COGNITIVE DISORDERS

Mirjana Milutinovic MD
Professor SJSM
Man is brought to the ED, muttering about being persecuted
by a secret organization.
During the evaluation he is disorganized, distractible, and
from time to time dozes off
in the middle of a sentence. Family members deny previous
psychiatric or substance abuse
history, but they add that lately the patient had complained of
fatigue and increased thirst.
The toxic screen is negative and glucose level is 500 mg/dL.
Choose the most likely diagnosis:
a. Delirium
b. Psychotic depression
c. Brief psychotic episode
d. Paranoid schizophrenia
e. Dementia
Cognitive Disorder

Delirium
Dementia
Amnesia
Goals
Know the difference between cognitive disorders
Understand and evaluate cognitive disorders
objectives
1.Understand the differentiation and differential
diagnosis of different types of cognitive disorders
2. Know the underlying pathophysiology of cognitive
disorders.
3. Understand the special susceptibilities of patients
with cognitive disorders
Literature
Bate`s guide to Physical Examination
Power point presentation and notes from the lessons
EBESCO journal
Swartz, Mark H: Textbook of Physical Diagnosis: History
and examination
Orientation
 Patient’s ability to know
who he or she is
 What date and time it is
 Who his or her present
circumstances are
 Order of loss:
 1st time
 2nd place
 3rd person
 (situation)
 Common causes of
orientation loss
 Alcohol, Drugs
 Fluid- electrolyte
imbalance
 Hypoglycemia
 Nutritional deficiency
 Head trauma
Congnitive disorder
 Amnesia

 Retrograde: inability to remember things

 that occurred before the CNS insult
 Anterograde: inability to remember things that
 occurred after the CNS insult
 Korsakoff’s: anterograde amnesia caused by thiamine deficiency
(may lead to retrograde amnesia)
 bilateral destruction of mammillary bodies
 in alcoholic, associated with confabulation
 Psychogenic: Dissociative: inability to recall important personal
information, usually subsequent to sever trauma or stress
 transient global amnesia and Situation-specific amnesia
most common etiologies for amnestic syndromes:
The etiologies for amnestic syndromes can be divided according to their anatomic location:
• Medial temporal lobes—hypoxia, herpes simplex encephalitis, early AD, posterior cortical atrophy
(PCA), strokes (thalamic and temporal lobe), surgery
• Diencephalon—Korsakoff’s syndrome (thiamine deficiency), thalamic strokes, surgery
• Basal forebrain—anterior communicating artery aneurysm bleed or clipping (with damage to the
small perforating arteries)
• Substances—alcohol, benzodiazepines (transient, not permanent)
 stages of memory storage

Registration
short-term memory
Consolidation

Retrieval
Memory: Declarative or explicit memories: semantic
and episodic
(recent memory, remote memory, prospective memory)
and
Nondeclarative or implicit memories

memory difficulties with frontal lobe lesions

 DELIRIUM

 Cause:delirium tremens due to

withdrowe of alcohol
 Uremia
 Acute hepatic failure
 Acute cerebral vasculitis
 Atropine poisoning
Cause
 Acute intermittent porphyria
 Cardiovascular diseases: Arrhythmias, congestive heart failure
 Central nervous system disorders: Brain trauma, epilepsy, infections, neoplasm, stroke,
 subdural hematoma, vasculitis
 Drugs of abuse (in intoxication or withdrawal): Alcohol, barbiturates, benzodiazepines,
 narcotics
 Electrolyte imbalances
 Endocrine disorders: Adrenal insufficiency, hypoglycemia, parathyroid dysfunction
 Medications: Anticholinergics, anticonvulsants, antihypertensive agents, antiparkinsonian
 agents, cimetidine, digitalis, ranitidine, steroids
 Pulmonary disorders: Hypercarbia, hypoxemia
 Sepsis
 Uremia
 Vasculitis
 Vitamin deficiencies: B12, folic acid, thiamine
 risk factors for delirium, the most common being age (particularly older than the age of
80), preexisting cognitive impairment, dehydration and electrolyte disturbances
 and gender (men more so than women)
DELIRIUM
 Onset ………………….acute
Course………………… fluctuating, with
 lucid intervals, worse at
 night-SUNDOWNING
 Duration……………….hours or weeks
 Sleep/woke …………… always disrupted
 Med.illnes/drug toxicity…either or both
 present
DELIRIUM Mental status:

 Level of consciousness
 disturbed , person less clearly aware of
the environment and les able to focus,
sustain or shift attention
behaviour:
 activity often abnormally decreased
(somnolence) or


increased (agitation, hypervigilance)

speech…
 may be hesitate, slow or rapid,
incoherent
mood
 fluctuating, labile, from fearful, or
irritable to normal or depressed
Tought process
Tought content
 disorganized, may be incoherent

delusions
Perceptions
 illusions, hallucinations, often visual
Judgment
 impaired, often to a varying degree
Orientation
 usually disoriented, especially for time,
a known Place may seem unfamiliar
Attention
 fluctuates, person easily distracted
unable to concentrate on selected task

memory
 immediate and recently memory
impaired
diagnosis

 Suspicious to delirium
 The presentation of acute mental status change, abnormal attention, and a
 fluctuating course, disorganized thinking

 The diagnosis
 History
 Evaluating level of attention
 Neurological examination (may not show focal signs or may show myoclonus, dysarthria,
tremor, motor abnormalities, or asterisks)

 Laboratory evaluation: glucose, blood urea nitrogen (BUN), liver function studies, electrolyte
levels, a complete blood count (CBC), or
 evaluate endocrinopathy
 pulse oximetry in patient with lung diseases
 urine toxicology in suspicious to drug abuse
 ECG in cardiology diseases
 EEG in encephalopathy, or CSF examination in suspicious of CNS infection
  
DIFFERENTIAL DIAGNOSIS
TREATMENT
 identification and correction of
 the underlying abnormality

 low doses of high potency

 antipsychotics (such as droperidol or
haloperidol),

 Other non pharmacologic approaches involve

strategies to help facilitate the orientation of
the patient
Example:
 An 82-year-old man presents to the emergency room with acute disorientation,
hallucinations, and agitation. He had been healthy until last year when he
developed diabetes mellitus and suffered a myocardial infarction. His
examination is normal except for the symptoms mentioned above. Which of the
following is the best next step?

 A. Obtain a stat CT scan of the head followed by a lumbar puncture

 B. Review his medication list and talk to family or caregivers about

 his cognitive state earlier that week

 C. Obtain a CBC with dialysis/plasma urea ratio (D-P), comprehensive

 metabolic panel, and urinalysis

 D. Begin treatment with risperidone 25

 Assessment of Mental Status
MMSE
guestion score

 Orientation:
 What is the (year) (season) (date)  1 point for each correct
(day) (month)? answer (5)
 Where are we?(state) (country)
(town) (office) (floor) 5 points
 1 point for each correct
answer (5)
 Registration:
 Name 3 objects, taking 1 second
to name each. Then ask the  1 point for each correct
patient to repeat them. 1 point for answer (3)
each correct.
 Attention and Calculation:
 Ask the patient to count
backwards from 100 in 7s. Stop  1 point for each correct
after 5 answers. answer
 Alternatively, ask the patient to
spell “world” backwards
MMSE
guestion score
 Recall:
 Ask the patient for the 3 objects  1 point for each correct answer
named under “Registration”. (3)
 Language:
 Point to two objects and ask the
patient to name them (pen and  1 point for each correct answer
watch). (2)
 Ask the patient to repeat “No ifs,
ands, or buts.”  1 point for correct answer (1)
 Ask the pt. to follow a 3-step
command: “Take this paper in your
right hand, fold it in half, and put it
on the table.”
 1 point for each correct task
(3)
 Ask the pt. to read and obey the
following: “Close your eyes.”  1 point for correct task (1)
 Write a sentence.
 Copy a drawing of intersecting  1 point for correct task (1)
pentagons.  1 point for correct task (1)
 Total (30)
 Interpretation of the MMSE

method score interpretation

Single cutoff <24 abnormal
severity 24-30 No cognitive impairment
18-23 Mild cognitive impairment
0-17 Severe cognitive impairment
 DEGENERATIVE
AND DEMENTING
DISORDERS

major neurocognitive disorder instead of dementia.

Goals and Objectives
 Goals: To learn about the difference between
degenerative disorders
 Understand and evaluate degenerative
disorders
 Objectives: At the end of this lecture,
students will be able to understand pathology
of degenerative disorders, its common features,
diseases and diagnosis. They will be able to
explain the clinical implications of these
diseases and demonstrate the understanding of
the principles of the diagnosis.
 dementia
Dementia: loss of cognitive ability, memory,
and function, with intact consciousness
 dementia
 symptoms
 Consciousness:
• Memory loss
• Confusion about the location of familiar places
• Taking longer to accomplish normal, daily tasks
• Trouble handling money and paying bills
• Compromised judgment, often leading to bad decisions
• Loss of spontaneity and sense of initiative
• Mood and personality changes; increased anxiety
dementia
 A syndrome characterized by prominent memory disturbance
coupled with other
 memory disturbances

 Risk factors/Etiology: Caused by at least 80 different diseases

and positive family history, (chromosome 21-Down Syndrome)
 Alzheimer type presents 65% of dementias in patients older
than 65, prevalence increased with age, more often in women
than in men
 Less risk for higher educated, not linked for early head trauma
 neurodegenerative disease with dementia: front-temporal
degenerations, Alzheimer, Parkinson, Huntington, Pick, and
Creutzfeldt-Jakob disease
 Other symptoms of severe AD can
include the following:

 Weight loss
 Seizures, skin infections, difficulty swallowing
 Groaning, moaning, or grunting
 Increased sleeping
 Lack of bladder and bowel control

 In end-stage AD, patients may be in bed much or all of

the time. Death is often the result of other illnesses,
frequently aspiration pneumonia.
dementia
Dementia-diagnosis
 Examination: CNS motor pathology
 Physical exam
 Neurologic exam
 Mental status exam
 Other: Multiinfarct (second most common in
elderly), normal pressure hydrocephalus (only
curable dementia)
 Syphilis, HIV, B12 deficiency, Wilson disease
Dementia
In dementia always assess TSH, B12, and VDRL

 Basic labs
 Thyroid function tests
 B12 (methyl malonic acid and homocysteine if
borderline)
 Serology VDRL
 HIV, drug screen, others, as indicated
 Neuroimaging study, usually
 EEG, rarely
CT and MRI
 Diffuse atrophy of the brain
 Flattened cortical sulci
 Enlarged ventricles
 Deficient blood flow in parietal lobes,
correlate with cognitive decline
 Reduction in choline acetyl transferase
 Reduced metabolism in parietal and
temporal lobe
 The Dementias

Frequent Less Frequent

Alzheimer disease Pick disease
Lewy body dementia Primary subcortical degenerations:
Parkinson disease, multiple system
atrophy, Huntington
disease, progressive supra nuclear
palsy
Vascular dementia Prion diseases (Creutzfeldt-Jakob)
Mixed Alzheimer Normal pressure hydrocephalus
and vascular dementia
 Alzheimer dementia
Alzheimer Diagnosis is clinical:
Excludes other, diagnosis is conformed on autopsy

In elderly in Down syndrome

Cortical atrophy, low Ach

Senile plaques-beta amyloid, neurofibrillary tangle in

cells-insoluble cytoskeletal elements
Tangle correlate with degree of dementia
Alzheimer disease

Alzheimer disease (AD) causes 60% of all cases

of dementia, with incidence of 2% at 65 years
and doubling every 5 years. Risk factors include
aging, significant head trauma, and familiarity;
aluminum is an epiphenomenon, not a risk
factor. Protective factors include a high level of
education and smoking.
a. Genetic factors. 5-10% of Alzheimer disease
cases are hereditary, early onset, and
transmitted as an autosomal dominant trait.
 Alzheimer disease

b. Pathology. Alzheimer disease is characterized by accumulation of abnormal proteins

intracellularly and extracellularly.
i. Abnormal proteins. AB amyloid is a 42-residue peptide derived from a normal
transmembrane protein, the amyloid precursor protein (APP). There is also an abnormal
tau (a rnicrotubule-associated protein) .
ii. Neritic plaques have a core of AB amyloid surrounded b y dystrophic neuritic/dendritic
processes and associated with microglia and astrocytes.
iii. Neurofibrillary tangles are intraneuronal aggregates of insoluble cytoskeletal elements,
mainly composed of abnormally phosphorylated tau forming paired helical filaments.
iv. Cerebral amyloid angiopathy refers to accumulation of AB amyloid within the media of
small and medium-size intracortical and leptomeningeal arteries; it may occur by itself and
cause intracerebral hemorrhage.
v. Additional changes include granulovacuolar degeneration and Hirano bodies, which
develop in the hippocampus and are less significant diagnostically.
vi. Location. Lesions involve the neocortex, hippocampus, and several subcortical nuclei
including forebrain cholinergic nuclei (i.e., basal nucleus of Meynert) . Affected areas are
involved in learning and memory. The earliest and most severely affected are the
hippocampus and temporal lobe. Small numbers of neuritic plaques and neurofibrillary
tangles also form in intellectually normal aging persons.
vii. Macroscopic changes include atrophy of affected regions, producing brains that are smaller
(atrophic), with thinner gyri and wider sulci. Hippocampi and temporal lobes are markedly
atrophic
Alzheimer disease

c. Clinical manifestations have insidious onset,

beginning usually in the seventh or eighth decade.
 They include progressive memory impairment,
especially related to recent events; alterations in
mood and behavior; progressive disorientation; and
aphasia (loss of language skills) and apraxia (loss
of learned motor skills) .
 Within 5-10 years, patients become mute and
bedridden.
 No effective treatment is available, but there is
mild improvement with inhibitors of
acetylcholinesterase (e.g., tacrine).
A 70-year-old man is under evaluation for memory
difficulty that, according to his wife, began insidiously
3 or 4 years earlier. He has difficulty remembering
recent events. For example, he forgets appointments
and recent conversations, and forgot that a close
relative had recently died. He is no longer able to
manage his own check book. Medical history is
unremarkable. Physical examination is normal. Mental
status examination shows prominent memory loss
and difficulty drawing a complex figure. What is the
most likely diagnosis
45
Lewy body dementia:
Parkinsonism with dementia
and hallucination
*Lewy body in neurons in
neocortex and subcortical nuclei
(basal of Meynert, amygdala, s
nigra)
Not known risk factors,
Lewy body dementia

Lewy body dementia is a progressive brain disease associated

with the formation of Lewy bodies in neurons involving
neocortex and subcortical nuclei. The etiopathogenesis is
obscure, with no known risk factors; it is the second leading
cause of degenerative dementia in the elderly.
a. Pathology. The histopathological hallmark is the Lewy body
(see Parkinson disease) . Neuron loss accompanies Lewy body
formation. Sites involved include the neocortex (especially the
limbic system and cingulate gyrus), and subcortical nuclei,
including basal nucleus of Meynert, amygdala, and substantia
nigra.
b. Pathophysiology. The involvement of the neocortex and
substantia nigra is responsible for cognitive deterioration and
parkinsonism. Clinical manifestations include memory loss,
parkinsonism, and visual hallucinations. There is a possible
treatment benefit from cholinesterase inhibitors.
 Case study
 A 70-year-old woman came to the clinic with her son for assessment of her cognitive
decline. The son is concerned about her short-term memory problems for the past 10
months. Patient had a fall 10 months ago; after that fall, she started to ask the same
questions over and over. Patient had another fall 4 months ago and also an episode of
dizziness 2 months ago. With these incidents, her son noticed further decline in cognition.
Recently, her son noticed that she has become a bit more suspicious of her daughter-in-
law and has been hoarding things. She has lost interest in her day-to-day activities and
forgets to include the right ingredients when cooking. Family has to remind her to take her
medications, and her son is helping with the management of her finances.

 The patient has hypertension, diabetes, coronary artery disease, osteoarthritis, and
osteoporosis. On the Mini-Mental Status Examination (MMSE), the patient scored 21/30
with abnormal clock drawing. On the Geriatric Depression Scale (GDS), the patient scored
2/15. CT scan of the head showed multiple lacunar infarcts in the right basal ganglia and
left cerebellar region.
 continue

The patient has hypertension, diabetes, coronary

artery disease, osteoarthritis, and osteoporosis.
On the Mini-Mental Status Examination (MMSE), the
patient scored 21/30 with abnormal clock drawing. On
the Geriatric Depression Scale (GDS), the patient
scored 2/15.
CT scan of the head showed multiple lacunar infarcts
in the right basal ganglia and left cerebellar region.
49
 Vascular dementia
Vascular-multi-infarct dementia-vascular cognitive impairment
The 3 most common mechanisms of vascular dementia are
multiple cortical infarcts,
a strategic single infarct, and
small vessel disease.
Mixed Alzheimer and vascular
is diagnosed when patients have evidence of Alzheimer dementia
and cerebrovascular disease, either clinically or based on
neuroimaging evidence of ischemic lesions. Growing evidence
indicates that vascular dementia and Alzheimer dementia often
coexist, especially in older patients with dementia. Autopsy studies
have shown an association between Alzheimer disease and vascular
lesions
Alzheimer/Vascular dementia
 Less frequent dementias
*Pick disease

*Primary subcortical degenerations:

Parkinson, Huntington,
progressive supranuclear palsy,
multiple system atrophy

*Prion

*Normal pressure hydrocephalus

 Dementia-Pick disease
Personality changes search for them on exam,
in practice it is rare dementia
Pick disease-fronto temporal
dementia before memory loss
cannot make decisions different to
Alzheimer
Change in personality, aphasia,
parkinsonian aspect
Spare parietal lobe
Picks body-aggregate tau protein
temporal lobe
Frontotemporal atrophy

ballooned neurons
Pick's disease
?
 A 62 y/o caucasian male is brought to your office by his daughter.The
daughter says that her father has been acting strangely over the last
yr.she says that he makes inappropriate jokes, is irritable and is even
aggressive at times.In speaking with the pt, u noticed dysarthria.This
pt most likely has a condition involving which of the following?

A-Substantia nigra
B-Nucleus cuadatus
C-Parietal Cortex
D-Hippocampus
E-Frontal Cortex
F-Subthalamic nucleus
 55
 Causes of Dementia

Creutzfeldt Jakob disease, Prion disease: rapidly

progressive dementia with myoclonus, extrapyramidal signs,
spongiform cortex

Vague somatic complains and unspecified anxiety, ataxia,

choreoathetosis, dysarthria
No treatment
Rapid, progressive (week to month) surviving
is about 7 month
Huntington Chorea

Huntington Chorea
Autosomal dominant, males and
females equally affected, defect in
chromosome 4
Basal ganglia and caudate atrophy
Choreoathetoid movements and
dementia
Dementia progressing later to
psychosis and infantile state
Suicide is common
Caused by chronic HIV encephalitis and myelitis In 95% of
patients before death
Early signs:
Dysphoric mood
Apathy
Social withdrawal
At the beginning misdiagnosed as depression
HIV levels in spinal fluid predictor of onset
Cognitive symptoms
Forgetfulness, loss of concentration, confusion
Behavioural symptom: Apathy, dysphoric mood, psychosis
Motor system: Loss of balance, leg weakness, poor handwriting
DIFFERENTIAL DIAGNOSIS
 dementias are
amnestic disorders
 generally progressive diseases acute
conditions
 of older individuals varying
ages
 cognitive deficits follow
head trauma

Pseudo dementia symptoms and

signs of dementia but not dementia
but depression
Ganser’s syndrome
DIFFERENTIAL DIAGNOSIS

 Dementia illnesses can often be

mistaken for depressive illnesses
 cognitive examination:
 patients with dementia minimize their
disability
 with depression make little effort
The goals of treatment

 (1) improve cognitive function

 (2) reduce behavioral and psychological
 symptoms
 (3) improve the quality of life
  
TREATMENT
 In Alzheimer dementia
 acetylcholinesterase inhibitors are used to increase
the levels of acetylcholine in the central nervous system
 Memantine (an N-methyl-D-aspartate [NMDA] receptor
antagonist) is indicated
 in moderate to severe Alzheimer dementia, often in
combination with
 acetylcholinesterase inhibitors
 Tacrine has been found to be somewhat effective in
patients with mild-to moderate
 symptoms
Example:

 Which one of these abnormalities on the

neurologic exam would be
 unusual in a patient with mild AD?

 A. Problems drawing a clock

 B. Impaired sense of smell
 C. Hyperreflexia with positive Babinski signs
 D. Impaired short-term memory
A 68-year-old man presents with several weeks of unsteady
gait, forgetfulness, and urinary incontinence. He denies
headache or any recent trauma. His past medical history is
significant only for meningitis as a child. On physical
examination, blood pressure is 130/85 mm Hg and heart
rate is 82 beats/min. His neurologic examination is normal
except for a stiff, “magnetic” gait. The patient scores a 22
on the mini-mental status examination. After a lumbar
puncture, the gait disturbance improves. What is the most
likely diagnosis?
DEGENERATIVE AND
DEMENTING DISORDERS
. Parkinson disease
1. Parkinson disease and syndrome. These conditions are both due
to loss of dopaminergic neurons in the substantia nigra, leading
to tremor, rigidity, and akinesia. Parkinson disease is the
idiopathic form. Parkinson syndrome is secondary to known
injuries to the substantia nigra (e.g., infections, vascular
conditions, toxic insults) .
a. Epidemiology. Parkinson disease is a common disease that
affects 2% of the population. It arises in the fifth to eighth
decade of life, and does not have any known genetic-familial,
sex, or race predisposition.
b. Etiopathogenesis. Loss of dopaminergic neurons is still
unexplained in Parkinson disease. Theories emphasize oxidative
stress. Accidental exposure to l -methyl-4-phenyl- 1 ,2,3,6-
tetrahydropyridine (MPTP) (a by-product of illicit synthesis of a
meperidine [Demerol] analogue) causes death of dopaminergic
neurons in substantia nigra.
Parkinson disease
 Parkinson disease
 Decreased dopamine in substantia nigra
 Symptoms
 Bradykinesia
 Resting tremor
 Pill-rolling tremor
 Mask-like facies
 Cogwheel rigidity
 Shuffling gait
Parkinson disease
c. Pathology. Grossly, there is pallor of the substantia nigra. Histology
shows loss of pigmented ( dopaminergic) neurons in the substantia
nigra. Other features include Lewy bodies, which are
intracytoplasmic round eosinophilic inclusions that contain a-
synuclein; electron microscopy shows filaments most likely of
cytoskeletal origin. There is also a secondary degeneration of
dopaminergic axons in the striatum.
d. Pathophysiology. Loss of the extrapyramidal nigrostriatal pathway
leads to inhibition of movement of proximal muscles and disruption
of fine regulation of distal muscles. The pathophysiologic basis of
Parkinson disease-associated dementia is not clear.
e. Clinically, there is slowing of all voluntary movements; tremor at rest
which disappears during movement; expressionless face; and
rigidity of limbs and trunk accompanied by an inability to initiate
voluntary movement. There is an increased incidence (20-40% of
patients) of dementia and depression. Levodopa is the treatment of
choice, usually combined with other drugs.

Initiate treatment of symptomatic Parkinson’s disease?

Carbidopa/levodopa is the appropriate first choice of medication
Amantadine is unlikely to have a major impact upon the symptoms
 Huntington disease 4

2. Huntington disease (HD) is an autosomal dominant disorder characterized

pathologically by the degeneration of GABA-ergic neurons of the caudate
nucleus, and clinically by chorea and dementia.
a. Epidemiology. HD affects those of northwestern European descent and has
an incidence in high-prevalence regions of 1 /12,000-20,000. No cases are
known due to new mutations. The HD gene is located on chromosome 4
and codes for a protein called huntingtin. Mutations are due to expansion of
an unstable trinucleotide repeat. HD shows features of anticipation and
genomic imprinting.
b. Pathology. Gross examination shows atrophy of the caudate nucleus with
secondary ventricular dilatation. Histology shows loss of small neurons in
the caudate nucleus followed by loss of the larger neurons. The
pathophysiology is that loss of caudate nucleus GABA-nergic neurons
removes inhibitory influences on extrapyramidal circuits, thus leading to
chorea.
c. Clinical manifestations. The disease manifests between age 20 and 40. The
chorea is characterized by sudden, unexpected, and purposeless
contractions of proximal muscles. Patients may also have changes in
personality, marked tendency for suicide, and dementia. Genetic diagnosis
is possible but controversial. Treatment is with antipsychotic drugs (e.g.,
haloperidol).
 Amyotrophic lateral
sclerosis

Amyotrophic lateral sclerosis (ALS) refers to degeneration and

loss of upper and/or lower motor neurons that usually
manifests in middle age. The clinical diagnosis is supported by
a biopsy of muscles. The etiopathogenesis is obscure, but 5-
10% of cases are hereditary, with a small number being due
to mutation of the gene encoding zinc-copper superoxide
dismutase on chromosome 2 1 .
a. Loss of upper motor neurons produces hyperreflexia and
spasticity. In some cases, involvement of cranial nerve nuclei
also occurs
b. Loss of lower motor neurons produces weakness, atrophy,
and fasciculation.
Amyotrophic Lateral Sclerosis
(ALS)
a. Primary lateral sclerosis
(corticospinal tract)
b. Progressive spinal muscular
atrophy (ventral horn)
Friedreich ataxia

Friedreich ataxia is an autosomal recessive disorder with onset in early

childhood leading to degeneration of nerve tissue in the spinal cord,
especially those sensory neurons connected to the cerebellum affecting
muscle movement of the arms and legs.
a. Genetics. Friedreich ataxia is due to the expansion of an unstable triplet
nucleotide repeat (GAA repeats in the first intron) in the frataxin gene on
chromosome 9. The frataxin protein is essential for mitochondrial function
by helping in mitochondrial iron regulation; in the absence of frataxin,
mitochondrial iron builds up, leading to free radial damage and
mitochondrial dysfunction.
b. Pathology. The mitochondrial dysfunction leads to degeneration
involving multiple groups of neurons:
 Dorsal root ganglia
 Clarke column (origin of spinocerebellar tract)
 Neurons of posterior column of spinal cord
 Cranial nerve nuclei of VII, X, and XII
 Dentate nucleus and Purkinje cells of cerebellum
 Betz neurons of primary motor cortex
c. Clinical manifestations include gait ataxia, dysarthria, hand clumsiness, loss
of sense of position, impaired vibratory sensation, and loss of tendon
reflexes. Patients become wheelchair-bound by age 5 years.
Wilson disease

Wilson disease is an autosomal recessive genetic abnormality

of the Wilson disease protein which leads to defective
synthesis of ceruloplasmin and copper accumulation in the
liver and brain.
 Some patients develop cirrhosis as children or teenagers,
while others present with neuropsychiatric symptoms and
ataxia (due to basal ganglia involvement) in their 20s and 30s.
 Other problems that may occur include Kayser-Fleisher
(golden brown) rings in Descemet membrane of the eye, renal
tubular acidosis, cardiomyopathy, and hormonal disturbances
Acute intermittent porphyria is an autosomal dominant
defect in porphyrin metabolism with deficient
uroporphyrinogen synthase. Both porphobilinogen and
aminolevulinic acid increase.
 Urine is initially colorless but on exposure to light turns dark
red. Patients may develop recurrent severe abdominal pain,
psychosis, neuropathy, and dementia.
Vitamin B l 2 deficiency
Vitamin B l 2 deficiency.
 In addition to megaloblastic anemia, vitamin Bl2 deficiency causes
demyelination of the spinal cord posterior columns and lateral
corticospinal tracts (subacute combined degeneration of the spinal
tract) .
 Vitamin B l 2 deficiency also causes dementia and peripheral
neuropathy.

Alcohol abuse causes generalized cortical and cerebellar atrophy, as

well as Wernicke-Korsakoff syndrome.
 The neurologic disease is usually related to thiamine deficiency.
There can be hemorrhages in mamillary bodies and walls of third
and fourth ventricles.
 Neuronal loss and gliosis may be prominent. Wernicke
encephalopathy has reversible confusion, ataxia, and nystagmus.
 Korsakoff psychosis is more severe and has irreversible anterograde
and retrograde amnesia.
 Central pontine myelinolysis (see earlier section in this chapter) may
cause death.