Demyelinating Diseases

Selective loss of myelin

a) MS is demyelinating, whereas
b) necrosis, etc. is not demyelinating
Leukodystrophies reflect inherited
disturbances in formation and
preservation of myelin
a) metachromatic leukodystrophy
i) most common leukodystrophy
ii) autosomal recessive disorder
of myelin metabolism
 - characterized by of a
cerebroside (galactosyl
sulfatide) in white matter of
brain and PNS
iii) predominates in infancy
iv) lethal within several years
b) Krabbe disease
i) fatal, early months of life
ii) deficiency of
galactocerbroside -
galactosidase
iii) autosomal recessive
 iv) almost complete loss of
oligodendroglia and myelin
v) presence of gobloid cells
found around blood vessels
c) adrenoleukodystrophy (ALD)
i) x-linked inherited disorder of
adrenal cortex and
demyelination of nervous
system
ii) children 3-10 yrs
iii) levels of very long chain FA
in tissues and body fluids
 iv) enzyme mutation
-impairs capacity to degrade
VLCFAs
v) more severe demyelination in
cortical white matter
- parieto-occipital regions
d) Alexander disease
i) rare neurological disease
ii) infants and children
iii) loss of myelin in brain
iv) accumulation of irregular,
extracellular fibers (Rosenthal fibers)
 v) psychomotor retardation,
progressive dementia,
paralysis death
vi) mutation of gene encoding
GFAP Rosenthal fibers
vii) deposited around blood
vessels
Multiple Sclerosis (MS)

a) chronic demyelinating disease

b) most common chronic CNS disease
of young adults in USA
c) affects sensory and motor
functions
d) acquired disease, mean age ~
30yrs
i) women 2:1
e) etiology remains obscure
i) genetic predisposition
f) colder climates risk
g) immune factors
i) chronic MS perivascular
lymphocytes, macrophages and
CD4+ and CD8+ T cells
h) infectious agents
i) wide variety of viruses
- mumps, rubella, herpes
simplex and measels (via
vaccination)
I) demyelinated plaque is hallmark of
MS
i) usually in white matter
ii) preference for optic nerves,
chiasm
iii) neurons are spared, while
axons degenerate when next
to plaque!
iv) MS has focal areas of injury
v) demyelination is complete when in
presence of plaque
vi) old MS plaque exhibit gliosis
(scar) impairs structural
integrity of axons
J) clinical
i) onset 30-40 yrs
ii) PNS are uniformly spared
iii) usually begins with symptoms
in optic nerves, brainstem or
spinal cord (loss of vision in
one eye usually presenting
complaint)
iv) lesions in spinal cord leg
weakness or numbness
 v) disease usually follows chronic
relapsing and remitting course
develop permanent lesions
vi) death usually from
respiratory paralysis or UTI
while in terminal coma
vii) survival 20-30 yrs following
initial symptoms
MS variants
a) neuromyelitis optica (Devic
disease)
i) Asians
 ii) present as bilateral optic
neuritis and spinal cord
involvement
iii) lesions similar to MS but
more destructive
- grey matter involvement
b) Acute MS (Marburg form)
i) young individuals
ii) fulminant course over several
months
 Acute disseminated encephalomyelitis
a) follow either
i) viral infection or
ii) viral immunization
b) symptoms develop 1-2 weeks
following (i or ii above)
c) clinical
i) headache
ii) lethargy or
iii) coma
iv) these occur rather than focal
findings
 v) symptoms progress rapidly
fatal in 20% and remaining
cases complete recovery
Acute necrotizing hemorrhagic
encephalomyelitis
a) fulminant syndrome of CNS
demyelination
b) usually preceded by upper
respiratory infection
i) mycoplasma pneumoniae
ii) most times of indeterminate
cause
 iii) highly fatal
Central pontine myelinolysis
a) loss of myelin
b) preservation of neurons and axons
c) believed to be caused by rapid
correction of hyponatremia
i) also to extreme
hyperosmolarity or
ii) other metabolic imbalances
d) clinical
i) rapidly developing quadriplegia
ii) lesion in basis pontis
 iii) can occur during setting of:
- alcoholism
- severe electrolyte/osmolar
imbalances
- orthopic liver
transplantation
Marchiafava Bignami disease
a) rare disorder of myelin
i) corpus callosum and
ii) anterior commissure
 Degenerative Diseases

Parkinson Disease
a) Common movement disorder
b) Characterized by loss of neurons
(substantia nigra)
i) accumulation of Lewy bodies
c) Tremors at rest
d) Muscle rigidity
e) Expressionless
 Epidemiology
a) 6-8 decades
b) more than 2% in North America
develop disease
c) men more than women
d) most cases are sporadic
i) missense mutations cause
rare autosomal dominant
e) most are idiopathic, exceptions
i) induced following viral
encephalitis
- Von Economo encephalitis
 ii) toxin intake
- MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine)
f) substantia nigra relays information
to basal ganglia through
Dopaminergic synapses
i) aging dopamine
ii) exaggerated in PD
iii) Lewy bodies are filamentous
aggregates seen in substantia
nigra
- also other areas
 iv) oxidative stress (of
catecholamines) during melanin
formation injures neurons in
substantia nigra
g) loss of pigmentation in substantia
nigra and locus ceruleus and
formation of inclusion bodies
(Lewy bodies)
h) clinical:
i) slowness of all voluntary
movement and muscle rigidity
- disappears with use
ii) coarse tremor of distal
extremities
- at rest
iii) face is expressionless
(mask-like)
- reduced rate of swallowing
(leading to drooling)
iv) incidence of
depression/dementia (~10-
15%)
 v) early PD tx with L-dopa
- after several years
becomes ineffective
vi) neural transplantation
(dopaminergic) into striatum
vii) deep brain stimulation can
provide relief of motor
symptoms of PD
Multiple system atrophy
a) rare disorder
b) mimics PD
 c) less severe changes in substantia
nigra and locus ceruleus
d) associated with Shy-Drager
disease and
olivopontocerebellar atrophy (i.e.,
these are known as
multiple system atrophy)
i) patients usually have symptoms
of both diseases
e) 2 principle symptoms
i) PD
 ii) Autonomic dysfunction
orthostatic hypotension
f) when present as isolated lesion

i) Shy-Drager
ii) Striatal degeneration
iii) Presentation of isolated
ataxic disorder with
cerebellar dysfunction
olivopontocerebellar atrophy
 Amyotrophic lateral sclerosis (ALS)
a) leads to profound weakness and
death
b) affects motor neurons of brain
and spinal cord
c) worldwide disease
i) 1:100,000
d) peaks in incidence in 5th
decade
e) ~ 2:1 incidence in men
f) Guam, Papua new guinea and
parts of Japan
 i) Chomoro people in Guam
disease is rich in tau NFT
now classified as
neurodegerative taupathies
g) familial cases
i) autosomal dominant (gene 21q)
ii) ~ 5 % of all cases
iii) missense mutation that codes
for SOD1
iv) disease not due to SOD
activity
h) affects motor neurons (3
locations)
i) anterior horn cells of cord
ii) motor nuclei of brainstem
- hypoglossal nuclei
iii) upper motor neurons of
cerebral cortex
iv) loss of large motor
neurons accompanied by mild
gliosis
- may cause inclusions
sphenoids
 v) loss of pyramidal Betz cells in
motor cortex
vi) loss of myelinated fibers in
lateral corticospinal tracts
vii) anterior nerve roots are
atrophic and affected muscles
are pale and shrunken
I) clinical
i) begins as weakness and wasting
of muscles
- hand (often with painful
cramps)
- irregular rapid contractions of
muscles that do not move limbs
(fasciculations)
- progressive disease
- speech unintelligent
- respiratory weakness
- intellectual capacity is
preserved
- clinical course usually does not
extend beyond 10 years
 Huntinton disease
a) inherited autosomal dominant
disease
b) progressive movement disorders
and dementia
c) degeneration of striatal neurons
d) movement disorder chorea
i) jerky
ii) hyperkinetic
iii) sometimes dystonic
movements
iv) affecting all parts of body
e) progressive
i) course ~ 15 years
f) HD gene 4p16.3 encodes a
protein
i) huntingtin
ii) repeat mutation
(trinucleotide repeat
disorder)
iii) greater the # of repeats
earlier onset of disease
g) clinical
i) 4-5th decade at onset
ii) motor symptoms usually
precede cognitive disorders
(in ~ 50% of patients)
iii) movement disorders are
chorioform
- jerky, involuntary movement of
all parts of body
- risk of suicide (genetic
screening)
 Spinocebellar ataxias
loss of neurons and neural tracts in
cerebellum, brainstem and spinal cord
a) ataxia
b) intention tremor
c) rigidity
d) tremor
e) loss of deep tendon reflexes and
f) vibration sense and
g) pain
 Friedreich ataxia
a) most common inherited ataxia
b) autosomal recessive
c) onset of symptoms less than 25
years
d) hallmark is
i) combined ataxia of both
upper and lower limbs
ii) Systemic abnormalities of
skeletal system
- scoliosis
- pes cavus
 - hypertrophic
cardiomyopathy which
commonly causes death
- diabetes mellitus
e) genetic defect
i) chromosome 9
ii) lack of frataxin production
iii) triplet expansion (GAA repeat
expansion)
- confirms diagnosis
 DEGENERATIVE DISEASES (AD)
(Alzheimer Disease)
principle cause of so-called senility
worldwide disease
most common cause of dementia in aged
a) more than half of all cases
age prevalence
a) before age 65 years 1-2 %
b) after 85 years ~ 10%
c) women 2:1
d) most cases are sporatic
i) familial variant is recognized
e) 2 associations
i) amyloid -protein (A)
- deposition in
neuritic plaques of AD
- plaques in cerebral
cortex
ii) NFT
Alzheimer Disease
1.- amyloid -protein (A)
a) evidence points to in
neuritic plaques of A
i) located in cerebral cortex
ii) linked to intellectual
function
iii) constant feature of AD
b) neurons and glial cells also
accumulate A in walls of
cerebral blood vessels
2.- Neurofibrillary tangles (NFT)
a) microtubule-associated
protein
i) abnormal helical form
which is termed tau
b) in AD phosphorylation of tau
in certain areas of brain form
NFT
c) mutations of tau gene on
chromosome 17 causes familial
dementia and parkinsonism
 d) most cases of AD are associated
with lots of LEWY bodies
e) genetic association

Pathology of AD:
a) during course of AD
i) neurons are lost
ii) gliosis occurs
iii) gyri narrow
iv) sulci narrow
v) cortical atrophy
- bilateral and symmetrical
 b) microscopic findings
i) senile plaques
ii) NFT
iii) neuron loss
iv) Lewy bodies and
granulovacuolar degeneration
Clinical:
a) patients usually present with:
i) gradual loss of memory and
ii) cognitive function
iii) difficulty with language
iv) changes in behavior
 b) AD is progressive
i) previously intelligent and
productive persons
- become demented
- mute
- incontinent
- bed ridden
- bronchopneumonia usually
cause of death
Pick disease
a) loss of function
b) dementia
c) difficult to distinguish from AD
d) most cases are sporadic
e) occurs in mid adult life
i) progress to death in 3-10 yrs
f) cortical atrophy
i) initially unilateral
- bilateral with progression
ii) localized to frontotemporal
g) severe atrophy
i) gyri reduced to thin edge
- knife-blade atrophy
 h) inclusions contain tau and
argentophilic and are referred to
as Pick bodies
i) densely aggregated straight
filaments

TUMORS

annual incidence 10-17 per 100,000

a) 1-2 per 100,000 for intraspinal
50-75% are primary tumors
a) remainder are metastatic
 rarely metastatic outside of CNS
classes:
a) gliomas
b) neuronal tumors
c) poorly differentiated
d) meningiomas

1.- GLIOMAS (astrocytomas,

oligodendrogliomas, ependymomas)
a) Astrocytoma
i) fibrillary astrocytoma
ii) glioblastoma
iii) pilocytic astrocytoma
iv) pleomorphic
xanthoastrocytoma
v) all these have histological
characteristics, distribution,
age and clinical course
vi) mean survival time is ~ 5 yrs
A) Fibrillary astrocytoma
i) ~ 80 % of adult primary tumors
ii) found in cerebral hemispheres
iii) 4-6th decade may occur in
cerebellum, brainstem, spinal cord
iv) most common presenting sign is
- seizures
- headache
- focal neurological deficits
v) grading predicts prognosis
- WHO classification
- grades 1-4
 - low grade astrocytoma show
inactivation of tumor
suppressor gene p53
- high grade astrocytoma show
inactivation of p53 as well as
RB gene, p16/CDKNZA gene
and tumor suppressor gene on
chromosome 19q
B) Glioblastoma
i) prognosis very poor
- 8 to 10 months following Dx
ii) 2 distinct clinical histories
1.
- short, rapidly progressive, arising
without preexisting low grade
tumor
- typically in older patients (primary
glioblastoma
2.
- younger patients
- previously diagnosed low grade
astrocytoma (secondary
astrocytoma)
- p53 mutations
C) Pilocytic astrocytoma
i) young adults
ii) relatively benign
iii) mainly cerebellum
- may occur in floor of 3rd
ventricle, optic nerves, and
occasionally in cerebral
hemispheres
iv) often cystic looking
v) grow slowly
vi) WHO grade 1
vii) rare p53 mutations
 Oligodendroglioma
a) 5-10 % of gliomas
b) most common in 4th and 5th
decades
i) may have had many years of
complaints
- seizures
c) lesions found most often in
cerebral hemispheres
i) mainly white matter
 d) most common genetic defect
i) involves chromosome 1 and
19q
e) clinical:
i) better prognosis re:
astrocytomas
ii) average survival 5 to 10 years

Ependymomas
a) arise next to ependyma-lined
ventricular system
i) also central canal of cord
 ii) first 2 decades of life
- near 4th ventricle
- 5-10 % of primary tumors
in this age group
iii) in adults spinal cord most
common location
b) clinical
i) posterior fossa ependymoma
- often with hydrocephalus,
secondary to obstruction,
rather than invasion
ii) poor prognosis
 - CSF dissemination is
common
- average survival ~ 4 years
iii) several other tumors occur
- lining of ventricles
- other cells that form wall
of ventricles choroid
plexus (rare)
iv) benign low grade tumor
- except the rare choroid
plexus carcinoma
 Subependymomas
a) solid
i) sometimes calcified
b) slow growing nodules
i) attached to ventricular lining
ii) protrude into ventricles
c) usually asymptomatic
i) may cause hydrocephalus
d) most often found in lateral and 4th
ventricles
i) difficult to remove
ii) have distinct histology
 Choroid plexus papillomas
a) occur anywhere along choroid
plexus
b) most common in children
i) lateral ventricles
ii) 4th ventricle in adults
c) usually present with hydrocephalus

Colloid cyst of 3rd ventricle

a) non-neoplastic lesion
b) young adults
c) attached to roof of 3rd ventricle
 i) causes noncommunicating
hydrocephalus
- may be rapidly fatal
d) headache (sometimes positional)
important symptom

NEURONAL TUMORS

Several types contain mature appearing

neurons (ganglion cells)
a) gangliocytoma
i) comprised only of ganglion cells
b) more commonly exist as admixture
i) with glioma neoplasm
- lesion termed
ganglioglioma
- usually presents with
seizures
c) most slow growing
i) glioma part may progress
rapidly
d) dysembryoplastic neuroepithelial
tumor
i) low grade, distinct tumor
 ii) childhood
- presents with seizures
iii) slow growth
- good prognosis after Tx
iv) located
- superficial temporal lobe

Tumors with only neuronal elements

a) cerebral neuroblastoma
i) rare
ii) children
iii) hemispheres
 iv) rapid and aggressive growth
b) central neurocytoma
i) low grade
ii) lateral and 3rd ventricle
POORLY DIFFERENTIATED
NEOPLASMS
most common is medullablastoma
a) ~ 20% of brain tumors in children
b) exclusive to the cerebellum
c) largely undifferentiated
i) glial and neuronal markers
occasionally
 d) clinical
i) highly malignant
ii) very radiosensitive
iii) prognosis also depends on
amount of tumor resected
iv) total resection plus radiation
- 5 year survival ~ 75 %
Atypical teratoid/rhabdoid tumors
a) highly malignant
b) young children
c) posterior fossa
d) presence of rhabdoid cells is Dx
 e) clinical
i) occur prior to 5 years of age
ii) death within a year following
diagnosis

OTHER PARENCHYMAL TUMORS

primary CNS lymphomas

a) ~ 2 % of extra nodal lymphomas
i) ~ 1 % of intracranial tumors
b) most common CNS neoplasm in
immunosuppressed patients
c) in nonimmunosuppressed
i) occurs after age 60
d) often presents at multiple sites
e) extra CNS involvement is rare
i) denotes late stage
ii) NHL arising outside CNS
rarely invades brain
parenchyma
f) majority are B-cell origin
i) in immunosuppressed patients
all neoplasms appear to contain
EBV genome
 g) very aggressive
i) poor response to treatment
compared to peripheral
lymphomas

Germ cell tumors

a) primary brain germ cell tumor
i) most commonly occur along
midline
- pineal
- suprasellar
b) young (90% in first 2 decades)
c) teratomas
i) most common tumor that
- presents as congenital
tumor
d) in pineal region
i) male predominance
ii) not seen in suprasellar region
as male predominance
e) unlike lymphomas
i) CNS germ cell tumors not
uncommon
 ii) similar classification to
seminoma in testis
- termed germinoma
pineal parenchymal tumors
a) arise from pineocytes
b) differentiation
i) well pinocytoma
ii) undifferentiated (high grade)
- pineoblastoma
- highly aggressive
- more common in children
- in pts. with retiniblastoma
 c) Gliomas also found in pineal region

meningioma
a) benign
b) occur in adults
c) usually attached to dura
d) clinical
i) slow growing
ii) uncommon in children
iii) small female preponderance
- 3:2
- 10:1 with spinal meningioma
 metastatic tumors
a) mostly carcinomas
i) 25-50 % of hospitalized
patients
b) sites (accounts for 80% of all
metastatic tumors)
i) lung
ii) breast
iii) skin (i.e., melanoma)
iv) kidney
v) GI
 c) meninges frequent site of
metastatic tumors
d) present as mass lesion

paraneoplastic syndromes
a) major underlying mechanisms
i) systemic development of
immune response against tumor
antigen
b) may be T-cell mediated neuronal
injury in some settings
BOARD QUESTIONS
Which of the following disorders
affecting myelin is most likely to be
found in a 30-year-old woman?

(A) multiple sclerosis

(B) Krabbe disease
(C) Alexander disease
(D) metachromatic leukodystrophy
A disease characterized by widespread
patches of demyelination with less
prominent axis cylinder destruction and
glial overgrowth is

(A) syphilis
(B) poliomyelitis
(C) multiple sclerosis
(D) pernicious anemia
(E) amyotrophic lateral sclerosis
Reactive astrocytes surrounding
eosinophilic fibers radiating from a
central core which stains for amyloid is
characteristic of

(A) Alzheimer disease

(B) amyotrophic lateral sclerosis
(C) olivopontocerebellar atrophy
(D) Parkinson disease
(E) Wilson disease
Lewy bodies are most commonly
encountered in

(A) idiopathic Parkinsonism

(B) post-encephalitic Parkinsonism
(C) rabies
(D) Tay-Sachs disease
(E) herpes simplex encephalitis
The most radiosensitive primary
intracranial neoplasm is

(A) ependymoma
(B) glioblastoma
(C) medulloblastoma
(D) oligodendroglioma
A child presents with nausea and
vomiting, a recent onset of ataxia, and
a posterior fossa tumor. The most
likely diagnosis is

(A) craniopharyngioma
(B) medulloblastoma
(C) meningioma
(D) neuroblastoma
(E) pinealoma