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Pathology > Neuro > Flashcards

Neuro Flashcards

1
Q

Acute Neuronal Injury

A
  • changes secondary to hypoxia/**ischemia **⇒ cell necrosis or apoptosis.
  • intense cytoplasmic eosinophilia and nuclear pyknosis = red neurons
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2
Q

Subacute and Chronic Neuronal Injury

A
  • degeneration = neuronal death and reactive gliosis
  • trans-synpatic degeneration when afferent inputs to neuron are lost.
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3
Q

Axonal Reaction

A
  • 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
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4
Q

Neuronal Inclusions

A
  • manifestation of aging (lipofuscin), disorders of metabolism (storage material), viral diseases (inclusion bodies), or neurodegenerative diseases with aggregated proteins.
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5
Q

Astrocytes

A
  • 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.
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6
Q

Glial Cell Injury

A
  • 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
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7
Q

Cerebral Edema

A
  • 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.
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8
Q

Hydrocephalus

A
  • 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
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9
Q

Subfalcine Herniation

A
  • aka cingulate herniation.
  • from ↑ ICP.
  • can compromise branches of anterior cerebral artery.
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10
Q

Transtentorial Herniation

A
  • 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.
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11
Q

Tonsillar Herniation

A
  • through foramen magnun ⇒ compress medulla and compromise cardiac and respiratory centers.
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12
Q

Neural Tube Defects

A
  • 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.
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13
Q

Encephalocele

A
  • malformed CNS diverticulum extending through defect in cranium (occiput or posterior fossa)
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14
Q

Anencephaly

A
  • malformation of anterior neural tube ⇒ failure of cerebrum development
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15
Q

Spina Bifida

A
  • occulta = asymptomatic bony defect
  • or a severe malformation with flattened, disorganized cord segment with overlying meningeal outpouching.
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16
Q

Myelomeningocele

A
  • CNS outpouching through vertebral column defect.
  • mostly lumbrosacral region with lower extremity motor and sensory deficits and disturbed bowel and bladder control.
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17
Q

Forebrain Anomalies

A
  • issues with brain size: microencephaly, lissencephaly, agyria, megalencephaly.
  • issues with gyral formation and organization: polymicrogyria, neuronal heterotopias, holoprosencephaly, agenesis of corpus callosum.
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18
Q

Microencephaly

A
  • small brain.
  • too many periventricular cells proliferate too soon.
  • from chromosomal abnormalities, fetal alcohol syndrome, in uter HIV.
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19
Q

Lissencephaly

A
  • aka agyria.
  • smooth brain, few to no gyri.
  • too many periventricular cells proliferate too soon.
  • from chromosomal abnormalities, fetal alcohol syndrome, in utero HIV.
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20
Q

Megalencephaly

A
  • large brain.
  • too few periventricular cells proliferate at early stages ⇒ overproduction of neurons.
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21
Q

Polymicrogyria

A
  • small, overabundant cerebral convolutions from focal injury near end of neuronal migration.
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22
Q

Neuronal Heterotopias

A
  • abnormal clusters of neurons in inappropriate locations along normal migratory routes.
  • associated with epilepsy.
  • mutations in filamin A or microtubule associated proteins.
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23
Q

Holoprosencephaly

A
  • incomplete separation of cerebral hemispheres.
  • midline facial abnormalities (cyclopia).
  • mutation of sonic hedgehog or other genes in neural development.
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24
Q

Agenesis of Corpus Callosum

A
  • normal white matter interhemispheric bundles not formed.
  • may have mental retardation but clinically most are normal.
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25
Q

Posterior Fossa Anomalies

A
  • Dandy-Walker Malformation
  • **Arnold-Chiari Malformation **
  • Chiari I malformation
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26
Q

Dandy-Walker Malformation

A
  • enlarged posterior fossa, absent cerebellar vermis, large midline cyst with brainstem nuclei dysplasias.
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27
Q

Arnold-Chiari Malformation

A
  • aka Chiari II malformation
  • small posterior fossa, malformed midline cerebellum, extension of vermis through foramen magnum, hydrocephalus, lumbar myelomeningocele.
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28
Q

Chiari I Malformation

A
  • low-lying cerebellar tonsils extend into vertebral canal.
  • clinically silent but can present with CSF flow obstruction.
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29
Q

Syringomyelia

A
  • 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.
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30
Q

Hydromyelia

A
  • expansion of central canal.
  • morphology: gray and white matter destruction surroudned by reactive gliosis.
  • presentation: loss of pain and temperature sensation in upper extremities.
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31
Q

Perinatal Brain Injury

A
  • 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
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32
Q

Perinatal Intraparenchymal Hemorrhage

A
  • in germinal matrix btw thalamus and caudate nucleus. can extend to ventricular system.
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33
Q

Periventricular Leukomalacia

A
  • ischemic infarcts in periventricular white matter.
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34
Q

Multicystic Encephalopathy

A
  • ischemic infarcts within the hemispheres.
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35
Q

Ulegyria

A
  • thin, gliotic gyri from perinatal cortical ischemia.
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36
Q

Status Marmoratus

A
  • ischemic neuronal loss and gliosis in basal ganglia and thalamus with aberrant and irregular myelin formation.
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37
Q

Skull Fractures

A
  • 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.
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38
Q

Concussion

A
  • transient trauma-related clinical syndrome with loss of consciousness, temporary respiratory arrest, loss of reflexes, amnesia of event.
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39
Q

Direct Parenchymal Injury (Brain)

A
  • 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
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40
Q

Diffuse Axonal Injury

A
  • 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.
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41
Q

Epidural Hematoma

A
  • rupture of **dural arteries (middle meningeal artery) **⇒ blood btw dura and skull ⇒ compress brain.
  • can have lucid period several hours after trauma
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42
Q

Subdural Hemorrhage

A
  • 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.
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43
Q

Sequelae of Brain Trauma

A
  • 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.
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44
Q

Spinal Cord Trauma

A
  • 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.
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45
Q

Global Cerebral Ischemia

A
  • 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.
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46
Q

Stroke

A
  • brain oxygen deprivation from global or focal ischemic necrosis.
  • outcome depends on collateral circulation, duration of ischemia, magnitude and rapidity of flow reduction.
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47
Q

Focal Cerebral Ischemia

A
  • 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.
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48
Q

Lacunar Infarcts

A
  • 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.
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49
Q

Slit Hemorrhages

A
  • when HTN causes small vessel rupture.
  • they resorb leaving hemosiderin-laden macrophages and gliosis.
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50
Q

Acute Hypertensive Encephalopathy

A
  • ↑ 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.
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51
Q

Chronic Hypertensive Injury

A
  • 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.
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52
Q

Intracerebral Hemorrhage

A
  • 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
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53
Q

Subarachnoid Hemorrhage

A
  • 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
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54
Q

Arteriovenous Malformation

A
  • 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
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55
Q

Cavernous Hemangiomas

A
  • distended, loosely organized vascular channels with thin, collagenized walls.
  • usually cerebellum, pons, and subcortical regions.
  • low flow without arteriovenous shunting.
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56
Q

Capillary Telangiectasias

A
  • microscopic foci of dilated, thin-walled vascular channels separated by normal brain parenchyma.
  • in pons.
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57
Q

Venous Angiomas

A
  • aka varices
  • aggregates of ecstatic veins.
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58
Q

Foix-Alajouanine Disease

A
  • venous angiomatous malformation in lumbosacral region.
  • slowly progressive ischemia and neuro symptoms.
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59
Q

Acute Bacterial Meningitis

A
  • 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.
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60
Q

Acute Viral Meningitis

A
  • meningeal irritation, CSF lymphocytic pleocytosis, mod ↑ protein, normal glucose.
  • self-limited.
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61
Q

Brain Abscess

A
  • 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.
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62
Q

Tuberculous Meningitis

A
  • 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.
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63
Q

Neurosyphilis

A
  • 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.
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64
Q

Neuroborreliosis

A
  • in Lyme disease.
  • includes septic meningitis, facial nerve palsies, encephalopathy.
  • microglial proliferation and scattered organisms.
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65
Q

Arthropod-Borne Viral Encephalitis

A
  • 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.
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66
Q

Hereps Simplex Virus Type I

A
  • 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.
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67
Q

Herpes Simplex Virus Type II

A
  • severe generalized encephalitis in 50% neonates born vaginally.
  • ⇒ meningitis in adults, severe hemorrhagic, necrotizing encephalitis in HIV pts.
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68
Q

Varicella Zoster (Brain)

A
  • shingles can cause persistent painful post-herpetic neuralgia syndrome.
  • granulomatous arteritis, or necrotizing encephalitis in immunocompromised
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69
Q

Cytomegalovirus (Brain)

A
  • 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.
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70
Q

Poliomyelitis

A
  • 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.
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71
Q

Rabies (Brain)

A
  • 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.
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72
Q

HIV (Brain)

A
  • 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.
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73
Q

Progressive Multifocal Leukoencephalopathy

A
  • 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.
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74
Q

Subacute Sclerosing Panencephalitis

A
  • 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.
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75
Q

Fungal Meningoencephalitis

A
  • 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.
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76
Q

Toxoplasma gondii (Brain)

A
  • 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.
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77
Q

Naegleria (Brain)

A
  • causes rapidly fata necrotizing encephalitis.
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78
Q

Acanthamoeba

A
  • associated with chronic granulomatous meningoencephalitis
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79
Q

Prion Diseases

A
  • 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.
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80
Q

Creutzfeldt-Jakob Disease

A
  • 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.
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81
Q

Variant Creutzfeldt-Jakob Disease

A
  • in young adults.
  • early behavior manifestations and slower neurologic progression.
  • linked to bovine spongiform encephalopathy.
  • extensive cortical plaques with surrounding halo of spongiform change.
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82
Q

Gerstmann-Strauss-Scheinker Syndrome

A
  • 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 PrPsc proteins on congo-red and PAS-pos.
  • presentation: chronic cerebellar ataxia, then progressive dementia.
    • death a few years after symptom onset.
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83
Q

Fatal Familial Insomnia

A
  • PRNP mutations substitute aspartate for asparagine at 178 of PrPc.
    • 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.
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84
Q

Multiple Sclerosis

A
  • 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 TH1 and TH17 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.
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85
Q

Neuromyelitis Optica

A
  • 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.
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86
Q

Acute Disseminated Encephalomyelitis

A
  • 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.
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87
Q

Acute Necrotizing Hemorrhagic Encephalomyelitis

A
  • 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.
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88
Q

Central Pontine Myelinosis

A
  • 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.
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89
Q

Alzheimer Disease

A
  • 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
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90
Q

Frontotemporal Dementia with Parkinsonism Linked to Tau Mutations

A
  • 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.
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91
Q

Pick Disease

A
  • 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)
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92
Q

Progressive Supranuclear Palsy

A
  • 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
93
Q

Corticobasal Degeneration

A
  • 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
94
Q

Vascular Dementia

A
  • 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.
95
Q

Parkinsonism

A
  • 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)
96
Q

Parkinson Disease

A
  • 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.
97
Q

Dementia with Lewy Bodies

A
  • dementia in 10-15% PD patients.
  • some have Alzheimers
  • most have alpha-synuclein-containing lewy bodies
  • flluctuating course with hallucinations and frontal signs.
98
Q

Multiple System Atrophy

A
  • 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.
99
Q

Striatonigral Degeneration

A
  • parkinsonism
    • atrophy of substantia nigra and striatum.
100
Q

Olivopontocerebellar Atrophy

A
  • cerebellar ataxia, eye and somatic movement abnormalities, dysarthria, rigidity.
    • atrophy of cerebellar peduncles, basis pontis, inferior olives.
101
Q

Shy-Drager Syndrome

A
  • autonomic dysfunction with loss of sympathetic neurons of intermediolateral column in spinal cord.
102
Q

Huntington Disease

A
  • 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.
103
Q

Friedreich Ataxia

A
  • 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.
104
Q

Ataxia-Telangiectasia

A
  • 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.
105
Q

Amyotrophic Lateral Sclerosis (ALS)

A
  • 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.
106
Q

Bulbospinal Atrophy

A
  • 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).
107
Q

Neuronal Ceroid Lipofuscinoses

A
  • inherited lysosomal storage disorders ⇒ neuronal accumulation of lipofuscin.
  • can ⇒ blindness, mental and motor deterioration, and seizures.
108
Q

Krabbe Disease

A
  • 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.
109
Q

Metachromatic Leukodystrophy

A
  • autosomal recessive
  • deficiency of arylsulfatase ⇒ accumulate cerebroside sulfate. may block oligodendrocyte differentiation.
  • morphology: myelin loss, gliosis, macrophages containing metachromatic material.
110
Q

Adrenoleukodystrophy

A
  • progressive disorder from loss of myelin and adrenal insufficiency ⇒ inability to catabolize very long chain fatty acids
111
Q

Pelizaeus-Merzbacher Disease

A
  • X-linked
  • mutation in gene encoding two alternatively-spliced myelin proteins (ex. PLP and DM20)
112
Q

Mitochondrial Encephalopathy with Lactic Acidosis and Strokelike Episodes (MELAS)

A
  • 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.
113
Q

Leigh Syndrome

A
  • 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.
114
Q

Thiamine (Vitamin B1) Deficiency

A
  • ⇒ 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.
115
Q

Vitamin B12 Deficiency

A
  • ⇒ 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.
116
Q

Hypoglycemia

A
  • affects large cerebral pyramidal cells, hippocampal pyramidal cells in CA1, and Purkinje cells.
  • prolonged, severe hypoglycemia ⇒ global neuronal injury.
117
Q

Hyperglycemia

A
  • from poorly controlled DM.
  • can ⇒ ketoacidosis.
  • hyperosmolar state has dehydration ⇒ confusion, stupor, coma.
  • gradually correct fluid depletion to prevent cerebral edema.
118
Q

Carbon Monoxide (Brain)

A
  • 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.
119
Q

Methanol (Brain)

A
  • toxicity affects retina.
  • degeneration of ganglion cells ⇒ blindness.
  • may be from formic acid (metabolite of methanol)
120
Q

Radiation (Brain)

A
  • 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.
121
Q

Pilocytic Astrocytoma

A
  • 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.
122
Q

Inflitrating Astrocytomas

A
  • 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.
123
Q

Diffuse Astrocytomas

A
  • 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
124
Q

Anaplastic Astrocytoma

A
  • infiltrating astrocytoma
  • grade III/IV.
  • ↑ nuclear anaplasia with numerous mitoses.
125
Q

Glioblastomas

A
  • 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.
126
Q

Pleomorphic Xanthoastrocytomas

A
  • 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%.
127
Q

Brainstem Gliomas

A
  • ages 0-20yrs.
  • pontine is most common, aggressive.
  • tecta are benign.
  • corticomedullary junction = intermediate.
128
Q

Oligodendroglioma

A
  • 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.
129
Q

Ependymoma

A
  • 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
130
Q

Myxopapillary Ependymoma

A
  • arises in filum terminale of spinal cord.
  • cuboidal cells, can have clear cytoplasm, around papillary core.
  • myxoid areas have neutral and acidic mucopolysaccharides
131
Q

Subependymoma

A
  • 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
132
Q

Choroid Plexus Papilloma

A
  • recapitulate normal choroid plexus.
  • CT papillae covered with cuboidal-columnar ciliated epithelium.
  • hydrocephalus from obstruction or CSF overproduction.
133
Q

Choroid Plexus Carcinoma

A
  • rare adenocarcinoma.
  • usually in kids
134
Q

Colloid Cysts of 3rd Ventricle

A
  • 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.
135
Q

Ganglioglioma

A
  • 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.
136
Q

Dysembryoplastic Neuroepithelial Tumor

A
  • 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.
137
Q

Central Neurocytoma

A
  • low grade neuronal neoplasm in ventricles.
  • evenly spaced, round, uniform nuclei and islands of neuropil.
138
Q

Medulloblastoma

A
  • 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.
139
Q

Atypical Teratoid/Rhabdoid Tumor

A
  • 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.
140
Q

Primary Central Nervous System Lymphoma

A
  • 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.
141
Q

Germ Cell Tumors

A
  • along midline in adolescents and young adults.
  • 0.2-1% caucasian CNS tumors, 10% Japanese
  • in pineal gland (men) and suprasellar regions.
142
Q

Meningioma

A
  • 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.
143
Q

Anaplastic Meningioma

A
  • grade III/IV.
  • aggressive, resemble sarcomas.
  • high mitotic rates
144
Q

Papillary Meningioma

A
  • pleomorphic cells arranged around fibrovascular cores.
  • grade III/IV
145
Q

Rhabdoid Meningioma

A
  • sheets of cells with hyaline eosinophilic cytoplasms composed of intermediate filaments.
  • grade III/IV.
  • high recurrence rate.
146
Q

Tumors Metastatic to Brain

A
  • 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.
147
Q

Subacute Cerebellar Degeneration

A
  • most common paraneoplastic syndrome.
  • have Purkinje cell loss, gliosis, and inflammatory infiltrates.
148
Q

Paraneoplastic Syndromes

A
  • 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.
149
Q

Limbic Encephalitis

A
  • paraneoplastic syndrome.
  • subacute dementia associated with perivascular inflammation, microglial nodules, neuronal loss, and gliosis.
  • anterior and medial temporal lobes.
150
Q

Eye Movement Disorders

A
  • paraneoplastic syndrome.
  • associated with childhood neuroblastomas.
151
Q

Subacute Sensory Neuropathy

A
  • paraneoplastic syndrome.
  • can be with limbic encephalitis.
  • marked by dorsal root ganglia inflammation and neuronal loss.
152
Q

Schwannoma

A
  • 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.
153
Q

Neurofibroma

A
  • 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.
154
Q

Malignant Peripheral Nerve Sheath Tumors

A
  • 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.
155
Q

Cowden Syndrome

A
  • dysplastic cerebellar gangliocytomas
  • due to PTEN mutation.
156
Q

Li-Fraumeni Syndrome

A
  • medulloblastoma from p53 mutation
157
Q

Turcot Syndrome

A
  • medulloblastoma or glioblastoma
  • APC or mismatch repair gene mutation
158
Q

Gorlin Syndrome

A
  • medulloblastoma from PTCH mutation
159
Q

Neurofibromatosis Type 1

A
  • 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).
160
Q

Neurofibromatosis Type 2

A
  • autosomal dominant.
  • inactivation of NF2.
  • form bilateral CN VIII schwannomas or multiple meningiomas.
161
Q

Tuberous Sclerosis Complex

A
  • 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.
162
Q

Von Hippel-Lindau Disease

A
  • 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.
163
Q

Epineurium

A
  • encases all fascicles of entire nerve
164
Q

Perineurium

A
  • encases each fascicle
165
Q

Endoneurium

A
  • surrounds individual nerve fibers.
166
Q

Anterior Spinal Root

A
  • has motor fibers
167
Q

Posterior Spinal Root

A
  • has sensory fibers
168
Q

Type 1 Muscle Fiber

A
  • 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
169
Q

Type 2 Muscle Fiber

A
  • for sudden, purposeful movements
  • type 2 fiber
  • fast-twitch
  • few lipids, abundant glycogen
  • white color
  • anaerobic: few mitochondria, narrow Z-band.
  • ex: pectoral
170
Q

Segmental Demyelination

A
  • 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.
171
Q

Wallerian Degeneration

A
  • 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.
172
Q

Denervation Atrophy

A
  • in muscle fibers of affected motor unit.
  • myocytes smaller and more angular but still viable.
173
Q

Nerve Regeneration

A
  • proximal stump regrows 1mm/day.
  • guided by Schwann cells.
174
Q

Reinervation of Muscle

A
  • 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
175
Q

Segmental Necrosis of Muscle Fiber

A
  • myofiber damage followed by myophagocytosis from infiltrating macrophages.
  • fibers replaced with collagen and fat.
176
Q

Regeneration of Muscle Fiber

A
  • satellite cells proliferate to reconstitute fibers.
  • new fibers have large internalized nuclei, prominent nucleoli, basophilic cytoplasm laden with RNA.
177
Q

Hypertrophy of Muscle Fibers

A
  • ↑ load ⇒ enlarged fibers
  • muscle fiber splitting = divide longitudinally
    • one large fiber with central membrane, have adjacent nuclei.
178
Q

Guillain-Barré Syndrome

A
  • 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.
179
Q

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

A
  • mixed sensorimotor neuropathy similar to Guillain-Barré.
  • has relapses and remissions.
  • have onion bulbs.
180
Q

Leprosy

A
  • 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.
181
Q

Diphtheria Neuropathy

A
  • from diphtheria exotoxin
  • segmental demyelination
  • presentation: paresthesias and weakness
182
Q

Varicella-Zoster Virus Neuropathy

A
  • 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.
183
Q

Hereditary and Sensory Autonomic Neuropathies

A
  • HSANs. 5 types.
  • presentation: numbness, pain, autonomic dysfunction.
184
Q

HSAN Type I

A
  • autosomal dominant.
  • mutated SPTLC-1 gene.
  • presentation: young adults. sensory neuropathy. axonal degeneration of myelinated fibers.
185
Q

HSAN Type II

A
  • autosomal recessive.
  • mutated HSN2 gene.
  • presentation: in childhood. sensory neuropathy. axonal degeneration of myelinated fibers.
186
Q

HSAN Type III

A
  • 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.
187
Q

HSAN Type IV

A
  • autosomal recessive dysautonomia type II
  • mutated NTRK1 gene.
  • presentation: infants. insensitivity to pain and anhidrosis. almost complete loss of small myelinated and unmyelinated fibers.
188
Q

HSAN Type V

A
  • autosomal recessive
  • mutated NGFB gene.
  • presentation: infants. insensitivity to pain and temperature. nearly complete loss of small myelinated fibers.
189
Q

Familial Amyloid Polyneuropathies

A
  • 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.
190
Q

Adrenoleukodystrophy

A
  • 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
191
Q

Porphyria (AIP or Variegate Coproporphyria)

A
  • 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.
192
Q

Refsum Disease

A
  • 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.
193
Q

Charcot-Marie-Tooth Disease

A
  • 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.
194
Q

HMSN II

A
  • autosomal dominant
  • axonal loss without demyelination
  • presents younger than HMSN type I.
  • mutated kinesin.
195
Q

Déjérine-Sottas Neuropathy

A
  • 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.
196
Q

Peripheral Neuropathy in Adult-Onset DM

A
  • 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.
197
Q

Distal Symmetric Sensory or Sensorimotor Neuropathy

A
  • axonal neuropathy with loss of small fibers.
  • sensory loss > motor loss.
  • loss of pain ⇒ cutaneous ulcers, heal poorly from diabetic microvascular disease.
198
Q

Autonomic Neuropathy

A
  • 20-40% diabetics.
  • presentation: postural hypotension, incomplete bladder emptying, sexual dysfunction.
199
Q

Focal or Multifocal Asymmetric Neuropathy

A
  • ex. unilateral ocular nerve palsy.
  • secondary to vascular insufficiency of peripheral nerves.
200
Q

Metabolic and Nutritional Peripheral Neuropathies

A
  • 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.
201
Q

Direct Infiltration or Nerve Compression

A
  • by tumor ⇒ mononeuropathy, brachial plexopathy, cranial nerve palsy, or polyradiculopathy of lower extremities (meningeal carcinomatosis of cauda equina)
202
Q

Paraneoplastic Syndrome of PNS

A
  • 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
203
Q

Toxic Neuropathies

A
  • from exposure to industrial/environmental chemicals, biologic toxins, heavy metals (lead, arsenic), therapeutic drugs.
204
Q

Traumatic Neuropathies

A
  • 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
205
Q

Spinal Muscular Atrophy

A
  • 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.
206
Q

Duchenne Muscular Dystrophy

A
  • 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.
207
Q

Becker Muscular Dystrophy

A
  • 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.
208
Q

Limb Girdle Muscular Dystrophy

A
  • autosomal muscular dystrophy.
  • affects proximal trunk and limb musculature.
  • mutations of transmembrane sarcoglycan complex of proteins that link dystrophin with ECM.
209
Q

Myotonic Dystrophy

A
  • 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.
210
Q

Channelopathies

A
  • 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.
211
Q

Fascioscapulohumeral Muscular Dystrophy

A
  • 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.
212
Q

Oculopharyngeal Muscular Dystrophy

A
  • 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.
213
Q

Emery-Dreifuss Muscular Dystrophy

A
  • X-linked.
  • mutated emerin (EMD1) gene
  • morphology: mild myopathic changes, absent emerin.
  • presentation: onset 10-20yrs, prominent contractures especially at elbows and ankles.
214
Q

Congenital Muscular Dystrophies

A
  • 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.
215
Q

Congenital Muscular Dystrophy with CNS Manifestations

A
  • aka Fukuyama type.
  • autosomal recessive.
  • mutated fukutin.
  • morphology: variable muscle fiber size and endomysial fibrosis, CNS malformations (polymicrogyria)
  • presentation: neonatal hypotonia and mental retardation.
216
Q

Congenital Muscular Dystrophy with CNS and Ocular Manifestations

A
  • 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.
217
Q

Lipid Myopathies

A
  • 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.
218
Q

Mitochondrial Myopathies

A
  • 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.
219
Q

Central Core Disease

A
  • 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.
220
Q

Nemaline Myopathy

A
  • 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.
221
Q

Myotubular Myopathy

A
  • 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.
222
Q

Dermatomyositis

A
  • 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.
223
Q

Polymyositis

A
  • 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.
224
Q

Inclusion Body Myositis

A
  • 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.
225
Q

Thyrotoxic Myopathy

A
  • 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.
226
Q

Ethanol Myopathy

A
  • binge drinking ⇒ acute toxic syndrome of rhabdomyolysis with myoglobulinemia.
  • can cause renal failure.
227
Q

Drug-Induced Myopathies

A
  • 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%.
228
Q

Myasthenia Gravis

A
  • 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.
229
Q

Lambert-Eaton Myasthenic Syndrome

A
  • 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.

Pathology (9 decks)

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