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
What are the genetic causes of PD
- AD -> point mutations and amplifications of chrom 4q21 (a-synuclein); major component of Lewy body; first appear in medulla and then ascend through brainstem and lambic structures
- mitochondrial dysfunction: AR; mutations in genes that encode DJ-1, PINK1, and Parkin; complex I are reduced in ppl with sporadic PD
- mutations in gene encoding LRRK2 (leucine rich repeat kinase 2) (AD); cytoplasmic kinase
What is the morphology of PD
Pallor of substantia nigra and locus ceruleus; Lewy bodies (in neurons and cells of basal nucleus of Meynert)
What are symptoms of dementia with Lewy bodies
Fluctuating course, hallucinations, prominent frontal signs; Lewy bodies have “spread” advanced PD
What is different between PD and atypical PD syndrome
Atypical do not respond to l-dopa and have other symptoms
What is progressive supranuclear palsy
Tauopathy (atypical Parkinsonism syndrome); developer progressive truncal rigidity, disequilibrium with frequent falls and difficultly with voluntary eye mvmnts; also see nuchal dystopia, pseudobulbar palsy and mild progressive dementia; males more than females; often fatal within 5-7 yrs
What is the morphology of progressive supranuclear palsy
Widespread neuronal loss in globus pallidum, subthalamic nucleus, substantia nigra, colliculi, peri aqueduct all gray matter, and dentate nucleus; globose fibrillation tangles found; 4R tau
What is corticobasal degeneration
Progressive tauopathy (atypical Parkinsonism syndrome) characterized by extrapyramidal rigidity, asymmetric motor disturbances (jerking mvmnts of limbs), impaired higher cortical function (apraxia); more cerebral cortical involvement than PSP (which has more brainstem and gray matter)
What is the morphology of CBD
Cortical atrophy, mainly of motor, promoter, and anterior parietal lobes; ballooned neurons* (neuronal achromasia)
What is multiple system atrophy
Sporadic disorder that affects several functional systems in the brain and is characterized by cytoplasmic inclusions of a-synuclein in oligo. *pathologica hallmark is observed in glial cells and associate with degeneration of white matter
What circuits are involved in MSA
- striatonigral circuit (leading to parkinsonism)
- olivopontocerebellar circuit (leading to ataxia)
- autonomic nervous system (leading to autonomic dysfunction with orthostatic hypotension)
What is the pathogenesis of MSA
A-synuclein is component of glial inclusions; sporadic dz; inclusions disappear as cells die in final stages; no upregulation of a-synuclein in white matter or oligo -> acquire it when neurons die
What is Huntington dz
AD dz characterized by progressive mvmnt disorders and dementia, caused by degeneration of striata neurons; hyperkinetic involving whole body (chorea); fatal (on avg about 15 yrs)
What gene is affected in Huntington’s
HTT on chrom 4pq16.3
What is anticipation in reference to Huntington’s
Repeats occur during spermatogenesis; paternal transmission is associated with early onset in next generation
Is there a sporadic form of Huntington’s
No
What is the morphology of Huntington’s
Small brain with atrophy of caudate nucleus and putamen; lateral and third ventricles dilated; atrophy frequent in frontal lobe; changes develop in medial to lateral direction in caudate and front dorsal to ventral in putamen; spared neurons: diaphorase positive that express NO synthase and cholinesterase positive
What are the two spinocerebellar degenerative diseases that are AR
Friedreich ataxia and ataxia-telangiectasia
What are spinocerebellar ataxias
Group of disorders that present with symptoms of cerebellum (ataxia), brainstem, SC, and peripheral nerves; caused by 3 types of mutations
- polyglutamine diseases: similar to HD; SCA1-3 (machado-Joseph dz), 6-7 (includes visual impairment) 17, and dentatorubropallidoluysian atrophy (DRPLA)
- expansion of non-coding region repeats; SC8,10,12,31,36
- Point mutations in variety of genes
What is friedreich ataxia
Progressive ataxia, spasticity, weakness, sensory neuropathy, and cardiomyopathy; begins in first decade of life with gait ataxia followed by hand clumsiness and dysarthria; DTRs depressed but extensor plantar reflex present; most develop pes cavus and kyphoscoliosis; wheelchair bound within 5 yrs; life expectancy 40-50 (die from heart failure); diabetes found in 25%
What causes friedreich ataxia
Expansion of GAA repeat in first intron of gene in chrom 9q13 that encodes frataxin (found in inner mit membrane - involved in assembly of iron-sulfur cluster enzymes of complex I and II); reduced frataxin -> reduced oxphos and increased free iron (oxidative stress)
What is the morphology of friedreich ataxia
Loss of axons and gliosis in posterior columns of SC, distal portions of corticospinal tracts, and spinocerebellar tracts; degeneration of neurons in SC (Clarke column), the brainstem (CN VIII, X, an XII), the cerebellum (dentate, pukinje of sup vermis), and betz cells of motor cortex; DRG also decreased; heart is enlarged and has pericardial adhesions
What is ataxia telangiectasia
Ataxic-dyskinesia syndrome beginning in early childhood with development of telangiectasias in conjunctiva and skins along with immunodeficiency; ATM mutated on chrom 11q22-33 - encodes kinases that repairs dsDNA breaks, facilitation of apoptosis, maintenance of telomeres, mit homeostasis, response to oxidative stress, and maintenance of ubiquitin-proteosomal degradation
What is the morphology of ataxia-telangiectasia
Predominantly in cerebellum; loss of purkinje and granule cells; degeneration of dorsal columns, spinocerebellar tracts, and antior horn; bizarre enlargement of nucleus (amphicytes); LN, thymus and gonads are hypoplastic
What are the clinical features of ataxia telangiectasia
Death in second decade; initial symptoms: recurrent sinopulmonary infections and unsteadiness in walking; speech becomes dysarthria and eye mvmnt ab develop; many develop T cell leukemia’s
Does ALS affect men or women more
Men
Is sporadic or familial ALS more common
Sporadic; genetic are AD
What mutations have been associated with familial ALS
- gene encoding copper-zinc superoxide dismutase (SOD1) on chrom 21; missense mutation (forms aggregates -> UPR); may contribute to sporadic form as well
- A4V mutation is most common in US; associated with rapid course and rarely involvement of UMN
- MOST COMMON: expansion of hexanucleotide repeat in 5’ UTR of C9orf72
What is the morphology of ALS
Anterior roots of SC are thin and precentral motor gyrus is atrophic; reduction in number of ant horn neurons associated with reactive gliosis; similar findings in hypoglossal ambiguous and motor trigeminal cranial nerve nuclei; remaining neurons contain bunina bodies (remnants of autophagic vacuoles)
What is progressive muscular atrophy
Uncommon cases of ALS in which LMN involvement predominates
What is primary lateral sclerosis
Cases of ALS with mostly UMN involvement
What is progressive bulbar palsy or bulbar ALS
Degeneration of lower brainstem cranial motor nuclei occurs early and progresses rapidly; abnormalities of deglutition and phonation dominate and clinical course is inexorable during 1 or 2 year period
Which motor neurons are the last to be involved in ALS
Those innervating extra-ocular mm
What is spinal and bulbar muscular atrophy (Kennedy dz)
X-linked polyglutamine repeat expansion dz; characterized by distal limb amyotrophic and bulbar signs (atrophy and fasciculations of tongue, dysphagia) assoc with. LMN in spinal cord and brainstem; expanded repeat occurs in first exon of androgen receptor and results in androgen insensitivity, gynecomastia, testicular atrophy, and oligospermia; cell injury is caused by androgens binding to deformed receptor; RX: decrease androgens
What is spinal muscular atrophy
Group of genetically linked disorders of childhood with marked loss of LMN -> weakness; SMA type I (werdnig-Hoffman) is most severe with onset during first year and death within 2; SMA III (Kugelberg-welander) motor disability emerges later childhood; severity repeated to level of SMN involved in assembly of spliceosome; assoc with disruption of SMN1
Describe the features of neuronal storage diseases
Predominately AR caused by deficiency of enzyme involved in catabolism of sphingolipids, mucopolysaccharides, or mucolipids
What are leukodystrophies
Mostly AR; caused by mutations in genes encoding enzymes involved in myelin synthesis or catabolism; some involve lysosomal enzymes or peroxisomal enzymes; diffuse involvement of white matter leading to deterioration in motor skills, spasticity, hypotonia, or ataxia
What are mitochondrial encephalomyopathies
Group of disorders of oxphos; affect multiple tissues including skeletal m; when involve brain, gray matter is more affected; can be caused by mutations in mit or nuclear genomes
What separates leukodystrophies from demyelinating diseases
Leukodystrophies present with progressive loss of cerebral function at younger ages and are associated with diffuse and symmetric changes on imaging
What is krabbe dz
AR leukodystrophy resulting from deficiency of galactocerebroside beta galactosidase (galactosylceramidase); required for catabolism of galactocerebroside to ceramide and galactose; alternative pathway shunts galactocerebroside to gaactosylsphingosine which are cytotoxic; onset btw 3-6 months; loss of myelin and oligo in CNS and PNS; *unique = aggregation of engorged macrophages (globoid cells); hematopoietic stem cell transplant needed
What is metachromatic leukodystrophy
AR; results from deficiency of lysosomal enzyme arylsulfatase A; cleaves sulfate from sulfate-containing lipids as first step in degradation; accumulation of sulfatides inhibits differentiation of oligo and elicits proinflamm response from microglia; *vacuoes contain sulfatides which bind to dyes like toluidine blue (metachromasia); can be found in urine
What is adrenoleukodystrphy
X-linked recessive; mutations in ATP-binding cassette transporter (ABCD1) which is involved in transport of molecules into peroxisome; typical: young males present w/ behavior changes and adrenal insufficiency; inability to cat VLCFA
What is mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes (MELAS)
Characterized by recurrent episodes of acute neurological dysfunction, cognitive changes, and muscle involvement with weakness and lactic acidosis; stroke-like - reversible not specific to vascular; areas of infarction are seen with focal calcification; neurons and vascular smooth m have altered expression of cytochrome c oxidase; *most common mutation is in gene encoding mit tRNA-leucine (MTTL1)
What is myoclonic epilepsy and ragged red fibers (MERRF)
Mit enceph.; maternally transmitted; causes myoclonus and myopathy; ragged red fibers on m biopsy; ataxia; mutation in tRNAs
What is Leigh syndrome
Disease of infancy characterized by lactic academia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, and weakness with hypotonia; death in 1-2 years; histo: multifocal regions of destruction of brain associated with spongiform appearance and proliferation of bv; brainstem, thalamus, and hypothalamus involved; nuclear and mit DNA mutations
What does thiamine (B1) deficiency cause
Wernickes encephalopathy; psychotic symptoms and ophthalmoplegia; can progress to korsakoff syndrome (short term mem loss and confabulation)
What is the morphology of wernickes encephalopathy
Hemorrhage and necrosis in mammillary bodies and walls of 3rd and 4th ventricles; progress to lesions in dorsomedial nucleus of thalamus
What does vitamin B12 deficiency cause
Subacute combined degeneration of SC; degeneration of ascending and descending spinal tracts; lesions are caused by defect in myelin formation; b/l symmetric numbness, tingling and ataxia in LE; complete paraplegia can occur; swelling of myelin layers, producing vacuoles; in early stages, mid-thoracic SC is affected
What does glucose deprivation lead to in the brain
Initially leads to selective injury of large pyramidal neurons in cerebral cortex (pseudolaminar necrosis of cortex); hippocampus and purkinje also vulnerable
What morphological changes does hyperglycemia have on the brain
None; individual becomes dehydrated and develops confusion, stupor and coma; fluid depletion must be corrected gradually to avoid severe cerebral edema
What would you see in the brain of someone with liver disease
Astrocytes (alzheimer type II cells) appear in cerebral cortex and basal ganglia in response to elevated ammonia
Injury to which neurons occurs as a result of CO poisoning
Neurons of layers III and V of cerebral cortex, sommer, and purkinje; b/l necrosis of globus pallidum may occur
What does methanol toxicity affect
Mostly retina; degeneration of retinal ganglion causes blindness; b/l necrosis of putamen occurs when severe; formate (metabolite) disrupts oxphos
What histological changes occur in the brain of a chronic alcoholic
Atrophy and loss of granule cells in anterior vermis; loss of purkinje cells and proliferation of adjacent astrocytes (Bergman gliosis)
What is the effect of radiation on the brain
Papillaedema; coagulative necrosis; edema in surrounding tissue; and fibrinoid necrosis; when given with methotrexate, cause lesions adjacent to lateral ventricles; can induce formation of gliomas, mengingiomas and sarcomas
Where do CNS tumors arise in kids compared to adults
Kids: post fossa
Adults: cerebrum above the tentorium
What is the most common type of primary brain tumor
Gliomas
What are gliomas
Astrocytomas, oligodendrogliomas, and ependymomas
What is an astrocytoma
Two categories
- diffusely infiltrating astrocytomas
- localized astrocytomas (most common is pilocytic astrocytoma)
What are infiltrating astrocytomas
Account for 80% of adult primary brain tumors; usually found in cerebral hemispheres; common presenting sign: seizures, HA< and focal neuro deficits; show spectrum of histo differentiation: diffuse astrocytomas (II/IV), anaplastic (III/IV) or glioblastoma (IV/IV); no grade I
What is the classic subtype of glioblastomas
Majority; mutations in PTEN (tumor suppressor), deletions in chrom 10, and amplification of EGFR oncogene; focal deletion of chrom 9p21 results in hemizyogous del of CDKN2A tumor suppressor
What are proneural type glioblastomas
Most common type associated with secondary glioblastoma; characterized by mutation in Tp53, point mutations in isocitrate DH genes (IDH1/2); overexpression of PDGFRA
What is the neural type of glioblastoma
Higher levels of NEFL, GABRA1, SYT1, and SLC12A5
What is the mesenchymal type of glioblastoma
Deletions of NF1 gene on chrom 187 and lower expression of NF1 protein; TNF and NF-kB highly expressed
What is associated with a better outcome in individuals with high grade astrocytomas (III/IV)
Presence of mutation in IDH1 (R132H)
What is the morphology of diffuse astrocytomas
Poorly defined, gray, infiltrating; expand and distort brain; cellular density greater than white matter; btw tumor cell ulcer, GFAP astrocytic processes create fibrillation appearance
What is the morphology of anaplastic astrocytomas
Densely cellular and have greater paleo or phish; mitotic figures seen
What is gemistocytic astrocytoma
Tumors in which predominant neoplastic astrocyte shows brightly eosinophilic cell body from which emanate abundant stout processes
What is a characteristic morphology of global stoma
Variation in appearance of tumor from region to region; histologica appearance is similar to anaplastic astrocytoma with additional features of necrosis(in a serpentine pattern) and vascular/endothelial proliferation (double layer of endothelial cells) - forms glomerloid body; tumors collect along edges of necrotic regions producing pattern referred to as pseudo-palisading
What is gliomatosis cerebri
Diffuse glioma with extensive infiltration of multiple regions of the brain; aggressive - grade III/IV
What causes glioblastoma to be “enhancing” on imaging
Has leaky vessels with permeable BBB
What is pilocytic astrocytoma
Grade I/IV; distinguished by their gross and micro appearance and benign behavior; typically in children and young adults; usually in cerebellum (but also optic n, wall and floor of 3rd ventricle) occurs with neurofibromatosis type I (loss of neurofibromin) not seen in sporadic forms; two alterations in BRAF signaling have been noted; translocation and activating point mutation (V600E); treat with BRAF inhibitors
What is the morphology of pilocytic astrocytoma
Usually cystic; tumor composed of bipolar cells with hairlike processes that are GFAP-positive and form fibrillary meshwork; rosenthal fibers and eosinophilic granular bodies characteristic; limited infiltration of surrounding brain
What kind of pilocytic astrocytoms have a more ominous clinical course
Those that grow into hypothalamic region from optic tract
What is pleomorphic xanthoastrocytoma
Occurs most often in temporal lobe in children and young adults usually w/ history of seizures; consists of neoplasticism astrocytes (sometimes filled w/ lipid); can suggest high grade astrocytoma, but presence of reticulum deposits, circumscription, and chronic inflam infiltrates distinguish it from malignancy (also lack of necrosis and mitosis activity) grade II/IV
What are brainstem gliomas
Subgroup of astrocytomas; occur in first 2 decades; intrinsic pontine gliomas (most common; aggressive and short survival) cervicomedullary (less aggressive); dorsally exophytic gliomas (even more benign); *pontine - most have Lys->Met at pos 27 in his tone H3.1/.3
What are oligodendrogliomas
Infiltrating gliomas comprise of cells that look like oligo.; may have history of seizures; lesions in cerebral hemi w/ predilection for white matter
How are oligodendrogliomas distinguished from astrocytic tumors
Most common mutation is isocitrate DH 1/2 (better prognosis); deletions of chrom 1p and 19q also seen; loss of 9p and 10q and must in CDKN2A; BUT EGFR gene amplification not seen (seen w/ astrocytomas); those w/out loss of 1p or 19q resistant to chemo
What is the morphology of oligodendrogliomas
Well circumscribed, gelatinous, gray, often w/ cysts; focal hem and calcification;mitotic activity minimal; grade II
What are anaplastic oligodendrogliomas
Grade III; higher cell density, nuclear, anaplasia, mitotic activity, and necrosis; grouped with glioblastoma
What are the clinical features of oligodendrogliomas
Better prognosis than astrocytomas
What are ependymomas
Tumors that arise next to ependyma-lined ventricular system including central canal of SC; in 1st 2 decades, occur near 4th ventricle; in adults, SC common location; *frequent in setting of NF2
What is the most common mutation seen in ependymomas
NF2 on chrom 22 (only if in SC); 2 subtypes - mesenchymal (younger w/ higher probability of Mets) and aberrations of large regions of chrom that tend to have better prognosis
What is the morphology of ependymomas
Hard to remove b/c of location in brain; easier to remove in SC; can form rosettes or canals that resemble embryo logic ependymal canal; *perivascular pseudorosettes (tumor cells arrange around vessels w/intervening zone of thin ependymal processes); grade II (anaplastic grade III)
What are myxopapillary ependymomas
Occur in filum terminals of SC and contain papillary elements; cuboidal cells arranged around pap cores containing conn tissue and bv; myxoid areas contain neutral and acidic mucopolysacc. Prognosis depends on resection; if tumor extends into subarachnoid space and surrounded roots of cauda equina, recurrence likely
What are the clinical features of ependymomas
Post fossa -> manifest as hydrocephalus; poor prognosis;
- subependymomas:: solid and sometimes calcified; slow growing; protrude into ventricle; asymptomatic and usually found at autopsy
- choroid plexus papilloma: most common in children in lat ventricles; in adults, 4th ventricle; look like normal choroid plexus; hydrocephalus
- choroid plexus carcinoma: rarer; resemble adenocarcinoma; in adults, must be determined if met;
- colloid cyst of 3rd ventricle: non-neoplasticism enlarging cyst attached to roof of 3rd ventricle; noncommunicating hydrocephalus (rapidly fatal) *headache (positional)
What are gangliogliomas
Most common Neuronal tumors; mixture of neuronal and glial cells; superficial lesions that present with seizures; slow growing but glial component can become anaplastic and progress rapidly; mutation in BRAF gene (V600E) and assoc w/ shorter recurrence-free survival; *found in temporal lobe and have cystic component; glial component usually low grade astrocytoma-like (no mitotic activity or necrosis)
What is dysembryoplastic neuroepithlial tumor
Rare, low grade (I) tumor of childhood that presents as seizure disorder; good prognosis following resection w/ low recurrence and seizure control; located in superficial temporal lobe; often attenuation of overlying skul; typically form discrete intracortical nodules of small, round cells arranged in columns around central processes; well-differentiated “floating neurons” that sit in pools of mucopolysacc fluid of myxoid
What are central neurocytomas
Low grade (II) neuronal neoplasms found in ventricular system; evenly spaced, round uniform nuclei; resemble oligodendroglioma but histo reveals neuronal lineage
What is medulloblastoma
Poorly differentiated neoplasm; malignant; occurs in children and cerebellum; grade IV; alterations in SHH and WNT/beta-cat pathways
What are the 4 groups of medulloblastoma
- WNT type: mutations in WNT; occurs in older children; classic medulloblastic histo; monopsony of chrom 6 and nuclear expression of beta Catenin; best prognosis
- SHH type: mutations in SHH; occurs in infants or young adults; modular desmoplastic histo and MYCN amplification; intermediate prognosis
- Group 3: MYC amplification and isochrom 17 (i17q); infants and children; large cell histology *worst prognosis
- Group 4: i17q cryogenic alteration, large cell histo, NO MYC amplification but sometimes MYCN amp. Intermediate prognosis
What is the morphology of medulloblastoma
Contain high levels of Ki-67 (marker of cell proliferation); form homer-wright rosettes (like neuroblastoma), express glial markers; modular desmoplastic variant - strongly response marked by collagen and reticulum deposits (forms pale islands); large cell variant: irregular vesicular nuclei, frequent mitosis and apoptosis; at edges, form linear chains of cell infiltrating cortex and penetrating Pia -> can disseminate to far places called drop Mets
What is an atypical teratoid/rhabdoid tumor
Malignant tumor of young children (grade IV); in posterior fossa and supratentorial compartments equally; divergent differentiation; alternations in chrom 22 are hallmark; end hSNF5/INI1 (encodes chromatin remodeling complex)
What is the morphology of rhaboid tumor
Cytoplasm has intermediate filaments; immunoreactive to epithelial membrane antigen and vimentin; may be reactive for actin and keratin but not Desmin or myoglobin;*mitotic activity extremely prominent
What is the most common CNS neoplasm in immunosuppressed individuals
Primary CNS lymphoma; risk increases after 60 yrs of age
What is the origin of the majority of primary brain lymphomas
B-cell
What is the prognosis for primary CNS lymphomas
Poor; aggressive and worse outcomes than tumors of comparable histo occurring at non-CNS sites
What staining pattern is characteristic of primary brain lymphoma
Hooping
What are intravascular lymphomas
Unusual large cell lymphoma that grows in small vessels; often involves brain; presents b/c of microscopic infarcts
Where do primary brain germ cell tumors occur
Midline, most commonly in pineal (males) and Suprasellar regions; more common in japan; tumors of the young; congenital tumors; Mets from gonadal tumor to CNS is common so must rule this out; CSF levels for alpha-fetoprotein and beta-hcg useful for diagnosis and tracking
What are pineal parenchymal tumors
Range from well-diff (pineocytomas): small, round nuclei, no necrosis or mitosis; adults High grade (pineoblastomas): no neuronal diff., smal cells, necrosis and frequent mitotic figures; children; mutations in RB
What are meningiomas
Predominately benign tumors of adults; usually attached to dura; arise from meningothelial cells of arachnoid; can be found on ext surface or in ventricular system; *risk factor: prior radiation
What are the genetic abnormalities linked to meningiomas
Most common: loss of chrom 22 (esp q); harbors NF2 gene which encodes merlin ; higher grade
-TNF receptor associated factor 7. (TRAF7); lower grade
What is the morphology of meningiomas
Easily removed from surface of brain; can grow en plaque, which is the tumor spreads in sheet like fashion along surface of dura; associated with hyperostotic changes in adjacent bone; can contain psammoma bodies; necrosis and hem absent; immunoreactive for epithelial antigen
Do mengiomas have a high risk of recurrence
No
What are the histo patterns seen in meningiomas
- syncytial: whorled clusters of cells that sit in tight groups without visible membranes
- fibroblastic: elongated cells and abundant collagen
- transitional
- psammomatous: calc of syncytial nests
- secretory: PAS positive intracytoplasmic droplets on electron micro
- microcystic: loose, spongy appearance
What are atypical meningiomas
Grade II; lesions w/ higher rate of recurrence and more aggressive growth; may require radiation; distinguished from low grade b/c have 4 or more mitosis per 10 high power fields or at least 2 atypical features (increased cell, small cells w/ high nuclear to cytoplasm ratio, prominent nucleoli, patternless growth, necrosis); clear cell and choroid also considered high grade
What is anaplastic (malignant) meningiomas
Grade III; highly aggressive; high grade sarcoma appearance, but retains evidence of meningothelial origin; high mitotic rate; papillary and rhabdoid meningiomas have high propensity to reoccur
Does invasion of meningiomas affect the grade
No; but does increase risk of recurrence
What are common sites of involvement that show clinical signs of meningiomas
Olfactory groove, parasagittal aspect of brain, dura over lateral convexity, wing of sphenoid, sella turcica, and foramen magnum
Who is most affected by meningiomas
Females; not common in children
What should be considered if you have multiple lesions of meningiomas
NF2; especially if in association with acoustic neuromas or glial tumors
When do meningiomas grow more rapidly
During pregnancy; have progesterone receptors
What are the 5 most common primary sites of tumors that met to the brain
Lung, breast, skin (melanoma), kidney, and GI; also choriocarcinoma
What is subacute cerebellum degeneration
Paraneoplastic syndrome; associated with destruction of purkinje cells, gliosis and chronic inflammatory cell infiltrate; circulating PCA-1 an that recognizes purkinje cells; occurs predominantly in women with ovarian, uterine, or breast carcinoma
What is limbic encephalitis.
Paraneoplastic syndrome; Subacute dementia; perivascular inflamm cuffs, microglial nodules, neuronal loss, and gliosis mostly in ant and med temporal lobe; micro resembles infectious process; circulating ANNA-1 ab (anti-hu) recognizes neuronal nuclei in CNS and PNS; associated with small cell carcinoma of lung; another group has circulating ab to NMDA receptor and cross-reacts with hippocampal neurons (assoc with ovarian teratomas); 3rd group has VGKC-complex ab that recognizes voltage-gated K channel
What are the eye movement disorders that are paraneoplastic syndromes
Commonly opsoclonus; associated with neuroblastoma
What is subacute sensory neuropathy
Paraneoplastic syndrome; associated with limbic encephalitis or alone; loss of sensory neurons from DRG due to lymphocytic inflammation
What is lambert-Eaton myasthenic syndrome
Paraneoplastic syndrome; ab against voltage gated Ca channel in presynaptic NMJ; can be seen in absence of malignancy as well
Which kinds of paraneoplastic syndromes respond better to immunotherapy
Those with plasma membrane reactive abs rather than intracellular antigens
What is cowden syndrome
Familial tumor syndrome; dysplastic gangliogliocytoma of cerebellum (lhermitte-Dulcos dz) caused by mutation in PTEN resulting in PI3K/AKT signaling pathway activity
What is li-fraumeni syndrome
Familial tumor syndrome caused by mutation in TP53; causes medulloblastoma
What is turbot syndrome
Familial tumor syndrome caused by mutation in APC or mismatch repair genes; causes medulloblastoma or glioblastoma
What is gorlin syndrome
Familial tumor syndrome caused by mutation in PTCH gene resulting in upregulation of SHH; causes medulloblastoma
What is tuberous sclerosis
AD; development of hamartomas and benign neoplasms involving brain; most frequent manifestations are seizures, autism, and mental retardation; hamartomas w/in CNS take form of cortical tubers; renal angiomyolipomas, retinal glial hamartomas, pulm lymphangioleiomyomatosis and cardiac rhabdomyomas develop over childhood and adolescence; cysts can form at various sites; cutaneous lesions (angiofibromas, shagreen patches - leathery thickening, hypopigmented ares - ash-leaf patches, and subungual fibromas) form
What is the genetic cause of tuberous sclerosis
TSC1 is found on chrom 9q34 and encodes hamartin; mutated locus is TSC2 at 16p13.3 and encodes tuberin; tuberin and hamartin inhibit mTOR; cells are huge; rx is symptomatic
What is von hippel-lindau dz
AD - develop hemangiolastomas of CNS (cerebellum and retina) and cysts involving pancreas, liver, kidneys and have propensity to develop renal cell carcinoma and pheochromocytoma; dysregulation of EPO is responsible for polycythemia observed in assoc with hemangioblastomas
What is neurofibromatosis
AD; NF1 and 2; familiar tumor syndromes characterized by tumors of CNS and PNS; NF1 is more common and is characterized by neurofibromas of peripheral n, gliomas of optic n, pigmented nodules of iris (Lisch nodules) and cutaneous hyperpigmented macules (cafe au lait spots); NF2 -> b/l schwannomas of vestibulocochlear n and multiple meningiomas; gliomas may occur and are commonly ependymomas of SC
What is proptosis
When eye is forced out of the socket; may be axial (directly forward) or positional; ie: enlargement of lacrimal gland displaces the eye inferior and medial; masses in the cone formed by horizontal rectus mm generate axial proptosis (also produced by glioma and meningiomas of optic n)
What are orbital inflammatory conditions
Uncontrolled sinus infection can spread to orbit; most common in immunosuppressed, diabetic ketoacidosis; systemic conditions like wegener granulomatosis may present in orbit and confined there; idiopathic orbital inflammation (pseudo tumor) can be uni or b/l; may affect all orbital tissue or just lacrimal gland (sclerosing dacryoadenitis), the extraocular mm (orbital myositis) or tenon’s capsule (post scleritis) *IgG4-related dz should be excluded b4 declaring idiopathic
What is the morphology of idiopathic orbital inflammation
Orbital fat replaced by fibrosis
What are the most common neoplasms of the orbit
Capillary hemangioma of infancy and early childhood and lymphangioma (both are unencapsulated) and cavernous hemangioma in adults (capsulated)
How can non-Hodgkin lymphoma affect the eye
Can affect entire orbit or confined to compartments of orbit
How does neuroblastoma or Wilms tumor met to the eye present
Periocular ecchymoses
What is blepharitis
Inflammation of eyelid margin; can obstruct sebaceous glad and cause lipid to extravasate into the surrounding tissue and provoke a granulomatous response (lipogranuloma or chalazion)
What is the most common malignancy of the eyelid
Basal cell carcinoma *distinct predilection for lower lid and medial canthus
What can sebaceous carcinoma resemble
Chalazion or ocular cicatricial pemphigoid b/c of predilection for intraepithlial spread as occurs in paget dz of nipple or vulva; tends to spread to parotid and submandibular nodes
What is the morphology of sebaceous carcinoma
Vacuolization of cytoplasm; can sometimes resemble basal cell carcinoma; pagetoid spread may mimic bowenoid actinic keratosis in eyelid and carcinoma in situ in the conjunctive; can spread to nasopharynx via lacrimal system
What can develop in the eyelid in ppl with AIDS
Kaposi sarcoma; in eyelid, purple, but in conjunctiva, bright red (confused with hemorrhage)
Is basal cell carcinoma or sebaceous carcinoma of the eyelid more severe
Sebaceous cell (metastasizes frequently)
What is the conjunctiva of the fornix lined with
Pseudostratified columnar rich in goblet cells; lacrimal ducts pierce through here; *in viral conjunctivitis, lymphoid follicles can enlarge enough to be visualized by slit-lamp exam; granulomas associated with sarcoidosis can be detected here; primary lymphoma of conjunctiva (b-cell) also most likely here
What is the bulbar conjunctiva
Part that covers the eye; nonkeratinizing strat squamous
Infection with what can cause severe conjunctival scarring
Chlamydia trachomatis
What can a reduction in the number of goblet cells in the conjunctiva cause
Caused by scarring; leads to decrease in surface mucin, which is necessary for adherence of aqueous component of tears to the corneal epithelium *dry eye
Why do physicians only remove the invasive part of conjunctival neoplasms
B/c can cause dry eye; treat the intraepithlial portions with cryotherapy or topical chemo
What is pinguecula and pterygium
Both are submucosal elevations on the conjunctiva; result from actinic damage therefore located in sun-exposed regions
What is ptyergium
Typically in conjunctiva astride the limbus; formed by submucosal growth of fibrovascular connective t issue that migrates into cornea; does not cross pupillary axis and does not pose a threat to vision besides mild astigmatism; most are benign
What is pinguecula
Appears astride limbus; small yellowish submucosal elevation; does not invade cornea* can result in uneven distribution of tear film over cornea; saucer-like depression (delle) results
What is conjunctival intraepithlial neoplasia
Mild dysplasia seen through carcinoma in situ in the conjunctiva
What are squamous papilloma and conjunctival intraepitleial neoplasia associated with
HPV types 16 and 18
What is mucoepidermoid carcinoma
Differentiates into squamous and goblet cells; much more aggressive
What are conjunctival nevi
Seldom invade cornea or appear in the fornix or over palpebral conjunctiva (pigmented lesions in these zones most likely melanomas); contain subepithlial cysts lined by surface epithelium; can acquire inflamm component rich in lymphocytes, plasma cells, and eosinophils (inflamed juvenile nevus- benign)
What are conjunctival melanomas
Unilateral; affect fair skinned people in middle age; most develop through primary acquired melanosis with atypia (equal to melanoma in situ); treatment is prevention through extirpation of precursor lesion; lesions spread to parotid or submandibular LN
What does the sclera consist of
Collagen, few bv, and fibroblasts; *tends to heal poorly
What can rheumatoid arthritis cause in the sclera
Necrotizing scleritis; immune complex deposition
What causes the sclera to look blue
- scleritis can make it thin and the normally brown color of uvea may appear blue b/c of optical Tyndall effect
- may be thinned in eyes w/ high intraocular pressure; results in staphlyoma which appears blue
- OI
- heavily pigmented congenital nevus of underlying uvula (known as congenital melanosis oculi); when also have periocular cutaneous pigmentation, known as nevus of ota)
What do myopia and hyperopia result from
Myopia: eye that is too long
Hyperopia: eye that is too short
What does LASIK stand for
Laser assisted in situ keratomileusis
What is the importance of the Bowman’s layer of the cornea
Sits beneath epithelial basement membrane; is acellular and forms barrier against penetration of malignant cells from epithlium to stroma
What is the structure of the corneal stroma
Lacks bv and lymphatics; makes cornea transparent and contributes to the high rate of success of corneal tranplantation (less immunologic graft rejection)
What causes corneal vascularization
Chronic corneal edema, inflammation and scarring; treat with topical VEGF ant.
What is corneal endothelium derived from
NC cells; rest on the basement membrane (Descemet membrane); decrease in endothelial cells results in stroma edema which can be complicated by bullous separation of epithelium (bullous keratopathy)
What is the site of copper deposition in Kayser-fleischer ring of Wilson dz
Descemet membrane
What causes keratitis
Dissolution of stroma by activation of collagenases and stroma fibroblasts; exudate and cells leaking from iris and ciliary body vessels into ant chamber may be visible by slit-lamp exam; can accumulate enough to be visible by penlight (hypopyon)- also occurs in ulceration; hypopyon doesn’t contain organisms
What is the difference between corneal degenerations and dystrophies
Degenerations: either uni or b/l; nonfamilial
Dystrophies: b/l and typically hereditary; may affect certain layers (Reisbuckler dystrophy affects Bowman and posterior polymorphous dystrophy affects endothelium) or can affect multiple layers
What types of band keratopathy serve as examples of corneal degenerations
- calcific band keratopathy: deposition of Ca in bowmans layer; can complicate chronic uveitis especially in individuals w/ chronic juvenile rheumatoid arthritis
- actinic band keratopathy: develops in ppl exposed chronically to UV light; solar elastics is develops in superficial layers of corneal collagen in interpalpebral tissue; horizontally distributed band of pathology; yellow hue (sometimes called oil-droplet keratopathy)
What is keratoconus
Common disorder - progressive thinning and ectasia of cornea *no inflammation or vascularization; results in cornea with conical rather than spherical shape; irregular astigmatism that is difficult to orrect; need rigid contact lenses OR corneal transplant; typically b/l; *associated with Downs, Marfan, atopic disorders (eye rubbing)
What is the morphology of keratoconus
Thinning of cornea w/ breaks in bowman layer; Descemet membrane can sometimes rupture allowing aqueous humor in ant chamber to gain access to corneal stroma = corneal hydrops; can cause scarring; seen w/infantile glaucoma (haab striae) or forceps injury to eye
What is fuchs endothelial dystrophy
Results from loss of endothelial cells and results in edema and thickening of stroma; *indicator for corneal transplant; 2 clinical manifestations - stroma edema and bullous keratopathy; early on, endo cells produce deposits of abnormal BM (guttata) that resembles fetal component of Descemet mem; ground-glass appearance of stroma; undergoes hydropic change and detachment of bowman from epithlium produces epithelial bull are that can rupture; fibrous tissue can be deposited btw epithlium and bowman (degenerative pannus)
What is pseudophakic bullous keratopathy
Similar to Fuchs endothelial dystrophy but caused by cataract surgery (decreases # of endothelial cells)
What are stromal dystrophies
Stromal deposits generate opacity in cornea that can compromise vision; can result in painful erosions; an example is caused by mutation in TGFB1 gene which encodes keratoepithelin
What are the boundaries of the anterior chamber
Anteriorly by cornea, laterally by trabecular meshwork, posteriorly by the iris
What makes aqueous humor
Pars plicata of the ciliary body -> enters posterior chamber, bathes the lens, and circulates through the pupil to gain access to anterior chamber (post chamber is behind iris and in front of lens)
What is a cataract
Lenticular opacity that can be congenital or acquired
What can cause cataracts
- systemic dz: galactosemia, DM, Wilson, atopic dermatitis
- drugs: corticosteroids
- radiation
- trauma
- intraocular disorders
- age related: results from opacification of lens nucleus (nuclear sclerosis); accumulation of urochrome can render nucleus brown and distort perception of blue color
What changes in the lens can generate opacities and cause cataracts
Lens cortex can liquify; migration of lens epithelium posteriorly can cause post subcapsular cataract secondary to enlargement of lens epithelium
What is the technique used to remove opacified lenses
Extracts lens contents, leaving lens capsule intact (extracapsular cataract extraction); prosthetic intraocular lens is usually inserted
What is a Morgagnian cataract
When lens cortex liquefies completely; high molecular weight proteins can leak through he lens capsule (phacolysis) and can clog trabecular meshwork and contribute to elevated intraocular pressure and optic n damage; phacolytic glaucoma is an example of secondary open-angle glaucoma
Where does aqueous humor drain
Trabecular meshwork located at the angle formed by the intersection btw corneal periphery and anterior surface of iris
What is the difference between open-angle and angle-closure glaucoma
- open-angle: aqueous humor has completely physical access to trabecular meshwork and elevation in pressure results from increased resistance to aqueous outflow in open angle
- angle-closure: peripheral zone of iris adheres to trabecular meshwork and physically impedes flow of aqueous humor from the eye
What is primary open-angle glaucoma
Most common form; angle is open and few changes seen structurally; mutations in myocilin (MYOC) gene have been associated with juvenile and adult primary open-angle glaucoma; mutations in optineurin (OPTN) may also be responsible for this in adults
What is secondary open-angle glaucoma
-pseudoexfoliation glaucoma (most common form) is associated w/ deposition of fibrillation material through ant segment; SNP in Lysyl oxidase like 1 gene (LOX1); deposits also seen in liver, kidney, and GB
What are examples of things that can clog the trabecular meshwork in presence of open angle
High molecular weight lens proteins produced by phacolysis, senescent red cells after trauma (ghost cell glaucoma), iris epithelial pigment granules (pigment are glaucoma) and necrotic tumors (melanomalytic glaucoma); all secondary open-angle; also caused by elevations in pressure on surface of eye (episcleral venous pressure) - assoc w/ surface ocular vascular malformations such as sturgeweber syndrome
What is primary angle closure glaucoma
Develops in eyes w/ shallow anterior chambers (often in ppl w/hyperopia) pupillary margin of the iris moves against he anterior surface of the lens and obstructs flow through the pupillary aperture (pupillary block) this may bow the iris forward (iris bombe); can damage lens epithelium b.c receives nutrition from aqueous humor; causes glaukomflecken (anterior subcapsuar opacities)
What are some causes of secondary angle-closure glaucoma
- Chronic retinal ischemia: up regulation of VEGF; induces development of thin, transparent fibrovascular membranes over surface of iris; contraction of these lead to occlusion of trabecular meshwork by the iris (neovascular glaucoma)
- necrotic tumors (RB) induce iris neovascularization and glaucoma
- tumors in ciliary body
What are keratic precipitates
During intraocular inflammation, vessels in ciliary body and iris become leaky and form exudate in anterior chamber; inflamm cells can adhere to corneal endothelium forming keratic precipitates; can inform of the underlying cause of inflamm (ie: mutton-fat precipitates indicative of sarcoid)
What can the formation of exudate in the anterior chamber cause
Adhesions between iris and trabecular meshwork or cornea (anterior synechiae - can lead to increase in intraocular pressure and optic n damage) or btw iris and anterior surface of lens (posterior synechiae - can induce fibrous metaplasia of lens epithelium called anterior subcapsular cataract)
Why do you induce pupillary dilation in ppl with intraocular inflammation
To prevent formation of synechiae
What is endophthalmitis
Inflammation in vitreous humor; suppurative inflammation is poorly tolerated by retina; few hours can cause irreversible retinal injury; classified as exogenous (originating in environment and gaining access to interior of eye through a wound) or endogenous (delivered to the eye through the blood)
What is panophthalmitis
Inflammation within the eye that involves the retina, choroid, and sclera and extends to the orbit
What makes up the uvea
Iris, choroid and ciliary body
What is uveitis
Any type of inflammation in one or more tissues that compose the uvea
What is granuomatous uveitis
Common complication of sarcoidosis; in anterior segment gives rise to exudate that evolves into mutton fat; in posterior segment may involve choroid and retina; *candle wax drippings on opthalmoscopic exam; use conjunctival biopsy to detect granulomatous inflammation and confirm diagnosis
What are common infections that cause uveitis
Toxoplasmosis; individuals with AIDS can develop CMV retinitis and unreal infection such as pneumocystis or mcobacterial choroiditis
What is sympathetic ophthalmia
Example of non infectious uveitis limited to eye; b/l granulomatous inflammation affecting all components of uvea (panuveitis); can complicate penetrating injury of eye; retinal antigens may gain access to lymphatics and set a delayed hypersensitivity rxn that affects both eyes; can develop 2 wk to many years after injury; eosinophils identified; treated with immunosuppressive agents
What is the most common intraocular malignancy in adults
Metastasis to uvea, typically the choroid; associated with extremely short survival
What is the most common primary intraocular malignancy in adults
Uveal melanoma; no association btw exposure to UV light and increased risk; GNAQ and GNA11 encode GPCRs - GOF mutations; uveal nevi are associated w/ these mutations yet rarely transform to melanoma, indicating other involvement of genetic events (ie: loss of chrom 3 which leads to deletion of BAP1)
What is the histo of uveal melanomas
Contain 2 types of cells: spindle (fusiform) and epitheliod (spherical and greater cytological atypicality); distinct feature: looping slit-like spaces lined by laminin that surround packets of tumor cells -> connect to bv and serve as extravascular conduits for transport of plasma and blood (promoted by vasculogenic mimicry); spread exclusively by blood first to liver)
What is the prognosis of choroid and ciliary body melanomas related to
Size (lateral extent), cell type (those containing epithlelioid have worse prognosis), proliferating index
What is the treatment of choice for uveal melanomas
Radiotherapy
What kind of uveal melanomas are more aggressive
Those that are situated in ciliary body and choroid - the iris has milder course
Is the prognosis for uveal melanoma better or worse than cutaneous melanoma
Usually worse
What is the retina a derivative of
Diencephalon
What do hemorrhage of the nerve fiber layer vs the external retinal layers look like
Nerve fiber layer: horizontal flames
External: dots (tips of cylinders)
Where do exudates tend to accumulate in the retina
Outer plexiform layers, especially in the macula
What is retinal detachment
Separation of neurosensory retina from the retinal pigmented epithelium; RPE maintains outer segments of photoreceptors; disturbances of RPE-photoreceptor interface implicated in hereditary retinal degenerations such as retinitis pigmentosa
Is the adult vitreous humor vascular
No, incomplete regression of fetal vasculature can produce persistent hyper plastic primary vitreous (retrolental mass)
What causes “floaters” due to age
Liquification and collapse of vitreous humor
What causes posterior vitreous detachement
Usually due to age, posterior face of vitreous humor called the posterior hyaloid can separate from the neurosensory retina
What is rhegmatogenous retinal detachment
Full thickness retinal defect; retinal tears can happen after vitreous collapses and posterior hyaloid exerts traction on points adhered to retinal internal limiting membrane; liquified vitreous humor seeps into tear and flows in btw retina and RPE; re-attachment requires relief of vitreous traction through indenting the sclera via putting strips of silicon on surface of eye (sclera bulking) and removal of. Vitreous material (vitrectomy)may be complicated by proliferative vitreoretinopathy (formation of epiretinal membranes by Muller cells)
What is non-rhegmatogenous retinal detachment
Retinal detachment without retinal break; may complicate retinal vascular disorders assoc w/ exudation and any condition that damages the RPE and permits fluid to leak from choroidal circulation under the retina; *choroidal tumors and malignant HTN are examples
What does retinal arterioloslerosis look like
Vessels are narrowed and color of blood column may change from bright red to copper or silver; arteriole can compress the vein
What are elschnig spots
Focal choroidal infarcts caused by malignant HTN
What is seen in the macula of ppl w/ malignant HTN
Macular star - spokelike arrangement of exudate in the macula; results from exudate accumulating in the outer plexiform layer that is orientated obliquely
What are cytoid bodies
Occlusion of retinal arterioles produces infarcts of nerve fiber layer of retina; accumulation of mitochondria at swollen ends of the damaged axons creates illusion of cells called cytoid bodies ; seen opthalmoscopically as cotton-wool spots; can develop with HTN or with AIDS
What is a histological marker of DM in the eye
Thickening of BM of the epithelium of pars plicata of ciliary body
What is nonproliferative diabetic retinopathy
Changes resulting from structural and functional abnormalities of retinal vessels; BM of bv is thickened; number of pericytes diminishes; *microaneurysms; breakdown of blood-retinal barrier -> macular edema (vision loss); exudate production;
What is proliferative diabetic neuropathy
New vessels sprouting on surface of optic n (neovascularization of the disc) or the surface of the retina (neovascularization elsewhere) “retinal neovascularization” only used when breaches internal limiting membrane of retina; forms neovascular membrane; if vitreous humor separates can cause massive hemorrhage; scarring can wrinkle retina and produce visual distortion
What is retinopathy of prematurity (retrolental fibroplasia)
At term, lateral (temporal) retinal periphery is incompletely vascularization; in premature infants treated w/ oxygen, retinal vessels constrict and cause ischemia in temporal region; unregulates VEGF leading to angiogenesis; contraction of resulting peripheral retinal neovascular membrane can drag the temporal aspect toward periphery zone, displacing the macula laterally; can cause retinal detachment
What are the types of sickle retinopathy
- nonproliferative (intraretinal angiopathic changes); occurs in patients with hemoglobin SS and SC genotypes; vascular occlusion contributes to hemorrhages, resolution of which gives rise to salmon patches, iridescent spots, and black sunburst lesions; can also lead to angiogenesis which gives risk to “sea-fans” or neovascularization of the periphery
- proliferative (neovascularization)
- common pathway in both types is vascular occlusion
What are hollenhorst plaque
Fragments of atherosclerotic plaques that lodge within the retinal circulation; when infarcted, retina swells and becomes opaque; fungus will appear white b/c the choroid is blocked
What does total occlusion of the central retinal a cause
Diffuse infarcts of the retina; following acute occlusion, retina appears opaque, cherry-red spots seen b/c fovea is thin and choroid is visible
What happens in ischemic retinal v occlusion
VEGF unregulated leading to neovascularization of iris and angle-closure glaucoma; non-ischemic retinal v occlusion leads to hem, exudate, and macular edema, but rarely retinal or iris neovascularization
Where does ganglioside material accumulate in tay Sachs
Retinal ganglion; this blocks transmission of orange-red color of fovea
What is the difference between wet and dry macular degeneration
Wet: neoangiogeneis
Dry: no neoangiogenesis; diffuse deposits in bruch membrane (drusen) and atrophy of the RPE; loss of vision severe
What genes have bee associated with AMD
CFH (complement factor H) - decreases function; excess complement activity plays a role in AMD
What environmental exposures have been linked to AMD
Cigarette smoking and intense light exposure
What is retinitis pigmentosa
Inherited condition resulting from mutations that affect rods and cones or RPE; can cause visual impairment and blindness; NOT inflammatory; x-linked, AR or AD (age of onset correlates with inheritance pattern - AD later in life); can be part of a syndrome (Bardet-Biedl, usher, or refsum dz) or develop in isolation
Mutations in what are linked to retinitis pigmentosa
Genes the regulate the function of photoreceptors or RPE; both rods and cones are lost due to apoptosis ; retinal atrophy is accompanied by constriction of retinal vessels and optic n atrophy (waxy pallor of optic disc) and accumulation of retinal pigment around bv
What pathogens can cause infectious retinitis
Candida (esp in IV drug abuse or systemic candidemia); causes retinal abscesses; CMV in AIDS patients
What is the cell of origin in retinoblastoma
Neuronal progenitor
What can retinoblastoma due to germline mutations be associated with
Pinealoblastoma (trilateral retinoblastoma) *dismal outcome
What is the morphology or retinoblastoma
In both hereditary and sporadic forms, can contain both undifferentiated and differentiated elements (former appear as small, round cells w/ hyperchromatic nuclei); in well-diff tumors, there are flexner-wintersteiner rosettes and fluerettes (photoreceptors differentiation); degree of differentiation does not correlate w/ prognosis; focal zones of dystrophic calcification are characteristic
Where does retinoblastoma spread
Brain and bone marrow
What adversely affects the prognosis of retinoblastoma
Extraocular extension and invasion along the optic n and choroidal invasion
What is a retinocytoma or retinoma
Premalingmant lesions; appearance of RB in one eye and retinocytoma in the other eye is characteristic of heritable RB
What is retinal lymphoma
Aggressive tumor that characteristically involves 2 retinal layers derived from brain (neurosensory retina and RPE); tends to occur in older ppl; spread to the brain occurs via optic n; diagnosis depends on demonstration of lymphoma cells in vitreous aspirates
What are the most common primary neoplasms of the optic n
Gliomas (usually pilocytic astrocytomas) and meningiomas
What is anterior ischemic optic neuropathy (AION)
Includes spectrum of injuries to optic n; optic n cannot regenerate so damage is permanent
What can cause edema of the head of the optic n
- compression of the n (by primary neoplasm -> unilateral disc edema)
- elevations in CSF pressure surrounding the n (b/l disc edema); papilledema
- leads to venous stasis and interferes w/ axoplasmic transport
What does the optic n head look like in papilledema
Swollen and hyper epic; *optic n head in AION appears swollen and pale
What is normal tension glaucoma
Glaucoma w/ normal intraocular pressure;
What is the morphology of glaucomatous optic n damage
Diffuse loss of ganglion cells and thinning of retinal n fiber layer; in advanced cases, optic n is cupped and atrophic (*unique to glaucoma); in infants and children, can lead to enlargement of the eye (buphthalmos) or cornea (megalocornea); in adult, can lead to focal thinning of sclera and uveal tissue may line ecstatic sclera (staphyloma)
What is leber hereditary optic neuropathy
Results from inheritance of mitochondrial gene mutations; neuronal health is dependent on axoplasmic transport of mitochondria; males are affected more; begins with clouding of vision that can progress to total vision loss
What is optic neuritis
Describes loss of vision secondary to demyelinization of optic n *MS most impt cause
What is phthisis bulbi
Eye that is small (atrophic) and internally disorganized; can result from trauma, intraocular inflammation, chronic retinal detachment and other conditions; different from congenitally small eyes (hypoplastic or microphthlamic eyes) b/c they are not disorganized; typically show changes: presence of exudate or blood btw ciliary body and sclera and the choroid and sclera (ciliochoroidal effusion), membrane extending across eye from one part of ciliary body to another (cyclonic membrane), chronic retinal detachment, optic n atrophy, intraocular bone (osseous metaplasia of RPE), thickened sclera (esp posteriorly); low intraocular pressure (hypotony) -> square rather than round eye
What can cause enlargement of the lacrimal gland
Sarcoidosis or neoplasm (lymphoma, pleomorphic adenoma, adenoid cyst)
If germinal cells are present when examining idiopathic orbital inflammation, what should that point you to
Reactive lymphoid hyperplasia
If vasculitis is present when examining idiopathic orbital inflammation morphology, what should that point you to
Systemic condition
If there is necrosis and degenerating collagen w/in vaculitis seen when examining idiopathic orbital inflammation, what should that point you to
Wegener granulomatosis
What do the majority of peripheral n sheath tumors show in terms of differentiation
Schwann cell
What are the types of peripheral nerve sheath tumors
Schwannomas, neurofibromas, malignant peripheral nerve sheath tumor (MPNST)
What are the unique features of peripheral n sheath tumors
Association w/ familial tumor syndromes (NF and schwanomatosis); MPSNT seen in context of NF1 thought to arise from malignant transformation of pre-existing benign plexiform neurofibromas (unusual for soft tissue tumors)
What are schwannomas
Benign tumors that exhibit Schwann cell differentiation and arise from peripheral nerves; component of NF2 (even sporadic assoc w/ loss of NF2 on chrom 22); loss of Merlin (normally restricts production of growth factor receptors)
What is the gross morphology of schwannomas
Well-circumscribed, encapsulated that do not invade nerve; gray
Which serotonin receptor is inotropic
The one in area postrema that triggers vomiting
What is the clinical relevance of Ach
Awareness and memory; RAS
What are the two GABA receptors
A- ionotropic
B- metabotropic
What kind of receptor does glycine have
Only inotropic
What is the composition of CSF compared to blood
Low protein, glucose and potassium; magnesium is higher
What are the circumventricular organs
Area postrema, ovlT and sub-fornical organ, posterior pituitary
What is “awake”
Sleep/wake cycles; volition, consciousness may not be present
What does getting to awake require
Medullary reticular activating system and parabrachial nuclei; glutamate (through thalamus - dorsal path and bypassing thalamus - ventral path)
Describe the characteristics of nociceptors
Bare nerve endings, slightly myelinated (A delta) or unmyelinated (C); activated by bradykinin or substance P -> sensitization
What is the difference between A and C fibers
A - spinothalamic path for fast sharp pain
C: spinoreticulothalamic path for slow dull pain
What does disruption of the lateral geniculate body cause
Inability to move eyes together or focus; also detection of motion and initial processing
What is the job of the primary visual cortex
Create a contour map
What do V2 and v4 do
V2: depth perception
V4: color perception
What is the dorsal versus ventral visual pathway
Dorsal : use of visual info in motion
Ventral: higher cognitive processing using visual info (naming objects)
What is the difference between endo and perilymph
Perilymph similar to ECF (high sodium, low potassium); endo is opposite
What do high pitched sounds do to the basilar membrane
Short wavelengths, high frequency; maximal bending close to oval window
What is the function of the superior olive in hearing
Localization of sound; medial detects intra0=-aural time diff and lateral detects intra-aural volume diff
What do the inferior and superior colliculus do
Inferior: suppresses info from echoes
Superior: creates 3D map of where sound is
What do the utricle and saccule do
Utricle: horizontal motion
Saccule: vertical motion
What do Ia and II fibers in the middle portion of the m spindle do
Ia: sensors length and rate of change
II: just length
What does the brainstem inhibitory region require
Activation by the cortex; if you have damage to cortex, will result in spasticity because cannot activate inhibitory region
What does the spinocerebellum control
Medial: posture
Lateral: correct ongoing motions
What does the vestibulocerebelllum do
Eye movements and postural movements for future motions
What is the direct pathway for motion
Dopamine from substantia Nigra -> D1 receptors -> activates them -> allows motion
What is the indirect pathway of motion
Ach activates GABAergic input; when active it inhibits motion; to inhibit indirect pathway dopamine binds to D2 -> inhibits neuron of indirect pathway
What does Huntington result from in terms of the motion pathways
Loss of indirect pathway results in excessive motio n
What parts of the brain are used in procedural memory
Cerebellum and nucleus accumbens
What is declarative memory
Explicit; conscious recognition of learned facts and experiences; two types: episodic (events) and semantic (words, language and rules)
What is post-tetanic potentiation
High-frequency discharge from pre-synaptic neuron increases changes of action potential in the post synaptic cell
What is long term potentiation
Series of changes in the pre and post synaptic neurons that leads to increased response to released NT; usually follows strong stimulation
What are examples of long term potentiation
-Calcium activating calmodulin -> increases adenylyl Cyclades -> phosphor of AMPA -> increased sodium flux
-calcium binding to calcineurin -> activation of NO synthase -> NO increases cGMP and increases NT release
Also assoc w/ gene transcription with CREB
What are the proteins produced from CREB
NT synthetic enzymes, NT receptors, proteins required for growth/synapse formation
What are the steps of creating declarative memories
Encoding, storage, consolidation, retrieval
What are the structures involved in short term memory
Hippocampus, parahippocampal cortex, prefrontal cortex; also interconnections to neocortex and amygdaloid via nucleus basalis of meynert (cholinergic projection - target in AD)
What is the physiological “substrate” of short term memory
LTP
What does consolidation of memory require
Hippocampus, temporal lobes, papez circuit; hypothalamus/mamm bodies -> anterior thalamus -> cingulate cortex -> hippocampus
What does retrieval of the memory require
Neocortex, parahippocampal regions, hippocampus; info. Related to each component is sent to parahippocampal region -> hippocampus where memory is reconstructed -> cortex via the parahippocampus (***impt in prolonging life of memory)
Where is the central executive located
Prefrontal cortex
Where is the phonological loop located
Brocas and wernickes
Where is the visual spatial loop located
Occipital Cortex associated with vision
Where are detailed memories of space stored
Hippocampus use it pyramidal cells in CA1 known as place cells; anchor for reconstruction of memory; only activated at specific places
What inputs do place cells receive
- Grid cells: entorhinal corex, create map of place you are in; triangular or hexogonal grid
- head direction cell
- border neurons
When are grid cells active
When you are IN an area
What are antoni A and B areas
Seen in schwannomas; A is dense eosinophilia with spindle cells arranged into fascicles; palisading of nuclei is common and nuclear free zones are termed verocay bodies; B loose hypocellular areas, spindle cells spread apart by myxoid ECM
What do schwannomas lacking antoni B mimic
Sarcoma
What are neurofibromas
Benign nerve sheath tumors that are more heterogenous in composition than schwannomas; either NF-1 associated or sporadic
What are the different types of neurofibroma
- superficial cutaneous: present as pedunculated nodules that can be isolated if sporadic or multiple if associated with NF-1
- Diffuse: present as large plaque like elevation of the skin and associated with NF-1
- Plexiform: found in deep or superficial locations in association with nerve roots or large nerves; uniformly NF-1 associated
What are the neoplastic cells in neurofibromas
Schwann cells; only ones that show loss of NF-1
How does neurofibromin work
Tumor suppressor that inhibits RAS activity by stimulating GTPase
What are NF-1 insufficient mast cells hypersensitive to
KIT ligand produced by schwanna cells; in response secrete factors that stimulate schwann cell growth
What is the morphology of localized cutaneous neurofibromas
Small, well-delineated by unencapsulated nodular lesions; arise in dermis and subcutaneous fat; contain schwanna cells, stromal cells (mast), perineurial cells, CD34 spindle cells and fibroblasts
What is the morphology of diffuse neurofibromas
Infiltrates the dermis and subcutaneous connective tissue; entrap fat and appendage structures and produces plaque-like appearance; focal collections of cells mimic appearance of Meissen corpuscles (tactile-like bodies)
What is the morphology of plexiform neurofibromas
Grow within and expand n fascicles; entrap assoc axons; encapsulated appearance; “bag of worms” appearance; contains collagen that looks like “shredded carrot”
What are most malignant peripheral nerve sheath tumors associated with
Larger peripheral nerves in chest, abdomen, pelvis, neck or limb girdle
What is the morphology of MPNST
Marbelized appearance; mitosis, necrosis and nuclear aplasia; poorly defined; *divergent differentiation - presence of focal areas that exhibit other lines of differentiation *Triton tumor: when shows rhabdomyoblastic morphology areas
What is NF-1
AD; associated with neurofibromas, MPNST, gliomas of pitc n, haramartomatous lesions, and pheochromocytoma; mental retardation and seizures; skeletal defects pigmented nodules of iris (lisch) and cafe au lait; LOF in NF-1; neoplastic cells lack neurofibromin; high penetrance but variable expressitivity
What is NF-2
AD; b/l 8th n schwannomas and multiple meningiomas; ependymomas of SC; schwannomas, meningioangiomatosis and glial hamartomas; less common; located on chrom 22; Merlin regulates receptor signaling; nonsense and frameshift mutations more severe than missense.
What is the significance of lower protein in CSF
Less buffering so it senses even small ph changes
What is Wallenberg syndrome
Aka lateral medullary syndrome; alternative hemianelgesia (ipsilateral face and contralateral body); *descending tract of V and spinal nucleus (swallowing difficulty b/c o nucleus ambiguus)
What is Benedict’s syndrome
Lesion to midbrain tegmentum; causes oculomotor palsy, ext strabismus, complete pots is, no spastic hemiplegia; affects AL, TL, and ML; involves red nucleus -> tremor at rest or intention tremor if lesion of cerebellar efferent
What is thalamic syndrome
Weird sensations on 1/2 of body
What is Millard-gubler syndrome
Lesion at pontomedullary junction; internal strabismus (VI), incomplete closure of eye (Bell’s palsy), hemoplegia of opposite limb (corticospinal tract)
What would a lesion to the posterior limb of the internal capsule cause
SNF palsy; hemianalgesia and anesthesia proprioception absence from 1/2 of face and body; spastic hemiplegia
What lesion would cause b/l spasticity and weakness
Paracentral lobule
