Robbins Ch 29- CNS Disorders Flashcards
Define cerebral edema
excess fluid (increased volume) within or around the brain parenchyma
What are the pathogenesis for cerebral edema?
- Vasogenci edema - bleeding within brain due to BBB fails and others
- Cytotoxic edema = cells swell and die due to hypoxia/ischemia or other
- Interstitial - CSF gets squeezed into brain due to obstructive hydrocephalus , faulure of CSF-brain barrier
- Osmotic - brain sucks the water up due to excess water intake or hyponatremia
morphologically how does cerebral edema appear?
gyri flatten, sulci narrow, ventricles get compressed.
What are the major types of herniations due to raised ICP?
Subfalcine herniation
Transtentorial herniation
Tonsilar herniation
What is subfalcine herniation?
Subfalcine herniation = cingulate gyrus.
- unilateral expansion of cerebral hemisphere displaces the cingulate gyrus under the falx cerebri, compressing pericollosal arteries (arteries of corpus callosum) and anterior cerebral circulation
What is transtentorial herniation and what clinical signs?
Aka uncal herniation. Medial aspect of temporal lobe goes through the tentorium cerebelli. CN III compression = ipsilateral pupil dilation and eye paralysis.
- Compression of PCA = infarc of visual cortex
Compression of contralateral penducle = ipsilateral hemiparesis (relative to herniation); called Kernohan’s notch
what is tonsilar herniation and what are some clinical signs?
Aka cerebellum herniation.
- fatal herniation of cerebellum through the foramen magnum. can compress brainstem and lead to death
what are some causes of hydrocephalus?
- increased production, normal outflow = cancer of choroid plexus
- normal production, decreased outflow = ventricular mass/obstruction
- Normal production, decreased resorption = arachnoid impairment
What is communicating hydrocephalus?
enlargement of all the ventricles. Due to functional impairment of the arachnoid granuloations. Can be due to subarachnoid bleed, meningitis, pacchioni granulation (agnesis)
What is noncommunicating hydrocaphlus?
If not all ventricles enlarged. Due to a functional obstruction, usually hemorrhage or tumor. ventricles proximal to obstruction are enlarged, distal are shrunken . it’s common in foramen of monrue
what is hydrocephalus ex vacuo?
Increased volume of CSF from loss of parenchyma. Basically CSF expands to fill in the space left by surgery/degeneration. Seen in tumor resection, Alzheimer’s and other degenerative disease
Neural tube defect has been linked to deficiency in _ in initial weeks of gestation.
Folate
What is anencephaly?
anterior neural tube defect, no brain. incompatible with life, occurring around day 28 gestation.
replaced by area cerebovascuolsa which is a flattened remnant of brain tissue
What is encephalocele?
protrusion of brain through a defect in skull. Protruding part is destroyed by mechanical disruption or ischemia.
What is Spina bifida?
Most common neural tube defect; failure of closure of caudal aspect usually occurring in the lumbosacral region.
Differentiate between oculta, meningocele and myelomeninogcele.
Occulta = no spine closure, Tuft of hair Meningoele = no spine closure, meninges attah to skin, CSF enlarge and bulges, spinal cord normal Myelomeningocele = no spine closure, meninges attach to ski, SCF enlarge and bulges, spinal cord exposed
What are some examples of forebrain abnormalities?
- Lissencephaly/agyria
- Polymicrogyria
- Mega and micro encephaly
- Holoprosencephaly
- Agenesis of the corpus callosum
What is Lissencephaly/Agyria?
“smooth brain”
Thick cortex with the absence of cortical sulci. Gray matter made of 3 layers instead of normal 6. Leads to pscyhomotor retardation + seizures
What is polymicrogyria?
- excessive number of small gyri. Grey matter is composed of 4 layers or less –> retardation + seizures
- can be induced by localized tissue injury during neuronal migration.
What are some common associated risk factors of microencaphly?
fetal alcohol syndrome, chromosomea abnormalities, HIV.
Migration dependent on chemical and physical signals that can go awry altering size and structure of brain parenchyma. Trapped bundles of migrating nurons is called neuronal heterotopias.
What is Holoprosencephaly?
Failure of cerebral hemisphere to separate = one giant lobe.
- associated with diabetic moms, trisomy 13, sonic hedge hog.
- can produce one ventricle, one nostril and one eye and other less severe events.
What is the cause of agenesis of corpus collaosum and what is the consequence?
- absence of white bundle fibers connecting the hemispheres, replaced by adipose tissue.
- mutation of L1 cell adhesion molecule. (neuronal migration)
- can be radiologically demonstrated as bat-wing ventricles.
What are some diseases associated with posterior fossa malformation?
- Arnold-chiari malformation
2. Dandy-Walker malformation
What is Arnold-chiari malformation?
- small posterior fossa + mishapen cerebellum + vermis of cerebellum extending throguh foramen magnum (herniation)
- associated with hydrocephalus and lumbar myelomeningocele
multple types, type II is the most common
What is dandy-walker malformation?
A type of posterior enlarged fossa malformation + absent ecrebellar vermis + midline cyst. Cyst is expanded 4th ventricle that usually is restricted by vermis. Dysplasia of brain stem is common, pt presents with mental retardation
What is Syringomyelia and hydromyelia?
Either an expansion of the central canal of the cord (hydromeylia) or the formation of a cleft-like cavity in the inner portion of the cord (syringomyelia).
- usually occurring in the cervical vertrbrae these compress and damage nearby nerves, essentially eating a functional hole from the inside out.
- Associated with arnold-chiari malformation, traumatic injuries, spinal tumors.
- symptoms occurring in a cape-like fashion
- destroys the anterior spinal commissure then ascending ALS fibers.
What is the significance of intraparenchymal hemorrhage/Germinal matrix hemorrhage?
Germinal matrix is present only in the fetal and neonatal brain around the ventricles. Hypoxia/ishcmia during delivary can cause bleeding in this region. It’s dividied into 4 grades: G1 = germinal matrix only. G2 = germinal matrix + ventricles w/o hydrocephlaus/dilation
G3= germinal matrix + ventricles with hydrocephalus
G4 = germinal matrix + ventriclces + parenchyma
what is periventricular leukomalacia?
infarcts occurring in white matter near to the ventricles, esp in premature babies.
- chalky yellow plaques consisting of discrete regions of white matter necrosis and mineralization (calcification)
What is multicystic encephalopathy?
Extensive version of periventricular leukomalacia involving both gray and white.
- Large cystic lesions throughout both hemisphere
- peirventricular leukomalacia = white matter only, small lesion
- multicystic encephalopathy = grey and white, large cystic lesions
What is ulegyria?
Ischemic injury occurring in cerebral cortex resulting in thinned-out gliotic gyri termed ulegryia
-Mushroom-shaped gyri
What is status marmoratus?
- basal ganglia and thalamus suffer ischemic injury and result in neuronal loss and reactive gliosis
- Later, with myelination, aberrant and irregular myelin formation gives rise to a marble-like appearance of the deep nuclei
What are some signs and symptoms of a basal skull fracture?
- occurs from occiput or lateral damage (fall of a ladder)
- symptoms = lower CN + cervicomedullary defects
- Get battle sign (swelling and discoloration of the mastoid) and raccoon eyes. (periorbital ecchymosis, aka double black eyes)
Clinical syndrome of altered mental status following a change in the momentum of the head. This is a type of parenchymal injury known as _
concussion
What transient neurologic dysfunction are common with concussion that usually recovers completely.
loss of consciousness, loss of reflexes, and a persistent amnesia
What are two types of direct parenchymal injury?
Contusion - brain bruise
Laceration - penetration of an object into the tissue
what is coup and ontracoup injuries?
they are direct parenchymal injuries such as contusions and laceeration. Coup is injury at the site of impact. contracoup is injury at the opposite of the point of impact. Contracoup injury is usually injury to the brain when the head was in motion.
In epidural hematoma: A. what artery? B. What side of brain? C. how does it appear on CT? D. what is the progression?
A. MMA
B. temporal trauma
C. lens, ellipical
D. Clinically lucid interval just prior to rapid progression to death
In subdural hematoma A. between what laters does it form? B. What vessel is involved? C. Which vessels are at highest risk in elderly? D. how does it appear on CT?
A. between dura and subarachnoid
B. Bridging veins and dural sinuses
C. Superior sagital sinus
D. Crescent
What are some sequelae of brain trauma?
- Post traumatic hydrocephalus from ventricular outflow obstruction
- Post traumatic dementia - comes from repeated, protected injury showing diffuse axonal injury, thinning of corpus callosum, and positive alpha beta fibers (AD)
- Others include epilepsy, tumors, infections and psychiatric disorder
What are the three major categories of causes of cerebrovascular disease?
- Stroke
- Vascular malformation
- HTN changes
What are two main types of stroke?
- Ischemic
2. hemorrhagic
In ischemia, which CNS cells die first?
neurons in the hippocampus CA1
For each of the following signs, indicate whether it’s coma vegetative state or brain death.
- positive reflexes, breathing, EEG, and negative consciousness
- Positive reflexes and breathing, but negative EEG
- negative reflexes, and breathing, but positive heartbeat
- Coma
- Vegetative state
- Brain death
Morphologically, in a global cerebral ischemia indicate the changes seen 12-24hrs, 24hrs- 2weeks, and 2 weeks and beyond.
Early changes: 12-24 horus: red neurons
Subacute changes: 24hrs-2 weeks: necrosis, macrophages, vascular proliferation, gliosis
3. 2 weeks and beyond = removal of necrosis, gliosis completed, loss of CNS architecture
What are watershed infarcts? Give example
- wedge-shaped infarcts at regions distal to vascular supply, often between two areas of perfusion = border zone.
- Particular form of infarct associated with hypoperfusion (opposite to blockage or bleed)
- example is between anterior and middle cerebral zone. There is no collateral circulation between these
During an infarction from obstruction,
A. how long till irreversible cell death?
B. Which receptors are responsible for cell death due to Ca influx after an ischemic event?
C. Which component of CNS is MOST susceptible?
A. 4-6 minutes
B. GLutamate activating NMDA receptors
C. peripheral gray matter
Due to atherosclerosis, Which CNS arteries are most susceptible for thrombosis?
Carotid bifurcation, MCA and Basilar artery
CNS arteritis is associated with which infectious disease?
- symphilis or TB
- oppotunistic infection with CMV, aspergillus, Toxoplasmosis
CNS primary angiitis is due to_
inflammation + giant cells in small to large arteries
What is cerebral amyloid angiopathy?
- Alzheimer’s protein Abeta deposits in vessels which weakens walls and increases risk of hemorrhage. ApoE has been linked to CAA and Alzheimer’s
What are the common causes of Focal cerebral ischmeia?
- Thrombosis - atherosclerosis
- Arteritis - infection
- Primary angiitis - inflammation
- Cerebral amyloid angiopathy - Alzheimers
Cerebral embolism is usually arrived from _
heart, mural embolis.
What are shower emboli?
Fat emboli that disperse and go all over the place, resulting in multiple, diffuse infarcts.
What is the most common cause of intracerebral (intraparenchymal) hemorrhage?
Hypertension. Causes hyaline changes in arterioles, sometimes with frank necrotization of the arterioles.
What is charcot-bouchard Microaneurysm and where do they usually occur?
They are a form of intracranial hemorrhage, minute hemmrhages cuased by HTN, appear in region supplied by small penetrating arteries especially in basal ganglia
Most commonly intracranial hemorrhage originates in what part of the brain?
Putamen
What are some common signs of intracranial hemorrhage?
- increased intracranial pressure
- headache,
nausea
projectile vomitting
-focal lesions
What is the most common cause of subarachnoid hemorrhage?
Rupture of a berry saccular aneurysm.
Subarachnoid hemorrhage due to ruptured saccular aneurysm is highly associated with what other genetic disorders?
- Autosomal dominant polycystic kidney disease
- Marfan’s or Ehler’s Danlos
- Coarctation of aorta
Saccular aneurysm are usually located in what portion of circle of willis?
Anterior circulation
What are some common vascular malformations?
- Arteriovenous malformation
- Cavernous hemangioma
- Capillary Telangectasis
- Venous angiomas (aggregates of venous channels)
What is arteriovenous malformation and what are some signs and symptoms?
It is a form of vascular malformation where arteries are connected to veins without an intervening capillary bed. They resemble a tangled worms with prominent, pulsatile, high flow AV shunt. They cause Seizures and hemorrhages
What is cavernous hemangioma? What are some signs and symptoms
Distended, loosely organized, low flow vasculature with thin collaginized walls devoid of intervening nervous tissue. They usually occur in cerebellum, pons, subcortex.
Causes seizures and hemorrhage.
What were capillary telangectasis usually occur?
Usually in the pons. It’s essentialy hemaniomas with inerveningbrain parenchyma. Usually asymptomatic
What are some common hypertensive vascular diseases?
- Hypertensive cerebral hemorrhage
- Lacunar infarcts
- Slit Hemorrhage?
- Hypertensive encephalopathy
Relating to Lacunar infarcts:
A. what is it caused by?
B. Where they do they usually occur?
A. HTN affecting the blood vessels that supply the basal ganglia and white matter developing arteriolar sclerosis that may become occluded. Forms small, multiple, cavitary infarcts
B. Thalamus, internal capsule, deep white, caudate, and pons. Caused by occlusion of small penetrating arteries in these regions
What is slit hemorrhage?
When HTN causes a hemorrhage due to rupture of small penetrating arteries. Grossly, when the when hemorrhage resolve, they leave slit like cavities. Microscopically they appear with focal tissue destruction, pigment-laden macrophages, and gliosis
What are some signs and symptoms of hypertensive encephalopathy?
- Dementia, loss of function, gait defects
- cerebral dysfunction, headache, confusion, vomitting, coma
Which artery is most vulnerable of embolic cerebral infarcts?
Middle cerebral artery
Which regions of the brain are most affected by hypotensive watershed infarcts?
Deep cortical areas such as hippocampus CA1, cerebellar purkinje, cortical pyramidals
Categorize thrombolic and embolic cerebral infarcts based on morphology
Thrombotic: nonhemorragic/white/pale infacts
Embolic: hemorrhagic/red infarcts
What is the most common artery that is ruptured in subarachnoid hematoma caused by ruptured berry aneurysm?
Anterior communicating artery
A subfalcine herniation can compress anterior cerebral artery causing visual disturbances on which side, Ipsi/contralateral?
Contralateral side.
A patient presents with pupillary dilation and paralysis of extraocular muscles; visual deficits; hemiparesis. On CT small linear of bleeding is seen around midbrain and upper pons. What is the most likely diagnosis?
Transtentorial (uncal) herniation
What are the two main types of acute meningitis?
- Acute pyogenic meningitis = Bacterial
2. Acute aseptic meningitis = viral
What organism is known to cause acute pyogenic meningitis? Categorize by age group
Neonates = E coli, graph B strep Adolescents = N. Meningiditis with possible pandemic spread Elderly = strep pneumo and Lissteria monocytogenes .
Strep Pneumo is most common overall
What are some clinical signs of meningitis?
headache, photophobia, neck stiffness, confusion.
In an acute pyogenic meningitis, describe how spinal tap findings would look.
Cloudy, purulent, increased pressure CSF with neutorphils. INCREASED proteins and decreased glucose
In an acute aseptic meningitis, describe how CSF findings would look
Normal sugar, increased protein, no purulence in CSF.
What is the most common causative agent of aseptic meningitis?
Enterovirus: echovirus, coxsaievirus, nonpralytic polio
What are some common conditions associated with focal supparative infections?
- Brain abscess
- Subdural empyema
- Epidural abscess
Morphologically, how is brain absces described?
descrete lesions with central liquefactive necrosis surrounded by a fibrous capsule found within brain parenchyma.
what are the most common causative agents and route of spread to cause brain abcess?
Most common cause is strep and staph. those cause endocarditis and infects lungs (bronchiectasis) and they can spread to brain. Also can spread due to R–> L shunts
what is subdural empyema and how is it spread?
Emergent collection of pus between dura and arachnoid. infected bones or hair spread to the dural space; arachnoid is spared. Can produce mass effect or spread into veins causing occlusion and infarction.
Epidural abscess is associated with infection of what?
Osteomyelitis. Pott’s Puffy tumor can lead to osteomyelitis.
What are the common diseases categorized as chronic bacterial meningocephalitis?
- Tuberculosis
- Neurosyphilis
- Lyme disease
Explain the CNS manifestation of tuberculosis
- found at the base of the brain
- May cause mass effect from tuberculoma
- may cause obliterative endarteritis leading to infarction
- May cause arachnoid fibrosis leading to hydrocephalus
What are the manifestations of neurospyhilis
- Meningovascular neurosyphilis = obliterative endarteritis usually occurring at the base of the brain or the spinal cord
- Paretic neurosypholis = dementia from damage to frontal lobe
- Tabes Dorsalis = demyelination of the DCMLS, loss of proprioception, vibratory sense, and complete ataxia
What neurological symptoms are associated with lyme disease?
Facial Nerve palsy, aseptic meningitis, mild encephalopathy
CNS manifestation of herpes simplex virus include what symptoms?
- alternations in mood, memory, behavior,
What lobe of brain is typically affected by herpes simplex virus?
Temporal lobe and orbital gyri with nectoizing hemorrhage.
Cowdry Type A, intranuclear inclusion, perineuclear halo, and nuclear molding are all morphologic findings of CNS infection by what ?
Herpes simplex
What viruses are known to cause meningocephalitis?
- Arthropod Borne (western/eastern, equine, St. Louis, La Crosse, West Nile)
- Herpes Simplex 1 and 2
- Varicella zoster
- CMV
- Polio
- Rabies
- Progessive multifocal leukoencephalopathy
- Subacute sclerosing panencephalitis
An previously unimmunized kid, presents with cognitive decline, spasticity of the limbs and seizure. On studies, it was found to have oligodendrocytic viral inclusion, demyelination, neurofibrillary tangles. What is the most likely diagnosis? and what is the likely organism?
Subacute sclerosing panencephalitis, caused by untreated measles
Pt presents with diaphragmatic paralysis. Studies shows infection of oligodendrocytes, leading to progressive demyelination as the virus replaces nucleus with a viral inclusion
Progressive multifolcal leukoencephalophaty (PML) caused by JC virus
Pt presents with hypersensitivity to pain, then contracture with the inability to swallow, and finally coma. Studies showed severe encephalitis that was likely transmitted by by the bite of animal. Pt was diagnosed rabies. What are you like to see on pathology? and where do the virus colonize?
Morphology; Negri bodies; eosinophilic cytoplasmic inclusions in the pyramidal cells. Colonizes Cerebellum and hippocampus
Pt dies due to diaphragm paralysis. You find out that pt have had gastroenteritis, and later developed neurological symptoms including paralysis. On exam, you find neurophagia of motor neurons of the ventral horn. What is the likely diagnosis /
Poliomyelitis.
A HIV patient, presents with severe neurological deficts. Exams show necrotizing hemorrhage of ventricles and choroid plexus. Further, intranulcear inclusion with perinuclear halo was found inside singular enormous cells. What agent is the likely cause of the patients presentation
CMV
What ganglion is affected with varicella zoster?
Dorsal root ganglion.
Pt presents with alteration in mood, memory, and behavior. On imaging studies, nectorizing hemorrhage was seen in temporal lobe and orbital gyri. Further studies shows cowdry Type A intranuclear inclusions, perinuclear halo, and nuclear molding.
Herpes simplex 1 and 2.
Which fungal infection is associated with vaculitis and hemorrhagic infarcts?
Mucor and aspergillus
Which fungal infection is associated with parenchymal invasion with microabscesses?
Candida and cryptococcus
Local pandemics that have been associated brain invasion is caused by which fungal infections
Blastomycosis, histoplasmossi, coccidiodes
which of the following is known to occur in diabetic ketoacidosis? A. Mucor B. Aspergillus C. Candida D. Toxoplasmosis?
A. mucor
Which of the following is known to cause multiple hemorrhagic lesions? A. Cryptococcus B. Candida C. Mucor D. Aspergillus
D. Aspergillus
Which version of neurosyphilis is known to cause frontal lobe defect, dementia and is commonly known as crazy syphilis?
Paretic
In transmissible spongiform encephlopathy, conformational change in the PrP _ to _ activates the protein
a-helix to beta-sheet. Activated prion is PrPsc
The genetic link, on chromosome 20, _ gene increase risk of PrPsc formation.
PRNP gene
PRNP gene alteration that which increase risk of PrPsc formation shows a change from _ amino acid to _ amino acid at codon 129
Met to Val
Microscopically, prion disease will show a transformation of _b_matter in the cerebral cortex, sometimes found in deep gray structures (caudate/putamen).
a. Spongiform.
b. gray
Microscopically, prion disease will show what morphological changes?
- neuronal loss, reactive gliosis, cyst-like vacuoles in advanced cases.
A 75 year old man returns to his doctors office for a follow up after a corneal transplant. He complains of some memory loss recently and some involuntary jerks. What is likely within the next 7 months?
Patient has Creutzfeldt-Jakob disease. It is likely that he will have rapidly progressively dementia with death within 7 months.
CJD is known to have iatrogenic transmission.
In varient CJD, what is the age population affected, what is the progression rate and how is it different from CJD?
Younger patients affect with slower progression and clinical course. But the symptoms are the same as the regular CJD. There is no PRNP mutation and it’s pandemic is limited to UK
This form of prion disease has a slower progression rate like vCJD but with a PNRP mutation (like CJD). On morphology you’ll see spongiform + PrPsc plaque and neurofibrillary tangles. Death is likely within years.
Gerstman-straussler-Scheinker
This form of prion disease starts off with insomnia followed by ataxia, stupor, coma and eventually death. The neuronal loss is seen in which part of the brain?
THis is fatal familail insomnia. The neuronal loss is in thalamus.
Multiple Sclerosis is defined as _
an autoimmune demyelinating disorder characterized by distinct neurologic deficits separated by time, caused by white matter lesions separated in space.
Genetic predisposition of MS is linked to _ haplotype.
DR2 HLA
in MS, the autoimmune response is against _
myelin antigens.
Explain the autoimmune reaction that leads to destruction in MS
CD4 TH1s starts the process via IFN-y; macrophages/CD8 do most of the damage. Demyelination occurs as a result of macrophages.
Clinically how does MS presents?
- Relapsing and remitting disease with gradual partial recovery of neurologic function with a gradual loss of function.
- symptoms are highly variable though optic nerve spinal cord and MLF are classically affected in full MS (vision disturbance, extremity weakness)
In the CSF of MS patients what are you likely to see and what is it due to?
increased IgG due to B cell proliferation
paraventricular “gray matter” is pathognomonic for what demyelinating disease?
MS
What are some variant forms of MS?
- Neuromyelitis optica = asians, bilateral optic neuritis, relentlessly destruction.
- Marburg MS = younger patients, fulminant in months, fatal in a year
what is the pattern of paralysis seen in Guillan-Barre syndrome?
ascending paralysis. Starts off at their toes and finishes at death due paralysis of the diaphgram
Guillan-Barre syndrome usually is followed by _ due to infections by _.
Respiratory or GI illness, by infection by C. Jejuni, and CMV.
What are the two virus induced acute demyelinating disease?
- Acute disseminated encephalomyelitis (ADEM)
2. Acute necrotizing hemorrhagic encephalomyelitis (ANHE)
ADEM is usually followed by?
viral infection or rarely viral immunizatoin. Symptoms begin 1-2 weeks after infection, are global, resemble meningitis
ADEM is usually followed by_
Upper respiratory infection in kids and adolescents
Describe the micro and macroscopic findings seen in acute necrotizing hemorrhagic encephalomyelitis
Macro = grayish discoloaration of white matter; multiple global lesions that can become one large lesion Micro = destruction of blood vessels, perivenular demyelination, inflammatory infiltrate and hemorrhage
What demyelination diseases are metabolically induced?
- Central pontine myelinosis
2. Subacute combined degeneration (B12 deficiency)
Patient became quadriplegic that rapidly progressed after his hyponatremia was corrected. what is the likely diagnosis?
Central pontine myelinosis. EtOH, electroyltes and osmolar imbalances have also been implicated.
What two population is subacute combined degeneration most likely seen in?
- long term strict vegans
2. pts with autoantibodies to intrinsic factor (pernicious anemia)
How does subacute combine degeneration present and progress?
Initially it presents as loss of vibration and proprioception ending in spastic paraplegia, ataxia and impairment of sensory modalities. Usually targets the dorsal columns medial meniscus system and corticospinal tract in the thoracic and cervical region evidenced by distention then degeneration of myelin sheaths and loss of axons
Metachromatic leukodystrophy is an autosomal recessive deficiency in _
arylsulftase which accumulates myelin lipid “sulfate” and kills oligodendroyctes and schwann cells, causing loss of myelin
What is the clinical signs of metachromatic leukodystrophy?
Childhood disease that is asymotomatic until age 1-2 and then shows progressive peripheral neuropathy, blindness, retardation, and adult dementia.
What is the pathogenesis of adrenoleukodystrophy?
X-linked mutation in the peroxisome protein ALD (ABCD1 family of proteins), a mitochondrial disease. without ALD, VLCFA cannot be transported into peroxisome and accumulates. VLCFA causes myelin breakdown and adrenal atrophy
What are the clinical signs of adrenoleukodystrophy?
adrenal insufficiency first, followed by neurological symptoms. Death occurs in a few years from onset of neurologic symptoms.
what is the pathogenesis of Krabbe’s disease?
Autosomal recessive deficiency of lysosomal beta-galactocerebrosidase. Accumulation of toxic psychosine, a side metabolite of galactosylphingosine which is normally not produed. pscyhosine is toxic to neurons and myelin.
how does krabbe’s disease present in Children and adult?
Children: seizure, feeding problems, vision problems, death
Adults = limb weakness, spastic parapersis, vision problems, dementia
Which of these is not a demyelinating disease? A. MS B. Guillan-Barre C. ADEM D. ANHE E. Central Pontine Myelinosis F. Subacute combined degeneration G. Metachromatic leukodystrophy H. Adrenoleukodystorphy I. Krabbe's disease
A through F is demyelinating
G-I are dysmelinating
A progressive degnerative disease of the cerebral cortex caused by accumulation of abnormal proteins, demonstrable as plaques and tangles is defined as what disease?
Alzheimer’s
What are the amyloid precursor protein that which leads to AD/
amyloid precursor protein (APP) and beta amyloid (Abeta)
which form of secretase when APP is cleaved leasd to the insoluble protien, A42 and leads to the extracellular aggregates called plaques or fibrils as seen in AD?
beta secretase.
Beta pleated sheaths as seen in AD can be stained with _
Congo red
_ has y-secretase acivity and such abberrant activation of this may also contribute to formation of Abeta42 and generation of plaques
Presenilin-1
How does AD present clinically?
- Insiduous onset, time course is approximately 10 years from onset to death.
- Cerebral atrophy, severity is increased with passage of time.
- Memory (short term then long term), logic and math, motor skills (incontinence, walking, fine motor) will be lost
- Death is usually due to secondary source like Pneumonia
What is a possible treatment of AD such which slows progression but is not curative?
Acetyl-choline agonists
_ are dilated, tortuous, silver staining neuritic processes (dystrophic neurites) surrounding a central amyloid core as seen in AD is most often found in what brain structures?
hippocampus and amygdala.
In what cells are neurofibrillary tangles as seen in AD commonly found?
THey are found in the cytoplasm of cortical pyramidal neurons
What causes the neurofibrillary tangles?
Hyperphosphorylated state of a microtubule associated protein called tau. Tau aggregates while microtubules fall apart; tau aggregates are insoluble, producing “ghost tangles’ that persist after neuron dies, in the classic flame shape seen on silver stain and H&E.
What are hirono lesions?
Granulovascular degeneration, vauoles within the neurons in a granular pattern. Seen in AD pts brain
What cerebral degeneration diseases are linked to tau pathology?
- AD
- Frontotemporal dementia with Chromosome 17. aka Pick disease
- Progressive supranuclear palsy
- Corticobasal degeneration (CBD)
What is Frontotemporal Lobar dementia (FTLD)
Dementia accompanied by frontal and temporal cerebral atrophy, caused by mutation in the tau gene.
How many tau repeats are seen in the mutated tua that which leads to FTLD?
4 repeat tau mutation
What is Pick disease?
Associated with FTLD-tau. rare, distinct, progressive dementia found in sporadic cases. Shows frontopolar atrophy severely accompanied by language involvement. Neuronal loss is severe in the outer three layers of cortex.
On histology, brilliantly stained with silver but not on H&E, Pick bodies were found. What is the diagnosis?
FTLD. seeing Pick bodies distinguishes FTLD from AD.
The risk of development of this disease is increased with specific tau haplotype, however, tau mutation is not seen. Pt presents with trunchal rigidity, ocular disturbances, abnormal speech, and nuchal dystonia describe this disease that causes progressive dementia and is fatal within5-7 years. Loss of vertical gaze and ataxia is also seen.
A. what is the disease
B. the loss of neurons are mainly seen in what part of the brain?
A. Progressive supranuclear palsy (PSP)
B. Midbrain structures such as globus, subthalamic nucleus, substantia nigra, cerebellum
This risk of develop of this disease is increased with specific tau haplotype althought no tau mutation is seen. pts presents with extrapyramydal rigidity, asymmetric jerking movements (alien hands),, with dementia. Cortical atrophy of motor, premotor, and sensory region are seen. What is the diagnosis?
Corticobasal degeneration (CBD)
This is a cerebral dementia that is not linked with tau. typically present in stepwise degradation rather than a gradual decline and are associated with strategic infarcts, which allow for significant loss of function. what is the diagnosis?
Vascular dementia. Vasculitis is a particular cause of vascular dementia that causes occlusion, stroke, and dementia and responds to therapy.
Parkinsonism is caused by
nigrostriatal dopamanergic system.
Clinically how is parkinsonism charactered?
diminished facial expression, stooped posture, slow movements, cog-wheel rigidity, pill-rolling tremor, and festinating gait (shuffling gait)
Presence and progression of parkinsonism without a toxic or underlying defect, is defined as
Parkinson’s disease
In parkinson’s disease, the loss of substantia nigra as seen in parkinsonism progresses to what anatomic brain location?
striatum.
Parkinson’s disease is primarily attributed to the decrease or absence of dopamine in what location?
Striatum
Although, a strong link between a particular protein mutation and parkinson’s disease has not been linked, there are some links to 1 gene mutation/duplication or mutations in 2.
- alpha-synuclein
2. parkin
_ is an elicit drug that have been used to study parkinson’s disease in mice.
MPTP
Diagnosis of Parkson’s disease is confirmed at autopsy by the presence of _
Lewy Bodies that may be associated with dementia, especially in advancing age. Lewy bodies are filamentous projections of protein a-synuclein or ubiquitin present in surviving neurons and can be found in cortex
alpha synuclein inclusion have been associated with what disease, that which is not mutated as seen in parksinson’s disease
Multiple system atrophy which is an overarching nomenclature that now includes 5 prevously distinct diseases all with alpha synuclein includsion but without mutations of a-syncluein as in PD.
Morphologically, how is multiple system atrophy diagnostic?
Degeneration of midbrain structures such as cerebellum, pons and peduncles and the presence of a-synuclein inclusions.
Parkinsonism, cerebellar ataxia, autonomic failure are all associated with what neurodegenerative disease?
Multiple system atrophy
APP, PS1 and PS2 are genetic causes associated with what disease?
AD
Tau, TDP-43, progranulin, C9orf72 and FUS all are associated as genetic causes of what disease?
FTLD
Huntington is a degenerative disease of the 1 and _ 2_ caused by an autosomal dominant inheritance of trinucleotide repeat 3 in the 4 gene which results in 5 and 6 and which demonstrates 7.
- Caudate
- putamen
- CAG
- Huntington gene (chromosome 4)
- Chorea
- Dementia
- Anticipation
What is the pathogenesis of Huntingtons Disease?
There is loss of inhibitory signal on motor output tha tpermits inappropriate spastic movement realized as jerky chorea.
Explain the mechanism by which motor output is increased as seen in Huntingon
Subthalamic nucleus (SN) is the final output and inhibition of movement. Striate is normally inhibitory to the globus pallidus (GP). GP is inhibitory to SN. So with degeneration of the striate neurons, there is decreased striate signal which then leads to decreased inhibition of GP and so GP signal increases and thus the inhibition of SN increases. Thus decrease in the SN signal then leads to decreased inhibition of movement leading to increased motor output
In Huntington, hydrocephalus ex vacuo is seen in which ventricle?
3rd ventricle. Caudate nucleus is dramatically atrophied, with accompanying atrophy of the putamen, cortex.
In what decade of life does Huntington Disease commonly present, and what symptoms present first?
Seen around 4-5th decade of life and presents with motor problems and then dementia.
What are the two most common spinocerebellar degeneration disorders?
- Friedreich’s Ataxia
2. Ataxia Telangiectasis
There are many different types of spinocerebellar ataxias based on inheritance patterns. They all involve some degeneration of _
cerebellum (progressive ataxia), brainstem, spinal cord, and peripheral nerves
A 5 year boy becomes wheelchair bound due to loss of vibratory sense and proprioception (DCMLS) and occasional loss of pain and temp and with absence of deep tendon reflex. He now presents to a cardiologist to get this consistent arrhythmia checked out. This disease is an autosomal recessive, GAA trinucleotide repeat in the _ 1_gene coding for 2 on chromosome 9.
- FXN gene
- Fratxin
Diagnosis: Friedreich’s ataxia
Friedreigh’s ataxia is considered both a degenerative disease and a metabolic encephalopathy because _
Fataxin is a mitochondrial matrix protein, thus when mutated shows presents with metabolic issues
True or Flase: In Friedreigh’s ataxia, neurons are degenerated while axons are are spared.
False. There is loss of both neurons and axons from all elements of nervous system as well as myocytes in the heart.
In Friedreigh’s ataxia, which nerves are degenerated?
There is degeneration of DCMLS, Dorsal roots, cerebellar peduncles and atrophy of peripheral nerves
In ataxia-telangiectasis, where is the mutation?
it’s autosomal recessive disease caused by mutation of the cell cycle protein ATM on chromosome 11 which normally orchestrates response to DS DNA break.
How does Ataxia-Telengiectasia present morphologically?
CNS, similar to Freidrich’s with preference for the cerebellum.
- Nuclei of cells in many organs show bizarre nuclear enlargemnt.
What are some clinical signs of ataxia-telaniectasia?
proliferative vessel proliferation and dilation on skin of the face, arms, torso as well as within the conjunctiva of the eye.
- lymph nodes, thymus and gonads are hypoplastic.
At around what decade does ataxia telangiectasia usually present
2nd
Pts with ataxia telangiectasia are at increased risk of infection, why?
They are immunocompromised from hypoplastic thymus/lymph nodes.
Pts with ataxia telangiectasia are at risk of developing what neoplasm?
lymphoid malignant disease like leukemia/lymphoma
An autosomal dominant mutation of superoxide dismutase resulting in degeneration of both lower and upper motor neurons with NO sensory deficits is defined as what disease?
ALS
In ALS, what destroys the neurons/axons and glia/myelin?
Toxic products of superoxide dismutase
Describe the early, mid, and late progression of ALS.
Early = weakness of hands, cramping, inability to perform fine motor
Mid: atrophy of muscles, weakness, spasticity (Upper + lower)
Later = complete paralysis (lower predominates)
What is bulbospinal atrophy?
AKA Kennedy syndrome. It is X linked adult onset disease characterized by distal limb amyotrophy and bulber signs such as fasiculation of the tongue.
What causes Bulbospinal atrophy?
An expansion of trinucleotide CAG repeat in adrogen receptor
what are the clinical findings of bulbospinal atrophy?
- adrogen insensitivity
- gynocomastia
- testicular atrophy
Vitamin B12 deficiency can lead to _
loss of sensation and possible spastic paralysis. seen in vegans.
An alcoholic, who seems to be sober today was brought to the clinic by his son who states that he has recently be showing changes in mood and behavior even when he’s sober. He seems to ramble on with logic in thought. What is the likely diagnosis?
Vitamin B1 deficiency due to chornic alcoholism.
Acute, reversible disease with psychotic symptoms termed Wernickles encephalopathy. If it persists chronic, irreverisble disease of memory loss and confabulation sets in termed Korsakoff syndrome.
What is the most common CNS tumors?
Meningiomas and Glioblastoma Multiforme (grade 4 astrocytoma)
In general, what are some signs and symptoms of a CNS tumor?
- headache that is worse at night and when awakening
- seizures when cortex is involved
- Focal neurologic symptoms related to location of growth
- increased intracranial pressure (herniation, hydrocephlaus, edema)
Location of tumor can be predicted by age of onset. In general where are childhood tumors located? adult tumors?
In kids it’s int he posterior fossa (cerebellum)
in adults it’s in the anterior fossa (cortex)
Fibrillary astrocytomas when it gets to grade 4, it’s called 1 and is characterized by 2
- Glioblastoma
2. Increased cellularity+atypia+mitoses+ vascular proliferation
This ring enhancing CNS tumor has rows of anaplastic cells lined up and around a region of central necrosis, called pseudopalasading necrosis, glomeruloid vascular proliferation and death occurs within 1 year becuase it is difficult to resect and unresponsive to chemo
Glioblastoma multiforme
this benign tumor usually occurs in kids around posterior fossa that is pretty amenable to resection. On MRI and histo it can be diagnosed by the presence of _
This is pilocytic astrocytoma. diagosed by presence of rosenthal fibers and is characterized by cystic lesion connected to a mural nodule seen on MRI
This tumor is usually seen in middle aged patients and its a lesion on white matter that does not cross corpus. Blood vessels has a chicken wire apearance and appears fried-egg ish with a perinulear clearing. What is the prognosis?
this tumor described is oligodendroglioma. It is a slow-growing tumor with decent prognosis (5-10 years) though they tend to recur.
Microscopically, these tumors appear as rosettes around a central lumen and perivascular pseudorosettes which origininate around central blood. In kids which ventricle is a common location of it’s growth?
Described is an ependymoma, in kids they grow in the CSF in 4th ventricle and in adult they grow in lateral ventricle or spinal canal.
Since ependymomas are free floating CSF, they may cause _ and may embolize down the spinal column
hydrocephalus
Meningiomas are derived from what cells?
Meningothelial cells of the arachnoid
in what age group and gender does meningiomas usually occur?
Tumors occur in adulthood, men more often than women.
Does meningioma usually invade brain parenchyma?
NO, it’s literally attached to the dura and does not invade. that is why it’s amenable to resection
Presence of cellular whorls + psammoma bodies is pathognomonic for _
Meningioma
The most frequent location of schwannomas is _
8th cranial nerve, called acoustic neuromas. patient presents with hearing disturbances tinnitus
histologically this tumor shows areas of hypercellularity (Antoni A region) mixed with areas of hypocellularity (antoni B regions). further more there are also verocay bodies and express S-100.
Schwannomas
What is the prognosis of schwannoma?
There is good prognosis with surgical resection
