Progressive Supranuclear Palsy (PSP) - Clinical Features and Diagnosis - UpToDate

06.02.
2020 Progressive supranuclear palsy (PSP): Clinical features and diagnosis - UpToDate
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Progressive supranuclear palsy (PSP): Clinical features

and diagnosis
Authors: Stewart A Factor, DO, Christine Doss Esper, MD
Section Editor: Howard I Hurtig, MD
Deputy Editor: April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2020. | This topic last updated: Nov 04, 2019.
INTRODUCTION
Symptoms and signs of Parkinsonism (ie, tremor, bradykinesia, rigidity, and postural instability)
can be prominent in neurodegenerative disorders other than idiopathic Parkinson disease,
particularly in atypical parkinsonian disorders, which include corticobasal degeneration, multiple
system atrophy, and progressive supranuclear palsy.
Progressive supranuclear palsy (PSP), also known as Steele Richardson Olszewski syndrome, is
an uncommon but not rare parkinsonian syndrome. Characteristic features of PSP and its variants
include vertical supranuclear gaze palsy, postural instability with unexplained falls, akinesia, and
cognitive dysfunction. This topic will review specifically the clinical features and diagnosis of PSP.
Management and prognosis are reviewed elsewhere. (See "Progressive supranuclear palsy
(PSP): Management and prognosis".)
Other neurodegenerative parkinsonian syndromes are discussed separately. (See "Clinical

manifestations of Parkinson disease" and "Corticobasal degeneration" and "Multiple system
atrophy: Clinical features and diagnosis" and "Diagnosis and differential diagnosis of Parkinson
disease", section on 'Differential diagnosis'.)
HISTORICAL BACKGROUND
In 1964, Steele, Richardson, and Olszewski were the first to describe PSP when their seminal
report of nine cases with neuropathology was published [1]. As a result of their pioneering work,
some have referred to the disease as the Steele-Richardson-Olszewski syndrome. Since that
time, hundreds of additional cases have been recorded, and the disease is now a well-recognized
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06.02.2020 Progressive supranuclear palsy (PSP): Clinical features and diagnosis - UpToDate
atypical parkinsonian syndrome (or Parkinson-plus disorder). As originally described, PSP was
characterized by progressive supranuclear ophthalmoplegia, gait disorder and postural instability,
dysarthria, dysphagia, rigidity, and frontal cognitive disturbance [1]. The consistent pathologic
features of PSP consist of neuronal loss, globose neurofibrillary tangles, tau-positive inclusions
found in tufted astrocytes, and gliosis mainly in the basal ganglia, cerebellum, brainstem, and to a
lesser extent, the cerebral cortex [2]. In addition, astrocytic plaques and tufts of abnormal fibers
are highly characteristic of typical PSP [3]. A set of diagnostic criteria for PSP was initially
proposed in 1996 [4], and revised in 2017 [5]. (See 'Diagnostic criteria' below.)
PSP is now recognized to encompass several phenotypic variants. The classical phenotype is
now referred to as Richardson syndrome (PSP-RS), and other common variants include PSP with
progressive gait freezing (PSP-PGF), PSP with predominant parkinsonism (PSP-P), and PSP with
predominant frontal presentation (PSP-F).
EPIDEMIOLOGY
PSP is the most common of the degenerative forms of atypical parkinsonism, with an estimated
prevalence of 3 to 7 per 100,000 [6-10].
Early studies found that the annual incidence rates of PSP ranged from 0.3 to 0.4 per 100,000
[11-13]. However, a study published in 1999 reported an annual incidence rate of 1.1 per 100,000
[6,14]. The greater incidence found in later studies may be a result of better case ascertainment
due in part to increased recognition of the disorder [6]. The annual incidence increases with age
from 1.7 cases per 100,000 at ages 50 to 59 years to 14.7 per 100,000 at 80 to 89 years [15]. The
true incidence may be higher still with the subsequent discovery of additional phenotypes. In a
report of 998 unselected serial autopsy cases from Japan, PSP diagnosed according to pathologic
criteria was present with a higher prevalence (approximately 3 percent) than expected [16]. (See
'Variant phenotypes' below.)
The mean age of onset for PSP is approximately 65 years [8,9,17], which is older than in
idiopathic Parkinson disease. Virtually no cases of autopsy-confirmed PSP have been reported in
patients younger than age 40 years [5]. The original clinical report noted a strong male
predominance of approximately eight to one [1]. However, later reports have found no definitive
sex predominance in PSP [18-26].
In a series of 121 patients with probable PSP, there were no significant male-female differences
for a variety of disease measures including age at onset, clinical characteristics, and disease
duration [27].
Risk factors — There are no proven risk factors for the development of PSP except age. Some
studies have reported that education level or environmental exposures may be associated with
increased risk, but the findings have been inconclusive.
● An early case-control study found that patients with PSP (n = 50) were more likely than
controls to have completed high school and college [28]. However, a subsequent study from
the same investigators with 113 patients found that lower levels of education were associated
with an increased risk of PSP, whereas no history of elevated toxic exposure was detected
[29].
● A cluster of PSP cases in northern France was linked to potential exposure to industrial
waste, specifically phosphate and chromate ore [30]. Two small case series reported
environmental exposure to organic solvents in 12 of 13 patients with PSP [31,32].
● A multicenter case-control study with 284 incident PSP cases reported that a greater number
of years of drinking well water, but not chemical exposure, was significantly associated with
PSP. They also found an inverse association with having a college degree [33].
● A retrospective case-control study suggested that high exposure to significant life stressors
may be associated with the development of PSP [34].
Further studies are needed to determine if environmental toxins play a role in the pathogenesis of
PSP.
Genetic susceptibility — Although PSP is considered to be a sporadic disorder, some

observations suggest that genetic susceptibility has a role:
A few reports have found a positive family history of PSP and other types of parkinsonism [35-37].
However, these are distinctly rare.
Other studies have suggested that rare mutations of the microtubule-associated protein tau gene
(MAPT) may lead to inherited phenocopies of sporadic PSP [5,38]. A genome-wide association
study reported an increased risk of PSP for two independent variants of MAPT [39]. In addition,
the study found an increased risk associated with several additional genes (STX6, EIF2AK3, and
MOBP), the significance of which is unclear. Furthermore, several reports have demonstrated an
increased risk of PSP associated with the MAPT H1 haplotype, driven by several subhaplotypes
(H1c, H1d, H1g, and H1o) [40-43]. This has implied biological plausibility, since the tau protein is
abundant in the brains of subjects with PSP. However, the H1 haplotype is also more common in
patients with Parkinson disease compared with controls, even though tau accumulation and
aggregation is not a part of the pathological picture of Parkinson disease [44]. Hence, the meaning
of this finding still needs to be clarified.
CLINICAL CHARACTERISTICS
With the most common "classic" phenotype of PSP, known as Richardson syndrome (PSP-RS),
the most frequent initial feature is a disturbance of gait resulting in falls. Supranuclear
ophthalmoparesis or ophthalmoplegia is the hallmark of PSP (hence the name of the disease).
Dysarthria, dysphagia, pseudobulbar palsy, rigidity, bradykinesia, frontal cognitive abnormalities,

and sleep disturbances are additional common clinical features. However, the clinical presentation
is quite varied and a large proportion of patients present with variant phenotypes [8,17]. (See
'Variant phenotypes' below.)
Postural instability and falls — Patients with classic PSP-RS have a stiff and broad-based gait,
with a tendency to have their knees and trunk extended (as opposed to the flexed posture of
idiopathic Parkinson disease), and arms slightly abducted. They demonstrate impulsivity, probably
from the frontal lobe involvement, and hence tend to lurch and stagger. Step length is varied, as is
base width. Instead of turning en bloc as seen in Parkinson disease, they tend to pivot quickly,
further compromising their balance and indicating an inability to take protective measures. This is
sometimes referred to as the "drunken sailor gait." When they fall, it is usually backwards. Over
the course of the illness, such falls can result in a spectrum of injuries that include bruises,
lacerations, bone/skull fractures, subdural hematomas, and sometimes death [45]. When postural
instability and falls are the only features of the disease, an abnormal response to the postural
reflex testing (pulling the patient gently but firmly by the shoulders from behind to see if he or she
staggers backward uncontrollably) may be the only abnormality in a patient's examination [46].
Oculomotor findings — Supranuclear ophthalmoparesis or ophthalmoplegia is the hallmark of

PSP, but it may take as long as ten years to develop. The average is three to four years [47]. This
distinctive ocular finding is first noted as slowing of vertical saccades (an important feature
allowing earlier diagnosis), followed by a limitation of saccadic range. Concomitant limitation of
lateral gaze is often present but is less prominent. Pursuit movements of the eyes are slow, jerky,
and hypometric with unstable fixation [48]. The ophthalmoparesis is initially overcome by the
oculocephalic (Doll’s eyes) maneuver, but with disease progression and brainstem involvement,
vestibuloocular reflexes may be lost.
Other oculomotor findings in PSP include saccadic intrusions into fixation ("square wave jerks"),
loss of optokinetic nystagmus (particularly in the vertical direction), loss of convergence,
blepharospasm, and eyelid-opening apraxia.
The combination of rare blinking, facial dystonia, and gaze abnormalities leads to the development
of a classic facial expression of perpetual surprise or astonishment [46]. Vertical gaze impairment
commonly leads to problems with reading, spilling food while eating, and tripping while walking
[45].
Motor involvement — Bradykinesia with marked micrographia is a primary feature of

parkinsonism in PSP, all types. Unlike the classic bradykinesia of Parkinson disease with slowing
and decrement of amplitude on a finger-tapping task, patients with PSP may show non-
decrementing, very low-amplitude, fast tapping. Rigidity in patients with PSP is usually more
apparent in axial muscles, especially the neck and upper trunk, than in limb muscles. It can be
demonstrated on examination by resistance to passive movement of the neck.

Retrocollis was emphasized as an important physical finding in the original description of the
disorder [1], but is now estimated to occur in less than 25 percent of cases [49]. In addition to the
retrocollis, other types of dystonia include blepharospasm and more rarely limb or hemidystonia
[50,51]. Apraxia of eyelid opening can be mistaken for typical blepharospasm but is distinguished
by the absence of forced closure of the eyes. In many patients this is not a true apraxia but may
be a form of blepharospasm due to isolated contraction of the pretarsal orbicularis oculi.
The face is stiff, immobile, and deeply furrowed (the look of surprise) due to dystonia [18]. About
one-third of patients with PSP develop pyramidal signs, including hyperreflexia and Babinski
signs. Facial and jaw jerks are exaggerated. The tongue is tightly contracted and movements are
slow. Spastic dysarthria, dysphonia, and dysphagia are profound in the middle to later stages of
disease. Other clinical features of PSP include stuttering and palilalia (the involuntary repetition of
words or phrases).
A proportion of patients with PSP show a moderate response to dopaminergic agents in the early
stages of disease (generally the PSP with predominant parkinsonism [PSP-P] variant), but most
do not [46]. In some, the gait and balance problems actually worsen with levodopa.
Cognitive and behavioral abnormalities — The neuropsychological profile of PSP primarily

involves frontal lobe dysfunction. The patients manifest impaired abstract thought, decreased
verbal fluency, motor perseveration, and frontal behavioral disturbances [46].
The presence of early and severe frontal cognitive (executive) deficits is a common finding in PSP
[52-54]. Executive dysfunction may be the presenting symptom of PSP in some patients but is
more characteristic of the later stages of the disease.
In a cohort of 311 PSP patients, global cognition was impaired in approximately 57 percent [55],
while impairment for a single or multiple domains was observed in 40 percent each and frontal
impairment was observed in 62 percent. Cognitive impairment was seen in the early stages in 50
percent. Ideomotor apraxia is seen in a proportion of patients with PSP, typically those manifesting
features of corticobasal syndrome (referred to as PSP with predominant corticobasal syndrome or
PSP-CBS). In a Queen Square Brain Bank series, CBS was linked to a number of diverse
pathologies including corticobasal degeneration, PSP-CBS, and Alzheimer disease [56].
Behavioral abnormalities are also common in patients with PSP. In a case series of 22 patients
with PSP, the most common behavioral symptoms were apathy (91 percent), disinhibition (36
percent), dysphoria (18 percent), and anxiety (18 percent) [57]. One study of 188 patients with
PSP demonstrated depression in 50 percent and anxiety in 37 percent [58], while another study of
74 patients with PSP reported obsessive-compulsive symptoms in 24 percent [59].
Pseudobulbar palsy is another characteristic feature of PSP. Emotional incontinence is much less
common than in other forms of pseudobulbar palsy [18], but patients with PSP commonly manifest
the characteristic hoarse groaning voice along with moaning. Speech perseveration and anomia,
but not true aphasia, are usually observed [46]. Some patients with PSP present with a variant of
nonfluent aphasia (PSP with predominant speech/language disorder, or PSP-SL). (See 'Variant
phenotypes' below.)
Sleep disturbances — Early or late insomnia and difficulties in maintaining sleep have all been
reported in patients with PSP. Polysomnographic evaluation of 10 patients with moderate to
severe PSP revealed marked sleep abnormalities, all with significant periods (two to six hours) of
insomnia [60]. Marked rigidity may result in the inability to remain comfortable in bed, further
contributing to the sleep complaints. A prospective case-control study found that circadian activity
rhythms are disrupted in individuals with PSP [61].
In contrast, rapid eye movement sleep behavior disorder (RBD) is infrequently associated with
PSP [62]. This negative finding, similar to the case of preserved olfaction (see 'Potential disease
markers' below) can be helpful in differentiating PSP, a tau disorder, from Parkinson disease and
multiple system atrophy, both of which are synucleinopathies and commonly demonstrate
symptoms of RBD.
Variant phenotypes — Evidence from pathologic studies suggests that there is a wide spectrum
of clinical variability in PSP. In a 2017 systematic review of 261 patients with pathologically
diagnosed PSP and 231 pathologically diagnosed disease controls, there was a high prevalence
of PSP phenotypes other than Richardson syndrome [8]. Similarly, an earlier multicenter report of
100 pathologically confirmed cases of PSP found that the Richardson syndrome accounted for
only 24 percent of cases, while various other presentations accounted for the remainder [17].
Many variants of PSP, with tau pathology at autopsy in a pattern that is typical of PSP, have
considerable clinical overlap with other neurodegenerative disorders [8]. The recognized
phenotypes of PSP included the following [5]:
● PSP with Richardson syndrome (PSP-RS), the classic form of PSP, is characterized by
early onset of postural instability and falls, slowing of vertical saccades followed by a
supranuclear vertical gaze palsy, and cognitive dysfunction [63]. Axial rigidity is more
prominent than appendicular rigidity and retrocollis is often present. It makes up about 24
percent of PSP cases.
The other phenotypes described are based on what features are early and predominant, but
this distinction fades with the progression and development of other features. This scheme
was developed to try to improve early diagnosis.
● PSP with predominant parkinsonism (PSP-P) is characterized by asymmetric onset of limb

symptoms, including tremor, and a moderate initial therapeutic response to levodopa [63-65].
These cases are frequently confused with idiopathic Parkinson disease. PSP-P has a slower
rate of disease progression than PSP-RS [66]. Falls and cognitive impairment occur later in
PSP-P than in PSP-RS.
● PSP with predominant oculomotor dysfunction (PSP-OM) is characterized by

presentation with oculomotor features of PSP (eg, vertical supranuclear gaze palsy, slow
velocity of vertical saccades) and minimal or no evidence of postural instability, akinesia, or
cognitive dysfunction [8,17,47].
● PSP with predominant postural instability (PSP-PI) is characterized by presentation with

postural instability and delayed development of oculomotor dysfunction [17,67].
● PSP with progressive gait freezing (PSP-PGF) is characterized by early (initial feature or
frequently present in the first year) gait freezing, bradykinesia, rigidity, and unresponsiveness
to dopaminergic medications [8,68-71]. However, this syndrome can be the result of several
underlying diseases [72], as shown in a prospective study of nine patients with progressive
gait freezing who were followed for 6 to 16 years [71]. Three were ultimately diagnosed
clinically with PSP, one was diagnosed on clinical grounds with corticobasal syndrome (which
could have been a variant phenotype of PSP), and one patient each was diagnosed
pathologically with dementia with Lewy bodies and pallidonigroluysian degeneration.
● PSP with predominant frontal presentation (PSP-F) is characterized by cognitive

impairment or behavioral change attributed to frontal lobe dysfunction, including behavioral
variant frontotemporal dementia [47,73-75]. The most common PSP-F syndrome
encompasses features such as apathy, bradyphrenia, executive dysfunction, decreased
verbal fluency, disinhibition, impulsivity, and perseveration [8].
● PSP with predominant speech/language disorder (PSP-SL) presents with the

nonfluent/agrammatic variant of primary progressive aphasia or with progressive apraxia of
speech [76-80].
● PSP with predominant corticobasal syndrome (PSP-CBS) is characterized by progressive

asymmetric apraxia, dystonia, cortical sensory loss, alien limb syndrome, and levodopa
unresponsiveness [56,81-85]. PSP-CBS is a rare presentation of PSP pathology, and was
only present in six of 179 pathologically diagnosed PSP cases in the Queen Square Brain
Bank series [56]. Nevertheless, among the causes of CBS, PSP is second only to
corticobasal degeneration. (See "Corticobasal degeneration".)
● PSP with predominant cerebellar ataxia (PSP-C) is characterized by cerebellar ataxia as

the initial and principal symptom before developing the cardinal features of PSP-RS [86-90].
● PSP with predominant primary lateral sclerosis (PSP-PLS) is characterized by upper

motor neuron disease and degeneration of the corticospinal tracts [91,92].
Neuroimaging — In patients with PSP-RS, neuroimaging studies using CT and MRI of the brain
demonstrate generalized and brainstem atrophy, particularly involving the midbrain. The radiologic
"hummingbird sign" (image 1), also called the "penguin silhouette" sign, results from the prominent

midbrain atrophy with a relatively preserved pons, resembling a hummingbird or penguin in

silhouette on midsagittal MRI of the brain [93-95]. Superior cerebellar peduncle atrophy is
common in PSP and correlates with disease duration [96]. On axial T2-weighted MRI, profound
midbrain atrophy with concavity of the lateral margin of the midbrain tegmentum is termed the
"morning glory" flower sign [97].
The application of volumetric measures to assess the specificity of brainstem/midbrain atrophy

observed in PSP is discussed below. (See 'Potential disease markers' below.)
PATHOLOGY AND PATHOPHYSIOLOGY
Gross examination of the brain in patients with PSP reveals midbrain and, to a lesser extent,
cerebral cortical atrophy, hypopigmentation of the substantia nigra and locus ceruleus, and
enlargement of the third ventricle and Sylvian aqueduct [18,98]. Microscopic findings in PSP are
distinctive and prominent. The most consistent sites of pathology are in the basal ganglia,
particularly in the substantia nigra, subthalamic nucleus, cerebellum, and internal globus pallidus,
in addition to the oculomotor complex, periaqueductal gray matter, superior colliculi, basis pontis,
dentate nucleus, and prefrontal cortex [98]. Involvement of the cerebral cortex is also increasingly
recognized [25]. PSP pathology has also been reported in the spinal cord, explaining the possible
urinary disturbances [99].
The histologic characteristics of PSP include neuronal loss, gliosis, and the presence of tau-
positive filamentous inclusions in specific anatomic areas involving astrocytes, oligodendrocytes,
and neurons (picture 1). Tau cytoplasmic inclusions in surviving neurons, known as globose
neurofibrillary tangles, are classically described in PSP, but are not specific to PSP. Neurofibrillary
tangles are found also in Alzheimer disease, postencephalitic parkinsonism, dementia pugilistica
and other traumatic encephalopathies, and the parkinsonism-dementia complex of Guam. Tau-
positive inclusions commonly seen in oligodendrocytes are called "coiled bodies." When seen in
astrocytes, the tau-positive inclusions are called "tufted astrocytes," and these are now considered
a hallmark of PSP [100,101].
Ultrastructurally, the neurofibrillary tangles of PSP are composed of single straight tau filaments, in
contrast to the paired helical filaments that predominate in Alzheimer disease [102]. In other
neurodegenerative diseases with tau pathology, the tangles are flame-shaped; in PSP, they are
predominantly of the globose (globular) type. In addition to the neuronal and glial tau inclusions
characteristic of PSP, other abnormal aggregated proteins (eg, amyloid-beta, alpha synuclein, and
TDP-4), termed copathologies, are commonly present at autopsy in patients with a pathologic
diagnosis of PSP [103].
The major structural element of the neurofibrillary tangles in PSP is an abnormally phosphorylated
tau protein. Tau is a protein that is involved in axonal transport and stabilization of neuronal

microtubules. It is thought that abnormal phosphorylation of tau interferes with microtubule

function, impairs axonal transport, and leads to tau aggregation into neurofibrillary tangles. Normal
brain tau contains six isoforms that are generated by the alternative splicing of a single tau gene
on chromosome 17. Mutations in the microtubule associated protein (MAPT) tau gene have been
associated with frontotemporal dementia with parkinsonism (see "Frontotemporal dementia:
Epidemiology, pathology, and pathogenesis", section on 'MAPT gene'). Studies have emphasized
that PSP shares degree of genotypic overlap with corticobasal degeneration, as both disorders
are more frequently associated with homozygosity for the H1 tau haplotype (an association also
seen in Parkinson disease) [104,105]. Furthermore, a genome wide association study (see
'Genetic susceptibility' above) confirmed that the risk of PSP is associated with two independent
variants of the MAPT gene, one which influences MAPT brain expression [39]. In addition,
isoforms common to both PSP and corticobasal degeneration tauopathies are aggregates of the
four-repeat (4R) microtubule-binding domains that occur because of splicing of exon 10, in
contrast to other tau disorders, where the three-repeat (3R) form dominates in the aggregates
[106]. The normal ratio of 3R and 4R tau is approximately equal.
Neurochemical studies indicate that the degenerative process in PSP involves dopaminergic
neurons that innervate the striatum, as well as cholinergic and gamma-aminobutyric acid (GABA)
interneurons and efferent neurons, respectively, in the striatum and other basal ganglionic and
brainstem nuclei [107,108]. Postmortem studies of patients with PSP have demonstrated a
marked reduction in striatal D2 receptors, whereas the striatal D1 receptors are relatively spared
[109,110]. In the brainstem, degeneration of cholinergic neurons is observed in the Edinger-
Westphal nucleus, rostral interstitial nucleus of Cajal, the medial longitudinal fasciculus, superior
colliculus, and the pedunculopontine nucleus [111,112]. A reduction in the acetylcholine vesicular
transporter potentially may differentiate PSP from other types of neurodegenerative disorders
[113]. Glutamate is increased in the striatum, pallidum, nucleus accumbens, and occipital and
temporal cortex [114]. One postmortem study demonstrated a 50 to 60 percent reduction of the
GABAergic basal ganglia output neurons, which may, in part, explain the poor response to
dopaminergic therapy in most patients who have this disorder [115].
DIAGNOSIS
The diagnosis of PSP during life is based upon the clinical features. Suspicion for PSP is raised
when new-onset neurologic, cognitive, or behavioral deficits progress in absence of other
identifiable causes in a patient ≥40 years of age. The core clinical features include early postural
instability with falls; oculomotor deficits, especially slowing of vertical saccades followed by a
vertical gaze palsy; akinesia/parkinsonism; frontal lobe impairments, including speech and
language problems and behavioral change; and lack of response to levodopa. However, early
diagnosis is difficult as the disease varies quite a lot clinically.

No laboratory or imaging studies are diagnostic. Imaging can be supportive if there is predominant
midbrain atrophy on MRI, but the absence of this feature does not rule out the diagnosis of PSP,
especially in patients at the earliest stages or presenting with a non-Richardson syndrome
phenotype.
A levodopa trial in patients with parkinsonism and suspected PSP can assist with the diagnosis; a
poor or unsustained response to levodopa therapy is generally observed in patients with PSP and
can help to distinguish PSP from idiopathic Parkinson disease. (See 'Supportive features' below
and "Progressive supranuclear palsy (PSP): Management and prognosis", section on
'Pharmacologic treatments'.)
Neuropathologic examination remains the gold standard for its definitive diagnosis. The pathologic
diagnosis of PSP is based upon the identification of neurofibrillary tangles in a distribution
considered typical for PSP [116]. The diagnosis requires a high density of neurofibrillary tangles
and neuropil threads in the basal ganglia and brainstem [98]. As mentioned earlier, astrocytic
plaques and tau-positive tufts of abnormal fibers are highly characteristic of typical PSP [3].
Diagnostic criteria — In 2017, the Movement Disorder Society (MDS) proposed new diagnostic
criteria for PSP [5]. The MDS-PSP criteria include the following components:
● Basic features (inclusion and exclusion criteria) necessary for the diagnosis (see 'Inclusion
and exclusion criteria' below)
● Four core functional domains (ocular motor dysfunction, postural instability, akinesia, and
cognitive dysfunction) as characteristic manifestations of PSP (see 'Core features' below)
● Supportive clinical features that increase diagnostic confidence (see 'Supportive features'
below)
● Operationalized definitions for the core features and supportive features (see 'Operationalized
definitions' below)
● Four levels of diagnostic certainty (see 'Certainty levels' below)
Inclusion and exclusion criteria — Basic features for the diagnosis of PSP of any phenotype
and at any stage include mandatory inclusion criteria, mandatory exclusion criteria, and context-
dependent exclusion criteria [5].
● Mandatory inclusion criteria:
• Sporadic occurrence
• Age 40 years or older at onset of first PSP-related symptom
Consider any new-onset neurologic, cognitive, or behavioral deficit that subsequently

progresses during the clinical course in absence of other identifiable cause as a PSP-related
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symptom. Note that rare variants (mutations) of the MAPT gene may lead to inherited
phenocopies of sporadic PSP.
● Mandatory clinical exclusion criteria:
• Predominant, otherwise unexplained impairment of episodic memory, suggestive of

Alzheimer disease
• Predominant, otherwise unexplained autonomic failure (eg, orthostatic hypotension
suggestive of multiple system atrophy or Lewy body disease)
• Predominant, otherwise unexplained visual hallucinations or fluctuations in alertness,
suggestive of dementia with Lewy bodies
• Predominant, otherwise unexplained multisegmental upper and lower motor neuron
signs, suggestive of motor neuron disease (pure upper motor neuron signs are not an
exclusion criterion)
• Sudden onset or step-wise or rapid progression of symptoms, in conjunction with
corresponding imaging or laboratory findings, suggestive of vascular etiology,
autoimmune encephalitis, metabolic encephalopathies, or prion disease
• History of encephalitis
• Prominent appendicular ataxia
• Identifiable cause of postural instability (eg, primary sensory deficit, vestibular
dysfunction, severe spasticity, or lower motor neuron syndrome)
● Mandatory imaging exclusion criteria:
• Severe cerebral leukoencephalopathy

• Relevant structural abnormality (eg, normal pressure or obstructive hydrocephalus; basal
ganglia, diencephalic, mesencephalic, pontine or medullary infarctions, hemorrhages,
hypoxic-ischemic lesions, tumors, or malformations)
● Context-dependent imaging exclusion criteria:
• In syndromes with sudden onset or step-wise progression, exclude stroke, cerebral

autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) or severe cerebral amyloid angiopathy, evidenced by diffusion-weighted
imaging (DWI), fluid attenuated inversion recovery, or T2* MRI
• In cases with very rapid progression, exclude cortical and subcortical hyperintensities on
DWI-MRI suggestive of prion disease
● Context-dependent laboratory exclusion criteria:
• In patients with PSP-CBS, exclude primary Alzheimer disease pathology (typical

cerebrospinal fluid constellation [ie, both elevated total tau and phospho-tau protein and
reduced beta-amyloid 42] or pathological beta-amyloid PET imaging)

• In patients <45 years of age, exclude:
- Wilson disease
- Niemann-Pick disease, type C
- Hypoparathyroidism
- Neuroacanthocytosis
- Neurosyphilis
• In rapidly progressive patients, exclude:
- Prion disease
- Paraneoplastic encephalitis
- In patients with suggestive features (ie, gastrointestinal symptoms, arthralgias, fever,
younger age, and atypical neurologic features such as myorhythmia), exclude
Whipple disease
● Context-dependent genetic exclusion criteria:
• MAPT rare variants (mutations) are no exclusion criterion, but their presence defines
inherited, as opposed to sporadic PSP.
• MAPT H2 haplotype homozygosity is not an exclusion criterion, but renders the diagnosis
unlikely.
• LRRK2 and Parkin rare variants have been observed in patients with autopsy confirmed
PSP, but their causal relationship is unclear so far.
• Known rare variants in other genes are exclusion criteria, because they may mimic
aspects of PSP clinically, but differ neuropathologically; these include:
- Non-MAPT associated frontotemporal dementia (eg, C9ORF72, GRN, FUS,

TARDBP, VCP, CHMP2B)
- Parkinson disease (eg, SYNJ1, GBA)
- Alzheimer disease (APP, PSEN1, PSEN2)
- Niemann-Pick disease, type C (NPC1, NPC2)
- Kufor-Rakeb syndrome (ATP13A2)
- Perry syndrome (DCTN1)
- Mitochondrial diseases (POLG, mitochondrial rare variants)
- Dentatorubral pallidoluysian atrophy (ATN1)
- Prion-related diseases (PRNP)
- Huntington disease (HTT)
- Spinocerebellar ataxia (ATXN1, 2, 3, 7, 17)

Core features — Four core functional domains (ocular motor dysfunction, postural instability,
akinesia, and cognitive dysfunction) are the characteristic manifestations of PSP [5]. Within each
domain, there are three characteristic clinical features (table 1), which are stratified by presumed
level of certainty as 1 (highest), 2 (middle), and 3 (lowest).
● Ocular motor dysfunction:
• (O1) Vertical supranuclear gaze palsy

• (O2) Slow velocity of vertical saccades
• (O3) Frequent macro square wave jerks or "eyelid opening apraxia"
● Postural instability:
• (P1) Repeated unprovoked falls within three years

• (P2) Tendency to fall on the pull test within three years
• (P3) More than two steps backward on the pull-test within three years
● Akinesia:
• (A1) Progressive gait freezing within three years

• (A2) Parkinsonism, akinetic-rigid, predominantly axial, and levodopa resistant
• (A3) Parkinsonism, with tremor and/or asymmetric and/or levodopa responsive
● Cognitive dysfunction:
• (C1) Speech/language disorder, ie, nonfluent/agrammatic variant of primary progressive

aphasia or progressive apraxia of speech
• (C2) Frontal cognitive/behavioral presentation
• (C3) Corticobasal syndrome
Levels with lower numbers are considered to contribute higher certainty to a diagnosis of PSP
than levels with higher numbers [5].
Supportive features — Supportive features can increase diagnostic confidence but do not
qualify as diagnostic features [5]. They are divided into clinical clues and imaging findings.
● Clinical clues:
• (CC1) Levodopa resistance

• (CC2) Hypokinetic, spastic dysarthria
• (CC3) Dysphagia
• (CC4) Photophobia
● Imaging findings:
• (IF1) Predominant midbrain atrophy or hypometabolism

• (IF2) Postsynaptic striatal dopaminergic degeneration
Operationalized definitions — The MDS-PSP criteria provide detailed descriptions (table 1)

for each of the core features and supportive features to standardize the application of the
diagnostic criteria [5].
Certainty levels — The MDS-PSP criteria specify four levels of diagnostic certainty (table 2),
which are derived by combinations of core clinical features and clinical clues [5].
● Definite PSP, the gold standard, can be diagnosed only postmortem by neuropathological
examination.
● Probable PSP is diagnosed when clinical features with a high specificity are present.
● Possible PSP is diagnosed in the presence of clinical features considered to substantially
increase the sensitivity for PSP.
● Clinical syndromes suggestive of PSP encompass syndromes with features that may
constitute early or subtle evidence for PSP.
Predominance types — The MDS-PSP criteria determine clinical predominance types (table
2) based upon the combination of clinical features [5]. Recognized predominance types
correspond to the variant phenotypes discussed previously (see 'Variant phenotypes' above):
● PSP with Richardson syndrome (PSP-RS)

● PSP with predominant parkinsonism (PSP-P)
● PSP with predominant oculomotor dysfunction (PSP-OM)
● PSP with predominant postural instability (PSP-PI)
● PSP with progressive gait freezing (PSP-PGF)
● PSP with predominant frontal presentation (PSP-F)
● PSP with predominant speech/language disorder (PSP-SL)
● PSP with predominant corticobasal syndrome (PSP-CBS)
The MDS-PSP diagnostic criteria omitted two other recognized but rare variant phenotypes (PSP
with predominant cerebellar ataxia and PSP with predominant primary lateral sclerosis) because
the sparse clinicopathologic evidence about them was inadequate for devising clinical diagnostic
criteria with sufficient specificity [5].
Potential disease markers — There are no established laboratory or imaging markers for the
diagnosis of PSP. However, imaging findings of predominant midbrain atrophy, midbrain
hypometabolism, and postsynaptic striatal dopaminergic degeneration are supportive features
(see 'Supportive features' above) that increase diagnostic confidence [5]. Routine analysis of
blood and urine are normal. Routine investigations of cerebrospinal fluid (CSF) in PSP are also
normal.

Potential markers of PSP include levels of neurotransmitters and brain metabolites in the CSF, but
these are not validated for routine use.
As noted earlier (see 'Neuroimaging' above), neuroimaging of patients with PSP using CT and
MRI of the brain demonstrates generalized atrophy and brainstem atrophy, most pronounced in
the midbrain. A number of small studies have used volumetric measures in an attempt to assess
the specificity of this pattern of atrophy, and the following observations have been made [117-123]:
● The anterior-posterior diameter of the suprapontine midbrain was significantly lower in

patients with PSP than in patients with idiopathic Parkinson disease [117].
● The average midbrain area of patients with PSP (56 mm2) was significantly lower than in
patients with Parkinson disease (103 mm2) or multiple system atrophy-parkinsonism (97
mm2) [118]. The ratio of midbrain to pontine area was found to reliably differentiate the three
disorders.
● Compared with matched controls, the ratio of the midsagittal pons area to midbrain area was
significantly higher in the PSP group [119].
● The midbrain-to-pons ratio, measured from the anterior-posterior distance on midsagittal MRI,
was significantly reduced for patients with pathologically confirmed PSP compared with
controls and patients with pathologically confirmed multiple system atrophy or Parkinson
disease [123].
● Other studies have suggested that the magnetic resonance-parkinsonism index (MRPI) can
distinguish patients with PSP from those with Parkinson disease and other atypical
parkinsonian syndromes such as multiple system atrophy [120-122]. The MRPI requires
measurement of the area of the pons (P) and midbrain (M) and width of the middle cerebellar
peduncle (MCP) on sagittal T1-weighted MRI and the width of the superior (SCP) on coronal
MRI. The index is calculated from the formula MRPI = (P/M) × (MCP/SCP).
Positron emission tomography (PET) scanning reveals decreased glucose metabolism in the
midbrain as the earliest sign of PSP [124], followed by decreased metabolic activity in the
caudate, putamen, and prefrontal cortex as the disease progresses [125-127]. PET measures of
striatal dopamine D2 receptor density using 11C-raclopride showed a 24 percent reduction in D2
density in the caudate and 9 percent reduction in the putamen of patients with PSP, but this finding
has also been observed with other atypical parkinsonian syndromes as well [128]. (See "Diagnosis
and differential diagnosis of Parkinson disease", section on 'DaTscan'.)
Resting-state functional MRI (fMRI) may be a promising imaging biomarker for PSP. A small
prospective case-control study showed significant connectivity disruptions in the brainstem,
cerebellar, diencephalic, basal ganglia, and cortical regions as opposed to healthy controls [129].

Longitudinal electro-oculographic recordings may help to distinguish PSP from other parkinsonian
syndromes at early stages [130]. Patients with PSP have normal latency but decreased saccade
amplitude and velocity, whereas the opposite is observed in patients with corticobasal syndrome.
Many of these electrophysiologic tests have been used for research purposes and are not
generally available.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of PSP by common clinical symptoms and signs is listed in the table
(table 3). The disorders that are the most difficult to differentiate from PSP are the other
neurodegenerative parkinsonian disorders such as idiopathic Parkinson disease, corticobasal
degeneration, multiple system atrophy, and dementia with Lewy bodies, as well as vascular
parkinsonism.
Unsteady gait and freezing of gait appear early in the course of PSP-Richardson syndrome (PSP-
RS) and PSP with progressive gait freezing (PSP-PGF) compared with Parkinson disease. The
parkinsonism of PSP-RS differs from that of idiopathic Parkinson disease in ways other than the
early falling. Resting tremor is rare in PSP and rigidity tends to be much more pronounced in the
neck than the limbs. In contrast to the symptomatic benefit of levodopa in Parkinson disease, an
absent, poor, or rapidly waning response to levodopa is a characteristic feature of PSP. In addition,
the relative preservation of olfaction in PSP can help distinguish it from Parkinson disease, which
is characterized by hyposmia early in the course. (See "Diagnosis and differential diagnosis of
Parkinson disease", section on 'Olfactory testing'.)
The initial clinical presentation of PSP-parkinsonism (PSP-P) may resemble idiopathic Parkinson
disease, and the two disorders can be difficult to distinguish early on. However, with disease
progression, symptoms such as levodopa-induced dyskinesia, autonomic dysfunction, and visual
hallucinations are much less common in PSP-P, which can help distinguish it from Parkinson
disease [66]. Furthermore, patients with early PSP-P often lose their levodopa response and
develop other clinical features suggestive of PSP (eg, oculomotor abnormalities).
PSP-CBS refers to the clinical CBS phenotype of neuropathologically defined PSP, characterized
by a variable combination of progressive limb rigidity, apraxia, cortical sensory loss, alien limb, and
bradykinesia that is unresponsive to levodopa. PSP-CBS is a rare presentation of PSP pathology
and was present in only 6 of 179 pathologically diagnosed PSP cases in the Queen Square Brain
Bank series [56,66]. Patients with CBS frequently present with asymmetric signs, whereas in PSP-
RS they are usually but not always symmetric. The development of cortical sensory features,
ideomotor apraxia, myoclonus, severe dystonia, and increased latency of saccades should
suggest a diagnosis of corticobasal degeneration. However, since PSP-CBS is the second most
common cause of CBS after corticobasal degeneration, distinguishing these disorders is
extraordinarily difficult in life. Multiple system atrophy is considered in younger patients and in the
presence of severe autonomic signs or cerebellar disturbances. Nevertheless, these disorders

overlap enough (including the presence of gaze-evoked nystagmus in PSP) that clinical
differentiation may be difficult, especially in the early course of illness.
PSP and multiple system atrophy are the most likely causes of unexplained postural instability and
falls occurring within the first year of symptom onset [46]. Instability and falls in multiple system
atrophy are usually a symptom of orthostatic hypotension and autonomic disturbances, although
this may not be the case in the multiple system atrophy with predominant parkinsonism, in which
autonomic signs occur later [131]. By contrast, orthostatic hypotension is uncommon in PSP [132].
Instability or falls may develop in patients with corticobasal degeneration in the first year,
particularly when the first symptom affects a leg [1,4]. However, falls may occur early in dementia
with Lewy bodies, usually in association with significant cognitive disturbances [46]. In a case
series of 58 patients diagnosed with PSP, evidence of a multi-infarct state by CT, MRI, or autopsy
was found in 19 patients (33 percent) [133]. Other incorrect diagnoses that are often assigned to
older adult patients who fall include vestibulopathy, myelopathy, basilar artery ischemia, cardiac
syncope, and epilepsy [134].
Although supranuclear gaze palsy is a key feature in diagnosing all subtypes of PSP, it may
occasionally be present in other disorders, such as dementia with Lewy bodies, Alzheimer
disease, idiopathic Parkinson disease, vascular parkinsonism, multiple system atrophy, prion
disease (eg, Creutzfeldt-Jakob disease), Whipple disease, or corticobasal degeneration
[46,131,135]. In PSP, the vertical supranuclear palsy precedes the development of the horizontal
gaze palsy, but in corticobasal degeneration, ocular motor apraxia usually precedes the
supranuclear gaze palsy, which usually affects both the horizontal and vertical gaze [46]. The
saccades in corticobasal degeneration have increased latency but normal speed, and are similarly
affected in the vertical and horizontal plane, whereas in multiple system atrophy, the saccades
have normal speed and latency. Blink rate, diminished in idiopathic Parkinson disease and multiple
system atrophy, is usually less impaired in PSP. In addition, the upward gaze palsy, which may be
the first indication of an ocular motor abnormality, should be differentiated from the limitation of
upward gaze observed in "normal" older adult patients, in whom saccades have normal speed
[46].
A midbrain or third ventricular tumor could cause vertical gaze palsy, extensor truncal rigidity, and
pyramidal symptoms and/or incoordination [1,136]. A tumor of the pineal gland can produce the
so-called Parinaud syndrome characterized by limited upgaze, sluggishly reactive and large
pupils, and retraction nystagmus.
Because patients with PSP usually exhibit early frontal lobe cognitive disturbances, and
sometimes frank dementia, they can be confused with cortical dementias such as frontotemporal
dementia or Alzheimer disease. Pseudobulbar palsy, especially early in the disease course, can
be confused with depression and other psychiatric illnesses. In cases of PSP with rapidly
progressive moderate to severe dementia, Creutzfeldt-Jakob disease might be suspected.
On rare occasions, patients who manifest classic features of PSP, including eye movement
abnormalities, early falls, and parkinsonism, will be found to have the pathology of other disorders
including multiple system atrophy, corticobasal degeneration, Alzheimer disease, and idiopathic
Parkinson disease [137].
MANAGEMENT AND PROGNOSIS
The management and prognosis of PSP is discussed in detail separately. (See "Progressive
supranuclear palsy (PSP): Management and prognosis".)
SUMMARY AND RECOMMENDATIONS
● As originally described, progressive supranuclear palsy (PSP) is characterized by progressive

supranuclear ophthalmoplegia, gait disorder and postural instability, dysarthria, dysphagia,
rigidity, and frontal cognitive disturbance. PSP is now recognized to encompass a number of
phenotypic variants. The two most common are Richardson syndrome (the classic form of
PSP) and PSP-parkinsonism. (See 'Historical background' above.)
● PSP is the most common degenerative form of atypical parkinsonism. The mean age of onset
for PSP is approximately 65 years. No cases of PSP have been reported in patients younger
than age 40 years. (See 'Epidemiology' above.)
● With the most common "classic" phenotype of PSP, known as Richardson syndrome (PSP-
RS), the most frequent initial feature is a disturbance of gait resulting in falls. Supranuclear
ophthalmoparesis or plegia is the hallmark of PSP but may come on later. An important earlier
manifestation is slowing of vertical saccades. Dysarthria, dysphagia, rigidity, frontal cognitive
abnormalities, and sleep disturbances are additional common clinical features. PSP with
predominant parkinsonism (PSP-P) is characterized by asymmetric onset of limb symptoms,
tremor, and a moderate initial therapeutic response to levodopa. It may be confused with
idiopathic Parkinson disease. (See 'Clinical characteristics' above and 'Variant phenotypes'
above.)
● Additional variant phenotypes of PSP are classified as early predominance types, based upon
their presentation and early clinical manifestations. These include (see 'Variant phenotypes'
above and 'Predominance types' above):
• PSP with predominant oculomotor dysfunction (PSP-OM)

• PSP with predominant postural instability (PSP-PI)
• PSP with progressive gait freezing (PSP-PGF)
• PSP with predominant frontal presentation (PSP-F)
• PSP with predominant speech/language disorder (PSP-SL)
• PSP with predominant corticobasal syndrome (PSP-CBS)
● The radiologic hummingbird sign (also called the penguin silhouette sign) results from the
prominent midbrain atrophy in PSP with a relatively preserved pons, resembling a
hummingbird or penguin in silhouette on midsagittal MRI of the brain (image 1). (See
'Neuroimaging' above.)
● The most consistent sites of microscopic findings in PSP are in the basal ganglia, particularly
in the substantia nigra, subthalamic nucleus, and internal globus pallidus, in addition to the
oculomotor complex, periaqueductal gray matter, superior colliculi, basis pontis, and dentate
nucleus. Involvement of the cerebral cortex is also increasingly recognized. The histologic
characteristics of PSP include neuronal loss, gliosis, and the presence of tau-positive
filamentous inclusions in specific anatomic areas involving astrocytes (most notably the
hallmark finding of tufted astrocytes), oligodendrocytes, and neurons (picture 1). Tau
cytoplasmic inclusions in surviving neurons, known as globose neurofibrillary tangles, are
classically described in PSP, but are not specific to PSP. (See 'Pathology and
pathophysiology' above.)
● The diagnosis of PSP during life is based upon the clinical features. Suspicion for PSP is
raised when new-onset neurologic, cognitive, or behavioral deficits progress in absence of
other identifiable cause in a patient ≥40 years of age. The core clinical features include
postural instability, oculomotor deficits, especially vertical gaze palsy, akinesia/parkinsonism,
and frontal lobe impairments, including speech and language problems and behavioral
change. No laboratory or imaging studies are diagnostic. Neuropathologic examination
remains the gold standard for its definitive diagnosis. (See 'Diagnosis' above and 'Diagnostic
criteria' above.)
● The differential diagnosis of PSP by common clinical symptoms and signs is listed in the table
(table 3). The disorders that are the most difficult to differentiate from PSP are the other
neurodegenerative parkinsonian disorders such as idiopathic Parkinson disease, corticobasal
degeneration, multiple system atrophy, and dementia with Lewy bodies, as well as vascular
parkinsonism. (See 'Differential diagnosis' above.)
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Topic 14136 Version 20.0

GRAPHICS
"Penguin" or "hummingbird" sign and midbrain atrophy

in progressive supranuclear palsy
Midsagittal MRI of the brain demonstrates prominent midbrain atrophy without

pontine atrophy (divided by white line), forming the silhouette of the "penguin"
or "hummingbird" sign.
MRI: magnetic resonance imaging.
Reproduced with permission from: Graber JJ, Staudinger R. Teaching NeuroImages:

"Penguin" or "hummingbird" sign and midbrain atrophy in progressive supranuclear
palsy. Neurology 2009; 72:e81. Copyright © 2009 Lippincott Williams & Wilkins.
Graphic 78365 Version 6.0

Microscopic neuropathology of progressive supranuclear palsy (PSP)
The patient was diagnosed clinicaly with PSP-parkinsonism, a variant of classic PSP. The substantia
nigra (A-E) shows neuronal loss and gliosis. Several surviving neurons contain globose
neurofibrillary tangles (NFTs) (A, arrows). Tau immunostaining (B) demonstrates the NFTs (arrows)
and numerous thread-like processes. The globose NFT expands the cytoplasmic profile of residual
neurons (A-C) and its characteristic coiled "ball of yarn configuration" is highlighted by routine
silver preparations (D) and tau (E). Tau-immunoreactive neuroglial lesions are widespread and
include NFTs (arrows), pretangles (arrowhead), tufted astrocytes (thin arrows), and threads in
neocortex (F) and striatum (G). Selective anti-4R tau decorates a tufted astrocyte in the
subthalamic nucleus (H) and an oligodendroglial coiled body (I) in the internal capsule, as well as
numerous thread-like deposits.
A, C: hematoxylin-eosin; B, E-G: anti-tau; D: Bielschowsky; H, I: anti-4R tau; A, B: original

magnification x200; C-E, H, I: original magnification x600; F, G: original magnification x400.
Reproduced with permission from: Golbe LI, Boeve BF, Keegan BM, Parisi JE. An 81-year-old man with
imbalance and memory impairment. Neurology 2007; 68:1147. Copyright © 2007 Lippincott Williams &
Wilkins.

Operationalized definitions of core clinical features, supportive clinical clues, and

supportive imaging findings for the diagnosis of progressive supranuclear palsy
(PSP)
Domain Feature Definition
Ocular motor dysfunction
O1 Vertical supranuclear gaze palsy A clear limitation of the range of voluntary gaze in the vertical
more than in the horizontal plane, affecting both upgaze and
downgaze, more than expected for age, which is overcome by
activation with the vestibulo-ocular reflex; at later stages, the
vestibulo-ocular reflex may be lost, or the maneuver prevented by
nuchal rigidity.
O2 Slow velocity of vertical Decreased velocity (and amplitude) of vertical greater than
saccades horizontal saccadic eye movements; this may be established by
quantitative measurements of saccades, such as infrared
oculography, or by bedside testing; gaze should be assessed by
command ("Look at the flicking finger") rather than by pursuit
("Follow my finger"), with the target >20 degrees from the position
of primary gaze; to be diagnostic, saccadic movements are slow
enough for the examiner to see their movement (eye rotation),
rather than just initial and final eye positions in normal subjects; a
delay in saccade initiation is not considered slowing; findings are
supported by slowed or absent fast components of vertical
optokinetic nystagmus (ie, only the slow following component may
be retained).
O3 Frequent macro square wave Macro square wave jerks are rapid involuntary saccadic intrusions
jerks or "eyelid opening apraxia" during fixation, displacing the eye horizontally from the primary
position, and returning it to the target after 200 to 300
milliseconds; most square wave jerks are <1 degree in amplitude
and rare in healthy controls, but up to 3 to 4 degrees and more
frequent (>10/minute) in PSP. [1] "Eyelid opening apraxia" is an
inability to voluntarily initiate eyelid opening after a period of lid
closure in the absence of involuntary forced eyelid closure (ie,
blepharospasm); the term is written in quotation marks because
the inability to initiate eyelid opening is often attributed to
activation of the pretarsal component of the orbicularis oculi (ie,
pretarsal blepharospasm) rather than failure to activate the levator
palpebrae.
Postural instability
P1 Repeated unprovoked falls Spontaneous loss of balance while standing, or history of more
within 3 years than one unprovoked fall, within 3 years after onset of PSP-related
features.
P2 Tendency to fall on the pull-test Tendency to fall on the pull-test if not caught by examiner, within 3
within 3 years years after onset of PSP-related features. The test examines the
response to a quick, forceful pull on the shoulders with the
examiner standing behind the patient and the patient standing
erect with eyes open and feet comfortably apart and parallel, as
described in the MDS-UPDRS item 3.12.
P3 More than two steps backward More than two steps backward, but unaided recovery, on the pull-
on the pull-test within 3 years test, within 3 years after onset of PSP-related features.
Akinesia
A1 Progressive gait freezing within Sudden and transient motor blocks or start hesitation are
3 years predominant within 3 years after onset of PSP-related symptoms,
progressive and not responsive to levodopa; in the early disease
course, akinesia may be present, but limb rigidity, tremor, and
dementia are absent or mild.
A2 Parkinsonism, akinetic-rigid, Bradykinesia and rigidity with axial predominance, and levodopa
predominantly axial and resistance (refer to Clinical Clue CC1 for operationalized definition).

levodopa resistant
A3 Parkinsonism, with tremor Bradykinesia with rigidity and/or tremor, and/or asymmetric
and/or asymmetric and/or predominance of limbs, and/or levodopa responsiveness (refer to
levodopa responsive Clinical Clue CC1 for operationalized definition).
Cognitive dysfunction
C1 Speech/language disorder Defined as at least one of the following features, which has to be
persistent (rather than transient):
1. Nonfluent/agrammatic variant of primary - Loss of grammar
and/or telegraphic speech or writing progressive aphasia
(nfaPPA) or
2. Progressive apraxia of speech (AOS) - Effortful, halting
speech with inconsistent speech sound errors and distortions
or slow syllabically segmented prosodic speech patterns with
spared single-word comprehension, object knowledge, and
word retrieval during sentence repetition.
C2 Frontal cognitive/behavioral Defined as at least three of the following features, which have to be
presentation persistent (rather than transient):
1. Apathy - Reduced level of interest, initiative, and spontaneous
activity; clearly apparent to informant or patient.
2. Bradyphrenia - Slowed thinking; clearly apparent to informant
or patient.
3. Dysexecutive syndrome - Eg, reverse digit span, Trails B or
Stroop test, Luria sequence (at least 1.5 standard deviations
below mean of age- and education-adjusted norms).
4. Reduced phonemic verbal fluency - Eg, "D, F, A, or S" words
per minute (at least 1.5 standard deviations below mean of
age- and education-adjusted norms).
5. Impulsivity, disinhibition, or perseveration - Eg, socially
inappropriate behaviors, overstuffing the mouth when eating,
motor recklessness, applause sign, palilalia, echolalia.
C3 CBS Defined as at least one sign each from the following two groups
(may be asymmetric or symmetric):
1. Cortical signs
a. Orobuccal or limb apraxia.
b. Cortical sensory deficit.
c. Alien limb phenomena (more than simple levitation.)
2. Movement disorder signs
a. Limb rigidity.
b. Limb akinesia.
c. Limb myoclonus.
Clinical clues
CC1 Levodopa resistance Levodopa resistance is defined as improvement of the MDS-UPDRS

motor scale by ≤30%; to fulfill this criterion patients should be
assessed having been given at least 1000 mg (if tolerated) at least
1 month OR once patients have received this treatment they could
be formally assessed following a challenge dose of at least 200 mg.
CC2 Hypokinetic, spastic dysarthria Slow, low volume and pitch, harsh voice.
CC3 Dysphagia Otherwise unexplained difficulty in swallowing, severe enough to

request dietary adaptations.
CC4 Photophobia Intolerance to visual perception of light attributed to adaptative

dysfunction.
Imaging findings
IF1 Predominant midbrain atrophy Atrophy or hypometabolism predominant in midbrain relative to

or hypometabolism pons, as demonstrated, eg, by MRI or [ 18F]DG-PET.
IF2 Postsynaptic striatal Postsynaptic striatal dopaminergic degeneration, as demonstrated,

dopaminergic degeneration eg, by [ 123I]IBZM-SPECT or [ 18F]-DMFP-PET.

Reference:
1. Otero-Millan J, Serra A, Leigh RJ, et al. Distinctive features of saccadic intrusions and microsaccades in progressive
supranuclear palsy. J Neurosci 2011; 31:4379.
From: Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The
Movement Disorder Society criteria. Mov Disord 2017; 32:853.
http://onlinelibrary.wiley.com/wol1/doi/10.1002/mds.26987/abstract. Copyright © 2017 International Parkinson and
Movement Disorder Society. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is
owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed.
Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by
clicking on the 'Request Permission' link accompanying this article on Wiley Online Library
(http://onlinelibrary.wiley.com).

Degrees of diagnostic certainty for progressive supranuclear palsy (PSP),

obtained by combinations of clinical features and clinical clues
Combinations
Diagnostic of clinical Predominance
Definition Abbreviation
certainty features and type
clinical clues
Definite PSP Gold standard Neuropathological Any clinical Definite PSP

defining the disease diagnosis presentation
entity.
Probable PSP Highly specific, but (O1 or O2) + (P1 or PSP with Probable PSP-RS
not very sensitive for P2) Richardson's
PSP. syndrome (PSP-RS)
Suitable for (O1 or O2) + A1 PSP with progressive Probable PSP-PGF
therapeutic and gait freezing (PSP-
biological studies. PGF)
(O1 or O2) + (A2 or PSP with Probable PSP-P

A3) predominant
parkinsonism (PSP-
P)
(O1 or O2) + C2 PSP with Probable PSP-F

predominant frontal
presentation (PSP-F)
Possible PSP Substantially more O1 PSP with Possible PSP-OM

sensitive, but less predominant ocular
specific for PSP. motor dysfunction
Suitable for (PSP-OM)
descriptive O2 + P3 PSP-RS Possible PSP-RS
epidemiological
A1 PSP-PGF Possible PSP-PGF
studies and clinical
care. (O1 or O2) + C1 PSP with Possible PSP-SL
predominant
speech/language
disorder (PSP-SL)*
(O1 or O2) + C3 PSP with Possible PSP-CBS

predominant
corticobasal
syndrome (PSP-
CBS)*
Suggestive of PSP Suggestive of PSP, O2 or O3 PSP-OM Suggestive of PSP-

but not passing the OM
threshold for
P1 or P2 PSP with Suggestive of PSP-PI
possible or probable
predominant
PSP.
postural instability
Suitable for early (PSP-PI)
identification.
O3 + (P2 or P3) PSP-RS Suggestive of PSP-
RS
(A2 or A3) + (O3, PSP-P Suggestive of PSP-P

P1, P2, C1, C2, CC1,
CC2, CC3, or CC4)
C1 PSP-SL Suggestive of PSP-

SL
C2 + (O3 or P3) PSP-F Suggestive of PSP-F
C3 PSP-CBS Suggestive of PSP-

CBS

The basic features (mandatory inclusion and exclusion criteria, and context-dependent exclusion criteria; refer to
UpToDate text for details) apply for all probable, possible, and suggestive degrees of certainty. Core clinical
features are defined by their functional domain (ocular motor dysfunction [O], postural instability [P], akinesia
[A], and cognitive dysfunction [C]), and stratified by presumed levels of certainty (1 = highest, 2 = middle, 3 =
lowest) that contribute to the diagnosis of PSP. Supportive clinical clues are described in the UpToDate text.
Operationalized definitions of clinical features and clinical clues are described in a separate UpToDate table.
CC1: levodopa resistance; CC2: hypokinetic, spastic dysarthria; CC3: dysphagia; CC4: photophobia.
* Probable 4R-tauopathy (ie, either PSP or corticobasal degeneration).
From: Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The Movement
Disorder Society criteria. Mov Disord 2017; 32:853. http://onlinelibrary.wiley.com/wol1/doi/10.1002/mds.26987/abstract.
Copyright © 2017 International Parkinson and Movement Disorder Society. Reproduced with permission of John Wiley &
Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be
downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email:
permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this
article on Wiley Online Library (http://onlinelibrary.wiley.com).

Differential diagnosis of progressive supranuclear palsy (PSP) by common

clinical symptoms and signs
Oculomotor Cognitive
Parkinsonism Falls
abnormalities dysfunction
Idiopathic Parkinson Multiple system atrophy Multiple system atrophy Alzheimer disease
disease Corticobasal Corticobasal Corticobasal
Corticobasal degeneration degeneration degeneration
degeneration Dementia with Lewy Vascular parkinsonism Frontotemporal
Multiple system atrophy bodies Alzheimer disease dementia
Dementia with Lewy Vascular parkinsonism Dementia with Lewy
bodies Vestibulopathy bodies
Vascular parkinsonism Myelopathy Whipple disease
Basilar artery ischemia Creutzfeldt-Jakob
Cardiac syncope disease
Epilepsy Huntington disease
Drop attacks Spinocerebellar ataxias
Midbrain/third ventricle
tumor
Niemann-Pick disease
type C
Kufor-Rakeb syndrome
Perry syndrome

Contributor Disclosures
Stewart A Factor, DO Grant/Research Support: Ipsen [Dystonia]; Medtronics [Parkinson
disease/Huntington disease]; Boston Scientific [Movement disorders (Deep brain stimulation system)]; Teva
[Tardive dyskinesia]; US World Meds; Voyager; Jazz Pharmaceuticals; Michael J Fox Foundation; Sunovion
[Parkinson disease]; Eli Lilly [Parkinson disease (LY3154207)]; Vaccinex; CHDI Foundation [Huntington
disease]; NIH [Neuroscience (Network for Excellence in Neuroscience Clinical Trials)]. Consultant/Advisory
Boards: Teva [Tardive dyskinesia]; Lundbeck [Orthostatic hypotension]; Sunovion; Biogen; Acadia;
Neuroderm; Acorda; CereSpir [Parkinson disease]. Other financial interest: Bracket [Video review for PD
trials]; Blackwell Futura; Demos; Springer [Royalties]. Christine Doss Esper, MD Consultant/Advisory
Boards: NeuroOne [Deep brain stimulation]. Howard I Hurtig, MD Nothing to disclose April F Eichler, MD,
MPH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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Progressive supranuclear palsy (PSP): Clinical features

Other neurodegenerative parkinsonian syndromes are discussed separately. (See "Clinical

https://www.uptodate.com/contents/progressive-supranuclear-palsy-psp-clinical-features-and-diagnosis/print?search=supranuclear palsy&sourc… 1/38

Genetic susceptibility — Although PSP is considered to be a sporadic disorder, some

Dysarthria, dysphagia, pseudobulbar palsy, rigidity, bradykinesia, frontal cognitive abnormalities,

Oculomotor findings — Supranuclear ophthalmoparesis or ophthalmoplegia is the hallmark of

Motor involvement — Bradykinesia with marked micrographia is a primary feature of

https://www.uptodate.com/contents/progressive-supranuclear-palsy-psp-clinical-features-and-diagnosis/print?search=supranuclear palsy&sourc… 4/38

Cognitive and behavioral abnormalities — The neuropsychological profile of PSP primarily

● PSP with predominant parkinsonism (PSP-P) is characterized by asymmetric onset of limb

● PSP with predominant oculomotor dysfunction (PSP-OM) is characterized by

● PSP with predominant postural instability (PSP-PI) is characterized by presentation with

● PSP with predominant frontal presentation (PSP-F) is characterized by cognitive

● PSP with predominant speech/language disorder (PSP-SL) presents with the

● PSP with predominant corticobasal syndrome (PSP-CBS) is characterized by progressive

● PSP with predominant cerebellar ataxia (PSP-C) is characterized by cerebellar ataxia as

● PSP with predominant primary lateral sclerosis (PSP-PLS) is characterized by upper

https://www.uptodate.com/contents/progressive-supranuclear-palsy-psp-clinical-features-and-diagnosis/print?search=supranuclear palsy&sourc… 7/38

midbrain atrophy with a relatively preserved pons, resembling a hummingbird or penguin in

The application of volumetric measures to assess the specificity of brainstem/midbrain atrophy

PATHOLOGY AND PATHOPHYSIOLOGY

https://www.uptodate.com/contents/progressive-supranuclear-palsy-psp-clinical-features-and-diagnosis/print?search=supranuclear palsy&sourc… 8/38

microtubules. It is thought that abnormal phosphorylation of tau interferes with microtubule

https://www.uptodate.com/contents/progressive-supranuclear-palsy-psp-clinical-features-and-diagnosis/print?search=supranuclear palsy&sourc… 9/38

● Four levels of diagnostic certainty (see 'Certainty levels' below)

● Mandatory inclusion criteria:

Consider any new-onset neurologic, cognitive, or behavioral deficit that subsequently

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● Mandatory clinical exclusion criteria:

• Predominant, otherwise unexplained impairment of episodic memory, suggestive of

● Mandatory imaging exclusion criteria:

• Severe cerebral leukoencephalopathy

● Context-dependent imaging exclusion criteria:

• In syndromes with sudden onset or step-wise progression, exclude stroke, cerebral

● Context-dependent laboratory exclusion criteria:

• In patients with PSP-CBS, exclude primary Alzheimer disease pathology (typical

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• In patients <45 years of age, exclude:

• In rapidly progressive patients, exclude:

● Context-dependent genetic exclusion criteria:

- Non-MAPT associated frontotemporal dementia (eg, C9ORF72, GRN, FUS,

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● Ocular motor dysfunction:

• (O1) Vertical supranuclear gaze palsy

• (P1) Repeated unprovoked falls within three years

• (A1) Progressive gait freezing within three years

• (C1) Speech/language disorder, ie, nonfluent/agrammatic variant of primary progressive

• (CC1) Levodopa resistance

• (IF1) Predominant midbrain atrophy or hypometabolism

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• (IF2) Postsynaptic striatal dopaminergic degeneration

Operationalized definitions — The MDS-PSP criteria provide detailed descriptions (table 1)

● PSP with Richardson syndrome (PSP-RS)

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● The anterior-posterior diameter of the suprapontine midbrain was significantly lower in

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presence of severe autonomic signs or cerebellar disturbances. Nevertheless, these disorders

MANAGEMENT AND PROGNOSIS

SUMMARY AND RECOMMENDATIONS

● As originally described, progressive supranuclear palsy (PSP) is characterized by progressive

• PSP with predominant oculomotor dysfunction (PSP-OM)