Neuro

Question 1

Acute Neuronal Injury

Answer 1

• changes secondary to hypoxia/**ischemia **⇒ cell necrosis or apoptosis.
• intense cytoplasmic eosinophilia and nuclear pyknosis = red neurons

Question 2

Subacute and Chronic Neuronal Injury

Answer 2

• degeneration = neuronal death and reactive gliosis
• trans-synpatic degeneration when afferent inputs to neuron are lost.

Question 3

Axonal Reaction

Answer 3

• response of neuronal cell body to challenge of regenerating damaged axons.
• cell body rounds up and nucleoli enlarge.
• Nissl substance dispersal and perinuclear cytoplasmic pallor (central chromatolysis) = ↑ protein synthesis and axonal sprouting

Question 4

Neuronal Inclusions

Answer 4

• manifestation of aging (lipofuscin), disorders of metabolism (storage material), viral diseases (inclusion bodies), or neurodegenerative diseases with aggregated proteins.

Question 5

Astrocytes

Answer 5

• principal cells for repair and scar formation in brain.
• important for blood brain barrier.
• with CNS damage, get enlarged vesicular nuclei and conspicuous eosinophilic cytoplasm (gemistocytic astrocytes)
• astrocyte hypertrophy and hyperplasia ⇒ gliosis
• directly injured ⇒ rosenthal fibers, corpora amylacea, alzheimer type II astrocytes.
  
  • rosenthal fibers = elongated, eosinophilic structure in astrocyte processes containing alphaB-crystallin and hsp27. see in long-standing gliosis or pilocytic astrocytomas.
  • corpora amylacea = lamellated polyglucosan bodies and hsp. ↑ with age, are degenerative change.
  • Alzheimer type II astrocytes = enlarged nucleus with intranuclear glycogen and pale chromatin. occurs with hyperammonemia.

Question 6

Glial Cell Injury

Answer 6

• oligodendroglial cell apoptosis feature of demyelinating disorders and leukodystrophies.
• viral inclusions in progressive multifocal leukoencephalopathy
• alpha-synuclein inclusions in multiple system atrophy (MSA)
• ependymal cells don’t regenerate. damage ⇒ proliferation of subependymal astrocytes = ependymal granulations

Question 7

Cerebral Edema

Answer 7

• vasogenic = ↑ vascular permeability ⇒ accumulate intercellular fluid.
  
  • focal or generalized.
  • absence of lymphocytes impairs resorption.
• cytotoxic = ↑ intracellular fluid 2° to endothelial, neuronal, or glial injury.
• interstitial = fluid from ventricular system transudates across ependyal lining from ↑ intraventricular pressure.

Question 8

Hydrocephalus

Answer 8

• obstruction of CSF flow ⇒ ventricular enlargement and ↑ CSF volume
• from impaired flow or resorption, overproduction uncommon.
• occurs prior to cranial suture closure ⇒ enlarged head.
• occurs after cranial suture closure ⇒ ventricular expansion and ↑ ICP
• non-communicating = enlargement of a portion of the ventricle system.
• communicating = entire system expanded
• hydrocephalus ex vacuo = extensive tissue loss ⇒ compensatory expansion of entire CSF compartment

Question 9

Subfalcine Herniation

Answer 9

• aka cingulate herniation.
• from ↑ ICP.
• can compromise branches of anterior cerebral artery.

Question 10

Transtentorial Herniation

Answer 10

• aka uncinate, mesial temporal herniation.
• distorts adjacent midbrain and pons.
• 3rd CN compromise ⇒ pupillary dilation
• compression of posterior cerebral artery ⇒ ipsilateral hemiparesis
• Duret hemorrhages = tearing of feeding vesels.

Question 11

Tonsillar Herniation

Answer 11

• through foramen magnun ⇒ compress medulla and compromise cardiac and respiratory centers.

Question 12

Neural Tube Defects

Answer 12

• primary failure to close or secondary reopening.
• abnormalities in some combo of neural tissue, meninges, and ovelrying bone and soft tissues.
• risk factors: folate deficiency.
• antenatal diagnosis through alpha-fetoprotein screening.
• encephalocele, anencephaly, spina bifida, myelomeningocele.

Question 13

Encephalocele

Answer 13

• malformed CNS diverticulum extending through defect in cranium (occiput or posterior fossa)

Question 14

Anencephaly

Answer 14

• malformation of anterior neural tube ⇒ failure of cerebrum development

Question 15

Spina Bifida

Answer 15

• occulta = asymptomatic bony defect
• or a severe malformation with flattened, disorganized cord segment with overlying meningeal outpouching.

Question 16

Myelomeningocele

Answer 16

• CNS outpouching through vertebral column defect.
• mostly lumbrosacral region with lower extremity motor and sensory deficits and disturbed bowel and bladder control.

Question 17

Forebrain Anomalies

Answer 17

• issues with brain size: microencephaly, lissencephaly, agyria, megalencephaly.
• issues with gyral formation and organization: polymicrogyria, neuronal heterotopias, holoprosencephaly, agenesis of corpus callosum.

Question 18

Microencephaly

Answer 18

• small brain.
• too many periventricular cells proliferate too soon.
• from chromosomal abnormalities, fetal alcohol syndrome, in uter HIV.

Question 19

Lissencephaly

Answer 19

• aka agyria.
• smooth brain, few to no gyri.
• too many periventricular cells proliferate too soon.
• from chromosomal abnormalities, fetal alcohol syndrome, in utero HIV.

Question 20

Megalencephaly

Answer 20

• large brain.
• too few periventricular cells proliferate at early stages ⇒ overproduction of neurons.

Question 21

Polymicrogyria

Answer 21

• small, overabundant cerebral convolutions from focal injury near end of neuronal migration.

Question 22

Neuronal Heterotopias

Answer 22

• abnormal clusters of neurons in inappropriate locations along normal migratory routes.
• associated with epilepsy.
• mutations in filamin A or microtubule associated proteins.

Question 23

Holoprosencephaly

Answer 23

• incomplete separation of cerebral hemispheres.
• midline facial abnormalities (cyclopia).
• mutation of sonic hedgehog or other genes in neural development.

Question 24

Agenesis of Corpus Callosum

Answer 24

• normal white matter interhemispheric bundles not formed.
• may have mental retardation but clinically most are normal.

Question 25

Posterior Fossa Anomalies

Answer 25

• Dandy-Walker Malformation
• **Arnold-Chiari Malformation **
• Chiari I malformation

Question 26

Dandy-Walker Malformation

Answer 26

• enlarged posterior fossa, absent cerebellar vermis, large midline cyst with brainstem nuclei dysplasias.

Question 27

Arnold-Chiari Malformation

Answer 27

• aka Chiari II malformation
• small posterior fossa, malformed midline cerebellum, extension of vermis through foramen magnum, hydrocephalus, lumbar myelomeningocele.

Question 28

Chiari I Malformation

Answer 28

• low-lying cerebellar tonsils extend into vertebral canal.
• clinically silent but can present with CSF flow obstruction.

Question 29

Syringomyelia

Answer 29

• formation of cleftlike cavity in spinal cord.
• morphology: gray and white matter destruction surrounded by reactive gliosis.
• presentation: loss of pain and temperature sensation in upper extremities.

Question 30

Hydromyelia

Answer 30

• expansion of central canal.
• morphology: gray and white matter destruction surroudned by reactive gliosis.
• presentation: loss of pain and temperature sensation in upper extremities.

Question 31

Perinatal Brain Injury

Answer 31

• non-aggressive motor deficits from pre- and perinatal neurologic insults.
• risk factor: prematurity.
• can have brain injury without reactive gliosis.
• intraparenchymal hemorrhage, periventricular leukomalacia, multicystic encephalopathy, ulegyria, status marmoratus.
• presentation: depends on location but includes dystonia, spasticity, ataxia/athetosis, and/or paresis

Question 32

Perinatal Intraparenchymal Hemorrhage

Answer 32

• in germinal matrix btw thalamus and caudate nucleus. can extend to ventricular system.

Question 33

Periventricular Leukomalacia

Answer 33

• ischemic infarcts in periventricular white matter.

Question 34

Multicystic Encephalopathy

Answer 34

• ischemic infarcts within the hemispheres.

Question 35

Ulegyria

Answer 35

• thin, gliotic gyri from perinatal cortical ischemia.

Question 36

Status Marmoratus

Answer 36

• ischemic neuronal loss and gliosis in basal ganglia and thalamus with aberrant and irregular myelin formation.

Question 37

Skull Fractures

Answer 37

• fracture resistance varies with skull bone thickness.
• displaced fracture = bone shifts into cranial vault by more than its thickness.
• accidental falls = occiput. 2° basal skull involved with lower CN or cervicomedullary symptoms, CSF discharge, and/or meningitis.
• syncope ⇒ frontal skull.
• diastatic fractures = transverse sutures.

Question 38

Concussion

Answer 38

• transient trauma-related clinical syndrome with loss of consciousness, temporary respiratory arrest, loss of reflexes, amnesia of event.

Question 39

Direct Parenchymal Injury (Brain)

Answer 39

• lacerations = penetrating injury causes tissue tearing.
• contusions = CNS bruises.
  
  • gyral crest very susceptible.
  • coup contusion = at site of impact
  • contrecoup = on opposite side of cranium from impact
• brain hemorrhage and edema resolves ⇒ depressed, yellow-brown glial scar going to pial surface = plaque jaune

Question 40

Diffuse Axonal Injury

Answer 40

• when mechanical forces (acceleration) disrupt axonal integrity and axoplasmic flow.
• widespread axonal swelling and focal hemorrhage ⇒ degenerated fibers and gliosis.
• 1/2 pts comatose after trauma have diffuse axonal injury even without contusions.

Question 41

Epidural Hematoma

Answer 41

• rupture of **dural arteries (middle meningeal artery) **⇒ blood btw dura and skull ⇒ compress brain.
• can have lucid period several hours after trauma

Question 42

Subdural Hemorrhage

Answer 42

• tearing of veins that stretch from cortical surface through subarachnoid and subdural spaces into draining veins (superior sagittal sinus).
• after traumatic shifting of brain.
• geriatric pts with cerebral atrophy susceptible.
• presentation: non-localizing headache, confusion within 48hrs of injury.
• chronic subdural hematoma = recurrent episodes of bleeding from hemorrhage of thin-walled vessels of granulation tissue.
• tx: surgical drainage and remove granulation tissue.

Question 43

Sequelae of Brain Trauma

Answer 43

• epilepsy, meningiomas, infectious disease, psychiatric disorders.
• post-traumatic hydrocephalus = hemorrhage into subarachnoid space obstructs CSF resorption
• post-traumatic dementia = dementia pugilistica. repeated head trauma ⇒ hydrocephalus, corpus callosum thinning, diffuse axonal injury, amyloid plaques, and neurofibrillary tangles.

Question 44

Spinal Cord Trauma

Answer 44

• displacement of spinal column.
• injury level:
  
  • thoracic vertebrae or below ⇒ paraplegia.
  • cervical vertebrae ⇒ quadriplegia.
    
    • C4 and above ⇒ respiratory compromise from diaphragm paralysis.
• acute = hemorrhage, necrosis, white matter axonal swellings
• later = cystic and gliotic. ascending and descending white matter tracts do 2° degeneration.

Question 45

Global Cerebral Ischemia

Answer 45

• hypoxia from reduced blood flow or hypotension.
• neurons more sensitive to hypoxia.
• severe ⇒ widespread neuronal cell death, pt vegetative state or brain dead.
  
  • brain dead = flat EEG, absent reflexes/respiratory drive/cerebral perfusion
  • kept on ventilator ⇒ brain autolyzes.
• watershed/border zone infarcts = oxygenation incompletely compromised. interface between major vessels.
  
  • btw anterior and middle cerebral arteries most vulnerable.
• morphology: edematous with widened gyri and narrowed sulci. poor gray/white demarcation.
  
  • red neurons 12-24hrs post injury. pyramidal neurons in hippocampus CA1 (Sommer sector), cerebellar Purkinje cells, cortical pyramidal neurons most susceptible.
  • then neutrophil infiltration ⇒ macrophage influx, neovascularization, reactive gliosis.
  • pseudolaminar necrosis = uneven cortical neuronal loss and gliosis alternating with preserved zones.

Question 46

Stroke

Answer 46

• brain oxygen deprivation from global or focal ischemic necrosis.
• outcome depends on collateral circulation, duration of ischemia, magnitude and rapidity of flow reduction.

Question 47

Focal Cerebral Ischemia

Answer 47

• infarction from obstruction of local blood supply ⇒ thrombotic or embolic arterial occlusion.
• thrombosis = from atherosclerosis. affects extracerebral carotid system and basilar artery.
• embolism = involves intracerebral arteries (middle cerebral). comes from atheromatous cerebrovascular plaques, cardiac mural trhombi, valvular lesions, or paradoxical embolisms.
• inflammatory lesions can ⇒ lumenal narrowing and cerebral infarct.
• venous infarcts after occlusion of superior sagittal sinus or deep cerebral veins. are hemorrhagic.
• morphology: nonhemorrhagic infarcts = bland/anemic infarcts. see at 48hrs as pale, soft regions of edematous brain with neutrophils. then liquefies ⇒ fluid-filled cavity with macrophages lined by reactive glia.
  
  • hemorrhagic infarcts = embolic occlusion with reperfusion injury, have blood extravasation.

Question 48

Lacunar Infarcts

Answer 48

• small cystic infarcts from cerebral arteriolar sclerosis and occlusion.
• lipid-laden macrophages and surrounding gliosis.
• affects: lenticular nucleus, thalamus, internal capsule, deep white matter, caudate nucleus, and pons.

Question 49

Slit Hemorrhages

Answer 49

• when HTN causes small vessel rupture.
• they resorb leaving hemosiderin-laden macrophages and gliosis.

Question 50

Acute Hypertensive Encephalopathy

Answer 50

• ↑ ICP ⇒ diffuse cerebral dysfunction (headaches, confusion, vomiting, convulsions, coma).
• need rapid intervention.
• post mortem shows edematous brain with petechiae and arteriolar fibrinoid necrosis. somtimes see herniation.

Question 51

Chronic Hypertensive Injury

Answer 51

• recurrent small infarcts ⇒ vascular (multi-infarct) dementia
  
  • dementia, gait abnormalities, pseudobulbar signs, focal neuro deficits.
• Binswanger disease = pattern of recurrent ischemic injury involves subcortical white matter with myelin and axonal loss.

Question 52

Intracerebral Hemorrhage

Answer 52

• spontaneous rupture of small intraparenchymal vessel.
• age >60yrs.
• causes:
  
  • HTN in 50%. ⇒ hyaline arteriosclerosis and vessel weakening, focal vessel necrosis, Charcot-Bouchard aneurysms. in putamen (50-60%), thalamus, pons, cerebellar hemispheres.
  • cerebral amyloid angiopathy (CAA): 2nd most common. ** amyloidogenic peptides deposited in vessel walls** ⇒ weakening. lesions have stiff amyloid deposits in leptomeningeal and cerebral cortical vessels.
  • cerebral autosomal dominanty arteriopathy with subcortical infarcts (CADASIL): mutation in Notch3 receptor. vessels have concentric medial and adventitial thickening with basophilic granular depostis and smooth muscle drop-out

Question 53

Subarachnoid Hemorrhage

Answer 53

• usually from berry (saccular) aneurysm rupture, traumatic hematomas, vascular malformations, HTN intracerebral hemorrhage, tumors, hematologic disturbances.
• pathogenesis: 90% berry aneurysms in anterior circulation near arterial branch points.
  
  • can be with polycystic kidney disease (autosomal dominant), HTN, aortic coarctation, collagen disorders, neurofibromatosis type I, and fibromuscular dysplasia
• morphology: small with red shiny translucent wall. at aneurysm neck, the muscular wall and intimal elastic lamina are absent. sac wall is only thickened hyalinized intima.
• presentation: rupture from ↑ ICP. excruciating headache, rapid loss of consciousness. re-bleeding common with worse episode each time the aneurysm bleeds.
  
  • blood in subarachnoid ⇒ arterial vasospasm.
  • blood resorption ⇒ meningeal fibrosis and hydrocephalus

Question 54

Arteriovenous Malformation

Answer 54

• tangles of abnormalled tortuous and misshapen vessels, shunting arterial blood into venous circulation.
  
  • usually MCA.
• 2:1 m:f
• presentation: btw ages 10-30yrs as seizure disorder, intracerebral hemorrhage, or subarachnoid hemorrhage

Question 55

Cavernous Hemangiomas

Answer 55

• distended, loosely organized vascular channels with thin, collagenized walls.
• usually cerebellum, pons, and subcortical regions.
• low flow without arteriovenous shunting.

Question 56

Capillary Telangiectasias

Answer 56

• microscopic foci of dilated, thin-walled vascular channels separated by normal brain parenchyma.
• in pons.

Question 57

Venous Angiomas

Answer 57

• aka varices
• aggregates of ecstatic veins.

Question 58

Foix-Alajouanine Disease

Answer 58

• venous angiomatous malformation in lumbosacral region.
• slowly progressive ischemia and neuro symptoms.

Question 59

Acute Bacterial Meningitis

Answer 59

• neonates = E. coli and group B strep
• infants & kids = S. pneumoniae
• adolescents & young adults = N. meningitidis
• elderly = S. pneumoniae and L. monocytogenes
• morphology: meningeal vessels engorged, purulent exudate.
  
  • neutrophils in subarachnoid space. may have cerebritis.
  • phlebitis ⇒ venous thrombosis and hemorrhagic infarction.
  • resolution ⇒ leptomeningeal fibrosis and hydrocephalus
• presentation: fever, headache, photophobia, irritability, clouded sensorium, neck stiffness.
  
  • CSF purulent with neutrophils and organisms, ↑ protein, and ↓ glucose.

Question 60

Acute Viral Meningitis

Answer 60

• meningeal irritation, CSF lymphocytic pleocytosis, mod ↑ protein, normal glucose.
• self-limited.

Question 61

Brain Abscess

Answer 61

• destructive lesion coming from bacterial endocarditis, congenital heart disease, chronic pulmonary sepsis, or immunosuppression.
• mainly strep and staph.
• morphology: central region of liquefactive necrosis. older have fibrous capsule with reactive gliosis and marked vasogenic edema.
• presentation: progressive focal neurologic deficits and signs of ↑ ICP.
  
  • subdural space infected ⇒ thrombophlebitis ⇒ venous occlusion and brain infarction.

Question 62

Tuberculous Meningitis

Answer 62

• can ⇒ arachnoid fibrosis, hydrocephalus, obliterative endarteritis
• morphology: diffuse meningoencephalitis. subarachnoid has gelatinous or fibrinous exudate of chronic inflammatory cells. granulomas at base of brain are rare ⇒ obliterate cisternae and encase cranial nerves.
  
  • arteries in subarachnoid may have obliterative endarteritis.
• presentation: headache, malaise, mental confusion, vomiting.
  
  • mod CSF mononuclear cell pleocytosis, ↑ protein, mod ↓ or normal glucose.

Question 63

Neurosyphilis

Answer 63

• tertiary stage of disease, 10%.
• ↑ risk in HIV pts.
• meningovascular neurosyphilis = chronic meningitis associated with obliterative endarteritis.
• paretic neurosyphilis = from brian invasion by spirochetes with neuronal loss and microglial proliferation
  
  • have insidious loss of mental and physical capacity with mood alterations ⇒ severe dementia.
• tabes dorsalis = from spirochete damage to dorsal root sensory neurons ⇒ impaired joint position sense, locomotor ataxia, loss of pain with secondary skin and joint damage (Charcot joints), absent deep tendon reflexes.

Question 64

Neuroborreliosis

Answer 64

• in Lyme disease.
• includes septic meningitis, facial nerve palsies, encephalopathy.
• microglial proliferation and scattered organisms.

Question 65

Arthropod-Borne Viral Encephalitis

Answer 65

• inflammed meninges or spinal cord.
• from Eastern and Wester Equine viruses, Venezuelan virus, St. Lous virus, La Crosse virus, West Nile virus.
• all have animal hosts and mosquito or tick vector.
• presentation: seizures, confusion, delirium, stupor or coma.

Question 66

Hereps Simplex Virus Type I

Answer 66

• inflammed meninges or spinal cord.
• most common in kids or young adults.
• morphology: hemorhagic, nectrotizing encephalitis of inferomedial temporal lobes and orbital gyri of frontal lobes.
  
  • perivascular infiltrates with Cowdry A intranuclear viral inclusion bodies in neurons and glia.
• presentation: alterations in affect, mood, memory, and behavior.
  
  • protracted course = weakness, lethargy, ataxia, and seizures.

Question 67

Herpes Simplex Virus Type II

Answer 67

• severe generalized encephalitis in 50% neonates born vaginally.
• ⇒ meningitis in adults, severe hemorrhagic, necrotizing encephalitis in HIV pts.

Question 68

Varicella Zoster (Brain)

Answer 68

• shingles can cause persistent painful post-herpetic neuralgia syndrome.
• granulomatous arteritis, or necrotizing encephalitis in immunocompromised

Question 69

Cytomegalovirus (Brain)

Answer 69

• in utero infection ⇒ periventricular necrosis, microcephaly, and periventricular calcification.
• in AIDS = opportunistic infection ⇒ subacute encephalitis with microglial nodules or periventricular hemorrhagic necrotizing encephalitis and choroid plexus.
• has classic CMV inclusions.

Question 70

Poliomyelitis

Answer 70

• inflammation confined to anterior horns but can extend to posterior horns.
• meningial irritation and CSF picture of aseptic meningitis.
  
  • involves lower motor neurons ⇒ flaccid paralysis with hyporeflexia and 2° muscle wasting.
  • can get myocarditis, death from respiratory muscle paralysis.
• presentation: post-polio syndrome = 25-35yrs after polio, progressive weakness associated with pain and ↓ muscle mass.

Question 71

Rabies (Brain)

Answer 71

• severe encephalitis from rabid animal or exposure to a bat without a bite.
• over 1-3 months the virus travels up peripheral nerves ⇒ CNS excitability, hydrophobia, flaccid paralysis.
• death from respiratory center failure.
• widespread neuronal necrosis and inflammation.
  
  • worst in basal ganglia, midbrain, medulla.
• Negri bodies in hippocampal pyramidal cells and Purkinje cells.

Question 72

HIV (Brain)

Answer 72

• 10% get aseptic meningitis within 1-2 wks of primary HIV infection.
• HIV encephalitis in symptomatic pts.
• only microglia express CD4 and chemokine receptors for efficient HIV infection.
• 80-90% get CNS lesions: direct viral pathogenic effects, opportunistic infections, and/or CNS lymphomas.
• HIV-associated dementia = related to extent of activated CNS microglia.
• morphology: chronic inflammatory reaction with widely distributed microglial nodules, multinucleated giant cells, with necrosis and gliosis.
  
  • most affects subcortical white matter, diencephalon, brain stem.

Question 73

Progressive Multifocal Leukoencephalopathy

Answer 73

• from oligodendrocyte infection by JC polyomavirus in immunosuppressed pts.
• have evidence of prior JC exposure so is reexposure.
• develop progressive neuro manifestations from focal myelin destruction.
• morphology: demyelinated patches, greatly enlarged oligodendrocyte nuclei with viral inclusions. astrocytes with enlarged atypical nuclei.

Question 74

Subacute Sclerosing Panencephalitis

Answer 74

• SSPE. progressive syndrome of cognitive decline, limb spasticity, and seizures.
• occurs months to years **after early age measles infection. **
• presistent but nonproductive CNS infection.
• widespread gliosis and myelin degeneration, associated with nuclear inclusions in oligodendrocytes and neurons.
• variable inflammation with neurofibrillary tangles.

Question 75

Fungal Meningoencephalitis

Answer 75

• in immunocompromised patients with widespread hematogenous dissemination
  
  • Candida, Mucor, Aspergillus, Cryptococcus.
• Histoplasma, Coccidioides, and Blastomyces involve CNS after pulmonary or cutaneous infections.
• meningitis: by Cryptococcus.
  
  • fulminant and fata within 2 wks or chronic and indolent over months-yrs.
• vasculitis: Mucor and Aspergillus.
  
  • vessel invasion with thrombosis and hemorrhagic infarction.
• granulomas or abscesses with Candida and Cryptococcus.

Question 76

Toxoplasma gondii (Brain)

Answer 76

• seen in HIV pts.
• symptoms over 1-2 wks, are focal.
• multiple ring-enhanced lesions.
• abscesses with fre tachyzoites and encysted bradyzoites.
• maternal infection can ⇒ fetal cerebritis with multifocal necrotizing lesions that calcify.

Question 77

Naegleria (Brain)

Answer 77

• causes rapidly fata necrotizing encephalitis.

Question 78

Acanthamoeba

Answer 78

• associated with chronic granulomatous meningoencephalitis

Question 79

Prion Diseases

Answer 79

• have spongiform changes (neuronal and glial intracellular vacuoles) caused by prion proteins. (PrP).
• infectious, sporadic, or familial.
• Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru.
• pathogenesis: disease when becomes abnormally folded as beta-pleated sheet.
  
  • can induce changes in normal PrP.
• polymorphisms at codon 129 (for methionine or valine) influence disease.
• heterozygosity at codon 129 is protective.

Question 80

Creutzfeldt-Jakob Disease

Answer 80

• 85% sporadic. peaks btw 60-70yrs.
• presentation: subtle memory and behavior changes, then rapidly progressive dementia, with involuntary jerking muscle contractions.
• fatal. die ~7months after symptom onset.

Question 81

Variant Creutzfeldt-Jakob Disease

Answer 81

• in young adults.
• early behavior manifestations and slower neurologic progression.
• linked to bovine spongiform encephalopathy.
• extensive cortical plaques with surrounding halo of spongiform change.

Question 82

Gerstmann-Strauss-Scheinker Syndrome

Answer 82

• inherited disease with PRNP mutations.
• morphology: spongiform transformation of cerebral cortex and deep gray matter structures (caudate and putamen).
  
  • advanced = severe neuronal loss, reactive gliosis, expansion of vacuolated areas into cystlike spaces (status spongiosus).
  • kuru plaques = extracellular aggregates of PrP^sc proteins on congo-red and PAS-pos.
• presentation: chronic cerebellar ataxia, then progressive dementia.
  
  • death a few years after symptom onset.

Question 83

Fatal Familial Insomnia

Answer 83

• PRNP mutations substitute aspartate for asparagine at 178 of PrP^c.
  
  • mutation and methionine at 129 ⇒ FFI.
  • valine at 129 ⇒ CJD.
• morphology: NO spongiform changes. ** neuronal loss and reactive gliosis in inferior olivary nuclei and anterior ventral and dorsomedial nuclei of thalamus**.
• presentation: sleep disturbances in initial stages.

Question 84

Multiple Sclerosis

Answer 84

• autoimmune demyelinating disorder with distinct episodes of neurologic deficit separated in time and attributable to white matter lesions that are separated in space.
• F>M. peak age btw childhood and 50yrs.
• relapsing and remitting with acute deficit onset and slow partial remission.
  
  • relapse frequency increases over time but have steady neuro deterioration.
• pathogenesis: cellular immune response against myelin.
  
  • susceptibility linked to DR2 locus of major histocompatibility complex and polymorphisms in IL-2 and IL-4 receptor genes.
  • initiated by T_H1 and T_H17 cells ⇒ myelin destruction.
    
    • TH1 ⇒IFNgamma ⇒ activate macrophages
    • TH17 ⇒ recruit leukocytes.
  • CSF has oligoclonal Ig response = B cell response.
• morphology: plaques are sharply defined areas of gray discoloration of white matter around ventricles.
  
  • active plaques have myelin breakdown, lipid-laden macrophages, and relative axonal preservation.
    
    • lymphocytes and mononuclear cells at plaque edges and venules.
  • inactive plaques lack inflammatory infiltrate, show gliosis.
  • axons remain but are unmyelinated.
• presentation: unilateral vision impairment from optic neuritis.
  
  • cranial nerve signs, ataxia, nystagmus, internuclear ophthalmoplegia from brainstem involvement.
  • limb and trunk motor and sensory impairment, spasticity, and bladder dysfunction from spinal cord lesions.

Question 85

Neuromyelitis Optica

Answer 85

• aka Devic disease.
• bilateral optic neuritis and spinal cord demyelinating lesions.
• white matter lesions = necrosis with acute inflammation, vascular Ig and complement deposits.
• Ab to aquaporins - important for astrocyte foot processes and BBB.

Question 86

Acute Disseminated Encephalomyelitis

Answer 86

• diffuse demyelinating disese after viral infection.
• perivenular demyelination with axonal preservation, early neutrophil infiltrates then mononuclear cell inflammation and lipid-laden macrophages.
• presentation: headache, lethargy, and coma. no focal deficits. 20% die.

Question 87

Acute Necrotizing Hemorrhagic Encephalomyelitis

Answer 87

• fulminant, commonly fatal, demyelinating syndrome in kids and young adults after upper respiratory tract infection.
• small vessel destruction and disseminated CNS necrosis.
• have perivascular demyelination with axonal preservation. early neutrophils then mononuclar cells then lipid-laden macrophages.

Question 88

Central Pontine Myelinosis

Answer 88

• myelin damage with axonal preservation but without inflammation in basis pontis and portions of pontine tegmentum ⇒ spastic paresis.
• associated with rapid correction of hypnatremic state.

Question 89

Alzheimer Disease

Answer 89

• begins after age 50yr. progressive insidious impairment of higher intellectual function over 5-10yrs.
• mostly sporadic.
• common cause of death = intercurrent disease (pneumonia)
• morphology: cortical atrophy with narrowed gyri and widelned sulci in frontal, temporal, and parietal lobes. ** hydrocephalus ex vacuo**, medial temporal structures involved early.
  
  • neuritic plaques and neurofibrillary tangles.
  • cerebral amyloid angiopathy (CAA) = alpha-beta amyloid deposition
  • granulovacuolar degeneration = formation of small clear intraneuronal cytoplasmic vacuoles.
  • Hirano bodies = elongated, glassy eosinophilic paracrystalline arrays of beaded filaments, mostly actin.
• pathogenesis: AB deposition can be neurotoxic ⇒ synaptic dysfunction, inflammation
  
  • familial forms = mutation in APP on chromosome 21
    
    • Down syndrome have early onset.
    • early onset from **mutations in presenilin (PS1 or PS2) **⇒ enhanced gamma-secretase activity.
    • apolipoprotein epsilon4 ⇒ ↑ risk

Question 90

Frontotemporal Dementia with Parkinsonism Linked to Tau Mutations

Answer 90

• have parkinsonian symptoms
• mutation in MAPT (tau) gene, affects tau in microtubules.
• morphology: frontal and temporal lobe atrophy.
  
  • neuronal loss, gliosis, tau-containing neurofibrillary tangles.
  • can have nigral degeneration or glial cell inclusions.

Question 91

Pick Disease

Answer 91

• causes dementia.
• prominent frontal signs.
• morphology: frontal and temporal lobe atrophy. spares posterior 2/3 of superior temporal gyrus. caudate and putamen can atrophy.
  
  • large ballooned neurons (Pick cells) and smooth agyrophilic inclusions made of straight and paired helical filaments (Pick bodies)

Question 92

Progressive Supranuclear Palsy

Answer 92

• men > 50yrs
• from gene polymorphisms, MAPT haplotype
• morphology: widespread neuronal loss and neurofibrillary tangles in globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, dentate nucleus.
  
  • tau pathology in glial cells
• presentation: loss of vertical gaze, truncal rigidity, dysequilibrium, loss of facial expression, mild progressive dementia.
• death within 5-7 yrs

Question 93

Corticobasal Degeneration

Answer 93

• disease of elderly
• same MAPT haplotype as progressive supranuclear palsy
• morphology: motor, premotor, and anterior parietal cortex have neuronal loss, gliosis, ballooned neurons.
  
  • loss of pigmented neurons and argyrophilic inclusions in substantia nigra and locus ceruleus.
  • tufted astrocytes = tau immunoreactivity
  • coiled bodies = tau immunoreactivity in oligodendrocytes
• presentation: extrapyramidal rigidity, asymmetric motor disturbances, sensory cortical dysfunction

Question 94

Vascular Dementia

Answer 94

• vascular injury ⇒ ↓ threshold for dementing effects of other disorders.
• from multiple lacunar infarcts, HTN disease (Binswanger disease), specially located large infarcts (hippocampus, dorsomedial thalamus, frontal cortex), vasculitis.

Question 95

Parkinsonism

Answer 95

• causes: Parkinson disease, multiple system atrophy, postemcephalitic parkinsonism (1918 flu pandemic), frontotemporal dementias, dopamine antagonists or toxins.
• presentation: diminished facial expression, stooped posture, slow voluntary movement, festinating gait (shortened and accelerated), rigidity, pill-rolling tremor (↓ function of nigrostriatal dopaminergic system)

Question 96

Parkinson Disease

Answer 96

• progressive L-DOPA responsive parkinsonism without toxic etiology.
• morphology: pallor of substantia nigra and locus ceruleus with loss of pigmented catecholaminergic neurons and gliosis
  
  • remaining neurons have lewy bodies = intracytoplasmic eosinophilic inclusions with alpha-synuclein.
• pathogenesis: autosomal dominant forms = overexpression of alpha-synuclein or gain of function in LRRK2 gene
  
  • juveninle recessive form = loss of function in parkin gene
  • recessive forms = mutated DJ-1 and PINK1 kinase
  • lose dopaminergic neurons in substantia nigra from alpha-synuclein aggregation, proteasome dysfunction, altered mitochondrial activity.
  • leads to striatal dopamine deficiency.
• presentation: autonomic and cognitive dysfunction with diminished facial expression, stooped posture, slowed voluntary movement, festinated gait, rigidity, pill-rolling tremor.
  
  • L-DOPA improves it but become refractory.
• tx: L-DOPA, neural transplantation, gene therapy, neurosurgical lesions in extrapyramidal system, deep brain stimulation.

Question 97

Dementia with Lewy Bodies

Answer 97

• dementia in 10-15% PD patients.
• some have Alzheimers
• most have alpha-synuclein-containing lewy bodies
• flluctuating course with hallucinations and frontal signs.

Question 98

Multiple System Atrophy

Answer 98

• atrophy in CNS regions with glial tubular cytoplasmic inclusions made of alpha-synuclein, ubiquitin, and alpha-B crystallin
• striatonigral degeneration = parkinsonism
  
  • atrophy of substantia nigra and striatum.
• olivopontocerebellar atrophy = cerebellar ataxia, eye and somatic movement abnormalities, dysarthria, rigidity.
  
  • atrophy of cerebellar peduncles, basis pontis, inferior olives.
• Shy-Drager syndrome = autonomic dysfunction with loss of sympathetic neurons of intermediolateral column in spinal cord.

Question 99

Striatonigral Degeneration

Answer 99

• parkinsonism
  
  • atrophy of substantia nigra and striatum.

Question 100

Olivopontocerebellar Atrophy

Answer 100

• cerebellar ataxia, eye and somatic movement abnormalities, dysarthria, rigidity.
  
  • atrophy of cerebellar peduncles, basis pontis, inferior olives.

Question 101

Shy-Drager Syndrome

Answer 101

• autonomic dysfunction with loss of sympathetic neurons of intermediolateral column in spinal cord.

Question 102

Huntington Disease

Answer 102

• autosomal dominant movement disorder.
• morphology: atrophy of caudate nucleus and putamen, loss of med-sized spiny striatal neurons that use GABA.
  
  • gliosis and intraneural huntingtin aggregates in striatum and cerebral cortex.
  • spares neurons with NO synthase and cholinesterase
• pathogenesis: expansion of CAG repeat in huntingtin (>36 repeats) ⇒ toxic gain of function, aggregation, sequester transcriptional regulators, dysregulate transcription pathways for mitochondrial biogenesis or protection from oxidative injury.
  
  • anticipation = parental transmission ⇒ earlier expression in kids.
• presentation: btw ages 20-50yrs, get chorea (jerky, hyperkinetic, dystonic movements)** ⇒ parkinsonism**
  
  • motor symptoms precede cognitive impairment ⇒ death in 15 yrs.

Question 103

Friedreich Ataxia

Answer 103

• autosomal recessive
• expansion of intronic GAA repeat in gene for frataxin (mitochondrial membrane protein for iron regulation).
• morphology: axonal loss and gliosis posterior columns of spinal cord, distal corticospinal and spinocerebellar tracts.
  
  • neuronal degredation of CN VIII, X, XII nuclei, dentate nucleus, Purkinje cells in superior vermis, and dorsal root ganglia.
• presentation: gait ataxia, hand clumsiness, dyarthria, depressed tendon reflexes, sensory loss.
  
  • wheelchair bound in 5 yrs.
  • death from cardiac arrhythmias or pulmonary infections.

Question 104

Ataxia-Telangiectasia

Answer 104

• autosomal recessive
• mutated ATM gene that repairs dsDNA breaks ⇒ ↑ risk malignancy and neurons more degradation prone.
• morphology: cerebellar Purkinje and granule cells lost.
  
  • degeneration of dorsal columns, spinocerebellar tracts, anterior horn cells.
  • Schwann cell nuclei in dorsal root ganglia and peripheral nerves are 2-5x enlarged.
• presentation: kids have cerebellar dysfunction, telangiectatic lesions in skin and conjunctiva, and immunodeficiency (lymph nodes and thymus hypoplastic).
  
  • death btw 10-20yrs old.

Question 105

Amyotrophic Lateral Sclerosis (ALS)

Answer 105

• aka Motor Neuron Disease
• loss of lower and upper motor neurons.
• pathogenesis: 5-10% familial and autosomal dominant.
  
  • 25% from gain of function in SOD1 gene for copper zinc superoxide dismutase ⇒ misfolded proteins that cause unfolded protein response.
  • may have abnormal axonal transport, protein accumulation, glutamate NT toxicity.
• morphology: upper motor neuron degeneration ⇒ demyelination in corticospinal tracts and reactive gliosis. can be atrophy of precentral gyrus.
  
  • remaining neurons have Bunina bodies = PAS-pos cytoplasmic inclusions.
  • affected skeletal muscles have neurogenic atrophy.
• presentation: m>f, age>40yrs. early clumsiness ⇒ muscle weakeness and fasciculations that ⇒ pneumonia when respiratory muscles involved
  
  • may have bulbar manifestations (involve motor CN) ⇒ problems with deglutition and phonation.
  • progressive, die from respiratory complications.

Question 106

Bulbospinal Atrophy

Answer 106

• aka Kennedy syndrome.
• X-linked.
• expansion of CAG/polyglutamine trinucleotide repeat in androgen receptor gene ⇒ intranuclear receptor aggregation.
• lower motor neuron loss ⇒ androgen insensitivity (gynecomastia, testicular atrophy, oligospermia).

Question 107

Neuronal Ceroid Lipofuscinoses

Answer 107

• inherited lysosomal storage disorders ⇒ neuronal accumulation of lipofuscin.
• can ⇒ blindness, mental and motor deterioration, and seizures.

Question 108

Krabbe Disease

Answer 108

• autosomal recessive
• deficiency of galactocerebroside beta-galactosidase ⇒ ↑ ceramide
• alternate pathway causes excess ⇒ galactosylsphingosine, toxic to oligodendrocytes.
• morphology: diffuse loss of myelin and oligodendrocytes
  
  • aggregates of Globoid cells = glycolipid-engorged macrophages.
• presentation: weakness and stiffness by age 3-6months. die by age 2 yrs.

Question 109

Metachromatic Leukodystrophy

Answer 109

• autosomal recessive
• deficiency of arylsulfatase ⇒ accumulate cerebroside sulfate. may block oligodendrocyte differentiation.
• morphology: myelin loss, gliosis, macrophages containing metachromatic material.

Question 110

Adrenoleukodystrophy

Answer 110

• progressive disorder from loss of myelin and adrenal insufficiency ⇒ inability to catabolize very long chain fatty acids

Question 111

Pelizaeus-Merzbacher Disease

Answer 111

• X-linked
• mutation in gene encoding two alternatively-spliced myelin proteins (ex. PLP and DM20)

Question 112

Mitochondrial Encephalopathy with Lactic Acidosis and Strokelike Episodes (MELAS)

Answer 112

• most common neurologic syndrome with mitochondrial abnormalities.
• involves mitochondrial tRNA.
• presentation: muscle and metabolic findings, recurrent neurologic dysfunction and cognitive changes.
  
  • strokelike episodes have reversible deficits.

Question 113

Leigh Syndrome

Answer 113

• aka Subacute Necrotizing Encephalopathy
• mutations in oxidative phosphorylation pathway.
• morphology: bilateral brain damage with vascular proliferation and spongiform changes.
  
  • symmetrically involves midbrain periventricular gray matter, pontine tegmentum, thalamus, and hypothalamus.
• presentation: 1-2yrs old with developmental arrest, feeding problems, seizures, extraocular palsies, hypotonia, and lactic acidemia.

Question 114

Thiamine (Vitamin B₁) Deficiency

Answer 114

• ⇒ Beriberi, Wernicke encephalopathy, Korsakoff syndrome.
• Beriberi = nutritional deficiency. associated with cardiac failure
• Wernicke encephalopathy = sudden onset psychosis and/or ophthalmoplegia
• Korsakoff syndrome = progresses from Wernicke’s to an irreversible memory disorder with conflabulation.
• common in alcoholics
• can come from gastric disease: carcinoma, chronic gastritis, persistent vomiting.
• morphology: mammilary body (and 3rd and 4th ventricle) hemorrhage and necrosis.
  
  • thalamic dorsomedial nucleus lesions ⇒ memory disturbances.

Question 115

Vitamin B₁₂ Deficiency

Answer 115

• ⇒ anemia and nervous system injury.
• morphology: vacuolar swelling of myelin affects both ascending and descending tracts starting at midthoracic cord.
• presentation: slight ataxia and lower extremity paresthesias ⇒ lower extremity spastic weakness and paraplegia, may be permanent.

Question 116

Hypoglycemia

Answer 116

• affects large cerebral pyramidal cells, hippocampal pyramidal cells in CA1, and Purkinje cells.
• prolonged, severe hypoglycemia ⇒ global neuronal injury.

Question 117

Hyperglycemia

Answer 117

• from poorly controlled DM.
• can ⇒ ketoacidosis.
• hyperosmolar state has dehydration ⇒ confusion, stupor, coma.
• gradually correct fluid depletion to prevent cerebral edema.

Question 118

Carbon Monoxide (Brain)

Answer 118

• causes hypoxia from ↓ oxygen carrying capacity of hemoglobin.
• injures neurons in layers III and V in cerebral cortex, hippocampal Sommer sector, and Purkinje cells.
• ⇒ bilateral necrosis of globus pallidus.

Question 119

Methanol (Brain)

Answer 119

• toxicity affects retina.
• degeneration of ganglion cells ⇒ blindness.
• may be from formic acid (metabolite of methanol)

Question 120

Radiation (Brain)

Answer 120

• causes acute CNS decompensation, can develop months to years later.
• late radionecrosis associated with large zones of coagulative necrosis and edema in white matter.
• blood vessels have thickened walls with intramural fibrin-like material. proteinaceous spheroids in adjacent tissues.
• can be synergistic with methotrexate.

Question 121

Pilocytic Astrocytoma

Answer 121

• kids and young adults.
• benign tumor in cerebellum, floor and walls of 3rd ventricle, optic nerve, cerebral hemispheres.
• usually a p53 mutation.
• morphology: grade I/IV tumor. cystic with mural nodule in wall of cyst.
  
  • bipolar cells with long, thin, hairlike processes.
  • Rosenthal fibers and microcysts.
  • narrow infiltrative border surrounding brain.

Question 122

Inflitrating Astrocytomas

Answer 122

• 80% of adult primary brain tumors.
• age: 30-60 yr.
• low grade: overexpress PDGF-alpha and receptor. mutated p53 function.
• high grade: mutation of RB, p16/CDKNaA ⇒ activate RAS and PI-3 kinase pathways, inactivate RB and p53
• morphology: grades II-IV.
• presentation: focal neurologic deficits, headaches, seizures, from mass effects or cerebral edema.
  
  • high grade have contrast enhancement on imaging.

Question 123

Diffuse Astrocytomas

Answer 123

• infiltrating astrocytoma
• grade II/IV
• poorly defined, gray-white. expands and distorts a region of the brain.
• hypercellularity and nuclear pleomorphism
• indistinct transition from normal to neoplastic

Question 124

Anaplastic Astrocytoma

Answer 124

• infiltrating astrocytoma
• grade III/IV.
• ↑ nuclear anaplasia with numerous mitoses.

Question 125

Glioblastomas

Answer 125

• infiltrating astrocytoma
• grade IV/IV.
• mixture of firm white areas, soft yellow areas of necrosis, cystic change, and hemorrhage.
• ↑ vascularity
• pseudopalisading = ↑ tumor cell density along necrotic edges.
• poor prognosis, typically survive about 15 months.

Question 126

Pleomorphic Xanthoastrocytomas

Answer 126

• temporal lobes of young patients with history of seizures.
• grade II/IV.
• neoplastic bizarre astrocytes, abundant reticulin and lipid deposits, chronic inflammatory cell infiltrates.
• 5 yr survival = 80%.

Question 127

Brainstem Gliomas

Answer 127

• ages 0-20yrs.
• pontine is most common, aggressive.
• tecta are benign.
• corticomedullary junction = intermediate.

Question 128

Oligodendroglioma

Answer 128

• 5-15% of gliomas.
• in mid life.
• usually loss of heterozygosity in chromosomes 1p and 19q.
• morphology: in white matter. well circumscribed, gelatinous, gray masses with cysts, focal hemorrhage, and calcification.
  
  • sheets of regular cells with round nuclei containing finely granular chromatin surrounded by halo of cytoplasm. sit in delicate capillary network.
  • calcification in 90%.
• presentation: better prognosis than astrocytomas. only have 1p 19q respond well to chemo and radiation.
  
  • survival 5-10 yrs
  • anaplastic = grade III/IV, worse prognosis.

Question 129

Ependymoma

Answer 129

• tumor arising from ependymal lining.
• ages 0-20yrs: usually in 4th ventricle.
• spinal cord central canal = middle age and neurofibromatosis type II.
• morphology: moderately well-demarcated solid or papillary lesions.
  
  • round-oval nuclei with abundant granular chromatin.
  • form elongated ependymal canals or pervascular pseudorosettes.
  • grade II/IV.
  • anaplastic = grade III/IV. have ↑ cell density, mitoses, necrosis with less evident ependymal differentiation.
• presentation: posterior fossa ependymomas have hydrocephalus. CSF dissemination common.
  
  • 50% 5 yr survival.
  • spinal cord lesions do better

Question 130

Myxopapillary Ependymoma

Answer 130

• arises in filum terminale of spinal cord.
• cuboidal cells, can have clear cytoplasm, around papillary core.
• myxoid areas have neutral and acidic mucopolysaccharides

Question 131

Subependymoma

Answer 131

• solid, calcified, slow growing nodules attached to ventricular lining, protruding into ventricle.
• usually asymptomatic, can cause hydrocephalus.
• morphology: clumps of ependymal-appearing nuclei scattered in dense, finely fibrillar background

Question 132

Choroid Plexus Papilloma

Answer 132

• recapitulate normal choroid plexus.
• CT papillae covered with cuboidal-columnar ciliated epithelium.
• hydrocephalus from obstruction or CSF overproduction.

Question 133

Choroid Plexus Carcinoma

Answer 133

• rare adenocarcinoma.
• usually in kids

Question 134

Colloid Cysts of 3rd Ventricle

Answer 134

• non-neoplastic lesion in young adult.
• in foramen of Monro.
• ⇒noncommunicating hydrocephalus. can be fatal.
• contains gelatinous, proteinaceous material in a thin fibrous capsule lined by cuboidal epithelium.

Question 135

Ganglioglioma

Answer 135

• most common CNS tumor of mature-appearing neurons (ganglion cells).
• slow growing even if aggressive.
• morphology: in temporal lobe, cystic component.
  
  • neoplastic ganglion cells irregularly clustered, randomly oriented neurites.
  • glial component resembles low grade astrocytoma without necrosis/mitotic activity.
• presentation: seizures that remit after resection.

Question 136

Dysembryoplastic Neuroepithelial Tumor

Answer 136

• rare, low grade childhood neoplasm.
• morphology: intracortical location, cystic changes, nodular growth, ‘floating neurons’ in mucopolysaccharide rich fluid, surrounding neoplastic glia without anapastic features.
• presentation: seizure disorder.
  
  • good prognosis with resection.

Question 137

Central Neurocytoma

Answer 137

• low grade neuronal neoplasm in ventricles.
• evenly spaced, round, uniform nuclei and islands of neuropil.

Question 138

Medulloblastoma

Answer 138

• 20% childhood brain tumors.
• in cerebellum.
• loss of material from 17p with isochromosome of 17q.
• MYC amplification = more aggressive.
• ↑ neurotropin receptor TRKC or ↑ intranuclear beta-catenin = better outcome.
• morphology: well circumscribed, gray and friable.
  
  • extremely cellular, has sheets of anaplastic cells with hyperchromatic nuclei and abundant mitoses.
  • little cytoplasm, devoid of differentiation markers. can have glial and neuronal features.
  • prominent desmoplasia if extend into subarachnoid space.
• presentation: midline lesion in kids, lateral in adults.
  
  • rapid growth ⇒ occlude CSF flow, hydrocephalus.
  • CSF dissemination
  • highly malignant, poor prognosis untreated.
  • with excision and radiation have 75% 5 yr survival.

Question 139

Atypical Teratoid/Rhabdoid Tumor

Answer 139

• highly malignant tumor in posterior fossa and supratentorium of young kids.
• survive <1yr.
• chromosome 22 deletions. hSNF5/INI1 that encodes protein in chromatin remodeling.
• large, soft tumor over brain surface.
• highly mitotic lesion with rhabdoid cells resembling rhabdomyosarcoma.

Question 140

Primary Central Nervous System Lymphoma

Answer 140

• 2% of extranodal lymphomas, 1% intracranial tumors.
• most common CNS neoplasm in immunocompromised.
• multifocal within CNS. outside metastasis is late complication.
• B-cell origin, infected with EBV
• aggressive, respond poorly to chemo
• morphology: diffuse large-cell B-cell lymphoma.
  
  • involve parenchyma of brain, see around blood vessels.

Question 141

Germ Cell Tumors

Answer 141

• along midline in adolescents and young adults.
• 0.2-1% caucasian CNS tumors, 10% Japanese
• in pineal gland (men) and suprasellar regions.

Question 142

Meningioma

Answer 142

• benign tumor of adult coming from arachnoid meningothelial cells, are attached to dura.
• loss of heterozygosity of long arm of chromosome 22. NF2 gene (merlin protein).
• morphology: rounded masses with well-defined dural bases compress brain but can separate it.
  
  • firm, lack necrosis or extensive hemorrhage.
  • gritty from calcified psammoma bodies.
  • patterns = synctytial, fibroblastic, transitional, psammomatous, secretory, and microcystic. grade I/IV.
  • proliferative index predicts behavior.
• presentation: solitary, slow growing lesion. manifest from CNS compression or vague non-localizing symptoms.
  
  • uncommon in kids.
  • 3:2 f:m. express progesterone receptors, grow faster during pregnancy.

Question 143

Anaplastic Meningioma

Answer 143

• grade III/IV.
• aggressive, resemble sarcomas.
• high mitotic rates

Question 144

Papillary Meningioma

Answer 144

• pleomorphic cells arranged around fibrovascular cores.
• grade III/IV

Question 145

Rhabdoid Meningioma

Answer 145

• sheets of cells with hyaline eosinophilic cytoplasms composed of intermediate filaments.
• grade III/IV.
• high recurrence rate.

Question 146

Tumors Metastatic to Brain

Answer 146

• 50% intracranial tumors.
• primary sites: lungs, breast, skin (melanoma), kidney, and GI tract.
• can also come from meninges.
• morphology: sharply demarcated, at gray-white junction. surrounded by edema.
  
  • meningeal carcinomatosis = tumor nodules studding brain surface, spinal cord, and nerve roots.
    
    • see in lung and breast carcinomas.

Question 147

Subacute Cerebellar Degeneration

Answer 147

• most common paraneoplastic syndrome.
• have Purkinje cell loss, gliosis, and inflammatory infiltrates.

Question 148

Paraneoplastic Syndromes

Answer 148

• from malignancy elsewhere.
• due to anti-tumor immune responses cross reacting with CNS and PNS antigens.
• subacute cerebellar degeneration, limbic encephalitis, eye movement disorders, subacute sensory neuropathy, Lambert-Eaton myasthenic syndrome.

Question 149

Limbic Encephalitis

Answer 149

• paraneoplastic syndrome.
• subacute dementia associated with perivascular inflammation, microglial nodules, neuronal loss, and gliosis.
• anterior and medial temporal lobes.

Question 150

Eye Movement Disorders

Answer 150

• paraneoplastic syndrome.
• associated with childhood neuroblastomas.

Question 151

Subacute Sensory Neuropathy

Answer 151

• paraneoplastic syndrome.
• can be with limbic encephalitis.
• marked by dorsal root ganglia inflammation and neuronal loss.

Question 152

Schwannoma

Answer 152

• benign tumor of schwann cells.
• associated with vestibular branch of CN VIII at cerebellopontine angle (vestibular schwannoma or acoustic neuroma).
  
  • have tinnitus and hearing loss.
• extradural = associated with large nerve trunks.
• inactivating mutation of NF2 ⇒ loss of merlin ⇒ hyperproliferation
• morphology: well-circumscribed encapsulated firm gray masses with cystic and xanthomatous changes.
  
  • attached to nerve but separable.
  • spinal tumors from dorsal roots, extend through vertebral foramen = dumbbell shape.
  • Antoni A = elongated cells with cytoplasmic processes, arranged in fascicles in areas of mod-high cellularity with little stromal matrix.
  • Antoni B = less densely cellular tissues with microcysts and myxoid changes.
  • basement membrane deposition encasing single cells and collagen fibers.

Question 153

Neurofibroma

Answer 153

• discrete localized mass.
• skin lesions = nodules. can be large and pedunculated.
• plexiform neurofibromas = infiltrating lesion that expands peripheral nerve.
  
  • loss of both NF1 genes ⇒ ↓ RAS GTPase, ↑ RAS function
• can’t separate from nerve.
• loose myxoid background, low cellularity.
• NF1 = multiple or plexiform lesions
  
  • diffucult to remove from nerve, ↑ risk malignancy.

Question 154

Malignant Peripheral Nerve Sheath Tumors

Answer 154

• highly malignant, locally invasive sarcomas.
• de novo or from plexiform neurofibroma transformation (NF1).
• ill-defined mass infiltrating parent nerve and adjacent soft tissue.
• resembles schwann cells. fascicle formation, mitosis, necrosis, anaplasia.

Question 155

Cowden Syndrome

Answer 155

• dysplastic cerebellar gangliocytomas
• due to PTEN mutation.

Question 156

Li-Fraumeni Syndrome

Answer 156

• medulloblastoma from p53 mutation

Question 157

Turcot Syndrome

Answer 157

• medulloblastoma or glioblastoma
• APC or mismatch repair gene mutation

Question 158

Gorlin Syndrome

Answer 158

• medulloblastoma from PTCH mutation

Question 159

Neurofibromatosis Type 1

Answer 159

• autosomal dominant.
• neurofibromas (cutaneous and plexiform), optic nerve gliomas, meningiomas, pigmented nodules of iris (Lisch nodules), and cutaneous hyperpigmented macules (café au lait spots)
• can be disfiguring, create spinal deformities.
• lack neurofibromin from biallelic gene inactivation (NF1).

Question 160

Neurofibromatosis Type 2

Answer 160

• autosomal dominant.
• inactivation of NF2.
• form bilateral CN VIII schwannomas or multiple meningiomas.

Question 161

Tuberous Sclerosis Complex

Answer 161

• autosomal dominant
• angiofibromas, seizures, mental retardation.
• hamartomas include cortical tubers = haphazardly arranged neurons and cells expressing phenotypes intermediate btw glia and neurons; subendymal hamartomas = large astrocytic and neuronal clusters forming subependymal giant cell astrocytomas
• can have renal angiomyolipomas, retinal glial hamartomas, cardiac rhabdomyomas, pulmonary lymphangioleiomyomatosis
• cutaneous lesions = angiofibromas, shagreen patches (leathery thickenings), sunungual fibromas, hypopigmented areas (ash-leaf patches)
• TSC1 encodes hamartin.
• TSC2 encodes tuberin
• TSC1 and TSC2 form complex that inhibits mTOR kinase ⇒ ↑ mTOR activity ⇒ ↑ protein synthesis and ↑ cell size.

Question 162

Von Hippel-Lindau Disease

Answer 162

• autosomal dominant
• causes hemangioblastomas in cerebellum, retina, or brainstem and spinal cord. cysts in pancreas, liver, and kidney.
• propensity for renal cell carcinoma and pheochromocytomas.
• mutated VHL ⇒ dysregulated HIF-1 ⇒ ↑ expression VEGF, erythropoietin, other growth factors.
  
  • VHL encodes part of ubiquitin-ligase complex that downregulates HIF-1.

Question 163

Epineurium

Answer 163

• encases all fascicles of entire nerve

Question 164

Perineurium

Answer 164

• encases each fascicle

Question 165

Endoneurium

Answer 165

• surrounds individual nerve fibers.

Question 166

Anterior Spinal Root

Answer 166

• has motor fibers

Question 167

Posterior Spinal Root

Answer 167

• has sensory fibers

Question 168

Type 1 Muscle Fiber

Answer 168

• mneumonic: ‘one slow fat red ox’
  
  • ONE: type 1
  • SLOW: twitch, sustained force, weight bearing.
  • FAT: lipid-rich.
  • RED: color is red.
  • OX: oxidative, many mitochondria.
• ex. soleus

Question 169

Type 2 Muscle Fiber

Answer 169

• for sudden, purposeful movements
• type 2 fiber
• fast-twitch
• few lipids, abundant glycogen
• white color
• anaerobic: few mitochondria, narrow Z-band.
• ex: pectoral

Question 170

Segmental Demyelination

Answer 170

• from schwann cell dysfunction or myelin sheath damage. axon is normal.
• denuded axons stimulate remyelination, precursor cells in endoneurium replace injured schwann cells.
  
  • internode distances shorter, myelin sheath thinner.
• onion bulbs = recurrent demyelination and remyelination causes layers of Schwann cell processes.
• chronic demyelinating disorders ⇒ axonal injury.

Question 171

Wallerian Degeneration

Answer 171

• rxn distal to a transected axon.
• reflects axonal and myelin breakdown with macrophage recruitment and phagocytosis.
• proximal uninjured nerve may have focal degeneration of distal 2-3 internodes before regenerative activity.

Question 172

Denervation Atrophy

Answer 172

• in muscle fibers of affected motor unit.
• myocytes smaller and more angular but still viable.

Question 173

Nerve Regeneration

Answer 173

• proximal stump regrows 1mm/day.
• guided by Schwann cells.

Question 174

Reinervation of Muscle

Answer 174

• neighboring motor units extend sprouts and incorporate muscle fibers into healthy motor unit.
  
  • get fiber type of the new innervating neuron ⇒ type grouping.
  • injury of nerve innervating the type grouping patch ⇒ group atrophy.
• type 2 fiber atrophy = disuse atrophy
  
  • see in corticosteroid myopathy

Question 175

Segmental Necrosis of Muscle Fiber

Answer 175

• myofiber damage followed by myophagocytosis from infiltrating macrophages.
• fibers replaced with collagen and fat.

Question 176

Regeneration of Muscle Fiber

Answer 176

• satellite cells proliferate to reconstitute fibers.
• new fibers have large internalized nuclei, prominent nucleoli, basophilic cytoplasm laden with RNA.

Question 177

Hypertrophy of Muscle Fibers

Answer 177

• ↑ load ⇒ enlarged fibers
• muscle fiber splitting = divide longitudinally
  
  • one large fiber with central membrane, have adjacent nuclei.

Question 178

Guillain-Barré Syndrome

Answer 178

• aka acute inflammatory demyelinating polyradiculoneuropathy
• acute life-threatening ascending paralysis.
• pathogenesis: immune-mediated. 60-70% preceded by vaccination or viral/bacterial infection.
  
  • viral = EBV, CMV
  • bacterial = Campylobacter, Mycoplasma
  • T cells or circulating Ab ⇒ demyelination.
• morphology: segmental demyelination with chronic inflammation involving nerve roots and peripheral nerves.
  
  • severe = axonal damage.
• presentation: muscle weakness, loss of deep tendon reflexes.
  
  • begins in distal limbs, rapidly includes proximal.
  • nerve conduction velocity slowed.
  • CSF protein ↑. no pleocytosis.
  • death in 2-5% from respiratory paralysis, autonomic instability, or cardiac arrest.
  • 20% permanent disability.

Question 179

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Answer 179

• mixed sensorimotor neuropathy similar to Guillain-Barré.
• has relapses and remissions.
• have onion bulbs.

Question 180

Leprosy

Answer 180

• aka Hansen’s Disease.
• by M. leprae invading Schwann cells. then proliferate and infect other cells.
• causes segmental demyelination and remyelination, axonal loss, endoneurial and epineurial fibrosis.
• lepromatous: disease more severe and diffuse. symmetric polyneuropathy in extremities.
  
  • predilection for pain fibers ⇒ don’t feel pain, get large ulcers.
• tuberculous: nodules of granulomatous inflammation, localized nerve injury.

Question 181

Diphtheria Neuropathy

Answer 181

• from diphtheria exotoxin
• segmental demyelination
• presentation: paresthesias and weakness

Question 182

Varicella-Zoster Virus Neuropathy

Answer 182

• latent infection of spinal cord and brain stem sensory ganglia.
• reactivation ⇒ shingles. trigeminal or thoracic nerve distribution.
• neuronal destruction with associated mononuclear cell infiltrates. peripheral nerves have axonal degeneration.

Question 183

Hereditary and Sensory Autonomic Neuropathies

Answer 183

• HSANs. 5 types.
• presentation: numbness, pain, autonomic dysfunction.

Question 184

HSAN Type I

Answer 184

• autosomal dominant.
• mutated SPTLC-1 gene.
• presentation: young adults. sensory neuropathy. axonal degeneration of myelinated fibers.

Question 185

HSAN Type II

Answer 185

• autosomal recessive.
• mutated HSN2 gene.
• presentation: in childhood. sensory neuropathy. axonal degeneration of myelinated fibers.

Question 186

HSAN Type III

Answer 186

• aka Riley-Day syndrome, familial dysautonomia.
• autosomal recessive.
• mutated IKAP gene.
• presentation: Jewish kids. autonomic neuropathy. axonal degeneration of unmyelinated fibers, atrophy and loss of sensory and autonomic ganglion cells.

Question 187

HSAN Type IV

Answer 187

• autosomal recessive dysautonomia type II
• mutated NTRK1 gene.
• presentation: infants. insensitivity to pain and anhidrosis. almost complete loss of small myelinated and unmyelinated fibers.

Question 188

HSAN Type V

Answer 188

• autosomal recessive
• mutated NGFB gene.
• presentation: infants. insensitivity to pain and temperature. nearly complete loss of small myelinated fibers.

Question 189

Familial Amyloid Polyneuropathies

Answer 189

• autosomal dominant.
• deposition of amyloid in PNS.
• mutated transthyretin (transports thyroxine and retinol).
• amyloid fibrils made of transthyretin.
• morphology: amyloid deposits in vessel walls and CT with axonal degeneration.
• presentation: numbness, pain, autonomic dysfunction.

Question 190

Adrenoleukodystrophy

Answer 190

• X-linked. 4% female carriers symptomatic.
• mutated ABCD1.
• morphology: segmental demyelination, onion bulbs, axonal degeneration (myelinated and unmyelinated).
  
  • linear inclusions in Schwann cells.
• presentation: mixed motor and sensory neuropathy, adrenal insufficiency, spastic paraplegia.
  
  • onset btw 10-20 yrs in men with leukodystrophy, 20-40 yrs in women with myeloneuropathy

Question 191

Porphyria (AIP or Variegate Coproporphyria)

Answer 191

• autosomal dominant
• mutated enzymes in heme synthesis
  
  • AIP = porphobilinogen
• morphology: acute and chronic axonal degeneration, regenerating clusters.
• presentation: acute episodes neuro dysfunction, psychiatric disturbances, abd pain, seizures, proximal weakness, autonomic dysfunction.
  
  • may be precipitated from drugs.

Question 192

Refsum Disease

Answer 192

• autosomal recessive.
• mutated PAHX gene.
• morphology: severe onion bulb formation.
• presentation: mixed motor and sensory neuropathy with palpable nerves, ataxia, night blindness, retinitis pigmentosa, ichthyosis.
  
  • onset before age 20.

Question 193

Charcot-Marie-Tooth Disease

Answer 193

• aka hereditary motor and sensory neuropathy (HMSN) type I.
• autosomal dominant demyelinating disorder.
• pathogenesis: HMSN-1A has duplicated segment on chrom 17 ⇒ ↑ PMP-22 that compacts myelin as Schwann cells wrap around axons.
  
  • HMSN-1B = mutated MPZ.
  • mutations in connexin 32, protein degradation pathway, and myelination induction genes.
• morphology: segmental demyelination and onion bulb.
• presentation: young adults with distal muscle weakness and calf atrophy.

Question 194

HMSN II

Answer 194

• autosomal dominant
• axonal loss without demyelination
• presents younger than HMSN type I.
• mutated kinesin.

Question 195

Déjérine-Sottas Neuropathy

Answer 195

• aka HMSN III.
• autosomal recessive. infantile.
• progressive upper and lower extremity weakness and muscle atrophy, enlarged palpable nerves.
• mutated PMP-22 or MPZ.
• severe segmental demyelination, onion bulbs, axonal loss.

Question 196

Peripheral Neuropathy in Adult-Onset DM

Answer 196

• present in about 50% DM.
• from nonenzymatic protein glycation and polyol-mediated damage.
• diabetic microvascular disease with secondary ischemic injury.
• types: distal symmetric sensory or sensorimotor neuropathy, autonomic neuropathy, focal or multifocal asymmetric neuropathy.

Question 197

Distal Symmetric Sensory or Sensorimotor Neuropathy

Answer 197

• axonal neuropathy with loss of small fibers.
• sensory loss > motor loss.
• loss of pain ⇒ cutaneous ulcers, heal poorly from diabetic microvascular disease.

Question 198

Autonomic Neuropathy

Answer 198

• 20-40% diabetics.
• presentation: postural hypotension, incomplete bladder emptying, sexual dysfunction.

Question 199

Focal or Multifocal Asymmetric Neuropathy

Answer 199

• ex. unilateral ocular nerve palsy.
• secondary to vascular insufficiency of peripheral nerves.

Question 200

Metabolic and Nutritional Peripheral Neuropathies

Answer 200

• from renal failure
  
  • presents with distal symmetric sensory and motor neuropathy.
• from chronic liver disease, respiratory insufficiency, thyroid dysfunction.
• from deficiencies of thiamine, B₆, B₁₂, or E.
• from excessive alcohol consumption by ethanol toxicity and thiamine deficiency.

Question 201

Direct Infiltration or Nerve Compression

Answer 201

• by tumor ⇒ mononeuropathy, brachial plexopathy, cranial nerve palsy, or polyradiculopathy of lower extremities (meningeal carcinomatosis of cauda equina)

Question 202

Paraneoplastic Syndrome of PNS

Answer 202

• progressive sensorimotor neuropathy (lower extremities) in 2-5% lung cancer.
• loss of dorsal root ganglia ⇒ sensory neuropathy
  
  • circulating Ab against RNA-binding protein shared by neurons and tumor cells.
• deposition of light-chain amyloid in pts with plasma cell dyscrasias
• secondary to autoantibodies against myelin-associated glycoprotein

Question 203

Toxic Neuropathies

Answer 203

• from exposure to industrial/environmental chemicals, biologic toxins, heavy metals (lead, arsenic), therapeutic drugs.

Question 204

Traumatic Neuropathies

Answer 204

• lacerations cutting a nerve
• avulsions when nerve under pressure
• traumatic neuromas from nerve transection or damage. painful nodules of tangled axons and CT from regenerating axonal sprouts.
• compression neuropathy = nerve compressed.
  
  • Carpal Tunnel Syndrome: median nerve entrapped in wrist. see in edema, pregnancy, degenerative joint disease, hypothyroidism, amyloidosis, excessive wrist use.
  • other nerves: ulnar nerve at elbow, peroneal nerve at knee, radial nerve in upper arm.
  • compression neuropathy of foot in women.
  • Morton neuroma: **involves interdigital nerve at intermetatarsal sites **⇒ pain

Question 205

Spinal Muscular Atrophy

Answer 205

• autosomal recessive motor neuron diseases, onset in childhood or adolescence.
• mutations of SMN1 gene on chromosome 5
  
  • # copies homologous SMN2 gene modifies gene severity.
  • SMN for axonal transport, NMJ integrity.
    
    • loss ⇒ neuronal cell death.
• morphology: large numbers of extremely atrophic muscle fibers, involve entire fascicle of muscle
• presentation: SMA type I = Werdnig-Hoffman disease: presents first 4 months of life with hypotonia and death by age 3 yr.
  
  • SMA type 2: presents later, die as kid after age 4.
  • SMA type 3: survive to adulthood.

Question 206

Duchenne Muscular Dystrophy

Answer 206

• most severe and most common form muscular dystrophy.
• X-linked. 1/3500 males.
• DMD gene at Xp21 encodes dystrophin that transduces contractile forces from intracellular sarcomeres to ECM.
  
  • 2/3 familial. 1/3 de novo
  • no detectable dystrophin
• morphology: enlarged, rounded, hyaline fibers lacking normal cross striations.
  
  • variation in myofiber diameter, ↑ internalized nuclei, degeneration/necrosis/phagocytosis of muscle fibers, regeneration of muscle fibers, proliferation of endomysial CT, muscles replaced by fat and CT, involves type I and type II fibers.
• presentation: by age 5, wheelchair by 10-12. death in early 20’s.
  
  • weakness in pelvic girdle muscles
  • pseudohypertrophy: lower muscles hypertrophied with weakness.
  • heart failure and arrhythmia, risk of cardiomyopathy
  • cognitive impairment
  • death from respiratory insufficiency, pulmonary infection, cardiac decompensation.

Question 207

Becker Muscular Dystrophy

Answer 207

• X-linked muscular dystrophy.
• starts later than DMD, not as severe.
• mutated DMD gene at Xp21 encoding dystrophin
  
  • 2/3 familial, 1/3 de novo.
  • ↓ amounts dystrophin that has abnormal molecular weight.
• morphology: variations in myofiber diameter, ↑ internalized nuclei, degeneration/necrosis/phagocytosis of muscle fibers, regenerated muscle fibers, proliferation of endomysial CT, muscle replaced by fat and CT, type I and type II fibers involved.
• presentation: weakness in pelvic girdle muscles, pesudohypertrophy, heart failure and arrhythmia, cardiomyopathy, cognitive impairment.
  
  • death by respiratory insufficiency, pulmonary infection, cardiac decompensation.

Question 208

Limb Girdle Muscular Dystrophy

Answer 208

• autosomal muscular dystrophy.
• affects proximal trunk and limb musculature.
• mutations of transmembrane sarcoglycan complex of proteins that link dystrophin with ECM.

Question 209

Myotonic Dystrophy

Answer 209

• autosomal dominant
• ↑ in severity and appear at younger age in successive generations = anticipation.
• myotonia = sustained involuntary muscle contraction. cardinal neuromuscular symptom.
• pathogenesis: CTG trinucleotide repeat expansion on 19q13. affects mRNA for DMPK.
• morphology: fiber size heterogeneity, ↑ numbers internal nuclei and ring fibers (subsarcolemmal band of cytoplasm with rim of myofibrils that wrap around longitudinally oriented fibrils).
  
  • changes in muscle spindles: fiber splitting, necrosis, regeneration.
• presentation: abnormalities in gait from foot dorsiflexor weakness, weakness in intrinsic hand muscles and wrist extensors, facial muscle atrophy, ptosis.
  
  • cataracts, frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, ↓ plasma IgG, abnormal glucose tolerance test.

Question 210

Channelopathies

Answer 210

• familial disease with myotonia and/or hypotonic palsies
  
  • hypotonic can be hyper, hypo, or normokalemic.
• hyperkalemic periodic paralysis: mutated SCN4A sodium channel protein - regulates Na entry during muscle contraction.
• hypokalemic periodic paralysis: mutated gene for voltage gated L-type Ca channel.
• malignant hyperpyrexia (malignant hyperthermia): dramatic hypermetabolic state triggered by anesthesia. mutated gene for voltage gated L-type Ca channel (ryanodine receptor).
  
  • anesthetic ⇒ uncontrolled sarcoplasmic Ca efflux ⇒ tetany, ↑ muscle metabolism, excess heat production.
  • tachycardia, tachypnea, muscle spasms, hyperpyrexia later.

Question 211

Fascioscapulohumeral Muscular Dystrophy

Answer 211

• autosomal dominant.
• type 1A: deletions from D4Z4 on 4q35.
• type 1B: mutated FSHMD1B.
• morphology: dystropic myopathy with inflammatory infiltrates in muscle.
• presentation: age 10-30yrs, weakness of muscles of face, neck, shoulder girdle.

Question 212

Oculopharyngeal Muscular Dystrophy

Answer 212

• autosomal dominant
• mutated PABP-2 gene.
• morphology; dystrophic myopathy with rimmed vacuoles in type 1 fibers.
• presentation: onset in mid adult life, ptosis and weakness of extraocular muscles, difficulty swallowing.

Question 213

Emery-Dreifuss Muscular Dystrophy

Answer 213

• X-linked.
• mutated emerin (EMD1) gene
• morphology: mild myopathic changes, absent emerin.
• presentation: onset 10-20yrs, prominent contractures especially at elbows and ankles.

Question 214

Congenital Muscular Dystrophies

Answer 214

• autosomal recessive
• three types: MDC1A = type 1a, merosin deficient (laminin alpha 2 gene).
  
  • MDC1B = type 1b, 1q42.
  • MDC1c = type 1c, fukutin related protein gene.
• morphology: variable fiber size, extensive endomysial fibrosis.
• presentation: neonatal hypotonia, respiratory insufficiency, delayed motor milestones.

Question 215

Congenital Muscular Dystrophy with CNS Manifestations

Answer 215

• aka Fukuyama type.
• autosomal recessive.
• mutated fukutin.
• morphology: variable muscle fiber size and endomysial fibrosis, CNS malformations (polymicrogyria)
• presentation: neonatal hypotonia and mental retardation.

Question 216

Congenital Muscular Dystrophy with CNS and Ocular Manifestations

Answer 216

• aka Walker-Warburg type.
• mutated POMT1, POMT2.
• morphology: variable muscle fiber size and endomysial fibrosis, CNS and ocular malformations
• presentation: neonatal hypotonia and mental retardation with cerebral and ocular malformations.

Question 217

Lipid Myopathies

Answer 217

• abnormalities of carnitine transport system or deficiency of mitochondrial dehydrogenase enzyme systems ⇒ block fatty acid catabolism, muscle lipid accumulation.
• limited ATP generation when exercising ⇒ pain, tightness, myoglobinuria.
• can have cardiomyopathies and fatty liver.

Question 218

Mitochondrial Myopathies

Answer 218

• oxidative phosphorylation diseases.
• from mutations in nuclear and mitochondrial genes.
• morphology: aggregates of abnormal mitochondria ⇒ irregular muscle fiber contour (ragged red fibers),
  
  • ↑ # and abnormalities in shape and size of mitochondria.
  • may contain paracrystalline arrays (parking lot inclusions) or alterations in cristae structure.
• presentation: young adults, proximal muscle weakness, severe eye muscle dysfunction. neurologic symptoms, lactic acidosis, cardiomyopathy.
  
  • from mtDNA mutation have maternal inheritance.
  • from pt mutations in mtDNA ⇒ myoclonic epilepsy, Leber hereditary optic neuropathy, MELAS.
  • from deletions or duplications of mtDNA ⇒ chronic progressive external ophthalmoplegia or Kearns-Sayer syndrome.
  • from mutated nuclear DNA = X-linked or autosomal dominant/recessive. subacute necrotizing encephalopathy, exertional myoglobinuria, X-linked cardioskeletal myopathy.

Question 219

Central Core Disease

Answer 219

• autosomal dominant
• mutation RYR1 gene.
• morphology: cytoplasmic cores slightly eosinophilic and distinct from sarcoplasm. in type I fibers on NADH stain.
• presentation: early onset hypotonia, nonprogressive weakness, skeletal deformities, sometimes malignant hyperthermia.

Question 220

Nemaline Myopathy

Answer 220

• autosomal dominant or recessive.
  
  • dominant = NEM1-TPM3 gene (tropomysin 3)
  • recessive = NEM2-NEB gene (nebulin)
  • dominant or recessive = ACTA1 gene (skeletal muscle actin alpha 1)
• morphology: aggregates of nemaline rods (subsarcolemmal spindle-shaped particles), in type I fibers, from alpha-actinin in Z-band. see on Gomori stain.
• presentation: weakness, hypotonia, delayed motor development in childhood (sometimes adults).
  
  • nonprogressive.
  • involves proximal limb muscles most.
  • can have skeletal abnormalities.

Question 221

Myotubular Myopathy

Answer 221

• aka centronuclear.
• X-linked, autosomal dominant, autosomal recessive.
  
  • X-linked = MTM1 gene.
  • autosomal dominant = MYF6 gene
  • autosomal recessive = unknown.
• morphology: abundance of centrally located nuclei involving majority of muscle fibers, in type I fibers with small diameter, can be in type II fibers.
• presentation: X-linked: infancy with hypotonia, poor prognosis.
  
  • autosomal = limb weakness, slowly progressive.
    
    • recessive = intermediate in severity and prognosis.

Question 222

Dermatomyositis

Answer 222

• lilac discoloration of upper eyelids and periorbital edema before or with weakness.
• Grotton lesions = scaling, erythematous patches over knuckles, elbows, knees.
• slow onset muscle weakness, bilaterally symmetric, proximal muscles first.
  
  • dysphagia in 1/3.
• may have interstitial lung disease, vasculitis, myocarditis.
• 25% have cancer.
• juvenile pts: GI symptoms, 1/3 have calcinosis.
• targets capillaries.
• morphology: perivascular inflammatory infiltrates, scattered necrotic muscle fibers and muscle fiber atrophy at periphery of fascicles from hypoperfusion.
• tx: immunosuppression.

Question 223

Polymyositis

Answer 223

• in adults.
• cytotoxic T cell driven myocyte damage
• autoAb against tRNA synthetases.
• slow onset muscle weakness, bilaterally symmetric, proximal muscles first.
• morphology: endomysial inflammation, scattered necrotic muscle fibers, no vascular injury (perifascicular atrophy)
• tx: immunosuppression.

Question 224

Inclusion Body Myositis

Answer 224

• starts with distal muscle involvement (extensors of knee, flexors of wrist).
• can be asymmetric.
• insidious onset, age > 50 yrs.
• CD8+ T cells present but immunosuppression not effective.
• intracellular deposits of beta-amyloid and hyperphosphorylated tau = abnormal protein folding.
• morphology: endomysial inflammatory infiltrates, rimmed vacuoles (clear cytoplasm with thin rim basophilic material), contain amyloid.

Question 225

Thyrotoxic Myopathy

Answer 225

• proximal muscle weakness, can precede clinical thyroid dysfunction.
• myofiber necrosis, regeneration, interstitial lymphocytosis.
• hypothyroidism: muscle cramping and slow movements from fiber atrophy, ↑ # internal nuclei, glycogen aggregates.

Question 226

Ethanol Myopathy

Answer 226

• binge drinking ⇒ acute toxic syndrome of rhabdomyolysis with myoglobulinemia.
• can cause renal failure.

Question 227

Drug-Induced Myopathies

Answer 227

• Cushing syndrome or corticosteroids ⇒ proximal muscles weakness and atrophy in type II fibers
• _chloroquine _⇒ proximal myopathy with autophagic membrane-bound vacuoles and intracellular curvilinear lamellar bodies.
• Statin-induced myopathy in 1-2%.

Question 228

Myasthenia Gravis

Answer 228

• autoAb against skeletal muscle Ach receptors.
• women < 40 yrs. m=f in elderly.
• pathogenesis: AchR autoAb ⇒ complement fixation and direct postsynaptic membrane damage, accelerate internalization and down-regulation of AchR, or block Ach binding.
• morphology: LM unremarkable, junctional folds reduced or gone at NMJ, ↓ AchR expression.
• Presentation: easy fatigability, ptosis, and diplopia. worsen with repeated stimulation.
  
  • thymic hyperplasia in 65%.
  • thymomas in 15%.
  • thymic resection can improve it.
• tx: anticholinesterase agents, prednisone, plasmapheresis.

Question 229

Lambert-Eaton Myasthenic Syndrome

Answer 229

• weakness and autonomic dysfunction.
• mostly paraneoplastic from small cell lung carcinoma.
• autoAb against pre-synaptic voltage gated Ca channel ⇒ ↓ amount synaptic vesicles released.
• improves with repeated stimulation.