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Neuro Flashcards

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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
**Posterior Fossa Anomalies**
* **Dandy-Walker Malformation** * **Arnold-Chiari Malformation ** * **Chiari I malformation**
26
**Dandy-Walker Malformation**
* enlarged posterior fossa, absent cerebellar vermis, large midline cyst with brainstem nuclei dysplasias.
27
**Arnold-Chiari Malformation**
* aka Chiari II malformation * small posterior fossa, malformed midline cerebellum, extension of vermis through foramen magnum, hydrocephalus, lumbar myelomeningocele.
28
**Chiari I Malformation**
* low-lying cerebellar tonsils extend into vertebral canal. * clinically silent but can present with CSF flow obstruction.
29
**Syringomyelia**
* formation of **cleftlike cavity in spinal cord**. * _morphology_: gray and white matter destruction surrounded by reactive gliosis. * **_presentatio_**n: **loss of pain and temperature** sensation in **upper extremities.**
30
**Hydromyelia**
* **expansion of central canal**. * _morphology_: gray and white matter destruction surroudned by reactive gliosis. * _presentation_: **loss of pain and temperature** sensation in **upper extremities.**
31
**Perinatal Brain Injury**
* **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**
32
**Perinatal Intraparenchymal Hemorrhage**
* in germinal matrix btw thalamus and caudate nucleus. can extend to ventricular system.
33
**Periventricular Leukomalacia**
* ischemic infarcts in periventricular white matter.
34
**Multicystic Encephalopathy**
* ischemic infarcts within the hemispheres.
35
**Ulegyria**
* thin, gliotic gyri from perinatal cortical ischemia.
36
**Status Marmoratus**
* ischemic neuronal loss and gliosis in basal ganglia and thalamus with aberrant and irregular myelin formation.
37
**Skull Fractures**
* 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.
38
**Concussion**
* **transient trauma-related** clinical syndrome with **loss of consciousness, temporary respiratory arrest, loss of reflexes, amnesia** of event.
39
**Direct Parenchymal Injury (Brain)**
* **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**
40
**Diffuse Axonal Injury**
* 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.
41
**Epidural Hematoma**
* rupture of **dural arteries (middle meningeal artery) **⇒ blood **btw dura and skull ⇒ compress brain**. * can have **lucid period** several hours after trauma
42
**Subdural Hemorrhage**
* **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.
43
**Sequelae of Brain Trauma**
* **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.
44
**Spinal Cord Trauma**
* 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**.
45
**Global Cerebral Ischemia**
* 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.
46
**Stroke**
* brain oxygen deprivation from **global or focal ischemic necrosis**. * outcome **depends on collateral circulation, duration of ischemia, magnitude and rapidity of flow reduction**.
47
**Focal Cerebral Ischemia**
* **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**.
48
**Lacunar Infarcts**
* **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.
49
**Slit Hemorrhages**
* when **HTN causes small vessel rupture**. * they resorb leaving **hemosiderin-laden macrophages** and gliosis.
50
**Acute Hypertensive Encephalopathy**
* **↑ 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.
51
**Chronic Hypertensive Injury**
* **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**.
52
**Intracerebral Hemorrhage**
* 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**
53
**Subarachnoid Hemorrhage**
* 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**
54
**Arteriovenous Malformation**
* **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**
55
**Cavernous Hemangiomas**
* **distended, loosely organized vascular channels with thin, collagenized walls**. * usually cerebellum, pons, and subcortical regions. * **low flow without arteriovenous shunting.**
56
**Capillary Telangiectasias**
* **microscopic foci of dilated, thin-walled vascular channels separated by normal brain parenchyma**. * in **pons**.
57
**Venous Angiomas**
* aka varices * **aggregates of ecstatic veins**.
58
**Foix-Alajouanine Disease**
* **venous angiomatous malformation in lumbosacral region**. * slowly progressive ischemia and neuro symptoms.
59
**Acute Bacterial Meningitis**
* 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.**
60
**Acute Viral Meningitis**
* **meningeal irritation, CSF lymphocytic pleocytosis, mod ↑ protein, normal glucose**. * self-limited.
61
**Brain Abscess**
* **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.
62
**Tuberculous Meningitis**
* 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**.
63
**Neurosyphilis**
* 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.**
64
**Neuroborreliosis**
* in **Lyme disease**. * includes **septic meningitis, facial nerve palsies, encephalopathy**. * microglial proliferation and scattered organisms.
65
**Arthropod-Borne Viral Encephalitis**
* 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**.
66
**Hereps Simplex Virus Type I**
* 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**.
67
**Herpes Simplex Virus Type II**
* **severe generalized encephalitis in 50% neonates** born vaginally. * ⇒ **meningitis in adults**, severe hemorrhagic, necrotizing **encephalitis in HIV pts.**
68
**Varicella Zoster (Brain)**
* shingles can cause **persistent painful post-herpetic neuralgia syndrome**. * **granulomatous arteritis, or necrotizing encephalitis** in immunocompromised
69
**Cytomegalovirus (Brain)**
* 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**.
70
**Poliomyelitis**
* **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**.
71
**Rabies (Brain)**
* **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.
72
**HIV (Brain)**
* **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.**
73
**Progressive Multifocal Leukoencephalopathy**
* 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**.
74
**Subacute Sclerosing Panencephalitis**
* 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.**
75
**Fungal Meningoencephalitis**
* 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**.
76
**Toxoplasma gondii (Brain)**
* 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.**
77
**Naegleria (Brain)**
* causes **rapidly fata necrotizing encephalitis**.
78
**Acanthamoeba**
* associated with **chronic granulomatous meningoencephalitis**
79
**Prion Diseases**
* 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.
80
**Creutzfeldt-Jakob Disease**
* **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.
81
**Variant Creutzfeldt-Jakob Disease**
* in **young adults**. * **early behavior manifestations and slower neurologic progression**. * linked to **bovine spongiform encephalopathy**. * **extensive cortical plaques** with surrounding **halo of spongiform change**.
82
**Gerstmann-Strauss-Scheinker Syndrome**
* **inherited disease with PRNP mutations**. * _morphology_: **spongiform transformation of cerebral cortex and deep gray matter structures** (caudate and putamen). * advanced = s**evere 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.
83
**Fatal Familial Insomnia**
* **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.
84
**Multiple Sclerosis**
* 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.
85
**Neuromyelitis Optica**
* 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.
86
**Acute Disseminated Encephalomyelitis**
* **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**.
87
**Acute Necrotizing Hemorrhagic Encephalomyelitis**
* **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.
88
**Central Pontine Myelinosis**
* **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**.
89
**Alzheimer Disease**
* 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
90
**Frontotemporal Dementia with Parkinsonism Linked to Tau Mutations**
* 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**.
91
**Pick Disease**
* 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**)
92
**Progressive Supranuclear Palsy**
* **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
**Corticobasal Degeneration**
* 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
**Vascular Dementia**
* 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
**Parkinsonism**
* _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
**Parkinson Disease**
* 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
**Dementia with Lewy Bodies**
* dementia in 10-15% PD patients. * some have Alzheimers * most have **alpha-synuclein-containing lewy bodies** * flluctuating course with **hallucinations and frontal signs.**
98
**Multiple System Atrophy**
* **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
**Striatonigral Degeneration**
* **parkinsonism** * atrophy of **substantia nigra and striatum**.
100
**Olivopontocerebellar Atrophy**
* **cerebellar ataxia, eye and somatic movement abnormalities, dysarthria, rigidity.** * atrophy of **cerebellar peduncles, basis pontis, inferior olives**.
101
**Shy-Drager Syndrome**
* **autonomic dysfunction** with loss of sympathetic neurons of **intermediolateral column in spinal cord**.
102
**Huntington Disease**
* **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
**Friedreich Ataxia**
* **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
**Ataxia-Telangiectasia**
* **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
**Amyotrophic Lateral Sclerosis (ALS)**
* 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
**Bulbospinal Atrophy**
* 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
**Neuronal Ceroid Lipofuscinoses**
* inherited lysosomal storage disorders ⇒ **neuronal accumulation of lipofuscin.** * can ⇒ **blindness, mental and motor deterioration, and seizures**.
108
**Krabbe Disease**
* **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
**Metachromatic Leukodystrophy**
* **autosomal recessive** * **deficiency of arylsulfatase** ⇒ **accumulate cerebroside sulfate**. may **block oligodendrocyte differentiation**. * _morphology_: **myelin loss, gliosis, macrophages containing metachromatic material**.
110
**Adrenoleukodystrophy**
* progressive disorder from **loss of myelin and adrenal insufficiency ⇒ inability to catabolize very long chain fatty acids**
111
**Pelizaeus-Merzbacher Disease**
* **X-linked** * mutation in **gene encoding two alternatively-spliced myelin proteins** (ex. PLP and DM20)
112
**Mitochondrial Encephalopathy with Lactic Acidosis and Strokelike Episodes (MELAS)**
* 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
**Leigh Syndrome**
* 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
**Thiamine (Vitamin B1) Deficiency**
* ⇒ 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
**Vitamin B12 Deficiency**
* ⇒ **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
**Hypoglycemia**
* affects **large cerebral pyramidal cells, hippocampal pyramidal cells in CA1, and Purkinje cells**. * prolonged, severe hypoglycemia ⇒ global neuronal injury.
117
**Hyperglycemia**
* from **poorly controlled DM**. * can ⇒ **ketoacidosis**. * hyperosmolar state has dehydration ⇒ **confusion, stupor, coma.** * gradually correct fluid depletion to prevent cerebral edema.
118
**Carbon Monoxide (Brain)**
* 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
**Methanol (Brain)**
* toxicity affects **retina**. * **degeneration of ganglion cells ⇒ blindness**. * may be from **formic acid** (metabolite of methanol)
120
**Radiation (Brain)**
* 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
**Pilocytic Astrocytoma**
* **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
**Inflitrating Astrocytomas**
* **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
**Diffuse Astrocytomas**
* 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
**Anaplastic Astrocytoma**
* infiltrating astrocytoma * **grade III**/IV. * **↑ nuclear anaplasia** with **numerous mitoses**.
125
**Glioblastomas**
* 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
**Pleomorphic Xanthoastrocytomas**
* **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
**Brainstem Gliomas**
* ages **0-20yrs**. * **_pontine_** is most common, **aggressive**. * **_tecta_** are benign. * **_corticomedullary junction_** = intermediate.
128
**Oligodendroglioma**
* 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
**Ependymoma**
* 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
**Myxopapillary Ependymoma**
* arises **in filum terminale** of spinal cord. * **cuboidal cells**, can have clear cytoplasm, **around papillary core.** * **myxoid areas have neutral and acidic mucopolysaccharides**
131
**Subependymoma**
* **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
**Choroid Plexus Papilloma**
* recapitulate normal choroid plexus. * **CT papillae covered with cuboidal-columnar ciliated epithelium**. * **hydrocephalus** from obstruction or CSF overproduction.
133
**Choroid Plexus Carcinoma**
* rare **adenocarcinoma**. * usually in **kids**
134
**Colloid Cysts of 3rd Ventricle**
* **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
**Ganglioglioma**
* **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
**Dysembryoplastic Neuroepithelial Tumor**
* 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
**Central Neurocytoma**
* **low grade neuronal neoplasm in ventricles**. * **evenly spaced, round, uniform nuclei** and **islands of neuropil.**
138
**Medulloblastoma**
* **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
**Atypical Teratoid/Rhabdoid Tumor**
* 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
**Primary Central Nervous System Lymphoma**
* 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
**Germ Cell Tumors**
* along **midline in adolescents and young adults**. * 0.2-1% caucasian CNS tumors, **10% Japanese** * in **pineal gland** (**men**) and **suprasellar regions**.
142
**Meningioma**
* **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
**Anaplastic Meningioma**
* **grade III**/IV. * **aggressive**, **resemble sarcomas.** * **high mitotic rates**
144
**Papillary Meningioma**
* **pleomorphic cells** arranged **around fibrovascular cores.** * **grade III**/IV
145
**Rhabdoid Meningioma**
* **sheets of cells with hyaline eosinophilic cytoplasms composed of intermediate filaments**. * **grade III**/IV. * high recurrence rate.
146
**Tumors Metastatic to Brain**
* **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
**Subacute Cerebellar Degeneration**
* **most common paraneoplastic syndrome**. * have **Purkinje cell loss, gliosis, and inflammatory infiltrates**.
148
**Paraneoplastic Syndromes**
* 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
**Limbic Encephalitis**
* paraneoplastic syndrome. * **subacute dementia associated with perivascular inflammation, microglial nodules, neuronal loss, and gliosis**. * **anterior and medial temporal lobes**.
150
**Eye Movement Disorders**
* paraneoplastic syndrome. * associated with **childhood neuroblastomas**.
151
**Subacute Sensory Neuropathy**
* paraneoplastic syndrome. * can be with limbic encephalitis. * marked by **dorsal root ganglia inflammation and neuronal loss**.
152
**Schwannoma**
* **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
**Neurofibroma**
* 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
**Malignant Peripheral Nerve Sheath Tumors**
* 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
**Cowden Syndrome**
* **dysplastic cerebellar gangliocytoma**s * due to **PTEN mutation**.
156
**Li-Fraumeni Syndrome**
* **medulloblastoma** from **p53 mutation**
157
**Turcot Syndrome**
* **medulloblastoma** or **glioblastoma** * **APC or mismatch repair gene mutation**
158
**Gorlin Syndrome**
* **medulloblastoma** from **PTCH mutation**
159
**Neurofibromatosis Type 1**
* **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
**Neurofibromatosis Type 2**
* **autosomal dominant**. * **inactivation of NF2.** * form **bilateral CN VIII schwannomas or multiple meningiomas**.
161
**Tuberous Sclerosis Complex**
* **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
**Von Hippel-Lindau Disease**
* **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
**Epineurium**
* encases all fascicles of entire nerve
164
**Perineurium**
* encases each fascicle
165
**Endoneurium**
* surrounds individual nerve fibers.
166
**Anterior Spinal Root**
* has motor fibers
167
**Posterior Spinal Root**
* has sensory fibers
168
**Type 1 Muscle Fiber**
* 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
**Type 2 Muscle Fiber**
* for **sudden, purposeful movements** * **type 2** fiber * **fast**-twitch * few lipids, **abundant glycogen** * **white** color * anaerobic: **few mitochondria, narrow Z-band**. * ex: pectoral
170
**Segmental Demyelination**
* 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
**Wallerian Degeneration**
* **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
**Denervation Atrophy**
* in **muscle fibers of affected motor unit**. * myocytes **smaller and more angular** but still **viable**.
173
**Nerve Regeneration**
* **proximal stump regrows 1mm/day**. * guided by Schwann cells.
174
**Reinervation of Muscle**
* 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
**Segmental Necrosis of Muscle Fiber**
* myofiber damage followed by **myophagocytosis** from infiltrating macrophages. * fibers replaced with **collagen and fat**.
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**Regeneration of Muscle Fiber**
* **satellite cells proliferate** to reconstitute fibers. * new fibers have **large internalized nuclei, prominent nucleoli, basophilic cytoplasm laden with RNA**.
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**Hypertrophy of Muscle Fibers**
* ↑ load ⇒ **enlarged fibers** * **muscle fiber splitting** = divide longitudinally * **one large fiber with central membrane**, have adjacent nuclei.
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**Guillain-Barré Syndrome**
* 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**.
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**Chronic Inflammatory Demyelinating Polyradiculoneuropathy**
* mixed **sensorimotor neuropathy** similar to Guillain-Barré. * has **relapses and remissions**. * have **onion bulbs**.
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**Leprosy**
* 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**.
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**Diphtheria Neuropathy**
* from **diphtheria exotoxin** * **segmental demyelination** * _presentation_: **paresthesias and weakness**
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**Varicella-Zoster Virus Neuropathy**
* **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.**
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**Hereditary and Sensory Autonomic Neuropathies**
* HSANs. 5 types. * _presentation_: **numbness, pain, autonomic dysfunction**.
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**HSAN Type I**
* **autosomal dominant.** * mutated **SPTLC-1** gene. * _presentation_: **young adults**. **sensory neuropathy**. axonal degeneration of **myelinated fibers**.
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**HSAN Type II**
* **autosomal recessive**. * mutated **HSN2** gene. * _presentation_: in **childhood**. **sensory neuropathy**. axonal degeneration of **myelinated fibers**.
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**HSAN Type III**
* 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.**
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**HSAN Type IV**
* **autosomal recessive** dysautonomia type II * mutated **NTRK1** gene. * _presentation_: **infants**. **insensitivity to pain and anhidrosis**. almost complete **loss of small myelinated and unmyelinated fibers**.
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**HSAN Type V**
* **autosomal recessive** * mutated **NGFB** gene. * _presentation_: **infants**. **insensitivity to pain and temperature**. nearly complete **loss of small myelinated fibers.**
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**Familial Amyloid Polyneuropathies**
* **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**.
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**Adrenoleukodystrophy**
* **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
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**Porphyria (AIP or Variegate Coproporphyria)**
* **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.
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**Refsum Disease**
* **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**.
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**Charcot-Marie-Tooth Disease**
* 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.**
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**HMSN II**
* **autosomal dominant** * **axonal loss without demyelination** * presents younger than HMSN type I. * mutated **kinesin**.
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**Déjérine-Sottas Neuropathy**
* 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.**
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**Peripheral Neuropathy in Adult-Onset DM**
* 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**.
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**Distal Symmetric Sensory or Sensorimotor Neuropathy**
* **axonal neuropathy with loss of small fibers**. * **sensory loss** \> motor loss. * **loss of pain ⇒ cutaneous ulcers**, **heal poorly** from diabetic microvascular disease.
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**Autonomic Neuropathy**
* 20-40% diabetics. * _presentation_: **postural hypotension, incomplete bladder emptying, sexual dysfunction.**
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**Focal or Multifocal Asymmetric Neuropathy**
* ex. unilateral ocular nerve palsy. * **secondary to vascular insufficiency of peripheral nerves**.
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**Metabolic and Nutritional Peripheral Neuropathies**
* 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.
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**Direct Infiltration or Nerve Compression**
* by tumor ⇒ **mononeuropathy, brachial plexopathy, cranial nerve palsy, or polyradiculopathy of lower extremities** (meningeal carcinomatosis of cauda equina)
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**Paraneoplastic Syndrome of PNS**
* 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**
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**Toxic Neuropathies**
* from exposure to **industrial/environmental chemicals, biologic toxins, heavy metals** (lead, arsenic), **therapeutic drugs**.
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**Traumatic Neuropathies**
* **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
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**Spinal Muscular Atrophy**
* **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**.
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**Duchenne Muscular Dystrophy**
* **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**.
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**Becker Muscular Dystrophy**
* **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**.
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**Limb Girdle Muscular Dystrophy**
* **autosomal** muscular dystrophy. * affects **proximal trunk and limb musculature**. * **mutations of transmembrane sarcoglycan complex of proteins** that link dystrophin with ECM.
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**Myotonic Dystrophy**
* **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**.
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**Channelopathies**
* **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.
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**Fascioscapulohumeral Muscular Dystrophy**
* **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.**
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**Oculopharyngeal Muscular Dystrophy**
* **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.**
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**Emery-Dreifuss Muscular Dystrophy**
* **X-linked**. * mutated **emerin (EMD1)** gene * _morphology_: **mild myopathic changes, absent emerin**. * _presentation_: onset **10-20yrs**, prominent **contractures especially at elbows and ankles**.
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**Congenital Muscular Dystrophies**
* **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**.
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**Congenital Muscular Dystrophy with CNS Manifestations**
* aka **Fukuyama** type. * **autosomal recessive**. * mutated **fukutin**. * _morphology_: **variable muscle fiber size and endomysial fibrosis, CNS malformations** (polymicrogyria) * _presentation_: **neonatal hypotonia and mental retardation.**
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**Congenital Muscular Dystrophy with CNS and Ocular Manifestations**
* 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**.
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**Lipid Myopathies**
* 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**.
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**Mitochondrial Myopathies**
* 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.
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**Central Core Disease**
* **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**.
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**Nemaline Myopathy**
* **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.
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**Myotubular Myopathy**
* 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.
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**Dermatomyositis**
* **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.
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**Polymyositis**
* 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.
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**Inclusion Body Myositis**
* 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**.
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**Thyrotoxic Myopathy**
* **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.**
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**Ethanol Myopathy**
* binge drinking ⇒ **acute toxic syndrome of rhabdomyolysis with myoglobulinemia**. * can cause **renal failure**.
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**Drug-Induced Myopathies**
* **_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%.
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**Myasthenia Gravis**
* **autoAb against skeletal muscle Ach receptors**. * **women \< 40 yrs**. m=f in elderly. * _pathogenesis_: AchR autoAb ⇒ c**omplement 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.
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**Lambert-Eaton Myasthenic Syndrome**
* **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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