Cns degeneration, demyelination and tumors

Demyelinating Diseases

• Selective loss of myelina) MS is demyelinating, whereasb) necrosis, etc. is not

demyelinating• Leukodystrophies reflect inherited disturbances in formation and preservation of myelin

a) metachromatic leukodystrophyi) most common

leukodystrophyii) autosomal recessive

disorder of myelin metabolism

www.freelivedoctor.comwww.freelivedoctor.com

- characterized by of a cerebroside

(galactosyl sulfatide) in white matter of brain and PNS

iii) predominates in infancyiv) lethal within several years

b) Krabbe diseasei) fatal, early months of lifeii) deficiency of

galactocerbroside ß- galactosidase

iii) autosomal recessivewww.freelivedoctor.comwww.freelivedoctor.com

iv) almost complete loss of oligodendroglia and myelinv) 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 yrsiii) levels of very long chain

FA in tissues and body fluids www.freelivedoctor.comwww.freelivedoctor.com

iv) enzyme mutation-impairs capacity to

degrade VLCFA’sv) more severe demyelination

in cortical white matter- parieto-occipital regions

d) Alexander diseasei) rare neurological diseaseii) infants and childreniii) loss of myelin in brainiv) accumulation of irregular,

extracellular fibers (Rosenthal fibers) www.freelivedoctor.comwww.freelivedoctor.com

v) psychomotor retardation, progressive dementia,

paralysis deathvi) mutation of gene encoding

GFAP Rosenthal fibers

vii) deposited around blood vessels

Multiple Sclerosis (MS)

a) chronic demyelinating diseaseb) most common chronic CNS

disease of young adults in USAwww.freelivedoctor.comwww.freelivedoctor.com

c) affects sensory and motor functionsd) acquired disease, mean age ~

30yrsi) women 2:1

e) etiology remains obscurei) genetic predisposition

f) colder climates riskg) immune factors

i) chronic MS perivascular lymphocytes,

macrophages and CD4+ and CD8+ T cells


h) infectious agentsi) wide variety of viruses

- mumps, rubella, herpes simplex and measels

(via vaccination)I) demyelinated plaque is hallmark

of MSi) usually in white matterii) preference for optic nerves, chiasm


iii) neurons are spared, while axons degenerate when

next to plaque!iv) MS has “focal” areas of injuryv) demyelination is complete

when in presence of plaquevi) old MS plaque exhibit gliosis (“scar”) impairs structural integrity of axons


J) clinicali) onset 30-40 yrsii) PNS are uniformly sparediii) 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 comavii) survival 20-30 yrs

following initial symptoms• MS variants

a) neuromyelitis optica (Devic disease)

i) Asianswww.freelivedoctor.comwww.freelivedoctor.com

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 individualsii) fulminant course over

several months


• Acute disseminated encephalomyelitis

a) follow eitheri) viral infection orii) viral immunization

b) symptoms develop 1-2 weeks following (i or ii above) c) clinical

i) headacheii) lethargy oriii) comaiv) these occur rather than

focal findingswww.freelivedoctor.comwww.freelivedoctor.com

v) symptoms progress rapidly fatal in 20% and remaining

cases complete recovery• Acute necrotizing hemorrhagic encephalomyelitis

a) fulminant syndrome of CNS demyelinationb) usually preceded by upper respiratory infection

i) mycoplasma pneumoniaeii) most times of

indeterminate causewww.freelivedoctor.comwww.freelivedoctor.com

iii) highly fatal• Central pontine myelinolysis

a) loss of myelinb) preservation of neurons and

axonsc) believed to be caused by rapid correction of hyponatremia

i) also to extreme hyperosmolarity orii) other metabolic imbalances

d) clinicali) rapidly developing

quadriplegiaii) lesion in basis pontis


iii) can occur during setting of:

- alcoholism- severe

electrolyte/osmolar imbalances

- orthopic liver transplantation

• Marchiafava – Bignami diseasea) rare disorder of myelin

i) corpus callosum andii) anterior commissure


Degenerative Diseases

• Parkinson Diseasea) Common movement disorderb) Characterized by loss of neurons (substantia nigra)

i) accumulation of Lewy bodiesc) Tremors at restd) Muscle rigiditye) Expressionless


• Epidemiologya) 6-8 decadesb) more than 2% in North

America develop diseasec) men more than womend) most cases are sporadic

i) missense mutations cause rare autosomal

dominant e) most are idiopathic, exceptions

i) induced following viral encephalitis- Von Economo

encephalitiswww.freelivedoctor.comwww.freelivedoctor.com

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 dopamineii) exaggerated in PDiii) 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 usewww.freelivedoctor.comwww.freelivedoctor.com


ii) coarse tremor of distal extremities

- at restiii) face is expressionless (mask-like)

- reduced rate of swallowing (leading to drooling)

iv) incidence of depression/dementia (~10-

15%)www.freelivedoctor.comwww.freelivedoctor.com

v) early PD tx with L-dopa- after several years

becomes ineffectivevi) neural transplantation

(dopaminergic) into striatum

vii) deep brain stimulation can provide relief of motor symptoms of PD

• Multiple system atrophya) rare disorderb) 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 diseasese) 2 principle symptoms

i) PD www.freelivedoctor.comwww.freelivedoctor.com

ii) Autonomic dysfunction orthostatic hypotension

f) when present as isolated lesion

i) Shy-Drager ii) Striatal degenerationiii) Presentation of isolated ataxic disorder with cerebellar dysfunction olivopontocerebellar

atrophy


• Amyotrophic lateral sclerosis (ALS)a) leads to profound weakness

and deathb) affects motor neurons of

brain and spinal cordc) worldwide disease

i) 1:100,000d) peaks in incidence in 5th decadee) ~ 2:1 incidence in menf) Guam, Papua new guinea

and parts of Japanwww.freelivedoctor.comwww.freelivedoctor.com

i) Chomoro people in Guam disease is rich in tau NFT

now classified as “neurodegerative

taupathiesg) familial cases i) autosomal dominant (gene 21q)

ii) ~ 5 % of all casesiii) missense mutation

that codes for SOD1iv) disease not due to SOD activity


h) affects motor neurons (3 locations)

i) anterior horn cells of cordii) motor nuclei of brainstem

- hypoglossal nucleiiii) upper motor neurons of

cerebral cortexiv) loss of large motor neurons accompanied by

mild gliosis- may cause inclusions

sphenoids www.freelivedoctor.comwww.freelivedoctor.com

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 shrunkenI) clinical

i) begins as weakness and wasting of muscles

- hand (often with painful cramps)www.freelivedoctor.comwww.freelivedoctor.com

- 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 diseasea) inherited autosomal dominant diseaseb) progressive movement

disorders and dementiac) degeneration of striatal

neuronsd) movement disorder chorea i) jerky

ii) hyperkineticiii) sometimes dystonic

movementsiv) affecting all parts of body


e) progressivei) course ~ 15 years

f) HD gene 4p16.3 encodes a protein

i) huntingtinii) repeat mutation (“trinucleotide” repeat

disorder)iii) greater the # of repeats

earlier onset of disease


g) clinicali) 4-5th decade at onsetii) 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

corda) ataxiab) intention tremorc) rigidityd) tremore) loss of deep tendon reflexes

andf) vibration sense andg) pain


• Friedreich ataxiaa) most common inherited

ataxiab) autosomal recessivec) onset of symptoms less than

25 yearsd) hallmark is

i) combined ataxia of both upper and lower limbsii) Systemic abnormalities

of skeletal system- scoliosis- pes cavus www.freelivedoctor.comwww.freelivedoctor.com

- hypertrophic cardiomyopathy

which commonly causes death

- diabetes mellituse) genetic defect

i) chromosome 9ii) lack of “frataxin”

productioniii) triplet expansion (GAA

repeat expansion)- confirms diagnosis www.freelivedoctor.comwww.freelivedoctor.com

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 2:1d) most cases are sporatici) familial variant is recognized


e) 2 associationsi) amyloid -protein (A)

- deposition in neuritic

plaques of AD- plaques in cerebral cortex

ii) NFT


Alzheimer Disease1.- amyloid β-protein (Aβ)

a) evidence points to in neuritic plaques of Aβi) located in cerebral

cortexii) linked to intellectual functioniii) constant feature of AD

b) neurons and glial cells also accumulate Aβ in walls

of cerebral blood vesselswww.freelivedoctor.comwww.freelivedoctor.com

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 lostii) gliosis occursiii) gyri narrowiv) sulci narrowv) cortical atrophy

- bilateral and symmetricalwww.freelivedoctor.comwww.freelivedoctor.com

b) microscopic findingsi) senile plaquesii) NFTiii) neuron lossiv) Lewy bodies and

granulovacuolar degeneration• Clinical:

a) patients usually present with:i) gradual loss of memory andii) cognitive functioniii) difficulty with languageiv) changes in behavior


b) AD is progressivei) previously intelligent and

productive persons- become demented- mute- incontinent- bed ridden- bronchopneumonia

usually cause of death• Pick disease

a) loss of functionb) dementia


c) difficult to distinguish from ADd) most cases are sporadice) occurs in mid adult life

i) progress to death in 3-10 yrs

f) cortical atrophyi) initially unilateral

- bilateral with progressionii) localized to frontotemporal

g) severe atrophyi) gyri reduced to thin edge

- “knife-blade” atrophywww.freelivedoctor.comwww.freelivedoctor.com

h) inclusions contain tau and argentophilic and are

referred to as “Pick bodies”i) densely aggregated straight filaments

TUMORS

• annual incidence 10-17 per 100,000a) 1-2 per 100,000 for intraspinal

• 50-75% are primary tumorsa) remainder are metastatic


• rarely metastatic outside of CNS• classes:

a) gliomasb) neuronal tumorsc) poorly differentiatedd) meningiomas

1.- GLIOMAS (astrocytomas, oligodendrogliomas, ependymomas)


a) Astrocytomai) fibrillary astrocytomaii) glioblastomaiii) pilocytic astrocytomaiv) pleomorphic

xanthoastrocytomav) all these have histological

characteristics, distribution, age and clinical course

vi) mean survival time is ~ 5 yrs


A) Fibrillary astrocytomai) ~ 80 % of adult primary

tumorsii) found in cerebral hemispheresiii) 4-6th decade may occur in cerebellum, brainstem,

spinal cordiv) 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 19qB) 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 glioblastoma2.

- younger patients- previously diagnosed low grade astrocytoma (secondary astrocytoma)- p53 mutations


C) Pilocytic astrocytomai) young adultsii) relatively benigniii) mainly cerebellum

- may occur in floor of 3rd ventricle, optic nerves, and

occasionally in cerebral hemispheres

iv) often cystic lookingv) grow slowlyvi) WHO grade 1vii) rare p53 mutations


• Oligodendroglioma a) 5-10 % of gliomasb) most common in 4th and 5th decades

i) may have had many years of complaints

- seizuresc) lesions found most often in cerebral hemispheres

i) mainly white matter


d) most common genetic defecti) involves chromosome 1

and 19qe) clinical:

i) better prognosis re: astrocytomasii) average survival 5 to 10

years

• Ependymomasa) arise next to ependyma-lined ventricular system

i) also central canal of cordwww.freelivedoctor.comwww.freelivedoctor.com

ii) first 2 decades of life- near 4th ventricle- 5-10 % of primary

tumors in this age groupiii) in adults spinal cord most

common locationb) clinical

i) posterior fossa ependymoma

- often with hydrocephalus,

secondary to obstruction, rather than invasion

ii) poor prognosis


- CSF dissemination is common- average survival ~ 4

yearsiii) 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


• Subependymomasa) solid

i) sometimes calcifiedb) slow growing nodules

i) attached to ventricular lining

ii) protrude into ventricles c) usually asymptomatic

i) may cause hydrocephalusd) most often found in lateral and

4th ventriclesi) difficult to removeii) have distinct histology


• Choroid plexus papillomas a) occur anywhere along choroid plexusb) most common in children

i) lateral ventriclesii) 4th ventricle in adults

c) usually present with hydrocephalus • Colloid cyst of 3rd ventricle

a) non-neoplastic lesionb) young adultsc) attached to roof of 3rd ventricle


i) causes noncommunicating hydrocephalus

- may be rapidly fatald) 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 growingi) glioma part may progress

rapidlyd) dysembryoplastic

neuroepithelial tumori) 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 neuroblastomai) rareii) childreniii) hemispheres


iv) rapid and aggressive growth

b) central neurocytomai) low gradeii) lateral and 3rd ventricle

POORLY DIFFERENTIATED NEOPLASMS

• most common is medullablastomaa) ~ 20% of brain tumors in

childrenb) exclusive to the cerebellumc) largely undifferentiated

i) glial and neuronal markers occasionally


d) clinicali) highly malignantii) very radiosensitiveiii) prognosis also depends on amount of tumor resectediv) total resection plus

radiation- 5 year survival ~ 75 %

• Atypical teratoid/rhabdoid tumorsa) highly malignantb) young childrenc) posterior fossad) presence of rhabdoid cells is Dx


e) clinicali) occur prior to 5 years of ageii) death within a year

following diagnosis

OTHER PARENCHYMAL TUMORS

• primary CNS lymphomasa) ~ 2 % of extra nodal

lymphomasi) ~ 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 sitese) extra CNS involvement is rare

i) denotes late stageii) NHL arising outside CNS rarely invades brain parenchyma

f) majority are B-cell origini) in immunosuppressed

patients all neoplasms appear to

contain EBV genome


g) very aggressivei) poor response to treatment compared to peripheral lymphomas

• Germ cell tumorsa) primary brain germ cell tumor

i) most commonly occur along midline

- pineal- suprasellar

b) young (90% in first 2 decades) www.freelivedoctor.comwww.freelivedoctor.com

c) teratomasi) most common tumor that

- presents as congenital tumor

d) in pineal regioni) male predominanceii) not seen in suprasellar

region as male predominance

e) unlike lymphomasi) CNS germ cell tumors not uncommon


ii) similar classification to seminoma in testis

- termed “germinoma”• pineal parenchymal tumors

a) arise from pineocytesb) differentiation

i) well – pinocytomaii) undifferentiated (high

grade)- pineoblastoma- highly aggressive- more common in children- in pts. with

retiniblastoma


c) Gliomas also found in pineal region

• meningiomaa) benignb) occur in adultsc) usually attached to durad) clinical

i) slow growingii) uncommon in childreniii) small female

preponderance- 3:2- 10:1 with spinal

meningioma



• metastatic tumorsa) mostly carcinomas

i) 25-50 % of hospitalized patients

b) sites (accounts for 80% of all metastatic tumors)

i) lungii) breastiii) skin (i.e., melanoma)iv) kidneyv) GI


c) meninges frequent site of metastatic tumorsd) present as mass lesion

• paraneoplastic syndromesa) major underlying mechanisms

i) systemic development of immune response

against tumor antigenb) may be T-cell mediated

neuronal injury in some settings www.freelivedoctor.comwww.freelivedoctor.com


BOARD QUESTIONSBOARD 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


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Cns degeneration, demyelination and tumors