Exam 2 Flashcards
What is acute neuronal injury
“Red neurons” - changes that accompany acute CNS hypoxia/ischemia; red neurons evident 12-24 hours after irreversible event; consists of shrinkage of cell body, pkynosis of nucleus, disappearance of nucleoli seems and loss of Nissl substance with intense eosinophilia
What is subacute and chronic neuronal injury
“Degeneration” refers to neuronal death occurring as a result of progressive disease ie: ALS and Alzheimer’s; characteristic histo feature is cell loss and reactive gliosis (best indicator); cell loss via apoptosis
What is axonal reaction
Change observed in cell body during regeneration of axon; best seen in anterior horn of SC when motor axons are cut or damaged; increased protein synthesis, enlargement and rounding of cell body, peripheral displacement of the nucleus, enlargement of nucleolus, dispersion of nissl substance from center to periphery (central chromatolysis)
What do neuronal inclusions occur as a result of
Aging (accumulate complex lipid - lipofuscin, proteins or carbs); or in disorders of metabolism, viral infection (herpes - cowdry bodies; rabies (negri bodies), CMV (both nucleus and cytoplasm)
What is the most important indicator of CNS injury
Gliosis - characterized by hypertrophy and hyperplasia of astrocytes; astrocytes enlarge, become vesicular and develop prominent nucleoli; cytoplasm expands to bright pink swath from which emerge stout, ratifying processes (called gemistocytic astrocytes)
What do astrocytes act as
Metabolic buffers and detoxifier within the brain; contribute to BBB
What is the Alzheimer type II astrocyte
Gray matter cell with large nucleus, pale staining chromatin, and intranuclear glycogen droplet, prominent nuclear membrane; seen in individuals with hyperammonemia due to chronic liver dz, Wilson dz, or hereditary met disorders of urea cycle
What are rosenthal fibers
Thick, elongated, eosinophilic irregular structures that occur within astrocytic processes; contain two heat-shock proteins (alphabeta crystallin and hsp27)and ubiquitous; found in longstanding gliosis; characteristic of pilocytic astrocytoma (glial tumor)
What is Alexander disease
Leukodystrophy associated with mutations in gene encoding GFAP; abundant rosenthal fibers found in periventricular, perivascular, and subpar locations; corpora amylacea also seen (polyglucosan bodies) - round basophilic scid Schaffer positive concentrically lamellated; consist of glycosaminoglycan polymers, hsp, and ubiquitin
Besides Alexander dz, where else do you seen corpora amylacea
Increasing age; represents degenerative change in astrocyte
What are Lafora bodies
Seen in cytoplasm of neurons in myoclonic epilepsy
What are microglia derived from
Mesoderm
How do microglia respond to injury
Proliferate, develop elongated nuclei (rod cells) *neurosyphillis, form aggregated around tissue necrosis (microglia nodules), congregate around cell bodies of dying neurons (neurophangia)
What is injury or apoptosis of oligodendroglial cells a feature of
Demyelination disorders and leukodystrophies
Where are glial cytoplasmic inclusions found
In oligodencdrocytes in multiple system atrophy (MSA): composed of alpha synuclein
What are ependymal cells
Ciliated columnaer cells lining ventricles; when inflammation of ventricular system, disruption of ependymal lining is paired with proliferation of sub ependymal astrocytes to produce small irregularities on ventricular surfaces (granulations); CMV can produce ependymal injury w/viral inclusions
When can he pressure in the cranial cavity rise
Generalized brain edema, increases CSF volume, focally expanding mass lesions
What causes cerebral edema (brain parenchymal edema)
Increased fluid leakage from blood vessels or injury to cells of CNS
What is vasogenic edema
Increase in extra cellular fluid caused by BBB disruption and increased vascular permeability; allows fluid shift from intramuscular compartment to spaces of the brain; can be localized (adjacent to inflammation or neoplasms) or generalized (ischemic injury)
What is cytotoxic edema
Increase in intracellular fluid secondary to neuronal, glial, or endothelial cell membrane injury (generalized hypoxia/ischemic insult or metabolic derangement that prevents normal maintenance of ionic gradient)
What happens with generalized edema
Gyri are flattened, intervening sulci are narrowed, ventricular cavities are compressed; herniation can occur
What is interstitial edema
Hydrocephalic edema; increase in intravascular pressure causes abnormal flow of fluid from CSF to ependymal lining
What is noncommunicating hydrocephalus
When ventricular system is obstructed and cannot communicate with subarachnoid space (mass in 3rd ventricle)
What is communicating hydrocephalus
Entire ventricular system enlarges
What is hydrocephalus ex vacuo
Compensatory increase in ventricular volume secondary to a loss of brain parenchyma
What is subfalcine (cingulate) herniation
Unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gurus under the falx; can lead to compression of anterior cerebral artery
What is transtentorial (uncinate or medial temporal) herniation
Occurs when medial aspect of temporal lobe is compressed against tentorium; the 3rd cranial n is compromised (leads to pupillary dilation and impairment of ocular movement on side of lesion); post cerebral a can also be compressed (ischemic injury to visual cortex); when herniation large enough, contralateral cerebral peduncle can be compressed resulting in hemiparesis ipsilateral to side of herniation (kernohan notch); often accompanied by secondary hemorrhagic lesions in midbrain and pons (duret hemorrhage; linear flame shaped lesions)
What is a tonsilar herniation
Displacement of cerebellar tonsils through foramen magnum; life threatening
What is spinal dysraphism
Spina bifida
What deficits do people with meningomyeloceles have
Motor and sensory in lower extremities and bowel and bladder control issues
What is an encephalocele
Diverticula of malformed brain tissue sentencing through defect in cranium most often in posterior fossa but can occur through cribriform plate (nasal glioma)
When must you give folate in order for it to be effective at preventing neural tube defects
All throughout reproductive years (neural tube is formed by day 28)
What is anencephaly
Malformation of anterior end of neural tube with absence of most of the brain and calvarium; forebrain development is disrupted at day 28 and all that remains is area cerebrovasculosa (flattened remnant of disorganized brain tissue with admired ependymal, choroid plexus, and meningothelial cells); post fossa may be intact
What causes malformation of the forebrain
Abnormalities in generation and migration of neurons; if excess cells exit proliferating pool too early, overall generation of neurons is reduced; if too few exit during early rounds, overproduction of neurons; follows 2 paths (radial -> become excitatory; tangential -> become inhibitory)
What controls radial migration
Reelin (protein) signals to migrating neuroblasts through surface receptor
Is megalencephaly or microcephaly more common
Micro
What is microcephaly associated with
Fetal alch syndrome, chrom ab, HIV infection in utero; simplification of gyri folding resulting from reduction in number o neurons that reach neurocortex
What is lissencephaly
Malformation characterized by reduction in number of gyri (agryia in extreme cases); type I: smooth surface type II: rough or cobblestones surface; type I is associated with mutations that disrupt signaling for migration and cytoskeetal motor proteins that drive migration; type II caused by geneti. Alterations that disrupt stop signal for migration (mutation in enzyme that places sugar onto migration proteins)
What is polymicrogyria
Small numerous irregularly formed cerebral convolutions; induced by local tissue injury at the end of migration; genetic forms are bilateral and symmetric
What are neuronal heterotopias
Group of migrational disorders commonly associated with epilepsy; presence of neurons in inappropriate locations along pathway of migration; ie: along ventricular surface (never leave place of birth); caused by mutations in gene encoding filamin A (actin-binding protein responsible for assembly of mesh work of filaments) on X chromosome -> male lethality
What does a mutation in double cortin (DCX) cause
In males: lissenephaly
Females: subcortical band heterotopias
What is holoprosencephaly
Malformations characterized by incomplete separation of cerebral hemispheres; severe: midline facial abnormalities (Cyclopia); less severe: arrhinencephaly (absence of olfactory n); assoc with trisomy 13; mutations in genes that encode SHH pathway cause this as well
What is batwing deformity indicative of
Agenesis of corpus callosum; misshapen lateral ventricles; associated with mental retardation
What is Arnold chiari malformation
(Chiari malformation type II); small posterior fossa, misshapen midline cerebellum with downward extension of remission through foramen magnum; hydrocephalus and lumbar myelomeningocele; associated change include audial displacement of medulla, malformation of tectum, aqueductal stenosis, cerebral heterotopias, hydromyelia
What is chiari type I malformation
Less severe; low lying cerebellar tonsils end down into vertebral canal; silent or symptomatic; corrected
What is dandy walker cyst malformation
Enlarged posterior fossa; vermis is absent or rudimentary in anterior portion, in its place is cyst lined by ependyma (expanded roofless 4th ventricle in absence of normally formed vermis); dysphasia of brainstem nuclei commonly found
What is Joubert syndrome
Hypoplasia of cerebellar vermis with elongation of superior cerebellar peduncles and altered shape of brainstem; *molar tooth sign; caused by mutations affecting genes that encode cilium
What is the difference btw hydromyeia, syringomyelia and synrigobulbia
Hydro: expansion of ependyma-lined central canal of cord
Synrigomyelia: fluid filled left like cavity in inner portion of cord
Bulbia: if extends into brainstem
What is the histo of syringomyelia/hydromyelia
Destruction of adjacent gray and white matter surrounded by relative lions is; manifests in second or third decade; loss of pain and temp in UE (anterior spinal commisure)
What kind of hemorrhage are premature infants at risk for
Intraparenchymal hemorrhage within germinal matrix near junction of thalamus and caudate; can lead to hydrocephalus
What is periventricular leukomalacia
Infarcts in supratentorial periventricular white matter (in premature infants); *chalky yellow plaques consisting of white matter necrosis and calcification; when both grey and white matter involved -> multicystic encephalopathy (cystic lesions develop)
What bears the brunt of perinatal ischemic lesions
Depths of sulci -> leads to thinned-out gliotic gyri called ulegyria; abberant and irregular myelinization gives rise to marble like appearance of deep nuclei called status marmoratus; lesions in caudate, putamen, and thalamus so movement disorders (choreoathetosis) are common
What is a displaced skull fracture
Where bone is displaced into cranial cavity by distance greater than thickness of the bone
What are signs of basal skull fracture
Lower cranial n damage, presence of orbital or mastoid hematoma; typically follows impact to occipital or sides of head; meningitis can follow
What are diastatic fractures
Fractures that cross sutures
What are examples of direct parenchymal injuries
Contusions and lacerations
What part of the brain is most susceptible to direct force
Crests of gyri
What are the most common locations for contusions of the brain
Frontal lobes along orbital ridges and temporal lobes; other sites are less common unless adjacent to a skull fracture (fracture contusions)
When do you see both coupe and countrecoup injuries
If head is in motion at time of trauma; if immobile, only see coup
What do sudden impacts that result in violent posterior or lateral hyper extension cause
Avulsion of pons from medulla causing instant death
What do contusions look like in cross section
Wedge shaped with broad base lying against surface of point of impact; on histo, morphological evidence of neuronal injury takes 24 hours; axonal swelling develop near or far
What do old traumatic lesions on the brain look like
Depressed, retracted, yelling brown patches involving crest of gyri most commonly on countrecoup side (inferior frontal cortex, temporal and occipial poles); referred to as plaque Jaune *can become epileptic Foci; in old contusions, gliosis and residual hemosiderin macrophages predominate
What are individuals in a coma shortly after trauma believed to have
Diffuse axonal injury *even in absence of cerebral contusions; characterized by asymmetric axonal swellings within hours of injury; best demonstrated with silver impregnating or immunoperoxidase stain (for a-synuclein); increased number of microglia seen and degeneration of involved fiber tracts
What can traumatic tear of the carotid artery, as it traverses the carotid sinus lead to
AV fistula
Besides trauma, what can cause subarachnoid hemorrhage
Vascular abnormalities (aV fistula or aneurysm); sudden onset of severe headache with rapid neuro deterioration
What can cause an intraparenchymal hemorrhage
Trauma (frontal and temp tips, orbitofrontal surface), hemorrhagic conversion of ischemic infarction (petechial hem), cerebral amyloid angiopathy (lobar hem.), HTN (centered in deep white matter, thalamus, basal ganglia, or brainstem), tumors (high grade gliomas or Mets - melanoma, choriocarcinoma, renal cell carcinoma)
What is the gross appearance of subdural hematoma
Collection of freshly clotted blood without extension into sulci; underlying brain is flattened and subarachnoid space is clear; usually self-limited and broken down via: Lysis of clot (1 wk), growth of fibroblasts from rural surface into hematoma (week 2) and development of hyalinized connective tissue (1-3 months); typically adhered to inner surface of dura and does not touch aranchnoid
What is post traumatic hydrocephalus
Due to obstruction of CSF resorption from hemorrhage into subarachnoid spaces
What is chronic traumatic encephalopathy
Dementia pugilistica; cementing illness that develops after repeated head trauma; brains are atrophic with enlarged ventricles and show accumulation of tau containing neurofibrillary tangles involving superficial frontal and temporal lobe cortex; repeated concussions
What lesions cause paraplegia vs quadriplegia
Para: thoracic
Quad: cervical
Lesions above what level can cause respiratory arrest
C4
What is the more common cause of hypoxia, ischemia and infarction of the brain
Embolism rather than thrombus
What is the penumbra
At risk area betwee necrotic tissue and normal brain; can be rescued with anti-apoptotic interventions
What causes global cerebral ischemia
Cardiac arrest, shock and severe hypotension
What are the most sensitive CNS to ischemia
Neurons - mostly in the pyramidal layer of hippocampus (especially CA1 - Sommer sector), cerebellar purkinje cells, and pyramidal neurons in cerebral cortex
What does watershed infarction in the brain look like
Sickle shaped band of necrosis over cerebral convexity lateral to the inter hemispheric tissue
What is the morphology of global ischemia
Edema - gyri widen and narrowing of sulci; poor demarcation btw white and gray matter; early changes: red neurons; subacute changes: 24-2wks after, include necrosis influx of macrophages, vascular proliferation, and reactive gliosis; repair: after 2 weeks is characterized by removal of necrotic tissue, loss of CNS architecture and gliosis; producing pattern called psudolaminar necrosis in cerebral neocortex
Which parts of the brain lack collateral flow
Thalamus, basal ganglia, and deep white matter
Which artery to the brain is most frequently affected by emboli infarction
Middle cerebral
What are widespread hemorrhagic lesions involving white matter characteristic of
Embolization of bone marrow after trauma
What are the most common sites of thrombotic occlusion
Carotid bifurcation, origin of middle cerebral a, and either end of basilar a
What causes infectious vasculitis
Syphilis, TB, and now more common in setting of immunosuppression and opportunistic infection (aspergillosis or CMV encephalitis)
What is poly arthritis nodosa
Non-infectious vasculitide that can cause single or multiple infarcts in the brain
What is primary angiitis of the CNS
Inflammatory disorder involving multiple small to medium sized parenchymal and subarachnoid vessels; characterized by chronic inflammation, multinucleated giant cells, and destruction of vessel wall; known as granulomatous angiitis of nervous system; manifests as a diffuse encephalopathy or multifocal clinical picture; Pts improve with steroids and immunosuppressants
Secondary hemorrhage after ischemia cause what kind of hemorrhage
Petechial
What is the gross appearance of nonhemorragic infarction
Little change in first 6 hrs; 48 hours: tissue becomes pale, soft and swollen and corticomedullary junction in distinct; 2-10 days: brain becomes gelatinous and friable and boundary btw normal and injured tissue becomes distant; 10 days-3 wks: tissue liquifies
What are the most significant effects of HTN on the brain
Lacunar infarcts, slit hemorrhages, HTN encephalopathy and massive HTN intraccerebral hemorrhage
What are lacunar infarcts
Small cavitary infarcts resulting from ateriolar sclerosis; occur in lenticular nucleus, thalamus, internal capsule, deep white matter, caudate nucleus, pons (descending order of frequency)can be clinically silent or symptomatic; affected vessels can also be associated with widening of perivasucular spaces without infarction (etat crible)
What are slit hemorrhages
HTN causes rupture of small penetrating vessels; these hemorrhage’s are small and resorb leaving behind a slit-like cavity surrounded by brown discoloration; on histo, show focal tissue destruction, pigment laden macrophages and gliosis
What is acute hypertensive encephalopathy
Characterized by diffuse cerebral dysfunction including headaches, confusion, vomiting, convulsions and can lead to coma; need rapid therapy
What causes multi-infarct (vascular) dementia
Numerous infarcts that causes dementia, gait abnormalities, and pseudobulbar signs; caused by: cerebral atherosclerosis, vessel thrombosis or embolism, cerebral arteriolar sclerosis from chronic HTN; *binswanger when just involved white matter with myelin and axon loss
What are the main causes of intraparenchymal hemorrhage
HTN (ganglionic hemorrhage’s) and cerebral amyloid angiopathy (lobar hemorrhage’s)
What are Charcot Bouchard microaneurysms
Small aneurysms associated with HTN
What is cerebral amyloid angiopathy
Amyloidogenic peptides deposit in medium and small meninges and cortical vessels -> weakens them and lead to hemorrhage; *effect of ApoE genotype on risk of occurrence (presence of epislon 2 or 4 allele)
What is different about the arteries in CAA compared to sclerosis
Do not collapse and no fibrosis
What is CADASIL
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; mutations in NOTCH3 gene that lead to misfolding of EC NOTCH3 receptor -> causes vascular smooth m dysfunction; characterized by recurrent strokes and dementia; first changes are in white matter; arteries show thickening of media and adventitious, loss of smooth m, and basophilic PAS positive deposits
What is the most common cause of a subarachnoid hemorrhage
Rupture of saccular (berry) aneurysm in a cerebral a
What are other types of aneurysms
Fusiform (atherosclerotic), mycotic, traumatic, dissecting (last 3 cause infarction rather than subarachnoid hemorrhage)
Where is the most common site for a saccular aneurysm
Junction of anterior communicating and anterior cerebral a
What disorders have an increased risk of saccular aneurysms
Polycistic kidny dz, NF1, ehlers Danilo’s type IV, Marian
What is the aneurysm sac made up of
Hyalinized intima and covering of adventitia
Is a ruptured saccular aneurysms more common in males or females
Females
What occurs in the first few days after a subarachnoid hemorrhage
Increased risk of additional ischemic injury from vasospasm *greatest significance in basal subarachnoid hemorrhage (spasm circle of Willis); during healing, meninges fibrosis and scarring occur (can obstruct CSF flow)
What are the classifications of vascular malformations
AV, cavernous, capillary telangiectasias, venous Angiomas ; *first 2 are associated with risk of hemorrhage and development of neuro symptoms
What are cavernous malformations
Consist of distended, loosely organized vascular channels arranged back to back with collagenized walls; no brain parenchyma between vessels; most often in cerebellum, pons, and subcortical regions; low flow channels
What are cap telangiectasias
Microscopic foci of dilated, thin walled vascular channels separated by normal brain parenchyma that occur most frequently in the pons
What are venous angiomas
Aggregates of ecstatic venous channels; Foix-Alajouanine dz (angiodysgenetic necrotizing myelopathy) is a venous angiomatous malformation of the SC and overlying meninges (lumbosacral region) associated with ischemic injury to SC
Are males or females more commonly affected by vascular malformations
Males
When do AV malformations usually present
10-30 years old as a seizure disorder, intracerebral hemorrhage or subarachnoid hemorrhage; most common in posterior branches of middle cerebral a
What can large AV malformations in the neonate lead to
CHF because of shunt effects; especially if involves vein of Galen
Which vascular malformation has familial forms
Cavernous (AD)
What is the most common way microbes enter the nervous system
Hematogenous spread
What are the classes of infectious meningitis
Aseptic (viral), acute pyogenic (bacterial), chronic (TB, spirochetal, or cryptococcal)
What bacteria cause acute pyogenic meningitis
E. coli and group B strep in neonates, strep pneumonia and listeria in elderly, neiserria meningiditis in adolescents and young adults; also H influenzae but vaccine has reduced this
What does the CSF show in bacterial meningitis
Increased protein, cloudy, high neutrophils, reduced glucose
What kind of meningitis causes Waterhouse friderihsen syndrome
Meningococcal and pneumococcal
What can cause meningitis in the immunosuppressed
Klebsiella; may have uncharacteristic CSF findings making timely diagnosis more difficult
What are the CSF findings of aseptic meningitis
(Usually caused by enteroviruses); lymphocytic pleocytosis, moderate protein elevation, normal glucose; usually self limited
What is aseptic-like meningitis
When epidermis cyst ruptures into subarachnoid space or introduction of chemical irritating; CSF is sterile, pleocytosis with neutrophils and increased protein, but glucose is normal
What are the two kinds of localized brain infections
Abscess (caused by strep or staph) and empyema (caused by staph or anaerobic gram -)
What viruses cause meningitis
Enterovirus, measles (subacute sclerosing panencephalitis), influenza, lymphocytic choriomeningitis
What viruses cause encephalitic syndromes
Herpes, CMV, HIV, JC polyomavirus (progressive multifocal leukoencephalopathy)
What viruses cause arthropod-borne encephalitis
West Nile, eastern/western/Venezuelan equine encephalitis virus, St. Louis/la crosse/Japanese/tick-borne encephalitis virus,
What virus causes rhombencephalaitis
Rabies
What virus causes spinal poliomyelitis
Polio and West Nile virus
What spirochetes and fungi cause meningitic syndromes
Rickettsia rickettsii, treponema pallidum, borrelia burgdorferi (Lyme), cryptococcal neoformans and Candida albicans (fungal)
What Protozoa and metazoa cause meningitic syndromes
Plasmodium falciparum (cerebral malaria) and naegleria (amebic encephalitis)
What protozoa/metazoa cause localized CNS infections
Toxoplasma Gondii and Taenia sodium (cysticercosis)
What is a brain abscess
Localized focus of. Necrosis of brain tissue (usually bacterial cause) *acute bacterial endocarditis, congenital heart dz (loss of pulm filtration of organism), chronic pulm sepsis, systemic dz with immmunosuppression all causes *strep and staph
Describe the morphology of brain abscess
Liquefactive necrosis; surrounding brain has neovascularization with very permeable vessels -> edema
What does the CSF look like with brain abscesses
High WBCC and increased protein concentration but glucose is normal
What is a subdural empyema
Results from bacterial (and rarely fungal) infection of skull bones or air sinuses that spread to subdural space; can produce thrombophlebitis or bridging veins that cross the subdural space resulting in venous occlusion and infarction of brain; most pts febrile, headache and neck stiffness; CSF similar to brain abscess
What does the CSF of someone with meningitis caused by TB look like
Mononuclear or mixed cells, elevated protein and reduced or normal glucose
What are the most serious complications of TB meningitis
Arachnoid fibrosis producing hydrocephalus and obliterative endarteritis producing arterial occlusion and infarction of brain; tuberculosis produce symptoms similar to space-occupying lesions and must be distinguished from tumors
What are the patterns of CNS involvement in syphilis
Meningovascular neurosyphilis, paretic neurosyphilis and tabes dorsalis; most common is combo of paretic and tabes
What is meningovascular syphilis
Chronic meningitis involving base of brain; can be associated endarteritis (huebner arteritis); gummas (plasma cell rich mass lesions) occur in meninges and extend into parenchyma
What is paretic neurosyphilis
Caused by invasion of brain by T pallidum; progressive cognitive impairment associated with mood alterations (delusions of grandeur) that terminate in severe dementia (general paresis of the insane); damage common to frontal lob; loss of neurons, proliferation of microglia, gliosis and iron deposits (Prussian blue stain)
What is tabes dorsalis
Damage to dorsal roots (sensory); no pain, locomotor ataxia, Charcot joints (damage), lighting pains and absence of DTRs; loss of axons and myelin with pallor and atrophy of dorsal columns; organisms not demonstrable in cord lesions
What are the neuro symptoms of borrelia
Facial n palsy and encephalopathy
What does the CSF of arthropod borne viral encephalitis look like
Colorless CSF, slightly elevated pressure, elevated protein, normal glucose, starts neutrophilic but rapidly converts to lymphocytes
What is the morphology of arthropod borne viral encephalitis
Multiple foci of necrosis of gray and white matter; evidence of single-cell neuronal necrosis with phagocytosis of debris (neuronophagia); microglia cells form aggregates around necrosis called microglia nodules
What has HSV encephalitis been observed in
Patients who have inherited LOF mutation in TLR3 signaling pathway
What is the morphology of HSV encephalitis
Starts in and most severely involves inferior and medial regions of temporal lobes and orbital gyri of frontal lobes; necrotizing and sometimes hemorrhagic; Cowdry type A inclusion bodies in neuron and glia
Who does CMV infection of the nervous system affect
Fetuses and immunosuppressed; outcome in utero is periventricular necrosis that produces severe brain destruction followed by microcephaly and periventricular calcification
What is the morphology of rabies
Edema and vascular congestion; widespread neuronal degeneration and inflammatory reaction most severe in brainstem; negri bodies are found in cytoplasm found in pyramidal neurons of hippocampus and purkinje cells of cerebellum
What does the incubation period of rabies depend on
Distance from wound to brain
What are the symptoms of rabies
CNS excitability (slight touch is painful), violent moron responses, contracture of pharyngeal m on swallowing produces foaming -> causes fear of swallowing (hydrophobia); flaccid paralysis; alternating mania and stupor progresses to coma and death from resp failure
What are the only CNS cells that can be infected by HIV
Microglia
What is immune reconstitution inflammatory syndrome
Identified in patients with AIDS after effective treatment; consists of exuberant inflammatory response while on therapy; in CNS causes exacerbation of symptoms from opportunistic infections
What is HIV-associated dementia associated with
Inflammatory activation of microglia cells
What does JC polyoma virus infect
Oligodendrocytes *causes demyelination; occurs in individuals with chronic lymphoproliferative or myeloproliferative illnesses, immunosuppressive chemo (monoclonal ab therapy targeting integrins), granulomatous dz, and AIDS
Is primary infection of JC usually symptomatic
No; reactivation in immunosuppressed causes symptoms
What is subacute sclerosing panencephalitis
Rare progressive clinical syndrome characterized by cognitive decline, spasticity of limbs and seizures; occurs in children or youn adults months or years after initial acute infection with measles; stems from infection if CNS by altered measles virus; characterized by gliosis and myelin degeneration; viral inclusions in oligodendrocytes and neurons and neurofibrillary tangles
What are the most common fungi that infect the CNS
Aspergillus fumigation, Candida albicans, Mucor species (can cause direct extension in ppl with diabetes), and cryptococcus neoformans
What are the 3 forms of injury seen with fungal infection of CNS
Meningitis, vasculitis (mucormyosis and aspergillosis; both invade bv walls), and parenchymal invasions (granulomas or abscesses; candida and cryptococcus)
What is the morphology of cryptococcus
Meninges are opaque and thickened that can obstruct CSF outflow; sections of brain have gelatinous material in subarachnoid space and small cysts within the parenchyma (soap bubbles) which are prominent in basal ganglia in distribution of lencticulostriate arteries; lesions consist of aggregates of organisms within expanded virchow robin spaces associated with absent inflammation *No gliosis
What does CT show with toxoplasma gondii infection
Ring enhancing lesions (also seen with CNS lymphoma, TB and fungal infection)
What is the morphology of T Gondi
Lesions exhibiting central necrosis, petechial hemorrhage’s surrounded by acute and chronic inflammation macrophages and vascular proliferation; free tachyzoites and encrypted bradyzoites found at periphery of necrotic foci *giemsa stain; surrounding vessels may show fibrinogen necrosis and thrombosis; after treatment -> lesions show well demarcated areas of coagulation necrosis
What causes cerebral malaria
Plasmodium falciparum
What are the prion diseases
Creutzfeldt-Jakob, gerstmann-Straussler-scheinker syndrome, fatal familial insomnia and Kuru in humans; in sheep; scrapie, mink transmissible encephalopathy, chronic wasting dz of deer and elk, and bovine spongiform encephalopathy
When do prion diseases form
When PrP undergoes conformational change from alpha helix to beta pleated sheet (acquires resistance to digestion with pro teases; induces development of cytoplasmic vacuoles *western blotting diagnostic
A polymorphism in what has been shown to influence development of familiar prion diseases
Codon 129 that encodes either Met or Val; if homozygous for either, overrepresented in CJD; heterozygosity is protective
How is creutzfeldt-Jakob transmitted iatrogenically
Corneal transplant, deep implantation of electrodes in brain, administration of contaminated preparations of naturally derived human growth hormone
What are the symptoms of CJD
Changes in memory and behavior followed by progressive dementia and involuntary jerking m contractions on sudden stimulation (startle myoclonus); fatal (7 month prognosis)
How does CJD-like dz differ from CJD
Affected young adults, behavioral disorders early on, neuro symptoms progressed slower; linked to exposure of bovine spongiform encephalopathy; variant CJD characterized by presence of extensive cortical plaques surrounded by halo of spongiform changes; NO alterations in PRNP and is limited to codon 129 Met/Met homozygotes
What are kuru plaques
Extracellular deposits of aggregated abnormal protein; Congo red and PAS positive; usually in cerebellum; abundant in cerebral cortex in vCJD
What is fatal familial insomnia
Also causes by mutation in PRNP gene; leads to asp substitution for asparagine at residue 178 of PrP; results in FFI when it occurs in a PRNP allele encoding met at codon 129 but causes CJD when present in tandem with a valine at this position; develop ataxia, autonomic disturbances, stupor and coma
What is unique about FFI as a prion disease
Only one that doesn’t show spongiform pathology; alteration is neuronal loss and reactive gliosis in anterior ventral and dorsal medial nuclei of thalamus and inferior Oliver you nuclei
What is MS
Autoimmune demyelination disorder characterized by episodes of neuro deficit separated in time, attributable to white matter lesions that are separated in space; women more than men; relapsing and remitting episodes of variable duration
What MHC is associated with MS
DRB1*1501
What is MS initiated by
Th1 and 17 that react against myelin antigens; also thought to involve B cells
What does MS look like in the “fresh state”
Lesions sure firmer than surrounding matter (sclerosis) and appear as well circumscribed depressed glassy gray-tan plaques; commonly occur adjacent to lateral ventricles and are frequent in optic nerves and Chiasm, brainstem, ascending and descending fiber tracts, cerebellum and SC; can extend to gray matter
What is the difference between active and inactive plaques
Active: ongoing myelin breakdown, preservation of axons, depletion of oligodendrocytes
Inactive: no myelin found, reduction in number of oligodendrocyte nuclei, astrocytic proliferation and gliosis
What are shadow plaques
Where border between normal and affected white matter isn’t sharply circumscribed; evidence of partial and incomplete demyelination by surviving oligodendrocytes
What are the common patterns of deficits seen with MS
Unilateral visual impairment due to involvement of optic n (optic neuritis, retrobulbar neuritis) - usually first sign but small percent go on to develop MS; involvement of brainstem produces nystagmus, ataxia, and internuclear ophthalmoplegia (medial longitudinal fasciculus); spasticity and bladder function problems
What does the CSF of someone with MS show
Elevated protein, moderate pleocytosis; IgG levels increased
What is neuromyelitis optica
Bilateral optic neuritis and SC demyelination; more women than men; abs against aquaporin 4 (major water channel in astrocytes); injure astrocytes via complement; cannot transfer dz; white cells common in CSF including neutrophils; damaged areas show necrosis and inflammation infiltrate and vascular dep of Ig; treat with anti-CD20 ab (kill B cells)
What is acute disseminated encephalomyelitis
Diffuse monophasic demyelination gets dz that follows viral infection (or immunization); headache, lethargy and coma
What is acute necrotizing hemorrhagic encephalomyelitis
(Aka acute hemorrhagic leukoencephalitis of Weston hurst); CNS demyelination affecting young adults and children; preceded by episode of URI; fatal in many patients with deficits seen in survivors
What is the morphology of acute disseminated encephalomyelitis
Grayish discoloration around white matter vessels; myelin loss with preservation of axons; neutrophils found in early stages, later mononuclear; lipid. Laden macrophages; all lesions appear similar (unlike MS)
What is the morphology of acute necrotizing hemorrhagic encephalomyelitis
Perivenular demyelination; damage is more severe than acute disseminated encephalomyelitis and include destruction of small bv and necrosis of white and gray matter w/ hemorrhage, fibrin deposition and neutrophils
What is central pontine myelinolysis
Loss of myelin in basis pontis and pontine tegmentum; arises afte rapid correction of hyponatremia *aka osmotic demyelination disorder; rapid increases in osmolality injure oligodendrocytes; no inflammation; neurons and axons preserved; periventricular and subpar regions are spared; *symptoms: rapidly evolving quadriplegia -> locked in syndrome (conscious but unresponsive)
What are neurodegenerative diseases associated with
Accumulation of protein aggregates
What are the inclusions of Alzheimer’s
Alphabeta plaques and tau tangles
What are the inclusions in frontotemproal lobar degeneration
Tau, TDP-43, FUS; causes behavioral changes and language disturbance
What are the inclusions in Parkinson’s dz
A-syuclein and Tau
What are the inclusions of progressive supranuclear palsy
Tau; causes Parkinsonism with abnormal eye mvmnts
What are the inclusions in corticobasal degeneration
Tau; causes Parkinsonism with asymmetric mvmnt
What are the inclusion in multiple system atrophy
A-synuclein; causes Parkinsonism, cerebellar ataxia, autonomic failure
What is the inclusion in huntington
Huntington (polyglutamine); causes hyperkinetic mvmnt
What is the inclusion in spinocerebellar ataxia
Polyglutamine containing proteins; causes cerebellar ataxia
What are the inclusions in ALS
Sod1, TDP-43, and FUS; causes weakness with upper and lower MN
What is the inclusion in spinal bulbar muscular atrophy
Androgen receptor (polyglutamine containing); causes LMN weakness and diminished androgen
What are the plaques and tangles in Alzheimer’s
Plaques: alpha beta peptides in neuropil
Tangles: aggregates of microtuble binding protein, tau; develop intracellularly and persist extracellularly after neuronal death
What is the initiating event for development of AD
Development of alpha beta peptides
Wha causes familial AD
Mutation in APP (which is what alpha beta is derived from)
How is alpha beta generated
APP can either be cleaved by alpha secretary (forming soluble form) or beta secretary (forms alpha beta)
Where is the gene that encode APP
Chromosome 21 in Down syndrome region
What loci are involved in early onset familial AD
PS1 on chrom 14 and PS2 on chrom 1; both encode for presenilins (part of gamma secretase)
What happens to tau in AD
Becomes hyperphosphorylated and loses ability to bind to microtubules
What is another genetic risk factor for AD
Locus on chrom 19 that encodes ApoE has strong influence on risk of developing AD; epsilon 4 increases risk and lowers the age of onset; ApoE isoform promotes alphabeta generation and deposition
Do plaques or tangles correlate better with degree of dementia
Tangles; biochemical markers that have been correlated with degree of dementia include loss of choline acetyltransferase, synaptophysin immunoreactivity, and amyloid burden; also presence of increased phosphorylated tau and reduced alpha beta in the CSF
What is the morphology of AD
Cortical atrophy, widening of sulci; ventricular enlargement (hydrocephalus ex vacuo); hippocampus, entorhinal cortex and amygdala involved early; microscopic changes: neuritis (sensible) plaques and tangles
What are diffuse plaques
Deposition of alpha beta peptides in absence of surrounding neuritis processes; believed to be early stage of plaque development (ie: seen in downs); made up of alpha beta 42
What do neurofibrillary tangles look like in pyramidal cells vs rounder cells
Pyramidal: flame shape
Round: rounded contour; globose tangles
*demonstrated by bielschowky (silver) stain
What is cerebra amyloid angiopathy
Accompaniment of AD, but can be found in absence of AD; vascular amyloid is alpha beta 40
What are frontotemproal lobar degeneration
Heterogenous set of disorders associated with focal degeneration of frontal and/or temporal lobes; distinguished from AD by the fact that alternates in personality, behavior and language precede memory loss
What is FTLD-Tau
Affected cortical regions demonstrate progressive neuronal loss and reactive gliosis along with presence of tau containing inclusion in cytoplasm; tangles can resemble AD or be smooth contoured inclusions called Pick bodies(contain 3R tau) *pick dz (spares posterior 2/3 of superior temporal gyrus)
What is FTLD-TDP
Contain TDP-43 (RNA-binding protein) inclusions; 3 diff mutations can cause it:
- )most common - expansion of hexanucleotide repeat in 5’ UTR of C9orf72 (also causes ALS)
- )mutation in gene encoding TDP-43 (also occur in familial ALS)
- )mutation in gene encoding progranulin (NOT linked to ALS); LOF mutation; progranulin expresssed in glia nd neurons that is cleaved into peptides that regulate inflammation in the brain
What is the form of FTLD that does not involve tau or TDP inclusions
Mutation in FUS (fused in sarcoma) gene can cause either FTLD or ALS
What is Parkinsonism
Diminished facial expression (masked facies), stooped posture, slowing of voluntary mvmnt, destinations gait, rigidity and pill rolling tremor
What is the central triad of Parkinsonism used to diagnose PD
Tremor, rigidity, bradykinesia
