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Transcript
Reactions of neurons to injury
- acute neuronal injury (“red neurons”) = acute CNS hypoxia/ischemia
- subacute & chronic neuronal injury (“degeneration”) from progressive dz
process; seen in ALS
- axonal rxn is regen. of the axon; best seen in anterior horn cells of spinal cord
when motor axons are damaged
- neuronal inclusions
o aging – lipofuscin
o herpetic infection – cowdry body in nucleus
o rabies – Negri body in cytoplasm
o CMV – nuclear & cytoplasmic inclusions
o Alzheimers – neurofibrillary tangles
o Parkinson’s – Lewy bodies
Reactions of astrocytes to injury
- astrocytes act as metabolic buffers & detoxifiers in brain
- gliosis = most important indicator of CNS injury; hypertrophy + hyperplasia
- gemistocytic astrocytes
- Alzheimer type II astrocyte (mainly in pts w/ longstanding hyperammonemia
from liver dz)
- Rosenthal fibers in areas w/ longstanding gliosis & characteristic for pilocytic
astrocytoma
- Alexander Dz = leukodystrophy assoc. w/ mutations in gene encoding GFAP;
abundant Rosenthal fibers
- corpora amylacea (polyglucosan bodies)
- Lafora bodies in cytoplasm of neurons in myoclonic epilepsy
Reactions of other glial cells to injury
- oligodendrocytes & ependymal cells not in active response to CNS injury
- oligodendroglial cells
o injury/apoptosis is feature of acquired demyelinating disorders &
leukodystrophies
o glial cytoplasmic inclusions (α-synuclein) are found in oligodendrocytes
in multiple system atrophy
- ependymal cells
o inflammation can cause ependymal granulations
o CMV may produce extensive ependymal injury w/ viral inclusions
Reactions of microglia to injury
- microglia = fixed macrophage system in CNS
- proliferation
- development of elongated nuclei
- formation of aggregates about small foci of tissue necrosis (microglial
nodules)
- congregation around cell bodies of dying neurons (neuronophagia)
- blood-derived macrophages = main phagocytic cell in inflammatory foci
Cerebral edema
- vasogenic edema – BBB disruption & increased vascular permeability
- cytotoxic edema –  intracellular fluid due to neuronal, glial, or endothelial
cell membrane injury (hypoxic/ischemic insult or metabolic damage)
- hydrocephalic edema (interstitial edema) – occurs esp. around lateral
ventricles
- generalized edema = flattened gyri, sulci narrowed, herniation may occur
Hydrocephalus
- accumulation of excessive CSF in ventricular system
- most due to impaired flow & resorption of CSF (overproduction is RARE
cause)
- communicating vs. noncommunicating
- hydrocephalus ex vacuo – dilation of ventricular system  compensatory
increase in CSF volume; due to loss of brain parenchyma
Raised intracranial pressure
- mostly assoc. w/ mass effect
- may cause reduced perfusion of brain
Herniations
- subfalcine (cingulate)
o cingulate gyrus displaced under falx cerebri
o may compress branches of ACA
- transtentorial (uncinate, mesial temporal)
o medial aspect of temporal lobe compressed against free margin of
tentorium
o CN III compromised  pupillary dilation, impairment of ocular
movements on side of lesion
o PCA may be compressed
o Kernohan’s notch = when contralateral cerebral peduncle compressed
due to large herniation
o progression can lead to 2 brainstem (Duret) hemorrhages;
linear/flame-shaped lesions in midline
- tonsillar
o displacement of cerebellar tonsils through foramen magnum
o life-threatening
Neural tube defects
- encephalocele – diverticulum of malformed CNS tissue extending through
defect in cranium; MC in occipital region or posterior fossa
- MC NTD involve spinal cord caused by failure of closure of caudal portions of
neural tube
- spinal dysraphism (spina bifida)
- spina bifida occulta = asymptomatic bony defect
- myelomeningocele = extension of CNS tissue through defect in vertebral
column
o MC in lumbosacral region
o motor & sensory deficits in LE & bowel/bladder control disturbances
- meningocele = only meningeal extrusion
- anencephaly = malformation at anterior end of neural tube; no brain &
calvarium; only remain is area cerebrovasculosa
- polymorphisms in enzymes of folic acid metabolism
-  AFP during pregnancy
Forebrain anomalies
- megaloencephaly or microencephaly (MC)
o chromosome abnormalities
o FAS
o HIV-1 inf. in utero
- lissencephaly (agyria)
o mutation in microtubule-assoc. protein LIS-1
- polymicrogyria
o can be induced by localized tissue injury
- neuronal heterotopias
o migrational disorders
o assoc. w/ epilepsy
o collections of neurons along ventricular surfaces
- holoprosencephaly
o incomplete separation of cerebral hemispheres across midline
o midline facial abnormalities (cyclopia)
o trisomy 13
o mutations in SHH
- agenesis of corpus callosum
o bat-wing deformity
Posterior fossa anomalies
- Dandy-Walker malformation
o enlarged posterior fossa
o cerebellar vermis absent
o large midline cyst lined by ependymal  expanded, roofless 4th
ventricle
- Arnold-Chiari malformation (Chiari II)
o small posterior fossa
o misshapen midline cerebellum w/ downward extension of vermis
through foramen magnum
o hydrocephalus & lumbar myelomeningocele
- Chiari I malformation
o low-lying cerebellar tonsils extend into vertebral canal
o may be silent or may obstruct CSF flow & medullary compression
Syringomyelia, hydromyelia
- hydromyelia
o expansion of ependymal-lined central canal of the cord
- syringomyelia, syrinx
o fluid-filled cleftlike cavity in inner portion of the cord
o may extend into brainstem (syringobulbia)
o may be associated with Chiari I malformation
o may occur with intraspinal tumors or after trauma
o isolated loss of pain & temp. sensation in UE
o cape-like distribution
Perinatal brain injury
- cerebral palsy
o nonprogressive neurologic motor deficit
o combo of spasticity, dystonia, ataxia/athetosis, paresis
o insults during prenatal & perinatal periods
- intraparenchymal hemorrhage w/in germinal matrix
o premature infants
o near junction of thalamus & caudate nucleus
o may lead to hydrocephalus
- periventricular leukomalacia
o infarcts in supratentorial periventricular white matter
o especially in premature
o chalky yellow plaques
- multicystic encephalopathy
o both gray & white matter involved by extensive ischemic damage
o large destructive cystic lesions throughout hemispheres
- ulegyria
o thinned-out gliotic gyri
o perinatal ischemic lesions of cerebral cortex damage depths of sulci
- status marmoratus
o aberrant myelinization from ischemic injury of basal ganglia & thalamus
o marble-like appearance of deep nuclei
Trauma
Skull fractures
- displaced skull fracture
o bone is displaced into cranial cavity by a distance greater than thickness
of the bone
- basal skull fracture
o impact to occiput or sides of head
o CSF discharge from nose or ear; meningitis may follow
- diastatic
o fractures that cross sutures
Parenchymal injuries
- concussion
o clinical syndrome of altered consciousness secondary to head injury
typically brought about by a change in momentum of head
o instant LOC
o temporary respiratory arrest
o loss of reflexes
o amnesia for the event
o post-concussive neuropsychiatric syndromes
- direct parenchymal injuries
o contusion (bruising)
 wedge shaped
 edema/hemorrhage
 evidence of neuronal injury in about 24 hrs
o laceration (penetration and tearing of tissue)
o crests of gyri most susceptible
o coup /contrecoup
o plaque jaune
 old traumatic lesions on surface of brain
 depressed, retracted, yellowish brown patches involving crests of
gyri
 most commonly located at sites of contrecoup lesions
 can become epileptic foci
- diffuse axonal injury
o widespread, sometimes asymmetric axonal swellings that appear within
hours of injury and may persist longer
o can affect deep white matter regions of brain
Traumatic vascular injury
- epidural hematoma
o middle meningeal a. tear from temporal skull fractures
o torn vessel cause dura to separate from inner surface of the skull
o lucid interval
- subdural hematoma
o bridging veins
o elderly and infants at risk
o lysis  growth of fibroblasts into hematoma  early development of
hyalinized CT,
o fresh clotted blood on brain surface; underlying brain flattened
o chronic subdural hematomas = repeat episodes of bleeding (greatest
risk after 1st hemorrhage)
o most common over lateral aspect of cerebral hemispheres
o B/L 10%
o headache/confusion
- subarachnoid and intraparenchymal hemorrhages often occur together
- traumatic tear of carotid a. where it traverses the carotid sinus may lead to
formation of AV fistula
Sequelae of brain trauma
- post-traumatic hydrocephalus from block of CSF resorption from hemorrhage
into subarachnoid spaces
- post-traumatic dementia & punch-drunk syndrome (dementia pugilistica) from
repeated head trauma
- hydrocephalus, thinning of corpus callosum, diffuse axonal injury,
neurofibrillary tangles, diffuse amyloid β-positive plaques
- others: post-traumatic epilepsy, meningiomas, infectious diseases, psychiatric
disorders
Spinal cord trauma
- lvl of lesion determines extent of neurologic manifestation
- in time, central necrotic lesion becomes cystic & gliotic
Hypoxia, ischemia, infarction
- penumbra = region of transition between necrotic tissue and normal brain; “at
risk” tissue
Global cerebral ischemia
- hypotension, hypoperfusion, low-flow states (MI, shock)
- hierarchy of sensitivity among CNS cells: neurons are most sensitive
- selective vulnerability
- border zone (“ watershed”) infarcts
o occur in regions that lie at distal reaches of arterial blood supply
o between ACA and MCA at greatest risk (causes sickle-shaped band of
necrosis)
o usually seen after hypotensive episodes
- morphology:
o brain swollen
o early changes (red neurons) subacute changes (necrosis,
macrophages, vascularization, reactive gliosis)  repair (removal of
necrotic tissue, gliosis)
o pseudolaminar necrosis = uneven destruction of neocortex,
preservation of some layers and involvement of others
Focal cerebral ischemia
- adequacy of collateral flow important
- major source of collateral flow is circle of Willis
- little collateral flow for deep penetrating vessels (supply thalamus, basal
ganglia, and deep white matter)
- majority of thrombotic occlusions are due to atherosclerosis
- MC sites of infarction:
o carotid bifurcation
o origin of MCA
o either end of basilar a.
- emboli come from mural thrombi, MI, valvular dz, and AFib
- MCA most frequently affected by embolic infarction
- infectious vasculitis from immune suppression & opportunistic inf
- primary angiitis of CNS
o inflammatory disorder of multiple vessels
o chronic inflammation
o multinucleated giant cells; granulomas
o destruction of vessel wall
o cognitive dysfunction
- hemorrhagic (red) infarct
o from embolic events
- nonhemorrhagic (pale, bland, anemic) infarct
o from thrombosis
- spinal cord infarction
o may occur from hypoperfusion or from interruption of feeding
tributaries from the aorta
Hypertensive cerebrovascular disease
Lacunar infarcts
- single, multiple, small, cavitary infarcts due to arteriolar sclerosis in deep
penetrating arteries that supply white matter & brain stem
- lake-like spaces
- lenticular nucleus, thalamus, internal capsule, deep white matter, caudate
nucleus, and pons
Slit hemorrhages
- rupture of small-caliber penetrating vessels  development of small
hemorrhages
- leave behind slitlike cavity surrounded by brownish discoloration
Hypertensive encephalopathy
- malignant HTN
- diffuse cerebral dysfunction
- HA, confusion, vomiting, convulsions, coma
- increased intracranial pressure
- vascular (multi-infarct) dementia
o dementia, gait abnormalities, pseudobulbar signs, superimposed focal
neurologic defects
o Binswanger disease = loss of large areas of white matter
Intracranial hemorrhage
Intracerebral (intraparenchymal)
- middle to late adult life
- most caused by rupture of small intraparenchymal vessel
- HTN is most common underlying cause
- Charcot-Bouchard microaneurysms = minute aneurysms from chronic HTN
most commonly in basal ganglia
- most commonly originate in putamen
- cerebral amyloid angiopathy (CAA)
o amyloidogenic peptides deposit in walls of medium/small meningeal &
cortical vessels  weakening  hemorrhage
o vessels appear stiff; no fibrosis; uniform deposits of amyloid present
- cerebral AD arteriopathy w/ subcortical infarcts & leukoencephalopathy
(CADASIL)
o rare hereditary stroke
o mutation in Notch3 receptor
o recurrent strokes and dementia
o abnormalities of white matter and leptomeningeal arteries (concentric
thickening of media & adventitia)
Subarachnoid hemorrhage/ruptured saccular aneurysms
- saccular (berry) aneurysm rupture = most common cause of subarachnoid
hemorrhage
- saccular aneurysm = most common intracranial aneurysm
- 90% of saccular aneurysms are near major arterial branch points in anterior
circulation
- most sporadic; ADPKD, Ehlers-Danlos syndrome type IV, neurofibromatosis
type I (NF1), Marfan syndrome
- smoking and HTN risk factors
- 5th decade; females more frequent
- “worst headache of my life”
Vascular malformations
- arteriovenous malformations (AVM)
o MC malformation
o vessels in subarachnoid space
o wormlike vascular channels
o prominent, pulsatile AV shunting with high blood flow
o enlarged BVs separated by gliotic tissue
o males > females; 10-30 years
o seizure disorder, intracerebral hemorrhage, or subarachnoid
hemorrhage
o MCA most common (post. branches)
- cavernous malformation
o distended, loosely organized vascular channels w/ thin collagenized
walls
o no intervening nervous tissue
o most often in cerebellum, pons, subcortical regions
o no AV shunting
o familial common
- capillary telangietasias
o microscopic foci of dilated, thin-walled vascular channels
o separated by normal brain parenchyma
o most frequently in pons
- venous angiomas (varices)
o aggregates of ectatic venous channels
o Foix-Alajouanine disease (angiodysgenetic necrotizing myelopathy) = in
spinal cord overlying meninges; lumbosacral region; slowly progressing
neuro symptoms
Infections
- principal routes of spread of microorganisms into CNS
o hematogenous spread (MC)
o direct implantation
o local extension
o transport along peripheral NS (viruses)
Acute meningitis
- inflammatory process of leptomeninges and CSF w/in subarachnoid space
- meningoencephalitis combines this w/ inflammation of brain parenchyma
- acute pyogenic (bacterial)
o neonates – E. coli, GBS
o elderly – S. pneumonia, Listeria monocytogenes
o adolescents – N. meningitidies
o HA, photophobia, irritability, clouding of consciousness, neck stiffness
o cloudy, purulent CSF, increased pressure, increased protein, reduced
glucose
o Waterhouse-Friderichsen syndrome = meningitis associated septicemia,
hemorrhagic infarction of adrenal glands, cutaneous petechiae; common
with meningococcal/pneumococcal meningitis
o pus tracts along BVs
o chronic adhesive arachnoiditis = pneumocaoccal meningitis causes
accumulations of capsular polysaccharide  gelatinous exudate 
arachnoid fibrosis
- aseptic (viral)
o less fulminant
o lymphocytic pleocytosis, moderate protein elevation, glucose normal
o chemical meningitis and rupture of epidermoid cyst into subarachnoid
space
Acute focal suppurative infections
- brain abscess
o acute bacterial endocarditis  multiple abscesses
o congenital <3 disease
o chronic pulmonary sepsis (bronchiectasis)
o immunosuppression
o streptococci and staphylococci are most common
o progressive focal defecits, raised ICP, raised CSF pressure, raised WBC,
raised protein, normal glucose
- subdural empyema
o bacterial/fungal infection of skull bones or air sinuses can spread to
subdural space
o mass effect
o thrombophlebitis in bridging veins  venous occlusion  infarction of
brain
o febrile, HA, neck stiffness
- extradural abscess
o osteomyelitis
o sinusitis
o surgical procedure
Chronic bacterial meningoencephalitis
- Tuberculosis
o gelatinous or fibrinous exudate at base of brain
o mostly diffuse meningoencephalitis
o obliterative endarteritis (may cause infarction of brain)
o acid-fast stains
o single or multiple tuberculoma (mass effect)
o HA, malaise, mental confusion, vomiting
o protein elevated, glucose low/normal
o arachnoid fibrosis (may produce hydrocephalus)
- neurosyphilis (T. pallidum)
o tertiary stage
o HIV increased risk
o meningovascular neurosyphilis
 chronic meningitis at base of brain
 obliterative endarteritis (Heubner arteritis)
 cerebral gummas in meninges
o paretic neurosyphilis
 insidious
 mental deficits (mood swings, delusions of grandeur)
 may terminate in severe dementia (general paresis of insane)
 granular ependymitis
o tabes dorsalis
 damage to sensory nerves in dorsal roots
 impaired joint position sense  locomotor ataxia
 loss of pain sensation (skin, joint damage, Charcot joints)
 “lightning pains”
 absence of DTR
 loss of axons and myelin in dorsal roots (pallor/atrophy in dorsal
columns)
o combo of tabes dorsalis + paretic neurosyphilis most common
(taboparesis)
- lyme disease (Borrelia)
o transmitted by Ixodes tick
o neuroborreliosis
Viral meningoencephalitis
arthropod-borne viral encephalitis
o West Nile in spinal cord  polio-like syndrome with paralysis; elevated
CSF pressure
o meningocytic encephalitis
o neuronophagia
o microglial nodules
o some viruses make inclusion bodies
o generalized neurologic defecits: seizures, confusion, delirium, stupor,
coma, focal signs, reflex asymmetriy, ocular palsies
- HSV 1
o MC in children and young adults
o alterations in mood, memory, and behavior
o involves:
 inferior & medial regions of temporal lobes
 orbital gyri in frontal lobes
o necrotizing hemorrhagic infection
o Cowdry type A intranuclear viral inclusion bodies in neurons and glia
- HSV 2
o meningitis in adults and neonates from birth
o with HIV may cause acute hemorrhagic, necrotizing encephalitis
- VZV (herpes zoster)
o shingles
o may be persistent postherpetic neuralgia syndrome after 60
o granulomatous arteritis
- CMV
o inf. in fetus and immunocomrpomised
o inf. in utero
 periventricular necrosis
 microcephaly
 periventricular calcification
o immunocompromised
 commonly in HIV
 subacute encephalitis
 CMV-inclusion bearing cells
 choroid plexitis
 painful radiculoneuritis
- Poliomyelitis
o mononuclear cell perivascular cuffs
o neuronophagia of anterior horn motor neurons of spinal cord
o inflammatory rxn limited to anterior horns
o flaccid paralysis, muscle wasting, hyporeflexia in corresponding region
of body
o myocarditis
o post-polio syndrome
 25-35 years after resolution of illness
 progressive weakness
 decreased muscle mass and pain
- Rabies
o intense brain edema and vascular congestion
o most severe in brainstem
o Negri bodies
o incubation period = 1-3 months
o clinical = extraordinary CNS excitability, hydrophobia, flaccid paralysis,
alternating mania and stupor  coma & death
- HIV
o only microglia have the right combo of CD4 and CCR5 or CXCR4 to be
infected by HIV
o microglial nodules
o multinucleated giant cell
o HIV-associated dementia
- progressive multifocal leukoencephalopathy (PML)
o viral enceohalitis from JC polyomavirus
o infects oligodendrocytes = demyelination
o immunosuppressed individuals (reactivation)
o glassy amphophilic viral inclusions
o bizarre giant astrocytes
- subacute sclerosing panencephalitis (SSPE; measles)
o cognitive decline, spasticity of limbs, seizures
o children or young adults after infection with measles
o altered measles virus
o viral inclusions
o neurofibrillary tangles
o measles virus antigen positive
Fungal meningoencephalitis
- hematogenous dissemination
- 3 patterns:
o chronic meningitis
 Cryptococcal meningitis
 common in HIV/AIDS
 CSF  protein
 mucoid-encapsulated; can be seen from India ink prep
 affect basal leptomeninges
 obstruct CSF outflow  hydrocephalus
 “soap bubbles” in basal ganglia
 expanded perivascular (Virchow-Robin) spaces
o vasculitis
 mucormycosis & aspergillosis
 hemorrhagic infarction
o parenchymal infection
 granulomas or abscesses
 coexists w/ meningitis
 Candida and Cryptococcus
 Candidiasis causes multiple microabscesses
Other infections
- cerebral amebiasis
o Naegleria causes rapidly fatal necrotizing encephalitis
o Acanthamoeba causes chronic granulomatous meningoencephalitis
- toxoplasmosis
o opportunistic
o common in HIV-related immunosuppression or maternal inf.
o multiple ring-enhancing lesions
o brain abscess in cerebral cortex
o Giemsa stain
Transmissible spongiform encephalopathis (Prion diseases)
- prion protein (PrP) is infectious & transmissible
- causes spongiform change from intracellular vacuoles in neurons & glia
- most pts develop progressive dementia
Creutzfeldt-Jacob disease (CJD)
- MC prion disease
- rapidly progressive dementia
- mostly sporadic; familial forms have mutations in PRNP
- subtle changes in memory and behavior  progressive dementia
- startle myoclonus, ataxia
- fatal 7 mo. from onset
- spike wave complex on EEG
- Kuru plaques = extracellular deposits of aggregated abnormal protein usually
in cerebellum
- CJD variant
o affects young adults
o more slowly
o extensive cortical plaques with surrounding halo of spongiform change
o no alteration in PRNP gene
Fatal familial insomnia (FFI)
- sleep distubances in initial stages
- mutation in PRNP gene
- lasts fewer than 3 years
- ataxia, autonomic disturbances, stupor, coma
- no spongiform pathology
- neuronal loss and reactive gliosis in anterior ventral and dosromedial nuclei
of thalamus
Demyelinating diseases
Multiple sclerosis
- MC demyelinating disorder
- autoimmune
- distinct episodes of neurologic deficits separated in time; attributable to white
matter lesions that are separated in space
- women twice as men
- immune response against components of myelin sheath
- multiple, well-circumscribed, depressed, glassy, irregular-shaped plaques
- active plaque = ongoing myelin breakdown
o pattern I = sharp demarcated, centered on BVs, deposition of Ig and
complement
o pattern II = sharp demarcated, centered on BVs, no deposition of Ig and
complement
o pattern III = less demarcated, not centered on BV, widespread
oligodendrocyte apoptosis
o pattern IV = less demarcated, not centered on BVs, central
oligodendrocyte apoptosis
- inactive plaque = no myelin
- shadow plaque = border between normal & affected white matter
- clinical:
o U/L visual impairment (optic neuritis, retrobulbar neuritis)
o brainstem involvement
 cranial nerve signs
 ataxia
 nystagmus
 internuclear ophthalmoplegia
o spinal cord lesions
 motor & sensory impairment of trunk and limbs
 spasticity and difficulties with bladder control
o CSF
 mildly elevated protein
 1/3 have pleocytosis
 oligoclonal bands
Neuromyelitis optica (Delvic disease)
- B/L optic neuritis and spinal cord demyelination
- white cells in CSF
- antibodies to aquaporins
Acute disseminated encephalomyelitis (ADEM)
- diffuse, monophasic demyelinating disease after a viral infection or
immunization
- HA, lethargy, coma, rapid clinical course
- all lesions appear similar (monophasic)
- may be autoimmune rxn to myelin
Acute necrotizing hemorrhagic encephalomyelitis (ANHE)
- fulminant syndrome of CNS demyelination
- young adults and children
- after upper respiratory infection
- much more severe than ADEM with destruction of small BVs
- hyperacute variant of ADEM
Central pontine myelinosis
- loss of myelin in roughly symmetric pattern involving basis pontis
- associated with rapid correction of hyponatremia
- monophasic nature
Degenerative diseases
- diseases of gray matter
- progressive loss of neurons
- presence of protein aggregates that are resistant to degradation through the
ubiquitin-proteasome system (seen as inclusions)
- dementia is not normal aging; always a pathologic process
Degenerative diseases affecting cerebral cortex
Alzheimer disease (AD)
- MC cause of dementia in elderly
- most cases are sporadic, 10% familial
- insidious impairment of higher intellectual function; changes in mood &
behavior
- eventually become disabled, mute, and immobile
- cortical atrophy
- neuritis (senile) plaques
o Aβ40 and Aβ42 protein is in the amyloid core of the plaque
- diffuse plaques made of Aβ42
- neurofibrillary tangles
o flame shape in pyramidal neurons
o globose tangles in rounder cells
o resistant to clearance in vivo  “ghost” or “tombstone” tangles long
after death of neuron
- abnormally phorphorylated protein tau
- neuropil threads (helical filaments not specific to AD)
- cerebral amyloid angiopathy (CAA)
o Aβ40
o granulovacuolar degeneration
o Hirano bodies
- deposition of Aβ peptides derived through processing of APP (on chromosome
21)
- forgetfulness, memory disturbance, language deficit, loss of math skills, loss of
learned motor skills
Frontotemporal dementias (FTD)
- group of disorders with:
o progressive deterioration of language & changes in personality
o degeneration and atrophy of temporal and frontal lobes
- 1) frontotemporal dementia with Parkinsonism linked to Tau mutations
o FTD with Parkinson’s symptoms
o mutations in MAPT gene encoding tau
o atrophic regions of cortex have tau-containing neurofibrillary tangles
o 4R tau or mix of 3R and 4R tau
o inclusions can be seen
- 2) Pick disease
o lobar atrophy
o early onset of behavioral changes with changes in personality &
language disturbances
o most are sporadic; some linked to familial mutated tau
o lobar atrophy prominent  wafer-thin “knife edge” gyri
o B/L atrophy of caudate nucleus and putamen
o Pick cells, pick bodies
o 3R tau
- 3) progressive supranuclear palsy
o truncal rigidity with disequilibrium and nuchal dystonia
o pseudobulbar palsy and abnormal speech
o ocular distrubances
o males, 50-60s
o MAPT polymorphisms
o contain 4R tau
- 4) corticobasal degeneration
o disease of elderly
o basal ganglia dysfunction
o “ballooned” neurons (neuronal achromasia)
o Tau immunoreactivity “tufted astrocytes” “coiled bodies”
o “astrocytic plaques”
o mostly 4R tau
o extrapyramidal rigidity, jerking of limbs, apraxias, language disorders
o MAPT polymorphisms
- 5) frontotemporal dementia without tau pathology
o tau-negative
o ubiquitin-containing inclusions in superficial cortical layers in temporal
and frontal lobes (FTD-U)
o mutation in gene for progranulin
Vascular dementia
- various etiologies:
o widespread areas of infarction
o diffuse white-matter injury
Degenerative diseases of basal ganglia and brainstem
- assoc. w/ movement disorders (rigidity, abnormal posturing, chorea)
- reduction of voluntary movement or abundance of involuntary movement
Parkinsonism
- diminished facial expression, stooped posture, slowness of voluntary
movements, festinating gait, rigidity, “pill-rolling” tremor
- damage to nigrostriatal dopaminergic system
- dopamine antagonists and toxins
Parkinson disease
- Dx: progressive L-DOPA-responsive signs of parkinsonism (tremor, rigidity,
and bradykinesia)
- pallor of substantia nigra
- Lewy bodies (composed of α-synuclein)
- juvenile PD caused by mutation of parkin (Lewy bodies are absent)
- pesticide exposure is a major risk factor
- autonomic dysfunction common, some cognitive impairment
- L-DOPA treatment very effective but decreases as disease progresses
Dementia with Lewy bodies
- Lewy bodies in wide range of cortical locations
- contain predominantly α-synuclein
- Lewy neurites
Multiple system atrophy (MSA)
- glial cytoplasmic inclusions in cytoplasm of oligodendrocytes
o contain α-synuclein (but not mutation in the gene like PD)
- MSA-P = dominant parkinsonism
- MSA-C = cerebellar dysfunction
- MSA-A = autonomic dysfunction
Huntington disease
- AD; progressive movement disorders and dementia
- degeneration of striatal neurons
- Jerky hyperkinetic dystonic movements (chorea)
- polyglutamine trinucleotide repeat expansion diseases
o HD gene encodes protein huntingtin w/ CAG repeats
o longer repeats = earlier onset
o anticipation (next generation will have earlier onset)
- atrophy of caudate nucleus
- onset in 40-50s
- increased & involuntary jerky movements all over body
- writhing movements of extremities
- progression to severe dementia
- intercurrent infection is MC cause of natural death
Spinocerebellar degenerations (spinocerebellar ataxias)
Friedreich ataxia
- AR; progressive illness
- begin in 1st decade of life w/ gait ataxia
o hand clumsiness and dysarthria
o DTRs depressed or absent; extensor plantar reflex present
o joint position & vibratory sense impaired
o wheelchair-bound within 5 years of onset
- pes cavus, kyphoscoliosis common
- CV problems:
o cardiac arrhythmias & CHF common
o heart enlarged with pericardial adhesions
- cause of death is pulmonary infection or cardiac disease
- expansion of GAA repeat on frataxin protein
o causes mitochondrial dysfunction
- spinal cord
o loss of axons and gliosis in post. columns
o degeneration of neurons in spinal cord, brainstem, cerebellum, and Betz
cells of motor cortex
Ataxia-Telangiectasia
- AR
- ataxic-dyskinetic syndrome beginning in early childhood
- telangiectasias in conjunctiva and skin
- immunodeficiency
- ATM gene mutated
- sensitivity to x-ray induced chromosome abnormalities
- increased risk of CA (esp. breast)
- predominant abnormality in cerebellum
- degeneration of dorsal column, spinocerebellar tract, and anterior horn cells
- cells in many organs have bizarre enlargement of nucleus (amphicytes)
- death early (2nd decade)
- recurrent sinopulmonary infections and unsteadiness in walking
Degenerative diseases affecting motor neuron
Amyotrophic lateral sclerosis (ALS)
- loss of LMN + UMN
- men > women (slightly)
- 5th decade or later
- familial cases sometimes caused by GOF of SOD1 on chromosome 21
- rapid course
- rarely has UMN signs
- anterior roots of spinal cord are thin
- bunina bodies
- clinical:
o asymmetric weakness of hands (dropping objects, difficulty w/ fine
motor tasks)
o cramping/spasticity of legs & arms
o fasciculations
o eventually involve respiratory muscles  pulmonary inf.
- progressive muscular atrophy = LMN loss predominates
- progressive bulbar paly (bulbar ALS) = early/rapid degeneration of lower
brainstem cranial motor nuclei
Bulbospinal atrophy (Kennedy syndrome)
- X-linked adult onset disease
- distal limb amyotrophy & bulbar signs (atrophy & fasciculations of tongue;
dysphagia)
- androgen insensitivity, gynecomastia, testicular atrophy, oligospermia
- expansion of CAG/polyglutamine repeat in androgen receptor
Spinal muscle atrophy
- mainly LMN in children
- selective loss of anterior horn cells & atrophy of anterior spinal roots
Genetic metabolic diseases
Neuronal storage diseases
Neuronal ceroid lipofuscinoses
- inherited lysosomal storage diseases
- accumulation of lipofuscin
- combo of blindness, mental & motor deterioration, and seizures
- infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL or
Kuf) disease
Tay-Sachs disease
- begins early in infancy
- developmental delay
- paralysis and loss of neuro fxn
- death after several years
Leukodystrophies
Krabbe disease
- AR
- galactocerebroside β-galactosidase (galactosylceramidase) deficiency
- accumulation of galactocerebroside
- rapidly progressive; onset at 3-6 mo.
- motor signs: stiffness, weakness, difficulty feeding
- loss of myelin in brain and oligodendrocytes in CNS
- aggregation of globoid cells
Metachromatic leukodystrophy
- AR
- deficiency of lysosomal enzyme arylsulfatase A
- accumulation of sulfatides (esp. cerebroside sulfate  myelin breakdown)
- late infantile form = MC
- motor symptoms; progress gradually; death in 5-10 yrs
- adult form show psychiatric or cognitive symptoms before motor symptoms
- demyelination w/ resulting gliosis
- membrane-bound vacuoles contain complex crystalloid structures of
sulfatides
- metachromatic material in urine
Adrenoleukodystrophy
- variably progressive disease
- myelin loss from CNS and peripheral nerves + adrenal insufficiency
- X-linked form presents in early school years; rapidly fatal
- adult form usually slowly progressive; predominant peripheral nerve
involvement
- mutations in ALD gene
- inability to metabolize very-long-chain FAs in peroxisomes
Pelizaeus-Merzbacher disease
- X-linked; invariably fatal
- begin in early childhood or right after birth
- slowly progressive
- early signs: pendular eye movements, hypotonia, choreoathetosis, pyramidal
signs
- later signs: spasticity, dementia, ataxia
- myelin nearly completely lost in cerebral hemispheres
o patches remaining give “tigroid” appearance
- gene duplication = MC mutation
Canavan disease
- megalocephaly, severe mental deficits, blindness
- white matter injury signs in early infancy
- progress to death within a few years
- spongy degeneration of white matter
- accumulation of N-acetylaspartic acid from LOF of deactylating enzyme
aspartoacylase
Alexander disease
- megalencephaly, seizures, progressive psychomotor retardation
- white matter loss in frontal  occipital gradient
- accumulation of Rosenthal fibers around BVs characteristic
- mutation in GFAP
Vanishing-white-matter leukodystrophy
- mutations in genes encoding any of 5 subunits of eukaryotic initiation factor
2B (EIF2B)
- insidious; 1st few years of life
- ataxia and seizures common
Mitochondrial encephalomyopathies
Mitochondrial encephalopathy, lactic acidosis, strokelike episodes (MELAS)
- MC neurologic syndrome caused by mitochondrial abnormalities
- recurrent episodes of:
o acute neurologic dysfunction
o cognitive changes
o evidence of muscle involvement w/ weakness & lactic acidosis
- areas of infarction w/ vascular proliferation and focal calcification
- mutations in tRNA
Myoclonic epilepsy and ragged red fibers (MERRF)
- maternally transmitted
- myoclonus, seizure disorder, evidence of myopathy
- ataxia (loss of neurons from cerebellar system)
- mutations in tRNA
Leigh syndrome (subacute necrotizing encephalopathy)
- early childhood
- lactic academia, psychomotor development arrest, feeding problems, seizures,
extra-ocular palsies, weakness w/ hypotonia
- death in 1-2 yrs
- multifocal, symmetric areas of destroyed brain tissue
- spongiform appearance & BV proliferation
- nuclear & mitochondrial DNA mutations
Kearn-Sayre syndrome
- “opthalmoplegia plus”
- sporadic
- large mitochondrial DNA deletion/rearrangement
- cerebellar ataxia, progressive external ophthalmoplegia, pigmentary
retinopathy, cardiac conduction defects
- spongiform change in gray & white matter
- neuronal loss mostly in cerebellum
Alpers disease
- neuro symptoms + hepatic dysfunction
- hepatitis & bile duct proliferation
- begins in first few years of life
- severe seizures, developmental delay, hypotonia, ataxia, cortical blindness
- neuronal loss in cerebral cortex & deeper structures
- spongiform degeneration of gray matter
Toxic and acquired metabolic diseases
Vitamin deficiencies
- thiamine (vitamin B1) deficiency
o seen in chronic alcoholism, gastric disorders, carcinomas, chronic
gastritis, persistent vomiting
o beriberi can cause cardiac failure
o Wernicke encephalopathy
 psychotic symptoms or abrupt opthalmoplegia
 hemorrhage & necrosis in mamillary bodies & walls of 3rd and 4th
ventricles
 macrophage infiltration  cystic space w/ hemosiderin-laden
macrophages
o Korsakoff syndrome
 caused by prolonged untreated condition
 memory disturbances and confabulation
- vitamin B12 deficiency
o causes anemia
o neuro symptoms = numbness, tingling, slight ataxia in LE (may progress
to spastic weakness of LE)
o swelling of myelin layers, producing vacuoles
o combined degeneration of both ascending and descending tracts of
spinal cord (subacute combined degeneration of spinal cord)
Neurologic sequelae of metabolic disturbances
- hypoglycemia
o selective injury to large pyramidal neurons of cerebral cortex
- hyperglycemia
o MC in inadequately controlled DM
o ketoacidosis or hyperosmolar coma
o dehydration, confusion, stupor, coma
o must be corrected gradually to prevent cerebral edema
- hepatic encephalopathy
o cellular response mostly glial
o Alzheimers type II cells
Toxic disorders
- carbon monoxide
o result of hypoxia
o selective injury of neurons of layers III and V of cerebral cortex, Sommer
sector of hippocampus, and Purkinje cells is characteristic
o B/L necrosis of globus pallidus
- methanol
o affects retina; may cause blindness
o formate (metabolite of methanol) may play role
- ethanol
o Wernicke-Korsakoff syndrome
o cerebellar dysfunction (truncal ataxia, unsteady gait, nystagmus)
o atrophy and loss of granule cells in anterior vermis
o Bergmann gliosis in advanced cases
- radiation
o high doses can cause nausea, confusion, convulsions, rapid onset coma,
and death
o delayed effects can be HAs, N/V, and papilledema
o can be months to yrs later
o large areas of coagulative necrosis and adjacent edema
o restricted to white matter
o can induce tumors years after therapy
- combined radiation & methotrexate induced injury
o begin w/ drowsiness, ataxia, confusion
o may progress rapidly
o focal areas of coagulative necrosis within white matter
Tumors
- 20% of all childhood CA are CNS tumors
- 70% of childhood tumors arise in posterior fossa
- 70% of adult tumors arise in cerebral hemispheres, supratentorial
- rarely metastasize outside CNS
- symptoms = seizures, HAs, focal neuro deficits, hydrocephalus, ataxia
Gliomas
Astrocytoma
- grade I = pilocytic
o often cystic, well circumscribed, grow slowly
o children & young adults
o in cerebellum
o bipolar cells w/ long thin hairlike processes that are GFAP+
o Rosenthal fibers and eosinophilic granular bodies present
- grade II = diffuse astrocytoma
o poorly defined, gray, infiltrative
o cystic degeneration
o infiltration always present
o pleomorphic xanthoastrocytoma = temporal lobe of kids and young
adults; hx of seizures; lipidized tumor cells
- grade III = anaplastic astrocytoma
o gemistocytic astrocytoma
o gliomatosis cerebri = aggressive, widespread infiltration
- grade IV = glioblastoma
o necrosis in serpentine pattern
o vascular or endothelial cell proliferation
o pseudopalisading
o glomeruloid body
- high grade astrocytomas have abnormal leaky vessels
- brainstem glioma
o 1st two decades of life
o intrinsic pontine gliomas are MC here
o aggressive with short survival
Oligodendroglioma
- 4th-5th decades
- several years of neuro complaints (seizures)
- predilection for white matter
- well-circumscribed, gelatinous, gray mass
- cysts, focal hemorrhage, calcifications
- WHO grade II/IV
- anaplastic oligodendrogliomas (grade III)
o  cell density, nuclear anaplasia,  mitotic activity, necrosis
Ependymoma
- 1st 2 decades of life common near 4th ventricle
- in adults, spinal cord MC
- solid papillary masses in ventricles and sharply demarcated masses in spinal
cord
- perivascular pseudorosettes
- myxopapillary ependymomas
o occur in filum terminale of spinal cord
o papillary elements in myxoid background mixed with ependymom-like
cells
- NF2 gene commonly mutated in spinal ependymomas
- posterior fossa ependymomas can cause hydrocephalus; worst outcome
Other paraventricular mass lesions
- subependymoma
o solid, calcified, slow growing nodules
o attached to ventricular lining, protrude into ventricle
o most often in lateral & 4th ventricle
- choroid plexus papillomas
o MC in children, involve lateral ventricles
o in adults, involve 4th ventricle
o present with hydrocephalus
- choroid plexus carcinomas
o usually in children
- colloid cyst of 3rd ventricle
o non-neoplastic lesion often in young adults
o roof of 3rd ventricle
o noncommunicating hydrocephalus
o headache = important clinical symptom
Medulloblastoma
- poorly differentiated
- occurs mainly in children (20% of childhood brain tumors)
- midline of cerebellum (lateral locations in adults)
- well-circumscribed, neurosecretory granules, Homer Wright rosettes
- desmoplastic variant
o areas of stromal response
o marked by collagen and reticulin deposition
o nodules of cells forming “pale islands” with more neuropil
- drop metastases = metastases to cauda equina
- loss of material from 17p
- MYC amplification = more aggressive
- highly malignant
Meningiomas
- benign tumor of adults
- usually attached to dura
- prior radiation therapy = risk factor
- may grow en plaque = tumor spreads in sheet-like fashion along surface of
dura
o may cause hyperostotic reactive changes in overlying bone
- various histologic patterns:
o syncytial (meningothelial); whorled clusters of cells
o fibroblastic
o transitional
o psamommatous
o secretory
o microcystic
- xanthomatous degeneration, metaplasia, and moderate nuclear pleomorphism
common
- atypical meningiomas (WHO grade II/IV)
o higher recurrence and more aggressive
- anaplastic (malignant) meningiomas
o malignant; WHO grade III/IV
o high aggressive
o mitotic rates extremely high
o papillary and rhabdoid meningiomas
- loss of chromosome 22
- uncommon in children; female predominance;
- often express progesterone receptors (may grow rapidly during pregnancy)
Metastatic
- mostly carcinomas
- ¼ to ½ of intracranial tumors in hospitalized pts
- most commonly from
o lung
o breast
o skin (melanoma)
o kidney
o GI tract
- choriocarcinoma have high likelihood of metastasizing to brain
- meninges frequent site of involvement (esp. from lung & breast CA)
Peripheral nerve sheath tumor
Schwannoma
- benign
- from neural crest-derived Schwann cell
- loss of expression of NF2 gene product, merlin
- mix of 2 growth patterns:
o Antoni A = elongated cells w/ cytoplasmic processes arranged in
fascicles in high cellularity areas; Verocay bodies
o Antoni B = less dense; loose meshwork of cells and myxoid stroma
- acoustic neuroma = tinnitus and hearing loss from touching CN VIII (actually
vestibular schwannoma)
Neurofibroma
-
most commonly as cutaneous neurofibroma
peripheral nerve = solitary neurofibroma or plexiform neurofibroma
multiple lesions = neurofibromatosis type 1 (NF1)
alterations in NF1 (protein neurofibromin)
cutaneous lesions
o grow as nodules w/ hyperpigmentation
o large and pedunculated
o dermis & subQ fat
o composed of spindle cells
o highly collagenized
- plexiform tumors
o can cause neuro deficits
o potential for malignant transformation
o large nerve trunks most commonly involved
o “shredded carrot” = areas of collagen bundles
Malignant peripheral sheath tumors
- highly malignant tumors
- NF1 lost at early stage
- Triton tumors = rhabdomyoblastic differentiation
- epitheloid malignant schwannomas = aggressive variants; tumor cells grow in
nests
Familial tumor syndromes
Neurofibromatosis type 1 (NF1)
- AD
- neurofibromas
- gliomas of optic n.
- Lisch nodules (pigmented nodules of iris)
- café au lait spots
- lack NF1 expression
Neurofibromatosis type 2 (NF2)
- AD
- BL CN VIII schwannomas
- multiple meningiomas
- NF2 mutation (merlin)
Tuberous sclerosis complex
- AD
- hamartomas (cortical tubers & subependymal nodules)
o tubers = potatoes
o subependymal nodules = droplike masses that bulge into ventricular
system (candle-guttering)
- benign neoplasms of brain
- renal angiomyolipomas, retinal glial hamartomas, pulmonary
lymphangioleiomyomatosis, cardiac rhabdomyomas
- cysts in liver, kidneys, pancreas
- cutaneous lesions (angiofibromas, shagreen patches, ash-leaf patches)
- subungual fibromas
- TSC1 (hamartin) or TSC2 (tuberin) mutations (TSC2 more common)
Von Hippel-Lindau disease
- AD
- hemangioblastomas (cerebellum & retina)
o highly vascular neoplasms that occur as a mural nodule
o large fluid-filled cyst
- cysts (pancreas, liver, kidneys)
- renal cell carcinoma and pheochromocytoma
- VHL is a tumor suppressor gene