Transcript Demyelinating and Neurodegenerative

CNS Pathology
- Demyelinating Diseases
- Neurodegenerative diseases
Associate Professor
Dr. Alexey Podcheko
Spring 2015
Demyelinating diseases
Conditions characterized by a preferential
damage to myelin, with relative preservation of
axons
Diseases of oligodendrocyte / myelin sheath
Clinical deficits are due to the effect of myelin
loss on the transmission of electrical impulses
along axons
Examples include:
– Leukodystrophies
– Multiple Sclerosis (MS)
– Acute Disseminated Encephalomyelitis
(ADEM)
Leukodystrophies
Inherited mutations in enzymes necessary for
production or maintenance of myelin
The characteristics of leukodystrophies are:
Age: infancy through adolescence
Lysosomal or peroxisomal enzyme defects
Involve both the CNS and the PNS
Disease is progressive, resulting in death at an
early age
Metachromatic Leukodystrophy
• Most Common type of
Leukodystrophy
• Genetic Deficiency of
arylsulfatase enzyme
• Myelin can not be
degraded – accumulates in
lysosomes
• Loss of myelin and gliosis
• Macrophages containing
sulfatides (when the
sulfatides bind some types
of dyes, they change the
absorbance spectrum, called metachromasia
Here the macrophages are
clustered around a vessel, as
well as scattered in the
parenchyma.
Krabbe's Disease (Globoid Cell
Leukodystrophy)
• Defect in galactocerebroside bgalactosidase
• A breakdown product of
galactocerebroside is toxic
causing oligodendrocyte injury
• Autosomal Recessive
• Pathology characterized by
– loss of myelin and
oligodendrocytes (and
Schwann cells in the PNS)
– reactive astrogliosis
– multinucleated macrophages
called globoid cells accumulate
around blood vessels (blue
arrows)
•Severe sensory, motor
and cognitive defects
•Death within 1-2 years
Adrenoleukodystrophy
• X-linked (Note: this is the disease that was the
topic of the film Lorenzo's Oil)
• Impaired addition coenzyme A to long-chain
fatty acids
• lack of catabolism of very long chain fatty acids
(VLCFA's) in peroxisomes, and increased
levels of VLCFA's can be found in serum
• Atrophy of the ADRENAL gland
• CNS Pathology consists of
– myelin loss - LEUKODYSTROPHY
– gliosis
– lymphocytic inflammation
Adrenoleukodystrophy
• Clinical Features:
• Children 3-10 years old
• Severe sensory, motor and cognitive
defects
• Adrenal failure (Addison Disease)
• Rx: Manipulation with dietary lipid
composition
Multiple Sclerosis
Autoimmune destruction of CNS myelin and
oligodendrocytes
Most common demyelinating disorder
More commonly seen in regions away from
equator
Prevalence ~ 1 per 1000 persons in US
Onset at any age
– Relatively rare in childhood or after age 50
Women > men
2:1
Multiple Sclerosis
Etiology:
– Not clearly established
– Implicated factors:
Environmental
Genetic
Immune Factors: associated with HLA DR2
Multiple Sclerosis - Clinical features
Demyelinating lesions can occur
anywhere in the central nervous
system and, as a consequence,
may induce a wide range of
symptoms
Common clinical presentation:
Blurred vision in one eye (optic
nerve)
Vertigo
Scanning speech (brainstem)
Internuclear ophtalomoplegia
(damage of medial longitudinal
fasciculus)
Multiple Sclerosis - Clinical features
Hemiparesis or unilateral loss of sensation
(cerebral white matter injury)
Lower extremity loss of sensation or weakness
(spinal cord)
Bowel, bladder and sexual dysfunction (ANS
injury)
Natural course of multiple sclerosis is variable
Episodes of neurologic deficits develop over
short periods of time (days to weeks) and show
gradual partial remission
Frequency of relapses tends to decrease over
the course of time
A 29-year-old Caucasian female complains of decreased
vision and pain around her eye, which is aggravated
by eye movement. Several months later she is found
to have an intention tremor of her left arm. This
patient’s condition is most likely caused by:
A. Bacterial infection
B. Vascular disease
C. Trauma
D. Autoimmune disease
E. Inherited metabolic disease
F. Intoxication
Corr D
Explanation:
The patient’s complaints of pain with ocular movements and decreased vision are consistent with
optic neuritis. Intention tremor is a sign of cerebellar dysfunction. Both of these symptoms are
commonly seen in multiple sclerosis. Waxing and waning neurological deficits in a 20-30 year
old patient are suggestive of this disorder.
The etiology of multiple sclerosis remains unknown. Currently, it is considered an autoimmune
disease, with viral and environmental factors also playing a role in its pathogenesis. The
autoimmune character of this disorder is supported by the following features:
1. There is an elevated immunoglobulin G (lgG) level in the cerebrospinal fluid (CSE). It is seen as
an oligoclonal band on electrophoresis and suggests an activation of B cells in multiple
sclerosis.
2. The incidence of multiple sclerosis is increased in people with certain HLA types.
3. Immunomodulatory agents, such as interferon beta, have a positive impact on multiple sclerosis.
Its mechanism is counteraction of the inflammatory action of immune cells.
Environmental factors are also important in the pathogenesis of MS. This disease is much more
common in temperate latitudes. Its prevalence is 30-50 times as high in the USA, Canada and
Northern Europe as it is in equatorial Africa.
The factors listed in the other choices do not participate in the development of multiple sclerosis.
Educational Objective:
Multiple sclerosis is viewed as an autoimmune condition. Viral and environmental factors are also
considered to play a role in its development. Increased levels of lgG in the CSF, detected as an
oligoclonal band on electrophoresis, supports the immunologic theory.
Diagnosis of MS
1. Lumbar puncture:
a. elevated immunoglobulin G
(lgG) level in the
cerebrospinal fluid seen as
oligoclonal band on
electrophoresis (due to
activation of B cells)
b. Increased level of
lymphocytes
c. Myelin basic protein
2. MRI : reveals plaques
Multiple Sclerosis-Morphology
MS is a white matter disease
Gross examination:
Foci of demyelination appear as glassy, gray
lesions
Microscopic examination:
Characteristic multiple lesions scattered in white
matter - Plaques
Plaque!!!
Subacute Sclerosing Panecephalitis
Progressive debilitating encephalitis leading to
death
Result of slowly progressing infection of the brain
by measles virus
Clinical signs develop several years after
measles, with extensive brain damage leading
to death usually within one to two years after
onset
Morphology –
intranuclear, eosinophilic inclusion bodies with
associated demyelination and gliosis
Subacute Sclerosing Panencephalitis (SSPE)
Associated with measles (rubeola) virus either
as a primary infection or , rarely, as a
complication of immunization against measles
since it is a live attenuated vaccine!!!!
Progressive Multifocal
Leukoencephalopathy
• JC virus infection of oligodendrocytes
• Immunosuppression leads to reactivation of
latent virus
• Prominent in the pathology of AIDS and
patients who are immunocompromised
(leukemia)
• Present with rapidly progressive neurological
signs leading to death
• Dementia, myoclonic fasciculations; normal
funduscopic exam; no other focal neurologic signs
Central Pontine Myelinolysis
Focal demyelination of pons
Caused by rapid Intravenous correction of hypo
Na emia
Occurs in severely malnourished patients
Present as acute paralysis (“Locked in”
syndrome)
Locked-in syndrome is a condition in which a patient is aware and awake but
cannot move or communicate verbally due to complete paralysis of nearly all
voluntary muscles in the body except for the eyes
Degenerative Diseases
Are diseases of gray matter
Characterized principally by:
– Progressive loss of neurons with associated
secondary changes in white matter tracts.
– Pattern of neuronal loss is selective, affecting one
or more groups of neurons, while leaving others
intact.
– Disease arises without any clear inciting event in a
patient without previous neurologic deficits
Degenerative Diseases
Degenerative Diseases Affecting the Cerebral
Cortex – lead to dementia!!!
– Alzheimer’s disease (AD)
– Vascular dementia
– Pick’s disease
Degenerative Diseases of Basal Ganglia and
Brain Stem – lead to movement disorders!!!
Spinocerebellar Degenerations
Degenerative Diseases Affecting Motor
Neurons
Degenerative Diseases Affecting the Cerebral Cortex
Major cortical degenerative diseases are
– Alzheimer’s disease (AD) – MC cause of dementia!
– Vascular Dementia
– Pick’s disease
– Levy body dementia
– Vascular disease (multi-infarct dementia)
– Creutzfeldt-Jakob disease
– Neurosyphilis
Dementia is not part of normal aging and
always represents a pathologic process.
Alzheimer’s Disease
Insidious impairment of higher intellectual function,
with alterations in mood and behavior, F:M=2:1
Later, progressive disorientation, memory loss, and
aphasia indicate severe cortical dysfunction, and
eventually, over 5 to 10 years, the patient becomes
profoundly disabled, mute, and immobile
Down Syndrome patients become symptomatic before
50 years of age
Although pathologic examination of brain tissue
remains necessary for the definitive diagnosis of AD,
the combination of clinical assessment and modern
radiologic methods allows for a diagnostic accuracy of
80 to 90%.
Alzheimer’s Disease (AD)-Morphology
Major microscopic abnormalities of AD are
– Neurofibrillary tangles
– Senile (neuritic) plaques
– Amyloid angiopathy
Diagnosis of AD is based on a clinicopathologic
correlation between the patient’s neurologic
status and the frequency of plaques and
tangles
Morphology
1. Hydrocephalus ex
vacuo
2. Neuritic plaques
(extracellular AB
amyloid + Neuritic
processes)
3. Neurofibrillary
tangles are
intracytoplasmic
intraneuronal
accumulations of
polymerized
hyperphosphorylate
d tau microtubular
protein (arrows).
Alzheimer’s Disease
• DIFFUSE!!!! Cortical atrophy (right side meninges
removed)
Pathogenesis of AD
1. hypothetical mechanism for the formation of senile plaques (SP) from soluble
APP peptides produced inside cells and secreted into the extracellular space.
Conversion of normal tau protein overlying two microtubules into paired helical filaments.
Overactive kinase(s) or hypoactive phosphatase(s) may contribute to this effect.
Abnormally phosphorylated tau loses the ability to bind microtubules, thus causing
their depolymerization, disruption of axonal transport and degeneration of neurons.
Clinical Features
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Slow-onset of memory loss
Progressive disorientation
Loss of learned motor skills and language
Behavior and personality changes
Patients become mute and bedrdden
Focal neurologic deficits not seen early
Risk Factors
Sporadic form of AD
a. Age
b. Presence of E4 allele of ApoE
(E2 allele decreases risk)
Early form of AD:
a. Presenillin 1 (MC) and 2
b. Down Syndrome due to APP is on the
chromosome 21
Vascular Dementia
• Due to multifocal infarction and injury
• Due to Hypertension, Atherosclerosis or
Vasculitis
• Second most common cause of dementia!!!!!
• Better prognosis, partially reversible
Pick’s Disease
Pick’s disease occurs far less frequently than
Alzheimer’s disease but is also clinically
manifested as profound dementia over a
comparable time course.
The brain in Pick’s disease invariably
exhibits a pronounced atrophy of the frontal
and temporal lobes with conspicuous sparing
of the posterior two-thirds of the superior
temporal gyrus
The atrophy can be severe, reducing the gyri to
a thin wafer (“knife-edge” appearance).
Behavioral and language symptoms arise early;
progress to dementia
Pick’s Disease
Microscopically:
Neuronal loss is most
severe in the outer three
layers of the cortex and
may be severe enough to
resemble superficially
(pseudo)laminar necrosis
Round aggregates of Tau
protein (not tangles as in
AD!!!!) in neurons (Pick
cells or Pick bodies)
Degenerative Diseases of Basal Ganglia and Brain Stem
Diseases affecting these regions of the brain
frequently are associated with movement disorders,
including rigidity, abnormal posturing, and chorea.
In general, they can be categorized as manifesting
either:
– A reduction of voluntary movement
– An abundance of involuntary movement.
The nigro-striatal pathway plays an important role in
the system of positive and negative regulatory
synaptic pathways that serve to modulate feedback
from the thalamus to the motor cortex.
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Parkinsonism
Idiopathic Parkinson’s Disease (IPD)
Progressive Supranuclear Palsy
Multiple System Atrophies
Huntington’s Disease
Normal interactions between nigra-striatal complex and
cortex of the brain
SN Pc
Substantia Nigra
parts compacta
Dopamine
BG (STRIATUM)
D2
D1
Dopamine
receptors
increase
stimulation
Dopamine receptors
Decrease inhibition
Cortex
Parkinsonism
Parkinsonism is a clinical syndrome characterized by
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Tremor “Pill-rolling” tremor
Rigidity
Akinesia/Bradikynesia
Postural instability and shuffling gait
Diminished facial expression
Stooped posture
Slowness of voluntary movement
Festinating gait (progressively shortened, accelerated steps)
This type of motor disturbance is seen in a number of
conditions that have in common damage to the nigrostriatal
dopaminergic system
Parkinsonism may also be induced by drugs that affect this
system
– Dopamine antagonists
– Toxins (notably, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
[MPTP ])
The principal diseases that involve the
nigrostriatal system are
– Idiopathic Parkinson’s disease
– Striatonigral degeneration
– Lewy body dementia
Idiopathic Parkinson’s Disease (IPD)
Patients with progressive parkinsonism in the
absence of a toxic or other known etiology.
As in Alzheimer’s disease, it is seen with
increasing frequency in older age cohorts.
In addition to the movement disorder, there are
other less well-characterized changes in mental
function, and a few patients with the pathologic
findings of idiopathic Parkinson’s disease
present with a dementia clinically similar to that
of Alzheimer’s disease.
Idiopathic Parkinson’s Disease
The dopaminergic neurons of the substantia nigra
project to the striatum, and their degeneration in
Parkinson’s disease is associated with a reduction in
the striatal dopamine content.
The severity of the motor syndrome is proportional to
the dopamine deficiency
Can be partly corrected by replacement therapy with
L-dopa (the immediate precursor of dopamine)
Treatment does not, however, reverse the
morphologic changes or arrest the progress of the
disease, and with progression, drug therapy tends to
become less effective, and symptoms become more
difficult to manage.
Idiopathic Parkinson’s Disease
The most dramatic recent development in the
treatment of IPD has been in the field of neural
transplantation.
Stereotactic implants of fetal mesencephalic
tissue into the striatum
Morphology
Pathologically, the typical gross findings are
pallor of the substantia nigra and locus ceruleus
Microscopically
Loss of the pigmented, catecholaminergic
neurons in these regions associated with gliosis
Lewy bodies may be found in some of the
remaining neurons
– These are intracytoplasmic, eosinophilic, round to
elongated inclusions that often have a dense core
surrounded by a paler rim – contain alphasynuclein protein!!!!
• Normal Substantia Nigra
Depigmented
Substantia Nigra
Lewy Body in Substantia Nigra
Dementia and Parkinson disease
Early-onset dementia suggests Lewy body
dementia disease:
A. Early dementia
B. Hallucinations!!!!!
C. Parkinsonism
D. Lewy bodies (filled with a-synuclein) in the
cortex of brain!!!
Progressive Supranuclear Palsy
Usually present with loss of vertical gaze
Progressing to difficulty with all eye movements
Associated with
– Truncal rigidity
– Dysequilibrium
– Loss of facial expression
– Progressive dementia
Onset: fifth and seventh decades
Male: females = 2:1
Death occurs often within 5 to 7 years
Huntington’s Disease
Appears between 20 and 50 years of age
Degeneration of GABAergic neurons in caudate
nucleus of basal ganglia
AD, Caucasians
Uncontrolled movements and progressive dementia
Chorea
– Jerky, hyperkinetic, sometimes dystonic movements
affecting all parts of the body – ATHETOSIS!!!!
May later develop parkinsonism with bradykinesia and
rigidity.
Early signs of higher cortical dysfunction
– Forgetfulness and thought and affective disorders
DEPRESSION, SUICIDE high rate
– An average course of about 15 years to death.
Morphology
Gross examination:
Brain is small
Striking atrophy of the caudate nucleus and putamen
Lateral and third ventricles are dilated
Microscopically:
Severe loss of striatal neurons
Huntington’s Disease
Hydrocephalus
Ex vacuo
Internal capsule
Corpus Striatum
GABA!!!
Caudate
Nucleus
Putamen
Nucleus
• Normal Cerebral Hemisphere (left)
• Atrophy of Striatum and ventricular dilatation (Right)
Huntington’s Disease
Expanded trinucleotide repeats (CAG)
Huntingtin gene (Ch.4)
Future expansion occurs during spermatogenesis
(meiosis)
Anticipation effect (grandfather, father and son –
60, 50 and 40 years manifestation of disease,
respectively)
Normal Pressure Hydrocephalus
• Increased CSF results in dilated
ventricles
• Causes dementia in adults
• Arachnoid granulations defect to
absorb excess of CSF
• Stretching of corona radiata
Clinical: triad of Urinary
Incontinence, Gait Instability,
Dementia
Lumbar Puncture improves
symptoms
Treatment: Ventriculo-peritoneal
shunting`
A 5-year-old boy is brought to the physician after he was hit
in the head with a baseball The incident occurred about
two hours ago He had no loss of consciousness, but was
a little dazed after being hit However he seemed to
improve after a short time About 30 minutes ago. the
patient began to complain of a headache vomited twice,
and is currently not acting nght according to his parents
On examination, the child is sleepy and his left pupil is
larger than his nght A CT scan of his head is shown below.
Which of the following is the most appropriate next step in
management?
A Cerebral angiogram
B MRI of the brain
C Repeat CT in 24 hours
D Dexamethasone
E Emergent craniotomy
PRIONS
•PrP found in neurons (PrPc – normal protein)
•Role of PrP in the cell –it is platform for the
assembly of signaling modules
•Conformational changes in the protein
structure (misfolding) makes it resistant to
action of proteases
•Misfolded PrP turns normal protein into
misfolded PrP
Cause transmissable diseases -Transmissable
spongioform encephalopathies:
•Kuru disease (cannibalism)
•Creutzfeldt-Jakob disease (from cattle to
human)
•Fatal familial insomnia
•Way of infection: via blood products, organ
transplant, surgery, meat products
Pathogenesis of Prion Diseases
Prion protein (PrP) is normally found in neurons
and has an a-helical structure. If the conversion
of a-helix into beta- pleated sheet occurs the
protein becomes resistant to proteases.
Accumulation of this abnormal protein in gray
matter is most likely causing prion diseases
Prion Diseases, Common Features:
1. They are associated with an abnormal prion protein (PrP).
This protein is normally present in host neurons. A change
in its secondary structure renders it resistant to enzymatic
digestion by proteases and leads to its accumulation
2. These diseases have long incubation periods. However
they are rapidly progressive after the onset of clinical
symptoms
3. Characteristic morphologic changes in brain are described
as spongiform encephalopathy
4. Vacuoles form in the cytoplasm of the neutrophils and
neurons. As the disease progresses, the vacuolated areas
transform into cysts.
5. No inflammatory changes are present
6. There is no treatment for prion diseases. These conditions
are invariably fatal
Vacoulization (sponginess) of
CNS tissue is the consistent
diagnostic finding
Bovine Spongiform Encephalitis, Creutsfeldt-Jakob Disease
Q: PrP is a normal cellular protein found in neurons that
has an a-helical secondary structure. In some
patients, this protein undergoes a conformational
change to a β-pleated sheet isoform, making it highly
resistant to proteases, thus causing intracellular
accumulation. Which of the following best describes
histological changes that may be seen in the brain of
these patients?
A. Cytoplasmic inclusions in oligodendrocytes
B. Neurofibrillary tangles and neocortical plaques
C. Microglial nodules and multi nucleated giant cells
D. Patches of white matter destruction
E. Spongiform transformation of gray matter
Creutzfeldt-Jakob disease, Clinical
Presentation
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Rapidly progressive dementia
Startle Myoclonus, Ataxia
Spike-wave complexes seen on EEG
Death in <1 year
May be history of transplant or usage extracts of
Hypophysis
A 42-year-old Caucasian male treated for impaired vision develops
rapidly progressive dementia and myoclonic jerks. He lapses into a coma
and dies six months later. A sample of brain tissue shows gray matter
changes with many uniform vacuoles between neuron cell bodies and in
the perikaryon of neurons. No inflammatory changes are present. This
patient most likely suffered from:
A. Myastenia gravis
B. Bacterial Meningitis
C. Creutzfeldt-Jakob disease
D. Multiple sclerosis
Other Prion Diseases
Variant CJD – due to exposure to bovine
spongioform encephalopathy (beef meat) in
young people
Familial fatal insomnia – inherited form of prion
disease – insomnia + exaggerated startle
response (The startle response or startle
reaction is a response to sudden, startling
stimuli, such as sudden noise or sharp involves
flexion of most skeletal muscles and a variety of
visceral reactions )
Spinocerebellar Degenerations
Group of diseases affecting the cerebellar cortex, spinal cord,
peripheral nerves
Pathologically:
– Degeneration of the neurons in the affected areas
Clinically:
– Combination of cerebellar and sensory ataxia
– Spasticity
– Peripheral motor and sensory defects
Types:
Paraneoplastic cerebellar degeneration
Alcoholic cerebellar degeneration also predominantly affects
Purkinje cells, especially in the superior vermis
Friedreich’s Ataxia (FA)
Ataxia-Telangiectasia
Friedreich’s Ataxia
Autosomal recessive condition
Frataxin gene (iron and mitochondrial metabolism)
accumulation of GAA repeats
Male preponderance
Average age at onset of about 11 years
Symptoms
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Gait ataxia
Hand clumsiness
Dysarthria
Deep tendon reflexes are absent
Extensor plantar reflex is typically present
Joint position and vibratory sense are impaired
Most patients become paralyzed over the course of about 20 years
There is a high incidence of concomitant diabetes and cardiac
disease
– Manifests as cardiac arrhythmias and Cardiomyopathy (congestive
heart failure)
Ataxia-Telangiectasia
Autosomal recessive disease
Presents in childhood
Loss of cerebellar function in the setting of recurrent
infections.
Neurologic signs appear before the appearance of the
numerous telangiectatic lesions in conjunctiva and in
other areas.
Pathologic findings:
Predominantly in the cerebellum
– Loss of Purkinje and granule cells
Systemic findings:
– Absence of a thymus as well as hypoplastic gonads.
Strong tendency for lymphoid malignancy
Degenerative Diseases Affecting Motor Neurons
Amyotrophic Lateral Sclerosis (ALS)
ALS is a degenerative disease of upper and lower
motor neurons of the brain and spinal cord, with
progressive weakness and wasting of the extremities
and tongue, a sometimes confusing combination of
hyperreflexia and hyporeflexia and eventual
impairment of respiratory muscles.
Patients have loss of both
– Lower motor neurons
Muscular atrophy
Fasciculations
Weakness
– Upper motor neurons
Hyperreflexia
Spasticity
Babinski reflex
Men > women
Amyotrophic Lateral Sclerosis (ALS)
Autosomal Dominant inheritance pattern in 5%
cases
Mutation in SOD1 – free radical detoxifying
enzyme
Intellectual capacities
preserved