
Traumatic Brain Injury, even if the injury occurred years prior.13 and (3) adaptation stage.
● The acquisition stage

NEURAL PLASTICITY involves patients learning
the purpose and procedure
Researchers have been interested in examining the neurobiological changes of the treatment model and
that accompany the functional changes resulting from rehabilitation. It is the therapist assessing their
known that neurons have the ability to modify their structure, connections, level of awareness, the
and function in response to changes in experience. Neural plasticity is the application stage involves
patients applying the
term to describe these changes; Warraich and Kleim14 defined neural plasticity strategy to simple tasks
as “any change in neuron structure or function that is observed either directly inside the therapy session,
from measures of individual neurons or inferred from measures taken across and the adaptation stage
populations of neurons.” involves applying the
strategy to everyday tasks
They also emphasize that when studying neural plasticity, researchers need outside the clinic.
both measures of neuronal change (eg, EEG, functional MRI [fMRI], positron
emission tomography [PET]) and measures of behavioral change. Both are ● Cognitive rehabilitation
needed to determine how neural plasticity supports functional improvements strategies can be external to
the patient, which include
during rehabilitation.
patient notebooks,
Experience-dependent neural plasticity means changes in neuron structure or calendars, electronic
function as a direct result of input. This input can be external, such as training and devices (eg, computers,
instruction, or it can be or internal, such as medications that affect neuronal smartpens, smartphones),
functioning. Experience-dependent neural plasticity involves a “complex cascade and visual cuing such as
sticky notes.
of molecular, cellular, structural, and physiologic events that change over time.”14
Cognitive rehabilitation is most likely to benefit patients because of ● Cognitive rehabilitation
induced neuroplasticity, detectable as changes in cortical activity in different brain strategies can also be
regions in response to a rehabilitation program. A 2017 comprehensive review internal to the patient and
include strategies that are
found eleven articles that focused on functional and neurophysiologic changes in self-generated processes
response to cognitive therapy in individuals who sustained a TBI.15 The authors (eg, consciously slowing
concluded that, independent of the severity of the head injury, a program of down to reduce mistakes,
cognitive rehabilitation was associated with measurable changes in cortical using mnemonics for
memory aids).
activation.15
More recently, neuromodulation has been suggested as possibly adding ● Making progress in
adjunctive effects to cognitive rehabilitation strategies. A review of published cognitive rehabilitation
literature shows repetitive transcranial magnetic stimulation, transcranial requires recognizing and
direct-current stimulation, and transcranial random noise stimulation as the focus treating other aspects that
affect cognition such as
of studies examining whether these new technologies may improve clinical emotional symptoms,
outcomes. Neuromodulation for mild TBI has demonstrated small, incremental headaches, and poor sleep.
benefits in several studies,16 but neither repetitive transcranial magnetic
stimulation nor transcranial direct-current stimulation was shown to be of benefit.17 ● Neural plasticity can be
defined as a change in
In one other study, transcranial random noise stimulation was shown neuron structure or function
to improve attention during complex situations by increasing alerting while directly observed from
simultaneously decreasing conflict in the executive network, but transcranial individual neurons or
direct-current stimulation had no statistically significant effect.18 Thus, it is clear populations of neurons.
that more research is needed to determine whether any forms of neuromodulation

FIGURE 8-1
The Neurobehavioral Symptom Inventory.
Modified from Cicerone KD, Kalmar K. J Head Trauma.12 © 1995 Williams & Wilkins.
1680 DECEMBER 2021

applied in conjunction with cognitive rehabilitation will lead to improved KEY POINT
clinical outcomes.
● Cognitive rehabilitation
most likely benefits patients
because it induces
CONCLUSION neuroplasticity, detectable
Cognitive rehabilitation, when correctly implemented as a rehabilitation as changes in cortical
activity in different brain
strategy, in conjunction with a multidisciplinary team, has the potential to help
regions in response to a
patients with acquired brain injuries to improve functioning. This can be by rehabilitation program.
either improving a cognitive deficit directly or learning to compensate for the
deficit. Providing a structured environment for the patient to learn, maintain,
and transfer the skills to new contexts is key.
REFERENCES
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Guilford Press, 2011. 27(6, Behavioral Neurology and Psychiatry):
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2 Ehlhardt L, Sohlberg MM, Kennedy M, et al.
Evidence-based practice guidelines for 11 Centers for Disease Control and Prevention. TBI
instructing individuals with neurogenic memory data. Accessed September 10, 2021. cdc.gov/
impairments: what have we learned in the past traumaticbraininjury/data/index.html
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evidence-based recommendations into
13 Department of Veterans Affairs, Department of
practice. Reston, VA: ACRM Publishing, 2012.
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4 Cicerone KD, Dahlberg C, Kalmar K, et al. the management of concussion-mild traumatic
Evidence-based cognitive rehabilitation: brain injury. Version 2. Accessed August 26, 2021.
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Phys Med Rehabil 2000;81:1596-1615. doi:10.1053/ guidelines/Rehab/mtbi/
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5 Cicerone KD, Dahlberg MA, Malec JF, et al. 14 Warriach Z, Kleim JA. Neural plasticity: the
Evidence-based cognitive rehabilitation: biological substrate for neurorehabilitation. PM R
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Arch Phys Med Rehabil 2005;86:1681-1692. doi:
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AM. The effect of non-invasive brain stimulation
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of “errorless” and “trial-and-error” learning memory in rehabilitation patients with traumatic
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Neuropsychol Rehabil 2008;18(3):257-299. doi:
10.1080/09602010701748644

REVIEW ARTICLE

Executive Dysfunction
ONLINE
and the Prefrontal Cortex
By David T. Jones, MD; Jonathan Graff-Radford, MD
Downloaded from http://journals.lww.com/continuum by wqLe/H3/oM2vx1Qs5A5qMemKKHLPqE4qkmGNpdheG3ikf1o85ttJSkFL2oTkgOkhMEmawHvsuTTE5xJG2ZjqccytIAhVn2qegy060KLcKJuPZsx5htaYiopRjp2zor2egUzWJAEWYNo/R1NuKT7SYsuBdzpo0ePV on 04/28/2022
ABSTRACT
PURPOSE OF REVIEW: This article summarizes the cognitive and behavioral
functions of the prefrontal cortex with an emphasis on executive cognitive
functions and the clinical consequences associated with executive
dysfunction. The clinical manifestations of lesions to the lateral prefrontal,
orbitofrontal, medial prefrontal, and frontopolar cortex are reviewed.
RECENT FINDINGS: Traditional lesion studies have emphasized the role of a

brain region in controlling a cognitive function. With advances in neurology,
neuropsychology, and neuroimaging, the participation of the prefrontal
cortex in large-scale networks has been established with recognition that
cognitive dysfunction can arise not only from a lesion within a network but
also from degenerative disease targeting these large-scale, dynamic
neural networks. Although executive dysfunction can result from frontal
lobe injury, this article highlights the role of distributed processes
CITE AS: subserving executive functions. An atypical phenotype of Alzheimer disease
has been described that selectively targets parietal-temporal-frontal
2021;27(6, BEHAVIORAL NEUROLOGY
AND PSYCHIATRY):1586–1601. networks important for core executive functions.
Address correspondence to SUMMARY: Executive function comprises working memory, cognitive

Dr Jonathan Graff-Radford,
Department of Neurology, Mayo
flexibility, and inhibition and depends on top-down (ie, goal-driven)
Clinic, 200 First St SW, control of distributed processes occurring throughout the brain. The exact
Rochester, MN 55905, Graff- behavioral output (ie, function) depends on the content of the processes
Radford.Jonathan@mayo.edu.
being controlled. Prefrontal cortex regions serve key cognitive functions
RELATIONSHIP DISCLOSURE: related to social, emotional, and motivational aspects of behavior. The
Dr Jones has received
dorsal lateral prefrontal cortex plays a role in working memory,
research/grant support from
the National Institutes of goal-driven attention, task switching, planning, problem-solving, and
Health (P30AG 62677-2) and novelty-seeking. The ventral lateral prefrontal cortex plays a role in
Race Against Dementia.
Dr Graff-Radford has received
inhibition, response selection, and monitoring; the medial prefrontal
personal compensation for cortex in self-knowledge, motivation, emotional regulation, and updating
serving on the editorial board goal-directed behavior; the orbitofrontal cortex in personality, inhibition,
for Neurology and research
funding from the National and emotional and social reasoning. Although dysexecutive syndromes
Institute on Aging have been traditionally associated with dorsolateral prefrontal cortex
(K76 AG057015). injury, it is now recognized that they can also result from an impaired
UNLABELED USE OF parietal-temporal-frontal system, which is targeted in a distinct form of
PRODUCTS/INVESTIGATIONAL atypical Alzheimer disease. This dysexecutive Alzheimer phenotype is
USE DISCLOSURE:
Drs Jones and Graff-Radford
characterized by impaired task performance on a wide battery of
report no disclosures. neuropsychological tests and simple daily tasks that require executive
control. In contrast, dysexecutive syndromes more localized to the frontal
© 2021 American Academy
lobe involve impaired executive control of social, emotional, and
of Neurology. motivational aspects of behavior.
1586 DECEMBER 2021

INTRODUCTION
T
his article focuses on syndromes commonly associated with prefrontal
cortex lesions with an emphasis on executive function. In many
situations, neural activity triggered from the environment or internal
milieu is sufficient to produce contextually appropriate behaviors
via a bottom-up mode of operation. However, in some situations
(eg, conflicting options or delayed objectives), it becomes necessary to exert
top-down influence to sculpt behaviors to fit the current or expected
environmental context to achieve desired outcomes. This is achieved through the
interplay of three core executive functions (working memory, cognitive
flexibility, and inhibition) used to modulate bottom-up activity patterns.1
Although executive functions have traditionally been associated with control of
social, personal, and emotional cognitive processes occurring in the frontal lobe,
they also control cognitive processes shaping tasks occurring in other areas of the
brain (FIGURE 4-1). Because of the executive dysfunction recognized in the
behavioral variant of frontotemporal dementia and other frontal lobe disorders, a
frontal lobe–centered view of executive function occurred. More recently,
executive dysfunction as a key feature of lesions of network-connected regions
and disorders such as young-onset Alzheimer disease has gained greater
attention. This article briefly highlights these relationships between executive
function and anatomy beyond the frontal lobe after providing a traditional
FIGURE 4-1
Conceptual schematic of executive control as a distributed top-down neocortical
modulator of bottom-up neural signals originating across the nervous system. A, Long-term
memory (LTM) and related stores across the brain interact with internal, environmental, and
intrinsic neuronal activity, which can trigger an action via direct bottom-up mechanisms.
Executive control processes may intervene and exert top-down control before an action is
triggered. B, The distributed nature of the associated neural activity that can be acted on by
executive control mechanisms is depicted as a neuronal network (three layers of nodes and
edges representing perception [white], cognition [light gray], and action [dark gray])
expanding in a bottom-up fashion and then contracting again for action execution in a
top-down mechanism. Distributed top-down control mechanisms can similarly influence
perceptual functions. The difference between segregated modular functioning (localized)
versus integrated global functioning (distributed) is depicted by the larger number of nodes
and distributed connections in the middle executive control portion of the network diagram.

EXECUTIVE DYSFUNCTION AND THE PREFRONTAL CORTEX
CASE 4-1 A 50-year-old man with untreated hypertension presented to the

behavioral neurology clinic for a change in thinking and personality. Two
years prior, he presented to the emergency department 2 days after
developing a severe headache and his wife noticed that his left face was
drooping. Brain MRI revealed an acute infarction involving the right
caudate extending to adjacent parts of the basal ganglia (FIGURE 4-2).
Afterward, his wife noticed a change in his behavior. He struggled to
perform his job as a mechanic, frequently performing tasks in the wrong
order. His family noted that he used to be a very kind and patient person,
but, subsequently, he had become quite impatient and easily agitated.
His wife reported that he showed no empathy for her when she lost a
parent. He entered into verbal altercations with strangers at the store
and the gas station, which was out of character for him.
The patient’s wife completed a Frontal Systems Behavior Scale and
described significant changes in apathy, disinhibition, and cognitive
features of executive dysfunction from before the injury.
FIGURE 4-2
Coronal T1-weighted brain MRI demonstrating a remote hemorrhagic infarct involving the
right caudate (A). Fludeoxyglucose positron emission tomography (FDG-PET) statistical map
(B) shows regions of significant hypometabolism relative to age-matched controls.
Hypometabolism is present in regions functionally connected to the caudate such as the
right medial prefrontal and dorsolateral prefrontal areas (white arrows). Striking
contralateral cerebellar hypometabolism (yellow arrows), which is part of the involved
network, can also be seen.
COMMENT This case highlights how a strategic stroke within a frontostriatal circuit
node (caudate) can lead to a frontal syndrome significant enough to mimic
the symptoms of behavioral variant of frontotemporal dementia due to
frontotemporal degeneration. The sudden onset and imaging features
allow distinction from a degenerative syndrome. In this case, the
connectivity of the caudate to the frontal lobe was disrupted, causing
executive dysfunction, a change in personality, and loss of empathy. The
Frontal Systems Behavior Scale allows for assessment of apathy and
executive functions before and after a frontal injury.6,7
1588 DECEMBER 2021

approach to clinical syndromes commonly associated with dysfunction in the KEY POINTS
prefrontal cortex.
● Executive functions,
Famous cases, such as the personality change in Phineas Gage reported by composed of working
Harlow2 have generated clinical interest in the frontal lobes and serve to illustrate memory, cognitive
the important effects of frontal lobe injury. The frontal lobe, in particular the flexibility, and inhibition,
prefrontal cortex, plays critical roles in controlling behavior, maintaining depend on top-down
control of distributed
working memory, organizing goal-directed behavior, planning, and theory of
processes occurring
mind. Numerous conditions are associated with frontal lobe dysfunction, throughout the brain and not
including traumatic brain injury, brain tumors, degenerative disease exclusively in the frontal
(frontotemporal degeneration, Alzheimer disease), normal pressure lobe.
hydrocephalus, stroke, and anterior communicating artery aneurysm rupture.
● Because of frontostriatal
Therefore, neurology practitioners will commonly encounter patients with connections, lesions within
frontal lobe syndromes, and a clinical framework for recognizing and the basal ganglia,
approaching common frontal lobe syndromes is necessary. particularly the caudate,
The prefrontal cortex can be roughly divided into lateral prefrontal, can lead to frontal lobe
syndromes.
orbitofrontal, medial prefrontal, and frontopolar regions. Other systems of
division exist, but they share the notion that these regions are part of distributed ● The dorsolateral
large-scale neural networks that subserve key cognitive and behavioral functions prefrontal cortex has been
and participate in subcortical circuits or loops.3 Although frontal syndromes have implicated in executive
function, including planning,
been linked to each of these prefrontal cortex regions, it is key to understand that
goal-directed behavior, and
lesions or degenerative disease targeting these regions may overlap. Dysfunction attentional control.
within network regions outside the prefrontal cortex can still present with similar
cognitive and behavioral manifestations as lesions of the prefrontal cortex.4
FRONTAL SUBCORTICAL CIRCUITS

Each frontal-striatal circuit follows similar pathways starting in the frontal
cortex, traveling through the striatum, globus pallidus, substantia nigra, and
thalamus before returning to the frontal cortex. Different portions of the
prefrontal cortex correlate with different portions of the subcortical structures.
Therefore, lesions of the subcortical structures manifest with prefrontal
syndromes (CASE 4-1).4,5
LATERAL PREFRONTAL CORTEX

The lateral prefrontal cortex can be divided into the dorsolateral prefrontal
cortex and the ventrolateral prefrontal cortex.
Dorsolateral Prefrontal Dysfunction

The dorsolateral prefrontal cortex has been implicated in executive function,
including planning, goal-directed behavior, and attentional control. Executive
function is necessary to identify and plan for a goal, measure progress toward
that goal, and change tactics to achieve that goal based on feedback.
Clinical features of dorsolateral prefrontal cortex injury include difficulty with
working memory and planning, trouble performing sequential tasks, increased
distractibility, and perseveration (TABLE 4-1).
Working memory represents the short-term (seconds to minutes) online
maintenance of memory, such as remembering a telephone number, but also
includes the use of online information in preparation for problem-solving and
multitasking. Dorsolateral prefrontal dysfunction is associated with impaired
working memory.8 Episodic memory refers to memory of episodes or past
experiences such as what one had for breakfast this morning. Although episodic

memory is typically thought to be hippocampal in origin, episodic memory can

also be impaired in dorsolateral prefrontal dysfunction, but the pattern is
different. Patients with dorsolateral prefrontal dysfunction benefit from cuing.
Because the dorsolateral prefrontal cortex is important for organizing memories,
patients with dorsolateral prefrontal cortex injury may make errors with the
temporal ordering of memories.9 Dorsolateral prefrontal cortex lesions have also
been associated with impairment in directing and sustaining attention to
novel events.10
In day-to-day activities, these problems may manifest as difficulty in
completing tasks associated with organization and planning, such as replacing
a showerhead, fixing appliances around the house, preparing a meal, and
using a computer. Several patients with executive dysfunction have been seen
in the authors’ clinic who have difficulty using remote controls, particularly
when more than one remote control is necessary to use the television and
sound system.
Several bedside tests have been proposed to evaluate dorsolateral prefrontal
dysfunction, but these tests are not specific for this region. Examples include
the impaired serial Luria fist-edge-palm test. Briefly, the patient is instructed
TABLE 4-1 Summary of Clinical Features of Prefrontal Cortex Syndromes
Ventrolateral
◆ Cognitive response disinhibition
◆ Impaired spatial attention (right greater than left)
◆ Aphasia (left greater than right)
Dorsolateral
◆ Poor planning
◆ Perseveration
◆ Disorganization
◆ Impaired working memory
◆ Distractibility
Medial prefrontal
◆ Apathy
◆ Utilization behavior
◆ Decreased motor initiation
◆ Decreased verbal initiation
◆ Impaired emotional experience
Orbitofrontal
◆ Behavioral disinhibition
◆ Personality change
◆ Impulsivity
◆ Lack of empathy
◆ Impaired social judgments
1590 DECEMBER 2021

to follow a sequence of hand gestures (fist, edge, palm).11 Patients with KEY POINTS
dorsolateral prefrontal injury may have difficulty ordering the task and
● The dorsolateral
performing the gestures in the correct sequence or may make perseverative prefrontal cortex is
errors and perform the same gesture over and over again. Luria also described important for working
the go/no-go test, in which a patient is asked to lift one finger in reply to a memory or the online
single tap (go) but must not respond to two taps (no-go).12 Patients are provided maintenance and
manipulation of memory.
a random sequence of single and double taps. Patients with dorsolateral
prefrontal cortex dysfunction have difficulty monitoring for errors during ● The ventrolateral
the task. prefrontal cortex functions
Asking a patient to copy alternating squares and triangles (alternating are lateralized with the right
sequences) can also test for dorsolateral prefrontal cortex dysfunction. Patients ventrolateral prefrontal
cortex subserving spatial
with dorsolateral prefrontal dysfunction may plan incorrectly and start with the attention and response
wrong shape (draw a triangle instead of a square) or make perseverative errors inhibition and left
(repeatedly draw the same shape). Several neuropsychological tests have been ventrolateral prefrontal
proposed as sensitive to dorsolateral prefrontal function. Impaired performance cortex subserving language
function; therefore, right-
on the Wisconsin Card Sorting Test, which tests the ability to use environmental sided lesions result in
feedback for set-shifting, organization, and strategy formation, has been impaired spatial attention
associated with dorsolateral prefrontal dysfunction.13 During the Wisconsin Card and response inhibition, and
Sorting Test, patients are provided stimulus cards with characteristics (color, left-sided lesions are
associated with aphasia.
shape, and number) and are instructed to match the cards in a pile based on one
of these characteristics, but they are not told which characteristic to match.
During testing, the rule for how to sort changes, and patients need to match the
cards according to different characteristics that require changing their approach.
Patients with dorsolateral prefrontal cortex injury fail to switch to the new rule
(set-shifting), making perseverative errors. Recent lesion-mapping techniques
have shown that right prefrontal cortex lesions are associated with perseverative
errors and punishment insensitivity (errors with avoidance of negative
consequences).14
On the Trail Making Test Part B, participants are provided numbers and
letters and are asked to draw a line between them, alternating between the
numbers and letters. This tests aspects of working memory, sequencing, and
set-shifting. Although the test is not specific for frontal lobe dysfunction, patients
with dorsolateral prefrontal cortex lesions may not switch between numbers and
letters correctly.15
Additional neuropsychological tests associated with dorsolateral circuit
dysfunction include verbal and design fluency. In verbal fluency tests, patients
are told to provide as many unique words beginning with a given letter as
possible in 60 seconds. Patients with left dorsolateral prefrontal cortex lesions
demonstrate impairment on this task and provide few words.16 In design fluency
tasks, patients receive an arrangement of dots and are told to create as many
unique designs as possible in 60 seconds by connecting lines between the dots.
Right dorsolateral prefrontal cortex injury is associated with impaired
performance on this task.17
Ventrolateral Prefrontal Dysfunction

The ventrolateral prefrontal cortex functions are lateralized with the right
ventrolateral prefrontal cortex subserving spatial attention and response
inhibition and left ventrolateral prefrontal cortex subserving language function;
therefore, right-sided lesions result in impaired spatial attention and response
inhibition, and left-sided lesions are associated with aphasia.

CASE 4-2 An 80-year-old man presented to the behavioral neurology clinic for a
second opinion regarding a personality change. Over the past 24 months,
his wife noticed that he was no longer engaged in his hobbies. Previously
an avid bridge player, he stopped attending his weekly card game. He
also gained 6.8 kg (15 lb) after developing a sweet tooth. She had to hide
the treats she kept on hand for their grandchildren because he would eat
an entire package of cookies if left out. He also became less interested in
his grandchildren’s activities, which was unusual for him. He was unaware
of any change in his personality. He scored 37/38 on the Short Test of
Mental Status, which was within normal limits. He underwent a brain MRI
with and without contrast, which revealed an olfactory groove
meningioma (FIGURE 4-3). On T2/fluid-attenuated inversion recovery
(FLAIR) imaging, vasogenic edema was present surrounding the
meningioma, and he was referred to neurosurgery.
FIGURE 4-3
Axial fluid-attenuated inversion recovery (FLAIR) MRI (A) and coronal postcontrast
T1-weighted image (B) of the patient in CASE 4-2. These scans demonstrate an orbitofrontal
meningioma resulting in vasogenic edema in the orbitofrontal cortex and underlying
white matter.
COMMENT The orbitofrontal cortex is an important hub for personality and social
behavior. This patient’s clinical course mimicked that of a patient
presenting with a neurodegenerative disorder with a gradual onset.
Although brain tumors are typically thought of as presenting subacutely,
some tumors occurring in the frontal lobe may present with a time scale
more associated with a degenerative condition. With a focal lesion,
bedside mental status testing may be normal, as in this case, but a careful
history will implicate frontal dysfunction. The change in personality,
decreased interest in family members, and development of hyperphagia
with a sweet tooth are all characteristic of orbitofrontal cortex
dysfunction.
1592 DECEMBER 2021

ORBITOFRONTAL CORTEX KEY POINTS
The orbitofrontal cortex receives projections from limbic and paralimbic areas of
● Orbitofrontal cortex
the brain, which have been associated with learning and memory and social and dysfunction has been
emotional functioning.18 Orbitofrontal dysfunction has been associated with associated with personality
disinhibition, personality change, impaired social judgments, reduced empathy, change and impaired social
lack of insight, hyperphagia or altered food preferences, hypersexuality, and judgment.
increased risk-taking.
● Normal
The orbitofrontal lobe is associated with learning value associations and neuropsychological testing
updating behavior when a change in stimulus or reward occurs. When given a can occur with
gambling task to measure risk-taking behavior, patients with orbitofrontal cortex circumscribed frontal
injury demonstrated increased risk-taking behavior and failed to alter their lesions, making
history-taking critical to the
behavior to nonreward stimuli.19 Therefore, patients with orbitofrontal lesions diagnosis.
continue to respond to stimuli even when a reward is stopped and have difficulty
using negative feedback to change behavior.20
Orbitofrontal cortex lesions are associated with impaired perspective-taking
(difficulties in understanding another person's perspective), despite intact
emotion recognition20 (CASE 4-2).
Many lesion cases emphasized the medial orbitofrontal cortex as the key area
to cause changes in personality, decision-making, and social norms and used the
term medial orbitofrontal cortex interchangeably with the ventral medial
prefrontal cortex, making the terminology challenging.
Eslinger and Damasio21 reported a case of an accountant who had an
orbitofrontal cortex injury from a meningioma resection. After the resection, he
underwent a dramatic personality change that resulted in divorce and career
setbacks. He subsequently made risky financial decisions. His condition was
termed acquired sociopathy. It was noted that the patient was able to provide
appropriate responses to questions about normative social behavior and the
future consequences of actions in the office and laboratory setting despite
impaired real-world performance.22 Even with the profound behavioral and
personality change, standard neuropsychology testing revealed no problems.
The personality change that occurs after orbitofrontal injury has been
examined with the Iowa Rating Scales of Personality Change; patients with
ventral medial frontal injury were characterized as having a blunting of
emotional experience, difficulty modulating emotional reactions, impaired social
decision-making, and a lack of insight into the personality change.23
Tranel and colleagues24 have shown a possible gender difference in deficits
associated with ventral medial prefrontal regions with right-sided lesions more
likely to cause significant impairments in men and left-sided lesions more likely
to cause impairment in women.
When lesions are circumscribed, patients may not demonstrate deficits on
traditional neuropsychological testing such as the Wisconsin Card Sorting Test.
In contrast, patients with orbitofrontal lesions may perform poorly on the Iowa
Gambling Task. During the Iowa Gambling Task, patients are presented with
four decks of cards that either reward or penalize them with game money; the
decks differ in the balance of rewards and penalties.25 Patients choose repeatedly
among the four decks in several trials. Two of the decks are advantageous,
providing moderate rewards with occasional penalties, whereas the other two
decks are disadvantageous, providing large rewards with significant penalties.
People without brain damage can identify the decks with more reward cards and
less severe penalties, whereas patients with orbitofrontal cortex damage continue

to use the highly penalizing decks despite losing money overall.26 Even more
remarkably, patients with orbitofrontal cortex damage fail to show autonomic
activation measured via skin-conductance response when choosing the highly
penalizing deck compared with people without brain damage, who develop an
anticipatory skin-conductance response.26,27
Since patients with orbitofrontal cortex lesions may score in the normal range
on assessments of executive function, a careful history is often necessary to
identify features. The Frontal Behavioral Inventory can be given to someone who
knows the patient well to determine the presence of socially inappropriate
behaviors and personality change.28 Specialized tests that measure impairment in
patients with orbitofrontal cortex dysfunction have been developed but are not
routinely given.
CASE 4-3 A 57-year-old man with a past medical history notable for hypertension,
hyperlipidemia, and untreated type 2 diabetes presented to the stroke
service with new-onset right leg weakness beginning the day prior to
presentation. In the emergency department, the neurologist noted that
the patient had moderate weakness of the right lower extremity and mild
weakness of the right upper extremity. He was not aphasic but answered
questions with single words and did not speak unless spoken to. MRI
revealed an acute infarct
in the left medial prefrontal
cortex (FIGURE 4-4).
After admission, he was
noted to be recurrently
incontinent of urine, which
his wife indicated was
unusual for him. He was not
interested in participating in
physical or occupational
therapy. He did not order or
eat his meals unless FIGURE 4-4
prompted by his wife. After Axial diffusion-weighted image (A) and apparent
his acute hospitalization, diffusion coefficient (B) MRI demonstrating an
acute infarction of the left medial prefrontal cortex
he was transferred to extending into the corpus callosum and anterior
inpatient rehabilitation. cingulate.
COMMENT This patient demonstrated abulia consistent with medial prefrontal cortex
involvement. Although the degree of apathy is less severe in patients with
unilateral lesions than in patients with bilateral lesions, unilateral lesions
can also cause apathy. The decreased verbal output and lack of initiation or
interest in completing therapy are characteristic of medial prefrontal
cortex lesions. This patient’s abulia improved with time, and he was
eventually able to participate in physical therapy.
1594 DECEMBER 2021

Interestingly, patients with orbitofrontal cortex damage favor making a KEY POINTS
utilitarian judgment when presented with high-conflict moral dilemmas, eg,
● The dorsomedial
sacrificing an individual’s life to save the lives of a group of people. Presented prefrontal cortex, including
with emotionally personal moral scenarios (eg, suffocating one’s child to save the the anterior cingulate, has
life of oneself and a larger group), patients with ventral medial prefrontal cortex been associated with
injury were more likely to make the utilitarian judgments compared with motivation, conflict
monitoring, relating actions
patients with lesions outside the orbitofrontal cortex or healthy controls.29
with value, and updating
goal-directed behavior.
MEDIAL PREFRONTAL CORTEX
The dorsomedial prefrontal cortex, including the anterior cingulate, has been ● Medial prefrontal cortex
associated with motivation, conflict monitoring, relating actions with value, and lesions involving the anterior
cingulate are associated
updating goal-directed behavior. Common pathologies that affect this area with impairments in
include parasagittal tumors, anterior communicating artery aneurysms, and motivation (apathy or abulia)
anterior cerebral artery infarcts. The key clinical features of medial prefrontal and decreased spontaneous
cortex lesions are apathy, decreased goal-directed behavior, decreased initiation speech or movement.
of motor activity, and aspontaneity of speech. ● Theory of mind refers to
Both unilateral and bilateral lesions can cause deficits with more severe the ability to attribute and
presentations associated with bilateral lesions. Unilateral lesions may present understand one’s own
with apathy, decreased behavioral initiation, reduced goal-directed behavior, mental state and the mental
states of others.
and reduced verbal and motor output (CASE 4-3). More severe presentations may
occur with bilateral lesions that affect the supplementary motor area and anterior ● The frontopolar cortex
cingulate, such as akinetic mutism, which is characterized by abulia (severe is involved in multitasking
apathy), limited verbal responses, and urinary incontinence.11 Patients with and metacognition (which
akinetic mutism may not initiate interactions and have an absence of expression involves the ability
to imagine the future),
or understanding of emotional experience.30 They may require assistance with reality monitoring, and
activities of daily living including feeding and self-hygiene. They may be theory of mind.
indifferent to pain. Therefore, it is not surprising that patients who undergo
cingulotomy for management of chronic pain develop a decrease in self-initiated ● Alzheimer disease can
present as a progressive
behavior and behavioral spontaneity.31 dysexecutive syndrome
Utilization behavior may occur with medial prefrontal dysfunction and refers without significant
to the automatic grasping and use of objects within sight even if inappropriate. behavioral symptoms and
The medial prefrontal cortex, in particular the anterior cingulate, has also been with characteristic early
involvement of the parietal
implicated in conflict monitoring (ie, when two competing responses are in
lobe on neuroimaging.
conflict, selecting the correct response and overriding the incorrect response).32
Patients with anterior cingulate damage failed to link an action (wrist movement) ● The young age of onset,
to a reward more often than controls.33 Patients with medial prefrontal cortex nonamnestic presentation,
injury show difficulty with the correct response in the go/no-go testing.34 and relative sparing of
medial temporal lobe
Neuropsychological testing may show impaired word and semantic fluency. structures can result in
The inferior medial prefrontal cortex located below the genu of the corpus patients with dysexecutive
callosum has been associated with self-regulation and emotional processing, and Alzheimer disease receiving
dysfunction in this area has been linked to bipolar disorder.35 Damage to this a delayed diagnosis.
region often occurs in the context of orbitofrontal cortex damage.
FRONTOPOLAR CORTEX (ROSTRAL PREFRONTAL CORTEX)

The frontopolar cortex is involved in multitasking, defined as the ability to hold
onto primary goals while other goals are being performed or planned, and
prospective memory.36 Prospective memory refers to the ability to remember to
carry out a future action while engaging in another task, effectively estimating
and managing time during tasks. The deficits in prospective memory that occur
with frontopolar region injuries may underlie the multitasking difficulty

CASE 4-4 A 56-year-old woman presented to the behavioral neurology clinic with a
5-year progressive decline in her cognitive abilities leading to her being
unable to perform her job as an accountant or tasks at home including
cooking by following a recipe. One of the first changes that she noticed
was difficulty completing multistep tasks. She described the problem as
“forgetting how to do” the task she was struggling to perform. She was no
longer able to perform her work duties, and she was let go by her
employer. Her symptoms progressed, and she eventually had to stop
driving because of difficulties with multitasking, following directions, and
navigation. Prior to her presentation to the behavioral neurology clinic,
she underwent a neurologic evaluation. The driving difficulties were
described as “spells of confusion,” and she underwent an extensive
epilepsy evaluation that was unrevealing. She was then diagnosed with a
possible functional neurologic disorder with cognitive symptoms in
relation to that. She had no significant behavioral symptoms other than
being more socially withdrawn given her concern for poor task
performance in social situations. Approximately 4 years into her clinical
course, she developed word-finding difficulties. At the time of
evaluation, she was thought to have aphasia within the context of broader
cognitive impairment.
Her behavioral neurology evaluation revealed that she could not
perform the Luria fist-edge-palm test and had impaired performance on
the written alternating sequence, initially with sequence errors (FIGURE 4-5).
She had subtle, distributed atrophy on brain MRI with normal hippocampal
volumes and significant hypometabolism on fludeoxyglucose positron
emission tomography (FDG-PET) in parietal, frontal, and temporal brain
areas. CSF biomarkers were consistent with Alzheimer disease as the
etiology of her cognitive symptoms (low CSF amyloid and increased CSF
phosphorylated tau). Amyloid and tau PET brain scans 2 years later were
positive (FIGURE 4-5). The Luria fist-edge-palm test demonstrated
perseverative errors when the test was repeated 2 years later.
Her presentation with a young-onset dementia characterized by early
dysexecutive features with imaging initially sparing the hippocampus and
the medial temporal lobe and positive Alzheimer disease biomarkers was
consistent with dysexecutive Alzheimer disease, which has been recently
recognized as an atypical phenotype.45
1596 DECEMBER 2021

FIGURE 4-5
Frontoparietal neurodegeneration in a patient with progressive dysexecutive
syndrome due to Alzheimer disease. A, Alternating sequences at initial presentation (5 years
after onset of symptoms). Note the sequencing errors and false starts. B, Alternating
sequences at follow-up 2 years after initial presentation (7 years after symptom onset).
Note the perseverative error and inability to move linearly across the page. C, Axial
T1-weighted (left) and coronal fluid-attenuated inversion recovery (FLAIR) (right) brain MRI
at initial presentation demonstrated parietofrontal atrophy with greater involvement of the
left hemisphere. D, Amyloid positron emission tomography (PET) scan demonstrates
deposition of amyloid with the typical diffuse high signal seen across Alzheimer disease
phenotypes. E, Fludeoxyglucose (FDG)-PET scan demonstrating distributed hypometabolism
across parietal, temporal, and frontal association cortex involved in executive dysfunction.
F, Tau-PET scan demonstrating high uptake across the association cortex (parietal and
frontal, in particular) involved in executive functioning.
CONTINUED ON
PAGE 1598

CONTINUED FROM
PAGE 1597
COMMENT This case highlights several common features of young-onset dysexecutive

Alzheimer disease. The symptoms are predominantly related to
performance of tasks under executive control and frequently lead to job
loss (if patients are still working). Behavioral symptoms are not prominent,
but patients are sometimes described as apathetic given their reluctance to
engage in tasks requiring executive control. Brain imaging may reveal normal
hippocampal volumes, but close inspection suggests more frontoparietal
atrophy with tissue loss being most prominent in the parietal lobe. The
pattern of neurodegeneration is often much more striking on brain FDG-PET
(FIGURE 4-5). Individuals may be misdiagnosed with a psychiatric disease
because of the young age of onset and initial hippocampal sparing on
imaging. Because of the dysexecutive cognitive profile, they may receive a
diagnosis of behavioral variant of frontotemporal dementia, but patients
with dysexecutive Alzheimer disease seldom have disinhibition or other
behavioral symptoms aside from apathy.
reported.36 Theory of mind refers to the ability to attribute and understand one's
own mental state and the mental states of others. This ability is also impaired
with frontopolar lesions. In addition, metacognition (eg, a group of cognitive
functions used to plan, monitor, and assess one’s own cognitive processes) such
as imagining the future and monitoring reality, is associated with the
frontopolar region.
Lesions of the frontopolar region, which can occur with coup or contrecoup
injuries, result in disorganized behavior in everyday situations (eg, making decisions
about what to wear or eat), impaired multitasking, decreased ability to switch
between cognitive contexts, impairment in time estimation, and deficits in
creativity, analogical reasoning, and original thinking.37 The Faux Pas Test can be
used to test theory of mind. Stories are provided to patients, some of which involve a
faux pas identification of whether a person unintentionally hurts or insults another
person. Patients are scored on their ability to recognize the faux pas.38
TREATMENT
A recent meta-analysis reviewed the benefits of cognitive rehabilitation for
individuals with traumatic brain injury or stroke.39 The working group
recommended metacognitive-strategy training involving problem-solving and
goal-management training for executive dysfunction and emotional
self-regulation after traumatic brain injury. Cognitive rehabilitation, including
computer-based training, was also recommended for working memory
impairment.39 Therefore, this treatment strategy can be offered to appropriate
patients with frontal lobe syndromes.
PROGRESSIVE DYSEXECUTIVE SYNDROME DUE TO ALZHEIMER DISEASE

A clinical syndrome characterized by predominant impairment in executive
functioning in individuals with Alzheimer disease has been reported for more
1598 DECEMBER 2021

than 3 decades.40,41 Early reports often relied on clinical criteria for a diagnosis
of Alzheimer disease without biomarker or pathologic confirmation. A
clinicopathologic case series with frontal lobe tau pathology and relatively
greater impairment in executive function compared with typical Alzheimer
disease raised increased interest in the phenotype.41,42 Prominent behavioral
symptoms were not characteristic of the clinical presentations. The terms
frontal variant or frontal Alzheimer disease were frequently used to refer to
Alzheimer disease presentations with predominantly dysexecutive features.
However, subsequent case definitions emphasized behavioral features,43 which
are not characteristic of the phenotype, and imaging studies did not support
using a “frontal” moniker to describe the pattern of degeneration.44 The
distributed nature of the neurodegeneration seen in this clinical syndrome, with
particular predilection for parietofrontal brain regions, is in keeping with the
distributive nature of top-down executive control (FIGURE 4-1). With careful
history and understanding of the key imaging features, the dysexecutive
phenotype (CASE 4-4) can be distinguished from typical Alzheimer disease
(TABLE 4-2).
It is also clear that other causes, beyond Alzheimer disease, can produce
a clinical picture of a progressive decline in executive functioning (eg,
frontotemporal lobar degeneration, dementia with Lewy bodies, or
Creutzfeldt-Jakob disease). Criteria for a progressive dysexecutive syndrome
have recently been proposed that require biomarker evidence of Alzheimer
disease before describing the clinical picture as a presentation of dysexecutive
Alzheimer disease.46 Therefore, the term frontal Alzheimer disease actually
referred to two phenotypes, a less common behavioral variant of Alzheimer
disease and a more common dysexecutive presentation of Alzheimer disease.
Distinguishing Typical and Dysexecutive Alzheimer Disease Phenotypes TABLE 4-2
Typical Alzheimer disease Dysexecutive Alzheimer disease
Common early Slowly progressive amnestic disorder (ie, Difficulty multitasking, conducting sequential
clinical presentation difficulty remembering details of conversations, tasks (eg, cooking, fixing appliances)
asking repetitive questions, forgetting upcoming
appointments)
Executive Commonly develop after amnestic problems Key early feature

dysfunction
Age at onset Most commonly after 65 Most commonly before 65
Structural Early medial temporal lobe atrophy Early parietofrontal atrophy, often sparing medial
neuroimaging temporal lobe structures
findings
FDG-PET Temporoparietal hypometabolism Parietofrontal hypometabolism in addition to

temporal involvement; parietal is most severely
affected; may lead to diagnostic confusion with
frontotemporal dementia
FDG-PET = fludeoxyglucose positron emission tomography.

CONCLUSION
The prefrontal cortex can be organized into lateral prefrontal, orbitofrontal,
medial prefrontal, and frontopolar regions with different cognitive and
behavioral syndromes associated with lesions of each of these regions. Core
executive functions include working memory, cognitive flexibility, and response
inhibition. Although frontal lobe dysfunction has been synonymous with
executive dysfunction, parietal regions are also recognized as playing a critical
role in core executive functions. An atypical phenotype of young-onset
Alzheimer disease can present with a progressive dysexecutive function
targeting parietofrontal networks, initially sparing the medial temporal lobe.
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1016/s0010-9452(75)80015-3

Language and Aphasias REVIEW ARTICLE

By Stephen E. Nadeau, MD CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This
article reveals how it is possible for a brain
composed of 100 billion highly interconnected, lipid-encased, reticular
electrochemical devices to support complex functions such as language
and how language disorders can be understood as a reflection of
degradation of one or more domains of knowledge.
RECENT FINDINGS: Ongoing research, building on landmark work regarding

parallel distributed processing (PDP), provides the basis for understanding
cognitive functions as a manifestation of the activity of populations of
millions or billions of neurons in various highly interconnected networks.
Population encoding networks have the following intrinsic properties that
provide an orderly explanation for normal and degraded language: (1) a
capacity for settling into stable “attractor” states; (2) processing occurs in
and knowledge (long-term memories) is stored in exactly the same network;
(3) a capacity for incorporating statistical regularities of experience,
frequency, and age of acquisition; (4) support of content-addressable
memory; and (5) graceful degradation, such that lesions increase the
probability of errors but do not fundamentally transform network operations.
Knowledge in parallel distributed processing networks resides in the strength
of connections between units (synapses in the brain). Aphasia, whether
stemming from stroke or dementing disorders, can be understood in terms of
the degradation of one or more domains of knowledge.
CITE AS:
SUMMARY: Understanding the brain as a population encoding machine 2021;27(6, BEHAVIORAL NEUROLOGY
incorporating vast interconnectivity provides an orderly explanation for AND PSYCHIATRY):1549–1561.
language function, both normal and abnormal.

Dr Stephen E. Nadeau Research
Service (151), Malcom Randall VA
Medical Center, 1601 SW Archer
Rd, Gainesville, FL 32608-1197,
INTRODUCTION snadeau@ufl.edu.
T
he neuroscience of language began with Paul Broca in 1861. He
reported that the language of his patient, Leborgne, was reduced to RELATIONSHIP DISCLOSURE:
Dr Nadeau has received
the production of one single utterance “tan” (meaning “so much”) publishing royalties from
after Leborgne experienced what proved to be a left inferior frontal Cambridge University Press and
infarction.1 In this and subsequent articles describing four additional Elsevier.
patients, Broca provided the first evidence of localization of a cognitive function UNLABELED USE OF
in the brain and hemispheric asymmetry and implicitly suggested that the mind PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
is a product of the brain and not a part of the soul. He escaped the fate of Galileo Dr Nadeau reports no
for this apostasy because of the increasing secularization of society and the rising disclosure.
public consciousness of science (On the Origin of Species2 was published in 1859).
Over the next 50 years, several brilliant scientists followed in Broca’s steps, © 2021 American Academy
including Wernicke, Lichtheim, Liepmann, Lissauer, Dejerine, Kussmaul, and of Neurology.

LANGUAGE AND APHASIAS
Freud.3 They detailed a host of language syndromes associated with cerebral

lesions in various locations, thereby providing a patchy landscape of language
function but also establishing a new specialty, cognitive neuropsychology, which
has been far and away the greatest contributor to our understanding of cognitive
function in general and language function in particular. The work of the
19th-century greats might be lost to us today, buried in dusty German and French
journals, had it not been for Norman Geschwind, who brought this work to us.
More importantly, as most expansively detailed in his magnum opus, “Disconnexion
Syndromes in Animals and Man,”4 he exhaustively reviewed data on animal and
human anatomy and behavioral-anatomic correlations to create a comprehensive
picture of the principles of higher neural functions and the mechanisms by which
lesions disrupt those functions. He emphasized the importance of white matter
connectivity between cortical regions. He even correctly posited certain cortical
regions, such as the angular gyrus, that serve as waystations in this
connectivity. Last but not least, Geschwind defined a long-term research
paradigm involving a dialectic between human and animal research.
The neuroscientific understanding of language function has advanced with
phenomenal speed over the past 40 years. This reflects the work of almost
innumerable investigators, but three groups have particularly advanced the field.
In the 1980s, Elizabeth Bates and her colleagues5 launched the cross-linguistic
aphasia study, an international effort to characterize aphasias in multiple
languages, including English, Dutch, German, Italian, Serbo-Croatian, Hungarian,
Turkish, and Chinese (reviewed by Nadeau6). Their studies particularly focused
on grammar, which involves syntax (the order of words in a sentence) and
grammatic morphology, the affixes, suffixes, infixes, and auxiliary words that tell
us who was the agent and who/what was the recipient of an action (case); number
(singular/plural); person (establishing the basis for noun-verb agreement, eg, the
dog chases the men/the men chase the dog); and verb tense (among others). It
turns out that English and Chinese are peculiar languages, grammatic morphology
being highly degenerate in English and almost completely absent in Chinese. All
the other well-defined languages of the world have very rich grammatic
morphology. And yet, before Bates’ work, most of our inferences about grammatic
function were based on studies of English and substantially misled us. The cross-
linguistic aphasia study demonstrated that, despite the complexity and variety of
grammars in the world’s languages, highly consistent patterns were discernable,
reflecting the fundamental underlying principles common to all (even English and
Chinese). Moreover, these studies settled a nature-nurture argument that had
been raging since the earliest publications of Noam Chomsky, a linguist at the
Massachusetts Institute of Technology. They provided conclusive evidence that,
whereas the brain provides the neural network scaffold for language function, the
actual patterns of connectivity reflect learning acquired through experience with a
language, incorporated as synaptic strengths in neural networks, probably
beginning in utero (contrary to Chomsky’s postulate).7
In the 1990s, Cambridge University neurologist John Hodges and his cognitive
neuroscientific collaborators (Patterson, Lambon Ralph, and Rodgers and their
American colleagues, McClelland and Plaut, among many others) conducted an
extensive series of studies of cognitive function in a variety of dementing
disorders, most importantly semantic dementia (reviewed by Nadeau6). This
extraordinary work provided the essential basis for our current understanding of
the neural basis for our knowledge of the world and the objects in it.
1550 DECEMBER 2021

Finally, in 1986, Jay McClelland and David Rumelhart and their colleagues KEY POINTS
published an epochal two-volume book titled Parallel Distributed Processing8
● Our current
that sought to answer what had been an enduring enigma: how was it possible understanding of language
for a brain composed of 100 billion highly connected neurons to support complex function is fully congruent
functions such as language, memory, visuospatial, emotional, and executive with the discoveries of the
function? Their work, and the hundreds of studies that have followed in its wake, greats of the 19th century,
including Wernicke and
has been highly productive and extensively validated and now provides the
Lichtheim and their model,
fundamental basis for our understanding of the neural basis of language and the subsequent work of
function.6,9 Much of what follows reflects this research. Norman Geschwind.
PARALLEL DISTRIBUTED PROCESSING ● The cross-linguistic

aphasia study of Elizabeth
This section describes the structure, function, and functional implications of Bates and her colleagues has
population encoding networks. been instrumental to our
understanding of the
The Structure of Population Encoding Networks commonalities of all human
languages. It clearly
For more than 40 years, evidence has been emerging that representations in the established that, although
central nervous system are population encoded, that is, encoded as patterns of neural networks provide the
activity involving very large numbers of highly interconnected neurons in one or scaffold for cognitive
more neural networks extending over large expanses of the brain.9 The function, the actual
knowledge stored in these
properties of population encoding networks have been extensively explored in networks derives from
computer simulations. Most of these involve fairly simple mathematics: unit learning through
activations between 0 and 1 defined as a sigmoid function (∫), reflecting existing experience.
activation levels and input from all afferent units; each afferent unit input
● The study of semantic
multiplied by the weight of its connection (corresponding roughly to synaptic
dementia by John Hodges
strengths in the brain); and output functions defined as a nonlinear function of and his colleagues at
unit activation, often incorporating a “firing” threshold.9 To one degree or Cambridge University
another, units are highly and reciprocally interconnected (hence the term provided the foundations of
connectionist model), as in the brain.10 our understanding of the
neural organization of our
Activity is understood to flow between units throughout a network and all knowledge of the world and
connected networks. Knowledge is represented in connection strengths, and the objects in it.
learning consists of alterations in connection strengths. These simple
mathematics do not do justice to all the subtleties of actual neural processing, but ● The vast research on
parallel distributed
they do capture the most essential property of neural activity and interactivity. processing, in large part
For this reason, they have given us powerful insights into brain function, and deriving from the seminal
they have been extraordinarily successful in predicting behavior in people with publication of McClelland
and without brain damage. The implicit properties of networks employing these and Rumelhart in 1986, has
helped us understand how a
mathematics provide an orderly explanation for a host of brain functions
brain composed of
and dysfunctions.9 100 billion neurons enables
cognitive functions.
The Function of Population Encoding Networks
A great deal has been written about the function of population encoding ● Representations in the
brain are encoded as
networks in general and those supporting language function in particular.6,9,11 patterns of activity involving
The picture that emerges is substantially different from traditional concepts of very large numbers of highly
how the brain operates. interconnected neurons,
First, many of the networks in the brain are “auto-associator networks.” These hence the term population
encoding.
networks provide the basis for a process of settling within “attractor basins”
(eg, the network representation of animals in general) and into attractor states
(eg, “dog”), which can be understood as minimal energy states.
Second, any concept we can think of reflects activity in multiple neural
networks supporting different types of knowledge. For example, the concept

“dog” corresponds first and foremost to patterns of activity in visual association

cortices because much of our knowledge about dogs has to do with what they
look like. The dog concept representation is also likely to include patterns of
activity within the orbitofrontal cortex and the limbic system reflecting how we
feel about dogs in general and our pet dogs in particular. It also includes patterns
of activity in the dominant perisylvian cortex that correspond to linguistic
representations of the word “dog.” Patterns of activity may also appear in the
somatosensory cortex (the feel of soft fur, a wet tongue, and a cold nose),
auditory cortex, and olfactory (piriform) cortex. And finally, it includes a
“predicative” component, substantially incorporated in the dorsolateral frontal
and posteroventral temporal cortex, corresponding to our knowledge of what
dogs are likely to do and the things that are most frequently done to dogs. This
predicative component corresponds to the neural representation of the verb
that is linked to the noun concept representation. Thus, the final neural
representation of “dog” corresponds to a constellation of attractor states.
The links between neural networks supporting the different components of an
attractor state constellation are provided by pattern associator networks, which
link many or all of the neurons in one attractor basin network to many or all
neurons in another attractor basin network. Pattern associator networks enable
translation of representations in one domain (eg, semantics) into representations
in other domains (eg, phonology, which has to do with the structure and
systematic patterning of sounds in a language).
With these ideas in mind, we can understand brain functions as reflecting a
process of settling into a constellation of linked attractor states (or a series of such
states as our thinking evolves rapidly over time). As this settling process proceeds
to completion, conclusions and behaviors emerge. This process may involve
hundreds of back-and-forth volleys of neural transmission (via pattern associator
networks) encompassing all of the attractor basins that have been engaged.
This process assures that optimal agreement is achieved between all of the
engaged attractor basins as they settle into the final constellation of attractor
states, something referred to as parallel constraint satisfaction.
Functional Implications of Population Encoding Networks

Neural networks incorporating these simple characteristics have several implicit
properties that are directly relevant to brain-behavior relationships.9
1 Processing occurs in and knowledge (long-term memories) is stored (as synaptic strengths) in
exactly the same network. For example, visual association cortices both process visual input
and store visual knowledge. The dominant (and to a lesser and variable extent, nondominant)
perisylvian cortex stores knowledge of phonologic sequences and supports phonologic
processing and auditory-verbal short-term memory.9 The fact that networks encoding
knowledge also support processing enables such things as stimulus recognition (or sense of
familiarity) and reactive attention driven by stimulus salience, familiarity, or context.12
2 Capacity for incorporating statistical regularities of experience, frequency of experience,

and age of acquisition.9,13 Each addition of knowledge or skill to the brain is coded as an
adjustment of neural connection strengths. Population encoding networks have been
shown to be highly proficient at capturing statistical regularities in these experiences. For
example, the English verbs that form a regular past tense are individually infrequent, but
because they all share the same pattern of past tense formation (add /t/ [dip/dipt], /d/
[film/filmed], or /ed/ [abscond/absconded]), they avail themselves of the implicit regular
past tense rule that has been instantiated in morphologic sequence connectivity through
accumulated experience.4 In contrast, the past tense rule for irregular past tense verbs
1552 DECEMBER 2021

(eg, swim/swam; hit/hit; go/went) is much less reflective of regularities in morphologic KEY POINTS
sequence knowledge (because few verbs share these regularities), and knowledge of
these forms is substantially reliant on the impact of frequency effects on the encoding of ● Parallel distributed
this type of verb past tense form. The 160 English verbs with an irregular past tense are processing models typically
among the most frequently used.9 employ simple mathematics
that, while certainly not
3 Content-addressable memory. Because knowledge is distributed throughout feature space capable of capturing all of
(for example, all of the visual features that, together, define a dog), engagement of the subtleties of cortical
individual features can elicit entire concept representations (ie, pattern completion).9 For neural network function,
example, perception of a feather can elicit a population-encoded representation of a bird. enable these models to
The capacity for pattern completion is essential to perceptual invariance, which is the ability account for the key
to recognize an object from different points of view.14,15 The phenomenon of pattern properties of cognition.
completion has recently been demonstrated through multicellular calcium imaging in living,
behaving mice.16-18 The facility for content-addressable memory enables the elicitation of ● Neural activity in neural
correct representations by corrupted input19,20; this is an essential capacity given the networks naturally settles
frequency with which an organism operates under conditions of degraded perception.9 into minimal energy states
known as attractor states.
4 Graceful degradation. Because knowledge is represented as synaptic connection
strengths throughout a network, degradation of connections in the network will not halt ● Neural processing
function. Rather, network output will contain more errors, yielding near-miss errors or consists of the process of
even nonresponses. Residual productivity will be proportionate to the strength of settling into constellations
encoding of particular knowledge in neural network connectivity. of linked attractor states,
each state corresponding to
Although innumerable focal processes can be identified in the course of settling a component of the meaning
of the concepts in play (eg,
into constellations of attractor states, even seemingly simple processes such as
the visual and limbic
naming a picture engage much of the brain. The order that emerges is chaotic representations of “dog”).
order,21 an order that emerges from the activity of billions of highly interactive
units, each expressing a limited spectrum of functional parameters. A great deal of ● In a parallel distributed
processing occurs automatically. What is not automatic is largely the province of processing system,
processing occurs in and
the frontal lobes: volitional planning, volitional decision making, the volitional knowledge (long-term
engagement of select neural networks that defines the processes of working memory memories) is stored (as
and volitional attention, and the volitional sequencing and modification of distributed connection strengths) in
concept representations in the processes of thinking and speaking (syntax).6,9 exactly the same network.
● Parallel distributed
DIASCHISIS processing systems have the
No discussion of the behavior of large populations of neurons in the context of capacity for incorporating
acute brain injury would be complete without mention of diaschisis. When statistical regularities of
experience, frequency of
neurons lose afferent input because of major damage to connected regions of the experience, and age of
brain, the probability of their firing to produce a signal may be markedly acquisition.
reduced. In their silence, they act like dead neurons. This is diaschisis, a
pioneering concept conceived by von Monakow22 more than 100 years ago. ● Parallel distributed
processing systems support
Gradually, over time, new afferent inputs are acquired from various sources as a
content-addressable
result of synaptic modification, and the neurons recover their normal physiology. memory. Thus, a single
Resolution of diaschisis probably accounts for the vast majority of spontaneous feature can elicit an entire
recovery from stroke; this is nicely illustrated in the results of a phase III trial of concept representation, a
phenomenon referred to as
treatment of walking impairment stemming from acute stroke23 in which 75% of
pattern completion.
the increase in gait speed occurred in the absence of treatment. Based on studies
of aphasia, diaschisis after stroke probably resolves over 6 to 12 months.24
THE APHASIAS
To understand the aphasias, it is necessary to enlarge a little on a property of the
brain that we have already mentioned several times in passing: that all knowledge
is encoded as connection strengths (synaptic weights). The human cerebral
cortex has approximately 40 billion neurons, and each of their axons makes

between 1000 and 10,000 synapses. A host of auto-associator networks and

pattern associator networks underlie language function. Each of these supports a
specific type of knowledge. Thus, the particular characteristics of a given aphasia
type reflect the loss of particular types of knowledge as a result of a lesion at a
specific location.
Broca Aphasia
Broca aphasia most commonly occurs as a result of very large left middle cerebral
artery distribution infarcts, at the least extensively involving the frontal lobe but
often extending well into the superior temporal lobe and into parietal regions.
Often, Broca aphasia is the result of spontaneous recovery (largely the resolution
of diaschisis) of a patient who initially had global aphasia (ie, little language
output and poor comprehension). A good argument could be made that the
language of patients with Broca aphasia is substantially the product of the
right hemisphere.25
The sine qua non of Broca aphasia, regardless of language spoken, is the
simplification of syntax. Patients may be reduced to short, simple declarative
sentences, if not to one- to two-word utterances. This reflects three things. First,
the large left frontal lesions that cause Broca aphasia destroy the knowledge
underlying language-specific habits of sequential ordering and modification of
concept representations, that is, the knowledge that underlies syntax.6 Second,
we have the ability to modify sentence plans to fit the unique demands of the
particular occasion, as with all volitional planning (eg, “This man robbed the
liquor store” or “It was this man who robbed the liquor store”). This ability is lost
with Broca aphasia. Third, large left frontal lesions seriously degrade working
memory capacity. Even a very simple sentence, for example, “The dog chases the
cat,” requires simultaneous generation of two concept representations (dog and
cat) and reciprocal modification of those two representations into “chaser dog”
and “chased cat.” Imagine how many concept representations have to be
simultaneously maintained with more complex sentences.
Many patients with Broca aphasia demonstrate impairment in grammatic
morphology. English speakers simply leave out grammatic morphemes (a
phenomenon known as morphologic agrammatism): articles (a, the), auxiliary
verbs (is eating), and suffixes signifying person and tense. Speakers of richly
inflected languages (nearly every language but English and Chinese) for the most
part keep all of these things, but they tend to make errors in their choices (a
phenomenon known as paragrammatism). It is believed that all of this stems, in
part, from loss of grammatic morphologic sequence knowledge because of
damage to the pathway (pattern associator network) linking the auditory cortex
to the midsuperior temporal gyrus to Broca area via the external and extreme
capsules.26 In addition, loss of connections between the frontal cortex and Broca
area likely interferes with the correct selection of the grammatic morphemes that
are available.
The major features of Broca aphasia in an English-speaking person, simplified
syntax and paucity of grammatic elements, are illustrated in the following
language sample from a patient describing events surrounding the massive left
brain stroke he experienced after being shot in the left carotid artery.
Stroke ... Sunday night... Navy, Army, Airforce ... Sunday night ... pool
(gestures motion for shooting pool) ... pay phone... “I got your
1554 DECEMBER 2021

girlfriend”. I don’t know ... memories … memories ... shot twice KEY POINTS
(gestures trigger pull with hand) ... pints of blood (holding his neck area)
● When damaged, parallel
... bar ... helpless ... helpless ... rescue ... helicopter ... coma ... helicopter distributed processing
... passed out ... helicopter… memories ... drugged up ... drill, networks tend to exhibit
drill (points to head) ... drugged up ... tragedy.25 graceful (incremental)
degradation rather than
Some patients with Broca aphasia make phonologic paraphasic errors (further catastrophic collapse because
discussed in the following section on Wernicke aphasia). Some have damage to the knowledge is distributed
throughout the network.
ventral area 4 and its subcortical projections, resulting in a loss of procedural
knowledge and leading to great difficulties with articulation and rendering ● Most processing in the
speaking a struggle. Most have impairment in grammatic comprehension.27 brain occurs automatically.
Thus, the distinction between expressive and receptive aphasias is, for the most What is not automatic is
part, not a useful one: all patients with serious language impairment as a result of largely the province of the
frontal lobes.
stroke (eg, those with Broca or Wernicke aphasia), have deficits in both
expression and comprehension. ● Diaschisis corresponds to
transient dysfunction of
Wernicke Aphasia undamaged neurons caused
by a sudden loss of afferent
Wernicke aphasia typically stems from large middle cerebral artery distribution input from acutely damaged
infarcts involving the left posterior perisylvian cortex, adjacent regions of the regions of the brain.
temporal lobe, the supramarginal gyrus, the angular gyrus, and adjoining regions Resolution of diaschisis
of the parietal lobe. accounts for much of
spontaneous recovery from
Wernicke aphasia, like Broca aphasia, reflects a loss of knowledge due to
stroke.
damage to several different auto-associator and pattern associator networks.
The syndrome is consistently characterized by phonologic paraphasic errors, ● Knowledge is
reflecting, as in conduction aphasia (see the following section), damage to the represented as the
perisylvian phonologic pattern associator network. Language is typically connection strengths (synaptic
weights) between neurons.
“empty,” or anomic (marked by a lack of meaningful content and a paucity of
nouns and verbs). Confrontation naming is also impaired. These deficits ● The characteristic
reflect some combination of damage to the substrate for two knowledge patterns of language
domains: semantic (association cortices, especially temporal) and the dysfunction observed in the
aphasias reflect degradation
connections between these association cortices and the perisylvian region. of particular domains of
These same lesions can also account for the impairment in comprehension that language knowledge.
is characteristic of Wernicke aphasia, although comprehension and production
of language content are not necessarily equally impaired. Impairment in ● The simplification of
syntax that is characteristic
comprehension may also be caused by damage to another knowledge domain: the
of Broca aphasia reflects
connectivity between auditory cortices (bilaterally) and the left superior loss of knowledge underlying
temporal gyrus. When this occurs in isolation, it produces the syndrome of pure language-specific habits of
word deafness.28 sequential ordering and
The following is a sample of language production by a patient with modification of concept
representations, loss of the
Wernicke aphasia: ability to modify sentence
plans to fit the unique
“I’ve been retired since 1972 with /cardimiapesun/ (cardiomyopathy). demands of the particular
Ten per cent [of] the people [of] the /catraps/ (cataracts) has the occasion, and degradation of
[problem with the] retina. I was in the /bizzet/ (business) of records … working memory.
/fotegraph/ (phonograph) records … for the /shusta/ (distribution?) … ● English-speaking patients
In other words, I was a /eksiev/ (executive). Look, I think it’s /porten/ with Broca aphasia often
(important). I can’t [say] /tivelsha/, /diveltsher/(television), leave out small words and
endings that convey
uh TV.”29
number, person agreement
between nouns and verbs,
The nonwords (neologisms) constitute phonologic paraphasic errors. The
and tense.
ellipses reflect anomia or word-finding difficulty. Words in parentheses have

been added for clarification; the patient was never able to actually produce them.
Words in brackets were simply omitted.
Conduction Aphasia
Conduction aphasia typically stems from stroke limited to the posterior superior
temporal gyrus/supramarginal gyrus region.
Conduction aphasia is a disorder related purely to damage to the substrate for
phonologic sequence knowledge in the left perisylvian cortex (from the auditory
cortex to the planum temporale/superior temporal gyrus to the supramarginal
gyrus to the Broca area) and the inadequacy of right hemisphere phonologic
sequence knowledge.6,25 Classically, affected patients make phonologic
sequencing errors, particularly in repeating sentences with many syllables
(eg, “The president lives in Washington” might become “The predident libs in
Washton ton”). They cannot repeat nonwords. These patients also have variable
impairment in auditory-verbal short-term memory (a working memory
supported by the perisylvian phonologic sequence pattern associator network
noted earlier). This is best assessed with forward digit span, which may be as low
as 2 (normal, 7 ± 2). Patients with conduction aphasia often exhibit some features
of Wernicke aphasia, indicating that ischemic damage is more widespread, but
so long as comprehension is relatively spared, their language disorder is classified
as conduction aphasia.
Anomic Aphasia
Anomic aphasia reflects damage to the same neural networks as in Wernicke
aphasia. However, affected patients do not produce phonologic paraphasic
errors. This suggests that the perisylvian phonologic cortex is spared, but it
is now known that some patients may exhibit phonologic dysfunction in
formal testing, suggesting at least some damage to this region, even in the
absence of paraphasic errors.30 Anomic aphasia may be the only manifestation
of an acute stroke (in which case it is often missed), but it is also often the
persisting language disorder seen after resolution of diaschisis in patients who
initially had a Wernicke or conduction aphasia. Subtle anomic aphasia may
be unmasked by poor performance on tests of letter fluency (eg, asking
patients to name as many words as they can beginning with the letter F in
CASE 2-1 A 65-year-old man presented with mild dysarthria and subtle right-sided
weakness that began 1 hour ago. He had a history of atheromatous
disease. When asked to repeat “The president lives in Washington,” he
made phonologic paraphasic errors.
COMMENT The low National Institutes of Health Stroke Score notwithstanding, the
patient’s response indicates ischemia of the left perisylvian cortex, hence
a distal M1 or M2 middle cerebral artery occlusion. The subtlety of the
paresis indicates sparing of the lenticulostriate vessels supplying the
posterior periventricular white matter, arguing against proximal M1
occlusion.32
1556 DECEMBER 2021

1 minute) or category fluency (eg, asking patients to name as many animals as
they can in 1 minute).
The following is an example of language produced by a patient with anomic
aphasia when she was asked to describe why she came to the hospital:
“Well, I was eating breakfast and then…I couldn’t…I said to my husband…

He said we had to go to the hospital. He thought maybe I was having
something. You know. So then we called them and they brought me
here.”
Transcortical Aphasias
Transcortical aphasia usually results from strokes involving the left hemisphere
but sparing the perisylvian cortex.
Transcortical motor aphasias are varied, reflecting their origin in frontal lobe
damage and the multiple domains of knowledge in the frontal lobes. Perhaps the
best characterized, adynamic aphasia,31 is not an aphasia at all. Affected patients
may be almost incapable of spontaneously producing language, even single
words. However, when asked to describe a picture, their language becomes
nearly normal. Thus, this appears to be a disorder of endogenous generation of
concept representations; when these representations are induced by visual
stimuli, language is shown to be essentially normal.
Transcortical sensory aphasia can be viewed and understood as a variant of
Wernicke aphasia in which repetition, even of very long sentences, is spared,
indicating preservation of phonologic sequence knowledge in the perisylvian
cortex even as semantic cortices are extensively damaged. Affected patients
often make near-miss semantic paraphasic errors, as in semantic dementia,
and they are often echolalic, repeating the examiner’s question rather than
answering it.
CLINICAL UTILITY OF THE LANGUAGE EXAMINATION

Testing of selected language functions can be useful in guiding treatment.
Stroke
Even in these days of heavy reliance on imaging, the language examination can
be of value in acute diagnosis, as shown in CASE 2-1 and CASE 2-2.
A 75-year-old man presented with acute severe right hemiparesis. He had CASE 2-2
a long history of hypertension and smoking. His language seemed to be
normal. The initial impression was lacunar infarction; however, he could
produce only three words beginning with the letter F in 1 minute (more
than 11 words is considered normal).
The poor performance on the letter fluency test indicates left hemisphere COMMENT
cortical dysfunction, frontal, postcentral, or both. This suggests M1
occlusion. In some cases, particularly those with greater postcentral
ischemia, a category fluency test may be more useful.

Dementia
Most of the most common causes of dementia are characterized by language
impairment, and the nature of the language impairment is of major value in making
the diagnosis (TABLE 2-1). For example, patients with Alzheimer disease typically
produce spontaneous language that is notable for its lack of content and paucity of
major lexical items such as nouns and verbs. On object-naming tests (eg, the Boston
Naming Test), these patients may make agnosic errors (ie, they are unable to even
describe the function of the object), anomic errors (ie, they can describe the
function of the object but cannot name it), superordinate errors (eg, pointing to a
picture of a zebra and calling it an animal), or coordinate errors (eg, calling a zebra
a donkey). Agnosic errors signal impairment in vision or visual processing.
Frequent agnosic errors raise the possibility of the posterior cortical atrophy form
of Alzheimer disease. Anomic errors most strongly suggest a semantic-phonologic
disconnection, but they can be caused by degraded semantic or phonologic sequence
TABLE 2-1 Language Manifestations of Dementias
Dementia type Knowledge domains affected Manifestations
Alzheimer disease Semantic Spontaneous language empty, lacking in

nouns and verbs, with excessive use of
Semantic-phonologic
determiners (eg, this, that, these, and those)
Agnosic, superordinate, coordinate, and
anomic naming errors
Reduced category and letter fluency
(category more severely reduced than
letter)
Behavioral variant frontotemporal Orbitofrontal-limbic systems, right to a Language spared until late in the disease
lobar degeneration greater extent than left course
Nonfluent primary progressive Habits of concept sequencing and Simplified syntax and impairment in
aphasia modification syntactic comprehension
Grammatic morphologic sequence Grammatic morphologic errors/
agrammatism
Semantic morphologic
Phonologic sequence Phonologic paraphasias
Substrate for translation of phonemes Dysarthria/apraxia of speech
into articulation
Severely reduced language fluency
Logopenic primary progressive Semantic-phonologic Anomia in conversation with frank word-

aphasia finding difficulty; impaired confrontation
naming
Phonologic sequence (late in the Phonologic paraphasias; repetition mildly
disease course) impaired for words and nonwords, severely
impaired for sentences (because of
word-finding difficulty)
Markedly reduced letter and category
fluency
1558 DECEMBER 2021

knowledge. Superordinate and coordinate errors signal semantic dysfunction; frequent
errors of this type raise the possibility of semantic dementia.
TABLE 2-1 serves to further illustrate the principle that aphasias, regardless of
their etiology, reflect the loss of specific domains of knowledge that are encoded
in neural connectivity in specific regions of the brain.
REHABILITATION
Unquestionably, speech language pathologists provide enormous service to
patients, particularly to those who have had a stroke. They guide patients and
their families in techniques to optimize communicative ability, by whatever
means. They provide considerable psychological support when it is most needed.
Even patients with relatively severe aphasia may be capable of learning at least a
limited repertoire of words that are particularly useful in daily life. What
language therapists cannot yet do is reconstitute language function. Most
Dementia type Knowledge domains affected Manifestations
Semantic dementia Semantic Severe anomia with superordinate,

coordinate, and anomic naming errors
Impoverished knowledge of objects and
people
Impaired single-word comprehension
Reduced letter and category fluency
Orthographic-semantic Surface dyslexia with coordinate reading
errors (eg, “ocean” becomes “sea”), and
impaired irregular word reading
(eg, yacht, colonel, ocean)
Posterior cortical atrophy Dorsal predominant

Occipital-parietal visuospatial Balint syndrome: optic ataxia, optic apraxia
Parietal-temporal and simultanagnosia
Ventral predominant Nearly normal spontaneous language
Visuoperceptual-semantic Agnosic/anomic naming errors
Visuoperceptual (orthographic)- Alexia
phonologic sequence
Visuoperceptual (orthographic)– Agraphia
semantic and inscriptional sequence
Late Alzheimer disease patterns
Semantic
Semantic-phonologic sequence

KEY POINTS particularly, after 50 years of research, no one has succeeded in developing a
therapy that generalizes to untrained words and to daily verbal communication
● Wernicke aphasia reflects
some combination of
with sufficient efficacy to justify such a labor-intensive therapy (effect sizes in
damage to the association the 0.18 to 0.33 range). Many techniques have been tested, some in substantial
cortices supporting phase II randomized controlled trials, including phonologic therapy, semantic
semantic knowledge, the feature analysis, constraint-induced language therapy, and intensive
connections between these
comprehensive aphasia programs. The potential mechanisms that might be
association cortices and the
perisylvian region, and the leveraged to achieve generalization have been elucidated.24 However, achieving a
perisylvian substrate for high-efficacy generalizing therapy has proven to be an enormous challenge.
phonologic sequence
knowledge.
● Conduction aphasia is a CONCLUSION

disorder related purely to Parallel distributed processing theory can now account for an enormous
damage to the substrate for spectrum of psychophysical and behavioral phenomena, most particularly
phonologic sequence language function.6,9,11 Maturity, coherence, empirical validation, and neural
knowledge in the left
perisylvian cortex.
verisimilitude (resemblance to actual neural network structure) inspire
confidence that the account elaborated in this article is basically correct, even if
● Anomic aphasia can be still a theory. A parallel distributed processing explanation of aphasias fully
viewed as a form of accords with discoveries of the 19th-century greats, and it considerably extends
Wernicke aphasia in which
Norman Geschwind’s vision of higher neural systems, linking them with the
impairment in phonologic
sequence knowledge is physiology of large populations of neurons incorporated in neural networks
inapparent and connected by short or long white matter pathways. Aphasia, whether due to
comprehension is relatively stroke or dementia, reflects the degradation of specific domains of knowledge
spared. Subtle anomic
encoded in neural connectivity in specific regions of the brain.
aphasia may be revealed by
poor performance on letter
and category fluency tests.
ACKNOWLEDGMENT
● Impaired repetition or The contents of this manuscript do not represent the views of the United States
poor performance on letter
and category fluency tests,
Department of Veterans Affairs, the United States Government, or the
indicating M1 or M2 University of Florida.
occlusion, might prioritize
intravascular thrombectomy
in patients with low National
Institutes of Health Stroke
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REVIEW ARTICLE

Memory Dysfunction
C O N T I N UU M A UD I O By Roberto Fernandez-Romero, MD, MPH, PhD; D. Malcolm Spica, PhD
ONLINE
Downloaded from http://journals.lww.com/continuum by wqLe/H3/oM2vx1Qs5A5qMemKKHLPqE4qkmGNpdheG3ikf1o85ttJSkFL2oTkgOkhMEmawHvsuTTE5xJG2ZjqccytIAhVn2qegy060KLcKJuPZsx5htaYiopRjp2zor2egUzWJAEWYNrC3bBuCzr1RdmqNUpjE4IY on 04/28/2022
ABSTRACT
PURPOSE OF THE REVIEW: This
article provides a practical overview of the
diagnostic process for patients with memory dysfunction through
exploration of the anatomic, physiologic, and psychological aspects of
human memory.
RECENT FINDINGS: As updated methods become available to neurologists, the

ability to accurately identify and treat patients with memory disorders
evolves. An appreciation of current concepts in the anatomic, physiologic,
and psychological aspects of memory, combined with a rational
application of everyday tools (such as clinical examination, bedside
testing, standardized cognitive screening, and formal neuropsychological
examination), allows the clinician to identify possible etiologies and track
longitudinal changes in functional memory status. Recent findings
regarding the interactions of limbic, anterior temporal, primary sensory,
parietal, and dorsal prefrontal structures shed new light on the putative
classifications of procedural and declarative memory and their
subfunctions.
SUMMARY: An understanding of memory profiles pertaining to registration,

encoding, consolidation, storage, and retrieval, as well as methods to
assess those functions, facilitates the clinician’s identification of
CITE AS: underlying pathology and affected cerebral territories. The memory profile
must be appreciated in the context of the entire individual, including
AND PSYCHIATRY):1562–1585. possible confounds of comorbid conditions, psychiatric disorders, and
normal healthy aging.
Dr Fernandez-Romero, The
University of Tennessee
Medical Center, Brain and Spine
Institute, 1932 Alcoa Hwy, Ste INTRODUCTION
L
C-150, Knoxville, TN 37920,
RFernandez@UTMCK.edu.
earning and memory are the most critical processes by which humans
gather information from the world around us and incorporate that
RELATIONSHIP DISCLOSURE: information into the knowledge that allows us to comprehend and adapt
Dr Fernandez-Romero has
received research/grant to our environment. Learning is the process of acquiring information,
support from The University and memory is the process of encoding, storing, and retrieving
of Tennessee Medical Center.
that information.
Dr Spica reports no disclosure.
Some consider memory the most critical of all higher-order cognitive
UNLABELED USE OF functions, with the understanding that it is never fully independent from other
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
domains. Erick Kandel, for example, famously stated, “We are who we are
Drs Fernandez-Romero and because of what we learn and what we remember.”1 While the extent of
Spica report no disclosures. preserved memory function in determining who we are may be debatable and
© 2021 American Academy acquired memory impairments will not necessarily strip individuals of their
of Neurology. sense of self or personality, the importance of memory in its broadest sense
1562 DECEMBER 2021

should not be underestimated. Thus, it is no coincidence that no other KEY POINTS
cognitive domain has been as broadly studied as memory. It is also the
● Working memory retains
reason why the public so often equates deficits in other domains with a information for seconds or
“memory problem.” minutes, usually while that
This article reviews the different types of memory, with an emphasis on information is relevant to an
episodic memory because of its clinical significance, and the anatomic structures ongoing task.
critical for different memory functions. Recommendations for the assessment of
● Long-term memory is
patients with memory problems, including the use of neuropsychological testing divided into episodic and
as an important diagnostic tool, are presented. Specific conditions affecting semantic. Episodic memory
memory functions are briefly discussed, with an emphasis on patterns of is characterized by the what,
memory loss observed in each condition. The overall goal is to provide the where, and when of a
particular episode that is
clinician with useful and updated information for the assessment and diagnosis being stored and available
of patients presenting with disorders of memory. for later retrieval. Semantic
memory involves the
CLASSIFICATION OF MEMORY retrieval of facts that may be
obtained over a period of
Memory can be divided into explicit (conscious) and implicit (unconscious) time and are not associated
memory.2 Explicit memory refers to information that is acquired through with a specific life episode.
conscious experience and awareness and later consciously retrieved. Implicit
memory refers to information such as skills that, once learned, are done mostly ● The Papez circuit is
crucially involved in the
automatically. Repetition priming is also linked to skill learning and refers to the
processing and transfer of
fact that repeated exposure to a stimulus will make learning it easier, even if the information for long-term
individual is not consciously attempting to learn that particular task or storage. Bilateral lesions to
information. any of its components can
cause significant episodic
Explicit memory is further divided into long-term and working (short-term)
memory deficits and
memory. Working memory retains information for seconds or minutes, usually predominantly anterograde
while that information is relevant to an ongoing task. An everyday example amnesia. Injury to the
might be looking up a phone number that has not been memorized. The numbers hippocampus will also result
are recalled only for the amount of time necessary to make the call. Once the task in temporally graded
retrograde amnesia, where
is completed, that information is no longer relevant and discarded. If the phone information acquired
number is relevant for future use, it can be stored in long-term memory, usually recently before the lesion
through a process of repetition or practice that leads to encoding and will be lost, but more
consolidation. remote memories will
remain intact.
Long-term memory is further divided into episodic and semantic memory.
Episodic memory is characterized by the what, where, and when of a particular ● The basolateral limbic
episode that is being stored and available for later retrieval. An example would be system is primarily involved
recalling the last visit with a doctor, when it happened, where it took place, and with the processing of
emotions, but it also plays a
what was discussed during that visit.
role in the assignment of
Semantic memory involves the retrieval of facts that may be obtained over a emotional value to
period of time and are not associated with a specific life episode. An example is experiences, which can
knowing that Vienna is the capital of Austria. One usually does not know or modulate their
consolidation. Bilateral
remember when, where, or how that information was acquired. Knowing the
injury to the basolateral
meaning of words and what a tool is used for are other examples of semantic limbic structures can result
memory. It should also be noted that these different types of memory may in varying degrees of
converge. For example, a neurologist may have an episodic memory of their first memory dysfunction, often
neurology rotation where a mentor taught how to use a reflex hammer. Over associated with other
behavioral symptoms such
time, the neurologist acquires semantic memory regarding the different ways as hypersexuality,
to use the hammer and what to look for when checking reflexes. The technique hyperorality, and
improves with time as the neurologist develops the procedural memory that hyperphagia (Kluver-Bucy
allows the neurologist to apply it automatically, without necessarily thinking syndrome).
about it.

MEMORY DYSFUNCTION
ANATOMY
The neuroanatomy of memory involves a complex group of networks and
interactions of multiple brain regions, some of which are selective to specific
types of memory. This specificity of neural substrates can be of great utility for
clinical diagnosis based on localization.
Episodic Memory
Primary sensory cortices and association areas receive and process information
from sensory systems, whereas frontal regions modulate motivation, attention,
and working memory that are necessary for encoding.3 The Papez circuit
(FIGURE 3-1) is crucially involved in the processing and transfer of information
for long-term storage.4 Highly processed information from multiple cortical
regions is conveyed to the hippocampus. This information enters through four
medial temporal cortical areas: the lateral entorhinal cortex, medial entorhinal
cortex, perirhinal cortex, and parahippocampal cortex. The dentate gyrus and
CA3 regions of the hippocampus integrate preprocessed sensory information,
which is then sent from CA1 back to the perirhinal cortex, entorhinal cortex, and
neocortex through projections to the subiculum for further consolidation into
long-term memory, which is thought to be stored in cortical regions involved in
FIGURE 3-1
The anatomy of episodic memory. A, Critical structures include the hippocampal formation,
the amygdala, paralimbic cortices (piriform cortex, entorhinal cortex, the parahippocampal
cortex on the medial surface of the temporal lobe, and the cingulate cortex), medial and
anterior nuclei of the thalamus and the mammillary bodies, the basal forebrain, and the
ventral striatum. The Papez circuit, which plays a critical role in the processing and transfer
of information for long storage, comprises the hippocampal formation, fornix, mammillary
bodies, mammillothalamic tract, anterior thalamic nucleus, cingulum, and entorhinal cortex.
B, Schematic of the medial temporal lobe memory system.
Panel B modified with permission from Squire LR, Wixted JT, Annu Rev Neurosci.2 © 2011 Annual Reviews.
1564 DECEMBER 2021

the initial processing of the sensory information. FIGURE 3-1B shows a schematic KEY POINTS
of anatomic structures and connections involved in these processes.
● Encoding and
Retrieval of long-term memory is initially dependent on the hippocampal consolidation is the set of
formation but becomes gradually independent of the hippocampus over time. processes that leads to the
Thus, in addition to anterograde amnesia, injury to the hippocampus will result establishment of long-term
in temporally graded retrograde amnesia, where information acquired recently memory. Consolidation
requires the reprocessing of
before the lesion will be lost, but more remote memories will remain intact.
acquired information over
Bilateral lesions to any of the components of the Papez circuit can cause time and is transiently
significant episodic memory deficits and predominantly anterograde amnesia, susceptible to amnestic
most notably due to injury to the hippocampal formation and the anterior and agents, such as interfering
stimuli or distractors.
medial nuclei of the thalamus.5 The basolateral limbic system is primarily
involved with the processing of emotions, but it also plays a role in the ● Consolidation over hours
assignment of emotional value to experiences, which can modulate their and days is thought to
consolidation.6 Because encoding of memory can be modulated by the emotional involve sleep. A period of
content associated with those memories, bilateral injury to the basolateral limbic sleep in the hours after the
encoding of new information
structures can also result in varying degrees of memory dysfunction, often has been shown to prevent
associated with other behavioral symptoms such as hypersexuality, hyperorality, rapid forgetting of the newly
and hyperphagia that may be present as part of the Kluver-Bucy syndrome. acquired material.
Injury to medial diencephalic structures, including mammillary bodies, the Slow-wave sleep, in
particular, may play a critical
medial dorsal nucleus of the thalamus, and the medial pulvinar can lead to role in supporting systems
significant anterograde memory deficits (Wernicke-Korsakoff Syndrome).7 This consolidation.
can be caused by thiamine deficiency, such as can be seen in people with alcohol
use disorder or individuals who are otherwise malnourished (eg, after gastric ● Lesions in the prefrontal
cortex may affect free recall
bypass surgery).8 Other injuries to these structures may result from stroke or
with preservation of cued or
space-occupying lesions.9 recognition memory.
Retrograde amnesia that
Working Memory equally affects recent and
Working memory is primarily an attention-mediated process. Lesion studies in remote events is most
commonly seen in functional
animal models and functional studies in humans have demonstrated that amnesias. The more
dorsolateral and ventrolateral prefrontal cortex, as well as parietal cortices, are all common form, wherein the
implicated in working memory.10 most recent events are also
the hardest to recall, is seen
in patients with pathology
Semantic Memory affecting medial temporal
Semantic memory retrieval is thought to depend on triggering mechanisms that lobes such as Alzheimer
originate in prefrontal and anterior-temporal regions. For more recent memories, disease and medial
retrieval appears to also depend on limbic structures.11 diencephalic lesions.
● Memory cannot be fully

Procedural Memory evaluated in isolation from
Memory for complex motor skills that are enacted automatically is dependent on other cognitive domains.
a network of cortical areas that include the supplementary motor cortex, parietal The type of memory deficits
reported in the clinical
lobes, basal ganglia, and cerebellum.12
history and observed during
evaluation and testing
MEMORY PROCESSES should be interpreted in the
The processing of information that ranges from working memory to the context of other deficits.
encoding, consolidation, and long-term storage of memories for future retrieval
● One should focus on the
involves multiple anatomic and physiologic substrates that are clinically relevant. first memory symptom
experienced by the patient
Encoding, Consolidation, and Storage or observed by family and
Encoding and consolidation is the set of processes that leads to the establishment determine how it has
progressed over time.
of long-term memory. Many anatomic and biological substrates for these

MEMORY DYSFUNCTION
complex processes have been identified, but mechanisms remain an active area
of research. Consolidation requires the reprocessing of acquired information over
periods of time ranging from seconds, minutes, and days to months and even
years. It is also transiently susceptible to amnestic agents, such as interfering
stimuli or distractors.13
At the molecular level, consolidation relies on activation of signaling cascades
that lead to posttranslational modifications and modulation of gene expression,
ultimately resulting in synaptic changes.14 Synaptic consolidation is thought to
occur at the beginning of the consolidation process and last for a few hours. At
the end of this process, the newly formed memory is relatively resistant to
distracting stimuli. Systems consolidation is the time-dependent reorganization
of long-term memory over distributed brain systems, in a process that may last
days, months, and years.
Anatomically, the first seconds of systems consolidation rely on the activity of
the hippocampus, striatum, and cerebellum. Over time, the role of the hippocampus
appears to wane but may still play a role in binding separate episodic elements into a
cohesive memory.13 As time progresses over minutes to hours, other neocortical
regions become engaged in a process of hippocampal-neocortical crosstalk. Cortical
areas involved in this process include the ventral-medial prefrontal cortex and the
lateral occipital cortex. Further consolidation over hours and days is thought to
involve sleep. A period of sleep in the hours after the encoding of new information
has been shown to prevent rapid forgetting of the newly acquired material. Slow-
wave sleep, in particular, may play a critical role in supporting systems
consolidation. The role of rapid eye movement (REM) sleep is still unclear.15
Storage of Information
Evidence suggests that storage of memory takes place across the association cortices.
The limbic system plays an important role in binding information during the process
of storage and is again engaged during retrieval in a time-dependent manner.16
Retrieval
Lesions in the prefrontal cortex may affect free recall with preservation of cued
or recognition memory. As an example, in brief standardized screening tests,
TABLE 3-1 Memory Processes and Their Anatomic Correlates
Memory process Definition Anatomic correlates
Registration Initial input of sensory information (visual, Sensory organs, primary sensory cortex,
auditory) association cortex
Working memory Information that is maintained for seconds Parietal and dorsal prefrontal cortex
to a few minutes
Encoding and consolidation Process of incorporating information into Association cortex and limbic system
longer-term storage
Long-term storage Information that is retained for minutes to years Association cortex and prefrontal cortex
Retrieval Recollection and recognition of previously Prefrontal and anterior temporal cortex,
acquired information limbic system
1566 DECEMBER 2021

patients are asked to repeat a list of words until they are able to do so without KEY POINTS
errors. When asked about those words later, they may not readily recall (free
● If information is readily
recall), but this may improve when given categories (cued) or shown a list that recalled with cuing, it may
includes the word (recognition). This memory pattern of improving with cueing be indicative of problems
or recognition suggests a retrieval deficit. Retrograde amnesia that equally affects with retrieval, with possibly
recent and remote events is most commonly seen in functional amnesias preserved encoding and
consolidation, and may
(discussed further in this article). The more common form of retrieval problems
indicate relative sparing of
is seen in patients with pathology affecting medial temporal lobes such as the limbic system.
Alzheimer disease and medial diencephalic lesions (bithalamic infarctions or
Korsakoff syndrome) in which the most recent events are the hardest to recall. ● Because memory
Although most often retrograde amnesia is accompanied by anterograde problems rarely occur in
isolation, establishing a
amnesia, the two can be dissociated both clinically and anatomically. Injury to timeline of both progression
prefrontal and anterior temporal regions, as well as the underlying uncinate and development of other
fasciculus, can lead to retrograde amnesia, with bilateral lesions causing a more cognitive and neurologic
severe syndrome.3 symptoms can greatly aid in
establishing a diagnosis. As
TABLE 3-1 shows a list of memory processes, their definition, and anatomic
diseases progress, different
structures known to play a role in each particular process. conditions begin to overlap
from a clinical perspective,
APPROACH TO THE PATIENT WITH MEMORY DISORDERS but those same conditions
may greatly differ in both
Memory cannot be fully evaluated in isolation from other cognitive domains. The onset and progression.
type of memory deficits reported in the clinical history and observed during
evaluation and testing should be interpreted in the context of other deficits.17 For ● Working memory can be
example, memory deficits that present along with visuospatial and language assessed by having the
patient perform mental
impairments may be indicative of Alzheimer disease, whereas similar amnestic
arithmetic or digit span.
deficits, along with executive dysfunction and a history of vascular risk factors, Frontal lobes, parietal
may suggest vascular dementia. lobes, and subcortical
It is also important to obtain cues during the history of deficits at different structures are involved in
stages of memory processing (ie, registration, working memory, encoding. and working memory.
retrieval) as previously described. Like any other neurologic assessment, ● Episodic memory can be
anatomic localization plays a critical role in the diagnostic process. evaluated by asking the
patient about recent
Clinical History autobiographic events or
recent news. Visual memory
History is one of the most crucial parts of the evaluation of a patient with can be evaluated by hiding
memory symptoms. One should focus on the first change from baseline (ie, first objects in the room while
symptom) experienced by the patient or observed by family and determine how the patient is observing and
it has progressed over time. Patients with memory disorders are often poor later asking the patient to
recall where the items are.
historians; thus, having other sources of history is critical.
Copying a complex figure
When focusing on memory symptoms, it is important to establish what the and redrawing or
patient and family mean by “memory,” what kinds of information is the patient recognizing after a latency
forgetting, and over what period of time. Common concerns are the patient’s period is another way to test
visual memory. Conditions
inability to recall recent conversations and events or repeating themselves within
affecting structures in
a short period of time, all typically indicative of deficits in episodic memory. If medial temporal lobes and
information is readily recalled with cuing, it may be indicative of problems with the Papez circuit can show
retrieval, with possibly preserved encoding and consolidation, and may indicate deficits in these tests.
relative sparing of the limbic system.
● Semantic memory is
Because memory problems rarely occur in isolation, establishing a timeline of evaluated by assessing the
both progression and development of other cognitive and neurologic symptoms patient’s fund of knowledge
can greatly aid in establishing a diagnosis. As diseases progress, different and should be tailored to the
conditions begin to overlap from a clinical perspective, but those same conditions patient’s cultural and
educational background.
may greatly differ in both onset and progression. As an example, a patient who

MEMORY DYSFUNCTION
has dementia with Lewy bodies (DLB) may initially present with difficulties with
working memory and REM behavior disorder, followed by the onset of visual
hallucinations and parkinsonism. By comparison, a patient with Alzheimer
disease may begin with deficits in episodic memory and visuospatial function,
followed over time by word-finding difficulty and eventually hallucinations in
more advanced stages of disease. Although current symptoms and even cognitive
test scores may overlap in both of these cases during initial clinical evaluation, the
onset and course of symptoms clearly differentiate the two. Likewise, the
timeline of symptom onset and progression will need to be established. Sudden
onset may suggest a vascular etiology or even an infectious process versus the
more typical insidious and gradually progressive nature of
neurodegenerative disorders.
Beyond purely cognitive symptoms, it is also important to inquire about
neuropsychiatric symptoms including apathy, disinhibition, depression,
hallucinations, and delusions. Behavioral symptoms can accompany affective
disorders, behavioral variant frontotemporal dementia (FTD), or DLB, among
others.18 Motor symptoms and signs such as tremor, gait abnormalities, ataxia, or
weakness, as well as sensory deficits such as loss of taste, vision, or hearing, or
somatosensory disturbances, should also be documented and carefully
considered in the context of the neurologic examination.
Establishing the current functional status is also important. Asking a caregiver
to complete a review questionnaire of activities of daily living can aid in that
determination. Functionality with daily activities can differentiate between mild
cognitive impairment and dementia, and an assessment of the time course over
which the patient lost independence with activities of daily living provides
insights about progression. This information can help in staging and also guide
management, prognosis, and support.
Other important aspects to consider are the presence of comorbid conditions,
history of head trauma, exposure to toxins, current and past recreational drug
use, and current medications that may affect cognition (eg, benzodiazepines,
opioids, and anticholinergics). A significant history of one or more vascular risk
factors that may include diabetes, hypertension, and hyperlipidemia almost
invariably accompanies vascular dementia. History of traumatic brain injury or
repeated concussion is associated with chronic traumatic encephalopathy19 and
may increase the risk of Alzheimer disease.20
Knowing the level of education can help contextualize the deficits. Patients
with higher levels of education or high premorbid intelligence may have
significant cognitive reserve and may perform better on screens, despite having
underlying pathology.21 A positive family history of neurodegenerative disorders
such as Alzheimer disease or FTD should also be considered a risk factor.22
Neurologic Examination
Patients with memory impairments often have normal neurologic examinations
(besides their findings on cognitive testing), but focal findings can be very
informative. For neurogenerative conditions, focal findings may be absent at first
but develop later as disease progresses. Ocular motor abnormalities may
accompany multiple neurodegenerative disorders such as corticobasal syndrome
(CBS) and posterior cortical atrophy (oculomotor apraxia), progressive
supranuclear palsy (vertical gaze deficits), and Wernicke-Korsakoff syndrome
(ophthalmoplegia or nystagmus). Asymmetric upper motor neuron findings can
1568 DECEMBER 2021

be present in vascular disease but also in focal variants of Alzheimer disease and KEY POINTS
CBS. Weakness, muscle wasting, and fasciculations in a patient with suspected
● The Montreal Cognitive
FTD should raise concern for motor neuron disease (FTD-amyotrophic lateral Assessment (MoCA) allows
sclerosis). Parkinsonism is common in DLB, CBS, FTD, and vascular dementia discrimination of encoding,
and invariably present with Parkinson disease dementia. Patients with storage, and retrieval
visuospatial variants of Alzheimer disease, DLB, and CBS may show asymmetric deficits through its use of
repeated presentation of
apraxia. Gait should also be evaluated for evidence of apraxia, ataxia, or
memory targets and
parkinsonism. Proprioceptive sensory loss should raise concern for nutritional cued-recall conditions.
deficiencies. Frontal release signs are also common in neurodegenerative Intact cued recall or
dementias. Palmomental and snout reflexes can be present in more advanced recognition in the context of
poor free recall points to
cases of most dementias but may also be present with aging. By contrast, grasp
retrieval deficits.
reflex is invariably pathologic and indicative of frontal lobe disfunction. It is
usually present in FTD and can also be seen in advanced Alzheimer disease and ● Standardized cognitive
vascular dementia. screens provide a rapid
assessment of the patient’s
cognitive function but may
BEDSIDE EVALUATION OF MEMORY not be sufficient to support
Assessment of cognitive function encompasses several domains and should start a diagnosis. Because of their
with an evaluation of the level of consciousness and observation of the patient’s relative brevity, cognitive
behavior. Details about the patient’s cognitive status can be obtained during screens are of important
practical use in clinical
casual conversation (ie, level of alertness and awareness, insight, thought process, settings and, if repeated at
language fluency), and further assessment can be accomplished by means of follow-up visits, may
qualitative evaluations and standardized screening tests. This section focuses on provide some measure of
bedside strategies for assessing memory and further discusses a selection of brief cognitive decline. Although
the total score is informative
cognitive screens and more comprehensive neuropsychological testing.
regarding normative data, it
is the pattern of deficits that
Working Memory is often most useful when
Working memory can be assessed by having the patient perform mental considering a differential
diagnosis.
arithmetic or digit span. Frontal lobes, parietal lobes, and subcortical structures
are involved in working memory. Consequently, patients with conditions such as ● The initial diagnostic
vascular dementia, Parkinson disease dementia, DLB,23 and FTD may have workup for memory
prominent deficits in these tests. dysfunction includes
laboratory tests, imaging
studies, and more
Episodic Memory comprehensive
Episodic memory can be evaluated by asking the patient about recent neuropsychological testing
autobiographic events (what they had for dinner, where they spent vacation to further assess the pattern
last summer) or recent news events and is based on the assumption that the and extent of cognitive
deficits and possibly
patient has previously acquired the information that is being asked. Verbal establish a baseline for
memory can be further tested by giving a list of words or a story to recall that tracking disease
the patient is later asked about. Cues can be provided (eg, categories or lists to progression.
choose from) to help differentiate encoding from retrieval deficits. Asking if the
● In cases in which the
patient recalls the examiner’s name is another simple way to assess verbal
cause of a memory disorder
memory. Visual memory can be evaluated by hiding objects in the room while remains uncertain, more
the patient is observing and later asking the patient to recall where the items are. specialized diagnostic
Copying a complex figure and redrawing or recognizing after a latency period is studies can be obtained.
another way to test visual memory. Conditions affecting structures in medial These may include
fludeoxyglucose positron
temporal lobes and the Papez circuit can show deficits in these tests. The emission tomography
amnestic presentation of Alzheimer disease, limbic-predominant age-related (FDG-PET), amyloid PET, and
transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) CSF studies.
(CASE 3-1), posterior circulation stroke (CASE 3-2), and Korsakoff syndrome
are prime examples of conditions that affect episodic memory. Visuospatial

MEMORY DYSFUNCTION
memory can be affected by involvement of occipitoparietal networks; the focal,

posterior-predominant variant of Alzheimer disease, known as posterior cortical
atrophy, and DLB are examples.
Semantic Memory
Semantic memory is evaluated by assessing the patient’s fund of knowledge and
should be tailored to the patient’s cultural and educational background. One can
present a series of pictures of famous personalities (eg, former presidents) and
ask the names, similarities, and differences among them. Testing category
CASE 3-1 An 85-year-old woman presented with a 5-year history of difficulties

with recollection of recent events and rapid forgetting of
conversations. She was a retired nurse. At the time of her first
evaluation, the patient was fully independent with all activities of daily
living, was able to manage the household finances, and was driving
without difficulty. During that initial examination, the patient was
alert, fully oriented, and socially appropriate. Her speech was fluent
with no word-finding difficulty on casual conversation or
confrontation naming. General neurologic examination was
unremarkable. Brief standardized cognitive testing showed deficits in
delayed recall of verbal information that partially improved with
cueing (Montreal Cognitive Assessment [MoCA]24 total score 25/30;
the patient recalled 2/5 with category cuing and an additional item
with multiple-choice cuing). MRI was notable only for mild
hippocampal atrophy (FIGURES 3-2A and 3-2B). A diagnosis of amnestic
mild cognitive impairment was made.
The patient was subsequently lost to follow-up but returned 4 years
later with a concern of further decline in episodic memory. She was
still independent with all activities of daily living but had given up
management of finances because she was forgetting to make
payments. She retained her ability to navigate in familiar environments
and reported no deficits in language or changes in behavior. On casual
conversation during the examination, the patient was fluent and
cogent but often repeated herself. She was oriented to self, place,
situation, and year but not to date, day, or month. She was not able to
provide details about recent news events. General neurologic
examination remained normal. MoCA showed deficits of delayed
recall, this time without cued improvement and now accompanied by
deficits in orientation (MoCA score of 22/30). Comprehensive
neuropsychological evaluation showed severe and selective deficits in
episodic memory for both visual and verbal material (Dementia Rating
Scale, Second Edition [DRS-2]25 memory index less than 1%) with
preserved function in all other domains and was still consistent with a
diagnosis of amnestic mild cognitive
1570 DECEMBER 2021

fluency and asking the meaning of words are also used in the context of assessing
semantic knowledge. Semantic dementia,18 which causes focal degeneration of
anterior temporal lobes, is the most well-known example of selective impairment
in this domain.
COGNITIVE SCREENING MEASURES

Some of the most routinely used in-office screening measures of cognitive
functioning for patients with memory symptoms are the Mini-Mental State
Examination (MMSE),26 the Saint Louis University Mental Status (SLUMS),27
impairment. Repeat MRI

(FIGURES 3-2C and 3-2D) showed
clear progression of
hippocampal atrophy, with
relatively preserved volumes
elsewhere. CSF analysis of
Alzheimer disease biomarkers
reported levels of amyloid-b
42, total tau, phospho-tau,
and amyloid-to-tau index
that were not consistent
with Alzheimer disease.
Six months after her last
visit, the patient died of
natural causes. Following
her wishes, a brain autopsy
was conducted and showed
FIGURE 3-2
changes in bilateral Imaging of the patient in CASE 3-1. A, Initial coronal
hippocampi and adjacent T1-weighted MRI showing mild hippocampal
limbic structures consistent volume loss. B, Axial fluid-attenuated inversion
with neuropathologic recovery (FLAIR) MRI showing only mild
generalized volume loss with particular
limbic-predominant preservation of parietal lobes. Repeat coronal
age-related transactive T1-weighted (C) and axial FLAIR (D) MRI 5 years
response DNA-binding after symptom onset shows severe atrophy of
protein 43 (TDP-43) bilateral hippocampi (C, arrow), with no
significant change in other cortical areas (D).
encephalopathy (LATE).
Alzheimer disease is highly prevalent in older adults with severe episodic COMMENT
memory deficits. However, lack of involvement of other cognitive domains
(eg, visuospatial and language), very gradual progression, and focal atrophy
that does not clearly progress to other brain regions should raise the
possibility of non–Alzheimer disease pathology. Biomarkers can be of
assistance in these cases and may help guide prognosis and management.

MEMORY DYSFUNCTION
and the Montreal Cognitive Assessment (MoCA). Each of these three measures
has a wealth of research to support its use in clinical settings, and each provides at
least some aspect of memory assessment (TABLE 3-2).
In contrast to the other screening measures listed, the MoCA isolates problems
with encoding, retention, and retrieval through use of cued-recall memory trials.
The MoCA memory procedure asks the patient to repeat the target words
immediately after they have been presented (similar to the MMSE procedure),
allowing the examiner to perceive on a qualitative level whether the patient is
able to register and encode the material. After a 5-minute delay, the patient is first
asked to recall the items freely and then is provided guided cues for missed items,
first categoric (eg, “it’s a type of flower”) and then multiple choice. If memory
storage proves to be the most affected, mesial temporal (or other Papez circuit
CASE 3-2 A 60-year-old right-handed woman presented with persistent but stable
memory difficulties that first developed 4 years earlier after a posterior
circulation stroke. At presentation, she described difficulties recalling
recent conversations and events, remembering when and how to take
medications, and recalling names of familiar people. She also was
concerned about mild word-finding difficulty and described having
trouble with organization, decision-making, and taking care of finances
and other personal affairs. She did not endorse visuospatial symptoms.
Per the patient and her
brother, cognitive symptoms
had a rather abrupt onset but
remained relatively stable
with only mild declines in
attention span and executive
function. She also reported a
history of residual right-sided
weakness from the stroke
that resolved over time. She
had 14 years of education and
had a history of multiple
cardiovascular risk factors.
She worked in retail but
resigned because of her
cognitive difficulties. Review
of past records confirmed a
FIGURE 3-3
history of sudden-onset right Imaging of the patient in CASE 3-2. Acute ischemic
hemiparesis and trouble with left hippocampal lesion (arrows) is evidenced by
memory at the time of her restricted diffusion on axial diffusion-weighted
stroke 4 years ago. Imaging MRI (A) and signal change on axial fluid-attenuated
inversion recovery (FLAIR) MRI (B). Coronal
studies at that time had
postcontrast T1-weighted MRI of the original scan
confirmed the presence of a shows normal hippocampal volume (C). Coronal
left posterior cerebral artery T1-weighted MRI 4 years after stroke shows left
territory stroke (FIGURE 3-3). hippocampal atrophy (D) (arrow).
1572 DECEMBER 2021

structures) pathology is suspected, as seen in Alzheimer dementia. The pathology
may be in widespread, distributed networks if the difficulties are found in initial
encoding or subsequent retrieval. For example, memory that improves with
cueing, combined with signs of impaired working memory and slow processing
speed (and other cardinal clinical features on presentation), would raise suspicion
of an α-synucleinopathy (eg, Parkinson disease dementia or DLB).
As with any other cognitive screen, the intent of these tests is to provide rapid
assessment of the patient’s cognitive function, but on its own may not be sufficient
to support a diagnosis unless the entirety of the clinical picture and diagnostic
evaluation is deemed by the clinician to be sufficiently supportive of a specific
diagnosis. Because of the relative brevity of screens, they are of important practical
use in busy clinical settings and, if repeated at follow-up visits, may provide some
At the time of her memory evaluation, the patient was alert, fully
oriented, and able to answer questions appropriately and follow all
commands. Her speech had normal pace, prosody, articulation, and
content and no word-finding difficulty or paraphasic errors during casual
conversation or anomia on a 30-item confrontation naming test. When
shown pictures of three famous presidents, she was able to name all of
them and identified similarities and differences, including historical facts.
Her responses were vague when she was recalling recent news events.
General neurologic examination was remarkable only for right-sided
hyperreflexia with a right Babinski sign. Montreal Cognitive Assessment
(MoCA) showed deficits in trail-making, attention, abstraction, and
delayed recall that did not improve with cuing (total score, 17/30).
Neuropsychological evaluation revealed weaknesses in processing
speed, verbal memory, new learning, and visual analysis, with relative
strengths in semantic fluency and confrontation naming. Her Dementia
Rating Scale, Second Edition (DRS-2) score of 118/144 ranked in the mild
dementia range. Repeat MRI showed white matter changes suggestive of
moderate macroangiopathic changes, as well as areas of gliosis in the left
posterior cerebral artery territory, including atrophy of the left mesial
temporal lobe and hippocampus. A diagnosis of vascular dementia was
made based on history, examination findings, pattern of cognitive test
results, and supporting imaging.
This case highlights the onset and course of vascular lesions involving COMMENT
mesial temporal lobes. In this case, the patient had a sudden onset of
deficits in anterograde memory that persisted over time without clear
progression. Because it was unilateral, her deficits were not as profound.
The presence of extensive small vessel disease likely contributed to
deficits in other domains (eg, processing speed), and occipital involvement
may have affected her performance in visual analysis.

MEMORY DYSFUNCTION
measure of cognitive decline. It is also important to remember that, although the

total score is informative regarding normative data, it is the pattern of deficits that
is often most useful when considering a differential diagnosis. TABLE 3-3 shows a
list of common memory symptoms with possible associated anatomic and
pathologic correlates, as well as relevant findings on cognitive screens.
DIAGNOSTIC WORKUP
The initial diagnostic workup includes laboratory tests, imaging studies, and
more comprehensive neuropsychological testing to further assess the pattern and
extent of cognitive deficits and possibly establish a baseline for tracking disease
progression (see the following section). Basic bloodwork may include complete
blood cell count; renal, liver, and thyroid function tests; and vitamin B12 and
folate levels. Depending on the level of suspicion, inflammatory (eg,
sedimentation rate) or infection (eg, syphilis serology) markers can be obtained.
Basic structural brain imaging (preferably MRI, although CT can suffice) should
be part of the initial workup and are intended to assess for patterns of focal
atrophy (eg, medial temporal lobe structures in Alzheimer disease, hippocampal
sclerosis, or LATE), evidence of cerebrovascular pathology (eg,
microangiopathic changes, lacunar infarcts, or susceptibility artifacts suggestive
TABLE 3-2 Examples of Cognitive Screening Measures
Measure Functions assessed Memory assessment features
Mini-Mental State Episodic memory, Registration: repetition of 3 words immediately after presented
Examination (MMSE) working memory,
Semantic memory: confrontation naming of a wristwatch and
confrontation naming,
pencil
orientation, verbal
comprehension, Working memory: serial 7 subtraction; follow 3-step command
visuoconstruction,
Episodic memory: recall of 3 words after a brief delay
verbal repetition,
linguistic expression Cued retrieval: none
Saint Louis University Episodic memory, Registration: none

Mental Status (SLUMS) working memory,
Semantic memory: identification of a triangle among 3 geometric
orientation, mental
shapes; name animals in 60 seconds
computation, semantic
fluency, semantic Working memory: digit span task; arithmetic task
memory
Episodic memory: recall of 5 words after a 2-minute delay; four
questions requiring recall of content from a 64-word paragraph
Cued retrieval: none
Montreal Cognitive Episodic memory, Registration: repetition of 5 words immediately after presented
Assessment (MoCA) working memory,
Semantic memory: identification of 3 animals in visual stimuli;
visuoconstruction,
name words beginning with a specified letter in 60 seconds
orientation,
confrontation naming, Working memory: digit span task; serial 7 subtraction
verbal repetition,
Episodic memory: recall of 5 words after a 5-minute delay
phonemic fluency,
executive functioning, Cued retrieval: category clues for 5 words; multiple-choice cues
cued retrieval, abstract for 5 words
reasoning, attention
1574 DECEMBER 2021

of microhemorrhages in cerebral amyloid angiopathy), abnormal ventricular
enlargement as seen in normal pressure hydrocephalus, or space-occupying
lesions, among other entities. In cases in which the diagnosis remains uncertain,
more specialized diagnostic studies can be obtained. These may include
fludeoxyglucose positron emission tomography (FDG-PET), amyloid PET, and
CSF studies, the last of which can be obtained to assess for markers of infection,
inflammation, paraneoplastic antibodies, or biomarkers of Alzheimer disease as
the case may indicate. FDG-PET can be used to assess for patterns of
hypometabolism (decreased FDG uptake) that may provide supporting evidence
for focal neurodegeneration, such as parietotemporal hypometabolism in
Alzheimer disease, asymmetric frontotemporal hypometabolism in FTD, or
occipitoparietal hypometabolism with preservation of the posterior cingulum in
DLB. Amyloid PET28 has been approved for determination of amyloid burden in
Common Memory Symptoms TABLE 3-3
Memory
Patient report Neuroanatomy Example conditions type Screening results
Misplaces objects, Medial temporal Alzheimer disease, Episodic Mini-Mental State Examination
cannot recall having (more left if verbal, dementia with Lewy memory (MMSE): intact registration with
conversation, cannot more right if visual), bodies (DLB), hypoxic poor recall of 3 words
recall details of Papez circuit brain injury,
Montreal Cognitive Assessment
recent meaningful encephalitis,
(MoCA): poor delayed recall
events hippocampal sclerosis,
of 5 words
limbic-predominant
age-related transactive Saint Louis University Mental Status
response DNA-binding (SLUMS): poor recall of 5 words,
protein 43 (TDP-43) poor recognition of narrative stimuli
encephalopathy (LATE)
Can no longer Supplementary Parkinson disease, Procedural MMSE: mis-sequence 3-step

operate television motor region, basal Huntington disease, memory command
remote, cannot ganglia, cerebellum cerebellar injury or
MoCA: not assessed
recall sequenced degeneration
steps for household SLUMS: not assessed
appliances
Can no longer Bilateral prefrontal Traumatic brain injury, Working MMSE: recall of 3-step command,
complete simple cortices, neurotoxin exposure, memory/ registration of 3 words, serial
calculations for subcortical regions, cerebrovascular insults, attentional subtraction by 7s
purchases, cannot association cortex frontotemporal lobar control
MoCA: repetition of 5 words, Trail
retain phone number degeneration, DLB
Making Test, digit repetition, serial
long enough to dial
subtraction by 7s, letter vigilance
SLUMS: mental calculation
problems; digit repetition
Difficulty recalling Anterior temporal Semantic dementia, Semantic MMSE: object naming, sentence
the meaning of lobes, inferior Alzheimer disease memory reading
words, difficulty temporal lobes
MoCA: animal naming, letter
naming objects, not
fluency
recalling what
objects are used for SLUMS: animal naming, identify
triangle

MEMORY DYSFUNCTION
patients with suspected Alzheimer disease and has high sensitivity and
specificity.29 Likewise, CSF levels of amyloid-b 42, total tau, and phospho-tau
can be used to determine the probability of Alzheimer disease pathology.30
However, these tests are still costly and may not be covered by insurance.
A Tau-PET agent has been recently approved for use in Alzheimer disease while
research in other conditions is ongoing.31 Likewise, blood biomarkers of
Alzheimer disease are in advanced stages of development.32
EEG can be helpful when epilepsy is suspected, and recent evidence has
supported its diagnostic utility in DLB.33 Given the role of sleep in memory
consolidation, a formal evaluation with polysomnography is recommended if
sleep disorders are suspected. If genetic predisposition is a concern (eg, familial
Alzheimer disease, FTD-amyotrophic lateral sclerosis) genetic counseling and
testing can be considered. As with any other neurologic disorder, diagnostic tests
performed in patients with memory dysfunction should always be interpreted in
the context of history, examination findings, and cognitive test results.
FORMAL NEUROPSYCHOLOGICAL EXAMINATIONS

Neuropsychologists administer batteries of well-validated tests assessing
multiple neurocognitive domains (TABLE 3-4) via standardized procedures under
controlled conditions to ensure the resultant data are valid and interpretively
useful (TABLE 3-534-38). By conducting precise measurements of the patient’s
functioning in each domain, the results reveal configurations of strengths and
weaknesses, forming a neuropsychological “fingerprint” (FIGURE 3-4). In
addition to testing the cognitive domains of interest, formal assessment of the
patient’s psychological status during the testing session is necessary to provide
context in which the resultant examination data may be interpreted, as some
behavioral health conditions have the ability to mimic the cognitive profiles of
neurologic conditions, such as in pseudodementia.
The results from neuropsychological examinations can aid in diagnosis, help
establish baseline status as well as longitudinal rate of change, assess treatment
response, and inform clinical decisions regarding mental capacities, fitness for
work, etc. Patients with more advanced illness may not be candidates for
TABLE 3-4 Neurocognitive Domains
◆ Intelligence
◆ Executive control
◆ Somatosensory functioning
◆ Visuospatial analysis
◆ Learning
◆ Attention/concentration
◆ Language (expressive and receptive)
◆ Motor speed
◆ Memory (linguistic and nonlinguistic)
◆ Psychological/mood status
1576 DECEMBER 2021

neuropsychological testing, as minimal levels of attention, receptive language,
and task persistence are required.
Serial Neurocognitive Testing

The study of human memory functioning over time, and cognition in general, is a
study of curves. Just as memory abilities in neurodegenerative conditions decline
over time, so follows the memory abilities of the healthy normal older patient.
However, the decline noted in any condition tends not to be unitary in character,
as disease processes exhibit differential degradation of functions across
neuropsychological domains. This adds dimensionality to envisioning functional
decline, with multidimensional shapes of the functional curves accommodating
pertinent domains.
Each examination is a “snapshot” of functioning at a particular point in time;
conducting an examination (taking the snapshot) at a different point along the
disease progression thus alters the resultant neuropsychological profile
(FIGURE 3-5). These patterns can be observed through serial neuropsychological
examinations, serial screenings (such as the MMSE, MoCA, or SLUMS), and
qualitative patient observations over multiple patient contacts.
OVERVIEW OF SELECTIVE DISORDERS AFFECTING MEMORY

Memory dysfunction is never global and is rarely selective for one type of memory
(episodic, semantic, working memory, or procedural) or memory process
(encoding, consolidation, storage, or retrieval) and seldom occurs in isolation from
other cognitive domains. This last section presents brief descriptions of selected
disorders that cause memory dysfunction. It also reviews memory changes that
occur with normal aging and those that are associated with functional neurologic
disorders and affective disorders, as they can often present a diagnostic challenge.
Commonly Used Neuropsychological Measures of Memory TABLE 3-5
Repeated trials Immediate Delayed Recognition

Test name learning recall recall trial
Verbal/linguistic
Hopkins Verbal Learning Test-Revised34 X X X X
California Verbal Learning Test, Third Edition35 X X X X
Wechsler Memory Scale, Fourth Edition (WMS-IV) X X X

Logical Memory Subtest36
Dementia Rating Scale, Second Edition (DRS-2)25 X X
Visual/pictorial
Brief Visuospatial Memory Test-Revised37 X X X X

38
Rey-Osterrieth Complex Figure Test X X X
WMS-IV Visual Reproduction Subtest36 X X X
DRS-225 X

MEMORY DYSFUNCTION
FIGURE 3-4
Example of a domain-specific cognitive profile.
Alzheimer Disease
Alzheimer disease is the most common age-related neurodegenerative dementia.
The amnestic phenotype is the most common presentation and is characterized
by deficits in anterograde episodic memory, with variable impairments in
semantic and working memory. Deficits in other domains may precede memory
impairment in many cases and invariably develop over the course of the disease.
Hallmark pathologic findings are the deposition of extracellular amyloid-β 42
plaques and intracellular hyperphosphorylated tau tangles. Typically, pathologic
changes and neurodegeneration follow a predictable pattern, with changes
FIGURE 3-5
Temporal effects on cognitive profiles in progressive condition. A cognitive evaluation takes
a “snap-shot” of patient abilities in a specific point in time. The pattern of findings may
change significantly as the condition progresses over time.
1578 DECEMBER 2021

developing first in medial temporal lobes (entorhinal cortex) and subsequently KEY POINTS
spreading to other areas within temporal, parietal, and eventually frontal lobes.
● Diagnostic tests
Common imaging findings include progressive generalized atrophy that is more performed in patients with
prominent in the hippocampus, entorhinal cortex, and parietal lobes. FDG-PET memory dysfunction should
may show hypometabolism of medial temporal lobes, parietal lobes, and always be interpreted in the
posterior cingulum, but frontal hypometabolism may be present with disease context of history,
examination findings, and
progression and occipital hypometabolism can be seen in posterior cortical
cognitive test results.
atrophy.29 Amyloid PET shows increased radiotracer uptake, and CSF biomarker
studies show decreased levels of amyloid-b 42, with elevated levels of total tau ● Neuropsychological
and phospho-tau.30 testing consists of batteries
of well-validated tests
assessing multiple
Dementia With Lewy Bodies neurocognitive domains and
DLB is characterized by a combination of several core features that include produces configurations of
fluctuating cognition, with pronounced variations in the level of alertness and strengths and weaknesses
attention, recurrent and well-formed visual hallucinations, REM sleep behavior that form a
neuropsychological
disorder, and parkinsonism. Patients usually have prominent deficits in “fingerprint” for the patient.
attention, executive function, and visuospatial function, with less pronounced
abnormalities in memory retrieval. Consequently, cognitive tests may show ● Neuropsychologists
deficits in working memory, encoding, and retrieval that improve with cuing. consider the patient’s
effort, validity, and
When overlapping with Alzheimer disease, patients may have a more rapid
emotional status when
decline and more pronounced episodic memory deficits. Parkinson disease interpreting examination
dementia may have a similar cognitive profile but with more pronounced data.
parkinsonism that precedes the onset of cognitive symptoms by a year or more.
Pathologically, DLB is characterized by the presence of Lewy bodies, which are ● Each neuropsychological
evaluation is a “snapshot” of
intraneuronal aggregates of α-synuclein. MRI may show loss of posterior cortical functioning at a particular
volume, and FDG-PET can reveal occipitoparietal hypometabolism with point in time; conducting
preserved uptake in the posterior cingulum (cingulate island sign). EEG may an examination at a
show posterior slow-wave activity with periodic fluctuations in the pre-alpha/ different point along the
disease progression alters
theta range.39 the resultant
neuropsychological profile.
Semantic Dementia
Semantic dementia, also known as semantic variant primary progressive aphasia, ● Memory dysfunction is
never global, rarely
is characterized clinically by fluent aphasia that starts with anomia and single-
selective for one type of
word comprehension deficits, later progressing to globally impaired knowledge memory (episodic,
of objects (what they are, what they do, where they are found). Semantic deficits semantic, working memory,
in other modalities beyond language are also present (visual, tactile, and or procedural) or memory
process (encoding,
olfactory). The impairment of semantic knowledge is related to the asymmetric
consolidation, storage, or
but bilateral involvement of anterior temporal lobes (temporal pole), which can retrieval), and seldom
be readily seen in structural imaging. Asymmetric anterior-temporal occurs in isolation from
hypometabolism is observed in FDG-PET. Episodic memory, visuospatial other cognitive domains.
function, and orientation are usually preserved. The right-sided variant may
have more prominent behavioral changes and difficulties with facial
recognition.40
Limbic-Predominant Age-Related Transactive Response DNA-binding

Protein 43 Encephalopathy
Late-onset hippocampal sclerosis has long been recognized as a cause of selective
memory decline in older patients.41 More recently, a proteinopathy characterized
by abnormal deposition of TDP-43 in limbic structures has been described as a
unique clinical and pathologic entity.42 This condition appears to be highly

MEMORY DYSFUNCTION
prevalent in patients older than 80 years of age who develop memory deficits that
mimic the amnestic presentation of Alzheimer disease but often without
significant involvement of other cognitive domains. As disease progresses,
hippocampal sclerosis becomes more pronounced and other cognitive domains
become affected, but the rate of cognitive decline in pure LATE cases may be
slower compared with Alzheimer disease (CASE 3-1). The incidence of this
condition appears to increase with extreme old age, whereas the incidence of
Alzheimer disease tends to decrease in that same age group. Neuropsychological
testing may show major deficits in delayed word list recall, with preserved verbal
fluency. Imaging studies show rather disproportionally atrophic hippocampi. As
the disease progresses, atrophy extends to frontal, anterior temporal, and insular
cortices, in a distribution that follows the TDP-43 pathology. No biomarkers are
currently available for this condition.
Cerebrovascular Syndromes
Strokes in anterior and middle cerebral artery territories can cause diverse
cognitive syndromes but often include deficits in working memory and retrieval.
Posterior cerebral artery occlusions may cause injury to the hippocampus and
other medial temporal lobe structures, leading to anterograde amnesia (CASE 3-2).
Thalamic infarction is associated with diencephalic amnesia,43 which mimics
bilateral medial temporal lobe pathology. Ischemic lesions caused by small vessel
disease can cause lacunar strokes or white matter ischemic changes (Binswanger
disease).44 Cognitive impairments are related to interruption of frontal cortical
circuits and disruption of cholinergic pathways. Consequently, memory deficits
TABLE 3-6 Cognitive Function and Aging
Course with normal aging Cognitive function Behavioral example
Decline Free recall (no-cue) Remembering items on a shopping list
Source of memory Recalling where or in what circumstances a fact was learned
Prospective memory Remembering to take a medication before going to bed
Processing speed Time to complete tasks, reaction times
Attention Divided, selective, and sustained attention
Executive function Abstraction, mental flexibility, and concept formation decline after
age 70; response inhibition
Stable Recognition memory Retrieving memory when given a cue (eg, recalling details of a story
when asked yes/no questions)
Temporal order Recalling the sequence of events
Procedural memory How to tie a shoelace, ride a bike
Language Overall intact with aging; vocabulary may improve; some decline
in confrontational naming and word search; sporadic
word-finding difficulty
Visual analysis Navigation, orientation, and depth perception tend to remain intact
1580 DECEMBER 2021

are related to inattention with retrieval deficits that are worse with free recall but KEY POINTS
improve with cuing and recognition.
● Alzheimer disease is the
most common age-related
Transient Global Amnesia neurodegenerative
Transient global amnesia (TGA) is commonly seen in patients 50 to 70 years old and dementia. The amnestic
is characterized by the sudden onset of anterograde amnesia, often with a limited phenotype is the most
common presentation and is
retrograde component, lasting for up to 24 hours and in the absence of other
characterized by deficits in
neurologic signs or symptoms. Patients present with acute inability to incorporate anterograde episodic
new memory, repeatedly asking the same questions within minutes, and are unable memory, with variable
to recall what they are told. They may also look anxious and confused, but cognitive impairments in semantic and
working memory. Deficits in
processes other than acquisition of new memory are preserved. Eventually, the
other domains may precede
patient experiences complete resolution with full recovery of their ability to memory impairment and
incorporate new memory, but amnesia for a period of time preceding the onset of invariably develop over the
symptoms through the duration of the episode will invariably persist.5 Clinical course of the disease.
investigations are usually unrevealing. In some cases, MRI may show hippocampal
● Dementia with Lewy
signal changes in diffusion-weighted imaging and fluid-attenuated inversion bodies is characterized by a
recovery (FLAIR) sequences that tend to be most apparent in the first 48 hours.45 combination of several core
The differential diagnosis includes posterior circulation stroke, focal seizures or features that include
postictal state, posttraumatic amnesia, hypoglycemia, and psychogenic amnesia. If fluctuating cognition,
recurrent and well-formed
the patient has a history of seizures or recent head trauma, presents with visual hallucinations, rapid
concomitant neurologic or systemic symptoms, or has focal findings on neurologic eye movement (REM) sleep
examination, conditions other than TGA should be considered and additional behavior disorder, and
tests pursued accordingly. The pathophysiology of TGA has not been established, parkinsonism. Cognitive
tests may show deficits in
but proposed mechanisms include venous congestion, arterial ischemia,
working memory, encoding,
and migraine. and retrieval that improve
with cuing.
Forgetfulness in Normal Aging
Cognitive aging is a well-known phenomenon and a common source of concern ● Limbic-predominant
age-related transactive
leading to referrals. Aging is associated with anatomic changes that include loss response DNA-binding
of volume31,46 that may be more prominent in specific cortical and subcortical protein 43 (TDP-43)
regions.47 Changes in the corpus callosum have also been found in normal aging and encephalopathy (LATE) is
associated with decreases in memory retrieval, efficiency, and processing speed.48 characterized by the
deposition of abnormal
These structural and molecular changes in the aging brain functionally TDP-43 protein in limbic
manifest across multiple cognitive processes. Older individuals are found to structures. It is highly
have diminished ability to lay down new memory traces, retrieve learned prevalent in patients older
material, access semantic information, and use prospective memory.49 than 80 years of age who
develop memory deficits
Salthouse50 reported that normal cognitive aging demonstrates near-linear that mimic the amnestic
declines in memory and reasoning, whereas vocabulary knowledge increases presentation of Alzheimer
until the sixth decade. Typically, memory concerns associated with normal disease but often without
aging will be reported by the patient and not the family, are not associated significant involvement of
other cognitive domains.
with loss of functional capacity, and tend to involve prospective memory.
Neuropsychological testing
In general, cognitive screen test scores that are normal and stable over time may show major deficits in
should be reassuring. Normal brain imaging, showing only age-appropriate delayed word list recall,
changes in volume, will not rule out underlying neurodegenerative pathology with preserved verbal
fluency.
but can provide further reassurances in the context of normal cognitive tests.
If cognitive screen results are abnormal, trending down over time, or
associated with functional decline in activities of daily living, further
evaluation with comprehensive neuropsychological testing and brain imaging
is recommended. TABLE 3-6 shows examples of cognitive functions in the
context of normal aging.

MEMORY DYSFUNCTION
Functional and Psychogenic Memory Impairment

Large numbers of patients who present with cognitive problems are ultimately
determined to be free of any underlying neurologic disorder that could reasonably
explain their self-perceived symptoms, as determined by neurologic examination,
cognitive testing, neuroimaging, and neurocognitive assessment. For instance, a
study from 30 Alzheimer disease centers in the United States indicated that 50% of
assessed patients were determined to have normal cognition.51
When poor memory performance is found on examination, confounds such as
medication side effects, sleep deprivation, low effort, and functional causes should
be considered. The clinician should be mindful of false-positive patterns, as causes
of low performance on memory testing may be either pathologic or nonpathologic.
Psychogenic memory dysfunction, caused by emotional rather than
physiologic factors, is described as “functional amnesia.” Such conditions are
often induced by extreme stress, interpersonal conflict, or other nonphysical
factors. For example, somatic symptom disorder involves multiple, current
symptoms that cause distress or interfere in daily life. The symptoms can be
specific (eg, focal pain) or nonspecific (eg, generalized fatigue), but the patient’s
distress is authentic whether or not a medical explanation is evident. It is
important to note that a somatic symptom disorder diagnosis can coexist with
other medical conditions. In the less common dissociative amnesia, patients
demonstrate an inability to recall autobiographic information, commonly of a
traumatic nature. This memory loss is viewed as a psychological defense
mechanism to protect the individual from upsetting memory content.
The distracted patient will also produce poor memory scores. Preoccupation
with pain, agitation, and noncompliance can all interfere with an individual’s
opportunities to submit information into the sensory register for subsequent
memory processing. The effect on standardized testing is similar to general
sedation (ie, low attention and working memory scores). Finally, although
relatively rare, patients who are malingering may attempt to feign memory
impairment for personal gain or avoid responsibility for their actions.
Mood disruption from anxiety and depression interferes with memory
encoding and retrieval. In such cases, patients tend to perform below premorbid
levels for initial recall of target information but then exhibit minimal decay of the
information that was encoded on delayed cued-recognition trials. That is,
whatever they learn, they keep.
Recently, efforts have been made to clarify and operationalize nonpathologic
memory dysfunction,52 including the proposed classifications of cogniform
disorder53 and functional cognitive disorder.54 The diagnostic criteria for
functional cognitive disorder proposed by Ball and colleagues appear particularly
promising, as they include positive signs (such as inconsistency of performance
within a cognitive domain on neuropsychological testing), rather than the
condition being a diagnosis purely of exclusion.
CONCLUSION
The evaluation and diagnosis of patients with memory symptoms require a
well-organized and systematic assessment that is supported by the
understanding of the complex interactions between brain structure, function,
and behavior. Assessment of neurocognitive disorders relies heavily on the
history provided by patients or caregivers. Knowledge of the classification of
1582 DECEMBER 2021

memory types and processes is crucial to obtaining an accurate history. It also KEY POINTS
supports the interpretation of cognitive tests, accurate neuroanatomic
● Ischemic lesions caused
localization, and the formulation of a differential diagnosis and ultimately by small vessel disease can
informs the diagnostic workup. The development of sophisticated diagnostic cause cognitive impairments
tools, including structural and functional imaging, standardized and related to interruption of
comprehensive neuropsychological tests, and molecular and imaging frontal cortical circuits and
disruption of cholinergic
biomarkers, have greatly enhanced our ability to make accurate diagnoses,
pathways. Consequently,
particularly for neurodegenerative disorders that cause memory dysfunction. As memory deficits are related
disease-modifying therapies become available in the future, the use of this body to inattention with retrieval
of knowledge and growing diagnostic arsenal will become even more critical in deficits that are worse with
free recall but improve with
everyday clinical practice.
cuing and recognition.
● Normal aging involves

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30 Molinuevo JL, Ayton S, Batrla R, et al. Current
group report. Brain 2019;142(6):1503-1527.
state of Alzheimer's fluid biomarkers. Acta
doi:10.1093/brain/awz099
Neuropathol 2018;136(6):821-853. doi:10.1007/
s00401-018-1932-x 43 Graff-Radford NR, Tranel D, Van Hoesen GW,
Brandt JP. Diencephalic amnesia. Brain 1990;
31 Jie CVML, Treyer V, Schibli R, Mu L. Tauvid: the
113(pt 1):1-25. doi:10.1093/brain/113.1.1
first FDA-approved PET tracer for imaging Tau
pathology in Alzheimer's disease. 44 O'Brien JT, Thomas A. Vascular dementia. Focus
Pharmaceuticals (Basel) 2021;14(2):110. (Am Psychiatr Publ) 2017;15(1):101-109. doi:10.1176/
doi:10.3390/ph14020110 appi.focus.15104
32 Zetterberg H, Burnham SC. Blood-based 45 Sander K, Sander D. New insights into transient
molecular biomarkers for Alzheimer's disease. global amnesia: recent imaging and clinical
Mol Brain 2019;12(1):26. doi:10.1186/s13041-019- findings. Lancet Neurol 2005;4(7):437-444.
0448-1 doi:10.1016/S1474-4422(05)70121-6
33 Law ZK, Todd C, Mehraram R, et al. The role of 46 Fjell AM, Walhovd KB. Structural brain changes in
EEG in the diagnosis, prognosis and clinical aging: courses, causes and cognitive
correlations of dementia with Lewy bodies—a consequences. Rev Neurosci 2010;21(3):187-221.
systematic review. Diagnostics (Basel) 2020;10(9): doi:10.1515/revneuro.2010.21.3.187
616. doi:10.3390/diagnostics10090616
47 Rogalski E, Stebbins GT, Barnes CA, et al. Age-
34 Brandt J. The Hopkins verbal learning test: related changes in parahippocampal white
development of a new memory test with six matter integrity: a diffusion tensor imaging study.
equivalent forms. Clin Neuropsychol 1991;5(2): Neuropsychologia 2012;50(8):1759-1765. doi:10.
125-142 doi.org/10.1080/13854049108403297 1016/j.neuropsychologia.2012.03.033
1584 DECEMBER 2021

48 Bucur B, Madden DJ, Spaniol J, et al. Age-related 52 McWhirter L, Ritchie C, Stone J, Carson A. KEY POINTS
slowing of memory retrieval: contributions of Functional cognitive disorders: a systematic
perceptual speed and cerebral white matter review. Lancet Psychiatry 2020;7(2):191-207.
integrity. Neurobiol Aging 2008;29(7):1070-1079. doi: 10.1016/S2215-0366(19)30405-5
● Psychogenic memory
doi:10.1016/j.neurobiolaging.2007.02.008 dysfunction, caused by
53 Delis D, Wetter S. Cogniform disorder and emotional rather than
49 Castel AD, Benjamin AS, Craik FIM, Watkins MJ. cogniform condition: proposed diagnoses for physiologic factors, is
The effects of aging on selectivity and control in excessive cognitive symptoms. Arch Clin
described as “functional
short-term recall. Mem Cognit 2002;30(7): Neuropsychol 2007;22(5):589-604. doi: 10.1016/j.
1078-1085. doi:10.3758/bf03194325 acn.2007.04.001
amnesia.” Such conditions
are often induced by
50 Salthouse TA. Trajectories of normal cognitive 54 Ball HA, McWhirter L, Ballard C, et al. Functional extreme stress,
aging. Psychol Aging 2019;34(1):17-24. doi:10.1037/ cognitive disorder: dementia’s blind spot. Brain interpersonal conflict, or
pag0000288 2020;143(10):2895-2903. doi: 10.1093/brain/
other nonphysical factors.
awaa224
51 Steenland K, Karnes C, Seals R, et al. Late-life
depression as a risk factor for mild cognitive ● Mood disruption from
impairment or Alzheimer's disease in 30 US anxiety and depression
Alzheimer's disease centers. J Alzheimers Dis
interferes with memory
2012;31(2):265-275. doi:10.3233/JAD-2012-111922
encoding and retrieval. In
such cases, patients tend to
perform below premorbid
levels for initial recall of
target information but then
exhibit minimal decay of the
information that was
encoded on delayed
cued-recognition trials. That
is, whatever they learn,
they keep.

REVIEW ARTICLE

Mood Disorders
C O N T I N UU M A UD I O By Shae Datta, MD; Uma Suryadevara, MD; Josepha Cheong, MD
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This
comprehensive review of mood disorders brings
together the past and current literature on the diagnosis, evaluation, and
treatment of the depressive and bipolar disorders. It highlights the primary
mood disorders and secondary neurologic causes of mood disorders that
are commonly encountered in a clinical setting. As the literature and our
CITE AS: understanding evolve, recent additions to the current literature are
2021;27(6, BEHAVIORAL NEUROLOGY important to bring forth to the readers.
RECENT FINDINGS: Advancements in clinical medicine have strengthened our

Dr Shae Datta, Department of
understanding of the associations of neurologic and psychiatric diseases.
Neurology, NYU Langone This article highlights the medications frequently used with newly
Hospital–Long Island, 1530 Front identified mood disorders and the common side effects of these
St, Ste 400, East Meadow, NY 11554,
shae.datta@NYUlangone.org.
medications. A paradigm shift has moved toward newer treatment
modalities, such as the use of ketamine, repetitive transcranial magnetic
RELATIONSHIP DISCLOSURE : stimulation, and complementary and alternative medicine. The risks and
Dr Datta has received personal
compensation for serving as an benefits of such therapies, along with medications, are reviewed in this
educational mentor for article.
Residency Success.
Dr Suryadevara has received
personal compensation for SUMMARY: Mood disorders are extraordinarily complex disorders with
serving as a senior editor for the significant association with many neurologic disorders. Early identification
Asian Journal of Psychiatry and
has provided witness testimony
of these mood disorders can prevent significant morbidity and mortality
for a trial. Dr Cheong has associated with them. With further expansion of pharmacologic options,
received personal more targeted therapy is possible in improving quality of life for patients.
compensation for serving on
the board of directors for the
Accreditation Council for
Graduate Medical Education
and the American Board of
Psychiatry and Neurology and as
INTRODUCTION
M
a section editor for the Journal ood disorders, also previously labeled affective disorders, are
of Clinical Psychiatry. emotional disturbances that may manifest as pervasive and
UNLABELED USE OF
sustained feelings of depression, mania, or both. The general
PRODUCTS/INVESTIGATIONAL category of mood disorders is divided into depressive disorders
USE DISCLOSURE : and bipolar disorders. Depressive disorders can be further
Drs Datta, Suryadevara, and
Cheong discuss the unlabeled/ categorized and include major depressive disorder, persistent depressive
investigational use of disorder, disruptive mood dysregulation disorder, and premenstrual dysphoric
bupropion, divalproex sodium,
disorder.1 Like the manifestations of depressive disorders, bipolar disorders can
and selective serotonin
reuptake inhibitors for the also be further classified; these include bipolar I disorder, bipolar II disorder,
treatment of bipolar cyclothymia, and substance-induced bipolar disorder.
depression; complementary
and alternative
Depressive disorders are exceedingly prevalent and can impair the quality of
Continued on page 1737 life. Per data from the National Health Interview Survey in 2019, 18.5% of the
general population experienced symptoms of major, moderate, or mild
© 2021 American Academy symptoms of depression.2 Depression is defined by the presence of symptoms
of Neurology. such as depressed mood, anhedonia, irritability, and emptiness along with other
1712 DECEMBER 2021

possible neurovegetative symptoms such as a decrease or increase in appetite and KEY POINTS
sleep, decreased energy, trouble with concentration, and decreased interest.
● Depressive disorders are
These combined features significantly impair one’s functioning. Insomnia, pain, exceedingly prevalent and
tiredness, and other broad constellations of associated symptoms sometimes can impair the quality of life.
mask the presentation, leading to patients seeking medical care instead of According to data from the
psychiatric care.2,3 National Health Interview
Survey in 2019, 18.5% of the
Bipolar disorder, first described in the 1850s, is typically characterized by
general population
biphasic mood episodes alternating between depression and mania/hypomania experienced symptoms of
but can also be a single episode of mania. The annual prevalence of bipolar major, moderate, or mild
disorders among US adults was estimated to be 2.8%.4 The Diagnostic and symptoms of depression.
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) separated “bipolar
● Bipolar disorder is
and related disorders” from depressive disorders, and it encompasses bipolar I typically characterized by
disorder, bipolar II disorder, cyclothymia, and other atypical variants that do not biphasic mood episodes
fit the earlier-mentioned forms. alternating between
Even with the current armamentarium of psychotropic medications for mood depression and mania/
hypomania but can also be a
disorders, morbidity and mortality continue to increase, especially from suicide.5 single episode of mania. The
annual prevalence of bipolar
DEPRESSIVE DISORDERS disorders among US adults in
Depressive disorders are highly prevalent disorders that impose a severe burden 2019 was estimated to be 2.8%.
on society and the economy.6 Depressive disorders include major depressive
disorder; persistent depressive disorder; disruptive mood dysregulation disorder;
premenstrual dysphoric disorder; depressive disorder secondary to general
medical conditions, medications, or substance use; other specified depressive
disorder; and unspecified depressive disorder (TABLE 10-1). Feelings of sadness,
emptiness, or irritable mood along with possible neurovegetative symptoms
mentioned above are common features for all the above-mentioned
depressive disorders.
Major Depressive Disorder

Major depressive disorder is a chronic psychiatric disorder that causes a
persistent feeling of sadness and emptiness. Major depressive disorder is
diagnosed when the depressive episode lasts longer than 2 weeks along with at
least four of the following symptoms: insomnia or hypersomnia, increase or
decrease in appetite, psychomotor agitation or retardation, decreased energy,
decreased concentration, suicidal ideation, and thoughts of worthlessness or guilt
(CASE 10-1). The symptoms cannot be in the context of substance use, general
medical conditions, or medication use. Lifetime prevalence of major depression
in the United States is around 21%, and the 12-month prevalence is around 10%.6
The most common comorbid diagnoses for major depressive disorder include
anxiety disorders, particularly generalized anxiety disorder and panic disorder.
Other associated variables for major depression include female sex, low
socioeconomic status, and younger adults. Major depressive disorder confers a
severe burden and impact on the functioning of the patient; more than 13% of
patients attempted suicide during their worst episode.6 Life expectancy is also
reduced through nonsuicidal mortality, especially in patients with medical and
neurologic disorders. The heterogeneity of major depression makes it even more
important to focus on the patient profile along with the presenting symptoms.
For example, the cognitive symptoms mentioned in the diagnostic criteria do not
always describe the full spectrum of cognitive deficits seen in depressive
disorders, such as a decline in executive functioning, attention, processing speed,

MOOD DISORDERS
and memory.7 These cognitive deficits cause a significant decline in quality of life
and have an impact on daily functioning. Insomnia is another such important
symptom, and it has a bidirectional association with depressive symptoms
(patients experience insomnia as a result of being depressed; however, patients
who are unable to sleep well end up feeling more depressed).8 When depressive
disorders are accompanied by anxious features, treatment response is poor, rates
of suicide are higher, and the risk for recurrence is increased.9
TABLE 10-1 Mood Disorders
Disruptive
Major Persistent mood Premenstrual
depressive depressive dysregulation dysphoric Bipolar Bipolar
disorder disorder disorder disorder disorder I disorder II Cyclothymia
Diagnostic Depressed Depression, Temper Marked Abnormally One or Periods of

and mood most of loss of interest, outbursts affective elevated or more elevated
Statistical the day, hopelessness, >3 times/wk, lability, expansive depressive mood
Manual of markedly tiredness, low tantrums irritability, mood, episodes; (hypomania)
Mental diminished self-esteem, >12 months, markedly increased one or alternating
Disorders, interest, trouble irritability depressed goal-directed more with
Fifth significant concentrating, most of the mood, activity, hypomanic depressed
Edition weight loss, irritability, day every day, hopelessness, grandiosity, episodes mood,
insomnia/ decreased trouble with marked decreased (3 or more periods of
hypersomnia, activity, functioning in anxiety, need for of the stable mood
psychomotor avoidance, more than decreased sleep, symptoms are less than
agitation/ feelings of one setting interest, talkative, persisted; 2 months
retardation, guilt, change in difficulty flight of ideas, 4 or more if
fatigue/loss appetite, sleep concentrating, distractibility the mood is
of energy, problems fatigue, only
feeling of change in irritable)
worthlessness/ appetite,
inappropriate hypersomnia
guilt, or insomnia,
decreased feeling
concentration, overwhelmed,
suicidal physical
ideation symptoms
(breast
tenderness or
swelling, joint
or muscle pain,
a sensation of
bloating or
weight gain)
Time At least 2 years >12 months 1 week before Manic Hypomanic At least
2 weeks with <3 cycle until a episode is episode 2 years with
symptom- few days after at least is at least less than
free months for a majority 1 week 4 days 2 symptom-
of cycles free months
Severity Severe Clinical Impairment Distress or Severe Severe Clinical

impairment during the some (especially impairment
episodes impairment in depressive
functioning episodes)
1714 DECEMBER 2021

Major depressive disorder is an etiologically complex disorder that is globally KEY POINTS
ranked among the top three in disease burden. The onset of symptoms is
● When depressive
bimodal, with its first peak in people in their twenties and the second peak in disorders are accompanied
people in their fifties. Heritability for major depression is only around 37%, by anxious features,
whereas disorders such as schizophrenia and bipolar disorder have 70% to 80% treatment response is poor,
heritability.10 Highly intricate genetic differences and psychosocial stressors rates of suicide are higher,
and the risk for recurrence is
together are typically the determinants for stress responses and the resiliency or
increased.
susceptibility for depression.11 The genome-wide association studies in patients
with major depressive disorder confirm that depression is a polygenic disorder, ● Major depressive
identifying multiple loci but none of which had a major effect.12 The combination disorder is an etiologically
of genetic and environmental factors is hypothesized to trigger epigenetic complex disorder that is
globally ranked among the
processes that are not clearly understood at this time. Decreases in top three in terms of disease
neurotransmitter (serotonin, norepinephrine, dopamine) functioning have also burden.
been implicated in the pathophysiology of depression.
Neuroimaging studies in patients with major depression show atrophy in the ● Heritability for major
depression is only around
cortical and limbic regions, as well as decreased prefrontal cortex and 37%, whereas disorders such
hippocampal volumes.13,14 However, not all patients with major depression had as schizophrenia and bipolar
the same pattern of biological dysfunction or neuroimaging findings. These disorder have 70% to 80%
changes were more prominent in patients with chronic stressors.13,14 Multiple heritability. Highly intricate
genetic differences and
biomarkers were studied for depression in the search for prospective evidence
psychosocial stressors
that will predict onset or relapse or both; they range from neuroimaging to together are typically the
gastrointestinal markers, neurotrophic markers, neurotransmitters, hormones, determinants for stress
oxidative stress–related markers, and immunologic markers. The evidence for responses and the resiliency
or susceptibility for
any leading biological models at this time is scarce. One biomarker that appears
depression.
to be slightly more reliable in predicting onset or relapse of depression is cortisol.15
Some studies show that dysregulation of the hypothalamic-pituitary-adrenal axis ● Depressive disorders
and increased cortisol levels are seen in around 40% to 60% of patients with often are chronic and
depression.16 However, the underlying mechanisms are incompletely understood. recurring disorders.
Remission of a full episode is
Neuroimaging biomarkers, such as brain volumetric MRI, functional MRI (fMRI), characterized by the
EEG, diffusion tensor imaging, magnetic resonance spectroscopy, positron absence of significant
emission tomography (PET) scans, and single-photon emission computed symptoms for at least
tomography (SPECT), were also used to find moderators for treatment response 2 months. However, one-
third to one-half of patients
in patients with depression.14 Results have been inconsistent. with depressive disorders
Depressive disorders often are chronic and recurring disorders. Remission of a experience another
full episode is characterized by the absence of significant symptoms for at least depressive episode within
2 months. However, one-third to one-half of patients with depressive disorders 1 year.
experience another depressive episode within 1 year.17,18 Seasonal pattern is an
additional timing specifier noted in cases of recurrent major depressive episodes,
in which a temporal pattern is seen relating the onset of depressive symptoms
with the time of year.
Further clinical specifiers that can be used to describe subtypes of major
depression include anxious distress, atypical features (reversed neurovegetative
signs of hypersomnia and increased appetite), melancholic features, mixed
features, psychotic features, and peripartum onset.
Persistent Depressive Disorder

Persistent depressive disorder is a nosologic entity first introduced in DSM-5, and
the term subsumes any of the chronic depressive illnesses including dysthymic
disorder, recurrent major depression without recovery between episodes, major
depressive episode superimposing on dysthymic disorder (“double depression”),

MOOD DISORDERS
and chronic major depression.19–22 Of those who present with major depressive
disorder, 26.5% experience a chronic episode of more than 2 years.22,23
It is a heterogeneous disorder that is characterized by predominant dysphoria
and has a lifetime prevalence ranging from 3% to 6%.21 The symptoms of this
disorder have variable manifestations. DSM-5 requires that the depressed mood
be accompanied by at least two or more of the following symptoms for a period
of at least two consecutive years: increased or decreased appetite, insomnia or
hypersomnia, fatigue, low self-esteem, decreased concentration, and
hopelessness.
Chronic depression, compared with acute episodes of depression, is
characterized by greater comorbidity, greater social dysfunction, more
hospitalizations, and frequent suicide attempts.22 Despite this burden, it is often
not recognized and not reported. The response to psychological and
pharmacologic treatments also remains slow and inadequate.23,24
Disruptive Mood Dysregulation Disorder

It should be noted that the criteria for depressive disorders may be different for
children and adolescents. The main presenting symptom in children and
adolescents may actually be irritability. Among children and adolescents,
disruptive major depressive disorder is a newer diagnostic entity in the
CASE 10-1 A 21-year-old woman was brought to the emergency department by her
husband after he found her sitting by the side of the bed with a
medication bottle in her hand. On the side table was a letter addressed to
the family for the pain and grief that she was about to cause. She
admitted having suicidal thoughts almost every day for the past 2 weeks.
During the interview, she talked about how she had mild depression on
and off for few years. But in the past month, the depression had gotten
worse; she had been losing weight due to decreased appetite, had
trouble sleeping, and was not able to concentrate at work. She lost her
job as a nurse. Her primary care physician noticed the symptoms 1 week
prior and started her on sertraline to help with symptoms along with a
mental health referral. Her past psychiatric history was insignificant other
than mild episodes of depression; she had no psychiatric hospitalizations
or suicide attempts. She had not been tried on any other antidepressants.
She denied any symptoms of mania or psychosis. Her family history was
significant for depression in her mother. The patient typically drank one
to two beers occasionally during social events. She denied any illicit drug
use or nicotine use. Her medical history was significant for
hypothyroidism for which she was on levothyroxine. Physical
examination was noncontributory. Blood work including complete blood
cell count, urine drug screen, metabolic panel, thyroid levels, folate, and
vitamin B12 were all within normal limits.
On mental status examination, the patient was pleasant and partially
cooperative, with some psychomotor agitation. She was upset that she
could not go through with her plan. She answered most questions in a curt
and brief manner with “yes” or “no.” She appeared her stated age but
1716 DECEMBER 2021

depressive disorder domain of DSM-5; it is a childhood disorder of irritability,
anger, and temper tantrums with persistent irritability or negative mood, and
anger that is disproportionate to the situation, manifested either verbally or
physically. These temper outbursts may last from 1 minute to less than 5 minutes
and occur 3 or more times a week.25,26 Although these symptoms may be present
in normal children, this disorder goes beyond the scope of what is considered
normal and may require clinical attention.26 The overall duration must be up to
12 months or more and must be present in two of three settings if symptoms are
mild and in one setting if symptoms are severe. The age of onset is usually
between 6 and 10 years, and disruptive major depressive disorder cannot be
diagnosed in patients before the age of 6 or after 18. However, more data from
empiric studies are needed for better validation of this new diagnostic entity. At
this point in time, well-researched standard guidelines for pharmacologic
management of the disruptive symptoms are lacking.26
Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder is also now recognized as a distinct disorder in
DSM-5. It includes both psychological and physical manifestations. The
psychological components include irritability, nervousness, anger, agitation,
insomnia, and depression. The physical components have common
was unkempt. Her thought process was linear and logical, and her speech
had a regular rate and rhythm. Her mood was “fine,” and her affect varied
from constricted to irritable. She denied hallucinations and delusions,
and her memory appeared intact with no cognitive deficits noted during
the interview.
During hospitalization, the medications were adjusted, family meetings
were held for psychoeducation, and psychology was consulted to help
her gain more coping skills as well as understand the triggers better.
The patient presented with an episode of major depressive disorder. She COMMENT
endorsed multiple symptoms including depressed mood, decreased
energy and concentration, decreased appetite with weight loss, insomnia,
psychomotor agitation, and suicidal ideation. Her medical history was
significant for hypothyroidism, but the thyroid levels were within normal
limits, and the rest of her physical examination was noncontributory. She
drank only occasionally, which makes alcohol-induced depression an
unlikely diagnosis. She denied any other symptoms that would suggest
bipolar disorder or other diagnoses for which the patient could have
depression as one of the symptoms. She was recently started on sertraline.
Two possible outcomes are (1) she was not on a therapeutic dose for a
reasonable duration for the medication to be effective or (2) she
developed suicidal ideation as a result of being on the medication. Most
antidepressants have a boxed warning of increased risk of suicide with use;
hence, it is essential to follow up soon after a patient starts taking an
antidepressant.

MOOD DISORDERS
gastrointestinal symptoms (nausea, bloating, constipation, abdominal cramps),

skin issues (acne), neurologic symptoms (headache, dizziness, fainting), and
ocular symptoms (vision changes and eye infection). Symptoms must improve
within a few days of the onset of menstrual cycles and resolve after menses. The
exact diagnosis is made when these symptoms are present in most menstrual
cycles over a year.27
A premenstrual pattern of at least five physical, affective, and/or behavioral
symptoms is key to the diagnosis of premenstrual dysphoric disorder. One or more
TABLE 10-2 Some Medications That Can Induce Mood Symptomsa
Medication Indication(s)/use Mood symptom that may be induced

b
Amiodarone Antiarrhythmic Depression
Antiepileptics Epilepsy, bipolar disorder Depression
Beta-blockers Hypertension, tremor Depression
Cholinesterase inhibitors Alzheimer dementia Depression

b
Clomiphene citrate Infertility Depression
Dopamine agonists Parkinson disease Mania
Efavirenz Human immunodeficiency virus (HIV) Depression, mania
Fluoroquinoloneb Bacterial infection Depression

b
Gonadotropin-releasing hormone agonists Infertility Depression
Integrase strand transfer inhibitors HIV Depression
Interferons Hepatitis C, multiple sclerosis Depression
Isotretinoin Acne Depression
Mefloquine Malaria Depression
Methyldopa Hypertension Depression
Montelukast Allergies, asthma Depression
Oral contraceptives Contraception Depression
Opioids Pain control Depression
Reserpine Hypertension Depression
Rilpivirine HIV Depression
Selegiline Parkinson disease Mania
Steroids Multiple sclerosis Depression, mania
Tricyclic antidepressants Migraine prophylaxis, neuropathic pain Mania
Vigabatrin Epilepsy Depression
Zidovudine HIV Mania
a
Updated with permission from Rakofsky J and Rappaport M, Continuum (Minneap Minn).31 © 2018 American Academy of Neurology.
b
New medication added since the previous publication of this table.
1718 DECEMBER 2021

of the symptoms, such as marked affective lability (mood swings, sadness, KEY POINT
tearfulness, increased sensitivity to rejection), marked anger or irritability,
● Although bipolar disorder
marked depressed mood, or marked anxiety/tension/feeling keyed up must be has high genetic loading, it is
present. Additionally, one or more of the following symptoms can be present to still considered
bring the total to at least five: decreased interest, decreased concentration, change multifactorial, influenced by
in appetite, change in sleep, feeling of being overwhelmed, decreased energy, environmental factors such
as life events.
physical symptoms such as breast swelling or tenderness, joint or muscle pain,
bloating, or weight gain.20 The potential etiology includes combinations of central
nervous system sensitivity to reproductive hormones such as estrogen and
progesterone, genetics, and stress. Current treatments include selective serotonin
reuptake inhibitors (SSRIs) that have been considered the gold standard for
treatment of premenstrual dysphoric disorder and some hormonal treatments.27-30
Postpartum depression is another disorder also thought to be associated with
female hormones. This form of depression is not recognized as a separate
disorder in DSM-5 but is identified as a major depressive disorder with
peripartum onset describing the onset of mood symptoms either during
pregnancy or within 4 weeks after delivery. Brexanolone is a newer
antidepressant developed specifically for postpartum depression. It has a newer
mechanism of action as an allosteric modulator of the GABAA receptor.
Substance/Medication-Induced Depressive Disorder and Depressive

Disorder Due to General Medical Condition
Various categories of drugs can lead to substance-related mood changes. These
include over-the-counter drugs, prescription medications, and illicit drugs; see
the section Substances and Commonly Used Medications That Cause Mood
Changes. TABLE 10-231 lists the commonly used medications that can induce
depressive symptoms.
Unspecified and Other Specified Depressive Disorders

Other specified depressive disorders in DSM-5 include patients who do not meet
the full criteria for any of the above categories. The unspecified depressive
disorder category includes patients who do not meet full criteria for any
depressive disorder but whose symptoms cause clinically significant distress in
social and occupational functioning.
BIPOLAR DISORDERS
Bipolar disorder, one of the most heritable psychiatric disorders, is a chronic and
complex disorder characterized by extreme shifts in mood and may include
combinations of mania, hypomania, and depression32,33 (TABLE 10-1).
Occurrence of at least one manic episode in a lifetime is diagnostic of bipolar I
disorder and has been frequently associated with increased mortality, functional
disability, medical and psychiatric comorbidity, and decreased quality of life.33-35
Lifetime prevalence is around 1% and around 10% to 25% when one of the
parents has a mood disorder. Although bipolar disorder has high genetic loading,
it is still considered multifactorial, influenced by environmental factors such as
life events. Most studies show that bipolar I disorder prevalence is equal in men
and women, although, compared with women, men may have more frequent
manic episodes. Bipolar II disorder is more frequent in women.35 A bimodal
distribution of onset has been suggested, the first peak around 15 to 24 years of
age and the second around 45 to 54 years of age. Rates of suicide are estimated to

MOOD DISORDERS
be 20 times higher in patients with bipolar II disorder compared to patients

without bipolar disorder.36
In addition to bipolar I disorder and bipolar II disorder, according to DSM-5,
bipolar disorders are further divided into cyclothymia, substance/medication-
induced bipolar disorder, bipolar and related disorder due to another medical
condition, unspecified bipolar and related disorder, and other specified bipolar
and related disorders. This section focuses on bipolar I disorder, bipolar II
disorder, and cyclothymia
Bipolar I Disorder
Bipolar I disorder is defined as at least one manic episode with elevated moods that
include symptoms such as distractibility, insomnia, grandiosity, flights of ideas,
CASE 10-2 A 71-year-old man presented to the emergency department with a

3-week history of insomnia, elevated mood, goal-directed behaviors, and
“out-of-character behaviors.” For the past 4 days, he believed he was
God and that he was there to help the “mere mortals,” leading to
unwarranted spending. He was started on a course of prednisone
3 weeks before presentation for an episode of transverse myelitis and
was just tapered off. He had no underlying psychiatric disorder or
substance use history. Family history was negative for any mental illness
or substance use.
On examination, he was dressed in brightly colored clothes and wore a
large hat. He was talkative and could barely stay focused on the
conversation. His speech was pressured, and he said he feels “excellent
because I figured out I am God and invincible.” His thought content was
positive for grandiose delusions and ideas of reference. Physical
examination was within normal limits, and a complete medical workup
was done, which did not reveal any abnormalities. MRI of the brain was
similar to a previous MRI 1 year before and did not show any pathology or
metastasis.
The patient was admitted to psychiatry with neurology service
following him for his recent transverse myelitis. He was started on
risperidone, and the dose was increased slowly. Symptoms improved
over the next 5 days, and he was discharged home to family. During his
third follow-up 7 months after discharge, the psychiatrist began a slow
taper to discontinue risperidone. A year later, the patient continued to do
well without any recurrence of symptoms.
COMMENT The patient presented with a new-onset manic episode and had no
psychiatric history. Symptoms correlated with the timing of the prednisone
initiation. Studies show that mania or hypomania is one of the most
common psychiatric side effects of corticosteroids.37 This patient’s
symptoms resolved with initiation of risperidone and discontinuation of
prednisone. This case highlights the complications associated with
differentiating primary late-onset mania from mania secondary to general
medical conditions.
1720 DECEMBER 2021

goal-directed activities, pressured speech, and thoughtlessness/risk-taking behavior. KEY POINT
These symptoms should last for at least 1 week with associated impairments in
● Incidence of suicide
social or occupational function. Depressive or mixed episodes may also be present. varies among regions based
These episodes can also be triggered by using substances or medications (CASE 10-2). on the classification of
suicide, social and cultural
Bipolar II Disorder attitudes toward suicide,
availability of treatment
Bipolar 2 is defined as major depressive episodes with at least one hypomanic
options, and access to lethal
episode. Hypomania is described as elevated mood and increased energy levels means. Rates are higher in
that last for at least 4 days, and it causes social disruption or occupational lower socioeconomic
impairment (TABLE 10-1). sectors and in men between
the ages of 45 and 64.
Although many of the symptoms of manic and hypomanic episodes overlap, a
hypomanic episode is a less serious form that does not include a break from
reality (psychosis) and does not require hospitalization1; the difference between
mania and hypomania is mainly the severity of the symptoms. The duration is
highly variable among patients. Between episodes, patients with bipolar
spectrum disorders tend to have residual symptoms, emotional dysregulation,
cognitive impairment, and increased medical and psychiatric comorbidities.35
Cyclothymia
Cyclothymia is defined as a low-grade subthreshold of mild hypomania and
major depression that lasts for at least 2 years. These patients do not meet the
criteria for mania, hypomania, or major depression. Adults diagnosed with this
condition show episodes that last for at least 2 years, whereas diagnosed
adolescents show episodes that last for more than 1 year.
SUICIDE RISK
Suicide is the 10th leading cause of mortality in North America and accounts for
1.5% of all deaths globally.34,38 Incidence of suicide varies among regions based on
the classification of suicide, social and cultural attitudes toward suicide,
availability of treatment options, and access to lethal means. Rates are higher in
lower socioeconomic sectors and in men between the ages of 45 and 64.38,39
Underlying psychiatric disorders such as depressive disorders, bipolar disorders,
schizophrenia, and substance use disorders significantly increase the suicide
rates in life course models. Other predisposing factors for suicide include family
history of suicide or suicidal behavior, childhood sexual trauma, and a previous
suicide attempt.38 These predisposing factors, when combined with precipitating
factors (eg, substance use, negative life events, medical/neurologic conditions
such as neurocognitive disorders, traumatic brain injury [TBI], multiple sclerosis
[MS], seizures, migraines) and access to lethal means, lead to suicide attempts/
suicide. Impulsivity is a common theme underlying most suicide attempts or self-
injurious behaviors. Nonsuicidal self-injurious behaviors are commonly seen in
patients with personality disorders, mainly cluster B (mood) personality
disorders.38-40 Two-thirds of patients who die by suicide were in contact with the
mental health system in the year prior, and at least 30% were either hospitalized
or were seen in the emergency department for a psychiatric problem. The most
common method of suicide in the United States is by using firearms, which are
used by 61% of men and 36% of women who die by suicide.39,40
Numerous suicide prediction tools have been developed over the years to help
identify these high-risk groups, but the tools have some limitations with how
they align with clinical value and translate into formulating an individualized

MOOD DISORDERS
treatment plan for the patients.40 Current guidelines from the US National
Strategy for Suicide Prevention recommends the use of suicide prediction
tools.39,40 The screening should include a thorough assessment of the
predisposing and precipitating factors, including any recent changes in life or
triggers. If the screening tool and further in-depth clinical interview suggest high
risk, moving the patient to a hospital setting is warranted to maintain safety.
Along with pharmacologic and psychological treatments, it is essential to
encourage family members to ensure a safe environment after hospital or
emergency department discharge by removing firearms and excess
medications.39,40 More importantly, throughout this time, developing and
maintaining a therapeutic relationship is key to suicide prevention.
NEUROLOGIC DISORDERS THAT CAUSE MOOD DISORDERS

This section focuses on some common neurologic disorders that can cause
depressive or manic symptoms.
Multiple Sclerosis
MS is a neurodegenerative inflammatory demyelinating disease of the central
nervous system affecting approximately 400,000 people in the United States and
2.3 million people worldwide.41 MS is the major cause of nontraumatic neurologic
disability in young adults, and the prevalence of depression is higher in these
patients. The prevalence of depression in studies has varied from 4.27% to 59.6%
due to the heterogeneity of sample size and variations in clinical evaluation
styles.42 The presence of depression is one of the determinants of poor quality of
life in patients with MS.43,44 Patients with depression and MS may have more
psychomotor retardation and suicidal ideation and may be noncompliant with
MS disease-modifying treatments. Because symptoms of depression align with
some symptoms of MS (eg, fatigue and poor concentration or memory),
diagnosis of depression can be challenging. The American Academy of
Neurology (AAN) recommends using the Beck Depression Inventory as a
screening tool in patients with MS.45 Genetic factors, immune and inflammatory
factors, psychosocial factors, and structural changes in the brain have all been
explored as potential causes of depression in patients with MS.46
Reports on the prevalence of bipolar disorder in patients with MS also vary
broadly, likely because of differences in the types of measures used, patient
populations, and the time frame for evaluation.44 The prevalence is estimated to
be around 5.83% for bipolar disorder in patients with MS.44
The AAN supports using treatments such as CBT to help with depression
management in patients with MS. Other treatment options including
psychopharmacologic approaches and transcranial magnetic stimulations have
been studied, but results are not supportive at this point and more research
is needed.46,47
Dementia
Depression is one of the neuropsychiatric symptoms that commonly accompany
or precede the onset of neurocognitive disorders.48 The prevalence of major
depression averages around 15.9% in patients with neurocognitive disorders.48 In
frontotemporal dementia, changes in personality are accompanied by depression
(80%), apathy (50% to 70%), and euphoria (10% to 30%).49 Moreover, patients
with dementia often experience insomnia, which can lead to increases in
1722 DECEMBER 2021

irritability, and may have rapid-onset behavior changes and aggressive behavior KEY POINTS
toward their caretakers because of frustration and emotional challenges
● Current guidelines from
associated with this disease.48 Thus far, nondrug interventions have been the US National Strategy for
preferred as they are effective for reducing mild to moderate symptoms of Suicide Prevention
depression in this patient population. Popular interventions used include animal recommend the use of
therapy, cognitive stimulation, exercise and social interaction, massage therapy, suicide prediction tools. The
screening should include a
reminiscence therapy, occupational therapy, multidisciplinary care, and
thorough assessment of the
environmental modification.48,50 Data regarding treatment of major depression predisposing and
in patients with neurocognitive disorders are mixed.48,50,51 precipitating factors,
including any recent
changes in life or triggers.
Headache
Headaches, more specifically migraines, have high rates of comorbidities with ● Multiple sclerosis is the
mood disorders, including depressive disorder and bipolar disorder. They are major cause of nontraumatic
more likely to be seen in women compared with men (18% of women experience neurologic disability in
migraines compared with 6% of men).52 Studies have shown that patients who young adults, and the
prevalence of depression is
frequently experience migraines have a 9% chance of developing a depressive higher in these patients. The
disorder and a 17% chance of developing anxiety. The number of patients with prevalence in studies has
comorbid depression or comorbid anxiety is significantly higher in patients who varied from 4.27% to 59.6%
visit the emergency department as a result of their headaches.53,54 There is an due to the heterogeneity of
sample size and variations in
increased prevalence of bipolar disorder in patients with migraine.55 A comorbid clinical evaluation styles.
mood disorder adds to the morbidity and poor quality of life and, if left
untreated, leads to poor outcomes with headache management. However, ● The American Academy
comorbid mood disorder does not add to lost productive time, but lost of Neurology supports using
treatments such as
productive time and depression do have a weak association.54
cognitive-behavioral
therapy to help with
Traumatic Brain Injury depression management in
Depression is a frequent psychiatric complication seen among patients who have patients with multiple
a TBI.56 It also amplifies the functional disability and cognitive burden after a sclerosis. Other treatment
options including
TBI.56,57 The prevalence of major depression in patients with TBI is around 9% to psychopharmacologic
15%.56 One meta-analysis found that depressive symptoms were more commonly approaches and transcranial
seen after a mild TBI than a severe TBI.56 Multiple TBIs, preexisting psychiatric magnetic stimulations have
conditions, and medical conditions such as diabetes, cancer, and heart disease been studied, but results are
not supportive at this point
further increase risk of depression.56 The lesion site has been studied as a possible and more research is
risk factor, but results have been inconsistent. Despite how common psychiatric needed.
sequelae have been after TBI, the majority of patients with TBI and depression do
not seek treatment. Untreated depression in patients with TBI has been
associated with poor quality of life, vocational outcomes, and psychosocial and
functional outcomes.56,58 At this point, no gold standard for treatment of
depression in patients with TBI is available.
Movement Disorders
Depression is common in Parkinson disease (PD) and affects 40% to 50% of all
patients with PD. It has been hypothesized that depression may present as a
premotor marker of PD.59 When patients with PD have depression, their quality
of life decreases, which has been associated with greater disease progression.59
The relationship between depression and PD remains unclear. Factors that may
increase the depression prevalence among patients with PD include the
progression of the disease itself (further progression of the disease makes it more
likely depression will develop), history of depression, and younger age.60
Depression may be related to PD-induced genetic alterations, and neuroimaging

MOOD DISORDERS
studies suggest a complex interplay among neurochemical, anatomic, and

functional changes. Evidence exists for dysfunction in all of the aminergic
systems in patients with PD and depression.59 The structural changes include
subcortical-cortical neural pathway degeneration, neuronal loss of the substantia
nigra, the presence of Lewy body inclusions, and a decline in monoamine
neurotransmitter systems.
Depression may also occur later in the disease process, again possibly related to
neurodegeneration. Alternatively, depression may stem from a psychological
reaction to PD; a person may become depressed in response to the stress and
disability of this chronic and progressive disease. Defining depression in the context
of PD is challenging, partly because of the overlap of symptoms of both disorders,
leading to difficulties in accurately diagnosing depression in PD. For example,
insomnia, tiredness, psychomotor retardation, difficulty with concentration, and
reduced appetite are symptoms of both conditions, which can make it challenging
to discern the underlying pathophysiology, particularly with concurrent onset.
The use of standard inclusive criteria to diagnose depression in the setting of PD,
compared with a more exclusive, diagnostic-etiologic method, has a considerable
impact on prevalence rates, and the implications for treatment are significant.
Manic episodes have been noted to occur in 2% to 12% of patients with
Huntington disease. Studies suggest that up to 76% of patients with Tourette
syndrome experience some kind of mood symptoms, with 13% meeting clinical
criteria for depression, and often present with anxiety, comorbid obsessive-
compulsive disorder, and irritability features in association with depression.
Mood symptoms have also been associated with other disorders such as multiple
system atrophy, progressive supranuclear palsy, and corticobasal
degeneration.61,62 Thus, patients with movement disorders should be routinely
screened for depression so that adjunctive treatment can be implemented.
Epilepsy
One of the most common mood disorders in patients who have epileptic seizures
is depression, and it is associated with decreased quality of life, increased
TABLE 10-3 Some Neurologic Medications Associated With Mood Symptoms
Medication Indication(s)/use Mood symptoms they may cause
Antiepileptic drugs Epilepsy, bipolar disorder Depression
Baclofen Multiple sclerosis Depression
Benzodiazepines Anxiety Depression
Beta-adrenergic blockers Hypertension, tremor Depression
Cholinesterase inhibitors Alzheimer dementia Depression
Corticosteroids Multiple sclerosis Depression, mania
Dopamine agonists Parkinson disease Mania
Interferon beta Multiple sclerosis Depression
Tricyclic antidepressants Migraine prophylaxis, neuropathic pain Mania
1724 DECEMBER 2021

utilization of health care services, premature mortality, and medication KEY POINTS
noncompliance.63 Another important disorder that is seen in patients with
● Defining depression in the
epilepsy is bipolar affective disorder. Studies have shown that people who have context of PD is challenging
epilepsy are twice as likely to have bipolar disorder compared with patients with partly because of the
other chronic illnesses such as migraine, asthma, and diabetes. The risk of suicide overlap of symptoms of
in patients with epilepsy and mood disorders is increased almost 32-fold.63 both disorders, leading to
difficulties in accurately
Studies suggest that epilepsy can alter the quality of sleep, indirectly affecting
diagnosing depression in PD.
mood, but the types of seizures, timing of seizures, and treatment regimen do not
result in differences in the overall effect on sleep; rather, it is just the presence or ● The risk of suicide in
absence of the epileptic episode itself that alters sleep patterns.64 patients with epilepsy and
mood disorders is increased
almost 32-fold.
Stroke
Poststroke depression is one of the most frequent neuropsychiatric sequelae that ● Diagnosis and treatment
worsen the outcomes in patients with stroke; the prevalence varies from 29% to of poststroke depression in
36%.65 The risk of developing poststroke depression is increased in patients who a timely manner may
facilitate motor recovery
have predisposing medical conditions, history of smoking, and prior psychiatric and improve functional
history and based on stroke characteristics itself.65,66 To improve emotional independence.
conditions after stroke, an important factor is patient acceptance of their
condition. Studies have shown that patient acceptance of outcomes leads to ● The most common risk
factor for patients to
significantly more positive mood changes and greater functional capacity and
develop substance-induced
mobility after poststroke rehabilitation.67 Reports on lesion location and mood mood disorders is a prior
disorders are varied; some have found that left anterior frontal strokes are family history of the
associated with depression and that right hemisphere strokes involving either disorder (eg, someone in the
cortical limbic areas or subcortical strokes are associated with mania. These family with a diagnosis of
depression).
stroke location relationships have not been consistent in subsequent studies.68
Diagnosis and treatment of poststroke depression in a timely manner may ● The mood change most
facilitate motor recovery and improve functional independence. The Patient frequently seen with the use
Health Questionnaire 9-item depression scale (PHQ-9) is one of the widely used of prescription medications
is depression.
tools to screen for depression in patients after stroke.
SUBSTANCES AND COMMONLY USED MEDICATIONS THAT CAUSE

MOOD CHANGES
Various categories of drugs can lead to substance-related mood changes. These
include over-the-counter drugs, prescription medications, and illicit drugs. The
focus here is on prescription medication–associated mood changes. The most
common risk factor for patients to develop substance-induced mood disorders is
a prior family history of the disorder (eg, someone in the family with a diagnosis
of depression).32,69 This section focuses on the most common substances
associated with mood disorders; however, this list is by no means
comprehensive. The mood change most frequently seen with the use of
prescription medications is depression. Common medications with this side
effect include beta-blockers, corticosteroids, benzodiazepines, stimulants,
anticonvulsants, statins, and those used to treat attention deficit hyperactivity
disorder (TABLE 10-3). Prescription medications that can lead to mania are far
less common than those that lead to depression. Some of the most common
medications include cyclosporine, levodopa, antidepressants, methylphenidate,
corticosteroids, and baclofen. The exact percentages of patients who are at risk
for developing these mood swings as a result are not known because they are
highly dependent on various external factors including variable metabolism,
polypharmacy, and other genetic factors.32,70

MOOD DISORDERS
EVALUATION AND MANAGEMENT OF DEPRESSIVE AND

BIPOLAR DISORDERS
This section details the evaluation and management of depressive and bipolar
disorders, including psychotherapy, pharmacotherapy, and neuromodulation.
Evaluation
Diagnosis of depressive or bipolar disorders is primarily based on obtaining a
thorough psychiatric history, temporal course of symptoms, general medical
history, family history, and substance use history. Obtaining collateral
information is important in cases in which patients cannot provide a complete
history. Information about risk factors for suicide attempts and death guide
clinicians when making decisions about treatment settings and developing
immediate safety plans. In addition to current symptoms, obtaining details about
the past mood episodes, such as the duration, frequency, and intensity, is
essential. Patients with bipolar disorder may not be diagnosed for at least 10 years
from when they first have a mood episode.71 Risk factors for bipolar disorder
include presence of family history of bipolar disorder, early onset of symptoms,
atypical features of depression, psychotic symptoms accompanying depression,
psychomotor retardation, and severe functional impairment.72
Mental status examination is an objective assessment of the patient’s
presentation, and it contributes to the diagnostic assessment. Particular attention
is paid to appearance, movement, speech, grooming, attitude, mood, affect, and
TABLE 10-4 A History of Antidepressantsa
Year Development
1952 Iproniazid, the first of the monoamine oxidase inhibitors (MAOIs), is developed after doctors realize that isoniazid, a
tuberculosis drug with a similar structure, has a mood effect on patients. The drug inhibits the monoamine oxidase
enzyme, which interacts with several neurotransmitters in the brain, including serotonin.
1957 Imipramine, the first tricyclic antidepressant, is introduced for medical use. Derived from antihistamine compounds, this
drug class blocks the reuptake of serotonin and norepinephrine into presynaptic neurons, thereby increasing
extracellular levels of the neurotransmitters in the brain.
1988 Fluoxetine makes its debut on the market as the first selective serotonin reuptake inhibitor (SSRI), still the class of
antidepressants most commonly prescribed today. By reducing the reuptake of serotonin, the drug increases the
extracellular concentration of the neurotransmitter.
1989 Bupropion, a type of antidepressant that does not fit into existing drug classes, is approved as a treatment for major
depressive disorder. It increases dopamine and norepinephrine levels in the brain by inhibiting the neurotransmitters’
reuptake.
1993 Venlafaxine, the first of the serotonin norepinephrine reuptake inhibitors (SNRIs), hits the market. Like the SSRIs, these
drugs inhibit the reuptake of serotonin, but they additionally do the same for norepinephrine.
2013 Vortioxetine, another atypical antidepressant, is approved. In addition to inhibiting the reuptake of serotonin,
vortioxetine acts as an agonist and antagonist of different serotonin receptors, with the net effect of increasing
extracellular amounts of serotonin and modulating the release of other, downstream neurotransmitters.
2019 Brexanolone and esketamine, the first of a new wave of drugs born of research into the underlying brain circuitry of
depression, are approved.
a
Reprinted with permission from Nogrady B.77 © 2019 LabX Media Group.
1726 DECEMBER 2021

behavior. Understanding the thought process, thought content, insight, KEY POINTS
judgment, cognition, and impulse control can help rate the severity and, in turn,
● Risk factors for bipolar
formulate a treatment plan. Screening instruments have been studied and used in disorder include presence
patients with both depression and bipolar disorder. The PHQ-9 is the most of family history of bipolar
widely used screening tool for depression73; however, its use may vary based on disorder, early onset of
the patient population. For example, Edinburgh Postnatal Depression Scale is an symptoms, atypical features
of depression, psychotic
in-depth tool for use in women postpartum.74 The Geriatric Depression Scale is a
symptoms accompanying
reliable tool for depression screening in older adults.75 Although screening tools depression, psychomotor
for bipolar disorder, such as the self-reported Mood Disorder Questionnaire or retardation, and severe
the Young Mania Rating Scale, are available, they are not recommended for functional impairment.
routine use.
● Selective serotonin
A thorough physical examination checking for signs or symptoms of any other reuptake inhibitors (SSRIs)
systemic illness, review of vital signs, and cognitive screening guide further and serotonin
investigation as needed. Laboratory workup, such as metabolic panel, complete norepinephrine reuptake
blood cell count; thyroid-stimulating hormone (TSH), folate, vitamin B12, and inhibitors (SNRIs) are the
preferred first-line
vitamin D levels; human immunodeficiency virus (HIV), syphilis serology, and medication choices for the
urine toxicology, also help confirm the diagnosis, especially when it is secondary treatment of depression.
to general medical conditions or substances. Neuroimaging studies are not Atypical antidepressants
routinely ordered in patients with depressive or bipolar disorders because of the like bupropion and
mirtazapine can also be used
lack of sensitivity and specificity; however, they are used to rule out a medical or as first-line treatments in
neurologic condition causing the depressive or manic symptoms.76 Several certain patient populations.
chronic medical conditions have depression as a comorbid diagnosis or can cause
depression or bipolar disorder. Once medical conditions have been ruled out,
thorough in-depth review of mood symptoms such as frequency, duration, and
the relationship with stressors will further clarify diagnostic assessment.
Management
Multiple treatment modalities are available for depression or bipolar disorder,
including pharmacologic treatments, psychotherapies, and various
neuromodulation techniques.
DEPRESSIVE DISORDERS. Researchers have been working for decades on new ways
to treat depression; the current market in the United States is still dominated by
drugs that were developed in the late 1980s and early 1990s (TABLE 10-477). SSRIs
and SNRIs are the preferred first-line medication choices for the treatment of
depression. Atypical antidepressants like bupropion and mirtazapine can also be
used as first-line treatments in certain patient populations. TABLE 10-531 lists the
current medications available for treatment of depression.
Matching the patient to the treatment modality is the first step in this process.
Once a detailed clinical assessment is completed and laboratory results are
obtained, the choice of medication largely depends on finding the balance
between effectiveness and tolerability, clinical symptoms, previous response to
antidepressants, and patient preference.78 If a patient is on concomitant
medications, potential drug-drug interactions should be considered before
choosing an antidepressant. Other medication factors that influence the decision
include simplicity of use, cost and availability, comparative efficacy, and
tolerability. For example, someone with mild depression, a first episode, would
be a good candidate for psychoeducation and psychotherapeutic treatments. A
patient with psychotic depression would benefit from an antipsychotic plus
antidepressant and/or neuromodulation, and a patient with bipolar depression

MOOD DISORDERS
would be a good candidate for mood stabilizer medications such as lamotrigine.79

Benzodiazepines and electroconvulsive therapy (ECT) are frequently used in
patients with depression plus catatonic features. Few antidepressants have been
studied for depression with somatic symptoms other than pain and fatigue.
SNRIs are used frequently in patients with pain. Bupropion and duloxetine are
used in patients with low energy or fatigue.80
Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs),
because of their adverse effects, are usually reserved for patients who have
treatment-resistant depression. Tricyclic antidepressants are avoided because of
TABLE 10-5 Antidepressants Used in Major Depressive Disordera
Class/drug Mechanism of action Possible adverse effects
Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, paroxetine, Blocks the 5-HT reuptake transporter Headache, nausea, yawning, sweating,
sertraline, citalopram, fatigue, insomnia, anxiety, sexual
escitalopram, fluvoxamine dysfunction, tremors, hyponatremia,
serotonin syndrome
Vortioxetine Blocks the 5-HT reuptake transporter and Headache, nausea, yawning, sweating,
blocks 5-HT7, 5-HT3, and 5-HT1D receptor; fatigue, insomnia, anxiety, sexual
agonizes 5-HT1A receptor; partial agonist at dysfunction, tremors, hyponatremia,
5-HT1B serotonin syndrome
Vilazodone Blocks the 5-HT reuptake transporter and is a Headache, nausea, yawning, sweating,
5-HT1A receptor partial agonist fatigue, insomnia, anxiety, sexual
dysfunction, tremors, hyponatremia,
serotonin syndrome
Serotonin norepinephrine reuptake inhibitors (SNRIs)
Venlafaxine, desvenlafaxine, Blocks 5-HT and norepinephrine reuptake Headache, yawning, fatigue, insomnia,
duloxetine, levomilnacipran transporters anxiety, decreased libido, tremors,
hypertension, nausea, diarrhea, sweating,
vomiting, increased blood pressure, sexual
dysfunction
Atypical antidepressants
Bupropion Blocks norepinephrine and dopamine Seizures, headaches, tremors, insomnia,

reuptake decreased appetite
Nefazodone Blocks 5-HT2A receptor; weak 5-HT reuptake Sedation, hepatotoxicity

Inhibition
Mirtazapine Blocks 5-HT2A/5-HT2C receptors, alpha 2A Weight gain, sedation

hetero- and autoreceptors, and histamine
receptors
Trazodone Blocks 5-HT2A receptor and alpha 1 receptor; Sedation, orthostatic hypotension,
inhibits 5-HT reuptake transporter and blocks priapism
5-HT2C receptor at high doses; partial 5-HT1A
receptor agonism
1728 DECEMBER 2021

cardiotoxic effects and lethality with overdose. A significant percentage of
patients with depression exhibit residual depressive symptoms following
treatment or a lack of response to treatments. The patient should be on a
therapeutic dose for at least 6 weeks before the efficacy of the treatment choice is
determined. Accurately diagnosing a depressive episode in the context of a
bipolar spectrum syndrome is important to distinguish from a depressive
syndrome. For patients with depression in the context of a bipolar spectrum
syndrome, an antidepressant may actually convert the patient to manic or
hypomanic symptoms.
Class/drug Mechanism of action Possible adverse effects
Tricyclic antidepressants
Nortriptyline, amitriptyline, Blocks 5-HT and norepinephrine Headache, yawning, fatigue, sedation,
imipramine, desipramine, transporters and acetylcholine, insomnia, anxiety, decreased libido,
clomipramine α-adrenergic, and H1 receptors tremors, seizures, delirium, arrhythmias,
orthostasis, dry mouth
Monoamine oxidase inhibitors
Tranylcypromine, phenelzine Inhibits monoamine oxidase A and B Serotonin syndrome, weight gain,
insomnia, sexual dysfunction,
hypertensive crisis, orthostatic
hypotension
Selegiline Selectively inhibits monoamine oxidase B at Serotonin syndrome, weight gain,

doses <20 mg; inhibits monoamine oxidase A insomnia, sexual dysfunction,
and B at doses ≥20 mg hypertensive crisis, orthostatic
hypotension
GABAA modulator
Brexanoloneb γ-Aminobutyric acid A (GABAA) modulator Dizziness, sedation/somnolence,

xerostomia, loss of consciousness, and hot
flashes
Tetracyclic antidepressantsb
Amoxapine, maprotiline Inhibition of presynaptic reuptake of Constipation, dry mouth, sedation, nausea,
norepinephrine and 5-HT vomiting, dizziness, insomnia, blurred
vision, anxiety, ataxia, tremor
5-HT = 5-hydroxytryptamine (serotonin).

a
Updated with permission from Rakofsky J and Rappaport M, Continuum (Minneap Minn).31 © 2018 American Academy of Neurology.
b
New medication added since the previous publication of this table.

MOOD DISORDERS
Psychotherapeutic modalities commonly used in patients with depression

include CBT, interpersonal therapy, and behavioral activation.81,82 Combining
them with pharmacologic treatments is an optimal treatment strategy to improve
outcomes for patients with depression.
TREATMENT-RESISTANT DEPRESSION. Combination treatments, augmenting or

switching medications, and neuromodulation strategies are effective tools for
treatment-resistant depression. The combination of antidepressant medication
and psychotherapy is more effective than pharmacotherapy alone.81 When
antidepressants are combined, it is important that the pharmacokinetics and the
pharmacodynamics of both medications are considered. For example,
combining an MAOI and an SSRI should be avoided because of the potential for
serotonin syndrome or hypertensive crisis. Options for augmentation strategies
would be lithium, triiodothyronine, atypical antipsychotic, stimulants, or a
second antidepressant. Some data support the use of aripiprazole, olanzapine,
quetiapine, and risperidone as adjunctive treatments for depression.83,84
Pharmacogenomic testing may be helpful in individual circumstances, such as
when patients are unable to tolerate low doses or when they have no response to
very high doses.
Some patients who have treatment-refractory depression have been treated
with IV ketamine administration in monitored settings. Based on these findings,
esketamine, which is administered as a nasal spray, is now a US Food and Drug
Administration (FDA)-approved medication. Both ketamine and esketamine are
N-methyl-D-aspartate (NMDA) receptor antagonists. Esketamine is also
required to be administered in a clinical setting with subsequent observation.
Neuromodulation treatments used in depression range from electrical
stimulations, such as electroconvulsive treatments and transcranial direct
current stimulation, and magnetic stimulations, such as repetitive transcranial
magnetic stimulation (rTMS), which is FDA approved, and magnetic seizure
therapy. Invasive surgical procedures, such as vagus nerve stimulation, which is
FDA approved, and deep brain stimulation, are also used in severe treatment-
refractory depression. rTMS can be used in patients who have not had a response
to one trial of antidepressant and is relatively more tolerable than
electroconvulsive therapy (ECT). ECT is generally considered a second-line
treatment but can be used as a first-line treatment in certain clinical situations
such as acute suicidal ideation, severe psychotic features, rapidly deteriorating
physical status, catatonic symptoms, treatment-refractory depression, and past
good response to ECT.85
BIPOLAR DISORDER. A wide range of treatments has been investigated for mania in
bipolar disorder. These include lithium, divalproex sodium, other
anticonvulsants, typical and atypical antipsychotics, and other treatment
modalities. After a thorough clinical assessment, symptoms due to substance use
or medical conditions should be ruled out. If a patient is on an antidepressant and
is currently presenting with mania, the antidepressants should be discontinued.
First-line monotherapy options for treatment of mania in bipolar disorder
include lithium, divalproex sodium, quetiapine, asenapine, aripiprazole,
paliperidone, risperidone, and cariprazine.86 Carbamazepine, olanzapine, and
ziprasidone are also used but have more side effects or drug-drug interactions.87
Depending on the severity and duration of symptoms, combination treatments
1730 DECEMBER 2021

are preferred in some cases. These typically include the use of lithium or KEY POINTS
divalproex sodium in combination with an antipsychotic. A response should be
● First-line monotherapy
seen within 1 or 2 weeks. If not, switching to another medication or augmenting options for treatment of
agents should be considered. ECT is also an alternative treatment, and studies mania in bipolar disorder
show that up to 80% of patients show marked clinical improvement.88 rTMS in include lithium, divalproex
the right frontal cortex can also be considered as a treatment option.89 Other sodium, quetiapine,
asenapine, aripiprazole,
options in patients with treatment-resistant mania include chlorpromazine
paliperidone, risperidone,
and clozapine. and cariprazine.
For patients with bipolar depression, first-line treatment options include
lamotrigine, quetiapine, lurasidone, and lithium. The choice of medication ● For patients with bipolar
depends on the urgency for rapid response. Quetiapine is the only first-line depression, first-line
treatment options include
treatment recommended for bipolar disorder II depression; if it fails to produce a lamotrigine, quetiapine,
response, divalproex sodium, aripiprazole, cariprazine, lurasidone, or an lurasidone, and lithium.
antidepressant such as an SSRI or bupropion may be added.90 ECT or vagus
nerve stimulation can be considered for treatment-resistant symptoms. Patients
with bipolar depression and anxious distress may have a better response to
quetiapine, lurasidone, or an olanzapine-fluoxetine combination.
Treatment adherence is an important element for patients because treatment
withdrawal predicts recurrence, risk for readmission, increased dysfunction, and
suicide. Psychoeducational and adjunctive psychosocial interventions integrated
into routine practice help with adherence. CBT, family-focused therapy,
interpersonal and social rhythm therapy, and peer support programs are all helpful
with maintaining treatment adherence and prevention of symptom recurrence.91
COMPLEMENTARY AND ALTERNATIVE THERAPY. Neurologists should be well prepared

to know about the efficacy and safety of complementary and alternative
medicine treatments available for mood disorders.92 Many patients believe
that terms such as “healthy” and “no side effects” are related to these “herbal”
remedies. These beliefs underestimate their potential harm. Potentially serious
adverse effects of herbal remedies include, for example, hepatotoxicity with
kava and anticoagulation with chamomile. The safety and efficacy of the use
of these remedies during pregnancy are not known. Epidemiologic studies
suggest that 30% to 43% of patients treated in primary care for depression use
complementary and alternative medicine remedies as at least part of their
treatment. It is always prudent for the clinician to take a detailed history of
supplement use. TABLE 10-693 lists alternative treatments available and in
use today.
A meta-analysis on curcumin use for depression found an overall significant
effect of curcumin on depressive episodes.94 Curcumin has received recognition
for its multiple health benefits, which appear to act primarily through its
antioxidant and anti-inflammatory mechanisms. Inflammation has been
identified as the precursor in the development of many conditions, including
Alzheimer disease, PD, MS, epilepsy, and traumatic brain injury.94
The combination of methylcobalamin 2 mg and N-acetylcysteine 600 mg is a
nutraceutical that increases glutathione and reduces oxidative damage. It is used
as an adjunctive to antidepressant therapy for psychiatric indications such as
depression and dementia.95 L-Methylfolate is another nutraceutical that has
shown promise in managing treatment-resistant depression as an add-on to
initial antidepressant therapy. L-Methylfolate is a prescription-strength form of
the B vitamin folate and helps regulate the neurotransmitters in the brain that

MOOD DISORDERS
control mood. L-Methylfolate was shown in a 2013 study to enhance

antidepressant response; 376 patients (67.9%) responded to treatment with
96
L-methylfolate and had a 50% reduction in PHQ-9 score, which reflected a
reduction of symptoms. The quality of life and responses to medication
satisfaction questions, with the primary outcome being a change in depression
severity from baseline to end point, showed improvement.
TABLE 10-6 Herbal Supplements and Nutraceuticals That Have Been Used to Treat
Mood Disordersa
Name Uses Interactions/side effects
St. John’s wort Depression Antidepressants, strong painkillers, oral

contraceptives, some cancer drugs, some epilepsy
drugs, digoxin, human immunodeficiency virus (HIV)
medicines, and some anticoagulation agents
Valerian Anxiety Sedatives, alcohol, oral contraceptives, HIV

medicines, cancer treatments, epilepsy medicines,
antifungal treatments, and anticoagulant agents
Passionflower Anxiety, nervous tension, as Some anticoagulant agents

a mild sedative
Flower essences Anxiety, panic, trauma Not known
Roseroot/rhodiola Anxiety, tiredness, improving None reported

concentration, and memory
Sage Depression and anxiety, Anticoagulant agents such as aspirin, ibuprofen and
improving memory warfarin, antidepressants, and anticonvulsants
Chamomile As a mild sedative Anticoagulant agents and oral contraceptives
L-Methylfolate (Deplin) Mild dementia, depression Rash, itching/swelling (especially of the face,
tongue, and throat), dizziness, trouble breathing
L-Methylfolate calcium, algae-S Depression Rash, itching/swelling (especially of the face,

powder, methylcobalamin, tongue, and throat), dizziness, trouble breathing
N-acetylcysteine
Curcumin/turmeric Depression Diarrhea, headache, rash, and yellow stool
Omega-3 fatty acids Mild dementia, depression Stomach upset, fishy taste, risk of bleeding when
combined with anticoagulants
Magnesium Depression, anxiety Diarrhea, muscle weakness, bradycardia
S-Adenosylmethionine Depression With tricyclic antidepressants, may accelerate

action
Phosphatidylserine Attention deficit No significant side effect

hyperactivity disorder,
mood disorders
Green tea Depression Headache, insomnia, diarrhea, vomiting, tachycardia,

dizziness
a
Data from Rethink Mental Illness.93
1732 DECEMBER 2021

CONCLUSION
Depressive disorders and bipolar disorders are pervasive emotional disturbances
that significantly affect the quality of life and increase the risk for suicide.
They are frequent comorbidities seen in patients with neurologic disorders
and chronic medical conditions. When untreated, they can lead to increases
in mortality and morbidity and a decrease in quality of life. Comprehensive
evaluation includes a thorough history, physical examination, relevant
laboratory investigations, and neuroimaging if needed. Treatment should focus
on pharmacologic management as well as psychological and psychosocial
interventions with increasing options for neuromodulation modalities.
USEFUL WEBSITES
NATIONAL ALLIANCE ON MENTAL ILLNESS AMERICAN PSYCHIATRIC ASSOCIATION
The National Alliance on Mental Illness (NAMI) is one The American Psychiatric Association is an
of the nation’s largest grassroots mental health organization of psychiatrists working together to
organizations that advocate for people with mental promote the highest-quality and effective care for
illness. NAMI provides education, public awareness, individuals with mental illness including substance
and support for people with mental illness and for use disorders.
their families. psychiatry.org
nami.org/About-Mental-Illness/Mental-Health- psychiatry.org/psychiatrists/practice/clinical-
Conditions/Bipolar practice-guidelines
nami.org/About-Mental-Illness/Mental-Health- psychiatry.org/psychiatrists/practice/dsm
Conditions/Depression
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96 Shelton RC, Sloan Manning J, Barrentine LW, Tipa
recovery-oriented psychosocial interventions
EV. Assessing effects of L-methylfolate in
for bipolar disorder: quality of life outcomes,
depression management: results of a real-world
stage-sensitive treatments, and mindfulness
patient experience trial. Prim Care Companion
mechanisms. Clin Psychol Rev 2017;52:148-163.
CNS Disord 2013;15(4):PCC.13m01520.
doi:10.1016/j.cpr.2017.01.002
doi:10.4088/PCC.13m01520
DISCLOSURE
:Continued from page 1712
medicine treatments for the treatment of mood

disorders; electroconvulsive therapy and
transcranial magnetic stimulation for mania;
ketamine infusion for depression; neuromodulation
techniques such as transcranial direct current
stimulation and deep brain stimulation for the
treatment of depression; psychopharmacologic
treatments and transcranial magnetic stimulation
for multiple sclerosis; and risperidone for
adjunctive treatment of depression.

REVIEW ARTICLE

Obsessive-Compulsive
ONLINE
Disorders
By Carol Mathews, MD
ABSTRACT
PURPOSE OF REVIEW: This article describes the phenomenology and clinical
presentation of obsessive-compulsive disorder (OCD), a common but
underdiagnosed psychiatric disorder. Guidance for effectively identifying
obsessive-compulsive symptoms is provided, and treatment options,
including psychotherapy, pharmacologic management, and
neuromodulation approaches for treatment-resistant OCD, are discussed.
RECENT FINDINGS: OCD affects 2% to 3% of adults worldwide and is associated

with substantial individual disability and societal costs. Lack of recognition
CITE AS: of common OCD symptom types, in addition to shame and fear of stigma on
CONTINUUM (MINNEAP MINN) the part of patients, has created an average delay in diagnosis by almost
10 years and a delay in effective treatment (ie, a treatment gap) of nearly
2 years. Cognitive-behavioral therapy (CBT), specifically a form of CBT that
Address correspondence to includes a type of behavioral intervention called exposure and response
Dr Carol Mathews, 100 S Newell
prevention, remains the most effective form of treatment for OCD. If CBT is
Dr, Gainesville Florida, 32610,
carolmathews@ufl.edu. not effective or not available, pharmacologic treatment with selective
serotonin reuptake inhibitors (SSRIs) or clomipramine, a nonselective
Dr Mathews has received
serotonin reuptake inhibitor, can also be of benefit. Neuromodulation
research/grant support from the approaches such as deep brain stimulation and transcranial magnetic
National Institutes of Health stimulation are rapidly emerging as effective treatments for OCD,
(R01MH117114, R01NS105746,
R61AT009988, R01NS102371) and particularly for patients who have not experienced an adequate response
publishing royalties from W. W. to psychotherapy or pharmacologic management.
Norton & Company, Inc.
UNLABELED USE OF SUMMARY: OCD affects more than one in every 50 adults in the United States
PRODUCTS/INVESTIGATIONAL but is recognized and adequately treated in fewer than half of those affected.
USE DISCLOSURE:
Dr Mathews discusses the
Early intervention and appropriate treatment can substantially reduce OCD
unlabeled/investigational use of symptom severity, improve quality of life, and minimize the functional
aripiprazole, celecoxib, disability associated with this chronic and often debilitating illness.
citalopram, duloxetine,
escitalopram, haloperidol,
ketamine, lamotrigine,
memantine, N-acetylcysteine,
ondansetron, pindolol, riluzole, INTRODUCTION
O
risperidone, topiramate,
bsessive-compulsive disorder (OCD) is a chronic and, at times,
transcranial direct current
stimulation, transcranial debilitating neuropsychiatric illness that affects approximately
magnetic seizure therapy, vagus one in every 50 people (more than 8 million in the United States
nerve stimulation, and
venlafaxine for the treatment of
alone). It is one of the most common psychiatric illnesses in
obsessive-compulsive disorder. adults worldwide; only depression, substance abuse, hoarding
disorder, and social anxiety disorder have higher prevalence rates.1,2 OCD has a
© 2021 American Academy profound negative impact on functioning and quality of life for those who are
of Neurology. affected and levies substantial costs at the individual, familial, and societal
1764 DECEMBER 2021

levels.3,4 According to the World Health Organization and the Global Burden of KEY POINT
Disease Study, OCD is one of most impairing noncommunicable diseases
● Although obsessions and
globally, with the number of years of life lost to disability and all-cause mortality compulsions are the core
similar to that of schizophrenia and higher than many neurologic disorders, features of obsessive-
including epilepsy.5,6 In addition to the direct costs associated with treatment for compulsive disorder (OCD),
OCD and increased utilization of health care services because of comorbidities or avoidance of situations or
events that may trigger
other related health conditions, OCD is associated with substantial indirect costs
obsessions is also common.
to society and national economies, including reduced productivity (>30% of
individuals with OCD are underemployed or unemployed), reduced income, and
a high number of days off work.6 OCD is also associated with increased caregiver
burden and therefore decreased productivity, functioning, and quality of life,
particularly for parents and intimate partners of individuals with OCD.7
Although OCD is considered to be a chronic (and therefore, incurable) illness,
for most patients, effective treatments do exist, both pharmacologic and
psychotherapeutic; appropriate treatment can reduce symptomatology, improve
individual functioning, decrease disability, reduce caregiver stress, and lessen
the economic costs of this common disorder. Unfortunately, OCD is
underrecognized by the lay public and underdiagnosed by clinicians; as a result,
many people with OCD remain untreated or experience a delay in appropriate
diagnosis and treatment. The average time from onset of symptoms to diagnosis
and treatment is 8 to 10 years; this lag is caused by the failure of clinicians, both in
primary care and in specialty settings, to effectively screen for or recognize OCD
symptoms and is exacerbated by shame, stigma, and fear of OCD symptoms
being misunderstood as psychosis or worse on the part of patients.6,7 Clinicians,
particularly those who are not mental health experts, may be reluctant to ask
about OCD symptoms for fear of asking the wrong questions, not knowing how
to discriminate between obsessions and other psychiatric or behavioral
problems, or concern that they would not know what to do if they do find that a
patient has OCD. However, it is clear that assessing for OCD symptoms, even if
imperfectly, can not only effectively identify individuals who have the disorder
but also help to destigmatize the condition, prompting many to then seek out
appropriate treatment.
EVALUATION OF OBSESSIVE-COMPULSIVE DISORDER

The core features of OCD are the presence of obsessions (thoughts) and/or
compulsions (behaviors) that are time-consuming, are distressing, cause
functional impairment, or all three.2 Most patients with OCD will have both
obsessions and compulsions, but some may have one type of symptom and not
the other. Avoidance behaviors, which are not listed in the formal diagnostic
criteria according to the Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5), are nevertheless also often prominent features of OCD.
Obsessions are defined as recurrent, repetitive, intrusive, unwanted, and
uncomfortable thoughts, images, impulses, or urges that cause sufficient distress
or anxiety that the person experiencing them will attempt to ignore, suppress, or
neutralize them, for example, by performing a compulsion.2 Compulsions are
repetitive ritualized behaviors that the person recognizes as unreasonable,
unrealistic, or excessive but feels driven to perform to reduce anxiety, usually
(although not always) in response to an obsession.2 Compulsions are often
performed a specific number of times or according to rigid rules and must be
reperformed if not done exactly according to those rules the first time. In some

OBSESSIVE-COMPULSIVE DISORDERS
TABLE 12-1 DSM-5 Diagnostic Criteria for Obsessive-Compulsive Disordera
A Presence of obsessions, compulsions, or both:

Obsessions are defined by (1) and (2):
1 Recurrent and persistent thoughts, urges, or images that are experienced, at some time
during the disturbance, as intrusive and unwanted, and that in most individuals cause
marked anxiety or distress.
2 The individual attempts to ignore or suppress such thoughts, urges, or images, or to
neutralize them with some other thought or action (i.e., by performing a compulsion).
Compulsions are defined by (1) and (2):
1 Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying,
counting, repeating words silently) that the individual feels driven to perform in response
to an obsession or according to rules that must be applied rigidly.
2 The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or
preventing some dreaded event or situation; however, these behaviors or mental acts are
not connected in a realistic way with what they are designed to neutralize or prevent, or are
clearly excessive.
Note: Young children may not be able to articulate the aims of these behaviors or mental
acts.
B The obsessions or compulsions are time-consuming (e.g., take more than 1 hour per day) or
cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
C The obsessive-compulsive symptoms are not attributable to the physiological effects of a
substance (e.g., a drug of abuse, a medication) or another medical condition.
D The disturbance is not better explained by the symptoms of another mental disorder
(e.g., excessive worries, as in generalized anxiety disorder; preoccupation with appearance,
as in body dysmorphic disorder; difficulty discarding or parting with possessions, as in
hoarding disorder; hair pulling, as in trichotillomania [hair-pulling disorder]; skin picking,
as in excoriation [skin-picking] disorder; stereotypies, as in stereotypic movement
disorder; ritualized eating behavior, as in eating disorders; preoccupation with substances
or gambling, as in substance-related and addictive disorders; preoccupation with having
an illness, as in illness anxiety disorder; sexual urges or fantasies, as in paraphilic
disorders; impulses, as in disruptive, impulse-control, and conduct disorders; guilty
ruminations, as in major depressive disorder; thought insertion or delusional
preoccupations, as in schizophrenia spectrum and other psychotic disorders; or repetitive
patterns of behavior, as in autism spectrum disorder).
Specify if:
With good or fair insight: The individual recognizes that obsessive-compulsive disorder
beliefs are definitely or probably not true or that they may or may not be true.
With poor insight: The individual thinks obsessive-compulsive disorder beliefs are probably
true.
With absent insight/delusional beliefs: The individual is completely convinced that
obsessive-compulsive disorder beliefs are true.
Specify if:
Tic-related: The individual has a current or past history of a tic disorder.
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

a
Reprinted with permission from American Psychiatric Association.2 © 2013 American Psychiatric
Association.
1766 DECEMBER 2021

cases, compulsions are performed not according to a specific set of rules but KEY POINT
instead until they feel “just right” or “complete” in some unpredefined way. For
● Formal assessment of
the majority of patients with OCD, obsessions are experienced as ego-dystonic, OCD is typically conducted
or inconsistent with their underlying belief systems, personalities, and view of using standardized
reality; in other words, they are recognized as illogical and not grounded in assessments, but one or two
reality. Similarly, the performance of compulsions gives no pleasure to the questions can be effective
screening tools in a busy
individual experiencing them.8 Instead, obsessions cause anxiety, and the
clinical practice.
resulting compulsions or avoidance behaviors provide a sense of relief rather
than a sense of reward. TABLE 12-1 outlines the current DSM-5 diagnostic
criteria for OCD.
As with most psychiatric disorders, no formal diagnostic testing or laboratory
evaluations are particularly useful in making a diagnosis of OCD. However,
medical conditions such as brain injury or peripheral neuropathy; metabolic or
endocrine disorders such as hypothyroidism or diabetes; infections of the
central nervous system; autoimmune disorders (in particular autoimmune
encephalopathy); and neurologic disorders such as Parkinson disease, dementia,
or multiple sclerosis can be associated with obsessive-compulsive symptoms. If
other clinical signs or symptoms raise suspicion for one of these disorders, the
appropriate workup should be pursued before initiating treatment for OCD.
Formal assessment of OCD is often conducted using a standardized
questionnaire such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),9
which asks about the presence or absence of specific types of obsessions and
compulsions and subsequently assesses the distress, amount of time consumed,
and functional impairment associated with OCD symptoms. Initial screening for
OCD in a clinical setting does not require administration of the Y-BOCS, which
can take up to an hour, but can instead be accomplished by asking two basic
questions that assess for the likely presence of obsessions and compulsions. If the
answer to both of the following questions is no, then the likelihood of OCD is
very low. If the answer to either of these questions is positive, further assessment
using the Y-BOCS or a similar instrument is warranted.
u To identify patients who may be experiencing obsessions, ask: “Have you ever been
bothered by repeated intrusive thoughts that did not make any sense to you and kept
coming back even when you tried not to have them or tried to suppress them?”
u To identify patients who may be experiencing compulsions, ask: “Do you have any rituals,
thoughts, or behaviors that you feel that you have to do or think over and over, cannot
resist doing, or have to do repeatedly until it is done exactly correctly or until it feels
just right?”
In a clinical setting, the proportion of patients who answer positively to either

or both of these questions (or to similar questions) is likely to be high; this does
not mean that everyone who has a positive screen will have OCD. Symptoms that
are superficially similar to obsessions and compulsions can also occur in many
other neuropsychiatric disorders (eg, ruminations in depression or generalized
anxiety disorder, tics in Tourette syndrome, or perseverations in autism
spectrum disorder). Obsessive-compulsive behaviors can also occur in conditions
other than OCD, such as autism spectrum disorder, dementia and other
neurodegenerative disorders, and schizophrenia. Because the prognosis and
treatment of each of these disorders differ, it is important that clinicians are able
to effectively differentiate OCD from other neuropsychiatric illnesses with
overlapping or similar presentations. The similarities and differences between

obsessions, compulsions, and other similar symptoms are outlined in TABLE 12-2
and TABLE 12-3.
Obsessions and compulsions can be subgrouped into thematic categories:
contamination and cleaning; taboo thoughts or fears; fear of harm; symmetry,
superstition, and perfectionism; somatic fears; and hoarding.10,11 Most people
with OCD will have many different types of obsessions and compulsions from
most, if not all, of these subtypes over the course of their lifetimes. Fear of
contamination and the resulting compulsions to clean excessively or ritualistically
are perhaps the most well-known type of OCD symptom. Contamination obsessions
take many forms and are not limited to fears of becoming sick. Individuals
with OCD may fear becoming contaminated from germs or sticky surfaces,
insects or animals, or food. They may also fear being contaminated by someone
else’s personality, sexuality, habits, or behaviors. Cleaning behaviors resulting
from contamination fears can involve oneself, others, or objects. Ritualized
handwashing or showering; excessive toilet or grooming routines; repeated or
ritualized washing of laundry, surfaces, or possessions; and excessive or
inappropriate use of cleaning agents are all examples of cleaning compulsions.
Taboo fears typically fall into three main types: sexual, religious, and
aggressive. Sexual obsessions can present as repeated fears that one has
inadvertently behaved in an inappropriate sexual manner, unwanted
uncomfortable sexual images or thoughts, or repetitive intrusive fears that one is
unknowingly of a different sexual orientation or gender. It is critical to remember
that these types of thoughts are OCD symptoms, and as such, they are
TABLE 12-2 Distinguishing Obsessions From Other Similar Thought Patterns
Obsessions Ruminations Delusions Overvalued ideas Perseveration
Ego-dystonic or Ego-dystonic Ego-syntonic Ego-syntonic Ego-syntonic Ego-syntonic

ego-syntonic
Pattern Content of specific Fluid reworking Typically Reasonable Excessive and

obsessions are of content over fixed conventional belief narrow focus on
fixed rather than and over to find content, can but oversubscribed a specific belief
fluid; can different/ generalize to by the individual or desire
generalize alternative
scenarios
Recognized Yes Yes No No No

as excessive
Examples Fear of contamination Repeated Belief that one Persistent belief Repeated thoughts
when touching a reworking of a past is being that one is regarding ways to
doorknob, unwanted social situation followed by overweight despite obtain a desired
urges to or thoughts (such as a romantic the Mafia or being of normal but inaccessible
that one might date) that did not being taken body weight, item or relationship,
inadvertently swerve go as expected in over by aliens insistence on overfocus and
car into traffic an attempt to proselytizing to a repeated thoughts/
identify possible specific belief discussion of a
different system in an perceived slight or
theoretical inappropriate injury out of
outcomes context proportion to the
event
1768 DECEMBER 2021

ego-dystonic, uncomfortable, and unwanted; they are not acted on, nor are they
realistic. Examples of common sexual obsessions include fearing that one is a
pedophile or has unknowingly or inadvertently inappropriately touched a child
(eg, when changing a diaper during babysitting), fearing that sitting next to
someone of the same sex in a movie theater or classroom will confer homosexuality
or trigger inappropriate sexual behavior in the person with OCD, and intrusive
unwanted sexual or explicit images of family members or friends or strangers.
Religious obsessions (which do not require a religious background or belief to
occur) include fears such as unintentionally or inadvertently offending God or
blaspheming, fears of religious objects or symbols, and superstitious fears of
symbols that have a religious history or meaning (eg, the fear that seeing the
number 666 will result in something bad happening or harm coming to someone).
Aggressive obsessions, which differ from fears of harm, include uncomfortable
ego-dystonic thoughts or urges to cause harm to oneself or others, including fears,
impulses, or urges to touch hot surfaces such as stoves or fires; fears of being around
knives or other sharp objects because of images of picking them up and cutting or
stabbing someone; urges to swerve a car or bicycle into oncoming traffic; and urges
or fears of blurting out something aggressive or offensive (eg, racial epithets).
Fears of harm, on the other hand, tend to be more passive in nature. These
obsessions include fears that one has inadvertently hit someone while driving,
with a concomitant urge to return to the scene and check for bodies or injured
people; fears that harm will come to another person because of something the
person with OCD either did or did not do; and fears that if an action or ritual is
not done in a particular way or a specific number of times, then someone will be
Distinguishing Compulsions From Other Similar Behaviors TABLE 12-3
Compulsions Habits Tics Stereotypies Perseverative behaviors
Involuntary versus Voluntary Both Involuntary Voluntary Voluntary

voluntary
Repetitive versus Ritualized Repetitive Repetitive Repetitive Repetitive

ritualized
Deliberate versus Deliberate Deliberate Nondeliberate Deliberate Nondeliberate

nondeliberate
Relief of anxiety or Relief Relief Relief Reward Reward

sensation or reward
Anxiety or discomfort Yes No Yes No No

generated when
attempting to stop
or suppress behavior
Examples Repeated ritualized Nail biting, Repetitive eye Hand flapping, Continued focus on
hand washing, hair twirling blinking, repeated body rocking a single topic of
checking multiple throat clearing conversation with
times to be sure inability to shift
stove is turned off topics, repeated
rereading of the
same comic book

harmed. Harm obsessions are often accompanied by checking behaviors,

including a frequent need to ask others for reassurance that the feared event did
not occur; checking to see that harm was not, in fact, done; and physically
checking oneself or others for injuries in the absence of a precipitating event that
could have caused injuries or harm. Superstitious obsessions (eg, worrying that
something bad will happen if a particular superstitious ritual is not followed) and
associated checking or avoidance behaviors also fall into this category.
Symmetry obsessions and compulsions include a perceived need for things to
be in a particular order or lined up in a certain way (eg, color coded), rewriting or
rereading over and over because of a perceived need for handwriting to look
“perfect” or a sentence to feel “just right,” evening up (such as doing the same
behavior with each arm to make it feel even or tying and retying shoelaces until
the pressure feels the same on both feet), or needing the television volume or
channel to be on an even or odd number. When symmetry symptoms are the
predominant or only type of OCD symptom, the clinician should spend some
time assessing for the underlying presence of a current or past tic disorder, as
these symptoms are much more common in individuals with Tourette syndrome
or other chronic tic disorders. Perfectionism obsessions and behaviors also fall
into the symmetry category. In addition to the symptom of needing things to look
or feel perfect as described above, perfectionism symptoms can also be expressed
as needing homework or other work or school assignments to be done perfectly
to the point that assignments will go unfinished because the patient can never
achieve perfection. Avoidance is also commonly seen when perfectionism is
present because of the feeling that if perfectionism cannot be achieved, then it is
futile to begin an assignment or a project at all.
Somatic fears tend to fall into two primary types: unreasonable excessive fears
that the person with OCD has contracted an illness (including noncommunicable
illnesses such as cancer) and fears that something (often something indefinable)
is wrong with a body part or feature. These symptoms can be difficult to
distinguish from symptoms of other related psychiatric illnesses, such as illness
anxiety disorder and body dysmorphic disorder. These disorders should be
carefully assessed for if somatic symptoms are identified. Somatic symptoms can
also occur in the context of contamination fears; for example, someone who
obsessively worries about contracting or transmitting herpes simplex (often in
the absence of any evidence of an actual infection) may compulsively check to
make sure they have no lesions on their lips or mouth. As with other OCD
symptoms, somatic obsessions are ego-dystonic. In contrast, when such somatic
preoccupations are the primary focus in body dysmorphic disorder or illness
anxiety disorder, the individuals experiencing these disorders are less likely to
have insight into the irrational or excessive nature of their fears.
The final category of OCD symptom types is hoarding behaviors.
Understanding and assessing for this category of symptoms is complicated by the
fact that hoarding disorder is a distinct neuropsychiatric illness, albeit one that
was once thought to be a subtype of OCD. The hoarding symptoms that occur in
hoarding disorder and those that occur in OCD differ in both content and intent.
Individuals with hoarding disorder tend to save everyday items such as papers,
containers, clothes, household items, tools, and sentimental objects, usually
because of the thought that the item might be needed or wanted again, either
for a concrete purpose or to preserve a memory or important piece of
information. In OCD, hoarding behaviors are explicitly due to obsessional fears
1770 DECEMBER 2021

(eg, contamination fears or fears of harm), and the items hoarded are more likely KEY POINTS
to be unusual or bizarre (eg, saving fingernail clippings for fear that someone
● The content of
could harvest DNA from them and cause harm to a person). Up to 30% of people obsessions and compulsions
who present with OCD will also have co-occurring hoarding disorder, however, can be grouped into several
as these two disorders are related. thematic categories (eg,
When evaluating someone for OCD, it is important to ask about symptoms in all contamination and cleaning
or taboo thoughts).
of the categories as well as asking about the person’s own understanding of their
symptoms. Most people with OCD will know that their fears and behaviors do not ● Obsessions and
make sense (ie, are irrational or excessive) (CASE 12-1). Some will suspect that they compulsions regarding
have OCD based on their knowledge of the illness from the media or their own symmetry are more
research, especially if they experience some of the better-known OCD symptoms common in individuals with
co-occurring chronic tic
such as contamination fears, cleaning obsessions, or repeated checking. Others, disorders.
however, particularly those who have taboo symptoms or some of the other lesser-
known symptom types, will fear that their symptoms indicate that something is ● Somatic and hoarding
fundamentally wrong with them as a person or that something is seriously wrong symptoms can occur either
in OCD or as a part of other
with their mental function (ie, that they are “crazy”). For this reason, patients with related disorders, such as
OCD may be reluctant to disclose their symptoms without specific prompting. body dysmorphic disorder,
illness anxiety disorder, or
EPIDEMIOLOGY OF OBSESSIVE-COMPULSIVE DISORDER hoarding disorder.
OCD is equally common in males and females (the male to female ratio is
● OCD affects
between 1:1 and 1:1.5), although the age of symptom onset differs somewhat approximately 2%
between the sexes. The lifetime prevalence of OCD is between 2% and 3%, and to 3% of adults.
the prevalence of subclinical OCD symptoms is estimated to be as high as 25% in
the adult population.6 For the vast majority of patients, symptoms begin in ● The presence of one or
more psychiatric disorders
adolescence or early adulthood; the age of onset is thought to be bimodal, with a co-occurring with OCD is the
first peak in childhood (75% of those affected, mean age of onset 11 years) and a rule rather than the
second peak in early adulthood (mean age of onset 23 years).6 Boys tend to have exception.
an earlier age of onset than do girls, with a substantial proportion experiencing
their first symptoms before age 10.6,9 Although most girls will also have symptom
onset in early adolescence, for some women, reproductive events such as
pregnancy or childbirth and even, in rare cases, menopause can trigger OCD
symptoms.9 Males with OCD, especially those whose symptoms begin early in
childhood, are more likely to have a co-occurring tic disorder; females with early
onset of symptoms, particularly those with prominent symmetry or “just right”
symptoms (the need to repeat a simple activity over and over again until it feels
“just right” or complete), may also be at higher risk for tic disorders. Girls (and,
increasingly, boys) who have somatic or body-related symptoms may also be at
risk for developing body dysmorphic disorder or an eating disorder.12
The majority of adults presenting for clinical care of OCD will meet lifetime
criteria for another psychiatric disorder, most commonly depression (up to 65%)
or an anxiety disorder (60% to 90%).1,9 Tic disorders occur in up to 30% of
individuals with OCD,2 and attention deficit hyperactivity disorder in up to
20%.9 These co-occurring disorders contribute to poorer quality of life and
worsened functioning when present, and, if not addressed, they can also
adversely impact effective treatment of OCD.9
ETIOLOGY AND PATHOPHYSIOLOGY OF OBSESSIVE-COMPULSIVE

DISORDER
The etiology of OCD is complex and multifactorial. Although genetic factors
clearly contribute to OCD susceptibility, heritability estimates are between 30%

and 65%, with symptom onset in childhood having a higher heritability than
symptom onset in adulthood. The moderate heritability estimates indicate that
environmental factors as yet unknown also contribute to the development of
OCD. Prenatal and perinatal complications, stress, traumatic brain injuries such
as mild concussion, and inflammatory responses to bacterial or viral infections
have all been postulated to contribute to the development of OCD symptoms,
although none of these has been consistently or reliably associated with OCD13
and thus no formal assessment of such potential contributors is recommended.
OCD is a disorder of neural circuitry. Although multiple brain regions are
associated with OCD pathogenesis, those involved in the cortico-striato-thalamo-
cortical circuits are the most strongly implicated.9,14 These parallel circuits
mediate emotional/affective, sensorimotor, cognitive, and motivational
processes, all of which are important in OCD pathophysiology. Roughly
speaking, the affective circuitry (ventromedial prefrontal cortex, anterior
cingulate cortex, nucleus accumbens, and thalamus) and cognitive circuitry
(dorsal: dorsolateral prefrontal cortex, caudate, and thalamus; and ventral:
anterolateral orbitofrontal cortex, putamen, and thalamus) are involved in
obsessive symptomatology (anxiety, uncertainty with regard to goal-directed
behaviors, and response inhibition). The sensorimotor circuitry (premotor
cortex, putamen, and thalamus) and the frontoparietal network (parietal lobe,
CASE 12-1 A 19-year-old man presented with fears of contamination and excessive
cleaning symptoms. His girlfriend, who suggested the appointment, was
concerned because he was spending up to 2 hours a day “cleaning” the
air in their apartment with air fresheners and felt compelled to shower
every time he left the home and returned, even when just going
downstairs to the lobby to get the mail from the mailbox. He reluctantly
agreed to come to the appointment because his behaviors were
beginning to cause problems in his relationship with his girlfriend, who
was worried about the potential adverse health effects of his excessive
use of air freshener and cleaning agents. Although he admitted to
spraying air freshener in the house over and over and to showering every
time he returned from leaving the house, he denied any fears of germs or
illness. He admitted to a variety of additional cleaning behaviors,
including needing to wash his clothing daily and to change his clothes
multiple times a day, as well as too frequent hand washing. He
recognized these behaviors as excessive and admitted that they were not
logical. When asked specifically about taboo symptoms, he admitted that
when he came into contact with, or was in the vicinity of, another person,
especially someone unknown to him, he was afraid that he would
somehow become contaminated by that person’s essence and take on
their characteristics, becoming less like himself and more like the other
person. He also feared that if the other person had a belief system that
differed from his, or expressed an idea that he did not agree with, he
would take on that belief or idea also just by being in their proximity. He
did not feel this way around family members. He fully recognized that his
fears were irrational but noted that he could not control them and felt
1772 DECEMBER 2021

sensorimotor area, inferior frontal gyrus, and ventrolateral prefrontal cortex) are
thought to be involved in the development of compulsive (habit-based)
behaviors.9,14
Although many neurotransmitters are likely to be relevant in the development
or maintenance of psychiatric symptoms, evidence from clinical and preclinical
studies indicates that serotonin, dopamine, and glutamate may be of particular
relevance for OCD. These neurotransmitter systems are active within the
cortico-striato-thalamo-cortical circuits, and pharmacologic agents that affect
the serotonergic and dopaminergic systems have proven to be effective
treatments for OCD. The evidence for the role of serotonin comes primarily from
the observation that clomipramine and the SSRIs effectively treat OCD
symptoms; less is known about its putative mechanism of action, although
serotonergic neurons project to key regions within the cortico-striato-thalamo-
cortical circuitry from the raphe nucleus. Dopamine has been implicated in OCD
symptomatology both from observations drawn from treatment studies using
neuroleptics and, more importantly, from the fact that dopamine plays a
significant role in the development of automatic grooming and other habit-based
behaviors in animals. The potential role of glutamate comes primarily from
knowledge of its key role in the cortico-striato-thalamo-cortical circuitry;
glutamatergic neurons project bidirectionally between the cortex and regions in
compelled to clean everything on his person and in his apartment,

including the air he breathed, to avoid being contaminated in the way that
he feared. The patient had tried to resist the thoughts and related
behaviors, which had been present since he was 16, without success. He
had recently also been experiencing depressive symptoms, including
social isolation, sadness and hopelessness, and excessive sleeping. He
was relieved to know that his symptoms had a name and a treatment and
was interested in both pharmacologic management and behavioral
therapy to treat them.
This man has contamination obsessions. Fear of being contaminated by COMMENT

another person’s personality, aura, or essence, although less common than
germ fears, are still quite common and are less likely to be disclosed unless
patients are directly asked about them because of fear of being ridiculed
or thought to be psychotic. Effective treatment for this type of symptom
involves exposure and response prevention approaches to reduce and
eventually eliminate the compulsive behaviors and to reduce the intensity
of the fears. Pharmacologic management with selective serotonin reuptake
inhibitors (SSRIs) can also be of benefit, not only for the obsessive-
compulsive disorder symptoms but also for the depression symptoms that
he has recently developed. Although each of these forms of treatment can
be effective on its own, combining exposure and response prevention and
pharmacologic treatment with an SSRI increases the likelihood of response
and often produces an additional reduction in symptoms over and above
either treatment alone.

FIGURE 12-1
Suggested treatment algorithm for obsessive-compulsive disorder (OCD) in adults.
CBT = cognitive-behavioral therapy; DBS = deep brain stimulation; ERP = exposure response prevention; rTMS = repetitive transcranial magnetic
stimulation; SSRI = selective serotonin reuptake inhibitor.
a
Severity of OCD as determined by Obsessive-Compulsive Inventory, Short Version (OCI-R) scores: mild (scores of 15-19), moderate (20-34), and
severe (≥35). If OCD is suspected according to OCI-R score or clinical history, the Yale-Brown Obsessive Compulsive Scale may be administered
for further assessment of obsessive-compulsive and associated symptoms.
b
There is insufficient evidence to support the superiority of one particular SSRI over any other; all appear to have similar efficacies.
Reprinted with permission from Hirschtritt ME, et al, JAMA.7 © 2017 American Medical Association.
1774 DECEMBER 2021

the striatum and are responsible for excitation of the cortex.9 Some early KEY POINTS
evidence also indicates a role of glutamatergic genes in the development of OCD.
● Early intervention is
Glutamatergic agents have been studied for the treatment of OCD, but, to date, critical for improving quality
none have been consistently demonstrated to be of benefit.7,9 of life in OCD and the
likelihood of functional
TREATMENT OF OBSESSIVE-COMPULSIVE DISORDER remission.
Although OCD is a chronic disorder, early intervention can be effective in
● Obsessive-compulsive
reducing symptom severity and improving quality of life and functioning.6,7,9 symptoms are often missed
For some patients, perhaps as many as 50%, functional remission (eg, minimal or misdiagnosed by
residual symptoms that are not perceived to be functionally impairing to the clinicians, in part because
patient) can be achieved with early and appropriate treatment.6,15-17 the symptoms are confused
with other similar
Unfortunately, the current treatment gap for OCD (the time between seeking symptoms.
help for a medical problem and receiving appropriate care) is approximately
2 years.18,19 This delay puts patients at higher risk for a more chronic and ● The most effective form
intractable course of illness and suggests that many providers, including mental of treatment for OCD is a
form of cognitive-behavioral
health professionals, do not effectively identify and treat OCD when patients do therapy called exposure and
present for care. Three contributors to this treatment gap have been identified: response prevention.
(1) misidentification of OCD symptoms (particularly sexual, religious, or
aggressive symptoms) as something else; (2) referral to non–evidence-based
forms of treatment, such as psychodynamic or supportive psychotherapy; and
(3) use of ineffective pharmacologic agents or use of effective pharmacologic
agents at subtherapeutic doses or for suboptimal lengths of time.20
Three primary types of effective treatment are available for OCD: (1)
cognitive-behavioral therapy (CBT), (2) pharmacologic management, and (3)
neuromodulation.9 For most people with OCD, the most effective forms of
treatment continue to be those that have been in place for decades.8 Despite
clinical trials examining other forms of treatment, the evidence base continues to
be the strongest for CBT and pharmacologic management or a combination of
the two.21-24 FIGURE 12-1 shows a suggested treatment algorithm.
For most providers, especially those who are not OCD specialists, the choice of
treatment is often driven by knowledge of, comfort with, and local availability of
the three primary treatment types. Although pharmacotherapy is the most
widely used, the most effective form of treatment for OCD is actually CBT, either
alone or in combination with medication; this form of treatment also has the
highest long-term response rates.7,25 Pharmacologic management primarily
consists of the use of high-dose SSRIs, with the use of additional agents as
augmentation as needed.7-9 Neuromodulation is a newer option and has shown
some benefit for patients who show inadequate response to more standard forms
of treatment, although it is still limited in availability and scope. Other important
interventions that are relevant and should be addressed regardless of the chosen
treatment modality include psychoeducation and the assessment and reduction
of family accommodation of symptoms.6,9,26,27 These interventions are not
considered to be actual treatments, but they can help to increase patient
engagement in treatment and facilitate treatment response.9
Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder

When it is available, the best treatment for OCD is CBT, particularly a form of
CBT that includes exposure and response prevention.7,21,22,28 Both the cognitive
and the behavioral components of CBT have some efficacy in treating OCD,
although somewhat stronger evidence exists for the efficacy of behavioral

interventions.29-32 The cognitive component of CBT consists primarily of cognitive

appraisal and cognitive restructuring.30,33 In the cognitive appraisal component,
patients are first asked to identify cognitive distortions, erroneous thought patterns,
and maladaptive beliefs associated with their OCD symptoms. Then, in the
cognitive restructuring component, they are asked to identify possible alternative
thought patterns or expected outcomes to distinguish what they fear will happen
from what they believe is the most likely logical outcome and to modify their
automatic and fear-driven interpretation or expectation to be more in line with
their own perception of reality. Acceptance of the thoughts or fears and tolerance of
the distress arising from them is also an important part of cognitive therapy.
The behavioral component of CBT, and exposure and response prevention
specifically, is the most common form of evidence-based psychotherapy for
OCD.7,34,35 In this treatment modality, the focus is on systematically reducing
and eventually eliminating the compulsive or avoidance behaviors that occur in
response to an obsession. Patients and therapists work together to identify and
rank the obsessions and associated compulsions according to the level of distress
they engender, creating a fear hierarchy. Potential behavioral exposures are then
identified for each fear listed, typically beginning with a fear that ranks
somewhat lower (ie, less distressing) on the fear hierarchy. As differences in
environment and situation may lead to different levels of fear or distress for the
same behavior (eg, eating at a possibly dirty table in one’s own home may be less
distressing than eating at a possibly dirty table in a restaurant for someone with
food contamination fears), the fear hierarchy typically includes behaviors
(including avoidance) in a variety of situations to create as rich a list of potential
exposures as possible.
A key element of exposure and response prevention is that exposure to the
feared situation or object occurs without the performance of the compensatory
compulsion; this is the response prevention piece of exposure and response
prevention. There are three forms of exposures: imaginal, in vivo, and
interoceptive.28 The first two are most commonly used in the treatment of OCD;
the third is more common in the treatment of panic and generalized anxiety
disorder.36 Imaginal exposures, which are usually fairly low on the fear hierarchy
and thus easier for a patient to complete, involve imagining the feared situation
and facing the anxiety associated with it without engaging in a compulsion or
avoidance behavior. In vivo exposures involve actual exposure to the feared
situation. A modified form of in vivo exposure that also sits lower on a typical
fear hierarchy is watching someone else in a feared situation, for example, in a
movie or other video clip. The next step in an in vivo exposure might be
watching, but not participating in, the feared situation in person (eg, watching a
therapist or family member eat a jellybean off a dirty surface), and the final step
might be having the patient perform the exposure along with the therapist.
Interoceptive exposures involve the same principles of exposure and response
prevention but are applied to the unpleasant physical sensations of anxiety, such
as hyperventilation or shortness of breath, rather than to a compulsion or other
behavior.36 In a clinical setting, these physical symptoms are typically induced by
standard exposure techniques, for example, by imagining or viewing a feared
object or experience (eg, seeing a picture of a spider if one is afraid of spiders).
Exposure and response prevention can be administered in multiple contexts
and multiple levels of intensity. Treatment sessions are typically an hour in
length and can be administered weekly or multiple times weekly in a standard
1776 DECEMBER 2021

outpatient setting or daily for several hours a day in intensive outpatient, partial KEY POINT
hospitalization, or residential treatment settings.9 Similarly, exposure and response
● The average number of
prevention can be administered in the context of individual or group treatment exposure and response
and is available via the internet and as a self-administration module.7,28,34,37,38 In all prevention sessions needed
forms, patients who are undergoing exposure and response prevention for OCD to attain a desired response
are typically asked to complete exposure and response prevention homework is 16 to 20.
between treatment sessions; usually, the homework is to be completed daily,
either for a prescribed period of time (eg, waiting for 15 minutes to wash one’s
hands) or for a prescribed number of repetitions (eg, driving by a particularly
feared intersection 2 times a day without going back to check whether an accident
had happened there). The assignment and completion of exposure and response
prevention homework is an integral part of effective treatment for OCD.
Multiple studies have examined the characteristics of CBT for OCD that are
the strongest predictors of treatment response, including the inclusion of a
cognitive component, the inclusion of a behavioral component (eg, exposure and
response prevention), the number and/or frequency of sessions, and treatment
adherence.9,28,31,34,39,40 Taken together, these studies indicate that number of
sessions matters (the minimum number of needed sessions for patients to show
an adequate response appears to be approximately 16 to 20) and that adherence
to both sessions and to assigned CBT homework are the strongest predictors of
treatment response.8,9,28,31,34,39-41 The modality (eg, group or individual) and
type of CBT (eg, cognitive therapy or exposure and response prevention) are not
clearly predictive of differential treatment response for patients with OCD,42
although some studies indicate increased benefit of exposure and response
prevention over purely cognitive approaches.31,32 The intensity or frequency of
treatment (eg, once or twice weekly, daily, or for multiple hours per day) does
not appear to predict treatment outcome in the long term, although some
evidence indicates that more intense treatment formats can lead to earlier
response.8,43 Predictors of lack of response that have been identified in some
studies but not others include severity of baseline symptoms, presence of
significant depressive symptoms, and level of insight into illness.28 It is important
to note that CBT for OCD can be effective in a variety of clinical settings and
under less-than-ideal conditions.34
Pharmacologic Treatment of Obsessive-Compulsive Disorder

Because patients with OCD may not have access to a therapist but will likely have
the ability to see a physician, most commonly a primary care provider,
pharmacologic management is often the first or most easily accessed treatment
option. Pharmacotherapy for OCD, as is the case for many psychiatric disorders,
began with a serendipitous discovery; clomipramine, a tricyclic antidepressant
that was used in the mid-1960s as a treatment for depression, was also associated
with an improvement in obsessional thoughts.8 This observation led to the use of
multiple tricyclic antidepressants for the treatment of OCD and the subsequent
finding that of all the medications in this class, only clomipramine was effective.8
The reason for this is likely because of an important difference in the chemical
structure of clomipramine compared to the other tricyclic antidepressants.
Although all tricyclic antidepressants act as inhibitors of norepinephrine
reuptake, as a tertiary amine, clomipramine acts as a more potent inhibitor of
serotonin reuptake than do the other tricyclics (eg, imipramine, desipramine, or
nortriptyline), which have little to no effect on serotonin reuptake.

Somewhat astonishingly, to date, medications that block serotonin reuptake

are the only class of drugs to have primary efficacy for the treatment of OCD; no
other class of medications, if used on its own, has been shown to be of benefit.
Today, although clomipramine remains an important treatment option, it is no
longer considered to be a first-line treatment, not because of lack of efficacy but
because of its substantial side effect burden at therapeutic doses. Instead, the
class of antidepressants called SSRIs has replaced clomipramine as the primary
treatment of choice for pharmacologic management of OCD.8 Although only
clomipramine and four SSRIs (fluoxetine, fluvoxamine, paroxetine, and
sertraline) have been approved by the US Food and Drug Administration (FDA)
for the treatment of OCD, evidence exists that all of the SSRIs (which, in the
United States, also include citalopram and escitalopram) are similarly
efficacious.44 Dual serotonin norepinephrine reuptake inhibitors (SNRIs) such as
duloxetine and venlafaxine have shown some efficacy but generally do not work
as well as SSRIs because the degree of serotonin reuptake blockade is lower.7,8
Current dosing recommendations for OCD treatment with SSRIs differ
substantially from those for depression treatment. OCD treatment guidelines
call for doses that are 2 to 3 times higher than are typically needed for
depression.7,9,44-46 In addition, for OCD, the SSRI dose should be titrated to the
highest expected effective dose at the beginning of treatment and maintained
throughout treatment. In contrast, treatment recommendations for depression
usually suggest titrating to the lowest expected effective dose and, once response
TABLE 12-4 Recommended Primary Pharmacologic Treatment Options for

Obsessive-Compulsive Disorder
Standard Recommended as FDA approved for treatment

Standard obsessive-compulsive first- or second-line of obsessive-compulsive
Medication depression dosesa disorder dosesa treatment disorder
Fluoxetine 40 mg 80 mg First Yes

b
Citalopram 40 mg 40 mg Second No
Clomipraminec 125 mg 250 mg Second Yes

d d
Duloxetine 60 mg 120 mg Second No
Escitalopram 20 mg 40 mg First No
Fluvoxamine 150 mg 300 mg First Yes
Paroxetine 40 mg 60 mg First Yes
Sertraline 100 mg 200 mg First Yes
Venlafaxine 150 mg 300 mg Second No
FDA = US Food and Drug Administration.

a
Doses are presented as dose equivalents using fluoxetine 40 mg as a reference and were derived from studies by Furukawa and colleagues46 and
Hayasaka and colleagues59 and are rounded to nearest available tablet/capsule.
b
Doses greater than 40 mg of citalopram are not recommended because of an FDA boxed warning regarding the potential for QT prolongation.
c
Despite evidence of primary efficacy in obsessive-compulsive disorder, clomipramine is recommended typically as a second-line agent because
of its high side effect burden.
d
Data on dose equivalents are not available; doses are based on FDA-recommended dosing for major depression.
1778 DECEMBER 2021

or remission is achieved, further titrating the dose down to a lower maintenance KEY POINTS
dose.46,47 TABLE 12-4 details the primary and secondary pharmacotherapeutic
● Only one class of
options for OCD, with associated doses. medications, the serotonin
Pharmacologic treatment for OCD should continue for 10 to 12 weeks to reuptake inhibitors, which
ensure adequate response before switching SSRIs or augmenting with another includes clomipramine and
agent.7,9,44 Results from two recent meta-analyses suggest that the highest the selective serotonin
reuptake inhibitors (SSRIs),
incremental gain from SSRI treatment occurs within 2 weeks of achieving an
is effective as a primary
adequate dose, but these studies also show that symptom improvement treatment for OCD; high
continues up through week 12.44,48 As most treatment studies do not follow doses and long treatment
participants past 12 weeks, little is known about whether continued treatment times are needed for
maximum benefit.
response occurs past that point. However, the slope of the curves in the primary
treatment studies and data from studies examining the role of augmentation of ● Adequate pharmacologic
SSRIs in treatment-resistant OCD indicate that continued response to an SSRI is response to treatment
seen as far out as 6 months in 10% to 30% of individuals (as indicated by the cannot be determined until a
response rate for the placebo arms of these augmentation studies).49,50 patient has been on a
selective serotonin reuptake
One possible way to integrate these findings clinically is to think of early inhibitor at an appropriate
robust response to treatment with an SSRI as a potential indicator of a good dose for at least 12 weeks.
prognostic outcome. Thus, patients who have an early response may not need
augmentation of their primary medication. In contrast, those who have a more ● Adjunctive medications
such as neuroleptics or the
delayed or less substantial response in the first few weeks of treatment may
addition of cognitive-
ultimately have insufficient benefit from an SSRI alone, and thus, the treating behavioral therapy to
clinician may consider augmenting the SSRI earlier in the course of treatment. As pharmacologic treatment
the first 2 to 4 weeks of treatment are typically dedicated to dose titration, leads to continued
improvement in up to 30%
noticeable treatment response is not necessarily expected to be apparent until
of patients with OCD.
weeks 4 to 6, that is, 1 to 2 weeks after reaching therapeutic doses.
So, what should be done for those who do not respond to an initial course of
SSRIs at the recommended higher doses? No answer to this question is
universally accepted, but the current literature suggests several possible courses
of action. The first is to add CBT to SSRI treatment; this approach has
consistently shown the most benefit for individuals who do not respond or who
have an inadequate response to an initial trial of medications.8,34,50 For those who
cannot or will not participate in psychotherapy, psychopharmacologic options
are also available. These include augmenting the SSRI with an additional agent,
switching the primary agent to another with known efficacy in OCD, switching
to a second-line agent, or using IV clomipramine. Of these, the first option is the
best studied and has the strongest evidence base.
Of the many drugs that have been examined as adjunctive medications in
OCD, the addition of a second-generation neuroleptic (in particular, either
aripiprazole or risperidone) has the strongest scientific support.8,49-51 Evidence
also supports the use of haloperidol, a first-generation neuroleptic.50,51 As many
as 30% of patients with an inadequate response to an SSRI will show benefit from
the addition of a neuroleptic medication. Other medications that have some
(albeit weak) evidence for potential benefit as an augmenting agent include
topiramate, pindolol, lamotrigine, memantine, and N-acetylcysteine.50 These
medications may be considered as augmenting agents in clinical practice only if
other choices have failed or are not an option and if the potential benefit is
thought to be higher than the potential risk, given that the current level of
evidence for their utility is low.
Another alternative is to switch primary agents, and some evidence also exists
for this approach.50 The preferred choice would be to switch to another SSRI

with an indication for OCD (TABLE 12-4); the second would be to switch to a
second-line agent such as clomipramine, venlafaxine, or duloxetine. If an
inadequate treatment response is seen with the second medication trial,
augmentation with a neuroleptic would again be suggested, particularly if adding
CBT is not an option, is not tolerated, or is ineffective. The final option before
moving to neuromodulation would be to try IV clomipramine.50 The evidence for
this strategy is limited to a few open-label trials and two randomized controlled
trials and indicates that for some patients, IV clomipramine may be effective,
although the appropriate doses and approach to maintenance are not determined.
For patients for whom these interventions have failed, neuromodulation
(specifically deep brain stimulation or transcranial magnetic stimulation) may be
an option.
Neuromodulation
Neuromodulation approaches such as deep brain stimulation and transcranial
magnetic stimulation are the most recent additions to the OCD treatment
armamentarium; in contrast to the psychotherapeutic and psychopharmacologic
approaches, which have remained stable for decades, neuromodulation
approaches are rapidly expanding as an area of scientific and clinical interest.
Although currently limited to patients with treatment-resistant OCD, if evidence
of their efficacy is confirmed, noninvasive approaches may also become widely
available to patients with less severe illness. Although neuromodulation can be
very effective, these interventions are rarely, if ever, appropriate for use as the
only form of treatment. Instead, they can best be thought of as increasing
neuroplasticity and thus as adjunctive treatments. Medication management
and/or cognitive behavioral therapy are still required in many, if not all, cases.
Deep brain stimulation is the most well-developed of the neuromodulation
approaches and is based on a fairly extensive literature demonstrating the
effectiveness of stereotactic ablative surgery for OCD combined with data on the
use and utility of deep brain stimulation for Parkinson disease and other neurologic
disorders with psychiatric symptomatology.52 Although surgical ablation targeting
specific brain regions (in particular, the anterior limb of the internal capsule in
capsulotomy and the cingulate bundle in cingulotomy) are effective in reducing
OCD symptom severity for many patients with treatment-refractory OCD, this
approach is not reversible and therefore is not acceptable to many patients and
clinicians.8 In contrast, deep brain stimulation, which uses microelectrodes
implanted in specific brain regions or white matter tracts to deliver electrical
stimulation in a controlled fashion, is not only reversible but the parameters and
specific targets can be modified to provide more individualized treatment.8,52
Deep brain stimulation is approved by the FDA for the treatment of refractory
OCD, which is defined as failure to achieve an adequate response to an
appropriate course of CBT in addition to three or more first-line pharmacologic
treatments. The anatomic sites most widely used in deep brain stimulation for
OCD are the ventral capsule/ventral striatum, the anterior limb of the internal
capsule, the nucleus accumbens, the subthalamic nucleus, and the bed nucleus of
the stria terminalis.8,52,53 In OCD, treatment response is defined as a 35%
improvement in obsessive-compulsive symptoms; remission is rarely achieved
and is not the expected outcome of any treatment modality to date.
By this metric, deep brain stimulation is remarkably effective in treating OCD.
More than half of patients treated with deep brain stimulation are classified as
1780 DECEMBER 2021

treatment responders.52 Across studies, symptoms are reduced by an average of KEY POINTS
nearly 40%, and response does not appear to differ substantially by choice of
● Deep brain stimulation in
anatomic target.52 Interestingly, examination of the fiber tracts that project from brain regions that activate a
each of the most common brain regions used in deep brain stimulation for OCD white matter fiber tract
demonstrates that stimulation in a single tract that connects the medial prefrontal connecting the medial
cortex to the subthalamic nucleus is the likely common mechanism of action for prefrontal cortex to the
subthalamic nucleus can
all deep-brain stimulation targets. The degree of stimulation of this fiber tract
lead to substantial symptom
strongly predicts OCD treatment response independent of the targeted brain improvement in patients
region and has been replicated in multiple independent cohorts.53 with treatment-refractory
Other forms of neuromodulation have been much less studied, but because OCD.
they are noninvasive (ie, do not require surgery), they have the potential to
● Transcranial magnetic
become additional primary treatment options for OCD, along with CBT and stimulation targeting the
pharmacotherapy. The modality that currently has the strongest evidence base is anterior cingulate cortex
deep transcranial magnetic stimulation (TMS).8 TMS involves stimulating and the dorsal medial
cortical structures using a magnetic coil placed next to the head with either low or prefrontal cortex is
emerging as a noninvasive
high frequency daily for several weeks. In OCD treatment, high-frequency form of neuromodulation
stimulation that can penetrate to the deeper cortical structures thought to be that may also be effective in
involved in OCD pathophysiology, specifically the anterior cingulate cortex and treating OCD.
the dorsal medial prefrontal cortex, is administered, paired with a personalized
OCD symptom provocation protocol designed to activate the target cortical
regions. Although still fairly sparse, the current evidence indicates that TMS (and
in particular, deep TMS) is effective for the treatment of OCD, with a response
rate of approximately 30% (compared to approximately 5% for sham treatment)
and sustained effects up to 4 weeks posttreatment.54,55 Individuals who have not
had an adequate response to either CBT or three or more medication trials appear
to benefit from deep TMS at similar rates to those who have not had prior CBT or
who have had fewer medication trials.56 As currently structured, deep TMS
requires someone with clinical expertise in OCD to devise the symptom
provocation protocols, thus potentially limiting the availability and utility of this
treatment. Studies examining the efficacy of deep TMS without symptom
provocation are thus needed.
Other forms of neuromodulation, including transcranial direct current
stimulation, transcranial magnetic seizure therapy, and vagus nerve stimulation,
have also been studied as potential treatments for OCD. Some early evidence
indicates that transcranial direct current stimulation may have some benefit;
however, so far, symptom improvements do not seem to persist for more than a
few hours or days posttreatment.57 To date, sufficient evidence is not available for
the efficacy of any of these newer approaches, including transcranial direct
current stimulation, to warrant their use for the treatment of OCD outside of a
clinical trial.57,58 However, as noted, the use of neuromodulatory approaches is a
fast-growing area of investigation and one that shows promise for improving the
lives of people with OCD. As noninvasive interventions continue to be developed
and tested, these neurostimulation approaches may soon come to be a realistic
alternative to psychotherapy and pharmacology for the management of OCD.
CONCLUSION
OCD is a chronic complex neuropsychiatric disorder that is frequently
underdiagnosed or misdiagnosed by clinicians. Appropriate treatment for OCD is
effective in reducing symptoms and improving quality of life, particularly when

begun early in the course of illness. Although treatment with a form of CBT
specifically designed for OCD has the best therapeutic outcomes, pharmacologic
management is more readily available and more suited for use by a nonspecialist.
Neurostimulation approaches, many of which are familiar to practicing
neurologists, are also rapidly becoming a part of the OCD treatment
armamentarium.
USEFUL WEBSITE
YALE-BROWN OBSESSIVE COMPULSIVE SCALE
This site provides the instructions, questions, and
checklist needed to obtain a patient’s score on the
Y-BOCS.
iocdf.org/wp-content/uploads/2014/08/
Assessment-Tools.pdf
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1784 DECEMBER 2021

REVIEW ARTICLE

Obsessive-Compulsive
ONLINE
Disorders
By Carol Mathews, MD
ABSTRACT
PURPOSE OF REVIEW: This article describes the phenomenology and clinical
presentation of obsessive-compulsive disorder (OCD), a common but
underdiagnosed psychiatric disorder. Guidance for effectively identifying
obsessive-compulsive symptoms is provided, and treatment options,
including psychotherapy, pharmacologic management, and
neuromodulation approaches for treatment-resistant OCD, are discussed.
RECENT FINDINGS: OCD affects 2% to 3% of adults worldwide and is associated

with substantial individual disability and societal costs. Lack of recognition
CITE AS: of common OCD symptom types, in addition to shame and fear of stigma on
CONTINUUM (MINNEAP MINN) the part of patients, has created an average delay in diagnosis by almost
10 years and a delay in effective treatment (ie, a treatment gap) of nearly
2 years. Cognitive-behavioral therapy (CBT), specifically a form of CBT that
Address correspondence to includes a type of behavioral intervention called exposure and response
Dr Carol Mathews, 100 S Newell
prevention, remains the most effective form of treatment for OCD. If CBT is
Dr, Gainesville Florida, 32610,
carolmathews@ufl.edu. not effective or not available, pharmacologic treatment with selective
serotonin reuptake inhibitors (SSRIs) or clomipramine, a nonselective
Dr Mathews has received
serotonin reuptake inhibitor, can also be of benefit. Neuromodulation
research/grant support from the approaches such as deep brain stimulation and transcranial magnetic
National Institutes of Health stimulation are rapidly emerging as effective treatments for OCD,
(R01MH117114, R01NS105746,
R61AT009988, R01NS102371) and particularly for patients who have not experienced an adequate response
publishing royalties from W. W. to psychotherapy or pharmacologic management.
Norton & Company, Inc.
UNLABELED USE OF SUMMARY: OCD affects more than one in every 50 adults in the United States
PRODUCTS/INVESTIGATIONAL but is recognized and adequately treated in fewer than half of those affected.
USE DISCLOSURE:
Dr Mathews discusses the
Early intervention and appropriate treatment can substantially reduce OCD
unlabeled/investigational use of symptom severity, improve quality of life, and minimize the functional
aripiprazole, celecoxib, disability associated with this chronic and often debilitating illness.
citalopram, duloxetine,
escitalopram, haloperidol,
ketamine, lamotrigine,
memantine, N-acetylcysteine,
ondansetron, pindolol, riluzole, INTRODUCTION
O
risperidone, topiramate,
bsessive-compulsive disorder (OCD) is a chronic and, at times,
transcranial direct current
stimulation, transcranial debilitating neuropsychiatric illness that affects approximately
magnetic seizure therapy, vagus one in every 50 people (more than 8 million in the United States
nerve stimulation, and
venlafaxine for the treatment of
alone). It is one of the most common psychiatric illnesses in
obsessive-compulsive disorder. adults worldwide; only depression, substance abuse, hoarding
disorder, and social anxiety disorder have higher prevalence rates.1,2 OCD has a
© 2021 American Academy profound negative impact on functioning and quality of life for those who are
of Neurology. affected and levies substantial costs at the individual, familial, and societal
1764 DECEMBER 2021

levels.3,4 According to the World Health Organization and the Global Burden of KEY POINT
Disease Study, OCD is one of most impairing noncommunicable diseases
● Although obsessions and
globally, with the number of years of life lost to disability and all-cause mortality compulsions are the core
similar to that of schizophrenia and higher than many neurologic disorders, features of obsessive-
including epilepsy.5,6 In addition to the direct costs associated with treatment for compulsive disorder (OCD),
OCD and increased utilization of health care services because of comorbidities or avoidance of situations or
events that may trigger
other related health conditions, OCD is associated with substantial indirect costs
obsessions is also common.
to society and national economies, including reduced productivity (>30% of
individuals with OCD are underemployed or unemployed), reduced income, and
a high number of days off work.6 OCD is also associated with increased caregiver
burden and therefore decreased productivity, functioning, and quality of life,
particularly for parents and intimate partners of individuals with OCD.7
Although OCD is considered to be a chronic (and therefore, incurable) illness,
for most patients, effective treatments do exist, both pharmacologic and
psychotherapeutic; appropriate treatment can reduce symptomatology, improve
individual functioning, decrease disability, reduce caregiver stress, and lessen
the economic costs of this common disorder. Unfortunately, OCD is
underrecognized by the lay public and underdiagnosed by clinicians; as a result,
many people with OCD remain untreated or experience a delay in appropriate
diagnosis and treatment. The average time from onset of symptoms to diagnosis
and treatment is 8 to 10 years; this lag is caused by the failure of clinicians, both in
primary care and in specialty settings, to effectively screen for or recognize OCD
symptoms and is exacerbated by shame, stigma, and fear of OCD symptoms
being misunderstood as psychosis or worse on the part of patients.6,7 Clinicians,
particularly those who are not mental health experts, may be reluctant to ask
about OCD symptoms for fear of asking the wrong questions, not knowing how
to discriminate between obsessions and other psychiatric or behavioral
problems, or concern that they would not know what to do if they do find that a
patient has OCD. However, it is clear that assessing for OCD symptoms, even if
imperfectly, can not only effectively identify individuals who have the disorder
but also help to destigmatize the condition, prompting many to then seek out
appropriate treatment.
EVALUATION OF OBSESSIVE-COMPULSIVE DISORDER

The core features of OCD are the presence of obsessions (thoughts) and/or
compulsions (behaviors) that are time-consuming, are distressing, cause
functional impairment, or all three.2 Most patients with OCD will have both
obsessions and compulsions, but some may have one type of symptom and not
the other. Avoidance behaviors, which are not listed in the formal diagnostic
criteria according to the Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5), are nevertheless also often prominent features of OCD.
Obsessions are defined as recurrent, repetitive, intrusive, unwanted, and
uncomfortable thoughts, images, impulses, or urges that cause sufficient distress
or anxiety that the person experiencing them will attempt to ignore, suppress, or
neutralize them, for example, by performing a compulsion.2 Compulsions are
repetitive ritualized behaviors that the person recognizes as unreasonable,
unrealistic, or excessive but feels driven to perform to reduce anxiety, usually
(although not always) in response to an obsession.2 Compulsions are often
performed a specific number of times or according to rigid rules and must be
reperformed if not done exactly according to those rules the first time. In some

TABLE 12-1 DSM-5 Diagnostic Criteria for Obsessive-Compulsive Disordera
A Presence of obsessions, compulsions, or both:

Obsessions are defined by (1) and (2):
1 Recurrent and persistent thoughts, urges, or images that are experienced, at some time
during the disturbance, as intrusive and unwanted, and that in most individuals cause
marked anxiety or distress.
2 The individual attempts to ignore or suppress such thoughts, urges, or images, or to
neutralize them with some other thought or action (i.e., by performing a compulsion).
Compulsions are defined by (1) and (2):
1 Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying,
counting, repeating words silently) that the individual feels driven to perform in response
to an obsession or according to rules that must be applied rigidly.
2 The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or
preventing some dreaded event or situation; however, these behaviors or mental acts are
not connected in a realistic way with what they are designed to neutralize or prevent, or are
clearly excessive.
Note: Young children may not be able to articulate the aims of these behaviors or mental
acts.
B The obsessions or compulsions are time-consuming (e.g., take more than 1 hour per day) or
cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
C The obsessive-compulsive symptoms are not attributable to the physiological effects of a
substance (e.g., a drug of abuse, a medication) or another medical condition.
D The disturbance is not better explained by the symptoms of another mental disorder
(e.g., excessive worries, as in generalized anxiety disorder; preoccupation with appearance,
as in body dysmorphic disorder; difficulty discarding or parting with possessions, as in
hoarding disorder; hair pulling, as in trichotillomania [hair-pulling disorder]; skin picking,
as in excoriation [skin-picking] disorder; stereotypies, as in stereotypic movement
disorder; ritualized eating behavior, as in eating disorders; preoccupation with substances
or gambling, as in substance-related and addictive disorders; preoccupation with having
an illness, as in illness anxiety disorder; sexual urges or fantasies, as in paraphilic
disorders; impulses, as in disruptive, impulse-control, and conduct disorders; guilty
ruminations, as in major depressive disorder; thought insertion or delusional
preoccupations, as in schizophrenia spectrum and other psychotic disorders; or repetitive
patterns of behavior, as in autism spectrum disorder).
Specify if:
With good or fair insight: The individual recognizes that obsessive-compulsive disorder
beliefs are definitely or probably not true or that they may or may not be true.
With poor insight: The individual thinks obsessive-compulsive disorder beliefs are probably
true.
With absent insight/delusional beliefs: The individual is completely convinced that
obsessive-compulsive disorder beliefs are true.
Specify if:
Tic-related: The individual has a current or past history of a tic disorder.
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

a
Reprinted with permission from American Psychiatric Association.2 © 2013 American Psychiatric
Association.
1766 DECEMBER 2021

cases, compulsions are performed not according to a specific set of rules but KEY POINT
instead until they feel “just right” or “complete” in some unpredefined way. For
● Formal assessment of
the majority of patients with OCD, obsessions are experienced as ego-dystonic, OCD is typically conducted
or inconsistent with their underlying belief systems, personalities, and view of using standardized
reality; in other words, they are recognized as illogical and not grounded in assessments, but one or two
reality. Similarly, the performance of compulsions gives no pleasure to the questions can be effective
screening tools in a busy
individual experiencing them.8 Instead, obsessions cause anxiety, and the
clinical practice.
resulting compulsions or avoidance behaviors provide a sense of relief rather
than a sense of reward. TABLE 12-1 outlines the current DSM-5 diagnostic
criteria for OCD.
As with most psychiatric disorders, no formal diagnostic testing or laboratory
evaluations are particularly useful in making a diagnosis of OCD. However,
medical conditions such as brain injury or peripheral neuropathy; metabolic or
endocrine disorders such as hypothyroidism or diabetes; infections of the
central nervous system; autoimmune disorders (in particular autoimmune
encephalopathy); and neurologic disorders such as Parkinson disease, dementia,
or multiple sclerosis can be associated with obsessive-compulsive symptoms. If
other clinical signs or symptoms raise suspicion for one of these disorders, the
appropriate workup should be pursued before initiating treatment for OCD.
Formal assessment of OCD is often conducted using a standardized
questionnaire such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),9
which asks about the presence or absence of specific types of obsessions and
compulsions and subsequently assesses the distress, amount of time consumed,
and functional impairment associated with OCD symptoms. Initial screening for
OCD in a clinical setting does not require administration of the Y-BOCS, which
can take up to an hour, but can instead be accomplished by asking two basic
questions that assess for the likely presence of obsessions and compulsions. If the
answer to both of the following questions is no, then the likelihood of OCD is
very low. If the answer to either of these questions is positive, further assessment
using the Y-BOCS or a similar instrument is warranted.
u To identify patients who may be experiencing obsessions, ask: “Have you ever been
bothered by repeated intrusive thoughts that did not make any sense to you and kept
coming back even when you tried not to have them or tried to suppress them?”
u To identify patients who may be experiencing compulsions, ask: “Do you have any rituals,
thoughts, or behaviors that you feel that you have to do or think over and over, cannot
resist doing, or have to do repeatedly until it is done exactly correctly or until it feels
just right?”
In a clinical setting, the proportion of patients who answer positively to either

or both of these questions (or to similar questions) is likely to be high; this does
not mean that everyone who has a positive screen will have OCD. Symptoms that
are superficially similar to obsessions and compulsions can also occur in many
other neuropsychiatric disorders (eg, ruminations in depression or generalized
anxiety disorder, tics in Tourette syndrome, or perseverations in autism
spectrum disorder). Obsessive-compulsive behaviors can also occur in conditions
other than OCD, such as autism spectrum disorder, dementia and other
neurodegenerative disorders, and schizophrenia. Because the prognosis and
treatment of each of these disorders differ, it is important that clinicians are able
to effectively differentiate OCD from other neuropsychiatric illnesses with
overlapping or similar presentations. The similarities and differences between

obsessions, compulsions, and other similar symptoms are outlined in TABLE 12-2
and TABLE 12-3.
Obsessions and compulsions can be subgrouped into thematic categories:
contamination and cleaning; taboo thoughts or fears; fear of harm; symmetry,
superstition, and perfectionism; somatic fears; and hoarding.10,11 Most people
with OCD will have many different types of obsessions and compulsions from
most, if not all, of these subtypes over the course of their lifetimes. Fear of
contamination and the resulting compulsions to clean excessively or ritualistically
are perhaps the most well-known type of OCD symptom. Contamination obsessions
take many forms and are not limited to fears of becoming sick. Individuals
with OCD may fear becoming contaminated from germs or sticky surfaces,
insects or animals, or food. They may also fear being contaminated by someone
else’s personality, sexuality, habits, or behaviors. Cleaning behaviors resulting
from contamination fears can involve oneself, others, or objects. Ritualized
handwashing or showering; excessive toilet or grooming routines; repeated or
ritualized washing of laundry, surfaces, or possessions; and excessive or
inappropriate use of cleaning agents are all examples of cleaning compulsions.
Taboo fears typically fall into three main types: sexual, religious, and
aggressive. Sexual obsessions can present as repeated fears that one has
inadvertently behaved in an inappropriate sexual manner, unwanted
uncomfortable sexual images or thoughts, or repetitive intrusive fears that one is
unknowingly of a different sexual orientation or gender. It is critical to remember
that these types of thoughts are OCD symptoms, and as such, they are
TABLE 12-2 Distinguishing Obsessions From Other Similar Thought Patterns
Obsessions Ruminations Delusions Overvalued ideas Perseveration
Ego-dystonic or Ego-dystonic Ego-syntonic Ego-syntonic Ego-syntonic Ego-syntonic

ego-syntonic
Pattern Content of specific Fluid reworking Typically Reasonable Excessive and

obsessions are of content over fixed conventional belief narrow focus on
fixed rather than and over to find content, can but oversubscribed a specific belief
fluid; can different/ generalize to by the individual or desire
generalize alternative
scenarios
Recognized Yes Yes No No No

as excessive
Examples Fear of contamination Repeated Belief that one Persistent belief Repeated thoughts
when touching a reworking of a past is being that one is regarding ways to
doorknob, unwanted social situation followed by overweight despite obtain a desired
urges to or thoughts (such as a romantic the Mafia or being of normal but inaccessible
that one might date) that did not being taken body weight, item or relationship,
inadvertently swerve go as expected in over by aliens insistence on overfocus and
car into traffic an attempt to proselytizing to a repeated thoughts/
identify possible specific belief discussion of a
different system in an perceived slight or
theoretical inappropriate injury out of
outcomes context proportion to the
event
1768 DECEMBER 2021

ego-dystonic, uncomfortable, and unwanted; they are not acted on, nor are they
realistic. Examples of common sexual obsessions include fearing that one is a
pedophile or has unknowingly or inadvertently inappropriately touched a child
(eg, when changing a diaper during babysitting), fearing that sitting next to
someone of the same sex in a movie theater or classroom will confer homosexuality
or trigger inappropriate sexual behavior in the person with OCD, and intrusive
unwanted sexual or explicit images of family members or friends or strangers.
Religious obsessions (which do not require a religious background or belief to
occur) include fears such as unintentionally or inadvertently offending God or
blaspheming, fears of religious objects or symbols, and superstitious fears of
symbols that have a religious history or meaning (eg, the fear that seeing the
number 666 will result in something bad happening or harm coming to someone).
Aggressive obsessions, which differ from fears of harm, include uncomfortable
ego-dystonic thoughts or urges to cause harm to oneself or others, including fears,
impulses, or urges to touch hot surfaces such as stoves or fires; fears of being around
knives or other sharp objects because of images of picking them up and cutting or
stabbing someone; urges to swerve a car or bicycle into oncoming traffic; and urges
or fears of blurting out something aggressive or offensive (eg, racial epithets).
Fears of harm, on the other hand, tend to be more passive in nature. These
obsessions include fears that one has inadvertently hit someone while driving,
with a concomitant urge to return to the scene and check for bodies or injured
people; fears that harm will come to another person because of something the
person with OCD either did or did not do; and fears that if an action or ritual is
not done in a particular way or a specific number of times, then someone will be
Distinguishing Compulsions From Other Similar Behaviors TABLE 12-3
Compulsions Habits Tics Stereotypies Perseverative behaviors
Involuntary versus Voluntary Both Involuntary Voluntary Voluntary

voluntary
Repetitive versus Ritualized Repetitive Repetitive Repetitive Repetitive

ritualized
Deliberate versus Deliberate Deliberate Nondeliberate Deliberate Nondeliberate

nondeliberate
Relief of anxiety or Relief Relief Relief Reward Reward

sensation or reward
Anxiety or discomfort Yes No Yes No No

generated when
attempting to stop
or suppress behavior
Examples Repeated ritualized Nail biting, Repetitive eye Hand flapping, Continued focus on
hand washing, hair twirling blinking, repeated body rocking a single topic of
checking multiple throat clearing conversation with
times to be sure inability to shift
stove is turned off topics, repeated
rereading of the
same comic book

harmed. Harm obsessions are often accompanied by checking behaviors,

including a frequent need to ask others for reassurance that the feared event did
not occur; checking to see that harm was not, in fact, done; and physically
checking oneself or others for injuries in the absence of a precipitating event that
could have caused injuries or harm. Superstitious obsessions (eg, worrying that
something bad will happen if a particular superstitious ritual is not followed) and
associated checking or avoidance behaviors also fall into this category.
Symmetry obsessions and compulsions include a perceived need for things to
be in a particular order or lined up in a certain way (eg, color coded), rewriting or
rereading over and over because of a perceived need for handwriting to look
“perfect” or a sentence to feel “just right,” evening up (such as doing the same
behavior with each arm to make it feel even or tying and retying shoelaces until
the pressure feels the same on both feet), or needing the television volume or
channel to be on an even or odd number. When symmetry symptoms are the
predominant or only type of OCD symptom, the clinician should spend some
time assessing for the underlying presence of a current or past tic disorder, as
these symptoms are much more common in individuals with Tourette syndrome
or other chronic tic disorders. Perfectionism obsessions and behaviors also fall
into the symmetry category. In addition to the symptom of needing things to look
or feel perfect as described above, perfectionism symptoms can also be expressed
as needing homework or other work or school assignments to be done perfectly
to the point that assignments will go unfinished because the patient can never
achieve perfection. Avoidance is also commonly seen when perfectionism is
present because of the feeling that if perfectionism cannot be achieved, then it is
futile to begin an assignment or a project at all.
Somatic fears tend to fall into two primary types: unreasonable excessive fears
that the person with OCD has contracted an illness (including noncommunicable
illnesses such as cancer) and fears that something (often something indefinable)
is wrong with a body part or feature. These symptoms can be difficult to
distinguish from symptoms of other related psychiatric illnesses, such as illness
anxiety disorder and body dysmorphic disorder. These disorders should be
carefully assessed for if somatic symptoms are identified. Somatic symptoms can
also occur in the context of contamination fears; for example, someone who
obsessively worries about contracting or transmitting herpes simplex (often in
the absence of any evidence of an actual infection) may compulsively check to
make sure they have no lesions on their lips or mouth. As with other OCD
symptoms, somatic obsessions are ego-dystonic. In contrast, when such somatic
preoccupations are the primary focus in body dysmorphic disorder or illness
anxiety disorder, the individuals experiencing these disorders are less likely to
have insight into the irrational or excessive nature of their fears.
The final category of OCD symptom types is hoarding behaviors.
Understanding and assessing for this category of symptoms is complicated by the
fact that hoarding disorder is a distinct neuropsychiatric illness, albeit one that
was once thought to be a subtype of OCD. The hoarding symptoms that occur in
hoarding disorder and those that occur in OCD differ in both content and intent.
Individuals with hoarding disorder tend to save everyday items such as papers,
containers, clothes, household items, tools, and sentimental objects, usually
because of the thought that the item might be needed or wanted again, either
for a concrete purpose or to preserve a memory or important piece of
information. In OCD, hoarding behaviors are explicitly due to obsessional fears
1770 DECEMBER 2021

(eg, contamination fears or fears of harm), and the items hoarded are more likely KEY POINTS
to be unusual or bizarre (eg, saving fingernail clippings for fear that someone
● The content of
could harvest DNA from them and cause harm to a person). Up to 30% of people obsessions and compulsions
who present with OCD will also have co-occurring hoarding disorder, however, can be grouped into several
as these two disorders are related. thematic categories (eg,
When evaluating someone for OCD, it is important to ask about symptoms in all contamination and cleaning
or taboo thoughts).
of the categories as well as asking about the person’s own understanding of their
symptoms. Most people with OCD will know that their fears and behaviors do not ● Obsessions and
make sense (ie, are irrational or excessive) (CASE 12-1). Some will suspect that they compulsions regarding
have OCD based on their knowledge of the illness from the media or their own symmetry are more
research, especially if they experience some of the better-known OCD symptoms common in individuals with
co-occurring chronic tic
such as contamination fears, cleaning obsessions, or repeated checking. Others, disorders.
however, particularly those who have taboo symptoms or some of the other lesser-
known symptom types, will fear that their symptoms indicate that something is ● Somatic and hoarding
fundamentally wrong with them as a person or that something is seriously wrong symptoms can occur either
in OCD or as a part of other
with their mental function (ie, that they are “crazy”). For this reason, patients with related disorders, such as
OCD may be reluctant to disclose their symptoms without specific prompting. body dysmorphic disorder,
illness anxiety disorder, or
EPIDEMIOLOGY OF OBSESSIVE-COMPULSIVE DISORDER hoarding disorder.
OCD is equally common in males and females (the male to female ratio is
● OCD affects
between 1:1 and 1:1.5), although the age of symptom onset differs somewhat approximately 2%
between the sexes. The lifetime prevalence of OCD is between 2% and 3%, and to 3% of adults.
the prevalence of subclinical OCD symptoms is estimated to be as high as 25% in
the adult population.6 For the vast majority of patients, symptoms begin in ● The presence of one or
more psychiatric disorders
adolescence or early adulthood; the age of onset is thought to be bimodal, with a co-occurring with OCD is the
first peak in childhood (75% of those affected, mean age of onset 11 years) and a rule rather than the
second peak in early adulthood (mean age of onset 23 years).6 Boys tend to have exception.
an earlier age of onset than do girls, with a substantial proportion experiencing
their first symptoms before age 10.6,9 Although most girls will also have symptom
onset in early adolescence, for some women, reproductive events such as
pregnancy or childbirth and even, in rare cases, menopause can trigger OCD
symptoms.9 Males with OCD, especially those whose symptoms begin early in
childhood, are more likely to have a co-occurring tic disorder; females with early
onset of symptoms, particularly those with prominent symmetry or “just right”
symptoms (the need to repeat a simple activity over and over again until it feels
“just right” or complete), may also be at higher risk for tic disorders. Girls (and,
increasingly, boys) who have somatic or body-related symptoms may also be at
risk for developing body dysmorphic disorder or an eating disorder.12
The majority of adults presenting for clinical care of OCD will meet lifetime
criteria for another psychiatric disorder, most commonly depression (up to 65%)
or an anxiety disorder (60% to 90%).1,9 Tic disorders occur in up to 30% of
individuals with OCD,2 and attention deficit hyperactivity disorder in up to
20%.9 These co-occurring disorders contribute to poorer quality of life and
worsened functioning when present, and, if not addressed, they can also
adversely impact effective treatment of OCD.9
ETIOLOGY AND PATHOPHYSIOLOGY OF OBSESSIVE-COMPULSIVE

DISORDER
The etiology of OCD is complex and multifactorial. Although genetic factors
clearly contribute to OCD susceptibility, heritability estimates are between 30%

and 65%, with symptom onset in childhood having a higher heritability than
symptom onset in adulthood. The moderate heritability estimates indicate that
environmental factors as yet unknown also contribute to the development of
OCD. Prenatal and perinatal complications, stress, traumatic brain injuries such
as mild concussion, and inflammatory responses to bacterial or viral infections
have all been postulated to contribute to the development of OCD symptoms,
although none of these has been consistently or reliably associated with OCD13
and thus no formal assessment of such potential contributors is recommended.
OCD is a disorder of neural circuitry. Although multiple brain regions are
associated with OCD pathogenesis, those involved in the cortico-striato-thalamo-
cortical circuits are the most strongly implicated.9,14 These parallel circuits
mediate emotional/affective, sensorimotor, cognitive, and motivational
processes, all of which are important in OCD pathophysiology. Roughly
speaking, the affective circuitry (ventromedial prefrontal cortex, anterior
cingulate cortex, nucleus accumbens, and thalamus) and cognitive circuitry
(dorsal: dorsolateral prefrontal cortex, caudate, and thalamus; and ventral:
anterolateral orbitofrontal cortex, putamen, and thalamus) are involved in
obsessive symptomatology (anxiety, uncertainty with regard to goal-directed
behaviors, and response inhibition). The sensorimotor circuitry (premotor
cortex, putamen, and thalamus) and the frontoparietal network (parietal lobe,
CASE 12-1 A 19-year-old man presented with fears of contamination and excessive
cleaning symptoms. His girlfriend, who suggested the appointment, was
concerned because he was spending up to 2 hours a day “cleaning” the
air in their apartment with air fresheners and felt compelled to shower
every time he left the home and returned, even when just going
downstairs to the lobby to get the mail from the mailbox. He reluctantly
agreed to come to the appointment because his behaviors were
beginning to cause problems in his relationship with his girlfriend, who
was worried about the potential adverse health effects of his excessive
use of air freshener and cleaning agents. Although he admitted to
spraying air freshener in the house over and over and to showering every
time he returned from leaving the house, he denied any fears of germs or
illness. He admitted to a variety of additional cleaning behaviors,
including needing to wash his clothing daily and to change his clothes
multiple times a day, as well as too frequent hand washing. He
recognized these behaviors as excessive and admitted that they were not
logical. When asked specifically about taboo symptoms, he admitted that
when he came into contact with, or was in the vicinity of, another person,
especially someone unknown to him, he was afraid that he would
somehow become contaminated by that person’s essence and take on
their characteristics, becoming less like himself and more like the other
person. He also feared that if the other person had a belief system that
differed from his, or expressed an idea that he did not agree with, he
would take on that belief or idea also just by being in their proximity. He
did not feel this way around family members. He fully recognized that his
fears were irrational but noted that he could not control them and felt
1772 DECEMBER 2021

sensorimotor area, inferior frontal gyrus, and ventrolateral prefrontal cortex) are
thought to be involved in the development of compulsive (habit-based)
behaviors.9,14
Although many neurotransmitters are likely to be relevant in the development
or maintenance of psychiatric symptoms, evidence from clinical and preclinical
studies indicates that serotonin, dopamine, and glutamate may be of particular
relevance for OCD. These neurotransmitter systems are active within the
cortico-striato-thalamo-cortical circuits, and pharmacologic agents that affect
the serotonergic and dopaminergic systems have proven to be effective
treatments for OCD. The evidence for the role of serotonin comes primarily from
the observation that clomipramine and the SSRIs effectively treat OCD
symptoms; less is known about its putative mechanism of action, although
serotonergic neurons project to key regions within the cortico-striato-thalamo-
cortical circuitry from the raphe nucleus. Dopamine has been implicated in OCD
symptomatology both from observations drawn from treatment studies using
neuroleptics and, more importantly, from the fact that dopamine plays a
significant role in the development of automatic grooming and other habit-based
behaviors in animals. The potential role of glutamate comes primarily from
knowledge of its key role in the cortico-striato-thalamo-cortical circuitry;
glutamatergic neurons project bidirectionally between the cortex and regions in
compelled to clean everything on his person and in his apartment,

including the air he breathed, to avoid being contaminated in the way that
he feared. The patient had tried to resist the thoughts and related
behaviors, which had been present since he was 16, without success. He
had recently also been experiencing depressive symptoms, including
social isolation, sadness and hopelessness, and excessive sleeping. He
was relieved to know that his symptoms had a name and a treatment and
was interested in both pharmacologic management and behavioral
therapy to treat them.
This man has contamination obsessions. Fear of being contaminated by COMMENT

another person’s personality, aura, or essence, although less common than
germ fears, are still quite common and are less likely to be disclosed unless
patients are directly asked about them because of fear of being ridiculed
or thought to be psychotic. Effective treatment for this type of symptom
involves exposure and response prevention approaches to reduce and
eventually eliminate the compulsive behaviors and to reduce the intensity
of the fears. Pharmacologic management with selective serotonin reuptake
inhibitors (SSRIs) can also be of benefit, not only for the obsessive-
compulsive disorder symptoms but also for the depression symptoms that
he has recently developed. Although each of these forms of treatment can
be effective on its own, combining exposure and response prevention and
pharmacologic treatment with an SSRI increases the likelihood of response
and often produces an additional reduction in symptoms over and above
either treatment alone.

FIGURE 12-1
Suggested treatment algorithm for obsessive-compulsive disorder (OCD) in adults.
CBT = cognitive-behavioral therapy; DBS = deep brain stimulation; ERP = exposure response prevention; rTMS = repetitive transcranial magnetic
stimulation; SSRI = selective serotonin reuptake inhibitor.
a
Severity of OCD as determined by Obsessive-Compulsive Inventory, Short Version (OCI-R) scores: mild (scores of 15-19), moderate (20-34), and
severe (≥35). If OCD is suspected according to OCI-R score or clinical history, the Yale-Brown Obsessive Compulsive Scale may be administered
for further assessment of obsessive-compulsive and associated symptoms.
b
There is insufficient evidence to support the superiority of one particular SSRI over any other; all appear to have similar efficacies.
Reprinted with permission from Hirschtritt ME, et al, JAMA.7 © 2017 American Medical Association.
1774 DECEMBER 2021

the striatum and are responsible for excitation of the cortex.9 Some early KEY POINTS
evidence also indicates a role of glutamatergic genes in the development of OCD.
● Early intervention is
Glutamatergic agents have been studied for the treatment of OCD, but, to date, critical for improving quality
none have been consistently demonstrated to be of benefit.7,9 of life in OCD and the
likelihood of functional
TREATMENT OF OBSESSIVE-COMPULSIVE DISORDER remission.
Although OCD is a chronic disorder, early intervention can be effective in
● Obsessive-compulsive
reducing symptom severity and improving quality of life and functioning.6,7,9 symptoms are often missed
For some patients, perhaps as many as 50%, functional remission (eg, minimal or misdiagnosed by
residual symptoms that are not perceived to be functionally impairing to the clinicians, in part because
patient) can be achieved with early and appropriate treatment.6,15-17 the symptoms are confused
with other similar
Unfortunately, the current treatment gap for OCD (the time between seeking symptoms.
help for a medical problem and receiving appropriate care) is approximately
2 years.18,19 This delay puts patients at higher risk for a more chronic and ● The most effective form
intractable course of illness and suggests that many providers, including mental of treatment for OCD is a
form of cognitive-behavioral
health professionals, do not effectively identify and treat OCD when patients do therapy called exposure and
present for care. Three contributors to this treatment gap have been identified: response prevention.
(1) misidentification of OCD symptoms (particularly sexual, religious, or
aggressive symptoms) as something else; (2) referral to non–evidence-based
forms of treatment, such as psychodynamic or supportive psychotherapy; and
(3) use of ineffective pharmacologic agents or use of effective pharmacologic
agents at subtherapeutic doses or for suboptimal lengths of time.20
Three primary types of effective treatment are available for OCD: (1)
cognitive-behavioral therapy (CBT), (2) pharmacologic management, and (3)
neuromodulation.9 For most people with OCD, the most effective forms of
treatment continue to be those that have been in place for decades.8 Despite
clinical trials examining other forms of treatment, the evidence base continues to
be the strongest for CBT and pharmacologic management or a combination of
the two.21-24 FIGURE 12-1 shows a suggested treatment algorithm.
For most providers, especially those who are not OCD specialists, the choice of
treatment is often driven by knowledge of, comfort with, and local availability of
the three primary treatment types. Although pharmacotherapy is the most
widely used, the most effective form of treatment for OCD is actually CBT, either
alone or in combination with medication; this form of treatment also has the
highest long-term response rates.7,25 Pharmacologic management primarily
consists of the use of high-dose SSRIs, with the use of additional agents as
augmentation as needed.7-9 Neuromodulation is a newer option and has shown
some benefit for patients who show inadequate response to more standard forms
of treatment, although it is still limited in availability and scope. Other important
interventions that are relevant and should be addressed regardless of the chosen
treatment modality include psychoeducation and the assessment and reduction
of family accommodation of symptoms.6,9,26,27 These interventions are not
considered to be actual treatments, but they can help to increase patient
engagement in treatment and facilitate treatment response.9
Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder

When it is available, the best treatment for OCD is CBT, particularly a form of
CBT that includes exposure and response prevention.7,21,22,28 Both the cognitive
and the behavioral components of CBT have some efficacy in treating OCD,
although somewhat stronger evidence exists for the efficacy of behavioral

interventions.29-32 The cognitive component of CBT consists primarily of cognitive

appraisal and cognitive restructuring.30,33 In the cognitive appraisal component,
patients are first asked to identify cognitive distortions, erroneous thought patterns,
and maladaptive beliefs associated with their OCD symptoms. Then, in the
cognitive restructuring component, they are asked to identify possible alternative
thought patterns or expected outcomes to distinguish what they fear will happen
from what they believe is the most likely logical outcome and to modify their
automatic and fear-driven interpretation or expectation to be more in line with
their own perception of reality. Acceptance of the thoughts or fears and tolerance of
the distress arising from them is also an important part of cognitive therapy.
The behavioral component of CBT, and exposure and response prevention
specifically, is the most common form of evidence-based psychotherapy for
OCD.7,34,35 In this treatment modality, the focus is on systematically reducing
and eventually eliminating the compulsive or avoidance behaviors that occur in
response to an obsession. Patients and therapists work together to identify and
rank the obsessions and associated compulsions according to the level of distress
they engender, creating a fear hierarchy. Potential behavioral exposures are then
identified for each fear listed, typically beginning with a fear that ranks
somewhat lower (ie, less distressing) on the fear hierarchy. As differences in
environment and situation may lead to different levels of fear or distress for the
same behavior (eg, eating at a possibly dirty table in one’s own home may be less
distressing than eating at a possibly dirty table in a restaurant for someone with
food contamination fears), the fear hierarchy typically includes behaviors
(including avoidance) in a variety of situations to create as rich a list of potential
exposures as possible.
A key element of exposure and response prevention is that exposure to the
feared situation or object occurs without the performance of the compensatory
compulsion; this is the response prevention piece of exposure and response
prevention. There are three forms of exposures: imaginal, in vivo, and
interoceptive.28 The first two are most commonly used in the treatment of OCD;
the third is more common in the treatment of panic and generalized anxiety
disorder.36 Imaginal exposures, which are usually fairly low on the fear hierarchy
and thus easier for a patient to complete, involve imagining the feared situation
and facing the anxiety associated with it without engaging in a compulsion or
avoidance behavior. In vivo exposures involve actual exposure to the feared
situation. A modified form of in vivo exposure that also sits lower on a typical
fear hierarchy is watching someone else in a feared situation, for example, in a
movie or other video clip. The next step in an in vivo exposure might be
watching, but not participating in, the feared situation in person (eg, watching a
therapist or family member eat a jellybean off a dirty surface), and the final step
might be having the patient perform the exposure along with the therapist.
Interoceptive exposures involve the same principles of exposure and response
prevention but are applied to the unpleasant physical sensations of anxiety, such
as hyperventilation or shortness of breath, rather than to a compulsion or other
behavior.36 In a clinical setting, these physical symptoms are typically induced by
standard exposure techniques, for example, by imagining or viewing a feared
object or experience (eg, seeing a picture of a spider if one is afraid of spiders).
Exposure and response prevention can be administered in multiple contexts
and multiple levels of intensity. Treatment sessions are typically an hour in
length and can be administered weekly or multiple times weekly in a standard
1776 DECEMBER 2021

outpatient setting or daily for several hours a day in intensive outpatient, partial KEY POINT
hospitalization, or residential treatment settings.9 Similarly, exposure and response
● The average number of
prevention can be administered in the context of individual or group treatment exposure and response
and is available via the internet and as a self-administration module.7,28,34,37,38 In all prevention sessions needed
forms, patients who are undergoing exposure and response prevention for OCD to attain a desired response
are typically asked to complete exposure and response prevention homework is 16 to 20.
between treatment sessions; usually, the homework is to be completed daily,
either for a prescribed period of time (eg, waiting for 15 minutes to wash one’s
hands) or for a prescribed number of repetitions (eg, driving by a particularly
feared intersection 2 times a day without going back to check whether an accident
had happened there). The assignment and completion of exposure and response
prevention homework is an integral part of effective treatment for OCD.
Multiple studies have examined the characteristics of CBT for OCD that are
the strongest predictors of treatment response, including the inclusion of a
cognitive component, the inclusion of a behavioral component (eg, exposure and
response prevention), the number and/or frequency of sessions, and treatment
adherence.9,28,31,34,39,40 Taken together, these studies indicate that number of
sessions matters (the minimum number of needed sessions for patients to show
an adequate response appears to be approximately 16 to 20) and that adherence
to both sessions and to assigned CBT homework are the strongest predictors of
treatment response.8,9,28,31,34,39-41 The modality (eg, group or individual) and
type of CBT (eg, cognitive therapy or exposure and response prevention) are not
clearly predictive of differential treatment response for patients with OCD,42
although some studies indicate increased benefit of exposure and response
prevention over purely cognitive approaches.31,32 The intensity or frequency of
treatment (eg, once or twice weekly, daily, or for multiple hours per day) does
not appear to predict treatment outcome in the long term, although some
evidence indicates that more intense treatment formats can lead to earlier
response.8,43 Predictors of lack of response that have been identified in some
studies but not others include severity of baseline symptoms, presence of
significant depressive symptoms, and level of insight into illness.28 It is important
to note that CBT for OCD can be effective in a variety of clinical settings and
under less-than-ideal conditions.34
Pharmacologic Treatment of Obsessive-Compulsive Disorder

Because patients with OCD may not have access to a therapist but will likely have
the ability to see a physician, most commonly a primary care provider,
pharmacologic management is often the first or most easily accessed treatment
option. Pharmacotherapy for OCD, as is the case for many psychiatric disorders,
began with a serendipitous discovery; clomipramine, a tricyclic antidepressant
that was used in the mid-1960s as a treatment for depression, was also associated
with an improvement in obsessional thoughts.8 This observation led to the use of
multiple tricyclic antidepressants for the treatment of OCD and the subsequent
finding that of all the medications in this class, only clomipramine was effective.8
The reason for this is likely because of an important difference in the chemical
structure of clomipramine compared to the other tricyclic antidepressants.
Although all tricyclic antidepressants act as inhibitors of norepinephrine
reuptake, as a tertiary amine, clomipramine acts as a more potent inhibitor of
serotonin reuptake than do the other tricyclics (eg, imipramine, desipramine, or
nortriptyline), which have little to no effect on serotonin reuptake.

Somewhat astonishingly, to date, medications that block serotonin reuptake

are the only class of drugs to have primary efficacy for the treatment of OCD; no
other class of medications, if used on its own, has been shown to be of benefit.
Today, although clomipramine remains an important treatment option, it is no
longer considered to be a first-line treatment, not because of lack of efficacy but
because of its substantial side effect burden at therapeutic doses. Instead, the
class of antidepressants called SSRIs has replaced clomipramine as the primary
treatment of choice for pharmacologic management of OCD.8 Although only
clomipramine and four SSRIs (fluoxetine, fluvoxamine, paroxetine, and
sertraline) have been approved by the US Food and Drug Administration (FDA)
for the treatment of OCD, evidence exists that all of the SSRIs (which, in the
United States, also include citalopram and escitalopram) are similarly
efficacious.44 Dual serotonin norepinephrine reuptake inhibitors (SNRIs) such as
duloxetine and venlafaxine have shown some efficacy but generally do not work
as well as SSRIs because the degree of serotonin reuptake blockade is lower.7,8
Current dosing recommendations for OCD treatment with SSRIs differ
substantially from those for depression treatment. OCD treatment guidelines
call for doses that are 2 to 3 times higher than are typically needed for
depression.7,9,44-46 In addition, for OCD, the SSRI dose should be titrated to the
highest expected effective dose at the beginning of treatment and maintained
throughout treatment. In contrast, treatment recommendations for depression
usually suggest titrating to the lowest expected effective dose and, once response
TABLE 12-4 Recommended Primary Pharmacologic Treatment Options for

Obsessive-Compulsive Disorder
Standard Recommended as FDA approved for treatment

Standard obsessive-compulsive first- or second-line of obsessive-compulsive
Medication depression dosesa disorder dosesa treatment disorder
Fluoxetine 40 mg 80 mg First Yes

b
Citalopram 40 mg 40 mg Second No
Clomipraminec 125 mg 250 mg Second Yes

d d
Duloxetine 60 mg 120 mg Second No
Escitalopram 20 mg 40 mg First No
Fluvoxamine 150 mg 300 mg First Yes
Paroxetine 40 mg 60 mg First Yes
Sertraline 100 mg 200 mg First Yes
Venlafaxine 150 mg 300 mg Second No
FDA = US Food and Drug Administration.

a
Doses are presented as dose equivalents using fluoxetine 40 mg as a reference and were derived from studies by Furukawa and colleagues46 and
Hayasaka and colleagues59 and are rounded to nearest available tablet/capsule.
b
Doses greater than 40 mg of citalopram are not recommended because of an FDA boxed warning regarding the potential for QT prolongation.
c
Despite evidence of primary efficacy in obsessive-compulsive disorder, clomipramine is recommended typically as a second-line agent because
of its high side effect burden.
d
Data on dose equivalents are not available; doses are based on FDA-recommended dosing for major depression.
1778 DECEMBER 2021

or remission is achieved, further titrating the dose down to a lower maintenance KEY POINTS
dose.46,47 TABLE 12-4 details the primary and secondary pharmacotherapeutic
● Only one class of
options for OCD, with associated doses. medications, the serotonin
Pharmacologic treatment for OCD should continue for 10 to 12 weeks to reuptake inhibitors, which
ensure adequate response before switching SSRIs or augmenting with another includes clomipramine and
agent.7,9,44 Results from two recent meta-analyses suggest that the highest the selective serotonin
reuptake inhibitors (SSRIs),
incremental gain from SSRI treatment occurs within 2 weeks of achieving an
is effective as a primary
adequate dose, but these studies also show that symptom improvement treatment for OCD; high
continues up through week 12.44,48 As most treatment studies do not follow doses and long treatment
participants past 12 weeks, little is known about whether continued treatment times are needed for
maximum benefit.
response occurs past that point. However, the slope of the curves in the primary
treatment studies and data from studies examining the role of augmentation of ● Adequate pharmacologic
SSRIs in treatment-resistant OCD indicate that continued response to an SSRI is response to treatment
seen as far out as 6 months in 10% to 30% of individuals (as indicated by the cannot be determined until a
response rate for the placebo arms of these augmentation studies).49,50 patient has been on a
selective serotonin reuptake
One possible way to integrate these findings clinically is to think of early inhibitor at an appropriate
robust response to treatment with an SSRI as a potential indicator of a good dose for at least 12 weeks.
prognostic outcome. Thus, patients who have an early response may not need
augmentation of their primary medication. In contrast, those who have a more ● Adjunctive medications
such as neuroleptics or the
delayed or less substantial response in the first few weeks of treatment may
addition of cognitive-
ultimately have insufficient benefit from an SSRI alone, and thus, the treating behavioral therapy to
clinician may consider augmenting the SSRI earlier in the course of treatment. As pharmacologic treatment
the first 2 to 4 weeks of treatment are typically dedicated to dose titration, leads to continued
improvement in up to 30%
noticeable treatment response is not necessarily expected to be apparent until
of patients with OCD.
weeks 4 to 6, that is, 1 to 2 weeks after reaching therapeutic doses.
So, what should be done for those who do not respond to an initial course of
SSRIs at the recommended higher doses? No answer to this question is
universally accepted, but the current literature suggests several possible courses
of action. The first is to add CBT to SSRI treatment; this approach has
consistently shown the most benefit for individuals who do not respond or who
have an inadequate response to an initial trial of medications.8,34,50 For those who
cannot or will not participate in psychotherapy, psychopharmacologic options
are also available. These include augmenting the SSRI with an additional agent,
switching the primary agent to another with known efficacy in OCD, switching
to a second-line agent, or using IV clomipramine. Of these, the first option is the
best studied and has the strongest evidence base.
Of the many drugs that have been examined as adjunctive medications in
OCD, the addition of a second-generation neuroleptic (in particular, either
aripiprazole or risperidone) has the strongest scientific support.8,49-51 Evidence
also supports the use of haloperidol, a first-generation neuroleptic.50,51 As many
as 30% of patients with an inadequate response to an SSRI will show benefit from
the addition of a neuroleptic medication. Other medications that have some
(albeit weak) evidence for potential benefit as an augmenting agent include
topiramate, pindolol, lamotrigine, memantine, and N-acetylcysteine.50 These
medications may be considered as augmenting agents in clinical practice only if
other choices have failed or are not an option and if the potential benefit is
thought to be higher than the potential risk, given that the current level of
evidence for their utility is low.
Another alternative is to switch primary agents, and some evidence also exists
for this approach.50 The preferred choice would be to switch to another SSRI

with an indication for OCD (TABLE 12-4); the second would be to switch to a
second-line agent such as clomipramine, venlafaxine, or duloxetine. If an
inadequate treatment response is seen with the second medication trial,
augmentation with a neuroleptic would again be suggested, particularly if adding
CBT is not an option, is not tolerated, or is ineffective. The final option before
moving to neuromodulation would be to try IV clomipramine.50 The evidence for
this strategy is limited to a few open-label trials and two randomized controlled
trials and indicates that for some patients, IV clomipramine may be effective,
although the appropriate doses and approach to maintenance are not determined.
For patients for whom these interventions have failed, neuromodulation
(specifically deep brain stimulation or transcranial magnetic stimulation) may be
an option.
Neuromodulation
Neuromodulation approaches such as deep brain stimulation and transcranial
magnetic stimulation are the most recent additions to the OCD treatment
armamentarium; in contrast to the psychotherapeutic and psychopharmacologic
approaches, which have remained stable for decades, neuromodulation
approaches are rapidly expanding as an area of scientific and clinical interest.
Although currently limited to patients with treatment-resistant OCD, if evidence
of their efficacy is confirmed, noninvasive approaches may also become widely
available to patients with less severe illness. Although neuromodulation can be
very effective, these interventions are rarely, if ever, appropriate for use as the
only form of treatment. Instead, they can best be thought of as increasing
neuroplasticity and thus as adjunctive treatments. Medication management
and/or cognitive behavioral therapy are still required in many, if not all, cases.
Deep brain stimulation is the most well-developed of the neuromodulation
approaches and is based on a fairly extensive literature demonstrating the
effectiveness of stereotactic ablative surgery for OCD combined with data on the
use and utility of deep brain stimulation for Parkinson disease and other neurologic
disorders with psychiatric symptomatology.52 Although surgical ablation targeting
specific brain regions (in particular, the anterior limb of the internal capsule in
capsulotomy and the cingulate bundle in cingulotomy) are effective in reducing
OCD symptom severity for many patients with treatment-refractory OCD, this
approach is not reversible and therefore is not acceptable to many patients and
clinicians.8 In contrast, deep brain stimulation, which uses microelectrodes
implanted in specific brain regions or white matter tracts to deliver electrical
stimulation in a controlled fashion, is not only reversible but the parameters and
specific targets can be modified to provide more individualized treatment.8,52
Deep brain stimulation is approved by the FDA for the treatment of refractory
OCD, which is defined as failure to achieve an adequate response to an
appropriate course of CBT in addition to three or more first-line pharmacologic
treatments. The anatomic sites most widely used in deep brain stimulation for
OCD are the ventral capsule/ventral striatum, the anterior limb of the internal
capsule, the nucleus accumbens, the subthalamic nucleus, and the bed nucleus of
the stria terminalis.8,52,53 In OCD, treatment response is defined as a 35%
improvement in obsessive-compulsive symptoms; remission is rarely achieved
and is not the expected outcome of any treatment modality to date.
By this metric, deep brain stimulation is remarkably effective in treating OCD.
More than half of patients treated with deep brain stimulation are classified as
1780 DECEMBER 2021

treatment responders.52 Across studies, symptoms are reduced by an average of KEY POINTS
nearly 40%, and response does not appear to differ substantially by choice of
● Deep brain stimulation in
anatomic target.52 Interestingly, examination of the fiber tracts that project from brain regions that activate a
each of the most common brain regions used in deep brain stimulation for OCD white matter fiber tract
demonstrates that stimulation in a single tract that connects the medial prefrontal connecting the medial
cortex to the subthalamic nucleus is the likely common mechanism of action for prefrontal cortex to the
subthalamic nucleus can
all deep-brain stimulation targets. The degree of stimulation of this fiber tract
lead to substantial symptom
strongly predicts OCD treatment response independent of the targeted brain improvement in patients
region and has been replicated in multiple independent cohorts.53 with treatment-refractory
Other forms of neuromodulation have been much less studied, but because OCD.
they are noninvasive (ie, do not require surgery), they have the potential to
● Transcranial magnetic
become additional primary treatment options for OCD, along with CBT and stimulation targeting the
pharmacotherapy. The modality that currently has the strongest evidence base is anterior cingulate cortex
deep transcranial magnetic stimulation (TMS).8 TMS involves stimulating and the dorsal medial
cortical structures using a magnetic coil placed next to the head with either low or prefrontal cortex is
emerging as a noninvasive
high frequency daily for several weeks. In OCD treatment, high-frequency form of neuromodulation
stimulation that can penetrate to the deeper cortical structures thought to be that may also be effective in
involved in OCD pathophysiology, specifically the anterior cingulate cortex and treating OCD.
the dorsal medial prefrontal cortex, is administered, paired with a personalized
OCD symptom provocation protocol designed to activate the target cortical
regions. Although still fairly sparse, the current evidence indicates that TMS (and
in particular, deep TMS) is effective for the treatment of OCD, with a response
rate of approximately 30% (compared to approximately 5% for sham treatment)
and sustained effects up to 4 weeks posttreatment.54,55 Individuals who have not
had an adequate response to either CBT or three or more medication trials appear
to benefit from deep TMS at similar rates to those who have not had prior CBT or
who have had fewer medication trials.56 As currently structured, deep TMS
requires someone with clinical expertise in OCD to devise the symptom
provocation protocols, thus potentially limiting the availability and utility of this
treatment. Studies examining the efficacy of deep TMS without symptom
provocation are thus needed.
Other forms of neuromodulation, including transcranial direct current
stimulation, transcranial magnetic seizure therapy, and vagus nerve stimulation,
have also been studied as potential treatments for OCD. Some early evidence
indicates that transcranial direct current stimulation may have some benefit;
however, so far, symptom improvements do not seem to persist for more than a
few hours or days posttreatment.57 To date, sufficient evidence is not available for
the efficacy of any of these newer approaches, including transcranial direct
current stimulation, to warrant their use for the treatment of OCD outside of a
clinical trial.57,58 However, as noted, the use of neuromodulatory approaches is a
fast-growing area of investigation and one that shows promise for improving the
lives of people with OCD. As noninvasive interventions continue to be developed
and tested, these neurostimulation approaches may soon come to be a realistic
alternative to psychotherapy and pharmacology for the management of OCD.
CONCLUSION
OCD is a chronic complex neuropsychiatric disorder that is frequently
underdiagnosed or misdiagnosed by clinicians. Appropriate treatment for OCD is
effective in reducing symptoms and improving quality of life, particularly when

begun early in the course of illness. Although treatment with a form of CBT
specifically designed for OCD has the best therapeutic outcomes, pharmacologic
management is more readily available and more suited for use by a nonspecialist.
Neurostimulation approaches, many of which are familiar to practicing
neurologists, are also rapidly becoming a part of the OCD treatment
armamentarium.
USEFUL WEBSITE
YALE-BROWN OBSESSIVE COMPULSIVE SCALE
This site provides the instructions, questions, and
checklist needed to obtain a patient’s score on the
Y-BOCS.
iocdf.org/wp-content/uploads/2014/08/
Assessment-Tools.pdf
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1784 DECEMBER 2021

REVIEW ARTICLE

Posttraumatic Stress
ONLINE
Disorder and
Anxiety-Related
Conditions
By John B. Williamson, PhD; Michael S. Jaffee, MD, FAAN;
Ricardo E. Jorge, MD
CITE AS: ABSTRACT

PURPOSE OF REVIEW: This article provides a synopsis of current assessment
AND PSYCHIATRY):1738–1763. and treatment considerations for posttraumatic stress disorder (PTSD)
and related anxiety disorder characteristics. Epidemiologic and
Address correspondence to neurobiological data are reviewed as well as common associated symptoms,
Dr John B. Williamson, McKnight
Brain Institute, University of
including sleep disruption, and treatment approaches to these conditions.
Florida, College of Medicine,
Department of Psychiatry, 1149 RECENT FINDINGS: PTSD is no longer considered an anxiety-related disorder in
Newell Dr, Gainesville, FL 32611,
john.williamson@ufl.edu. the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
classification and instead is associated with trauma/stressor-related
disorders. PTSD symptoms are clustered into four domains including
Dr Williamson serves on the
scientific advisory board for intrusive experiences, avoidance, mood, and arousal symptoms. Despite
Evren Technologies, Inc, and has this reclassification, similarities exist in consideration of diagnosis, treatment,
received research/grant support
from the Department of Defense
and comorbidities with anxiety disorders. PTSD and anxiety-related disorders
(DN180041), McKnight Brain are heterogeneous, which is reflected by the neural circuits involved in the
Research Foundation, genesis of symptoms that may vary across symptom domains. Treatment is
Continued on page 1763
likely to benefit from consideration of this heterogeneity.
Research in animal models of fear and anxiety, as well as in humans,
UNLABELED USE OF suggests that patients with PTSD and generalized anxiety disorder have
USE DISCLOSURE:
difficulty accurately determining safety from danger and struggle to
Drs Williamson, Jaffee, and suppress fear in the presence of safety cues.
Jorge discuss the unlabeled/ Empirically supported psychotherapies commonly involved exposure
investigational use of
pharmacologic compounds
(fear extinction learning) and are recommended for PTSD. Cognitive-
including 3,4- behavioral therapy has been shown to be effective in other anxiety-related
methylenedioxymethamphetamine disorders. Selective serotonin reuptake inhibitors (SSRIs) and serotonin
(MDMA), D-cycloserine,
ketamine, oxytocin, and norepinephrine reuptake inhibitors (SNRIs) are commonly used in the
propranolol for the treatment of treatment of PTSD and anxiety disorders in which pharmacologic
posttraumatic stress disorder
intervention is supported. Treating sleep disruption including sleep apnea
and the use of neuromodulation
techniques such as repetitive (continuous positive airway pressure [CPAP]), nightmares, and insomnia
transcranial magnetic (preferably via psychotherapy) may improve symptoms of PTSD, as well as
stimulation, which is not
currently approved for the
improve mood in anxiety disorders.
treatment of posttraumatic
stress disorder. SUMMARY: PTSD has a lifetime prevalence that is close to 10% and shares
© 2021 American Academy neurobiological features with anxiety disorders. Anxiety disorders are the
of Neurology. most common class of mental conditions and are highly comorbid with
1738 DECEMBER 2021

other disorders; treatment considerations typically include cognitive-
behavioral therapy and pharmacologic intervention. Developing
technologies show some promise as treatment alternatives in the future.
INTRODUCTION
E
motions influence cognitions and behaviors mediating the adaptation
of an organism to the varying demands of its environment. They shape
the ways in which we cope with stressful events and are integrated
with accompanying homeostatic responses.
This article examines the events triggered by exposure to severe
stress that lead to posttraumatic stress disorder (PTSD) and provides a definition
of this clinical condition, as well as the anxiety disorders. It then analyzes the
structure of symptoms for these conditions; describes the major epidemiological
features; mentions some pathophysiologic mechanisms; and places emphasis on
both nonpharmacologic and pharmacologic treatments for PTSD. With the
publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5),1 PTSD was reclassified as a trauma-related disorder, an
emphasis, perhaps, on etiology over phenomenology. Although PTSD is no
longer considered an anxiety-related disorder, diagnostic and treatment
considerations overlap, and further, PTSD has elevated rates of anxiety-related
symptom expression. Thus, this article also discusses anxiety-related conditions,
mechanisms, and treatment considerations.
Broadly, anxiety disorders are characterized by features of excessive fear and
worry with related behavioral disruptions. Expressions of anxiety may include both
internalizing and externalizing features and may be tied to different types of
situations, objects, and contexts. These situations and contexts are how anxiety
disorders are differentiated, from fears of specific objects to generalized worry. The
World Health Organization’s International Classification of Diseases, Tenth Revision
(ICD-10)2 defines anxiety disorders by frequent symptoms of apprehension, motor
tension, and autonomic overactivity. The DSM-5 includes developmental and
adult-onset disorders. Currently listed as anxiety disorders are separation anxiety
disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder,
agoraphobia, generalized anxiety disorder, substance/medication-induced anxiety
disorder, and anxiety disorder due to another medical condition. It should be noted
that, although PTSD does often share worry or fear-based features, like anxiety
disorders, heterogeneity exists, and subtypes of PTSD have clinical characteristics
that may manifest as dysphoria, aggression, or dissociation. These variable
manifestations are why PTSD is now grouped under a separate category.
Sleep disruption is common in PTSD and anxiety-related disorders; thus, the
frequent occurrence of sleep disturbance among patients with PTSD and
anxiety-related disorders is discussed, along with the effect that sleep disorders
have on the type and severity of symptoms, their longitudinal course, and their
response to established treatments.
DEFINITION AND SYMPTOM STRUCTURE OF POSTTRAUMATIC

STRESS DISORDER
PTSD, unlike anxiety-related disorders, is, by definition, tied to exposure to a
Criterion A event, (ie, an actual or threatened death, serious injury, sexual

POSTTRAUMATIC STRESS DISORDER AND ANXIETY-RELATED CONDITIONS
violence, or learning that a relative or close personal friend experienced an event

of this nature). Repetitive exposure to intense aversive situations including those
that involve significant injury to others (eg, combat, natural disaster, rescue
operations) may also result in PTSD.
PTSD diagnosis requires persistence of symptoms that meet the criteria for at
least 30 days, not necessarily immediately following trauma (delayed onset is
possible and common in military populations [CASE 11-1]), that are not the result
CASE 11-1 A 37-year-old man presented to the emergency department reporting

worsening depressive symptoms and recent onset of suicidal thoughts.
The patient was a veteran who was deployed 4 times to Iraq and
Afghanistan over the course of 7 years.
Sleep disturbance, depressive symptoms, and irritability manifested a
few months after he returned to the United States. During deployments,
the veteran experienced multiple mild traumatic brain injuries, as well
close blast exposures resulting from mortars, rocket-propelled
grenades, and improvised explosive devices. He also described a host of
war-related experiences, including being encircled by enemy fire,
witnessing children that were hurt or killed in terrorist attacks, and
collecting the dismembered corpses of his comrades. He reported that,
on multiple occasions, he was horrified, nauseated, and confused.
Approximately 1 year after he returned to the United States from his last
deployment, he experienced progressively disturbed sleep and
increasingly frequent nightmares and dream-enactment behaviors. He
also had severely distressing flashbacks of stressful events, as well as
intrusive thoughts with paranoid and self-deprecating content.
Occasionally, he reported the occurrence of perceptual disturbances,
such as hearing the voice of a close friend killed in combat or suddenly
smelling particular odors that reminded him of his days in the Middle East.
The patient had become socially withdrawn. He also avoided any
situation that would remind him of his military experiences, possibly
exacerbating social withdrawal. He felt ashamed and guilty. Furthermore,
he was easily startled, hypervigilant, and suspicious. He reported that he
increased his alcohol and cannabis use to help with chronic insomnia. His
friends and relatives noticed increased irritability and violent outbursts in
response to minor frustrations. He was unable to keep a job. His wife left
the house 1 week before he presented to the emergency department.
COMMENT The clinical picture points to a diagnosis of posttraumatic stress disorder

(PTSD) with delayed onset (not atypical in veterans returning from
deployment or disconnecting from the structure of military service) with
prominent intrusive experiences, avoidance, dysphoric cognitions, sleep
disturbance, and hypervigilance symptoms. The presence of active suicidal
ideation, social isolation, and coexistent substance misuse prompted
admission to a psychiatric unit for acute stabilization and treatment
adjustment.
1740 DECEMBER 2021

of another medical condition or toxic effect of drugs or other chemical KEY POINTS
substances.
● Diagnosis of
Symptoms may occur shortly after trauma. In these cases, if symptoms last at posttraumatic stress
least 3 days but less than 30 days, the diagnosis is acute stress disorder. This acute disorder (PTSD) requires the
response is characterized by a prominence of dissociative symptoms, such as experience of a Criterion A
depersonalization or altered experience of the environment. Not everyone with event, which is a specific
event of exposure to actual
acute stress disorder will develop PTSD, although these symptoms are strong
or threatened death, sexual
predictors for the development of PTSD. Both acute stress disorder and PTSD are violence, or serious injury.
classified as stress-related disorders by the current nomenclature. Symptoms must persist for
The DSM-5 articulates four symptom clusters that characterize PTSD: (1) at least 1 month and have a
clinically significant
intrusive symptoms, (2) active avoidance, (3) disturbed emotional states, and
functional impact. Acute
(4) alterations of arousal and reactivity (FIGURE 11-1). Intrusive symptoms stress disorder is the
include distressing memories of the Criterion A event, sleep disruption appropriate diagnosis if
(nightmares), and dissociative experiences (eg, flashbacks). It should be noted symptoms are present for
that sleep disruption manifests in different ways across criteria. less than 1 month.
At least one form of active avoidance of distressing memories must be present ● The Diagnostic and
to make a diagnosis of PTSD. These behaviors may include avoiding external Statistical Manual of Mental
reminders such as people, places, activities, or objects. Disturbed emotional Disorders, Fifth Edition
states include pervasive negative cognitions and beliefs such as feelings of (DSM-5) articulates four
symptom clusters of PTSD:
worthlessness, hopelessness, shame, and guilt; emotional numbing (a sense of (1) intrusive thoughts, (2)
detachment in interpersonal relationships); and anhedonia (the inability to active avoidance, (3)
experience positive emotions). At least two of these disturbed emotional states disturbed emotional states,
must be present. Alterations of arousal and reactivity include heterogeneous and (4) alterations of arousal
and reactivity.
conditions such as exaggerated startle response, irritability, anger, aggressive
behavior, hypervigilance, and sleep disturbance. This cluster may be composed
of two related components, namely, dysphoric arousal (anger, sleep disruption)
and physiologic arousal (increased startle response and hypervigilance) with
different neurobiological attributes.3
Bryant and colleagues4 used network analysis to prospectively study a group
of 1138 patients with PTSD early after trauma and at 12 months of follow-up. In
the acute phase, they identified a core network of reexperiencing and avoidance
symptoms that turned out to be consistent predictors of PTSD in the chronic
phase. This core group of PTSD symptoms might be related to disruption of the
fear-processing system, particularly with respect to the discrimination of threat
and safety cues and the consolidation of traumatic memories. Furthermore, some
evidence shows that this cluster of symptoms is also prominent among veterans
with blast-related neurotrauma, years after the traumatic events.5 It is
conceivable that alterations in prefrontal regulation associated with traumatic
brain injury (TBI) contribute to the enhancement and persistence of this
symptomatic core.6
PTSD is a heterogeneous disorder with subtypes possessing distinct
pathophysiologic mechanisms requiring specific therapeutic approaches. For
instance, complex PTSD has been associated with a history of early traumatic
experiences and an altered developmental process resulting in maladaptive
personality traits with significant alterations in emotional regulation. Complex
PTSD is characterized by a poorly integrated self-image, disturbed interpersonal
relationships, frequent dissociative experiences, somatization, defective impulse
control, and self-destructive behaviors.7
PTSD rarely presents as an isolated condition. Its presentation is
heterogeneous; the several subtypes include, for example, complex PTSD, which

FIGURE 11-1
Posttraumatic stress disorder (PTSD) symptom clusters. Symptoms from each cluster
should be present to support a PTSD diagnosis.
is associated with a history of early Criterion A experiences that affect brain

development and personality. PTSD is highly comorbid with mood disorders,
anxiety disorders, chronic pain, and substance misuse, as well as increased rates
of intermittent explosive disorder, particularly in military veterans.8 It should be
noted that this comorbidity does not necessarily imply that these are
independent conditions. The chronic maladaptive states associated with PTSD
may contribute to the manifestation of comorbid conditions, and, likewise,
preexisting conditions involving similar brain networks may increase the
likelihood of developing PTSD when presented with a qualifying stressful event.
SYMPTOM STRUCTURE OF ANXIETY DISORDERS

Specific phobias are anxiety or fear of a particular circumstance or object (eg,
flying or insects). Social anxiety disorder is the current term for social phobia in
which an individual may have a fear and actively avoid any social situation that
may lead to scrutiny by others. Agoraphobia and panic disorder are now
independent diagnoses. Agoraphobia is a marked fear or anxiety of situations
outside the home, which can include the use of public transportation, being in
open spaces, being in enclosed spaces such as shops or theaters, standing in line
1742 DECEMBER 2021

or being in a crowd, or simply being outside of the home alone. Current criteria KEY POINTS
for panic disorder include having recurrent panic attacks and for at least 1 month
● Comorbidities are
after the panic attack having a persistent concern or worry about having another common with PTSD and
panic attack or maladaptive behaviors related to the attacks, such as avoidance of include substance misuse,
situations that may be triggering. Panic attacks require at least four different mood disorders, and chronic
symptoms, which may include palpitations, chest pain, sweating, sensations of pain. In the case of complex
PTSD, which is typically
shortness of breath, feelings of choking, dizziness, sensations of chills or heat,
associated with childhood
paresthesia, derealization, sweating, trembling, fear of dying, or fear of losing abuse, maladaptive
control. Each of these diagnoses requires a duration of 6 months or longer and personality traits may
whose active avoidance can result at times in some form of functional manifest with associated
poor impulse control and
impairment.
the occurrence of
Generalized anxiety disorder refers to the syndrome of excessive worry more self-injurious behaviors.
days than not for at least 6 months about several events or activities, and this PTSD may contribute to the
anxiety is also associated with at least three physical symptoms. These physical development of comorbid
symptoms may include restlessness, fatigue, difficulty concentrating, irritability, conditions.
muscle tension, and sleep disturbance. As with other categories in DSM-5, the ● The gold standard
section on anxiety disorders also includes entries for substance/medication- instrument for assessing and
induced anxiety disorder, anxiety disorder due to another medical condition, diagnosing PTSD is a
other specified anxiety disorder, and unspecified anxiety disorder. semistructured interview,
the Clinician-Administered
The DSM-5 also includes additional diagnoses classified as anxiety disorders PTSD Scale for the DSM-5
that more typically are found in children. These include separation anxiety (CAPS-5). Several
disorder, which includes developmentally inappropriate fear and distress when inventories for quantifying
separated from people the patient is attached to. Selective mutism is the diagnosis the severity and distribution
of PTSD symptoms also
used when a patient has a specific failure to speak in social situations (eg, school)
exist; the most commonly
when expected to do so; these patients are able to speak in other situations. used is the Posttraumatic
Stress Disorder Checklist for
SIMILARITIES IN POSTTRAUMATIC STRESS DISORDER AND the DSM-5.
ANXIETY DISORDERS
PTSD shares phenomenologic similarities with anxiety disorders, including
elements of hyperarousal, increased startle response, irritability, avoidance, and
difficulty sleeping. It should be noted that obsessive-compulsive disorder also
shares both heterogeneity in the presentation of hyperarousal symptoms and
genetic risk with anxiety-related disorders.9 Anxiety exists on a continuum of
normal and pathologic; anxiety disorders are defined by fear or worry that is
excessive and/or persistent beyond that which is developmentally appropriate.
Persistence is defined most often as lasting at least 6 months, although this is, in
part, a clinical judgment call, and the timeline is shorter for childhood disorders.
DIAGNOSIS
PTSD is diagnosed on the basis of the subjective reports of the affected
individuals by using the DSM-5 criteria. Several structured interviews were
developed to inform a PTSD diagnosis, with the gold standard being the
Clinician-Administered PTSD Scale for the DSM-5 (CAPS-5).10 This instrument
addresses all four domains and associated PTSD symptoms described in the
DSM-5, including characterization of the time of symptom onset and the
duration, as well as functional impact. More quickly administered screeners such
as the PTSD Checklist for the DSM-5, a 20-item self-report questionnaire that
measures the severity of PTSD symptoms on 4-point ordinal scales ranging from
0 (not at all) to 4 (extremely), are useful but need supplementation with a
clinical interview to establish the occurrence of Criterion A events.11 Both the

CAPS-5 and PTSD Checklist for the DSM-5 (PCL-5) allow for analysis of
symptom clusters represented in the DSM-5 criteria (ie, intrusive symptoms,
active avoidance, disturbed emotional states, and alterations in arousal and
reactivity).12 Common instruments used for the diagnosis of PTSD are presented
in TABLE 11-1.
Anxiety disorder diagnosis should include psychiatric interview and medical
evaluation. Disorders are diagnosed based on DSM-5 or ICD-10 criteria by using
self-report, clinical observation, collateral information, and structured interview
and personality assessment tools. The gold standard assessment approach
remains structured interviews. The Structured Clinical Interview for DSM-5
(SCID-5) is a widely used semistructured interview tool broken into modules. If
an anxiety disorder is suspected, the anxiety disorders diagnostic module may be
used. Psychometric properties are excellent with high reliability and specificity.
Severity may also be assessed.13 Anxiety self-report scales may be informative
(eg, the State-Trait Anxiety Inventory, the Beck Anxiety Inventory) as well as
personality tests (eg, Minnesota Multiphasic Personality Inventory [MMPI]
and Personality Assessment Inventory [PAI]). Key features of specific
anxiety-related disorders are presented in TABLE 11-2. In both anxiety-related
disorders and PTSD, it is important to assess suicidality risk. If not addressed
during clinical interview, commonly used scales include the Patient Health
Questionnaire 9-item depression scale (PHQ-9) and Beck Depression Inventory-II
(BDI-II). Both scales may indicate suicidal ideation. Additional risk assessment
may include the use of a tool such as the Columbia-Suicide Severity Scale.14
TABLE 11-1 Instruments for the Assessment of Posttraumatic Stress Disordera
Instrument Characteristics
Diagnostic Interview Schedule Structured interview, dichotomous measure (presence or absence) of 17

posttraumatic stress disorder (PTSD) symptoms
Structured Clinical Interview for Diagnostic Structured interview, dichotomous measure (presence or absence) of PTSD
and Statistical Manual of Mental Disorders, symptoms as described in the DSM-5 nomenclature
Fifth Edition (DSM-5) (SCID-5)
Clinician-Administered PTSD Scale for A 30-item questionnaire corresponding to the DSM-5 diagnosis for PTSD
DSM-5 (CAPS-5)
Comprehensive scale embedded within a structured interview that allows
making current and lifetime diagnosis of PTSD, as well as the severity of PTSD
symptoms during the past week
Assesses frequency and intensity of symptoms as well as their repercussion
on social and occupational functioning
Is considered the gold standard for PTSD diagnosis
PTSD Checklist for DSM-5 (PCL-5) A 20-item self-report measure corresponding to the DSM-5 symptom criteria
for PTSD
Rating scale of 0 to 4 for each symptom corresponding to the following
descriptors: not at all, a little bit, moderately, quite a bit, and extremely
a
Updated with permission from Jorge RE, Continuum (Minneap Minn).7 © 2015 American Academy of Neurology.
1744 DECEMBER 2021

EPIDEMIOLOGIC ASPECTS
Prevalence and risk factors for PTSD and anxiety-related disorders demonstrate
common features. These elements are highlighted in this section.
Prevalence of Posttraumatic Stress Disorder

Traumatic events that may result in the development of PTSD are common,
ranging from 50% to 90% depending on region and country.12 However, in 2009
survey research, between 7% and 12% of people exposed to a traumatic event go
on to develop PTSD.12 The type of trauma is associated with different rates of
PTSD, with assaultive violence incurring the greatest risk. In a study of 1484
veterans, lifetime and past-month prevalence of PTSD was estimated at 8% and
5%, respectively, by using the DSM-5 criteria.15 Younger people appear most
vulnerable, when controlling for type and severity of trauma, but age is not
immunity; Spitzer and colleagues16 reported a prevalence of PTSD of 3.1% in a
sample of 851 people older than 64 years. In summary, sexual-related violence is
the preeminent etiology for PTSD among women, and combat-related violence is
the more frequent antecedent among men. Women and younger people appear
Key Features of Anxiety-Related Disorders TABLE 11-2
Disorder Key characteristics

Separation anxiety disorder Worry regarding separation from attachment figures; developmentally inappropriate,
present for at least 4 weeks (in children) and 6 months (in adults)
Selective mutism Failure to speak in certain social situations; normal ability in other settings; average age
at onset is 2 to 5 years; most common setting is school
Specific phobia Fear of environment (eg, water/heights), situations (eg, flying), animals (eg, spiders),
and needles and blood (exposure may lead to syncope); more than one phobia is more
common than just one
Panic disorder Recurrent unexpected panic attacks (palpitations, sweating, trembling, or shaking,
shortness of breath, sense of choking, chest pain/discomfort, nausea, dizzy/light-
headedness, chills/heat sensations, paresthesia, derealization, fear of “going crazy,”
fear of dying)
Agoraphobia Fear/anxiety about two or more of the following situations: using public
transportation, open spaces, enclosed spaces, standing in line or a crowd, being
outside of the home alone
Social anxiety disorder Fear/worry related to one or more social situations in which the individual perceives
scrutiny (conversations, meeting unfamiliar people, being observed, performing in
front of others)
Generalized anxiety disorder Excessive worry occurring more days than not for at least 6 months about many
events/activities; poor control of worry and worry associated with symptoms such as
restlessness, fatigue, irritability, poor concentration, muscle tension, sleep
disturbance, and irritability
Substance/medication-induced Anxiety as the result of a medication or other substance; not attributable to another
anxiety disorder anxiety disorder
Anxiety disorder due to another Anxiety as the result of another medical condition; not attributable to another anxiety
medical condition disorder

to be more vulnerable to develop PTSD after trauma. PTSD is increasingly

recognized in older people.
However, it is important to mention that PTSD is itself a risk factor for other
important clinical conditions. For instance, a large epidemiologic study
conducted in Sweden that followed 136,637 participants with stress disorders,
their unaffected full siblings, and 1,366,370 matched unexposed controls up to
27 years concluded that stress disorders are strongly associated with multiple
types of cardiovascular disease, independent of family background, history of
medical conditions, and psychiatric comorbidity.17
PTSD and dementia appear to have a bidirectional relationship by which PTSD
increases the risk for late-onset dementia and dementia increases the risk for
delayed-onset PTSD,18 possibly with variance accounted for by genetic factors
and allostatic load (the cumulative burden of the effects of chronic stress)
associated with chronic stress. Finally, in a nationwide cohort of US Veterans, it
was reported that both TBI and PTSD are independently associated with an
increased relative risk for Parkinson disease, as well as a potential modest
synergistic excess risk in those with comorbid TBI/PTSD.19
Sleep disruption is a prevalent symptom of PTSD and is the most common
symptom reported in patients with PTSD. Sleep disruption contributes to poor
health outcomes as well as cognitive and mood dysfunction.20 Common sleep
symptoms associated with PTSD include nightmares, night terrors, nocturnal
panic attacks, and insomnia.21
Prevalence of Anxiety-Related Disorders

Anxiety-related disorders are common, affecting between 2.5% and 7% of the
world’s population.22 Further, anxiety is a frequent comorbidity in many
disorders. Anxiety disorders occur more frequently in women, according to the
DSM-5, at a ratio of 2:1. The prevalence/incidence is affected by criteria used to
determine the diagnosis. By using DSM-5 criteria, generalized anxiety disorder,
for example, is more prevalent than DSM-IV–defined generalized anxiety
disorder with a lifetime prevalence of 3.7% and a 12-month prevalence of 1.8%.
Anxiety disorders typically are first noticeable in childhood.23 Further, exposure
to adversity including events that may qualify as Criterion A instances in children
increases vulnerability to the development of anxiety disorders, PTSD, and
depression in military personnel, suggesting a common vulnerability factor.24
Suicidal ideation is common in both PTSD and anxiety-related disorders.
Bipolar disorder is strongly associated with suicide attempts, and this is amplified
in those patients with comorbid PTSD and social anxiety disorder.25 The risk of
suicide attempts is elevated in patients with panic disorder, PTSD, and
generalized anxiety disorder even in the absence of a comorbid mood disorder,
although the latter substantially increases risk.26
Risk Factors for Posttraumatic Stress Disorder and Anxiety-Related

Disorders
Several factors are related to both resilience and vulnerability to development of
PTSD after trauma exposure. It is not surprising that childhood sexual abuse and
physical abuse are established risk factors for PTSD. Abuse experienced early in
life may modify hypothalamic-pituitary-adrenal axis response, manifesting as
changes in stress reactivity (eg, autonomic response, startle).27 Childhood
impulse control disorders also appear to present as vulnerability factors for the
1746 DECEMBER 2021

development of PTSD. For example, attention deficit hyperactivity disorder KEY POINTS
increases the risk for subsequent development of PTSD after trauma exposure;
● The experience of
mechanistic linkages are suggested by animal studies.28 Criterion A events is
Autonomic features prior to trauma exposure predict the development of common, with between 50%
PTSD. In a large study of 2430 combat veterans, predeployment heart rate and 90% of people
variability features predicted development of PTSD. Further, those exposed to experiencing at least one in
their lifetime. However, of
trauma with subclinical features of PTSD evidenced lower heart rate variability,
those exposed, between 7%
as did those with clinically significant PTSD.29 and 12% go on to develop
Variations in hormonal levels may contribute to women’s vulnerability to PTSD.
developing PTSD. Testosterone and dehydroepiandrosterone levels have been
associated with resilience30 whereas levels of ovarian hormones are associated ● Sexual-related violence is
the preeminent etiology for
with stress reactivity.31 However, oxytocin levels may protect against stress PTSD among women, and
reactivity.32 combat-related violence is
Several other factors have been reported to modify the risk for developing the more frequent
PTSD. People with lower cognitive performance on measures of fluid ability antecedent among men.
Women and younger people
(abstract reasoning ability) are more vulnerable to developing PTSD following appear to be more
trauma.33 In military samples, exogenous factors including leadership style and vulnerable to develop PTSD
unit cohesiveness modify the risk of developing PTSD. Postdeployment social after trauma. PTSD is
support is also influential after return to civilian life.34 increasingly recognized in
older people.
Genetic Risk Factors and Integrative Models of Risk

Genetic factors increasing the vulnerability for PTSD include the presence
of polymorphisms in the serotonin transporter receptor (SLC6A4),35
glucocorticoid receptor binding protein (FKBP5),36 and BDNF37 genes.
However, polymorphisms in the corticotropin-releasing hormone receptor 1
(CRHR1)38 and neuropeptide Y (NPY)39 genes have been associated with
decreased risk. Epigenetic modification of the glucocorticoid receptors may
also influence stress response. Chronic stress may influence changes in gene
expression that can affect development, chronicity of PTSD symptoms, or
resilience (eg, decreased methylation of the glucocorticoid receptor gene40).
Heritability of PTSD and anxiety-related disorders derived from twin studies
are similar, between 0.3 and 0.5 h2 (narrow-sense heritability).41 Perhaps the
most well-supported genetic association with an anxiety-related disorder is
panic disorder via COMT Val158Met.42 COMT is mainly expressed in the
prefrontal cortex, with Val158Met related, although not consistently, to
activity in the prefrontal cortex and amygdala,43 as well as in association with
startle reactivity.44
PATHOPHYSIOLOGY
Pathophysiologic features of PTSD and anxiety-related disorders include
differences in adrenal, autonomic, structural, functional, and
inflammatory characteristics.
Hypothalamic-Pituitary-Adrenal Axis Changes

The hypothalamic-pituitary-adrenal axis is integral to regulating stress
responses. Although lower basal cortisol levels were once considered a biomarker
of PTSD,45 cortisol levels are difficult to interpret in the context of comorbidities,
including depression. Further, the time of day of cortisol measurement, hormone
levels (eg, menstrual cycle variation), and the method of acquisition and analysis
may influence differences in findings and reflect different mechanisms.

Fear and worry are components of PTSD, and systematic overlap exists with
anxiety-related disorders in pathophysiology. Indeed, although dysphoria and
major depressive disorder may confound interpretation of cortisol suppression in
PTSD, both are also frequent comorbidities in anxiety spectrum disorders.
Similar to the findings in PTSD, evidence of hyporesponsiveness of
saliva-derived cortisol in social anxiety disorder has been found.46 However,
results are mixed with elevations in saliva amylase and cortisol reported in
generalized anxiety disorder.47 As in PTSD, interpretation of cortisol findings is
complicated by diurnal factors in cortisol levels and potentially heterogeneity
and state-related factors. Hair cortisol metrics offer a more stable indicator than
saliva-derived metrics; increased hair cortisol concentration is associated with
chronic stress, and this is worse during ongoing stress. Replication of saliva
hyporesponsiveness of cortisol with reductions in hair cortisol is observed in
anxiety disorders (generalized anxiety disorder), as well as PTSD.48
Autonomic Changes
Patients with PTSD might have strong autonomic responses, including increased
heart rate and blood pressure, decreased heart rate variability, and increased
sympathetic response to a perceived threat. These autonomic responses are
associated with the severity of general and dysphoric arousal.49 Over time,
chronic elevation of noradrenergic tone may contribute to the development of
dysfunction in multiple physiologic systems, with evidence of increased risk of
heart failure, metabolic syndrome, and sleep disturbance.
Hyperarousal autonomic features in adults are associated with anxiety-related
symptom presentation. In adults with generalized anxiety disorder, higher heart
rate and lower heart rate variability have been reported at rest. Further, with
stress, higher connectivity between the right amygdala and superior frontal
gyrus has been associated with less decrease in heart rate variability in patients
with generalized anxiety disorder.50 Like PTSD, anxiety disorders are associated
with increased cardiovascular disease risk.51
Fear-Processing in Posttraumatic Stress Disorder and Anxiety-Related

Disorders
Patients with PTSD show impairments in fear responses. Determination of safety
is diminished because patients with PTSD struggle to discriminate danger and
safety cues.52 Increased amygdala activation resulting from faulty modulatory
input from the left ventromedial prefrontal cortex may underlie abnormal fear
responses in PTSD.53 The amygdala has a role in determining the salience of
aversive cues and integrating responses mediated by the diencephalon and
brainstem nuclei. However, results are heterogeneous with regard to the
direction of abnormality with some cases showing increased prefrontal activation
on cognitive-emotional control tasks and others showing decreases.54,55
Learning is a critical component in both the development and successful
treatment of PTSD. The hippocampus modulates amygdala function in
contextual fear conditioning and fear extinction memory.56 Patients with PTSD
demonstrate normal extinction of conditioned cues but altered retention of
extinction memories along with decreased ventromedial prefrontal cortical
activation during recall.57
Differences in processing fear are related to both intrusive and hyperarousal
symptoms of PTSD.58 PTSD is heterogeneous in its presentation, and this may
1748 DECEMBER 2021

account for some heterogeneity in the behavior of frontal limbic systems. For KEY POINTS
example, patients with PTSD with severe dissociative symptoms demonstrate
● Hormonal variations
increased ventromedial prefrontal cortex activation during aversive processing.59 might be an important factor
This is consistent with observed reductions in autonomic arousal and cortisol explaining the increased
levels in some patients with PTSD and may suggest the occurrence of a different vulnerability of women
neurophysiologic state. developing PTSD.
In people with anxiety-related disorders, there are common brain network
● Autonomic features of
differences from people without anxiety-related disorders, as well as divergences PTSD associated with
in connectivity depending on the specific anxiety-related disorder and hypothalamic-pituitary-
expression of symptoms; it is important to note that heterogeneity exists. adrenal axis disruption
Activation of fear-related circuitry including limbic-cortical systems during an including reduced
parasympathetic activity
emotion recognition task is associated with both state and trait levels of anxiety and increased sympathetic
in patients with anxiety disorders.60 Fear-related circuitry activation differences responses to stress
have been observed at rest61 and during cognitive control tasks devoid of associated with chronic
emotional content.62 elevation of noradrenergic
tone have significant impact
on multiple physiologic
Inflammation in Posttraumatic Stress Disorder and Anxiety-Related systems. Chronic elevation
Disorders of adrenergic tone is
Evidence has shown that, at least in a subgroup of patients, PTSD is associated associated with increased
cardiovascular risk, sleep
with increased levels of proinflammatory biomarkers, such as interleukin-1β, disturbance, and the
interleukin-6, tumor necrosis factor-α, and C-reactive protein.63 Given the metabolic syndrome.
extensive crosstalk among neuroendocrine, autonomic, and immune systems,
it is conceivable that peripheral and central nervous system inflammation ● Patients with PTSD have
difficulty discriminating
(via microglial and astrocytic activation) play a role in PTSD pathogenesis
danger from safety cues and
and may also be exacerbated by the effects of PTSD on neurophysiologic problems suppressing fear
state.64 in the presence of safety
Evidence of increased inflammation has been found in both central and cues. Functional MRI (fMRI)
peripheral markers in anxiety-related disorders. Patients with anxiety-related studies show increased
amygdala activation
disorders and PTSD show evidence of chronic low-grade inflammation. resulting from abnormal
Increased blood markers of cytokines (eg, interleukin-6, tumor necrosis factor-α, modulatory activity of the
and C-reactive protein) in patients with anxiety-related disorders have been ventromedial prefrontal
reported.65 Inflammation may contribute to degraded performance of reward cortex. This response is
heterogeneous with more
circuitry, as well as to dysfunction in prefrontal limbic circuitry, both elements prominent dissociative
that might perpetuate and exacerbate symptoms of anxiety.66 symptoms associated with
inhibition of the amygdala
Structural Brain Changes and less autonomic
reactivity to stress.
Structural differences have been demonstrated in patients with PTSD, including
in areas that have demonstrated functional differences, namely reduced ● PTSD and anxiety-related
prefrontal cortex and limbic brain volumes.67 It is unclear, however, whether disorders are both
these differences represent a vulnerability to the development of PTSD or associated with
inflammation (systemic and
represent brain changes as a result of chronic neurophysiologic states associated
peripheral).
with the disorder; it may be both. Chronic stress, in animal models, has been
shown to affect hippocampal neuronal quality and health.68 Further, volumetric ● PTSD is a risk factor for
differences in hippocampal structures are associated with glucocorticoid cognitive decline and may
receptors69; corticosteroids may decrease neuronal health and contribute to contribute to reductions in
brain health.
poorer memory performance, a common cognitive problem in patients with
PTSD. Structural differences are also associated with treatment success;
thickness of the prefrontal cortex and volume of the anterior cingulate cortex are
associated with extinction retention and cognitive-behavioral therapy (CBT)
outcomes, respectively.70,71

Reduced fractional anisotropy of the uncinate fasciculus, a frontal limbic

white matter tract, is associated with startle and subthreshold PTSD symptoms in
recently deployed military service members.72 Mild TBI, a common occurrence
in military personnel diagnosed with PTSD (elevated rates of PTSD subsequent
to mild TBI), may impact this circuit and potentially contribute to the
manifestation of symptoms of PTSD, although causality is unclear because of a
lack of longitudinal studies.6,73
In addition to differences in activity of fear circuitry, structural differences are
also evident in anxiety-related disorders, even in children. Specifically, uncinate
fasciculus fractional anisotropy is lower in boys with anxiety disorders.74 This
relationship is also seen in adults with generalized anxiety disorder75 and
obsessive-compulsive disorder and, further, the degree of white matter integrity
decrement is associated with the severity of symptoms.76
Sleep
Hyperarousal symptoms of PTSD are associated with sleep disruption. In
part, this is because of the inclusion of difficulty sleeping in Criterion E
(alterations in arousal and reactivity, hyperarousal symptoms), but also several
physiologic indicators associated with hyperarousal may contribute to poor
sleep. For example, patients with PTSD demonstrate reduced vagal activity
and increased adrenocorticotropic hormone levels during the night.77
Differences in sleep architecture are noted. A meta-analysis of polysomnography
studies in patients with PTSD demonstrated longer sleep latencies, decreased
time in slow-wave sleep, and increased time in rapid eye movement (REM)
sleep.78 Further, nightmares are associated with increased REM and non-REM
instability.79
Sleep disruption is also common in anxiety-related disorders. Also,
insomnia appears to increase anxiety levels. Much of the data in the literature
across anxiety disorders are self-reported. Limited objective data exist. Patients
with generalized anxiety disorder show increased sleep-onset latency, reduced
sleep efficiency, increased waking after sleep onset, and, like patients with PTSD,
decreased slow-wave sleep.80 In a meta-analysis of controlled polysomnography
studies, REM sleep pressure and sleep depth were associated with anxiety
disorders.81
Sleep disruption is multifactorial and regulated through complicated
interactions among several brain regions and neuromodulators. Vagally
mediated elements of the limbic system are important in achieving normal sleep
function and appear to be one conduit through which patients with PTSD and
anxiety-related disorders experience sleep disruption.82 Patients with PTSD have
higher rates of sleep apnea and cardiovascular disease including heart failure,83
which may be influenced by sleep disruption.
Consideration of sleep disorders and associated medical issues in the medical
evaluation process for anxiety disorders and PTSD is critical. Sleep apnea should
be evaluated; it is an independent risk factor for cardiovascular and
cerebrovascular disease, as well as cognitive and mood dysfunction. It is also
treatable. Use of CPAP is associated with a reduction in these risk factors, as well
as improved cognitive and mood function. Further, CPAP adherence in patients
with PTSD with sleep apnea may be associated with a reduction in both
nightmare occurrence and overall severity of symptoms of PTSD.84
Unfortunately, CPAP adherence may be lower in patients with PTSD than those
1750 DECEMBER 2021

without PTSD.85 CPAP use does not appear to affect anxiety symptoms in KEY POINTS
anxiety-related disorders, although it does reduce symptoms of depression.86
● Reduced hippocampal
volumes have been
TREATMENT OF POSTTRAUMATIC STRESS DISORDER AND consistently reported
ANXIETY-RELATED CONDITIONS among patients with PTSD.
Efficacy for both psychological and pharmacologic treatments has been Chronic stress may be
causal; animal models
demonstrated in anxiety-related disorders and PTSD. Psychoeducation may be
demonstrate stress impacts
helpful. Self-help interventions (eg, books, internet-based programs) may have neuronal quality and health
moderate effects on symptom reduction in anxiety disorders.87 in the hippocampus.
Psychotherapy ● Sleep disruption is

common in PTSD and
CBT protocols, particularly exposure-based, have been demonstrated to be effective anxiety-related disorders.
treatments in patients with PTSD, generalized anxiety disorder, social anxiety Sleep disruptions in PTSD
disorder, specific phobia, and panic disorder. Exposure-based therapies are the commonly include
treatment of choice for agoraphobia, which often is associated with comorbid panic nightmares and, although
results in the literature are
disorder and may require medication; however, without panic disorder, no evidence mixed, a meta-analysis of
supports the use of pharmacotherapy. In a recent meta-analysis, the overall polysomnographic features
remission rate for anxiety-related disorders is about 51%, with PTSD having the indicates that patients with
highest remission rate and social anxiety disorder the lowest.88 CBT may be PTSD have longer sleep
latencies, as well as
considered a first-line option in panic disorder, generalized anxiety disorder, social decreased time in slow-
anxiety disorder, specific phobia, selective mutism, and separation anxiety disorder. wave sleep and increased
Several psychotherapy approaches for treating PTSD are empirically supported. time in REM sleep.
Common elements in these approaches include exposure to aversive memories
● Sleep apnea is a common
and cognitive processing (see TABLE 11-3 for current exposure-based and
comorbidity in patients with
cognitive-based therapies). PTSD and is possibly
Cognitive processing and exposure-based therapies produce moderate to large associated with increased
effect sizes in patients with PTSD, with smaller and mixed effects evident in rates of metabolic
combat-related PTSD.89 Evidence shows that CBT affects functional connectivity syndrome. Continuous
positive airway pressure
among amygdalocortical networks associated with a reduction in symptoms.90 (CPAP) adherence may be
Acceptance and commitment therapy and mindfulness-based cognitive therapy associated with reduction in
are “third-wave” cognitive and behavioral approaches and have not proven to be nightmare occurrence and
more efficacious than other established treatments. Dropping out and lack of overall severity of
symptoms of PTSD. CPAP
response to psychotherapeutic treatment are significant problems for patients with adherence appears to be
PTSD. Thus, although efficacy differences may not be apparent, an individual’s lower in patients with PTSD
willingness and ability to complete different forms of psychotherapy may vary. compared with those
Although CBT and cognitive processing therapy, if completed, do without.
significantly reduce symptoms of PTSD, sleep disruption is not consistently
● Both controlled exposure
improved.91 Successful treatment of sleep disruption in patients with PTSD may to aversive memories and
improve symptoms of PTSD. For sleep elements of PTSD, the American cognitive reprocessing are
Academy of Sleep Medicine recommended image rehearsal therapy for efficacious psychotherapies
for treatment of PTSD, but
nightmares and CBT for insomnia.91
they tend to be less
effective in combat-related
Pharmacologic Treatment of Posttraumatic Stress Disorder PTSD.
Medication interventions may be preventively administered after trauma exposure
and before the onset of PTSD or reduce symptoms of PTSD after its onset.
Hydrocortisone given after trauma and before the onset of PTSD may prevent the
onset of PTSD; however, evidence is poor for preventive effects of propranolol,
benzodiazepines, or selective serotonin reuptake inhibitors (SSRIs). Methodologic
flaws and small sample sizes limit interpretability.92 Overall, preventive interventions
are still in an experimental phase and have not been incorporated in clinical practice.

However, pharmacologic agents have good support for being more effective
than placebo. Effect sizes in rigorously controlled trials have been modest and
smaller than those demonstrated for psychotherapeutic methods. Few trials have
compared pharmacologic and psychotherapeutic methods; a recent meta-analysis/
systematic review identified two with high heterogeneity in outcomes and
insufficient evidence to determine if a difference in effectiveness exists.93
The heterogeneity of presentation of PTSD poses a challenge in management
given different physiologic mechanisms. The course of PTSD is also variable and may
require different approaches depending on the chronicity of the presentation and
the involvement of comorbidities (eg, sleep disruption, depression). Medications
that have shown some efficacy in treating PTSD are presented in TABLE 11-4.
MOOD MEDICATIONS. SSRIs are the agents of choice for patients with PTSD with a
modest reduction in the severity of PTSD symptoms (eg, sertraline94 and
fluoxetine95). These effects are impacted by the type of traumatic event and
presentation of symptoms of PTSD. As in psychotherapy, PTSD in military
populations appears to be less responsive to treatment. Sertraline has not been
found to be more effective than placebo in patients with combat-related PTSD.96
TABLE 11-3 Psychotherapy for the Treatment of Posttraumatic Stress Disordera
Therapy Content
Exposure-based
Prolonged exposure Education, exposure to traumatic memories, confrontation, cognitive restructuring
Eye movement desensitization and Combines traumatic image exposure with simultaneous performance of lateral eye
reprocessing movements
Stress inoculation Education, relaxation training, exposure to aversive memories, role-playing, guided
self-dialogue
Virtual reality exposure Exposure to computerized, vividly recreated environments
Cognitive-based
Trauma-focused psychodynamic Education, free association, dream interpretation, cognitive restructuring

therapy
Cognitive processing therapy Education, limited exposure to traumatic memories, Socratic questioning,
identification of maladaptive cognition and automatic thoughts, cognitive
restructuring
Acceptance and commitment Acceptance, defusion, contact with the present moment, self as context, values,
therapy committed action
Sleep-based
Cognitive-behavioral therapy (CBT) Education, stimulus control, sleep restriction/hygiene, environmental improvement,
for insomnia relaxation training, biofeedback
Image rehearsal therapy CBT-based approach, education, create nonfrightening endings to recurring
nightmares, rehearse nonthreatening endings, learn how to monitor nightmares and
gauge efficacy
a
1752 DECEMBER 2021

Serotonin norepinephrine reuptake inhibitors (SNRIs) may also be more KEY POINTS
effective in treating PTSD than placebo.97 Side effect profiles for SSRIs and
● Medications are modestly
SNRIs demonstrate good tolerability. more effective than placebo
Lithium, valproate, and carbamazepine are largely ineffective in treating PTSD in treating PTSD symptoms.
but may be helpful in those patients with coexistent bipolar disorder98; data quality Selective serotonin
is poor. reuptake inhibitors (SSRIs)
are considered a safe initial
choice. Psychotherapeutic
ANTIADRENERGIC AGENTS. Initial evidence showed that prazosin and guanfacine approaches (image
were effective in reducing symptoms of combat-related PTSD. However, a rehearsal therapy for
rigorous multicenter study conducted in Veterans Affairs settings failed to nightmares and
demonstrate a clinical benefit of prazosin over placebo,99 and the α2 receptor
therapy for insomnia) are
agonist guanfacine was also found to be ineffective.100 recommended treatments
The process of reconsolidation of traumatic memories also emerged as a target for sleep disruption.
for autonomic nervous system drugs. Patients with PTSD were given propranolol Benzodiazepines should be
or placebo before actively recalling their traumatic memories during weekly avoided if possible.
sessions for 6 consecutive weeks. Propranolol therapy showed a significant ● Given the increased risk
reduction in symptoms compared with placebo,101 although results have of cognitive problems in
been mixed. patients with PTSD, it is
worthy to note that in older
patients benzodiazepines
ANTIPSYCHOTIC MEDICATIONS. Although risperidone was frequently prescribed to and benzodiazepine
treat SSRI-resistant PTSD symptoms (including psychotic symptoms), a large receptor agonists used for
multicenter randomized controlled trial conducted at 23 Veterans Affairs insomnia ("Z-drugs" such as
outpatient centers demonstrated that risperidone was not better than placebo in zolpidem, zaleplon,
eszopiclone) are both
treating PTSD and depressive and psychotic symptoms.102
associated with increased
Aripiprazole (a newer-generation antipsychotic with several mechanisms of risk of dementia. In addition
action to include being a partial agonist of 5-HT1A receptor) has also been used as to concerns with substance
augmentation therapy for resistant symptoms. In a retrospective study, Cheng use/abuse in PTSD,
benzodiazepine use may
and colleagues103 examined the outcomes of patients with PTSD who were given
exacerbate cognitive
aripiprazole as add-on therapy to decrease auditory verbal hallucinations; they dysfunction in these
reported that aripiprazole augmentation might be associated with a reduction in patients.
the severity of auditory verbal hallucinations. However, the methodologic
limitations of the study impede inferring a conclusion about the efficacy of
the intervention.
Antipsychotics were also used as a monotherapy for PTSD. In the first
double-blind, controlled trial, 80 veterans with PTSD were randomly assigned to
quetiapine or placebo for 12 weeks. Quetiapine monotherapy was superior to
placebo in reducing the severity of PTSD symptoms, most significantly in the
improvement of insomnia symptoms.104 The use of antipsychotics in patients
with PTSD should be pondered against safety considerations. For instance, a
retrospective cohort study reported an increased risk of dementia in patients
with PTSD who were using antipsychotics.105
BENZODIAZEPINES. Although occasionally used to treat patients with worsening

anxiety and insomnia, benzodiazepines should be avoided in patients with PTSD,
particularly among those with comorbid substance use disorders. To that end, the
US Food and Drug Administration (FDA) recently issued stronger warnings on
the use of benzodiazepines regarding risks for misuse and abuse, as well as
addiction. Also, it should be noted that, in older individuals, benzodiazepines and
benzodiazepine receptor agonists used for insomnia (known as “Z-drugs”) may
increase the risk for dementia.106

NEWER TREATMENTS. Corticotropin-releasing factor type 1 (CRF1) receptor

antagonists and modulators of glutamate neurotransmission may be effective,
although evidence is scarce. A 2019 study showed beneficial effects of the
N-methyl-D-aspartate (NMDA) antagonist ketamine when given
intravenously.107 Intranasal oxytocin and N-acetylcysteine have both shown
potential in affecting neurophysiology and symptoms of PTSD. Further, it was
reported that oxytocin administration increases cognitive functions among
patients with PTSD.108
COMBINED STRATEGIES. Exposure therapy works by consolidating new, more

adaptive memories of traumatic events. Glutamate transmission and NMDA
receptors partly mediate the reconsolidation process of memory, which is
TABLE 11-4 Summary of Medications Used in Treating Posttraumatic Stress Disordera
Class/group Drug Total daily dosage
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine 20-60 mg/d
Sertraline 50-200 mg/d
Paroxetine 20-60 mg/d
Citalopram 20-40 mg/d
Escitalopram 20-40 mg/d
Fluvoxamine 20-60 mg/d
Serotonin norepinephrine reuptake inhibitors Venlafaxine 75-300 mg/d

(SNRIs)
Venlafaxine extended release 75-225 mg/d
Duloxetine 40-60 mg/d
Tricyclic antidepressants Amitriptyline 50-300 mg/d
Imipramine 50-300 mg/d
Monoamine oxidase inhibitor (MAOI) Phenelzine 15-90 mg/d
Other Mirtazapine 7.5-45 mg/d
Sympatholytic
Beta-blockers Propranolol 40-160 mg/d
α2 Receptor agonists Clonidine 0.2-0.6 mg/d
Guanfacine 0.5-3 mg/d
α1 Receptor antagonists Prazosin 2-10 mg/d
Doxazosin 1-2 mg/d
1754 DECEMBER 2021

relevant to the mechanism of exposure therapy. Although initial studies were
encouraging, a larger trial of D-cycloserine, a modulator of the glycine site of
NMDA receptors, combined with exposure therapy had negative results.109
However, repetitive transcranial magnetic stimulation (rTMS) as
augmentation therapy for cognitive processing therapy produced significant
sustained benefits in PTSD symptoms.110 rTMS is FDA approved for treating
depression. Noting the heterogeneity of PTSD symptoms, perhaps rTMS may
have additional value in those patients with PTSD who exhibit prominent
symptoms of depression, though this needs to be evaluated in future research.
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has
led to some beneficial results in patients with PTSD. Mithoefer and colleagues111
showed that the active doses of 75 mg and 125 mg of MDMA were effective and
Class/group Drug Total daily dosage
Mood stabilizers Divalproex sodium or valproic acid 500-2000 mg/d
Lithium 600-1500 mg/d
Carbamazepine 400-1000 mg/d
Topiramate 50-200 mg/d
Antipsychotics Risperidone 0.5-6 mg/d
Olanzapine 5-20 mg/d
Quetiapine 25-300 mg/d
Aripiprazole 5-15 mg/d
Asenapine 5-20 mg/d
Anxiolytics
Benzodiazepines Alprazolam 0.25-4 mg/d
Clonazepam 0.5-4 mg/d
5-HT1A receptor agonists Buspirone 15-60 mg/d
Other (investigational)
N-methyl-D-aspartate (NMDA) antagonists D-cycloserine 8-12 mg/d
Ketamine 0.5 mg/kg/d IV
Hormonal Intranasal oxytocin 40 IU 2 times a day for 8 days
Empathogen-entactogen stimulant 3,4-Methylenedioxymethamphetamine 100-125 mg per

(MDMA) 8-hour MDMA-assisted
psychotherapy session,
up to 3 sessions
Mucolytic agent N-Acetylcysteine 2400 IU/d
IV = intravenous.
a

well tolerated. A phase 2 clinical trial showed the response of patients with PTSD
to MDMA-assisted psychotherapy sessions was maintained at 12 months of
follow-up, giving some credibility to the hypothesis that MDMA catalyzes a
therapeutic process lasting a long time after drug administration.112
Overall, although different pharmacologic agents have proven to be more
efficacious than placebo to reduce the severity of PTSD, response is modest, and
for many people, especially veterans, these agents have been ineffective. There
continues to be a need to develop new pharmacologic treatment and integrative
care models including psychotherapeutic options.
Pharmacologic Treatment of Anxiety-Related Disorders

Recommended pharmacologic options for the treatment of anxiety disorders vary
depending on the presenting condition. For specific phobia and for agoraphobia
without panic disorders, pharmacologic solutions are not recommended. In social
anxiety disorders that are performance oriented, it is not uncommon to prescribe
propranolol, a beta-blocker that crosses the blood-brain barrier. However, this is
an off-label use, and evidence is mixed on efficacy. Further, FDA-approved
medications for social anxiety disorder include SSRIs and SNRIs.
FDA-approved medications to treat panic disorder include SSRIs, SNRIs,
and benzodiazepines. According to a Cochrane review, the quality of evidence
of possible superiority of benzodiazepines over placebo in short-term treatment
of panic disorder is low. Treatment of choice, however, relies on SNRIs
and SSRIs.113
Generalized anxiety disorder may require long-term treatment.
Responsiveness to psychotherapy and medications is similar. FDA-approved
medications to treat generalized anxiety disorder include SSRIs, SNRIs, and
azapirone antipsychotics. In a large meta-analysis, duloxetine, pregabalin,
venlafaxine, and escitalopram were effective compared with placebo and well
tolerated. Despite smaller sample sizes, mirtazapine, sertraline, fluoxetine,
buspirone, and agomelatine were also found to be effective and well tolerated.
Paroxetine and benzodiazepines were effective but not well tolerated.114
No medications are FDA approved for separation anxiety disorder. However,
in children (ages 3 to 18 years) with anxiety disorders, including separation
anxiety disorder, a 2017 review and meta-analysis concluded that, in 7719
patients across 115 studies, SSRIs and SNRIs significantly reduce anxiety
symptoms whereas benzodiazepines and tricyclic antidepressants do not.115 The
combination of sertraline and CBT significantly reduced symptoms of anxiety
compared with either method in isolation. CBT in these children was associated
with fewer dropouts than medications and with fewer reported side effects.115
OTHER THERAPIES
Development of other therapies, including nerve blockades and brain
stimulation approaches, is an active area of investigation.
Brain Stimulation Techniques

Currently, no therapeutic brain stimulation approaches for PTSD or
anxiety-related disorders are approved, although several technologies have
shown promise. Perhaps, the most developed of those is rTMS, having already
been successfully deployed for the treatment of depression. Although rTMS has
shown some efficacy in treating PTSD,116 controversy continues regarding the
1756 DECEMBER 2021

optimal stimulation parameters. This problem is not specific to rTMS and KEY POINT
impacts all the stimulation techniques. Although rTMS has been most widely
● Pharmacologic
studied in the treatment of PTSD and depression, some data suggest modulation of fear
effectiveness in treating generalized anxiety disorder.117 conditioning and extinction
A small randomized controlled trial on the efficacy of transcranial direct-current is an area of active research
stimulation, 10 sessions over the bilateral dorsolateral prefrontal cortex, found that for the treatment of PTSD.
Brain stimulation
transcranial direct-current stimulation was more effective than sham stimulation
technologies (eg, repetitive
in relieving PTSD symptoms.118 Similarly, deep brain stimulation use in the transcranial magnetic
basolateral nucleus of the amygdala (aimed to cause fear extinction) in patients stimulation) are also being
with treatment-refractory PTSD led to substantial clinical improvements.119 investigated.
In humans, a noninvasive version of vagus nerve stimulation has shown
potential impact on autonomic as well as brain features of PTSD.120,121
Transcutaneous vagus nerve stimulation reduces worry in people with high trait
worry (ie, dispositional worrying).122 Thus far, no randomized controlled trial
studies of the effect of noninvasive vagus nerve stimulation on PTSD or
anxiety-related disorders have been published.
Stellate Ganglion Blockade

The stellate ganglion blockade is a direct sympathetic nervous system intervention.
Using right-sided stellate ganglion block in active-duty service members with PTSD
produced a significant reduction in PTSD symptoms at an 8-week follow-up.
Patients with higher initial CAPS-5 scores showed greater improvements.123 The
nonblinding of treating physicians and the possible recognition of Horner
syndrome by the participants might present some bias in the study results.
CONCLUSION
PTSD is a common stress-related psychiatric condition. Historically, PTSD was
grouped with anxiety-related disorders. However, because of heterogeneity in
the presentation of PTSD and the linkage to a specific event, with the publication
of the DSM-5, PTSD was reclassified as a traumatic stress-related disorder.
Nonetheless, anxiety-related disorders share many similar considerations in
vulnerability, genetics, structural and functional neuroanatomy, autonomic
nervous system involvement, sleep disruption, and treatment. The heterogeneity
in the presentation of symptoms of PTSD and anxiety disorders is reflected in the
involvement of different brain networks and physiologic responses. The
presentation of symptoms of PTSD may be delayed from a traumatic event
(delayed onset), may shift over time, and may present differently based on the
number and severity of traumatic event presentations, as well as individual
context and vulnerability factors (eg, childhood exposure, complex PTSD). Sleep
disruption, including insomnia and nightmares, is the most common symptom of
PTSD and is also quite common in anxiety disorders. Sleep apnea is also prevalent
in patients with PTSD. Along with allostatic load associated with hyperarousal
symptoms, these features may contribute to the development of metabolic
syndrome, cardiovascular disease, and accelerated aging. Comorbidities,
including sleep disorders and other anxiety disorders, need to be part of a
management plan. Treatment for sleep issues (eg, for sleep apnea [CPAP],
nightmares, and insomnia) may improve symptoms of PTSD and improve mood.
Psychotherapy for insomnia has some empirical support, although randomized

controlled trial studies are necessary, especially in PTSD-related sleep

dysfunction.
Efficacious treatments of anxiety-related disorders and PTSD are currently
available, including pharmacotherapy and psychotherapy. Psychotherapeutic
approaches including exposure-based therapies appear to have the highest effect
sizes in randomized controlled trial studies, although direct comparison with
pharmacotherapies has not been published. SSRIs are well tolerated, have shown
efficacy, and are considered to be a safe initial choice for treatment for PTSD.
Combat veterans tend to show a more modest response to intervention. The
retention rate in psychotherapy is often poor. In anxiety disorders, CBT is the
treatment of choice in specific phobia, agoraphobia (without panic), and
separation anxiety disorder (no FDA-approved medications for these conditions)
and is considered the first-line treatment in panic disorder, generalized anxiety
disorder, social anxiety disorder, and selective mutism. Some evidence shows
that SSRIs may help people with separation anxiety disorder. Although
benzodiazepines are efficacious for short-term treatment of panic disorder,
SSRIs and SNRIs are preferred as a long-term pharmacologic option. SSRIs and
SNRIs are also effective in generalized anxiety disorder. Because of potential
cognitive risk and other adverse effects and complications, benzodiazepines and
antipsychotics may not be the best choice in older adults.
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DISCLOSURE
Continued from page 1738 University of Florida and a grant from the National
Institutes of Health (R01NS058487). Dr Jorge has
National Institutes of Health (NIH R21AG054876), and received research/grant support from CDMRP
US Department of Veterans Affairs (VAMC (GW160106), CDMRP/Department of Defense
I0RX003140). Dr Jaffee has received personal (GW200072), US Department of Veterans Affairs
compensation for serving on the scientific advisory (B9268-X), the VA Cooperative Studies Program
board for Novo Nordisk A/S and as a subject matter (CSP2016 and CSP2018), and the Veterans Office of
expert for McDermott Will & Emery on behalf of the Research, Rehabilitation Research and
NCAA and has received research support from the Development Service (1 I01 RX003117-01A1).

REVIEW ARTICLE

Psychosis
C O N T I N UU M A UD I O By Parunyou Julayanont, MD; Uma Suryadevara, MD
ONLINE
ABSTRACT
PURPOSE OF REVIEW:Psychosis can manifest in primary psychotic disorders,
neurologic diseases, and medical conditions. This article reviews the
definition of psychotic symptoms and the evaluation and management of
psychosis in primary psychiatric and neurologic disorders frequently seen
in neurologic practice.
RECENT FINDINGS: Emerging evidence supports significant connections

between psychosis and structural and functional brain changes in both
primary psychotic and neurologic disorders. In addition to antidopaminergic
CITE AS: activity, the mechanism of new-generation antipsychotics shifts to act on
CONTINUUM (MINNEAP MINN) serotonin receptors, which potentially contributes to their benefits in the
treatment of negative symptoms of psychosis and a lesser frequency
of extrapyramidal side effects compared with typical antipsychotics.
Address correspondence to This is also helpful in the treatment of psychosis in patients who have
Dr Parunyou Julayanont, neurodegenerative diseases and are vulnerable to developing
Department of Neurology,
Texas Tech University Health extrapyramidal side effects from typical antipsychotics.
Sciences Center, School of
Medicine, 3601 4th St, Lubbock, SUMMARY: Even with significant overlap, management of psychosis in
TX 79430, p.julayanont@ttuhsc.
edu. primary psychotic disorders differs from the approach of psychosis in
neurologic diseases. This article helps clinicians learn how to practically
Dr Julayanont has received a
evaluate psychosis from both psychiatric and neurologic perspectives.
grant from the Texas
Alzheimer’s Research and Care
Consortium (2020-45-25-CR).
Dr Suryadevara has received INTRODUCTION
T
personal compensation for
serving as a senior editor for the
he term psychosis can be described as a clinical construct where,
Asian Journal of Psychiatry and because of severe impairment in thoughts and emotions, a person is
has provided witness testimony unable to distinguish the internal experience of the mind and external
for a trial.
reality. Psychosis is seen not only in primary psychiatric disorders; it
UNLABELED USE OF may be secondary to neurologic or medical conditions. The presence
of psychosis can be very disruptive and impair social cognition and functional
USE DISCLOSURE:
Drs Julayanont and Suryadevara independence. This article discusses the definition of various psychotic
discuss the unlabeled symptoms, criteria for diagnosis of schizophrenia spectrum and other psychotic
investigational use of
antipsychotics in the treatment
disorders, psychosis in common neurologic disorders, and evaluation and
of dementia with psychosis, management of psychosis in both psychiatric and neurologic perspectives.
cholinesterase inhibitors in the
treatment of psychosis in
dementia with Lewy bodies, and DEFINING PSYCHOSIS
pimavanserin in the treatment
of non–Parkinson disease
Since the term psychosis was first used more than 175 years ago, its definition has
dementia with psychosis. changed to achieve greater diagnostic precision. In 1994, the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)1 defined
© 2021 American Academy psychosis as part of psychiatric disorders characterized by hallucinations,
of Neurology. delusions, disorganized thoughts, clang associations, echolalia, and abnormal
1682 DECEMBER 2021

motor behaviors such as strange postures or stereotypy. In DSM-5,2 psychotic KEY POINTS
disorders are clinical syndromes that can be distinguished from one another by
● In all the psychotic
their duration, nature of the symptoms, relationship between psychotic disorders, abnormalities are
symptoms and mood symptoms, and the etiology of the symptoms. In all the noticed in one or more of the
psychotic disorders, abnormalities are noticed in one or more of the five domains: five domains: delusions,
delusions, hallucinations, disorganized thoughts, disorganized behaviors, and hallucinations, disorganized
thoughts, disorganized
negative symptoms. The severity of the symptoms should be sufficient to
behaviors, and negative
substantially impair daily functioning to be classified as a disorder. A significant symptoms. The severity of
number of patients with primary psychotic disorders are at increased risk for the symptoms should be
suicide attempts, substance use, homelessness, medical complications, and legal sufficient to substantially
impair daily functioning to
problems. Psychosis can be the core determining symptom of a primary
be classified as a disorder.
psychiatric disorder such as schizophrenia or could be a symptom of other
psychiatric, medical, substance use, and neurologic conditions. The age of ● Most common psychotic
symptom onset and the temporal evolution might shine a light on the underlying disorders such as
disorder. For example, most common psychotic disorders such as schizophrenia schizophrenia and mood
disorders with psychosis
and mood disorders with psychosis begin in the second or third decade of life. begin in the second or third
Delusional disorders are commonly seen in middle age, and psychosis secondary decade of life. Delusional
to neurodegenerative disorders usually present at older ages. Psychosis disorders are commonly
secondary to other medical or neurologic conditions or substance use can occur at seen in middle age, and
psychosis secondary to
any age. In addition to delusions, hallucinations, and disorganized thinking or neurodegenerative
behaviors, other commonly seen symptoms include illogical thought process, disorders usually present at
tangentiality, neologisms, thought blocking, and catatonia. older ages.
● Many hypothetical
Hallucinations
frameworks are possible for
A hallucination is described as the false perception of sensation that does not visual hallucinations in
correspond with an external stimulus. Hallucinations can occur in any sensory neurologic conditions,
modality: auditory, visual, olfactory, gustatory, tactile, nociceptive, including impairments of the
thermoceptive, proprioceptive, and others. TABLE 9-1 provides examples of “top-down” attentional and
“bottom-up” perceptual
conditions associated with different hallucinatory modalities. A good clinical aspects of visual
interview can help further assess the underlying phenomena that could be perception, chronic sensory
causing the hallucinations. For example, auditory hallucinations have been deafferentation and
historically linked to schizophrenia.3-5 The distinguishing features that were used hyperexcitability of the
adjacent cortical networks,
diagnostically include command hallucinations, commenting voices about the cortical irritation causing
individual in the third person, lack of insight, and derogatory auditory hallucinations in various
hallucinations. In DSM-IV, these Schneiderian first rank symptoms of sensory modalities, and
schizophrenia were diagnostic of the disorder. In addition to schizophrenia, dysfunction of the
ascending reticular
schizoaffective, and other schizophrenia spectrum disorders, hallucinations are activating system.
frequently reported in a range of other psychiatric conditions including bipolar
disorder, major depressive disorder, posttraumatic stress disorder, and ● Some other perceptual
personality disorders.6 disturbances that should be
considered for the
Patients with neurologic conditions may have visual hallucinations. Many
differential diagnosis of
hypothetical frameworks are possible for visual hallucinations in neurologic hallucinations include
conditions. First, impairments of the “top-down” attentional and “bottom-up” derealization,
perceptual aspects of visual perception may contribute to an intrusion of a depersonalization,
hallucinatory proto-object into a scene perception.7 This framework is believed pseudohallucination,
synesthesia, jamais vu, and
to partially explain visual hallucinations in dementia or Parkinson disease (PD). déjà vu.
Second, hallucinations may be secondary to chronic sensory deafferentation and
hyperexcitability of the adjacent cortical networks, resulting in cortical release
phenomenon.8 This mechanism explains visual hallucinations secondary to
visual impairment (Charles Bonnet syndrome) and auditory hallucinations from

PSYCHOSIS
severe deafness. Third, cortical irritation can cause hallucinations in various

sensory modalities, implicating seizure-related hallucinations. Finally,
dysfunction of the ascending reticular activating system may contribute to visual
hallucinations as seen in peduncular hallucinosis secondary to a lesion on the
brainstem or thalamus affecting the ascending reticular activating system.
Intrusions of the dream imagery of rapid eye movement (REM) sleep into
TABLE 9-1 Hallucinatory Modalities and Common Differential Diagnoses
Hallucinatory modality Examples of conditions

Auditory Schizophrenia spectrum
Mood disorders with psychotic features
Temporal lobe epilepsy
Substance-induced disorders (stimulants, hallucinogens, cannabis, alcohol withdrawal, etc)
Acquired deafness
Extreme physiologic and psychological stress (dissociative identity disorder, bereavement, etc)
Visual Charles Bonnet syndrome

Peduncular hallucinosis
Migraine
Occipital stroke
Occipital lobe seizure
Parkinson disease and dementia with Lewy bodies
Delirium
Hallucinogens (mescaline, psilocybin, lysergic acid diethylamide, phencyclidine, 3,4-
methylenedioxymethamphetamine [MDMA], etc)
Medication side effects (anticholinergics, benzodiazepines, dopaminergic medications, etc)
Schizophrenia spectrum
Olfactory Migraine with olfactory aura

Temporal lobe epilepsy
Olfactory nerve, orbitofrontal lobe, and anterior cranial fossa tumor
Depressive disorder with psychotic features
Gustatory Temporal lobe epilepsy

Medication side effects such as methylphenidate
Substance use disorders
Tactile Substance use disorders (cocaine, amphetamines, narcotics, etc)

Peripheral neuropathy
Medication effect (dopaminergics, stimulants, etc)
1684 DECEMBER 2021

wakefulness secondary to dysfunction of the ascending reticular activating KEY POINTS
system may explain visual hallucinations in Lewy body diseases.
● The primary delusion is a
Hallucinations can also occur transiently when an individual is under extreme direct unmediated
physiologic or psychological stress as in sensory deprivation, bereavement, phenomenon, whereas the
severe fatigue, etc.9 Hypnogogic and hypnopompic hallucinations can be other forms of belief are
mistaken for nightmares but are common perceptual phenomena occurring mediated by thought. They
are incomprehensible and
during sleep transition. Hallucination can also be clinically mistaken for an
ambiguous and may be seen
illusion, which is a distorted version of an objective sensory stimulus. Some other in individuals with
perceptual disturbances that should be considered for the differential diagnosis schizophrenia,
of hallucinations include: schizoaffective disorder,
and other psychotic
disorders and cannot be
u Derealization: one perceives the world and external stimulus as unreal. explained by cultural
background, education,
u Depersonalization: one feels the thoughts and feelings seem unreal and is detached
personality, or other
from them.
circumstances of life.
u Pseudohallucination: a vivid sensory experience but the individual recognizes that it is not
an external stimulus but it is coming from their mind. ● Secondary delusions are
understandable in terms of
u Synesthesia: a perceptual condition in which external stimulus in one sensory modality
the patient’s emotional
elicits a concurrent sensation in another, for example, in color synesthesia, letters or
state, circumstances of life,
numbers are shaded with a color.
beliefs of peer group, and
u Jamais vu: a situation happens that ought to be familiar but is not. personality. They typically
present secondary to some
u Déjà vu: unlike jamais vu, one perceives that they already experienced the present
other psychopathologic
situation even though they did not.
condition.
● Delusional
Delusions misidentification syndromes
Delusions can be described as tenacious false beliefs that are maintained represent a group of
despite every incontrovertible evidence of the contrary. Delusional themes disorders defined by the
range from bizarre content that is clearly implausible to nonbizarre that may misidentification or
impairment in recognition of
be possible but no convincing evidence exists. An example of a bizarre one or more people despite
delusion is the belief that the Federal Bureau of Investigation is stealing a the normally functioning
person’s genes and using them to make clones and create an army in the sensory recognition
Middle East. Other examples of bizarre delusions include (1) thought pathways. The four main
subtypes are Capgras
insertion, in which the person believes that alien thoughts have been inserted syndrome, Frégoli
into their brain, (2) delusions of control, in which the person’s actions are syndrome,
being manipulated by some outside force, and (3) thought withdrawal, in intermetamorphosis
which a person believes that their thoughts were removed by someone or syndrome, and subjective
doubles syndrome.
some outside force. An example of a nonbizarre delusion is the police are
looking for that person although no evidence supports that belief. Another ● Neuropsychological
way to classify delusions would be based on the nature of delusions or the testing in patients with
themes (TABLE 9-2). misidentification syndromes
shows subtle abnormalities
Yet another way to classify delusions would be whether they are primary or
in facial recognition with
secondary. The primary delusion is a direct unmediated phenomenon whereas nondominant cerebral
the other forms of belief are mediated by thought. Primary delusions are compromise.
incomprehensible and ambiguous. Some people describe delusional
phenomenology as an experience as opposed to a judgment or belief.10 For
patients with primary delusions, things appear to mean something entirely
different. For example, the patient sees people in uniform on the street and, for
that patient, those people are from the US Secret Service; another man in a crisp
black suit is an assassin who is sent to kill the patient. Primary delusions may be
seen in individuals with schizophrenia, schizoaffective disorder, and other

PSYCHOSIS
psychotic disorders and cannot be explained by cultural background,

education, personality, or other circumstances of life. Secondary delusions
are understandable in terms of the patient’s emotional state, circumstances of
life, beliefs of peer group, and personality. They may stem from a previous
abnormal experience, and the brain is trying to explain strange, senseless
experiences. It typically presents secondary to some other psychopathologic
condition, for example, a person with cocaine use disorder who believes that the
drug dealer set up surveillance cameras to monitor their movements and will
hurt them.
Delusional Misidentification Syndromes

Delusional misidentification syndromes represent a group of disorders
defined by the misidentification or impairment in recognition of one or
more people despite the normally functioning sensory recognition pathways.
The four main subtypes are Capgras syndrome, Frégoli syndrome,
intermetamorphosis syndrome, and subjective doubles syndrome.11 Other
syndromes identified include reduplicative paramnesia, mirrored-self
misidentification, delusional companion syndrome, and clonal pluralization of the
self. Misidentification syndromes show a great degree of overlap and at times
may evolve into another type12,13:
TABLE 9-2 Types of Delusions and Their Descriptions
Delusions Description of the delusions
Persecutory delusions Most common kind, in which the individual is convinced that they are being followed and
will be harmed by someone or a group of people or an institution; overvalued ideas of
persecutory nature are common reasons for litigious obsession in patients with paranoid
personality disorder
Delusions of infidelity Morbid or malignant jealousy in which the patient has an overwhelming sense of entitlement and
conviction that others are abrogating their rights; in the jealous type, the central theme is of an
unfaithful partner and the person usually tries to confront the significant other or attempts to
intervene in the imagined infidelity
Referential delusions The person believes that unsuspicious occurrences or media stories refer to them personally
Grandiose delusions The individual falsely believes in their own greatness or that they have supernatural powers; the
person may have an inflated sense of worth, power, knowledge, or identity
Erotomanic delusions The person falsely believes that another person, often someone important or famous,
is in love with them, and stalking is commonly seen in people with these delusions
Religious delusions Delusions involve religious themes; beliefs are idiosyncratic and not accepted within any
particular culture or subculture; these delusions are more difficult to treat
Nihilistic delusions False beliefs that nothing exists or that a significant aspect of self, like the brain or outside world,
does not exist
Somatic delusions Focus on the preoccupation with appearance and bodily function
Delusional parasitosis The person has an unshakeable false belief that they are infested with parasites, insects, lice,
fleas, worms, or other organisms; other terms used to describe delusional parasitosis are
delusional infestation, parasitophobia, pseudoparasitic dysesthesia
1686 DECEMBER 2021

u Capgras syndrome stems from problems with hypoidentification, in which the person has KEY POINTS
a delusional conviction that friends or family members have been replaced by a “double”
or impostor.14 They believe the original has disappeared, and the absence is not ● The essential feature of
questioned. It can occur in the context of primary psychiatric disorders such as brief psychotic disorder is
schizophrenia and mood disorders or secondary to organic disorders, medication, or onset of at least one of the
neurodegenerative disorders. The rest of the delusional misidentification syndromes are following symptoms within
considered hyperidentifications. the previous 2 weeks:
u Frégoli syndrome is the delusional belief that one or more familiar people repeatedly hallucinations, delusions,
change their disguise/appearance and follow the person. These delusions typically have a disorganized speech, and
persecutory quality to them. disorganized behavior
including catatonia. Brief
u Intermetamorphosis is another misidentification syndrome in which the person believes psychotic disorder has no
that familiar people have exchanged identities. prodrome, and the
u In subjective doubles syndrome, patients believe that they have a “double” or symptoms might last for
doppelgänger with the same appearance, but different character traits, living their 1 day to 1 month. Once the
own life. symptoms resolve, patients
are back to their baseline
u Mirrored-self misidentification involves the misperception that the person’s reflection in level of functioning.
the mirror is a stranger, typically a younger or second version of one’s self.
u Delusional companion syndrome is the misperception that nonliving objects possess ● The characteristic
consciousness, can think independently, and feel emotions. symptoms of
schizophreniform disorder
u Clonal pluralization of the self is somewhat opposite of subjective doubles; the patient are similar to the symptoms
believes multiple psychologically and physically similar copies of themselves exist. of schizophrenia except for
the duration of symptoms,
u Reduplicative paramnesia is the misperception that a place has been relocated
which should last for more
or duplicated.
than 1 month but less than
6 months. Another unique
Neuropsychological testing in patients with misidentification syndromes feature of schizophreniform
shows subtle abnormalities in facial recognition with nondominant cerebral disorder is it does not
compromise.13 During evaluation of patients with delusional misidentification require impairment in social
or occupational functioning
syndromes, organic causes, structural lesions, or metabolic conditions must be for diagnostic reasons.
ruled out or treated, as appropriate. It is then imperative to identify if this
misidentification syndrome is a distinct phenomenon or if this is in the context of ● Schizophrenia is
another psychiatric condition. Antipsychotics are often used for the treatment of hypothesized to be an
outcome of a complex
delusional misidentification syndromes.15
interplay of genetic and
environmental risk factors
that affect the early
SCHIZOPHRENIA SPECTRUM AND OTHER PSYCHOTIC DISORDERS development of the brain.
DSM-5 made modest changes to the diagnosis of schizophrenia spectrum and
other psychotic disorders with the aim of simplification and incorporation of the ● Overwhelming evidence
latest research using the National Institute of Mental Health Research Domain shows eye movement
abnormalities including
Criteria framework.16 The new organization of the chapter is based on
saccade control and smooth
developmental aspects of the respective disorders and the severity of the disease. pursuit eye movements in
Psychosis, in general, can be the primary psychiatric symptom in disorders such patients with schizophrenia
as schizophrenia spectrum disorders or can also occur in other psychiatric and in their biological family
members. The abnormalities
conditions such as bipolar disorder and major depressive disorder.
were proposed to be used
Schizophrenia spectrum and other psychotic disorders include schizotypal as one of the
(personality) disorder, schizophrenia, other psychotic disorders such as neurophysiologic
schizoaffective disorder, schizophreniform disorder, delusional disorder, brief biomarkers for the disorder.
psychotic disorder, substance- or medication-induced psychotic disorder,
psychotic disorder due to general medical condition, and unspecified or other
specified schizophrenia spectrum disorders. They are characterized by
abnormalities in one or more of the following five domains: delusions,
hallucinations, disorganized thinking, disorganized behaviors, and negative
symptoms. Delusions and hallucinations are explained in the earlier sections.

PSYCHOSIS
Disorganized behaviors may present in the form of childlike silliness or

unpredictable aggression. Catatonic behavior is also a form of disorganized
behavior, in which the patient has a marked decrease in reactivity to the
environmental stimuli. Catatonic behaviors can range from negativism, in which
the patient does not respond to instructions, to mutism or stupor, in which the
patient has a complete lack of verbal or motor responses. Some patients also
present with catatonic excitement; they exhibit purposeless excessive
motor activity.
Negative symptoms may range from diminished emotional expression (decreased
eye contact, prosody, and general body movements that would complement
the affect in a person) to avolition. Patients with avolition have decreased
self-initiated purposeful activities. Other negative symptoms seen commonly in
patients with psychotic disorders include alogia, anhedonia, and asociality.
Schizotypal (Personality) Disorder

Diagnostic criteria for schizotypal (personality) disorder remain unchanged
from DSM-IV and include five or more of the nine criteria: cognitive-perceptual
disturbances and cognitive distortions ([1] ideas of reference; [2] odd beliefs or
magical thinking; [3] unusual perceptual experiences and illusions; and [4]
suspiciousness or paranoid ideation), disorganized or oddness-related symptoms
([5] odd, eccentric, or peculiar behaviors; and [6] odd thinking and speech),
marked interpersonal disturbances ([7] lack of close friends or confidants other
than first-degree relatives), inappropriate or constricted affect ([8] excessive
social anxiety that does not decrease with familiarity; and [9] inappropriate or
constricted affect). However, in DSM-5, schizotypal (personality) disorder is
listed under both personality disorders as well as schizophrenia spectrum
disorders. The lifetime prevalence of schizotypal personality disorder is higher in
men than women and in lower socioeconomic groups.17,18 It is a heritable
condition with both genetic and environmental risk factors. Attentional and
memory difficulties along with social anxiety, difficulty connecting with others,
and paranoia leading to interpersonal difficulties are common presenting
symptoms of patients with schizotypal personality disorder in the clinical setting.
In terms of the neurobiology of schizotypal personality disorder, many elements
are similar to the neurobiology of schizophrenia.19 Neuroimaging shows
decreased left temporal lobe volumes, but the extent and progression of these
changes in volumes are much lower in these patients compared with those with
schizophrenia.20 One hypothesis is that patients with schizotypal personality
disorder develop new neuronal connections to compensate for the dysfunction,
and this protects against the dopamine hyperactivity in the subcortical areas.
Delusional Disorder
Delusional disorder is diagnosed with the presence of one or more delusions for
at least 1 month or more. The requirement for nonbizarre delusions was
eliminated in DSM-5. These delusions cannot meet the criteria for schizophrenia,
and the dysfunction related to the delusion is generally more circumscribed
compared with other psychotic disorders. These delusions cannot be in the
context of substance use, medications, or medical conditions. Symptoms also
cannot be explained by other psychiatric conditions such as obsessive-
compulsive disorders, body dysmorphic disorders, or cultural beliefs. Delusional
disorder typically has a later age of onset than schizophrenia, and the different
1688 DECEMBER 2021

kinds of delusions are explained in the earlier Delusions section. Persecutory and KEY POINTS
jealous types of delusions are common in men with delusional disorder, whereas
● Diagnosis of
erotomanic delusions are more common in women with delusional disorder.21,22 schizoaffective disorder
People who have a language barrier, patients with sensory impairment such as requires an uninterrupted
visual or auditory impairments, and older adults are more vulnerable to period of active or residual
delusions. The prognosis of delusional disorder is better with treatment, but symptoms of psychosis
during which the criterion A
medication compliance is a big obstacle in this patient population.23 People with
symptoms of schizophrenia
early-onset or sudden-onset symptoms, women, and those with higher social and are met, along with a major
occupational functioning have better prognosis.24-26 mood episode. In contrast to
mood disorder with
psychotic features where
Brief Psychotic Disorder
psychotic features are
The essential feature of brief psychotic disorder is onset of at least one of the present only during the
following symptoms within the previous 2 weeks: hallucinations, delusions, mood episodes, a diagnosis
disorganized speech, and disorganized behavior including catatonia. Brief of schizoaffective disorder
psychotic disorder has no prodrome, and the symptoms might last for 1 day to requires 2 weeks of
psychotic features without
1 month. Once the symptoms resolve, patients are back to their baseline level of mood symptoms.
functioning. The symptoms are not in the context of any other psychiatric
disorders, medical conditions, substance use, or medications. Personality ● Delirium-onset dementia
disorders such as schizotypal or borderline personality disorders could predispose with Lewy bodies (DLB) is
one of the proposed
the individual to development of brief psychotic disorder. The level of impairment prodromal subtypes of DLB.
may be severe in these patients, and they could experience intense stress or When delirium is resolved,
confusion.27 This puts these individuals at high risk for poor judgment, cognitive clinicians should thoroughly
impairment, and acting on their delusions or hallucinations. Some people with evaluate patients for
cognitive impairment and
brief psychotic disorder also tend to have an increased risk of suicide.28
other features of DLB in
whom delirium occurs
Schizophreniform Disorder without triggers and in those
The characteristic symptoms of schizophreniform disorder are similar to the with prolonged or recurrent
delirium after treatment of
symptoms of schizophrenia except for the duration of symptoms, which should
provoking factors.
last for more than 1 month but less than 6 months. Another unique feature of
schizophreniform disorder is it does not require impairment in social or ● Minor hallucinations,
occupational functioning for diagnostic reasons. Two-thirds of patients with including passage and
schizophreniform disorder eventually receive a diagnosis of schizophrenia or presence hallucinations, are
reported in 42% of drug-
schizoaffective disorder.29 One-third of them recover within 6 months and naïve patients with
maintain their diagnosis of schizophreniform disorder.30 Parkinson disease and may
manifest months to years
Schizophrenia before the onset of motor
symptoms.
Schizophrenia is a chronic psychiatric disorder with heterogeneous symptoms,
which have historically been divided into positive, negative, and cognitive ● Because many patients
symptom categories. To establish a clinical diagnosis of schizophrenia, at least with Parkinson disease may
two symptoms of the following should be present for more than 1 month: not spontaneously report
their experiences of
delusions, hallucinations, disorganized speech, disorganized or catatonic
psychotic symptoms,
behavior, and negative symptoms. Negative symptoms typically include social clinicians should always
withdrawal, flat affect, anhedonia, and decreased energy and motivation. DSM-5 evaluate for any existing or
eliminated the subtypes of schizophrenia because their symptoms overlapped emerging psychotic features
among the subtypes and the outcomes could not be predicted based on the during each visit.
subtypes. Schizophrenia typically presents in early adulthood or late adolescence.

Some patients have a classic prodromal phase before their first-episode
psychosis, in which there is a decline in social and occupational functioning.
Outcomes of schizophrenia range from complete recovery to a need for care. Life
expectancy in patients with schizophrenia is reduced by almost 20 years

PSYCHOSIS
CASE 9-1 A 21-year-old man with no past psychiatric or other significant medical
history was brought to the emergency department by law enforcement
for worsening paranoia. He was seen outside a local restaurant refusing
to leave the area because he was waiting for the Federal Bureau of
Investigation. People witnessed him shouting “Go away. He got the
infinity stones. This is war. We are all going to die.” His girlfriend, who was
there by his side, talked about how his behavior had been “weird” lately.
He was seen responding to internal stimuli for the past 9 months. He quit
meeting with friends and family, including his girlfriend. He was
suspended from college recently for lack of attendance. Family history
reported by his family was significant for “some mental illness in [his]
grandmother who died at the state hospital.” His girlfriend reported that
he grew up with his aunt because his mother lost custody because she
was “crazy.” The girlfriend denied any alcohol or illicit drug use by the
patient. He was never hospitalized before this and had not been on any
psychotropic medications.
On examination, he was guarded, preoccupied, and uncooperative and
got more agitated with each question. “It’s a war. Yondu has the stones.
We are going to die.” He refused to eat or drink, stating the food and
water were poisoned. He was oriented to time, place, and situation and
did not appear to have any cognitive deficits. A thorough psychiatric
assessment ruled out the possibility of affective disorders with
psychosis, personality disorders, or other medical conditions that cause
psychosis. Physical examination, including complete neurologic
examination, did not reveal any focal signs or deficits. MRI of the brain
ruled out a structural etiology for this first-episode psychosis.
Laboratory test results including complete blood cell count,
comprehensive metabolic panel, lipid profile, thyroid studies, and
vitamin B12 level were all within normal limits. Urine drug screen was
negative for any illicit drugs. He was started on risperidone, and the dose
was titrated to a therapeutic level during the subsequent appointments at
the psychiatry clinic. His symptoms resolved over time, and his family
confirmed that he was doing better. He had to drop out of college for the
time being but enrolled in vocational training.
COMMENT The patient had no past psychiatric history and presented with first-
episode psychosis (delusions, negative symptoms). He had a classic
prodromal phase during which he was getting more dysfunctional. The
symptoms of psychosis without any mood symptoms had been present for
more than 9 months, family history was positive for significant mental
illness, and routine medical workup revealed no other etiology for the
presenting symptoms. These symptoms suggest schizophrenia as the most
probable diagnosis. An antipsychotic was started, and eventually the
symptoms resolved. The level of functioning in patients diagnosed with
schizophrenia does not always go back to baseline, and symptoms tend to
be more chronic in some.
1690 DECEMBER 2021

compared with the general population.31,32 The ability to maintain social KEY POINTS
relationships, live independently, and sustain employment is harder for these
● Psychiatric-onset
patients even when the psychotic symptoms are in remission (CASE 9-1). prodromal DLB (late-onset
Schizophrenia is hypothesized to be an outcome of a complex interplay of major depressive disorder or
genetic and environmental risk factors that affect the early development of the late-onset psychosis) may
brain.33 Formation and functioning of the brain in patients with schizophrenia be a solely initial symptom
of DLB before subsequent
are impaired long before the onset of the symptoms. It is hypothesized that
development of
synaptic disturbances occur because of abnormal pruning during parkinsonism or other DLB
neurodevelopment. Possible mechanisms underlying this include less synapse features.
production or overpruning.34 When the synapse development is suppressed,
resulting in fewer synapses, patients may function temporarily, but they develop ● Compared with visual
hallucinations in Parkinson
symptoms by their late teens to twenties. The synapse densities in brain areas disease, the characteristics
associated with higher cognitive functions are lower in patients with of visual hallucinations in
schizophrenia. The synaptic pruning hypothesis was further strengthened by DLB are more well formed
genomic and neuroimaging studies.35 The genome-wide association study of (seeing children, people,
animals, or scenes), are
schizophrenia identified 108 schizophrenia-associated loci that are involved in associated with greater
dopamine synthesis, calcium channel regulation, glutamate neuroreceptors, and severity of cognitive
immunity.36 Nongenetic risk factors that may contribute to illness include impairment, and occur
advanced parental age, maternal infections during pregnancy or delivery, fetal earlier in the course of
disease.
malnutrition, prematurity, and hypoxic-ischemic events.37 Childhood adversity
and trauma, victimization, parental death, social inequality, immigration, and ● Pareidolia, which is the
growing up in urban environments are also associated with an increased risk of perception of meaningful
schizophrenia.38 When an additive interaction with a polygenic risk score, objects (faces or animals)
embedded in visual scenes,
substance use, and the above risk factors are present, the patient is even more
is a complex visual illusion in
prone to developing schizophrenia.39 patients with Lewy body
Neuroimaging and systems neuroscience have helped us understand the gaps diseases, including DLB and
between the course of the disorder, symptoms, and cellular alterations. Total Parkinson disease.
gray and white matter, as well as whole-brain volume, are reduced compared
● When strokes are
with those in healthy controls, and ventricular volume is increased.40 Cortical unilateral, right hemispheric
volume reductions gradually increase with the progression of illness, which lesions are associated with
correlates with worsening cognition.41 Overwhelming evidence shows eye poststroke psychosis more
movement abnormalities in patients with schizophrenia and in their biological than lesions on the left
hemisphere.
family members. The abnormalities were proposed to be used as one of the
neurophysiologic biomarkers for the disorder. Ocular motor function is ● A midbrain or thalamic
significantly impaired, which includes saccade control and smooth pursuit eye lesion rarely causes
movements. These abnormalities are independent of neuroleptic medication use, peduncular hallucinosis,
which consists of
duration of illness, severity of the illness, or age at the onset of illness.42,43
naturalistic and vivid visual
Saccadic abnormalities were also noticed in a preclinical/high-risk group hallucinations usually
of patients.36,44 associated with preserved
insight.
Schizoaffective Disorder
Schizoaffective disorder was first introduced in DSM-III,45 positioned between
schizophrenia and mood disorders. Diagnosis of schizoaffective disorder requires
an uninterrupted period of active or residual symptoms of psychosis during
which Criterion A symptoms of schizophrenia are met, along with a major mood
episode. DSM-5 requires that the mood symptoms should meet criteria for manic
and/or depressive episodes for the majority of the time. However, social
dysfunction and exclusion of autism spectrum disorder criteria are not required.
To distinguish mood disorder with psychotic features from schizoaffective
disorder, in schizoaffective disorder delusions or hallucinations must be present

PSYCHOSIS
for at least 2 weeks in the absence of mood symptoms during the patient’s
lifetime. The symptoms cannot be in the context of substance use, medications,
or medical conditions. Research in this area has been particularly difficult
because of the lack of tests or biological measures specific for this diagnosis.
Neuroimaging findings in patients with schizoaffective disorder are similar to
those in patients with schizophrenia.46 Prognosis for schizoaffective disorder is
slightly better than the prognosis for schizophrenia.47
Substance- or Medication-Induced Psychotic Disorder

Prominent delusions or hallucinations due to the physiologic effects of a
substance/medication intoxication or withdrawal are characteristic features for
the diagnosis of substance- or medication-induced psychotic disorder. A good
clinical history related to the onset, progression, and other factors helps
differentiate from a primary psychotic disorder. Physical examination, blood
work, or urine drug screen complement the history obtained.48 Alcohol;
cannabis; hallucinogens, including phencyclidine and related substances;
stimulants such as cocaine and methamphetamines; inhalants; sedatives and
hypnotics; and anxiolytics can all cause psychosis with intoxication. Withdrawal
from alcohol, sedatives, hypnotics, and anxiolytics can also cause psychosis. The
medications that are frequently associated with psychosis as a side effect include
anesthetics, antihistamines, anticholinergic agents, analgesics,
antihypertensives, dopaminergic medications, muscle relaxants, corticosteroids,
chemotherapy agents, antimicrobial medications, antidepressants, and others.49
Psychotic Disorder Due to Another Medical Condition

Characteristic of this disorder is the presence of prominent delusions or
hallucinations that can be attributed to another medical condition and cannot be
explained by any other psychiatric condition. This is described in detail in the
section Secondary Psychotic Disorders.
Unspecified and Other Specified Schizophrenia Spectrum and Other

Psychotic Disorders
DSM-5 introduced the category of other specified schizophrenia spectrum and
other psychotic disorders to include patients who do not meet the full criteria for
any of the earlier categories mentioned in this article. Common terminology used
in this section includes persistent auditory hallucinations, delusions with
significant overlapping mood episodes, attenuated psychosis syndrome, and
delusional symptoms in a partner of an individual with delusional disorder.
The category of unspecified schizophrenia and other psychotic disorder includes
patients who do not meet full criteria for any psychotic disorder but have symptoms
that cause clinically significant distress in social and occupational functioning.
SECONDARY PSYCHOTIC DISORDERS

Psychosis is seen not only in primary psychiatric disorders; it may be secondary
to neurologic or medical conditions. This section reviews psychotic symptoms in
neurologic conditions that are commonly seen in clinical practice.
Psychosis in Delirium
Delirium is categorized based on motor symptoms divided into two subtypes: (1)
hyperactive delirium associated with motor agitation and aggressiveness and (2)
1692 DECEMBER 2021

hypoactive delirium manifesting with motor retardation or without motor KEY POINTS
agitation.50 Psychosis is reported in 43% of patients with delirium.51 Visual
● Strokes on the primary
hallucinations and delusions are the most common psychotic symptoms reported visual cortex can cause
in one-fourth of patients with delirium whereas other hallucinatory modalities simple visual hallucinations
are less observed in these patients.51 (light, colorless, shadow of
The DSM-5 indicates that delirium is not directly explained by major objects or shapes, etc) on
the hemianopic visual field.
neurocognitive disorder or dementia; however, patients with dementia are
Visual hallucinations after
vulnerable to developing delirium, and delirium increases the risk of progression occipital stroke occur more
to dementia. In the past decade, evidence of an association between delirium and frequently after focal
dementia with Lewy bodies (DLB) in many aspects has been increasing.52,53 First, damage to the striate cortex
that spares the extrastriate
psychotic symptoms with prominent visual hallucinations are very common in
cortex than a stroke that
both conditions. Because visual hallucinations are usually well formed and extensively affects both the
patients with delirium often have concurrent cognitive impairments, insight into striate and extrastriate
those visual hallucinations is usually impaired. Second, fluctuation of cognition cortices.
and consciousness is the core feature in both conditions. Third, patients with
● Poor memory function
DLB have prominent impairments in attention, working memory, and may manifest as
visuoperception similar to the pattern of cognitive deficits found in delirium.54,55 confabulation, which is
For these reasons, delirium-onset DLB is one of the proposed prodromal often not a firm belief and
subtypes of DLB.53 When delirium is resolved, clinicians should thoroughly must be distinguished from a
fixed belief typically seen in
evaluate patients for cognitive impairment and other features of DLB in whom delusion.
delirium occurs without triggers and in those with prolonged or recurrent
delirium after treatment of provoking factors.53 ● In Alzheimer disease,
Capgras delusion and
prosopagnosia are
Psychosis in Idiopathic Parkinson Disease
secondary to degeneration
Minor hallucinations, vivid hallucinations, and delusions are very common in of the parietotemporal
PD. The severity of symptoms ranges from benign hallucinations with intact region affecting face
insight to psychosis with disabling hallucinations and delusions. Visual recognition systems.
hallucinations are the most common hallucinatory modality in PD. Minor Prosopagnosia is not a
psychotic symptom, but
hallucinations, including passage and presence hallucinations, are reported in Capgras delusion is a type of
42% of drug-naïve patients with PD and may manifest months to years before the delusional misidentification
onset of motor symptoms.56 Passage hallucination is a poorly defined vision of a syndrome found in 10% of
person, animal, or shadow briefly passing sideways in the peripheral visual field. patients with Alzheimer
disease.
Patients with presence hallucination explain that they feel a presence of a known
person in the room or behind them, and the sense of presence hallucination is ● Psychoses in epilepsy are
often vivid but with preserved insight. Approximately 6% to 25% of patients with classified according to the
PD may experience object misidentification illusions (eg, seeing a hose as a temporal relationship
between psychotic
snake) and kinetopsia (perception of a stationary object as being in motion).56-59
symptoms and ictal events
Once α-synuclein protein is more widespread, formed visual hallucinations into ictal psychosis,
develop with initially preserved insight then later loss of insight, fulfilling the postictal psychosis, and
criteria for PD with psychosis. Formed visual hallucinations are reported in interictal psychosis (brief
and chronic).
approximately 20% to 30% of patients during the course of PD.58-60 Auditory,
tactile, and olfactory hallucinations occur less frequently. Unlike in DLB,
delusions are reported in less than 10% of cases of PD and are likely to occur
when the disease is more advanced.59,61 Because many patients with PD may not
spontaneously report their experiences of psychotic symptoms, clinicians should
always evaluate for any existing or emerging psychotic features during each visit.
The recommended scales to assess psychosis in PD by the Movement Disorder
Society are available for further review.62
Psychosis in PD can be secondary to antiparkinsonian medications,
anticholinergics, narcotics, and benzodiazepines. It is important to review

PSYCHOSIS
a list of medications for every patient with PD and psychosis. Discontinuation

of non–antiparkinsonian anticholinergics, narcotics, and sedatives should be
attempted first. If psychosis is severe and requires treatment, decreasing or
discontinuing antiparkinsonian medications may be indicated, starting with
antiparkinsonian anticholinergics (benztropine, trihexyphenidyl) and
followed by monoamine oxidase B inhibitors, amantadine, dopamine agonists,
catechol-O-methyltransferase inhibitors, and finally levodopa. Patients may
CASE 9-2 A 71-year-old man presented with 1 year of recurrent visual

hallucinations. He had no underlying psychiatric disorder. One year ago,
he underwent laparoscopic gallbladder surgery and developed
prolonged 1-month delirium with visual hallucinations (seeing people and
insects). He developed progressive gait shuffling. He had a decreased
sense of direction and got lost while driving. Six months after the surgery,
visual hallucinations recurred, and he occasionally saw kids and dogs
running in his house; the hallucinations lasted for less than 1 minute and
often disappeared after he focused on them. He felt those visual
hallucinations were real but not bothersome. His wife reported that the
patient had dream enactment behavior for 3 years.
On examination, his Mini-Mental State Examination score was 17/30.
He had signs of parkinsonism, manifested as rigidity and bradykinesia of
all extremities, mild resting tremor on both hands, parkinsonian gait, and
postural instability.
He fulfilled the criteria for probable dementia with Lewy bodies (DLB).
Rivastigmine was started and titrated up to a 13.3-mg patch daily. At his
3-month follow-up, visual hallucinations were slightly decreased. One
year later, the family reported that he started having persecutory
delusions and thought that his belongings were stolen by a male stranger
that he saw in his house. Visual hallucinations and delusions made him
agitated. After a discussion with the patient and wife about the
cardiovascular risks, quetiapine was started at 12.5 mg nightly and slowly
titrated up to an effective dose at 50 mg nightly.
COMMENT This patient presented with late-onset psychosis (prominent and early
visual hallucinations); thus, the diagnosis of primary psychotic disorders
must be made cautiously. Visual hallucinations during an episode of
delirium are common; however, recurrent visual hallucinations in the
absence of triggers and prolonged delirium in this case raised concern for a
prodromal phase of DLB. Observation is reasonable if symptoms are not
disabling. Acetylcholinesterase inhibitors may slightly improve visual
hallucinations and delusions in DLB.65 In severe cases, after discussion
about the cardiovascular risks, antipsychotics may be indicated. The
starting and effective doses of antipsychotics for the treatment of
dementia-related psychosis are significantly lower than the doses used in
primary psychotic disorders.
1694 DECEMBER 2021

eventually require antipsychotics if discontinuation of antiparkinsonian KEY POINTS
medications is not possible or if psychotic symptoms are severe or
● Chronic interictal
disruptive. psychosis usually manifests
with better preserved
Psychosis in Dementia With Lewy Bodies premorbid personality,
In DLB, visual hallucinations manifest early in the course of disease. Psychiatric- lesser negative symptoms
(social withdrawal and
onset prodromal DLB (late-onset major depressive disorder or late-onset
blunted affect), lesser
psychosis) may be a solely initial symptom of DLB before subsequent command hallucinations,
development of parkinsonism or other DLB features.53,63,64 Compared with and more visual
visual hallucinations in PD, the characteristics of visual hallucinations in DLB are hallucinations than in
schizophrenia.
more well formed (seeing children, people, animals, or scenes), are associated
with greater severity of cognitive impairment, and occur earlier in the course of ● Geschwind syndrome is a
disease. CASE 9-2 illustrates the typical psychotic manifestations and distinct interictal behavioral
management in a patient with DLB. syndrome observed in
Pareidolia, which is the perception of meaningful objects (faces or animals) patients with temporal lobe
epilepsy and characterized
embedded in visual scenes, is a complex visual illusion in patients with Lewy by alterations in sexual
body diseases, including DLB and PD.66,67 Unlike in PD, delusions are commonly behaviors, hyperreligiosity,
reported in 25% to 50% of patients with DLB and may occur in the early stage of circumstantiality of speech,
disease.68,69 Approximately half of patients with DLB reported delusional a tendency to pedantry
(mental stickiness, or being
misidentification syndromes.70 overly concerned with minor
rules or details), and
Psychosis in Cerebrovascular Diseases excessive or compulsive
Delusions and hallucinations are reported in approximately 5% of patients writing and drawing
(hypergraphia) with
after stroke.71 The neural basis of poststroke psychosis is still unclear;
meticulous details. This
however, when strokes are unilateral, right hemispheric lesions are associated syndrome can
with poststroke psychosis more than lesions on the left hemisphere. A concomitantly occur with or
midbrain or thalamic lesion can rarely cause peduncular hallucinosis, which mimic interictal psychosis.
produces naturalistic and vivid visual hallucinations usually associated with
● In patients presenting
preserved insight. with late-onset psychosis, it
Peduncular hallucinosis is hypothetically related to release phenomenon is always the rule to
from damage to the ascending reticular systems and thalamocortical circuits. extensively evaluate for an
The dorsomedial, pulvinar, and anterior nuclei of the thalamus are the common organic etiology before
making a diagnosis of
locations contributing to peduncular hallucinosis secondary to thalamic primary psychiatric
damages. The majority of peduncular hallucinosis occurs within the first week disorders.
after damage, but a late onset can manifest up to 1 year after strokes.72 Damage
to the thalamus rarely causes auditory and musical hallucinations from ● Cognitive screening with
the Mini-Mental State
dysregulation of the neural circuits between the thalamus and the superior
Examination or the Montreal
temporal gyrus.72 Cognitive Assessment is
Strokes on the primary visual cortex can cause simple visual hallucinations essential because this may
(light, colorless, shadow of objects or shapes, etc) on the hemianopic visual field. assist in the diagnosis of
dementia and guide further
Visual hallucinations after occipital stroke occur more frequently after focal
investigations for dementia-
damage to the striate cortex that spares the extrastriate cortex than a stroke that related psychosis.
extensively affects both the striate and extrastriate cortices. This suggests that the
release phenomenon from the damaged primary visual cortex requires intact
adjacent visual cortices to cause visual hallucinations.73
Sensory aphasia after stroke may clinically mimic disorganized speech and
thoughts seen in psychosis; thus, sensory aphasia must be distinguished from
true psychotic symptoms.
Delusional misidentification syndromes may occur after strokes and
usually spontaneously resolve within 1 to 2 months after the onset of

PSYCHOSIS
symptoms.74 Damage to the right hemisphere more frequently results in

delusional misidentification syndromes than damage to the left hemisphere.74
Psychosis in Alzheimer Disease

Psychotic features increase the risk of cognitive decline and institutionalization
in patients with Alzheimer disease (AD). Delusions are reported in 31% and
hallucinations in 16% of patients with AD.75 Delusional misidentification
syndromes occur in 30% of patients with AD.69 Paranoia and delusion of theft are
common and relate to the severity of memory loss. Poor memory function may
manifest as confabulation, which is often not a firm belief and must be
distinguished from a fixed belief typically seen in delusion. In AD, atrophy
of the right anterior inferior temporal and right insular cortices was associated
with the presence of psychosis, which suggested that psychosis in AD may be
secondary to an impairment of visual processing and misperception of
salience stimuli.76
In AD, Capgras delusion and prosopagnosia are secondary to degeneration of
the parietotemporal region affecting face recognition systems. Capgras delusion
is the belief that a significant other has been replaced by an imposter who is
physically identical to the replaced person without an emotional relationship to
the patient. In contrast, prosopagnosia is an inability to recognize familiar faces
but a preserved ability to recognize those familiar people in other aspects (eg,
voices, gaits) and intact emotional connection. Prosopagnosia is not a psychotic
symptom, but Capgras delusion is a type of delusional misidentification
syndrome found in 10% of patients with AD.77
Psychosis in Epilepsy
The association between epilepsy and schizophrenia is bidirectional. Although
the prevalence of schizophrenia is 1% in the general population, psychosis
develops in 5.6% of patients with epilepsy, and that prevalence increases to 7%
when seizures originate from the temporal lobes.78 In the opposite direction,
patients with schizophrenia have a 2 to 3 times higher risk of epilepsy than the
general population.79 Risk factors of psychosis in temporal lobe epilepsy are early
age at epilepsy onset, history of status epilepticus, hippocampal sclerosis, and left
hemisphere abnormalities.80 Reduction of the posterior hippocampal volumes is
associated with development of psychosis in patients with temporal lobe,
extratemporal lobe, and generalized epilepsy.81
Psychoses in epilepsy are classified according to the temporal relationship
between psychotic symptoms and ictal events into ictal psychosis, postictal
psychosis, and interictal psychosis (brief and chronic).82 Ictal psychosis occurs
suddenly and concurrently with epileptic discharges manifesting with behavioral
changes, affective disturbances, anxiety, fear, fluctuation of consciousness, and
thought incoherence. Patients may have automatism with or without loss of
awareness. Delusions and hallucinations occur but less frequently than in
postictal psychosis. Postictal psychosis occurs a few hours to days after ictal
events with a prevalence of 2% in patients with epilepsy.78 Various delusions
(persecutory, grandiose, somatic, and religious), hallucinations, and affective
symptoms (manic or depressive) are the key manifestations in postictal
psychosis.
For interictal psychosis, it is challenging to differentiate chronic interictal
psychosis from schizophrenia because they share many similar psychotic
1696 DECEMBER 2021

manifestations. However, chronic interictal psychosis usually manifests with KEY POINTS
better preserved premorbid personality, lesser negative symptoms (social
● For first-episode
withdrawal and blunted affect), lesser command hallucinations, and more visual psychosis, an antipsychotic
hallucinations than in schizophrenia.83 with a lower risk of
Geschwind syndrome is a distinct interictal behavioral syndrome observed in extrapyramidal symptoms,
patients with temporal lobe epilepsy and characterized by alterations in sexual weight gain, and metabolic
problems would be the
behaviors, hyperreligiosity, circumstantiality of speech, a tendency to pedantry
preferred choice. If no
(mental stickiness, or excessive concern over minor details and rules), and response is seen in 2 to
excessive or compulsive writing and drawing (hypergraphia) with meticulous 4 weeks with a good
details.84 This syndrome can concomitantly occur with or mimic interictal therapeutic trial of
medication, the
psychosis.
antipsychotic can be
switched to a different one.
Psychosis in Other Neurologic Diseases The new antipsychotic being
Psychosis is one of the key features of limbic encephalitis. Autoantibodies used should preferably be
commonly associated with autoimmune limbic encephalitis are antibodies pharmacologically different
from the previous one and
against intracellular antigens (eg, Hu, Ma2, glutamic acid decarboxylase [GAD]), can be cross tapered.
synaptic receptors (eg, N-methyl-D-aspartate [NMDA], α-amino-3-hydroxy-5- However, if the patient has
methyl-4-isoxazole propionic acid [AMPA], γ-aminobutyric acid B [GABAB] no response to two
receptor), and ion channels (leucine-rich glioma inactivated protein 1 [LGI1], adequate trials of dissimilar
antipsychotics, clozapine
contactin-associated proteinlike 2 [CASPR2]). When the limbic encephalitis is would then be indicated.
associated with paraneoplastic autoantibodies and Purkinje cell cytoplasmic
antibody type 2 (PCA-2), it is called paraneoplastic limbic encephalitis, ● The typical
which is usually associated with neoplasm of the lung, ovary, breast, thymus, antipsychotics are further
classified into lower-,
and testes.
medium-, or higher-potency
Anti-NMDA encephalitis is a rare, but treatable, immune-mediated agents. The potency is
encephalitis that should be considered in a patient, particularly in girls determined by the
or young adult women, presenting with acute to subacute onset of dopamine receptor affinity,
and the side effect profile is
psychiatric disturbances (psychosis, mania, agitation, insomnia, disorganized
based on the degree of
thinking, and catatonia), cognitive dysfunction, seizures, movement cholinergic receptor
abnormalities (orofacial-lingual dyskinesia, parkinsonism, dystonia, and blockade, α1-adrenergic
chorea), decreased level of consciousness, central hypoventilation, and blockade, and histaminergic
dysautonomia.85 In girls and young adult women, the association of anti-NMDA blockade. Lower-potency
antipsychotics have
encephalitis and ovarian teratoma warrants further investigation to include prominent cholinergic
transvaginal ultrasound and subsequent tumor removal if ovarian teratoma is receptor blockade and,
detected in patients with this syndrome. hence, lower
Psychosis is an uncommon neuropsychiatric symptom in Huntington disease. extrapyramidal symptom
rates.
Delusions may occur in the later stage of disease, and hallucinations are less
common than delusions. In Huntington disease, the parkinsonism-dominant ● The second-generation
motor phenotype and frontal executive dysfunction are associated with a higher (atypical) antipsychotics
risk of psychosis.86 have antagonistic properties
at both 5-HT2A and
Psychosis is a rare presentation of a discrete cerebral lesion from neoplasm or
dopamine receptors, hence
vascular malformation. Seizure-related musical and auditory hallucinations are improving the positive
rare phenomena in patients with lesions on the superior temporal gyrus and symptoms but causing fewer
thalamus, which may be either caused by the cerebral damage itself or secondary extrapyramidal symptoms.
to lesion-related seizures.
Psychosis can be a clinical manifestation of central nervous system infections
including, but not limited to, herpes simplex virus type 1 or herpes simplex
virus type 2, treponema pallidum, and human immunodeficiency virus (HIV).
TABLE 9-3 presents the diagnostic tests and clinical clues for the evaluation of
these infectious conditions.

PSYCHOSIS
Patients with traumatic brain injury can develop schizophrenialike psychosis.

Early-life traumatic brain injury increases the risk of the later development of
schizophrenia and schizophrenialike psychosis.87 When traumatic brain injury
results in focal brain damage, lesions on the temporal and frontal lobes increase
the risk of development of psychosis.88 In chronic traumatic encephalopathy, a
tau-related neurodegenerative disease secondary to repetitive head injuries, tau
deposition in white matter is positively associated with the severity of long-
term psychosis.89
EVALUATION
Diagnosis of psychotic disorders is primarily based on a thorough history,
including family history and the temporal course of symptoms, substance use
history, exposure to infectious agents or chemicals, collateral information,
and observed behaviors. The differential diagnosis of primary and secondary
psychotic disorders is extensive, and a sensitive inquiry into the timeline and
symptoms can help with diagnostic evaluation. New-onset symptoms warrant
medical evaluation for possible alternative explanations of symptoms. In
patients presenting with late-onset psychosis, it is always the rule to
extensively evaluate for an organic etiology before making a diagnosis of
primary psychiatric disorders. Isolated visual hallucinations warrant further
evaluation for secondary psychosis. Characteristics of visual hallucinations
may help in localizing and identifying the etiologies. It is essential to ask about
head injury to rule out subdural hematomas and to obtain other relevant
information to eliminate neurologic disorders such as seizures, migraine, or
stroke. Cultural history must be obtained if relevant and it includes details
about beliefs, values, and practices shared by other individuals of the same
group. Travel history may give details of exposure to any infection. Sexual
history might suggest the possibility of exposure to syphilis or HIV. Dietary
and occupational history helps rule out nutritional deficiencies or
environmental exposures.
Examination should include a thorough physical, neurologic, and mental
status examination. Clinicians should check for signs of systemic illness,
cognitive deficits, abnormal vital signs, and visual hallucinations. Cognitive
screening with the Mini-Mental State Examination or the Montreal Cognitive
Assessment (MoCA) is essential because this may assist in the diagnosis of
dementia and guide further investigations for dementia-related psychosis.
Elevated blood pressure suggests the possibility of drug toxicity or
thyrotoxicosis. Gait abnormalities are commonly seen with conditions such as
multiple sclerosis, PD, or DLB. Movement abnormalities, including tremor,
myoclonus, ataxia, dystonia, or chorea, may suggest psychosis related to
neurologic conditions.
Routine laboratory values, including complete blood cell count,
comprehensive metabolic panel, thyroid function tests, vitamin B12 level, HIV,
syphilis, and urine drug screen should be obtained in every patient presenting
with new-onset psychosis. TABLE 9-3 summarizes various diagnostic tests, clinical
cues, and conditions that should be considered in the evaluation of patients
with psychosis.
Once medical or neurologic conditions have been ruled out, careful evaluation
of the timeline of symptoms is essential for the diagnosis of a primary psychotic
disorder. Details such as the sequence of symptoms, correlation with stressors,
1698 DECEMBER 2021

duration, and intensity of symptoms will help with the differential diagnosis for KEY POINTS
psychotic disorders.
● Risperidone is one of the
atypical antipsychotics for
ANTIPSYCHOTIC MEDICATIONS which D2 receptor
Biological treatments and side effects for schizophrenia have been centered on occupancy can be higher,
dopamine and its four key pathways as follows: resulting in side effects such
as extrapyramidal
u Dysregulation in the mesolimbic tracts has been the core belief for the positive symptoms symptoms or elevated
of schizophrenia models for decades. These pathways are made up of projections from prolactin levels. Clozapine
the midbrain ventral tegmental area to the nucleus accumbens. and quetiapine do not have a
D2 receptor occupancy
u The deficiency of dopamine in the mesocortical pathway, from the midbrain ventral greater than 80% and,
tegmental area projecting to the limbic cortex, is associated with the negative symptoms hence, have the lowest risk
of schizophrenia.93 The negative symptoms could also be explained by a secondary for extrapyramidal
dopamine deficiency caused by excess serotonin. symptoms.
u Inhibition of dopamine in the tuberoinfundibular pathway results in increased prolactin
hormone, which may lead to symptoms such as gynecomastia, galactorrhea, amenorrhea, ● The effective dose ranges
sexual dysfunction, and breast engorgement in females. This pathway includes dopamine for the treatment of
neurons that project from the hypothalamus to the anterior pituitary. psychosis in primary
psychotic disorders are
u Deficiency of dopamine in the nigrostriatal pathway is associated with extrapyramidal significantly higher than the
symptoms such as dystonic reaction, parkinsonism, and akathisia. The nigrostriatal dose ranges used for the
pathway is the pathway that connects the substantia nigra in the midbrain to the dorsal treatment of psychosis
striatum in the forebrain. related to neurologic
conditions. Patients with
Medications that inhibit dopamine neurotransmission are currently the neurodegenerative
mainstay of pharmacologic treatment for idiopathic psychotic disorders as well disorders are particularly
vulnerable to developing
as psychosis secondary to other medical conditions or substances.90 More than 20
side effects from
different antipsychotic medications are marketed in the United States antipsychotics. “Start low,
(TABLE 9-4).91 The choice of antipsychotic agent depends on efficacy, side effect go slow” is recommended in
profile, cost considerations, and the accurate diagnosis being treated. For managing antipsychotics in
this population.
example, when the psychosis is secondary to medical conditions, the focus of
treatment would be on the underlying disorder such as electrolyte imbalances, ● Antipsychotics with low
infections, fever, and endocrine abnormalities before starting antipsychotics. In D2 antagonistic activity,
any patient with psychosis, a thorough review of the patient’s symptoms, including quetiapine and
medications, vital signs, complete blood cell count, comprehensive metabolic clozapine, are preferably
used off-label for the
panel, lipid panel, height and weight, ECG, and a basic screening for any treatment of psychosis in
abnormalities in gait or other movements should be completed before starting DLB, Parkinson disease, and
medications. Another important aspect that could dictate the choice of Alzheimer disease because
medication is the history of medication noncompliance. In these patients, it is of their low prevalence of
extrapyramidal effects.
important to consider antipsychotics that have long-acting injectable
formulations, such as haloperidol, fluphenazine, olanzapine, aripiprazole, ● Pimavanserin is a newer
and paliperidone. second-generation
Since chlorpromazine was first introduced in 1952, more than 60 other antipsychotic approved for
the treatment of psychosis
antipsychotic medications have been developed that predominantly modulate
associated with Parkinson
dopamine in the mesolimbic and mesocortical areas of the brain. The optimal disease. The mechanism of
medication choice is often based on the stage of the illness. For first-episode action is different as it has
psychosis, an antipsychotic with a lower risk of extrapyramidal symptoms, no affinity for dopamine
weight gain, and metabolic problems would be the preferred choice. Most receptors but instead is a
highly selective 5-HT2A
patients respond to the medication, but at least 30% of people will have a partial inverse agonist; thus, it does
response and at least 20% will have no response. If no response is seen in 2 to not worsen parkinsonism.
4 weeks with a good therapeutic trial of medication, the antipsychotic can be
switched to a different one. When relapses increase because of medication
nonadherence, substance use, or stressful life events, the antipsychotic choice

PSYCHOSIS
would be based more on the patient’s previous response, preference, side effects,
or comorbid conditions. The new antipsychotic being used should preferably be
pharmacologically different from the previous one and can be cross tapered.
However, if a patient does not respond to two adequate trials of dissimilar
antipsychotics, clozapine would then be indicated.92 Loading dose of
medications, drastic dose changes, and doses greater than the recommended
range typically are not effective strategies and increase the rate of adverse events.
TABLE 9-3 Diagnostic Tests and Clinical Clues in the Evaluation of Psychosis
Tests Clinical clues and conditions
Urine drug screening Should be performed routinely

Substance intoxication or withdrawal
Complete blood cell count, comprehensive Should be performed routinely

metabolic panel, urinalysis, blood and urine culture
Delirium associated with psychosis
Acute onset of psychosis in older adult and cognitively impaired
patients
Presence of symptoms and signs of infection
Endocrine laboratory values (calcium, parathyroid Clinical suggestion of endocrine conditions such as Cushing
hormone, adrenocorticotropic hormone [ACTH], syndrome, signs of severe hypothyroidism (myxedema) or
thyroid-stimulating hormone [TSH], and thyroxine thyrotoxicosis
levels)
Severe hypercalcemia associated with either hyperparathyroidism or
malignant neoplasm
Antinuclear antibody and erythrocyte sedimentation Clinical suggestion of rheumatologic conditions (neuropsychiatric
rate lupus, etc)
Vitamin B1, B3, and B12 levels Clinical suggestion of malnutrition

Chronic alcohol use disorder
Confabulation and Korsakoff psychosis associated with thiamine
deficiency
Clinical suggestion of pellagra (dermatitis, diarrhea, dementia)
Neoplasm screening imaging (lung, ovary, breast, Acute to subacute onset of psychosis associated with cognitive
thymus, and testes) and autoimmune encephalitis dysfunction, seizures, and movement abnormalities
antibodies in CSF and serum
Positive result of paraneoplastic autoimmune encephalitis antibodies
Lumbar puncture for viral encephalitis panel Acute onset of psychosis associated with fever, seizure, and altered
(including herpes simplex virus type 1 and herpes mental status
simplex virus type 2)
Abnormalities on neuroimaging (medial temporal lobe lesions, etc)
EEG abnormalities, especially periodic lateralized discharges
Screening for human immunodeficiency virus (HIV) Previous diagnosis of syphilis or risk for syphilis with neurologic,
and neurosyphilis ophthalmologic, or audiologic symptoms
Neurocognitive disorder in patients with established diagnosis of HIV
infection or acquired immunodeficiency syndrome (AIDS)
1700 DECEMBER 2021

Although the core application of antipsychotics is the treatment of psychosis
in schizophrenia, some antipsychotics also have indications for mood disorders
with or without psychosis. Antipsychotics are grouped into two major categories:
first-generation (also called typical or conventional) antipsychotics and second-
generation (also called atypical) antipsychotics. First-generation antipsychotics
have nonspecific D2 receptor blockade, and second-generation antipsychotics are
a heterogeneous group of medications that exert more specific mesolimbic
Tests Clinical clues and conditions
Neuroimaging (head CT or MRI either with New-onset headache associated with red-flag symptoms or signs of
or without contrast) concern for tumors
Clinical suggestion of psychosis related to localized seizure (simple
visual hallucinations, musical hallucinations)
Abnormal focal neurologic examination or presence of movement
abnormalities
Clinical suggestion of central nervous system infection (altered
mental status, fever, signs of meningeal irritation)
Patients with immunocompromised conditions (on
immunosuppressant, HIV infection)
Psychosis after head injury (rule out intracranial hemorrhage and
chronic insult of traumatic brain injury)
Acute-onset of psychosis associated with neurologic symptoms
concerning for acute stroke
Evaluation of the pattern of cerebral atrophy in patients with
dementia associated with psychosis
EEG Clinical suggestion of seizure-related psychosis (intermittent short-

lasting episodes of olfactory, auditory, musical, or visual hallucination
with similar symptomatology in each episode)
May need extensive EEG monitoring in an epilepsy monitoring unit if
the routine EEG is unremarkable but clinically suggestive of seizure-
related psychosis
Clinical suggestion of infectious or autoimmune encephalitis
CSF = cerebrospinal fluid; CT = computed tomography; EEG = electroencephalography; MRI = magnetic resonance imaging.

PSYCHOSIS
TABLE 9-4 Indications of First- and Second-Generation Antipsychotics
Drug name US Food and Drug Administration–approved conditions
Haloperidol Schizophrenia
Tourette syndrome
Disruptive behavior/agitation
Haloperidol decanoate (long-acting injectable) Schizophrenia
Fluphenazine Schizophrenia
Fluphenazine decanoate (long-acting injectable) Schizophrenia
Trifluoperazine Schizophrenia
Nonpsychotic anxiety
Pimozide Tourette syndrome
Perphenazine Schizophrenia
Perphenazine/amitriptyline Schizophrenia with depression

Depression with anxiety
Loxapine Schizophrenia
Loxapine Acute agitation in schizophrenia and bipolar I disorder
Thiothixene Schizophrenia
Chlorpromazine Schizophrenia
Bipolar disorder (mania)
Severe disruptive behaviors
Thioridazine Schizophrenia
Aripiprazole Schizophrenia
Bipolar I disorder (manic or mixed episodes)
Adjunct to treatment for major depression
Irritability associated with autistic disorder
Tourette syndrome
Aripiprazole monohydrate (long-acting injectable) Schizophrenia

Bipolar I disorder (mania)
Asenapine (sublingual and transdermal) Schizophrenia

Bipolar disorder (manic or mixed episodes; sublingual form only)
Brexpiprazole Schizophrenia
Adjunct to treatment for major depression
Cariprazine Schizophrenia
Bipolar disorder (depressive, manic, or mixed episodes)
1702 DECEMBER 2021

Drug name US Food and Drug Administration–approved conditions
Clozapine Schizophrenia (refractory)

Suicidal ideation in schizophrenia and schizoaffective disorder
Iloperidone Schizophrenia
Lurasidone Schizophrenia
Bipolar disorder (depressive episode)
Olanzapine Schizophrenia
Bipolar disorder (manic or mixed episodes)
Acute agitation in schizophrenia and bipolar disorder
Olanzapine/fluoxetine Treatment for refractory depression

Bipolar disorder (depression)
Olanzapine pamoate Schizophrenia
Paliperidone Schizophrenia
Schizoaffective disorder
Paliperidone palmitate Schizophrenia

Schizoaffective disorder
Pimavanserin Parkinson disease psychosis
Quetiapine Schizophrenia
Quetiapine extended-release Schizophrenia

Adjunct treatment for depression
Risperidone Schizophrenia
Autism spectrum disorder (irritability)
Risperidone (long-acting injectable) Schizophrenia

Bipolar disorder
Ziprasidone Schizophrenia
Bipolar disorder (manic or mixed episodes)
Acute agitation in schizophrenia

PSYCHOSIS
dopamine blockade. Typical antipsychotics strongly inhibit dopamine receptors,

and the individual side effect profiles of these drugs tend to depend on the
potency and the binding property of each drug. The typical antipsychotics are
further classified into lower-, medium-, or higher-potency agents. The potency is
determined by the dopamine receptor affinity, and the side effect profile is based
on the degree of cholinergic receptor blockade, a1-adrenergic blockade, and
histaminergic blockade. Lower-potency antipsychotics have prominent
cholinergic receptor blockade and, hence, lower extrapyramidal symptom rates.
The dopamine and acetylcholine in the nigrostriatal pathway have a reciprocal
relationship, which usually determines the severity of extrapyramidal
symptoms.93 Side effects such as hyperprolactinemia are strongly correlated to
the D2 receptor dissociation kinetic and, hence, are commonly seen with the
typical antipsychotics, especially the high-potency ones such as haloperidol.
The second-generation (atypical) antipsychotics emerged after the 1970s and
were also known as the serotonin-dopamine antagonists. They have antagonistic
properties at both 5-HT2A and dopamine receptors, hence improving the positive
symptoms (hallucinations, delusions, and disorganized behaviors) but causing
fewer extrapyramidal symptoms.94 Although the D2 receptor occupancy for the
typical antipsychotics in the striatum is 65% to 80%, the therapeutic window
for D2 receptor occupancy in atypical antipsychotics is not as stringent.
When occupancy is greater than 80%, the side effects such as extrapyramidal
symptoms are more commonly seen.95 Risperidone is one of the atypical
antipsychotics for which D2 receptor occupancy can be higher, resulting in
side effects such as extrapyramidal symptoms or elevated prolactin levels.
Clozapine and quetiapine do not have a D2 receptor occupancy greater than
80% and, hence, have the lowest risk for extrapyramidal symptoms. Other G
protein–coupled receptors such as 5-HT2C/5-HT1A, muscarinic, noradrenergic,
histaminergic, and glutamatergic receptors are also found to be the target sites
for atypical antipsychotics. Three of the second-generation antipsychotics,
aripiprazole, brexpiprazole, and cariprazine, are partial agonists at both D2 and
5-HT1A receptors and antagonists at 5-HT2A receptors. They act as antagonists
when dopamine is in excess but intrinsically can activate the D2 receptor up to 40%.
Both first- and second-generation antipsychotics are equally efficacious for
the treatment of psychosis, except for clozapine, which has superior efficacy
for the treatment of refractory psychosis. Based on the pharmacologic properties,
the atypical antipsychotics were grouped by Stahl93 into “the pines, the dones,
two pips, and a rip.” For example, the “pines” include clozapine, quetiapine,
olanzapine, asenapine, and others; the “dones” include risperidone, paliperidone,
ziprasidone, iloperidone, and lurasidone; the “pips” include aripiprazole and
brexpiprazole; and the “rip” is cariprazine.93 This classification is based on their
effects (on neurochemical transmission) and their affinity to different receptor sites.
It is important to note that the effective dose ranges for the treatment of
psychosis in primary psychiatric disorders are significantly higher than the dose
ranges used for the treatment of psychosis related to neurologic conditions.
Patients with neurodegenerative disorders are particularly vulnerable to
developing side effects from antipsychotics. “Start low, go slow” is
recommended in managing antipsychotics in this population. Antipsychotics
with low D2 antagonistic activity, including quetiapine and clozapine, are
typically used off-label for the treatment of psychosis in DLB, PD, and AD
because of their low prevalence of extrapyramidal effects. Pimavanserin is a
1704 DECEMBER 2021

newer second-generation antipsychotic approved for the treatment of psychosis KEY POINTS
associated with PD. The mechanism of action is different as it has no affinity for
● Dystonic reaction is a
dopamine receptors but instead is a highly selective 5-HT2A inverse agonist; thus, side effect that is typically
it does not worsen parkinsonism. Recent clinical trials showed its efficacy in the seen soon after initiation
treatment of AD psychosis at the 6-week follow-up; however, it had no of an antipsychotic agent.
significant advantage at up to 12 weeks.96 It is being investigated for the It is uncomfortable and
life-threatening if left
treatment of agitation and aggression in AD, other dementia-related psychosis,
untreated. Along with
adjunctive treatment for the negative symptoms of schizophrenia, and hemodynamically
adjunctive therapy in refractory major depressive disorder. A 2021 retrospective supportive treatment,
cohort study has shown an increased risk of hospitalization at 1 month and higher IV or IM anticholinergic
agents and antihistamines
mortality for up to 1 year after initiation of pimavanserin in adult patients with
with potent anticholinergic
PD residing in long-term care facilities.97 TABLE 9-2 summarizes the current effects (eg, diphenhydramine)
antipsychotics with their US Food and Drug Administration (FDA)-approved are used for the treatment of
indications. dystonic reactions.
Side effect profile is one of the important considerations when choosing an
● Medications that have
antipsychotic for a patient. Most common side effects include extrapyramidal been used to treat tardive
side effects such as rigidity, bradykinesia, tremor, akathisia/severe restlessness, dyskinesia symptoms
and tardive dyskinesia. These extrapyramidal side effects have been less of a include vesicular
problem with the use of second-generation antipsychotics compared with monoamine transporter type
2 inhibitors such as
first-generation. Dystonic reaction is a side effect that is typically seen soon valbenazine, tetrabenazine,
after initiation of an antipsychotic agent. It is uncomfortable and life- and deutetrabenazine.
threatening if left untreated. Along with a hemodynamically supportive
treatment, an IV or IM anticholinergic agent (eg, benztropine) and ● One of the more dangerous
side effects of antipsychotics
antihistamines with potent anticholinergic effects (eg, diphenhydramine) are
to look for is neuroleptic
used for the treatment of dystonic reactions. Treatment options for malignant syndrome in which
parkinsonism-like symptoms include dose reduction or switching to a the patient experiences
different antipsychotic. If a patient is otherwise doing well on the current dystonia, fever, autonomic
antipsychotic despite having parkinsonian side effects, anticholinergic agents instability, rigidity, elevated
creatine kinase, increased
such as benztropine or diphenhydramine may be added. Akathisia or inner myoglobin in urine, and
restlessness can sometimes be hard to differentiate from agitation. A low-dose delirium.
beta-blocker such as propranolol can be added to the regimen for patients with
akathisia if dose reduction is not an option. ● For clozapine, absolute
neutrophil count is
Long-term treatment with antipsychotics increases the risk of developing monitored frequently to
tardive dyskinesia. Abnormal movements may include tics, chorea, dystonia, or check for agranulocytosis.
myoclonic jerks. The risk is even higher in older patients, women, patients on
high doses of medications, and patients with comorbid affective conditions.
Symptoms may not be reversible and can be decreased by switching to another
antipsychotic such as clozapine. Anticholinergic medications may worsen the
tardive dyskinesia symptoms. Dose reduction of the antipsychotic might not
always be a feasible option clinically. Withdrawal of an antipsychotic may lead to
an initial worsening of tardive dyskinesia, but eventually the side effects
improve. Other medications that have been used to treat tardive dyskinesia
symptoms include vesicular monoamine transporter type 2 inhibitors such as
valbenazine, tetrabenazine, and deutetrabenazine.98
Side effects such as hyperprolactinemia may necessitate switching to
antipsychotics such as aripiprazole or quetiapine. One of the more dangerous side
effects to look for is neuroleptic malignant syndrome in which the patient
experiences dystonia, fever, autonomic instability, rigidity, elevated creatine
kinase, increased myoglobin in urine, and delirium. QTc prolongation,
myocarditis, tachycardia, and orthostatic hypotension are a few cardiovascular

PSYCHOSIS
side effects to monitor for. Side effects such as weight gain, diabetes, and
hyperlipidemia are more commonly seen with the use of clozapine, olanzapine,
quetiapine, and risperidone. Hence, monitoring of vital signs, weight, complete
blood cell count, metabolic panel, and lipid panel and obtaining ECG is essential
when an antipsychotic is started or the dose is changed. Once a patient is
stabilized on an antipsychotic, these parameters can be monitored once a year or
once every 6 months.
For clozapine, absolute neutrophil count is monitored more frequently to
check for agranulocytosis. Other major side effects associated with the use of
TABLE 9-5 Side Effect Profiles of Antipsychotics
Extrapyramidal symptoms/ Anticholinergic Orthostatic

Antipsychotics tardive dyskinesia side effects Weight gain hypotension
Aripiprazole + - + -
Asenapine ++ - ++ +
Brexpiprazole + +/- + +/-
Cariprazine + +/- +/- +/-
Chlorpromazine + +++ +++ +++
Clozapine +/- +++ ++++ +++
Fluphenazine +++ +/- + -
Haloperidol +++ +/- + -
Iloperidone +/- + ++ +++
Loxapine +++ + - ++
Lurasidone ++ - +/- +
Olanzapine + ++ ++++ +
Paliperidone +++ - +++ ++
Perphenazine ++ - + +
Pimavanserin +/- + + ++
Pimozide +++ + + +
Quetiapine +/- ++ +++ ++
Risperidone +++ + +++ +
Thioridazine + ++ + ++
Thiothixene +++ + + +
Trifluoperazine +++ + + +
Ziprasidone + - +/- +
- = no risk or rarely causes side effects at the therapeutic dose; + = mild or occasionally causes side effects at the therapeutic dose;
++ = moderate or sometimes causes side effects at the therapeutic dose; +++ = severe or frequently causes side effects at the therapeutic dose;
++++ = most frequently causes side effects at the therapeutic dose.
1706 DECEMBER 2021

clozapine that need close monitoring include myocarditis, seizures, pulmonary KEY POINTS
embolism, orthostatic hypotension, and severe constipation. Irrespective of the
● To monitor for life-
side effects, clozapine is the only medication that has been proven to be superior threatening side effects,
in efficacy compared with all other antipsychotics. To monitor for life- patients are enrolled in a
threatening side effects, patients are enrolled in a registry with routine blood registry with routine blood
monitoring by the prescriber, in the Clozapine Risk Evaluation and Mitigation monitoring by the prescriber,
in the Clozapine Risk
Strategy Program.99 Prescribers must be certified to be able to prescribe
Evaluation and Mitigation
clozapine. They are required to obtain an absolute neutrophil count for these Strategy Program. Prescribers
patients and submit it directly to the registry. If no absolute neutrophil count is must be certified to be able to
on file for the patient, clozapine dispensation is not authorized. prescribe clozapine. They are
required to obtain an absolute
The use of antipsychotics in older patients with dementia increases the risk of
neutrophil count for these
mortality by 1.6 to 1.7 times compared with placebo, and a boxed warning was patients and submit it directly
issued by the FDA.100 The most common causes of death in this patient to the registry. If no absolute
population include pneumonia and heart failure or cardiac death. The risk of neutrophil count is on file for
sudden death and cerebrovascular events are major concerns for long-term the patient, clozapine
dispensation is not authorized.
treatment of psychosis or agitation in patients with neurocognitive disorders.
TABLE 9-5 summarizes the side effects of antipsychotics. ● The use of antipsychotics
Other medications that are frequently used along with antipsychotics include in older patients with
benzodiazepines, lithium, anticonvulsants such as valproic acid and dementia increases the risk
of mortality by 1.6 to 1.7
carbamazepine, and antidepressants. The choice of treatment is based on the times compared with
severity of psychosis, comorbidities, and symptoms. Electroconvulsive therapy is placebo, and a boxed
considered in patients with severe psychosis with or without catatonic symptoms.92 warning was issued by the
Psychological interventions include cognitive-behavioral therapy, family US Food and Drug
Administration.
psychoeducation, and personal therapy. Cognitive-behavioral therapy is focused
more on the coping mechanisms that the patient develops to deal with the
psychosis but does not challenge the patient’s beliefs as irrational. Social
interventions that have been effective thus far include assertive community
treatment and vocational training.
CONCLUSION
Psychosis is a group of symptoms defined by an impairment of a person’s thoughts and
perception of reality. Even though psychosis is a hallmark of a class of primary
psychiatric disorders, diagnosis must be made by excluding other neurologic or medical
conditions. Evaluation should include thorough history, general and neurologic
examination, relevant laboratory investigations, and appropriate neuroimaging.
Metacognition and social cognition are significantly impaired in patients with
psychosis; thus, management should focus on both pharmacologic management
with antipsychotics and psychological interventions with cognitive-behavioral
therapy, family psychoeducation, personal therapy, and vocational training.
USEFUL WEBSITES
NATIONAL ALLIANCE ON MENTAL ILLNESS AMERICAN PSYCHIATRIC ASSOCIATION
The National Alliance on Mental Illness (NAMI) is one The American Psychiatric Association is an
of the nation’s largest grassroots mental health organization of psychiatrists working together to promote
organizations that advocates for people with the highest-quality and effective care for individuals
mental illness. NAMI provides education, public with mental illness including substance use disorders.
awareness, and support for people with mental
psychiatry.org
illness and for their families.
psychiatry.org/psychiatrists/practice/clinical-
nami.org/About-Mental-Illness/Mental-Health- practice-guidelines
Conditions/Psychosis psychiatry.org/psychiatrists/practice/dsm

PSYCHOSIS
RECOVERY AFTER AN INITIAL SCHIZOPHRENIA EPISODE

Recovery After an Initial Schizophrenia Episode is a
large-scale research initiative focused on different
aspects of coordinated specialty care treatments for
individuals who experienced first-episode psychosis.
nimh.nih.gov/health/topics/schizophrenia/raise/
index.shtml
nimh.nih.gov/health/topics/schizophrenia/
index.shtml
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REVIEW ARTICLE

Spatial Neglect and
CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
Anosognosia After Right
Brain Stroke
By A. M. Barrett, MD, FAAN, FANA, FASNR
ABSTRACT
PURPOSE OF REVIEW: Up to 80% of survivors of right brain stroke leave acute
care without being diagnosed with a major invisible disability. Studies
indicate that a generic cognitive neurologic evaluation does not reliably
detect spatial neglect, nor does it identify unawareness of deficit after
right brain stroke; this article reviews the symptoms, clinical presentation,
and management of these two cognitive disorders occurring after right
brain stroke.
RECENT FINDINGS: Stroke and occupational therapy practice guidelines stress

a quality standard for spatial neglect assessment and treatment to reduce
adverse outcomes for patients, their families, and society. Neurologists
may attribute poor outcomes associated with spatial neglect to stroke
CITE AS: severity. However, people with spatial neglect are half as likely to return to
home and community, have one-third the community mobility, and require
AND PSYCHIATRY):1624–1645. 3 times as much caregiver supervision compared with similar stroke
survivors. Multiple randomized trials support a feasible first-line
Address correspondence to rehabilitation approach for spatial neglect: prism adaptation therapy;
Dr A. M. Barrett, Executive
Director, Center for Visual and more than 20 studies reported that this treatment improves daily life
Neurocognitive Rehabilitation independence. Evidence-based treatment of anosognosia is not as
(151R), Atlanta VA Health Care
developed; however, treatment for this problem is also available.
System, 1670 Clairmont Rd,
Decatur, GA 30033,
ambarr5@emory.edu. SUMMARY: This article guides neurologists’ assessment of right brain
RELATIONSHIP DISCLOSURE :
cognitive disorders and describes how to efficiently assemble and direct a
Dr Barrett has received treatment team to address spatial neglect and unawareness of deficit.
research/grant support from
the Kessler Foundation, and
her institution has received
research/grant support from INTRODUCTION
the National Institutes of
U
Health/Veteran Health p to 80% of survivors of right brain stroke are not diagnosed with
Association and the Wallerstein cognitive disorders of spatial cognition or awareness1,2 during
Foundation for Geriatric
routine acute stroke care, and thus, they cannot receive a plan for
Improvement.
personalized cognitive treatment. Worse, right brain stroke itself is
UNLABELED USE OF underdiagnosed, so survivors of right brain stroke are at risk of
USE DISCLOSURE :
undertreatment or incorrect treatment3–5 because of the difficulty in identifying
Dr Barrett reports no disclosure. the cognitive hallmarks of right brain disorders during routine care.
This article reviews the symptoms and clinical presentation of two of the
© 2021 American Academy cognitive syndromes occurring after right brain stroke. They are not rare;
of Neurology. probably about half or even up to 60% to 80% of survivors of right brain stroke
1624 DECEMBER 2021

have these symptoms for the first weeks and months after stroke
(TABLE 6-16–15).11,14,16
Cognitive symptoms after right brain stroke are important to neurologic care
for two major reasons. First, they may be the only indication of a stroke event or
right brain dysfunction (eg, seizure) requiring medical care. Thus, for example,
detecting cognitive symptoms after right brain stroke may allow the clinician to
give acute stroke treatment to more patients and improve community outcomes
and quality of life. Second, by identifying cognitive symptoms of the spatial
neglect syndrome, defined as asymmetric reporting, responding, or orienting to
one side of space after a brain lesion, causing functional disability, one can
provide management, education, and treatment.17 Assessment of spatial neglect
and rehabilitation of this cognitive disorder, which can improve daily life
function and independence, are also discussed. Anosognosia, or pathologic
unawareness of deficit, is also covered in this article.18 Although both spatial
neglect and anosognosia may occur after other forms of focal brain injury (eg,
after brain tumor resection), they have only been studied in systematic ways in
the context of right brain stroke. Thus, clinical practice guidelines for the
assessment and treatment of spatial neglect are only available for stroke care.19
People with anosognosia may be pathologically unaware of several different
kinds of deficits; however, anosognosia for left body paralysis is very strongly
associated with right brain injury.20 Although rehabilitation approaches for
anosognosia are not as well-researched as those for spatial neglect, evidence
shows they may improve deficits and so this article describes how these
treatments can be used. Neurologists need to advocate for patients with right
brain syndromes to ensure quality care and good outcomes.
Right brain stroke is a major identified cause of spatial neglect.21 Spatial
neglect symptoms may occur in other disorders associated with focal brain
Prevalence of Spatial Neglecta TABLE 6-1
Total Left brain Right brain

Study study, N stroke, % stroke, % Setting Country
7
Gainotti et al, 1972 222 31 42 Outpatient clinic Italy
Denes et al, 19828 48 21 33 Geriatric hospital Italy
Fullerton et al, 19869 205 25 49 General hospital Ireland
Stone et al, 199310 171 65 82 General hospital United Kingdom
McGlone et al, 199711 138 31 62 General hospital Canada

12
Kalra et al, 1997 145 21 43 General hospital United Kingdom
Ringman et al, 200413 750 20 43 Acute care hospital United States

14
Chen et al, 2015 121 47 76 Inpatient rehabilitation United States
Hammerbeck et al, 201915,b ~90,000 37 41.5 Acute care hospital England, Wales,
Northern Ireland
a
Modified with permission from Chen P, et al, Top Stroke Rehabil.6 © 2012 Taylor & Francis Ltd.
b
Side of stroke assigned based on side of arm weakness on the National Institutes of Health Stroke Scale.

SPATIAL NEGLECT AND ANOSOGNOSIA AFTER RIGHT BRAIN STROKE
injury, such as traumatic brain injury and brain tumor, and spatial neglect
symptoms may even occur in multiple sclerosis and Parkinson disease.22–25
However, in contrast to the high-quality evidence available supporting the use of
spatial neglect assessment and treatment in quality stroke care,26 no prospective,
systematic studies of the clinical presentation and treatment of spatial neglect in
these disorders have been performed. Thus, the evidence is not yet appropriate to
use as a basis for planning routine clinical care in these areas. This is an important
area for future research.
SPATIAL NEGLECT
Clinically identifying spatial neglect is important; a challenge exists in diagnosing
this problem, and routine care processes are insufficient to identify this disorder.
Clinical Presentation
Spatial neglect is a common disorder, occurring in about half of patients with
stroke during the first months after their event (TABLE 6-1). The unsafe behaviors
observed as symptoms of spatial neglect can be misattributed to intellectual,
reasoning, personality, or generic cognitive problems, which can be devastating
to patient dignity. Misattribution of spatial neglect symptoms can also delay
diagnosis of right brain stroke past the window for acute stroke interventions; thus,
clinicians should be alert to new spatial bias in patients with stroke risk factors.
SPATIAL NEGLECT SYMPTOMS. Considerable inequity exists in management and

outcomes between strokes based on which side of the brain is affected. Although
cognitive symptoms caused by right brain stroke are characteristic and disabling,
clinicians frequently miss them and, thus, fail to offer appropriate treatment.27
This is probably true in other disorders that cause focal brain damage and spatial
neglect (eg, brain tumor); however, formal examination of underdiagnosis of
spatial neglect and its impact on the management of right versus left brain issues
have not been studied in other brain disorders.
The most common reason why the symptoms are missed is that they are not
assessed. An acute stroke assessment tool, the National Institutes of Health
Stroke Scale, which is a quality care standard in stroke centers,28 underestimates
the severity of right brain stroke29 because, on this 47-point scale, only 2 points
(for item 11: involves testing extinction to bilateral simultaneous stimulation, see
below) are specific to right brain stroke and spatial neglect, compared with 7
points total (for items 1b, 1c, and 9: answering questions, obeying a command,
and aphasia testing) that are sensitive to detect aphasia after left brain stroke.
How to Assess for Spatial Neglect

This section describes the principles and testing methods used to approach
accurate evaluation for spatial neglect.
NOT A VISION PROBLEM. One of the reasons that neurologists underestimate

right brain stroke symptoms is that they have often been informed that spatial
neglect is a higher-order visual problem.30 However, people with vision
problems do not behave like people with spatial neglect. People with vision
problems report that they cannot recognize objects or that they struggle with
reading. Although people with spatial neglect may have trouble reading the left
side of sentences or words (neglect dyslexia), which is disabling, they may not
1626 DECEMBER 2021

seem at all concerned about their partial reading. People with vision issues report KEY POINTS
they cannot see well. However, spatial neglect is characteristically accompanied by
● The unsafe behaviors
unawareness of deficit (anosognosia), and the overwhelming majority of patients observed as symptoms of
with spatial neglect deny having visual issues. Unawareness of deficit (anosognosia) spatial neglect can be
is reviewed later in this article. misattributed to intellectual,
reasoning, personality, or
generic cognitive problems,
EXTINCTION TO BILATERAL SIMULTANEOUS STIMULATION. Frequently, spatial neglect
which can be devastating to
occurs in patients who do not have hemianopia. Patients may be able to see patient dignity.
single stimuli on the contralesional side of space; however, when a stimulus is
presented in both visual fields (bilateral simultaneous stimulation), especially in ● Misattribution of spatial
the lower visual fields, patients with spatial neglect after right brain stroke may neglect symptoms can delay
diagnosis of right brain
confidently respond that the stimulus is on the right only (ie, extinction to double stroke past the window for
simultaneous stimulation). Extinction can occur in the visual, tactile, and acute stroke interventions;
auditory modalities. Clinicians should bear in mind that extinction to double thus, clinicians should be
simultaneous stimulation is not always present in 100% of trials. In many alert to new spatial bias in
patients with stroke risk
patients, a deficit of “Where” perceptual attention causes unawareness of some factors.
stimuli on the left side, and yet not 100% of stimuli are extinguished in the
presence of a right-sided stimulus: perhaps only 40%, 60%, or 80% of left-sided
stimuli are extinguished. Because extinction of the left-sided stimulus may be
present only some of the time, examiners need to do enough trials (at least six or
eight simultaneous stimulation trials) to capture errors; of six or eight trials, even
one or two errors in which only the ipsilesional side stimulus is reported raises
suspicion for spatial neglect.
Extinction to double simultaneous stimulation that is detected in two modalities
is strongly suggestive of spatial neglect. To test tactile extinction, the examiner
touches the patient on both hands, arms, knees, legs, or feet and asks where
the stimulus was felt. If a single stimulus can be felt on the side of the body
suspected to be contralesional, but the contralesional stimulus is not felt during
double stimulation of both sides of the body, extinction is present. If a patient
has extinction in two modalities (visual and tactile, for example), this helps
clarify that the problem is spatial neglect and not a sensory issue because, clearly,
a visual deficit should not, for example, cause errors in detecting a tactile
stimulus.
EXTINCTION OR SPATIAL NEGLECT? OR ANOTHER TERM? Clinicians will sometimes use

three or four terms to describe spatial neglect symptoms. They may separate
extinction from spatial neglect, and they may use other terms such as hemi-
inattention. Although this may be interesting when looking at laboratory-based
analysis, this author discourages this approach in clinical practice. With the goal
of increasing the clinical utility of spatial neglect diagnosis, this author and
colleagues defined spatial neglect as pathologically asymmetric behavior caused
by a brain lesion, resulting in functional disability.31 Thus, many symptoms can
all be called part of the spatial neglect syndrome. Patients who do not have a
visual field cut may yet collide with a door frame; thus, with extinction to double
simultaneous stimulation, they can meet criteria for spatial neglect because
it appears to be the basis of functional disability (a collision and safety risk)
(CASE 6-1). Here, the extinction is a feature of, or sign within, the spatial
neglect syndrome. The evidence of difficulty with safety while walking should,
additionally, be enough to trigger physical therapy evaluation for fall risk, as well
as gait and balance training.

“AIMING” SPATIAL NEGLECT: MOTOR-RELATED SYMPTOMS. Another reason why

clinicians can miss spatial neglect if they think of it as a higher-order visual
problem is that it can manifest with only maladaptive spatial movements (eg,
disinclination to move in one direction with the eyes, head, arms, or whole body
[TABLE 6-2]). Patients may have head and eye deviation and spontaneous rotation
rightward after a right brain lesion, as in CASE 6-2 (FIGURE 6-134). Even when lying
in bed, they may rotate, positioning their bodies crookedly, lying unevenly and
pushing their bodies farther to one side until one leg hangs off. These asymmetric
movements are well-established as a primary manifestation of spatial neglect17
and may actually be associated with a better response to spatial retraining during
rehabilitation.35 Maladaptive and spatially asymmetric movements may be limb-
specific. The arm opposite the side of a stroke may not be particularly weak;
however, it may not move well or may demonstrate poor persistence of
movement.36
Asymmetric gaze and movements (eg, in ambulation) are integral
components of Aiming spatial neglect as it is observed during functional
CASE 6-1 An 80-year-old woman who resided in an assisted living facility reported
having heartburn one morning. The symptoms were gone a few hours
later; however, she got out of bed and started moving around the facility,
going into the rooms of three other residents and insisting they were in
her space and needed to leave. The nurses could not redirect her; she
kept breaking away and going into other resident rooms. The geriatrician
on staff found her only mildly tachycardic, possibly dehydrated, and
unable to tell him the day of the week or date, although she knew the
month and year. She insisted she was in her room, although she was in the
cafeteria lounge. About an hour after her symptoms started, the
geriatrician diagnosed delirium, calling the patient’s behavior “impulsive,”
but no medical condition could be identified on screening laboratory
tests, ECG, and urine evaluation. Her past medical history was notable for
hypertension, high cholesterol, and a possible past episode of atrial
fibrillation.
Her family insisted on an assessment from a neurologist 2 days later.
The neurologist found her irritable and saying “I’m fine. I want to go
home.” Her gaze drifted to the right when not stimulated (right gaze
preference), although she easily looked leftward when the examiner
wiggled fingers on the left or told her to look leftward. She had no visual
field cut to single stimuli; however, she made errors about half the time
when tested with double simultaneous stimulation in the left and right
lower visual fields, responding “right.” She also sometimes responded
before the examiner showed a stimulus or when the examiner was not
actually showing her anything, reporting she saw a stimulus on the left.
The examiner gave her a pamphlet to read, and she started in the middle
of the page, read the right side of several sentences in the first
paragraph, then tossed the pamphlet aside, angrily saying “This is stupid.”
She had no weakness; however, when drift was tested, her left palm rose,
and she veered when walking. Sometimes she veered leftward, and she
1628 DECEMBER 2021

performance. As illustrated in CASE 6-2 and FIGURE 6-1, Aiming spatial neglect
can cause an abnormal, persistent ipsilesional turning tendency that affects
the eye, head, and body. The abnormally asymmetric posture caused by
Aiming spatial neglect may explain the greatly increased risk of falls in people
with spatial neglect, which is at least 50% higher and may be as much as 5
times higher than in survivors of stroke who do not have spatial neglect with
attendant increased risk of accidental injury.37,38 Aiming spatial neglect also
causes rightward bias in environmental movements; affected survivors of
stroke with right brain stroke and Aiming spatial neglect can have a right-
turning bias, as they move in the home, in the neighborhood, and even when
driving (CASE 6-2).
Identifying Aiming Spatial Neglect

Unfortunately, spatial neglect has been traditionally regarded as a visual
problem, and thus, no method of bedside screening has been established for
neurologists to use to reliably identify Aiming spatial neglect. The abnormalities
collided with the door frame as she left the examination room; however,
within the examination room and when trying to find a chair, she moved in
a tight, rightward circle, looking for the seat that was directly in front of
her as she entered: she finally found it by nearly tripping over it. The
neurologist ordered a brain MRI, which revealed a right parietal stroke;
the geriatrician was much surprised, saying “she had no symptoms, just
delirium.”
Spatial neglect symptoms can be misclassified or misattributed to COMMENT

problems with concentration or motivation. Losing orientation in space, in a
patient who does not have an obvious hemiparesis, can be mistaken for a
problem of continuous attention. A patient can have both problems;
spatial neglect is a strong risk factor for developing delirium after stroke,32
either because cognitive problems increase delirium vulnerability or
because right brain systems play a role in delirium development.33
Further, this patient not only failed to report a left-sided visual stimulus
when one was simultaneously present on the right side, she also
sometimes falsely reported a left-sided stimulus when none was there.
Higher visual processing that occurs after stimuli is processed in the
occipital lobes occurs in two parallel association cortex pathways in which
dysfunctions can lead to agnosias. The dorsal pathway extends to the
parietal lobe and processes location and motion and is therefore known as
the Where pathway. The ventral pathway extends to the temporal lobe and
processes shape, form, and color and is therefore known as the What
pathway. This case is consistent with Where spatial neglect, in which
distorted perceptual-attentional input lowers the resolution of sensory
perception and thus reduces the accuracy of simple stimulus detection.
Patients will make false-positive as well as false-negative (omission) errors.

that can be caused by Aiming spatial neglect after right brain stroke do occur
independently of perceptual-attentional Where spatial neglect; thus, survivors of
stroke with Aiming spatial neglect may have intact awareness and ability to
detect stimuli in both sides of space.
Aiming spatial neglect at the bedside can be identified when patients
have marked leaning, veering, or postural rotation to the ipsilesional side
(FIGURE 6-1), although contralesional leaning (“pushing”) can sometimes be
observed. The “hanging eyeglasses” sign shown in FIGURE 6-2 may be seen;
it is caused by hypometric leftward movement of the hand when placing the
eyeglasses on the head. Key components of Aiming spatial neglect are also
described in TABLE 6-2.
Visual extinction to double simultaneous stimulation may indicate the
presence of Where spatial neglect because of dysfunctional perceptual-
attentional spatial processing. However, paper-and-pencil tasks, such as
bisecting a line (CASE 6-2) or marking all the lines scattered on a piece of paper
(the Albert line cancellation task39), seem to require both Where and Aiming
spatial skills. Therefore, the clinician can use these paper-and-pencil tests to help
with screening anyone suspected of having spatial neglect.40
Screening for extinction to double simultaneous stimulation and for abnormal
performance on paper-and-pencil tests is not sufficient to evaluate Aiming
spatial neglect, however. Some survivors of stroke have only the body movement
and postural abnormalities that are characteristic of Aiming spatial neglect
(TABLE 6-2) without demonstrating any abnormalities on paper-and-pencil
screening.41 Because these spatial movement abnormalities are not assessed in
any of the available bedside tests such as the National Institutes of Health Stroke
TABLE 6-2 Key Components of Aiming Spatial Neglect
Symptom Abnormality (after right brain damage) Finding (after right brain damage)
Motor extinction Difficulty moving both sides of the body at the Patient raises only the right arm when asked to
same time, with the left body failing to move raise both arms; however, strength tested to
properly when the right body is activated confrontation is good in both arms
Directional hypokinesia Problems moving leftward with the eyes, head, Patient sits, stands, and moves with rightward
limbs, or axial body; not accounted for by rotation; veering while ambulating can cause
paralysis alone collisions
Hemispatial hypokinesia Smaller or weaker movements in left space as The patient's grip with either hand is weaker to
compared with right space the left of the body than it is with the hand
positioned in the right body space
Limb hypokinesia Smaller or weaker movements by the left hand, Similar to motor extinction, except that
arm, and even leg compared with the right spontaneous left arm movements are weak or
limbs; not accounted for by paralysis alone small even when that limb moves in isolation;
however, strength tested to confrontation is
good in both arms; patient may “forget” arm and
leave it in an unsafe position
Defective motor Stimulus-evoked responses in a leftward Patient cannot inhibit leftward glances or
response inhibition direction or with the left body; cannot be cannot inhibit grasp or reach (leftward or with
inhibited by goal-oriented, conscious intention left hand or arm) while walking, during transfers,
although the right body can be inhibited or during complex activities (eg, using power
equipment); can interfere with safety
1630 DECEMBER 2021

Scale or paper-and-pencil tests and are likely responsible for motor disability, fall
risk, and other limitations that affect function and freedom in spatial neglect, an
assessment is needed that examines movement performance. Thus, in any
survivor of stroke suspected of having spatial neglect, this author recommends
referral to an occupational or physical therapist who can screen for functional
performance errors with a standardized measure.
The Catherine Bergego Scale,42 which has been validated in many medical and
rehabilitation settings, is one measure used by those professionals that is strongly
recommended to detect spatial movement abnormalities that affect daily life
function and safety. The test captures asymmetric functional body movements
and predicts daily life disability related to spatial neglect.6 Because of the time
required to administer the scale and its ease in combining with a functional
assessment in therapy care, a therapist rather than a neurologist is most likely to
use this scale. If performed as a completely separate evaluation, the Catherine
Bergego Scale takes about 15 to 20 minutes. If it is combined with a clinically
standard therapy assessment of activities of daily living, the Catherine Bergego
Scale takes only about 5 minutes of documentation time in addition to the therapy
A 45-year-old man was brought to the emergency department by his CASE 6-2
employer because the employer noted that the patient suddenly “can’t
turn left.” His employer found that the patient, a food service delivery
driver, had made only four deliveries after a full day of driving and was
behaving strangely. The global positioning system (GPS) records in his
vehicle revealed he had been making deliveries by making exclusively
right turns. The patient showed how he operated the steering wheel using
only his right hand, and when asked why he was not using his left hand, he
said it “is lazy” and “won’t work right.”
On examination, he had head and eye deviation to the right; when the
examiner moved the patient’s head to the right, his eyes moved about
5 degrees conjugately leftward, supporting a cortical cause of his gaze
deviation. He had left pronator drift and reduced left grip strength;
however, during most of the examination, his left arm hung motionless, as
if it were plegic. When asked to bisect a long line drawn on a piece of
printer paper, he made a mark about 7.6 cm (3 in) to the right of the actual
line center. While he was sitting on the gurney in the emergency
department, he leaned to the right, and although when urged, he could sit
straight again, his posture quickly returned to an asymmetrical lean; it
looked like this postural bias could cause him to slip off the gurney. A
nurse found him on the floor about 1 hour later. When the team reviewed
the patient’s brain imaging, they found he had a right-sided putaminal
ischemic stroke with some extension into subcortical white matter.
Accurate line bisection cannot rule out spatial neglect, but a survivor of COMMENT
stroke who errs more than 1 cm (0.4 in) rightward in bisecting a horizontal
line longer than 22 cm (8.7 in) is highly likely to have spatial neglect.

KEY POINTS assessment. It also requires the

examiner to be reliability-trained
● Aiming spatial neglect
causes several different
at observing and scoring spatial
movement-related performance in patients while they
problems. Spatial neglect actually perform daily life tasks.
can cause an ipsilesional
turning tendency and
“WHERE” REPRESENTATIONAL
disinclination to move in the
direction opposite the brain FUNCTION IN SPATIAL NEGLECT.
lesion. This symptom is Spatial cognition entails an
disabling beyond the intermediate information
effects of hemiparesis or
processing stage between Where
awareness problems.
perceptual-attention and Aiming
FIGURE 6-1
● In-hospital fall risk can be Photo of a patient with a right brain stroke and left motor-intention in which
more than 5 times higher in spatial neglect who maintained an abnormal, explicit and implicit spatial
people with spatial neglect asymmetric posture. His rightward head and eye representations (ie, knowledge
than in those without it. turning (apparent rotation of his torso) caused
Further, active movements
in the form of imagery, maps,
severe neck and back pain.
that are posturally biased Image courtesy of Victor W. Mark, MD. Reprinted with
and internal descriptions) are
means that the best permission from Mark VW, Front Biosci.34 © 2003 The Author. required. These can be visual-
supervision and guarding by spatial, auditory-spatial,
nursing assistants and other
personnel may not be
and even spatial-somesthetic
effective. representations, and any of these may be impaired in spatial neglect. Although
disordered spatial representations may sound like a theoretical problem, this
● Line bisection is a simple issue has functional consequences. In the modern world, we need internal maps
spatial neglect screening
while we are working, completing our social activities, and even interacting with
test. Accurate line bisection
cannot rule out spatial groups and navigating crowded environments. The survivors of stroke who have
neglect, but more than 1 cm an isolated deficit of Where spatial neglect affecting representational function
(0.4 in) of rightward error in may have trouble drawing or interpreting maps or charts and may be perceived
bisecting a horizontal line as confused, intellectually impaired, or perseverative when the problem is a loss
longer than 22 cm (8.7 in) is
highly likely to indicate that of spatial knowledge.
a patient has spatial neglect. At the bedside, one sign of
representational spatial neglect is
● Many survivors of stroke right-sided bias affecting the way
benefit from continuing
rehabilitation, but most
we use a mental number line.43
receive no outpatient Mathematical operations rely on
rehabilitation. Referring our ability to spatially map
patients with spatial neglect numeric information in our
for spatial retraining, as
minds; the left side of these
endorsed by professional
organizations, helps them operations may be distorted
recover to greater when people have Where
independence and quality of representational spatial neglect.
life.
To test this ability, the examiner
can ask the patient to “tell me FIGURE 6-2
what number is halfway between Photo of a man with spatial neglect after right
brain stroke manifesting the hanging eyeglasses
11 and 55.” Giving two numbers
sign, which is evidence of asymmetric movement.
that require little analysis to The left temple of the eyeglasses rests on the side
calculate a midpoint (eg, 10 and of the head, above the ear, because the leftward
30) should be avoided. When movement of the hand is too small to seat the
eyeglasses on the ear on the left side.
administering this test to a
Image courtesy of Victor W. Mark, MD. Reprinted with
survivor of stroke whose permission from Mark VW, Front Biosci.34 © 2003 The
educational level and general Author.
1632 DECEMBER 2021

ability to perform intellectually demanding tasks are appropriate for this testing
of mental mathematics (eg, a college professor), the examiner may be surprised
by a “rightward” biased response (eg, 50).
Summary of Spatial Neglect Subtypes

Although the daily life performance errors made by people with spatial neglect
are often interpreted as being exclusively related to perceptual or attentional
problems, many functional impairments and limitations on daily life activities
and participation also result from Where, representational problems, or Aiming
spatial neglect. For example, because people with directional hypokinesia have
difficulty initiating leftward movement, they may find themselves unable to
dress on the left or may steer a wheelchair rightward just as the patient in
44-46
CASE 6-2 steered his truck with exclusively right turns. TABLE 6-3 summarizes
some of the potential relationships between spatial neglect subtypes and
observed daily life limitations.
Trends
This section describes treatment that is now established to be effective in
reducing daily life disability for people with spatial neglect. These protocols have
been demonstrated to be effective in stroke; further research in spatial neglect
associated with other disorders is needed.
REHABILITATION OF SPATIAL NEGLECT. Although the Centers for Disease Control and
Prevention reported that 30% to 35% of survivors of stroke receive rehabilitation
after leaving acute hospital care in many states,47 the National Institute of
Neurological Disorders and Stroke estimates that about twice as many would
benefit from rehabilitation.48 Neurologists frequently find that survivors of stroke
Spatial Neglect Subtypes and Potential Associated Deficitsa TABLE 6-3
Key behaviors demonstrating Frequently observed functional

Spatial neglect subtype spatial neglect impairmentsb
Where, perceptual-attentional Extinction to double simultaneous Accidents due to failure to respond to

awareness45 stimulation, decreased vigilance in left left-sided events; failure to respond in social
body space interaction; difficulty in eating entire meal
Where, representational Visual imagery incomplete on left, neglect Poor environmental navigation; illusions,
imagery46 dyslexia, right bias on mental number line difficulty recognizing objects especially
under unfamiliar conditions; difficulty
reading or completing mathematical
operations accurately for work, financial
activities
Aiming, motor intention Abnormalities listed in TABLE 6-2 Postural imbalance, veering while ambulating
while walking or in a wheelchair, augmented
hemiparesis (weakness out of proportion to
motor dysfunction)
a
Modified with permission from Barrett AM, et al, Handb Clin Neurol.44 © 2019 Elsevier Ltd.
b
Proposed, further systematic research demonstration is needed.

who received meticulous attention to highest-quality standards of care in the first

hours and days after their stroke received little or no rehabilitation once they left
acute settings. This treatment gap needs to be closed for all patients with spatial
neglect, and, in particular, for survivors of stroke with the spatial neglect syndrome.
At least 10% of people who have spatial neglect acutely continue to have chronic
symptoms.49 As discussed earlier, ipsilesional bias can be observed in people with
spatial neglect. It is not uncommon to observe that, years after stroke, a patient may
have trouble eating from the left side of a plate (CASE 6-3). This is not only
interesting to observe, it is pragmatically important. The Intercollegiate Stroke
Working Party50 in the United Kingdom warns that people with stroke and spatial
neglect should “be monitored to ensure that they do not eat too little through
missing food on one side of the plate.” Patients with spatial neglect after right brain
damage may fail to dress the left side of their body or may favor right space when
navigating a wheelchair. This limits their independence, but it also has a devastating
effect on their dignity.
The American Heart Association19 and American Occupational Therapy
Association,51 as well as stroke organizations worldwide, recommend spatial
neglect treatment as part of quality stroke care. Neurologists cannot usually
administer spatial neglect treatment in their offices; however, the neurologists’
efforts are very important in assembling and directing a treatment team to
administer rehabilitation. Evidence on which professional guidelines and
CASE 6-3 A 62-year-old man presented to a neurologist after his wife noticed that
he ate only from the right side of his plate and was falling frequently. He
had a right middle cerebral artery ischemic stroke 1 year before.
On examination, he had a mild left hemiparesis. Screening for
extinction in the visual and tactile modalities and errors on line bisection
and cancellation tasks revealed chronic spatial neglect. The patient had
received acute stroke care at a comprehensive stroke center and had
sought care from tertiary-care specialists at the local academic medical
center for his cardiology and internal medicine needs. He had also
received nursing and some kind of therapy (unspecified in his records;
possibly physical therapy) through home health for the first few weeks
after the stroke to address left-sided weakness; however, since the
home health therapy ended, the patient and his wife reported that he
received no specific outpatient therapy and no therapy targeted to
improve spatial neglect.
COMMENT The classic teaching to clinicians was that spatial neglect invariably
resolves spontaneously. However, 10% or more of survivors of stroke have
chronic spatial neglect years after a stroke.49
The Centers for Disease Control and Prevention reports that more than
60% of survivors of stroke receive absolutely no outpatient rehabilitation.47
Referring patients with spatial neglect for spatial retraining, as endorsed by
professional organizations, helps them recover to greater independence
and quality of life.19
1634 DECEMBER 2021

recommendations are based is not yet available for other neurologic disorders
associated with spatial neglect. Further research in this area is needed.
PRACTICE-BASED IMPROVEMENT. Guideline-based early rehabilitation protocols for

spatial neglect are available. Keeping this information for reference is an area for
practice-based improvement.
Practice-based improvement for spatial neglect also requires the neurologist to
digest information about personalized care (spatial neglect subtypes, noted earlier)
because spatial neglect is undiagnosed in patients who receive no formal assessment
or who have Aiming spatial neglect symptoms. However, a second reason, beyond
the need to diagnose the presence of spatial neglect, is that personalized care is
important. Just as different kinds of cardiac disease (eg, arrhythmia, heart failure,
ischemia) should be prioritized and addressed differently in a treatment plan,
patients with Aiming spatial neglect symptoms35 may be especially likely to improve
after early spatial retraining (see TABLE 6-452-57 for treatment options).
Aiming spatial neglect may predict an excellent response to treatment as
compared with Where spatial neglect.58 The brain mechanisms explaining this
Professional Guidelines for Spatial Neglect Treatmenta TABLE 6-4
Targeted treatment to
Professional organization Spatial neglect treatment improve Aiming spatial How might this treatment work
endorsement for any patient neglect and arousal/activation to improve outcomes?b
American Heart Prism adaptation therapy17 Prism adaptation therapy May reduce Aiming spatial
Association (AHA),19 neglect, making leftward and
American Occupational left-body movements more
Therapy Association,51 adaptive
Intercollegiate Stroke
Working Party50
US Department of Compensatory, self- Not applicable Not a treatment, rather a

Veterans Affairs,52 mediated cuing strategies53 management technique that
Intercollegiate Stroke may reduce the possibilities for
Working Party error
AHA, Intercollegiate Visual scanning training54 Not applicable Neuropsychological

Stroke Working Party mechanisms uncertain
AHA, Intercollegiate Limb activation55,56 Limb activation Proposed to stimulate body-

Stroke Working Party based spatial systems, alter
interhemispheric interaction;
may also improve limb
hypokinesia and Aiming spatial
neglect
Canadian Partnership for Medications Medications (dopaminergic, May improve attention,

Stroke Recovery57 (acetylcholinergic, noradrenergic) alertness, arousal, generative
nicotine, noradrenergic) behavior, persistence, memory;
paradoxical worsening can
occur with dopaminergic
treatment
a
Modified with permission from Barrett AM, et al, Handb Clin Neurol.44 © 2019 Elsevier Ltd.
b
Proposed, further research is needed.

observation are under research; however, this may be related to frontal lobe
disconnection in spatial function. Different neuroanatomic regions might play
different roles in the networks supporting Where versus Aiming spatial cognitive
processing, with posterior, temporal-parietal cortical sensory association networks
more critical in supporting information input (Where spatial neglect) or storage
(Where, representational spatial neglect59) whereas anterior or motor-related
subcortical networks are more critical to output cognition (Aiming spatial neglect17).
Treatment
Because it is supported by both the American Heart Association and American
Occupational Therapy Association and because it is a low-risk, 10-day protocol
that therapists can learn to use in a few days, prism adaptation therapy is
appropriate as a first-line treatment. This author recommends that neurologists
refer survivors of stroke with spatial neglect, especially if Aiming spatial neglect
is suspected, for this treatment protocol. FIGURE 6-360 illustrates improvement in
daily life function after prism adaptation therapy, in multiple studies; although
the impact of treatment varied in different studies, better-designed studies
showed stronger benefit, supporting the value of this treatment approach.
During prism adaptation therapy for left-sided spatial neglect,61 patients wear
left-based, yoked optical prisms, which shift what they see rightward. They then
make multiple goal-directed hand movements for a prescribed session of about
20 to 30 minutes. Although in randomized clinical trials of this approach some
parameters of the treatment varied, in one standard regimen, patients wore 20-
diopter wedge prisms and completed 10 sessions over 14 days.58 Patients wear
prisms only during treatment sessions; at other times, they may engage as usual
in other activities or rehabilitation.
FINDING A TREATMENT TEAM. A neurologist may be tempted to delegate all of the

tasks of evaluation and treatment for rehabilitation to the therapist with whom
FIGURE 6-3
Evidence of prism adaptation treatment effects on daily living skills: reading/writing, activities
of daily living (ADL) direct tests, ADL questionnaires, and environmental navigation tests.
Sig. = significant; non-sig. = non-significant.
Reprinted with permission from Champod AS, et al, Neuropsychol Rehabil.60 © 2016 Taylor & Francis Ltd.
1636 DECEMBER 2021

care is being shared. However, as evidence-based protocols of treatment emerge, KEY POINT
it is very helpful for a neurologist to share the responsibility with the therapy
● Ten percent or more of
clinicians to ensure that patients receive quality care. When neurologists work survivors of stroke have
with a partner organization to whom they send stroke therapy referrals, it is very chronic spatial neglect years
helpful to meet with this partner, project the need for quality standard care, later.
estimate the potential volume of referrals, and describe the benefit in improved
outcomes, providing information about how therapists may need to be trained or
what equipment may be needed. In the experience of this author, many
therapists or therapy business administrators have busy day-to-day experiences
that have prevented them from researching new treatment options. However,
they are often willing to consider how their organization can offer a new
treatment protocol, which can distinguish their therapists as experts, drive
referrals, and help engage their staff and enhance staff retention.
DIRECTING SPATIAL NEGLECT TREATMENT PROTOCOLS. In the past, allied health

professionals received little support from neurologists about how to plan or
execute rehabilitation care. Fortunately, most therapy clinicians are very
resourceful and can make treatment decisions independently. However, focus
group studies indicate, consistent with this author’s personal experience, that
evidence-based treatments recommended by professional associations are not
being selected by therapists in this kind of independent consultation
partnership.62 Therapists may have learned about spatial neglect during training
and may feel more comfortable with continuing to use other treatment
approaches (eg, self-reminders to “look left,” or prism exposure, in which
patients wear prisms without making visually guided movements).
To be successful in leading a spatial neglect treatment team, the neurologist
should take a collaborative, decisive leadership role. Unlike the isolated practitioner
of the past, the modern neurologist “leads and facilitates clinical teams, builds tools
to implement new therapies, and communicates the vision and purpose of team-
based care.”63 Because most neurologists do not directly employ or supervise
speech-language pathologists or occupational or physical therapists, this means that
the neurologist should use interpersonal leadership skills (persuasion and influence)
to motivate and engage the treatment team and help the team examine and
continuously improve performance. In a 2018 article, this author and colleagues in
the American Academy of Neurology Transforming Leaders Program63 described
this vision for the 21st century: neurologist-led team-care pathways are “essential to
achieving the triple aim … improving functional outcomes, cost-effectiveness, and
the patient experience. The care pathway from diagnosis to treatment for spatial
neglect, using prism adaptation, traverses this new territory...”
UNAWARENESS OF DEFICIT (ANOSOGNOSIA) AFTER RIGHT BRAIN STROKE

Anosognosia means, literally, “without knowledge of disease.” People with
neurologic disorders can demonstrate reduced awareness, or complete
disavowal, of disabling consequences of brain dysfunction; notably, after right
brain stroke, patients can appear unaware of left hemiparesis.64,65
Clinical Presentation
Anosognosia for hemiparesis has long been identified as a sign of right brain
stroke,66 especially when it is moderate to severe.67 However, people with
anosognosia after right brain stroke can also be unaware of visual and other

sensory disturbance67 and other problems such as memory and cognitive deficits
and gait disorder.18
Unawareness of deficit is a major barrier to receiving health care, although
formal studies of this relationship are not available. Numerous anecdotal reports
suggest that unawareness of deficits after right brain stroke prevents patients
from presenting promptly for stroke evaluation. Many patients continue to drive
under unsafe circumstances after having a stroke, unaware of their signs and
symptoms. For example, a patient may have a stroke caused by the effect of
recreational stimulant use on preexisting hypertension and cerebrovascular
disease, lose control of the car while driving, and have an accident. Anosognosia
after right brain stroke also interferes with reporting other medical symptoms
that require immediate attention. In one report, a patient who was previously
able to report angina reliably lost awareness of this left-body symptom after
a stroke.68
The inability to recognize functional limitations poses a significant safety risk,
is associated with falls,69 and is known to be a major barrier to effective
rehabilitation.70 Anosognosia can take several forms, with different degrees of
disavowal of the neurologic deficit (TABLE 6-571). It can be associated with a loss
of the feeling of ownership of an impaired body part (asomatognosia) or a
distorted experience of an impaired body part (somatoparaphrenia) and, at the
far end of the continuum, a dislike or hatred of a dysfunctional body part
(misoplegia).72 Although misoplegia is uncommon, it can cause dramatic
behavioral problems, such as patients throwing themselves from their beds “in
order to get rid of that awful leg.” Although classic studies support an association
of right brain dysfunction with anosognosia for hemiparesis,65 awareness
networks for motor and cognitive function are complex and still being
investigated.73
TABLE 6-5 Different Forms of Anosognosia That Can Manifest After Right Brain Strokea
Term Anosognosia type
Anosodiaphoria Lack of emotional concern for deficits that are verbally acknowledged
Anosognosia with causal attribution abnormality Acknowledgment of the deficit without linking the problem to a
neurologic issue (eg, a patient saying, “I don’t feel like moving my left arm
right now.”); inconsistent verbal acknowledgment (patient reports that
others believe the deficit is present)
Anosognosia with implicit awareness Conscious disavowal of deficits that are acknowledged through behavior
(eg, patient claims the ability to walk but never actually tries to get out
of bed)
Anosognosia with modality specificity Acknowledgment of one deficit but not others (eg, patient is aware of a
visual field cut but not aware of hemiplegia)
Anosognosia without implicit awareness Combined explicit and implicit disavowal of deficits (both behavioral and
verbal reports) without acknowledgment of deficits
a
Data from Ofrei MD, et al.71
1638 DECEMBER 2021

How to Assess for Anosognosia KEY POINT
Formal assessment of awareness of deficit is very important because of its
● The degree of
potential impact on the outcomes of survivors of stroke and their caregivers.74 unawareness of deficit can
It is also easy to miss anosognosia for hemiparesis when patients have an be varied; patients with
amotivational state, are saying little, or have depression or decreased anosognosia may “know
engagement. When a survivor of stroke is aware of other symptoms, the what to say,” about their
deficits and yet they may not
neurologist may incorrectly assume that the patient is aware of hemiparesis.
believe they are disabled.
Thus, this author recommends that neurologists always assess awareness of
hemiparesis as part of acute care of stroke or right brain injury. People with right
brain stroke and anosognosia for hemiparesis experience the same range of
emotions as control subjects.75 In many of these people, awareness of the
disabling consequences of their stroke and hemiparesis may be implicit
(unconscious). This means they may not be able to articulate the awareness or
their distress.76 Thus, they may even be at higher risk of depression than other
patients with right brain stroke. It also means that we should not assume
survivors of stroke are aware of deficits just because they have dysthymia
or depression.
Formal screening for anosognosia for hemiparesis is described in CASE 6-4 and
can be completed in just a few seconds. Although with this quick formal
screening it is not possible to identify anosognosia that causes relatively
small-magnitude overestimation of self-performance, large-magnitude
inconsistencies between self-rating and performance are regularly identified
by using this method.
Some patients “know what to say” when asked about their deficits after
stroke; however, they do not seem concerned about this information
(anosodiaphoria) (TABLE 6-5)71; this represents a form of anosognosia. They may
report, for example, “Everyone tells me that my arm is weak.”
It is very helpful to communicate with other clinicians (nurses, therapists,
social workers) and with caregivers about the anosognosia assessment because
many people confuse this disorder with psychological denial or think that it is
protective from the emotional impact of having a brain disorder. The vertical line
rating is a convenient way of introducing the message that this problem is a
reality distortion caused by the brain injury. Neurologists can, for example, show
the vertical line as in CASE 6-4 and communicate that the patient actually
experiences left arm strength as being normal. Researchers specifically
examining whether anosognosia protects patients from depression found no
evidence that it does.78 In the past, when members of the care team assumed
that anosognosia was protective to the patient, efforts to provide cognitive
rehabilitation were reduced, and this would be expected to increase disability.
Trends
This section reviews the need for rehabilitation of anosognosia after right brain
stroke and approaches to this rehabilitation.
REHABILITATION OF ANOSOGNOSIA AFTER RIGHT BRAIN STROKE. It is, first, extremely

important for the neurologist to understand that studies very clearly
demonstrate that patients with right brain disorders and anosognosia still
benefit from intensive multidisciplinary rehabilitation, such as inpatient
rehabilitation hospitalization. Second, specific approaches have been
developed to improve anosognosia in stroke and traumatic brain injury. Even

CASE 6-4 A 27-year-old man was seen in neurologic consultation on a brain injury
unit at a rehabilitation hospital after admission subsequent to a car
accident that had occurred while he was intoxicated with stimulants and
cocaine. He reportedly experienced a “hemorrhagic brain injury,” a
pelvic fracture, and multiple other injuries. Medical record review
revealed elevated blood pressure since admission (systolic blood
pressure approximately 150 mm Hg to 170 mm Hg).
On examination, his memory was normal for orientation and three-
object recall and calculations were intact. He demonstrated
psychomotor slowing; however, all of his reporting about his history and
prior work experience was consistent with the chart and with normal
reasoning ability. His apparent mood was euthymic. Spontaneously, he
appeared to have left hemiparesis affecting his face, arm, and leg, with
the greatest weakness in his arm and hand. Effort was decreased on
confrontation strength testing; the examiner had to reposition the
patient’s left arm several times when testing pronator drift because,
although he was strong enough to elevate his hand, he kept dropping it, as
if tired. At the end of the interview, the examiner drew a vertical line on a
piece of paper, wrote “normal strength” at the top of the line and
“cannot move” at the bottom of the line, and told the patient “I want you
to rate the strength you showed on the testing just now for the left side of
your body and your left arm. You might mark here [gesturing to the top of
line] if your strength is normal; you might mark here [gesturing to the
bottom of line] if you cannot move your left body at all. Or, you might
mark your strength somewhere in between [gesturing to show the whole
line].” The patient took the pen and, without hesitation, made a mark at
the very top of the vertical line. The examiner asked, “Does this mean you
don’t feel weak on the left side?” The patient looked at the examiner
mildly and said, “Everyone says I am weak, but I don’t feel weak at all.”
The examiner was subsequently able to view the patient’s brain image
from the acute care hospital; it revealed a right putaminal hemorrhage.
COMMENT A classic teaching about anosognosia is that only patients with global
cognitive impairment have unawareness of deficit.77 However, many
patients, like the one described in this case, have relatively normal memory
and yet are unaware of their neurological deficits. Testing for unawareness
of deficit (anosognosia) with a visual analog scale (the line the patient
marked) can be very helpful and useful to show to staff or caregivers so
that the neurologist can discuss anosognosia as a neurologic deficit
independent of motivation, psychological denial, or willingness to recover.
1640 DECEMBER 2021

though randomized controlled trials of these treatments to improve
anosognosia for hemiparesis after stroke are not yet available, several
treatment approaches have been associated with improved rehabilitation
outcome benefits in open-label studies, including self-awareness training,79
spatial neglect interventions such as vestibular stimulation,80 and self-observation
via video feedback.81 As described earlier, many therapy clinicians delivering
stand-alone care may not implement specific anosognosia treatment because
they are familiar with using techniques based on expert wisdom, such as
reminders, caregiver counseling, or management for safety. However, for
best-quality care, neurologists may want to ensure that their patients receive
specific treatment for anosognosia, which may often require an interprofessional
program that administers particular behavioral protocols. This is yet another
justification for considering inpatient rehabilitation if a survivor of stroke is
otherwise eligible.
Such a therapy team includes neuropsychology, speech-language pathology,
and occupational and physical therapy, and clinicians may have certification as
“brain injury specialists.” Frequently, clinicians cross-apply approaches to
remediate awareness, approaches that were developed in traumatic brain injury
settings, to survivors of stroke or people with brain tumors or other focal brain
disorders who are enrolled in therapy.
CONCLUSION
In this article, two major cognitive syndromes resulting from right brain injury,
spatial neglect and anosognosia, were reviewed. As stroke centers begin to
evaluate cognitive assessment with standardized measures during inpatient
stroke care, it is likely that more and more people with these disorders after
stroke will be diagnosed and that neurologists will play a greater role in leading a
treatment team to address these important invisible disabilities. Unfortunately,
not much evidence is available at present to guide assessment and treatment of
spatial neglect due to other focal brain disorders, and this is an appropriate topic
for future research.
The diagnosis and treatment of spatial neglect and the feasibility and utility of
using prism adaptation treatment as a first-line therapy with a rehabilitation
team were also reviewed in this article. Although randomized controlled trials
and professional guideline recommendations strongly support specific
identification and treatment of poststroke spatial neglect, neurologists can help
this move forward.
For unawareness of deficit, neurologists can play a vital role in counseling
caregivers and other clinicians about the crucial distinction between anosognosia
and psychological denial and steering the patient to an interdisciplinary setting
where specific protocols of care for anosognosia are used. Both stroke and
traumatic brain injury are associated with anosognosia to left hemiparesis. In a
broader sense, this author is concerned that anosognosia presents a public health
barrier to allocation of resources to people with right brain dysfunction. People
who have experienced a right brain injury may be unable to report their
significant disability, leading to falsely inflated reports of good quality of life or
well-being. It is also concerning how anosognosia affects access to health care and
rehabilitation. In recent years, patients with unawareness of deficit have been
systematically limited from admission to inpatient rehabilitation or other

intensive treatments. However, if patient-reported outcomes become the main

path of entry to rehabilitation care, it is up to the neurology community to assure
access to inpatient rehabilitation and other forms of intensive therapy for our
patients who cannot self-advocate.82
USEFUL PRESENTATION
TEDx TALKS: A VISION OF BRAIN INJURY REHABILITATION
Dr Barrett discusses how we move through the
world. Her talk identifies new methods for brain
injury rehabilitation.
youtube.com/watch?v=QJ-OBXTA5AE
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REVIEW ARTICLE

Upper Limb Apraxia
C O N T I N UU M A UD I O By Kenneth M. Heilman, MD, FAAN
ONLINE
ABSTRACT
PURPOSE OF REVIEW:Limb apraxia is one of the most common and most
disabling disorders caused by brain damage. However, apraxia is one of the
least recognized disorders associated with cerebral disease. This article
discusses the signs and symptoms of, means of testing for, the
pathophysiology of, and possible management of upper limb apraxia.
RECENT FINDINGS:Upper limb apraxia has four major forms: ideomotor,

limb-kinetic, conceptual, and ideational. Although recent findings are
included in this article, a full understanding of these disorders, including
the means of testing, their possible pathophysiology, and the diseases that
may cause these disorders, requires that some older literature is also
discussed.
SUMMARY: This article guides clinicians in testing for and diagnosing the
different forms of upper limb apraxia, identifying the underlying diseases
that may cause apraxia, managing the different forms of the disorder, and
possible forms of rehabilitation.
INTRODUCTION
A
ll animals must interact with their environment. Humans have an
exceptional ability to make physical changes in their own bodies and
CITE AS:
CONTINUUM (MINNEAP MINN) physically interact with other living creatures and their environment.
2021;27(6, BEHAVIORAL NEUROLOGY The human corticospinal (pyramidal) motor system, together
with the motor units, can perform an almost infinite number of
movements; however, to successfully perform interactions, the pyramidal motor
Dr Kenneth M. Heilman, 1601 NW neurons must be guided by instructions or programs. Learned or copied-imitated
107 Terr, Gainesville, FL 32606, skilled movement programs provide the motor cortex with information about how
heilman@neurology.ufl.edu.
to contract the muscles that move the limbs. Diseases of the brain may injure
RELATIONSHIP DISCLOSURE: these programs, and a loss of these programs produces the disorder called apraxia.
Dr Heilman has received Limb apraxia is one of the most common and most disabling disorders caused by
publishing royalties from
Appleton-Century-Crofts, brain damage and can be caused by a stroke, degenerative dementing diseases, and
Cambridge University, Elsevier, parkinsonian disorders.
Guilford Press, Informa UK
As with many other neurobehavioral disorders, the diagnosis of apraxia is one
Limited, Oxford University Press,
and Xlibris. of both exclusion and inclusion. To diagnose apraxia, the inability to perform
skilled movements should not be caused by sensory loss or by elemental motor
UNLABELED USE OF
disorders, such as weakness, rigidity, abnormal postures (eg, dystonia), or
USE DISCLOSURE: abnormal movements (eg, tremor, chorea, ballismus, athetosis, myoclonus, or
Dr Heilman reports no disclosure. seizures). Severe impairments in cognition, attention, and intention-action (eg,
© 2021 American Academy abulia-akinesia) can cause a reduction in a person’s ability to perform skilled acts.
of Neurology. However, patients with these impairments may also have apraxia, and clinicians
1602 DECEMBER 2021

should be certain that these other impairments do not fully account for a patient's
inability to perform skilled acts.
The four major forms of upper limb apraxia are ideomotor, limb-kinetic,
conceptual, and ideational; all four may cause major disability.1 The behavioral
deficits associated with each of these forms are listed in TABLE 5-1; however, the
forms of limb apraxia that are most common and most often associated with
disability are limb-kinetic and ideomotor. This article discusses the clinical
presentation of and means of testing for each of these apraxic disorders as well as
the diseases that may cause these disorders, the possible brain mechanisms that
may account for them, and possible treatments.
TESTING FOR UPPER LIMB APRAXIA

It is rare that patients report to their health care provider any form of upper
limb apraxia, even patients who are terribly disabled by one of these disorders.
When questioned, some patients are unaware of their disorder (a form of
anosognosia2) and some patients who are aware of their performance deficits
appear to be unconcerned about their disability (a form of anosodiaphoria).
Since it is rare for patients with any form of limb apraxia to present with
this disorder as their chief complaint, this failure to report a disability may be
one of the reasons that few clinicians test patients for apraxia, but assessment
is nevertheless important. Therefore, when assessing for apraxia, the clinician
cannot rely on history but must test the patient. Based on the outcome of this
testing, specific forms of apraxia can be diagnosed. The following sections
discuss the most important tests for the different forms of apraxia. When
possible, the clinician should test both upper limbs; however, the order of
testing of the limbs does not appear to be important.
Coin Rotation
In the coin rotation test, the patient is given a nickel and asked to rotate the nickel
between the thumb, index finger, and middle finger of each hand as rapidly as
possible for twenty 180-degree revolutions.3 Patients with limb-kinetic apraxia
Behavioral Deficits in Forms of Upper Limb Apraxia TABLE 5-1
Ideomotor Limb-kinetic Conceptual Ideational

Behavioral deficit apraxia apraxia apraxia apraxia
Disability Yes Yes Yes Yes
Incorrect sequencing of a series of movements May be present No May be present Yes
Hand-arm postural errors Yes No No No
Joint movement errors Yes Yes No No
Target location error Yes No No No
Loss of finger deftness and ability to make May be present Yes No No

independent but coordinated finger movements
Loss of mechanical knowledge No No Yes No

UPPER LIMB APRAXIA
may not be able to rotate the coin, may frequently drop the coin, or rotate the
coin very slowly.
Pantomime to Command
When assessing pantomimes to command, the clinician should ask the
patient to pantomime the use of tools or implements (transitive gestures),
for example, “Show me how you would use a pair of scissors to cut a piece of
paper in half.” Some clinicians test intransitive gestures that are nonverbal
gestural communications, such as waving goodbye. However, patients with
ideomotor apraxia are more likely to make errors when attempting to perform
transitive pantomimes than intransitive gestures.
When asked to pantomime the use of a tool, patients (and even healthy
people) often first use their body part as the tool. If a patient uses a body
part as the tool, their performance should be corrected (eg, “Do not use
your fingers like they are the blades of this scissors; please make believe
you are really holding a pair of scissors and show me how you cut a piece
of paper in half”). Testing patients for their ability to pantomime transitive
actions to command is one of the most sensitive tests for ideomotor
apraxia.
Pantomime Imitation
Whereas having patients pantomime transitive acts to command is often the
most sensitive test for detecting certain forms of apraxia, many clinicians
use imitation as their primary means of testing. The examiner would request
that the patient make the same arm, hand, and finger postures and movements
as the examiner. The examiner might then make pantomimes of real actions,
such as transitive movements (an action in which physical objects, such as a
hammer or screwdriver, are used) or intransitive or communicative
movements such as holding the thumb up to express agreement. Tests of
intransitive movements be helpful with some patients with aphasia who have
verbal comprehension disorders.
Conduction apraxia is a rare form of apraxia in which patients are more
impaired in imitating gestures than in performing to command. Testing
pantomime imitation of meaningless gestures may also be useful in determining
whether patients have an impairment of their visuospatial-kinesthetic movement
working memory.
Pantomime in Response to Viewing Tools

Pantomime in response to viewing tools is when the examiner shows the patient
actual or pictures of handheld tools or pictures of them, such as a hammer or
screwdriver, and asks the patient to show how the tool is used. This test might be
especially useful when a patient has a language comprehension deficit and it is
unclear whether the failure to correctly gesture to command results from a
language disorder or an apraxic disorder.
Pantomime in Response to Seeing the Objects Upon Which Tools Work

In this test, the examiner shows the patient objects that receive the action of
specific tools (eg, a nail partially driven into a block of wood). The patient
is asked to show how they would use a tool to complete the task. This test
may be helpful in diagnosing certain forms of apraxia because seeing a tool
1604 DECEMBER 2021

before pantomiming how the tool should be used may provide cues as how to KEY POINTS
position the hand; therefore, this type of object viewing test may be sensitive for
● Limb apraxia is one of the
the diagnosis of apraxia. most common and most
disabling disorders caused
Using Tools by brain damage and can be
A series of tools are presented to the patient, and the patient is asked to caused by a stroke,
degenerative dementing
demonstrate how they would use each tool. This test may be more sensitive if the
diseases, and parkinsonian
objects upon which the tools work are not present. disorders.
Discriminating Between Correct and Incorrect Transitive Actions ● To diagnose apraxia, the
Pantomimed by the Examiner inability to perform skilled
movements should not be
In this test, the examiner tells the patient the name of the tool that will be caused by sensory loss or by
pantomimed. Some of the pantomimes the examiner performs should be correct, elemental motor disorders,
and some should be incorrect. After the examiner correctly or incorrectly such as weakness, rigidity,
pantomimes the use of the tool, the patient is asked to tell the examiner whether abnormal postures (eg,
dystonia), or abnormal
the action was correct or incorrect. movements (eg, tremor,
chorea, ballismus, athetosis,
Comprehending Pantomimes and Gestures myoclonus, or seizures).
In this test, the examiner makes a series of pantomimes of transitive movements.
● The four major forms of
After the examiner completes each pantomime, the examiner asks, “What tool
upper limb apraxia are
am I using?” ideomotor, limb-kinetic,
conceptual, and ideational,
Serial Set of Actions and all four may cause major
disability.
In this test, the patient is provided with the materials to complete a multistep
task and asked to complete the task. For example, they may be provided
with bread, mustard, ham, cheese, and a knife and prompted, “Show me
how you would make a sandwich.” This test assesses patients for ideational
apraxia.
Action-Tool Associations
The examiner displays an array of five or more tools on a table in front of the
patient. The examiner then pantomimes a transitive action that is normally
associated with one of these tools, (eg, pounding). After each pantomime, the
examiner asks the patient to point to the tool associated with the action.
Tool-Object Associations
The examiner displays an array of objects on which tools work (eg, nail, screw,
bolt) and an array of tools. After each of the objects is shown to the patient, the
examiner asks the patient to point to the best tool to perform the correct action
on this object. Poor performance on this task suggests the presence of
conceptual apraxia.
Mechanical Knowledge
This test is performed in association with the tool-object association test and
with a similar array of objects. However, in this test, the correct tool for each
trial is removed from the array. The patient is asked to select the best alternative
tool that could accomplish the same goal. For example, when shown a partially
driven nail, tools such as a wrench, screwdriver, hand drill, and hacksaw are
shown to the patient and the patient is asked, “What would be the best
alternative tool to complete this task?”

UPPER LIMB APRAXIA
TYPES OF APRAXIA
The term apraxia is often used for any type of motor disorder that clinicians
have trouble classifying. Some movement action disorders are specific for one
type of activity, such as apraxic agraphia, dressing apraxia, and constructional
apraxia, and are tested for by having patients attempt to perform these specific
activities. These special forms of apraxia, however, are beyond the scope of
this article.
Although the term apraxia was initially used by Steinthal4 in 1881, it was
Liepmann5 who described the three major forms of upper limb apraxia
(limb-kinetic, ideomotor, and ideational) in 1920. The fourth major form of
apraxia, conceptual apraxia, was described several decades after Liepmann’s
important articles were published. The following sections describe the clinical
and pathophysiologic aspects of the four most common and most disabling forms
of upper limb apraxia: ideomotor, limb-kinetic, conceptual, and ideational.
Ideomotor Apraxia
Ideomotor apraxia is the loss of the ability to perform skilled movements with a
limb when needed to perform an action or to follow a verbal command.
CLINICAL PRESENTATION. When asked to pantomime or imitate a movement,

patients with ideomotor apraxia make several types of spatial movement errors,
but they may also make temporal errors.6,7 Most often, patients with ideomotor
apraxia have the greatest difficulty when attempting to pantomime the use of a
tool, which is a transitive movement.8 Often some improvement is seen with
imitation, but the movements made with imitation often remain incorrect.
Further improvement can be seen when using actual objects, such as tools. This is
because many tools limit the positions that can be used to hold them and the
actions that can be made when using them. However, even when the actual tools
are used, errors can often be seen.6 Therefore, testing for ideomotor apraxia
CASE 5-1 A 67-year-old man noticed that his recent memory was getting worse. He
was also having trouble finding words. When he presented to the clinic
for testing, he performed poorly on naming tests and memory tests.
When the examiner tested him for apraxia by asking him to pantomime
using scissors to cut a paper in half, he used his fingers as if they were the
blades. Since even healthy people often do this, he was asked not to do
this, but he continued to use his fingers as blades. When asked to
pantomime pounding a nail into a board that was on the table, he again
performed abnormally. He flexed and extended his arm at his elbow but
did not move his wrist. His laboratory studies were unrevealing, and brain
imaging revealed atrophy of the hippocampus and some parietal atrophy.
COMMENT This patient was diagnosed as most likely having Alzheimer disease.
Patients with Alzheimer disease often have ideomotor apraxia, but most
screening instruments (such as the Mini-Mental State Examination [MMSE]
and the Montreal Cognitive Assessment [MoCA]) do not test for apraxia.
1606 DECEMBER 2021

includes having patients pantomime transitive actions to verbal command, KEY POINTS
imitate actions, and use actual tools.
● Testing for ideomotor
Goodglass and Kaplan8 noted then that, when asked to use a tool, many apraxia includes having
patients with ideomotor apraxia will use their hands and fingers as the tool. For patients pantomime
example, when asked to pantomime using a pair of scissors to cut a piece of paper transitive actions to verbal
in half, they will use their index and middle fingers as if they are the blades of the command, imitate actions,
and use actual tools.
scissors (CASE 5-1). When asked to show how to pound in a nail with a hammer,
they will use their closed fist as if it is the head of the hammer. These errors are ● Patients with ideomotor
called body part as tool errors. When healthy people are tested and asked to show apraxia may make several
how they would use a tool, at first, they will also often use their body part as the types of errors, including
tool. However, unlike patients with ideomotor apraxia, when they are asked to using a body part as the tool,
moving the incorrect joint,
act as if they were actually holding and using the tool rather than using their hand incorrectly coordinating
and fingers as the tool, healthy subjects will stop using the body part as the tool.9 joint movements, and the
In contrast, many patients with ideomotor apraxia will continue to use their body incorrect spatial directing of
part as the tool. their actions, as well as
timing errors.
When asked not to use their body part as the tool, some patients will also show
positional errors. For example, when asked to pantomime the use of scissors,
they may keep their index finger fully extended.
Patients with ideomotor apraxia may make several other types of spatial
errors. For example, when pantomiming the use of a knife cutting bread, they
may not keep the imaginary knife on the same sagittal plane or when
pantomiming using a screwdriver to put a screw into a wall, they may not
keep the head of the screwdriver at the same point. These errors are called
spatial orientation errors.
Movement errors are some of the most common errors displayed by patients
with ideomotor apraxia. Often, patients with ideomotor apraxia will move the
incorrect joint when responding during testing. For example, when asked to
pantomime how they would pound a nail into a piece of wood lying on a table,
they might flex and extend their arm at the elbow and not move their wrist.
Using these movements, the head of the hammer would not hit the nail. Many
transitive movements, such as slicing a loaf of bread with a knife, require the
coordination of several joints. When patients with ideomotor apraxia attempt
to perform these movements, they may only move one joint (such as the
shoulder) or may not properly coordinate their shoulder movements with
elbow movements.6
In addition to these spatial postural and movement errors, patients with
ideomotor apraxia can also make movement speed errors.6 For example, when
using a hammer, the upswing is normally slower than the downswing, but
patients with ideomotor apraxia might not show this difference or may even
reverse the movement speeds. In summary, patients with ideomotor apraxia may
make several types of errors, including using a body part as the tool, moving the
incorrect joint, incorrectly coordinating joint movements, incorrect spatial
directing of their action, and timing errors.
In addition to the methods of testing patients for limb apraxia discussed
earlier, one of the most frequently used standardized tests is the test of upper
limb apraxia (TULIA) (TABLE 5-210). This test includes nonsymbolic
(meaningless), intransitive (communicative), and transitive (tool-related)
gestures and was found to have good reliability and validity; however, since
TULIA is a 48-item test, a shorter bedside 12-item test based on the TULIA has
also been developed and also appears to have good specificity and sensitivity.

UPPER LIMB APRAXIA
TABLE 5-2 Test of Upper Limb Apraxia Itemsa,b
Imitation, nonsymbolic
1 Put index finger on top of nose
2 Bring thumb extended on forehead, other fingers point upward
3 Bring back of the hand under chin, shoulder 90 degrees abducted
4 Place the hand flat on top of the head
5 Lift only the hand from the table (forearm stays on the table)
6 Spread little finger outward
7 Extend the arm sideward up to shoulder height
8 Lift middle finger
Imitation, intransitive
9 Make a catholic cross sign
10 Show as if someone is crazy*
11 Wipe dust from shoulder*
12 Salute like a soldier
13 Hitch for a car*
14 Make a stop sign
15 Clasp fingers
16 Point to a bird in the sky
Imitation, transitive
17 Drink from a glass
18 Comb hair*
19 Pick up telephone
20 Smoke a cigarette
21 Use a hammer*
22 Use a key
23 Use scissors*
24 Use a stamp to postmark
Pantomime, nonsymbolic
25 Place your hand flat on your head
26 Put your hand on your right (or left) shoulder
27 Take your left (or right) ear between thumb and index finger
28 Put your extended thumb on your forehead, other fingers point upward
29 Extend your arm sideward up to shoulder height
30 Bend your elbow and look at the palm of your hand
31 Lift only your hand from the table
32 Lift your index finger from the table
1608 DECEMBER 2021

Pantomime, intransitive
33 Salute like a soldier
34 Throw me a kiss
35 Show as if someone is crazy*
36 Scratch your head*
37 Point to a bird in the sky
38 Wave goodbye*
39 Make a stop sign
40 Make a threatening sign
Pantomime, transitive
41 Brush your teeth*
42 Comb your hair*
43 Eat soup*
44 Smoke a cigarette
45 Use a screwdriver*
46 Use a key
47 Use a stamp to postmark
48 Cut bread that is put on the table*
Scoring method
5: Normal movement or identical to the demonstrated movement.
4: Goal of the movement is achieved, but errors occur not affecting trajectory (normal
movement plane relative to goal object [tool or own body], normal joint coordination and
movement shape). Movement is too slow, hesitating, robot-like, or sloppy with minor spatial
errors such as reduced amplitudes.
3: Goal of the movement is achieved; errors subtly affecting trajectory occur but are corrected.
Extra movements and omissions are present (mainly distal). Even brief content errors
(substitutions, perseverations) may occur; however, corrections are made in the ongoing
movement.
2: Goal of the movement is achieved; errors subtly affecting trajectory occur but are not
corrected. Body-part-as-object errors, extra movements, and omissions (mainly distal) occur
without correction.
1: Goal of the movement is not achieved; errors grossly affecting trajectory occur or semantic
content is incorrect. Final position is false, and major errors in spatial orientation, overshoot,
and extra movements (particularly proximal) occur; however, overall movement pattern
remains recognizable. Persisting substitutions (related or unrelated) and perseverations occur.
0: No movement, unrecognizable movement. Seeking and amorphous movements, no temporal
or spatial relationship to the requested gesture.
a
Reprinted with permission from Vanbellingen T, et al, Eur J Neurol. © 2009 The Authors.
b
Within each subtest, the first group of four items are proximal, the second group are distal. All nonsymbolic
items are simple in nature. For symbolic gestures (intransitive and transitive), simple and repetitive items
(denoted with the *) were selected. Twelve items (shown in italics) of the imitation part were repeated in the
pantomime domain allowing direct comparison of performances at individual item level.

UPPER LIMB APRAXIA
PATHOPHYSIOLOGY. The normal ability to perform skilled movements is

dependent upon several different stores of knowledge and several programming
modules. Therefore, injury to several different areas of the brain can produce the
errors associated with ideomotor apraxia. In right-handed people, apraxia of the
left hand can be seen with lesions of the corpus callosum. In right-handed
patients, ideomotor apraxia of both upper limbs can be seen with injury to the
left inferior parietal lobe, the left supplementary motor and convexity premotor
area of the left hemisphere, or the connections between the premotor cortex and
the inferior parietal lobe. However, injury to these different areas can produce
differences in patients’ performance.
In 1907, Liepmann and Maas11 reported a patient with right hemiplegia who
developed a disorder of performing skilled movements with his left upper limb to
verbal command. On postmortem examination, he was found to have a lesion in
the left basis pontis and a lesion of the anterior four-fifths of the corpus callosum.
Whereas the lesion in the pons accounted for his right hemiplegia, the authors
thought that the callosal lesion accounted for his left hand’s impaired ability to
make the correct movements to verbal command. Two possible mechanisms
could account for this. One possible mechanism is that since the left hemisphere
comprehends speech, with callosal disconnection the patient was unable to
transfer the information contained in the command from the left to the right
hemisphere. The other possible mechanism is that the left hemisphere also stores
the knowledge of how to program movements, and with the corpus callosum
disconnection, this information could not be transmitted from the left to the
right hemisphere. To determine whether the callosal lesion induced a language
disconnection or disconnection of movement programs, the patient’s ability to
correctly imitate skilled movements and to use actual tools was tested. Since this
patient was impaired when attempting to perform these nonverbal tasks and had
an intact right hemisphere, the authors concluded that the left hemisphere of the
patient contained movement formulas that are important in the programming of
purposeful skilled movements of both the right and left hands and that the
callosal disconnection resulted in an inability of the right hemisphere’s
sensorimotor areas to access the movement representations (movement
formulas) stored in the patient’s left hemisphere.
In 1920, Liepmann5 proposed that the movement formulas stored in the left
hemisphere of right-handed people contain the temporal-spatial representations
of learned skilled movements. These representations provide the brain’s
premotor cortex information about the kinesthetic-temporal and visual-spatial
characteristics of the required movements. Then the premotor cortex translates
these representations into movement programs and provides the motor cortex
with information about the nerves that must be either activated or inactivated so
that the muscles that need to be contracted or relaxed can correctly make this
movement. This postulate suggested that with a callosal lesion, a right-handed
patient who had an intact left hemisphere would be able to carry out commands
normally and imitate and use actual tools correctly with their right hand but
would be impaired when performing these tasks when using their left hand.
However, this hypothesis was unable to be tested since the patient had a right
hemiparesis from his pontine stroke.11
More than a half-century later, Geschwind and Kaplan12 reported the findings
of a patient with a left hemisphere glioblastoma. This patient had undergone
surgery, and during the surgery developed an infarction in the distribution of the
1610 DECEMBER 2021

left anterior cerebral artery, which included damage to the anterior four-fifths of KEY POINT
the corpus callosum. Although the patient could not correctly carry out verbal
● In right-handed people,
commands and could not write with his left hand, he could normally perform apraxia of the left hand can
transitive action pantomimes with his left upper limb and could normally use be seen with lesions of the
actual tools with his left hand. This patient’s callosal lesion caused a language corpus callosum; ideomotor
disconnection, and these findings were inconsistent with the earlier report by apraxia of both upper limbs
can be seen with injury to
Liepmann and Maas.
the left inferior parietal
A study of patients with epilepsy who underwent a surgical lesion of the lobe, the left supplementary
corpus callosum to help control their seizures reported that these callosal motor and convexity
disconnections were not associated with impaired imitation or an inability to premotor area of the left
hemisphere, or the
correctly use tools with the left upper limb.13
connections between the
Whereas the findings of Geschwind and Kaplan12 as well as Gazzaniga and premotor cortex and the
colleagues13 did not support the postulate of Liepmann and Maas11 that, in inferior parietal lobe.
right-handed people, the left hemisphere contains the movement formulas and
callosal disconnection prevents these movement representations from gaining
access to the right hemisphere’s motor systems, Watson and Heilman14 as well as
Graff-Radford and colleagues15 reported that patients with acute naturally
occurring callosal lesions had severe apraxia of their left upper limb when tested
by command, imitation, and even the use of actual tools and implements.
It is not entirely known why some right-handed patients with callosal injury
demonstrate an ideomotor apraxia when imitating and using objects with the left
upper limb and others do not.
This variability suggests that some people, although right-handed, have their
movement representations stored in their right hemisphere. However, it is very
rare that right hemisphere lesions produce ideomotor apraxia in right-handed
people. It has been reported that left hemisphere lesions that damage cortical
areas known to induce both aphasia and apraxia more often induce aphasia than
ideomotor apraxia.12 This asymmetry provides some evidence that action spatial-
temporal movement representations (movement formulas) are more likely to be
bilaterally represented than language representations.
The action spatial-temporal representations (movement formulas) of people
who are left-handed should be stored in their right hemispheres. The majority of
left-handed people have their language mediated by their left hemisphere. Thus,
with a callosal disconnection, most left-handed people should reveal an apraxia
of their left hand with verbal commands but an apraxia of their right hand with
imitation or object use. However, Lausberg and colleagues16 reported a left-
handed patient with infarction of the corpus callosum who revealed an apraxia of
the left hand to command, imitation, and the use of objects. With this patient’s
language and praxis being mediated by his left hemisphere, it is not clear why he
claimed to be left-handed; perhaps his left hand was simply more deft than his
right hand. Deftness-dexterity is discussed in the section on limb-kinetic apraxia.
With left hemisphere lesions, the frequent association of aphasia with apraxia
led to Goldstein’s17 hypothesis that both apraxia and aphasia are manifestations
of a symbolization defect, called asymbolia. However, support for the postulate
that apraxia is a disorder of skilled movements rather than a symbolic defect
comes from reports of patients with left hemisphere lesions who were aphasic
and not apraxic as well as of patients who were apraxic but not aphasic.8
In 1874, Karl Wernicke proposed that speech stimuli travel along auditory
pathways and reach the primary auditory cortex in the left superior temporal
lobe called the Heschl gyrus, where the incoming sounds are processed.18 This

UPPER LIMB APRAXIA
information is then sent to the posterior superior portion of the left temporal lobe
(the auditory association cortex), also known as the Wernicke area. This area
contains the sound representations of previously heard and learned words and
thus is critical in the comprehension of speech. Wernicke area is connected to
ventral convexity frontal premotor areas in the left hemisphere, called the Broca
area. This connection is made by a white matter pathway called the arcuate
fasciculus. The Broca area is then connected to the primary motor cortex, which
controls the articulatory apparatus. According to Geschwind’s18 apraxia
hypothesis, when someone is told to carry out a command with their right hand,
this perisylvian pathway is used. However, rather than terminating in the Broca
area, this portion of the arcuate fasciculus connects with the premotor cortex
above the Broca area. Geschwind18 proposed that a lesion of the arcuate
fasciculus that disconnected the Wernicke area from the premotor cortex
accounted for most cases of ideomotor apraxia. Therefore, patients with injury to
the arcuate fasciculus with sparing of the convexity premotor cortex should be
able to comprehend verbal commands but not be able to perform skilled
movements in response to these commands. Because imitation does not require
language comprehension, patients with a left arcuate fasciculus lesion who have a
normal right hemisphere should be able to correctly imitate transitive
movements using their left hand. However, patients with a left parietal lesion
that involves the arcuate fasciculus most often cannot correctly imitate with their
left upper limb.19 Geschwind’s arcuate fasciculus hypothesis also cannot explain
why many of these patients are clumsy when they attempt to use actual tools and
implements with their left hand.
After a person learns a skilled motor behavior, the behavior can be performed
in response to a verbal command and even can be visually or somesthetically
imagined. The ability to perform these functions suggests that action
temporal-spatial representations (movement formulas) are developed, and this
knowledge is required to program learned skilled actions. With a left inferior
parietal lobe (supramarginal gyrus) injury, these movement representations may
be destroyed; this may help to explain why patients with a dominant parietal
lesion cannot properly pantomime or imitate transitive actions or correctly
demonstrate the correct use of actual tools and implements.1 These
visual-kinesthetic temporal-spatial movement representations (or praxicons)
provide critical information to the premotor cortex, which, in turn, helps to
implement the required movements by selectively activating the motor cortex.
Based on this action representation-implementation hypothesis, damage to
the action representations stored in the inferior parietal lobe network connection
to the premotor cortex or damage to the connections between these modules
should cause an ideomotor apraxia. However, damage to the parietal lobe’s action
representations should differ from a defect in the implementation-motor
programming mediated by the premotor cortex. It was found that patients who
had an ideomotor apraxia from a parietal lesion that destroyed these movement
representations (praxicons) were not able to discriminate the type of action
being performed by an actor or able to determine if the action was being
performed correctly or incorrectly.19,20 In contrast, patients with an ideomotor
apraxia from a more anterior lesion performed better on these recognition and
discrimination tests. Further, a loss of movement representation should impair
action-motor imagery, and Ochipa and colleagues21 demonstrated that
ideomotor apraxia can be associated with deficits in movement imagery. Further
1612 DECEMBER 2021

evidence supporting the hypothesis that the dominant parietal lobe stores
action-movement representations (praxicons) comes from functional imaging
studies of healthy subjects.22
Destruction of the parietal cortex, which stores movement representations
(praxicons), should not only cause ideomotor apraxia but should also cause
impairment in learning new motor skills such as new gestures. Heilman and
colleagues23 studied motor learning of right-handed aphasic patients with
hemiparesis and apraxia and compared their performance with that of controls
who were aphasic and hemiparetic but not apraxic. To test motor learning,
participants performed five acquisition trials and one retention trial on a rotary
pursuit apparatus. All participants used their left nonparetic upper limb. The
control group’s performance on the sixth trial was significantly better than on
their first trial. The apraxic group, however, revealed no improvement.
Therefore, it appears that patients with ideomotor apraxia have a defect in motor
learning. In addition, Rothi and Heilman24 studied the ability of patients with
apraxia to learn a list of gestures and found that patients with apraxia made
significantly more consolidation errors than did the controls. Pistarini and
colleagues25 studied gesture and skill learning and found that patients with
ideomotor apraxia were impaired.
As previously mentioned, the dominant inferior parietal lobe stores the
visual-kinesthetic temporal-spatial representations of learned skilled
movements. However, before a person can make a learned skilled movement, the
neurons in the motor cortex must be properly activated.
The supplementary motor area, a portion of the premotor cortex in the
medial frontal lobe, appears to play an important role in the programming of
actions. The supplementary motor area receives projections from parietal
neurons and projects to the primary motor neurons. When performing an
action, the neurons in the supplementary motor area discharge before the
neurons in the primary motor cortex.26 Stimulation of the primary motor
cortex (Brodmann area 4), produces simple single movements. In contrast,
stimulation of the supplementary motor area produces complex movements
of the fingers, arms, and hands.27 Studies using functional imaging that
measured cerebral blood flow as an indicator of cerebral metabolism have
shown that simple repetitive movements can increase activation of the
contralateral primary motor cortex. In contrast, complex movements have
been shown to increase cerebral blood flow not only in the contralateral
primary motor cortex but also in the supplementary motor area. Even thinking
and planning to make a complex movement increases the activity of the
supplementary motor cortex but not activity of the primary motor cortex.28
These studies suggest that the supplementary motor area is important in
translating the visual-kinesthetic temporal-spatial movement representations
(praxicons) stored in the inferior parietal lobe into motor programs. The
supplementary motor area is highly connected to both the convexity premotor
cortex and the primary motor cortex. When making a complex skilled
movement, the supplementary motor area is activated before the primary motor
cortex and provides the motor cortex with information about the neurons that
need to be excited and the order of their excitement.
Watson and colleagues29 described several patients with left-sided medial
frontal lesions that included the supplementary motor area who had bilateral
ideomotor apraxia. Unlike patients with parietal lesions, however, these patients

UPPER LIMB APRAXIA
could discriminate well-performed from incorrectly performed pantomimes and

could determine the meaning of pantomimes. Based on its connectivity, its
physiology, and the neurobehavioral alterations with injury, it appears that the
supplementary motor area is the area of the brain where movement
representations are translated into motor programs or innervatory patterns that
activate the motor cortex.
The role of the basal ganglia in praxis is unclear. It is known that patients with
basal ganglia disorders such as Parkinson disease,30 Huntington disease,31 and
corticobasal degeneration32 often reveal signs of ideomotor apraxia; these
patients also often have cortical dysfunction. Basso and collagues33 as well as
Agostini and colleagues34 reported that patients with basal ganglia lesions had
ideomotor apraxia. However, Pramstaller and Marsden35 in a meta-analysis
concluded that lesions confined to the basal ganglia (putamen, caudate nucleus,
and globus pallidus) rarely, if ever, cause apraxia and that it is often the white
matter injury associated with these lesions that may be responsible for the
apraxia. However, Rothi and colleagues36 described patients with left-sided
lenticular infarctions that did not involve the cerebral cortex or associative
pathways (longitudinal fasciculi) who made spatial movement errors that were
similar to the errors seen in patients with cortical lesions, Nadeau and
colleagues37 reported a patient with apraxia from a thalamic infarction.
Alexander and colleagues38 described five discrete cortical striatal-pallidal-
thalamic-cortical circuits. The supplementary motor area is a part of the
putaminal-globus pallidus-ventrolateral thalamic nucleus circuit; disruption of
this circuit may impair supplementary motor area function and induce an
ideomotor apraxia.
Ideomotor apraxia can be associated with many diseases, including
cerebrovascular diseases such as stroke and hemorrhage and degenerative diseases
such as Alzheimer disease, frontotemporal dementia (both nonfluent and
behavioral subtypes), logopenic variant primary progressive dementia, Parkinson
disease, Huntington disease, corticobasal degeneration, and supranuclear palsy. It
has also been reported with head trauma, and some patients with traumatic brain
injury even appear to have a form of callosal apraxia.39
TREATMENT AND MANAGEMENT. It is important that patients, families, and

caregivers understand the disabilities associated with ideomotor apraxia, and it is
critical that these patients not be allowed to perform an instrumental activity that
could cause injury to themselves or others. Bjørneby and Reinvang40 studied
patients with stroke who had left hemisphere lesions and found that the presence
of apraxia was a predictor of dependency. Patients with this disorder may be
unable to correctly perform many activities of daily living, such as slicing bread
or shaving, and thus will need help.
Basso and colleagues33 studied recovery of ideomotor apraxia after stroke and
found that many patients do appear to have some recovery, but those with
posterior temporoparietal strokes had the poorest prognosis for recovery.
When possible, the underlying disease causing ideomotor apraxia should be
treated. Although treating some of the causative diseases (eg, Parkinson disease)
can reduce many of the symptoms and signs of the diseases, apraxia is often not
significantly improved with these treatments.
When possible, patients with apraxia should undergo behavioral training.
Behavioral training treatment programs for ideomotor apraxia use
1614 DECEMBER 2021

gesture-production exercises and exercises related or nonrelated to the use of KEY POINTS
objects.41,42 Rehabilitative behavioral training treatments for apraxia are usually
● Patients with ideomotor
50-minute sessions conducted 3 times a week for a total of 30 sessions. Patients apraxia should not be
who received treatment for apraxia were found to improve in both praxis and allowed to perform any
performing activities of daily living when compared to patients who received activity that can injure
treatment for aphasia but not apraxia.43 However, based on these reports, the themselves or others.
sustainability of such improvement is unclear, and it has been claimed that
● When possible, patients
apraxia training alone is likely insufficient for sustained benefit.43 with apraxia should undergo
Noninvasive brain stimulation, such as transcranial direct current stimulation, behavioral training.
has been used to treat a variety of neurobehavioral disorders, and some studies
have used this treatment for the apraxia associated with corticobasal degeneration ● Limb-kinetic apraxia is
the loss of the ability to
and left hemisphere damage. Although patients treated with anodal perform deft-dexterous
transcranial direct current stimulation over the left parietal lobe showed movements of the hands
improvement, further studies are needed to examine this and other forms of and fingers.
brain stimulation.44
● The two best methods for
assessing patients for
Limb-Kinetic Apraxia limb-kinetic apraxia are the
Humans have the remarkable ability to perform deft-dexterous movements of coin rotation test and the
their fingers and hands. Many skilled acts, such as buttoning a shirt, are grooved pegboard test.
performed by the hands and fingers. The loss of the ability to make deft
movements was first called limb-kinetic apraxia by Liepmann5 in 1920.
CLINICAL PRESENTATION. Most tests for limb-kinetic apraxia assess the

manipulation of actual objects with the hand and fingers. The two best methods
for assessing patients for limb-kinetic apraxia are the coin rotation test and the
grooved pegboard test. The grooved pegboard test is used in neuropsychologic
test batteries; patients are instructed to pick up pegs and place them in small
holes. However, visuospatial disorders can also impair performance in this test.
The coin rotation test, in which the patient is asked to rotate a nickel between the
thumb, index finger, and middle finger of each hand as rapidly as possible for 20
180-degree revolutions, is easy to perform and has been found to be
very sensitive.3
Whereas patients with hemispheric damage often have a loss of deftness in
their contralateral hand, the author and colleagues3,44 have found that
right-handed people who have left hemisphere lesions more often have
limb-kinetic apraxia of their ipsilesional left hand than those with right
hemisphere lesions have with their ipsilateral right hand.
PATHOPHYSIOLOGY. Several localizations of lesions have been hypothesized for

causing limb-kinetic apraxia. Injury to the corpus callosum can cause
limb-kinetic apraxia of the left hand. In right-handed people, a lesion of the
premotor cortex or the sensory-motor cortex can cause limb-kinetic apraxia of
both hands. Limb-kinetic apraxia can also be caused by diseases that impair basal
ganglia function.
Liepmann5 thought that injury to the sensorimotor cortex caused this disorder.
However, subsequent studies appear to indicate that injury to the convexity
premotor cortex can also induce limb-kinetic apraxia.45
As mentioned above, a left hemisphere injury in a right-handed patient can
produce ipsilateral (left hand) limb-kinetic apraxia.3,44 In addition to the main
crossing motor pathways, the corticospinal tracts have smaller ipsilateral

UPPER LIMB APRAXIA
pathways, and these ipsilateral pathways are asymmetric, with the left
hemisphere influencing the ipsilateral left hand more than the right hemisphere
influencing the right hand. Thus, since the corticospinal system of the left
hemisphere has both contralateral and ipsilateral pathways, a left hemisphere
injury might cause a bilateral limb-kinetic apraxia. Alternatively, the left
hemisphere’s motor programming system might influence the right
hemisphere’s motor system by transferring information by way of the corpus
callosum. Watson and Heilman14 described a woman with an infarct of the
corpus callosum who had a severe ideomotor apraxia of her left upper limb but
did not have a limb-kinetic apraxia of her right upper limb. In contrast,
Verstichel and Meyrignac46 reported on a right-handed man who had an
infarction of the anterior cerebral artery that injured the anterior and middle
parts of the corpus callosum that resulted in a loss of deftness of his left hand.
However, this patient’s infarction also caused injury to several areas of the
cerebral cortex. Acosta and colleagues47 reported a patient who was assessed
before and after a surgical callosal disconnection. Although this patient’s
performance was normal before surgery, after surgery he revealed a limb-kinetic
apraxia of his left hand, suggesting that in right-handed people, deftness of the
left hand is, at least in part, mediated by the left hemisphere.
Limb-kinetic apraxia is a common disorder that can be easily diagnosed with
the coin rotation test. This disorder can be very disabling and can be induced by
almost all diseases that injure the cerebral cortex, including stroke, trauma, and
tumors. Limb-kinetic apraxia can also often be seen in patients with Parkinson
disease (CASE 5-2) and is commonly seen in patients with corticobasal
degeneration.48 Unfortunately, the specific role of the basal ganglia in
performing deft actions is still not entirely understood. Patients with Parkinson
disease are often assessed with a finger-tapping test, and although this test may
detect bradykinesia, it is not sensitive to the presence of limb-kinetic apraxia.
Patients with Parkinson disease are not commonly tested for limb-kinetic apraxia
but should be.
TREATMENT AND MANAGEMENT. More than a decade ago, Buxbaum and

colleagues49 noted that surprisingly few studies have focused on the
development of treatment paradigms for limb-kinetic apraxia. Unfortunately,
CASE 5-2 A 62-year-old man with a 4-year history of Parkinson disease was overall
doing well on carbidopa/levodopa, except he had trouble buttoning his
shirt. When he was evaluated in clinic, he was tested for limb-kinetic
apraxia using the coin rotation test. He was given a nickel and asked to
rotate it 20 times between his thumb, index finger, and middle finger.
When he attempted to perform the task, he repeatedly dropped the
nickel.
COMMENT Limb-kinetic apraxia is commonly associated with Parkinson disease. In

many patients, it does not appear to respond well to dopaminergic
therapy.
1616 DECEMBER 2021

systematic studies of the treatment of limb-kinetic apraxia have yet to be KEY POINT
conducted. However, as discussed above, patient safety is an important focus for ● Injury to the corpus
management of this disorder, and practicing deft movements may be helpful for callosum can cause
patients. Future studies that examine possible treatments such as brain limb-kinetic apraxia of the
stimulation and motor training are needed. left hand. In right-handed
people, a lesion of the
Conceptual Apraxia premotor cortex or the
sensory-motor cortex can
Many tasks cannot be accomplished by using just the fingers, hands, and arms. cause limb-kinetic apraxia
Therefore, in addition to knowing how to make deft and transitive movements, of both hands. Limb-kinetic
people often need to use tools. Tools provide the user with mechanical advantages. apraxia can also be caused
However, several steps are necessary to correctly use a tool or implement. by diseases that impair basal
ganglia function.
Disorders of tool and mechanical knowledge are two forms of conceptual apraxia.
Conceptual apraxia is the loss of mechanical knowledge, including knowledge of
needed mechanical alterations, knowledge about the needed tool to perform
alterations, and knowledge about possible alternative tools.
CLINICAL PRESENTATION. When an alteration is needed, the first step is the

recognition of what needs to be altered and how it should be altered. Some
patients cannot identify that an alteration action is required.50 This subtype of
conceptual apraxia is called problem unawareness. Some patients understand what
needs to be done (eg, the need to tighten a bolt) but cannot recognize the tool
that is needed to perform the required action; this form of conceptual apraxia is
called a tool-selection deficit. In addition, some patients can no longer even recall
the type of action that is associated with specific tools and implements (eg, that
hammers are used to pound), which is known as a tool-action-association deficit.
A more complex form of mechanical knowledge is knowing the characteristics
of a tool that allow it to perform a given action. For example, if when attempting
to drive a nail into a piece of wood, no hammer is available in the toolbox, the
patient with impaired tool mechanical advantage knowledge might select a
screwdriver rather than a more appropriate tool (eg, a wrench) from the toolbox.
Mechanical knowledge is also important for tool development, and patients with
conceptual apraxia are often unable to correctly develop tools,51 for example,
using a metal clothes hanger to open a car door when the car keys are locked
inside. Patients with conceptual apraxia may also have an impaired
understanding of the mechanical problems that need to be altered. In addition,
they may have impaired knowledge of the mechanical advantages that specific
tools provide (a tool-selection deficit). They may also have a loss of knowledge of
the actions associated with specific tools.
To test problem awareness, Schwartz and colleagues50 developed a test in
which patients are shown a series of pictures, each of which illustrates a task that
needs to be completed (eg, a picture of a board with a partially driven nail); the
participant is asked to demonstrate the type of action that is needed to complete
the task. To perform the task correctly, the patient would have to show a
pounding type of movement.
To test tool selection, the patient is again shown a series of pictures of
incomplete tasks, such as the picture of a board with a partially driven nail. With
each picture, the patient is also shown an array of five different tools (eg, with
the partially driven nail, they might be shown a handsaw, wrench, hammer,
screwdriver, and knife) and asked to select the tool that would be best to use to
complete the task.

UPPER LIMB APRAXIA
Further knowledge about mechanical advantage is tested with the alternative

tool test, in which the patient is shown a series of pictures similar to those described
above showing an incomplete task. However, in this mechanical knowledge test,
the tool that usually performs the action is not in the array presented to the patient.
The patient is then asked to select an alternative tool that can complete the task.
For example, when shown the partially driven nail, the patient may be shown a
picture of five tools (eg, handsaw, wrench, screwdriver, knife, and wire cutter) and
asked to point to the tool that would be able to complete the task.
PATHOPHYSIOLOGY. Conceptual apraxia was first described in a patient with an

infarction of the anterior two-thirds of the corpus callosum.14 In addition to
ideomotor apraxia of her left upper limb, the patient also showed a conceptual
apraxia of the nonpreferred (left) hand. Heilman and colleagues52 studied
right-handed patients who had either right or left hemisphere cerebral
infarctions and reported that conceptual apraxia was associated with left
hemisphere injury. Liepmann5 posited that conceptual mechanical knowledge is
stored in the caudal parietal lobe. De Renzi and Luccelli,53 who called this
CASE 5-3 A 74-year-old man was referred for a neurologic evaluation for cognitive
symptoms. He had recently moved into a new apartment and noticed a
screw protruding from one of the walls, and he wanted to remove it. He
went to his toolbox to get a screwdriver, but although his toolbox was full
of all types of tools, he could not find a screwdriver. He told his wife, “I
cannot remove this screw because we do not have a screwdriver.” His
wife asked whether he could use another tool. He replied, “No, I need a
screwdriver to remove a screw.” His wife was concerned because he
could have used another tool, such as pliers. She also noticed that he was
having progressive problems with his memory and finding words and was
often getting lost while driving.
The presence of conceptual apraxia, together with a disorder of
episodic memory and a word-finding impairment, suggests a disorder of
the left cerebral cortex and in the Papez circuit. The progressive onset
suggests that this was not caused by cerebrovascular disease.
After a thorough examination, MRI, and multiple blood tests, he was
diagnosed with Alzheimer disease and prescribed an anticholinesterase
medication.
COMMENT This patient’s reduced ability to know the mechanical advantage of tools is
one of the major signs of conceptual apraxia. With increased severity,
patients with this disorder may fail to even recognize the correct tool.
Although clinicians rarely evaluate patients for this disorder, it can be seen
in patients with left hemispheric strokes or degenerative dementias such
as Alzheimer disease. Because, in this patient, this disorder was
progressive, it was most likely caused by Alzheimer disease. Laboratory
and brain imaging studies helped confirm this diagnosis.
1618 DECEMBER 2021

disorder ideational apraxia, also located these representations in the
temporoparietal junction, whereas Heilman and colleagues52 found no specific
anatomic region in the left hemisphere that appeared to be critical for inducing
conceptual apraxia. The failure to find a specific locus may have been related to
having an inadequate number of participants. It is also possible that, in right-
handed people, mechanical knowledge may be widely distributed in the left
hemisphere or that each of the subtypes of conceptual apraxia described above
may have a different localization. In a 2016 study, Markus and colleagues54 found
that patients with damage within ventral stream regions, including the anterior
temporal lobe, were more likely to make tool selection errors; however, further
research is needed.
In addition to being associated with diseases that cause focal brain damage,
such as stroke, conceptual apraxia is also commonly seen in patients with
degenerative dementia, such as Alzheimer disease and semantic dementia
(CASE 5-3).51,55
TREATMENT AND MANAGEMENT. No treatment is known for conceptual apraxia. As

with other forms of apraxia, it is important that patients, families, and caregivers
understand the disabilities associated with conceptual apraxia and provide help
when needed.
Ideational Apraxia
The impaired ability to correctly perform a sequence of actions needed to
complete a task has been called ideational apraxia (CASE 5-4).56,57 Although
A 42-year-old woman was in a head-on collision on a two-lane road when CASE 5-4
a car going in the opposite direction tried to pass another car and moved
into her lane. After the crash, she was comatose and was found to have a
large subdural hematoma, which was removed. She slowly regained
consciousness but was abulic, amnestic, and anomic. She was, however,
able to perform basic activities of daily living and many instrumental
activities of daily living. Her husband noted that when performing
household chores, she often sequenced a series of acts incorrectly. For
example, one day she was making ham and cheese sandwiches for her
husband and her two children. She took out all the correct materials,
including bread, ham, cheese, mustard, and a knife. Her first action was
putting the two slices of bread on top of each other and then slicing this
bread in half. She then took off the top piece of bread and put on the ham
and cheese, replaced the top slice of bread, and then recut the sandwich
in half. She then saw the mustard, took the top slice off again, and put on
the mustard.
This patient’s main problem when making the sandwich was the correct COMMENT
sequencing of actions, and this impairment of action sequencing has been
called ideational apraxia.

UPPER LIMB APRAXIA
KEY POINTS De Renzi and Lucchelli53 used this term for patients who had the signs of
ideomotor apraxia who are impaired when using actual tools and implements,
● No treatment for
limb-kinetic apraxia is well
this diagnostic term was and is used for patients with a different disorder.
established, but practicing Hugo Liepmann5 suggested that the term ideational apraxia be used for the
deft movements may be disorder in which patients have an inability to correctly sequence a series of acts
helpful for patients. that lead to a goal. Klaus Poeck58 wrote the following about ideational apraxia:
“the main feature is an impairment in carrying out sequences of actions requiring
● Conceptual apraxia is
the loss of mechanical the use of various objects in the correct order necessary to achieve an
knowledge, including intended purpose.”
knowledge of needed
mechanical alterations,
knowledge about the CLINICAL PRESENTATION. Many patients who may have ideational apraxia may also
needed tool, and knowledge have other forms of apraxia discussed above and thus may also be impaired when
about possible alternative performing tasks requiring the use of tools or skilled movements. To assess
tools. ideational apraxia, as defined by Liepmann,5 Qureshi and colleagues59 developed
● Conceptual apraxia can
a test in which participants were shown 10 sets of four pictures that show the
be seen in patients with steps needed to complete a task (eg, preparing a sandwich, wrapping a gift, or
strokes of the left opening a locked door). However, the steps were shown out of order, and the
hemisphere and is perhaps participants were asked to point to the pictures in the correct sequence to
most likely with anterior
temporal lobe lesions. This
complete each task.
disorder is also seen with
degenerative dementias PATHOPHYSIOLOGY. Ideational apraxia is often associated with frontal-executive
such as Alzheimer disease
and semantic dementia.
dysfunction and may be seen in disorders such as stroke and vascular dementia.
The incorrect sequencing of actions may be considered an executive disorder.
● Ideational apraxia is the The pathophysiology of ideational apraxia has not been fully explored. However,
loss of the ability to lesion60 and functional imaging studies61 suggest that the frontal lobes are critical
correctly sequence the
for programming sequencing. Regarding hand sequencing, Heim and
series of actions needed to
completely perform a task. colleagues62 used functional imaging and found that sequencing was associated
with increased perisylvian activation, including the Broca area (left Brodmann
● Ideational apraxia is often area 44) and areas medially adjacent to left area 45 as well as left Brodmann area
associated with 7A. Starkstein and colleagues63 reported that disorders of sequencing are more
frontal-executive
dysfunction and may be
commonly associated with vascular dementia than with Alzheimer disease.
caused by disorders such as However, most clinicians do not test for this disorder and thus, further studies
stroke and vascular about localization and pathology are needed.
dementia.
● Upper limb apraxic TREATMENT AND MANAGEMENT. Little has been written about the treatment and
disorders are common and management of ideational apraxia, and this also needs to be further studied.
disabling disorders that However, it appears that, when possible, either written or verbal instructions on
should be assessed in all
sequencing may help patients with this disorder.
patients with cerebral
dysfunction. When upper
limb apraxia is present,
patients and caregivers
should be made aware of
CONCLUSION
the disability and, when This article described the behavioral deficits and pathophysiology of four
possible, treatment should common forms of upper limb apraxia. Patients with ideomotor apraxia often
be obtained. make postural and joint movement errors when attempting to perform transitive
movements. A loss of hand and finger deftness-dexterity is seen in patients with
limb-kinetic apraxia. Patients with conceptual apraxia have a loss of mechanical
knowledge causing a misuse of tools. The correct completion of many activities
requires a series of actions, and patients with ideational apraxia have a loss of the
ability to correctly sequence a series of movements.
1620 DECEMBER 2021

Upper limb apraxia is one of the most common and most disabling disorders
caused by brain damage; it is also one of the least tested and least recognized
disorders associated with cerebral disease. It is important for clinicians to test for
these common and disabling disorders, and further research is needed to
understand the pathophysiology of the disorders and develop
effective treatments.
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REVIEW ARTICLE

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axons and cytoskeletal components, as well as altered neurotransmission, may

THE SYMPTOM LANDSCAPE OF CONCUSSION

TABLE 7-1 Presentation, Evaluation, and Treatment of Concussion-Related Symptoms

Cognitive Fogginess, concentration Computerized or paper-and-pencil Cognitive rehabilitation,

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study, a proportion of participants with mild TBI demonstrated deficits in

Ocular Motor Dysfunction

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injured person’s reaction to it. Anxiety symptoms can include nervousness, an

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CONCUSSION CLINICAL SUBTYPES

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The Concussion Subtype Workgroup12 further refined the model proposed by

CASE 7-1 A 23-year-old man sustained a concussion due to a multivehicle accident

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ADVANCED DIAGNOSTICS FOR TRAUMATIC BRAIN INJURY

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(functional MRI [fMRI], convolutional neural networks).62 Several

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other conditions to the neuropsychological effects of concussion, and the results

PERSISTING SYMPTOMS AFTER CONCUSSION

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Rest, Activity, and Exercise

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Medical and Psychiatric Conditions

Fear-Avoidance and Coping Style

Expectations for Recovery

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TREATMENT OF MILD TRAUMATIC BRAIN INJURY AND CONCUSSION

Neuropsychological and Psychological Interventions

Physical Therapy Interventions

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followed by gradual reintroduction of normal activity, which was supported by a

Occupational Therapy Interventions

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● During the early

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intervention; behavioral therapy targeting cognitive functioning, mood

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