Demyelinating Diseases

Selective loss of myelina) MS is demyelinating, whereasb) necrosis, etc. is not demyelinating Leukodystrophies reflect inherited disturbances in formation and preservation of myelina) metachromatic leukodystrophyi) most common leukodystrophyii) autosomal recessive disorder of myelin metabolism

- characterized by of a cerebroside (galactosyl sulfatide) in white matter of brain and PNSiii) predominates in infancyiv) lethal within several yearsb) Krabbe diseasei) fatal, early months of lifeii) deficiency of galactocerbroside - galactosidaseiii) autosomal recessive

iv) almost complete loss of oligodendroglia and myelinv) presence of gobloid cells found around blood vesselsc) adrenoleukodystrophy (ALD)i) x-linked inherited disorder of adrenal cortex and demyelination of nervous systemii) children 3-10 yrsiii) levels of very long chain FA in tissues and body fluids

iv) enzyme mutation-impairs capacity to degrade VLCFAsv) more severe demyelination in cortical white matter- parieto-occipital regionsd) Alexander diseasei) rare neurological diseaseii) infants and childreniii) loss of myelin in brainiv) accumulation of irregular, extracellular fibers (Rosenthal fibers)

v) psychomotor retardation, progressive dementia, paralysis deathvi) mutation of gene encoding GFAP Rosenthal fibersvii) deposited around blood vesselsMultiple Sclerosis (MS)

a) chronic demyelinating diseaseb) most common chronic CNS disease of young adults in USA

c) affects sensory and motor functionsd) acquired disease, mean age ~ 30yrsi) women 2:1 e) etiology remains obscurei) genetic predispositionf) colder climates riskg) immune factorsi) 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 variantsa) neuromyelitis optica (Devic disease)i) Asians

ii) present as bilateral optic neuritis and spinal cord involvementiii) 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 encephalomyelitisa) follow eitheri) viral infection orii) viral immunizationb) symptoms develop 1-2 weeks following (i or ii above) c) clinicali) headacheii) lethargy oriii) comaiv) these occur rather than focal findings

v) symptoms progress rapidly fatal in 20% and remaining cases complete recovery Acute necrotizing hemorrhagic encephalomyelitisa) fulminant syndrome of CNS demyelinationb) usually preceded by upper respiratory infectioni) mycoplasma pneumoniaeii) most times of indeterminate cause

iii) highly fatal Central pontine myelinolysisa) loss of myelinb) preservation of neurons and axonsc) believed to be caused by rapid correction of hyponatremiai) also to extreme hyperosmolarity orii) other metabolic imbalancesd) 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 myelini) 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 sporadici) missense mutations cause rare autosomal dominant e) most are idiopathic, exceptionsi) 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 synapsesi) 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 nigrag) 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 restiii) 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 ineffectivevi) neural transplantation (dopaminergic) into striatumvii) 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

ii) Autonomic dysfunction orthostatic hypotensionf) 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 diseasei) 1:100,000d) peaks in incidence in 5th decadee) ~ 2:1 incidence in menf) Guam, Papua new guinea and parts of Japan

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

v) loss of pyramidal Betz cells in motor cortexvi) loss of myelinated fibers in lateral corticospinal tractsvii) anterior nerve roots are atrophic and affected muscles are pale and shrunkenI) clinicali) 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 diseasea) inherited autosomal dominant diseaseb) progressive movement disorders and dementiac) degeneration of striatal neuronsd) movement disorder chorea i) jerkyii) hyperkineticiii) sometimes dystonic movementsiv) affecting all parts of body

e) progressivei) course ~ 15 yearsf) HD gene 4p16.3 encodes a proteini) 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 isi) combined ataxia of both upper and lower limbsii) Systemic abnormalities of skeletal system- scoliosis- pes cavus

- hypertrophic cardiomyopathy which commonly causes death- diabetes mellituse) genetic defecti) chromosome 9ii) lack of frataxin productioniii) 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 ageda) more than half of all cases age prevalencea) 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 -protein (A)a) evidence points to in neuritic plaques of Ai) located in cerebral cortexii) linked to intellectual functioniii) constant feature of ADb) neurons and glial cells also accumulate A in walls of cerebral blood vessels

2.- Neurofibrillary tangles (NFT)a) microtubule-associated proteini) abnormal helical form which is termed taub) in AD phosphorylation of tau in certain areas of brain form NFTc) mutations of tau gene on chromosome 17 causes familial dementia and parkinsonism

d) most cases of AD are associated with lots of LEWY bodiese) genetic association

Pathology of AD:a) during course of ADi) neurons are lostii) gliosis occursiii) gyri narrowiv) sulci narrowv) cortical atrophy- bilateral and symmetrical

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 diseasea) loss of functionb) dementia

c) difficult to distinguish from ADd) most cases are sporadice) occurs in mid adult lifei) progress to death in 3-10 yrsf) cortical atrophyi) initially unilateral- bilateral with progressionii) localized to frontotemporalg) severe atrophyi) gyri reduced to thin edge- knife-blade atrophy

h) inclusions contain tau and argentophilic and are referred to as Pick bodiesi) 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 coursevi) mean survival time is ~ 5 yrs

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 deficitsv) 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) Glioblastomai) prognosis very poor- 8 to 10 months following Dxii) 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 hemispheresiv) 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 hemispheresi) 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 systemi) also central canal of cord

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) clinicali) posterior fossa ependymoma- often with hydrocephalus, secondary to obstruction, rather than invasionii) 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) solidi) sometimes calcifiedb) slow growing nodulesi) attached to ventricular liningii) 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 childreni) lateral ventriclesii) 4th ventricle in adultsc) usually present with hydrocephalus Colloid cyst of 3rd ventriclea) 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 seizuresc) most slow growingi) glioma part may progress rapidlyd) dysembryoplastic neuroepithelial tumori) low grade, distinct tumor

ii) childhood- presents with seizuresiii) slow growth- good prognosis after Txiv) located- superficial temporal lobe

Tumors with only neuronal elementsa) cerebral neuroblastomai) rareii) childreniii) hemispheres

iv) rapid and aggressive growthb) central neurocytomai) low gradeii) lateral and 3rd ventriclePOORLY 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 tumorsb) most common CNS neoplasm in immunosuppressed patients

c) in nonimmunosuppressed i) occurs after age 60d) often presents at multiple sitese) extra CNS involvement is rarei) denotes late stageii) NHL arising outside CNS rarely invades brain parenchymaf) 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 tumori) most commonly occur along midline- pineal- suprasellarb) young (90% in first 2 decades)

c) teratomasi) most common tumor that- presents as congenital tumord) in pineal regioni) male predominanceii) not seen in suprasellar region as male predominancee) unlike lymphomasi) CNS germ cell tumors not uncommon

ii) similar classification to seminoma in testis- termed germinoma pineal parenchymal tumorsa) arise from pineocytesb) differentiationi) 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) clinicali) slow growingii) uncommon in childreniii) small female preponderance- 3:2- 10:1 with spinal meningioma

metastatic tumorsa) mostly carcinomasi) 25-50 % of hospitalized patientsb) 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 mechanismsi) systemic development of immune response against tumor antigenb) 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