|
This study guide was prepared
by Fanconi.
Coma
Normal Cells and Their Reactions to Injury
 | Axonal Reaction
 | Axon damaged, cell
body undergoes change: chromatolysis = pale, swollen nucleus |
|
| Acute Injury
| Red neuron: anoxia,
ischemia, pyknosis of nucleus |
|
| Atrophy and Degeneration
| Loss of neurons
without other change = slowly progressive or systemic dz |
|
| Intraneuronal deposits
| Aging = lipofuschin |
| Metabolism = storage
material |
| Viral = inclusion
bodies |
| Degenerative =
neurofibrillary tangles (Alzheimer’s), Lewy Bodies (Parkinson’s) |
|
| Astrocytes
| GFAP, structural
support, BBB, detoxifiers |
| Rosenthal fibers =
aB-crystallin = gliosis, pilocytic astrocytomas, Alexander’s dz |
| Corpora amylacea =
lamellated bodies, increase in number with age |
| Alzheimer II
astrocytes = enlarged nucleus with pale chromatin = hyperammonemia |
|
| Oligodendrocytes
| Maintain CNS myelin |
| Side note:
attacked by JC virus in PML, occurs in advanced HIV dz |
|
| Ependyma
| Cuboidal cells lining
ventricles, do NOT regenerate after injury (subependyma proliferates) |
|
| Microglia
| CD4+, CR3+ mononuclear
cells (mesenchyme) |
| Injury -®
rod cells = elongated nuclei |
|
Common Pathophysiologic Complications
| Herniations
| Subfalcine =
cingulated gyrus herniates “sideways” under falx, bad for anterior cerebral
artery |
| Transtentorial = uncus
passes thru tentorium, Duret hemorrhages of pons, CN III palsy |
| Tonsillar = thru
foramen magnum, death due to choking off respiratory center in medulla |
|
| Cerebral Edema
| Vasogenic = brain is
heavy, swollen, wet. White matter absorbs most edema fluid. |
| Cytotoxic = brain is
heavy and dry (fluid is intracellular), toxic or metabolic problems. |
| Interstitial =
transudation across ependymal lining (
intraventricular pressure) |
|
| Hydrocephalus
| Noncommunicating =
blockage usually in aqueduct or foramina of Monro |
| Communicating =
obstruction of reabsorption (arachnoid villi) |
| Normal Pressure =
elderly people, mental slowness, incontinence, gait problems, hydrocephalus
ex vacuo |
|
Nerve and Muscle Pathology
Inflammatory Myopathies
| Dermatomyositis
| Lilac discoloration of
eyelids, periorbital edema, scaly and red knuckles |
| Proximal muscle
weakness first, women have tendency to form visceral cancers |
| Antibodies to
microvasculature in perimysial connective tissue |
| Perifascicular atrophy
of myofibers |
|
| Polymyositis
| Like above, without
skin discoloration and cancers |
| Damage to muscle
fibers by Cd8+ cytotoxic T cells, necrotic and regenerating fibers |
|
| Inclusion Body Myositis
| Unlike above, muscle
involvement is asymmetric and involves distal muscles first (extensors of
foot and flexors of fingers) |
| Vacuoles in myocytes,
rimmed by basophilic granules |
|
Motor Unit
| Motor unit = lower motor
neuron, axon of that neuron, muscle fibers it innervates |
| Single Schwann cells
innervate axonal segments |
| Protein synthesis does
not occur in axon (axoplasmic flow delivers the goods and retrograde transport
serves as feedback to cell body). |
| Skeletal muscles cells
are syncytial cells. Z bands = a-actinin. |
| Type 1 muscle fibers
| Sustained force, NADH
dark stain, lots of lipids, many mitochondria = “red meat” |
|
| Type 2 muscle fibers
| Sudden force, ATP pH
9.4 = dark stain, lots of glycogen = “white meat” |
|
Reactions to Injury
| Denervation atrophy =
small, angulated shapes |
| Reinnervation = “type
grouping” = a cluster of similarly staining muscle fibers |
| Group atrophy = a type
group becomes denervated |
| Myopathic changes
| Segmental necrosis =
may be followed by myophagocytosis by macrophages |
| Myocyte regeneration
via satellite cells = prominent nucleoli, basophilic cytoplasm |
| Increased central
nuclei |
| Variation in fiber
size, hypertrophy, muscle fiber splitting |
|
Immune-Mediated Neuropathies
| Guilllain-Barre Syndrome
(AIDP)
| Life-threatening
ascending paralysis, nerve conduction velocity is slowed, CSF protein is
elevated without increased cell count |
| Segmental
demyelination and chronic inflammatory cells in nerve roots |
| Often follows a viral
infection |
|
| Chronic Inflammatory
Demyelinating Polyneuropathy (CIDP)
| Like above, but
subacute or chronic course, relapses and remissions |
| Onion bulbs (demyelination
and remyelination) |
|
| Infectious
Polyneuropathies
| Leprosy = infection of
Schwann cells |
| Varicella-Zoster virus
infects neurons of sensory ganglia, causes shingles |
| Diphtheria = damage
due to exotoxin, segmental demyelination |
|
Hereditary Neuropathies
| Charcot-Marie-Tooth (HMSN
I)
| Autosomal dominant,
myelin genes involved, calf muscle atrophy |
|
| Riley-Day syndrome =
familial dysautonomia
| Autosomal recessive,
Jewish, no tears, excessive sweating, axonal degeneration |
|
| Adrenoleukodystrophy
| X-linked, peroxisonal
transporter, mixed motor and sensory with adrenal insufficiency, onion bulbs |
|
| Familial Amyloid
Polyneuropathies
| Autosomal dominant,
transthyretin, sensory and autonomic dysfunction |
|
| Porphyria
| Autosomal dominant,
problem with heme synthesis, psychiatric disturbances, axon degeneration |
|
| Refsum disease
| Autosomal recessive,
peroxisomal enzyme, palpable nerves, severe onion bulb formation |
|
Acquired Metabolic and Toxic Neuropathies
| Adult-Onset DM
| Distal symmetric
neuropathy (small fibers affected first), autonomic, and focal (ocular nerve
palsies) |
|
| Ethanol
| Nutritional
deficiencies, progressive distal sensorimotor neuropathy |
|
| Acrylamide
| Large fibers affected
most, numbness and sweating of hands and feet |
|
| Hexane
| Protein alkylation,
enlarged axons filled with neurofilaments, distal, large caliber axons |
|
| Organophosphorous esters
| Altered protein
phosphorylation, rapidly progressive distal sensorimotor neuropathy |
|
| Vinca alkaloids
| Impaired assembly of
microtubules, diminished ankle jerk earliest sign |
|
Neuropathies Associated With Malignancy
| Direct Effects
| Infiltration of nerve
by tumor |
|
| Paraneoplstic syndromes
| Progressive
sensorimotor neuropathy, worst in legs, small cell CA, loss of dorsal root
ganglion cells and CD8+ T-cell infiltrates, axonal loss of posterior columns |
| Amyloid deposition in
plasma cell dyscrasias |
| IgM binding to
myelin-associated glycoproteins |
|
Traumatic Neuropathies
| Laceration = bone
fractures |
| Avulsions = excess
tension applied to a nerve (hanging from a chandelier) |
| Compression = Most
common is carpal tunnel syndrome, seen in pregnancy, DJD, hypothyroidism,
amyloidosis (B2-microglobylin in renal dialysis patients), excessive usage of
write |
Muscle Denervation Atrophy
| Spinal muscular atrophy
(SMA) = infantile motor neuron disease |
| Autosomal recessive,
chromosome 5 |
| Most common = Werdnig-Hoffman,
death within three years of birth |
Muscular Dystrophies
| X-linked
| Duchenne = death by
early twenties, cognitive impairment
 | Variation in fiber
size |
| Increased central
nuclei |
| Degeneration,
regeneration |
| Endomysial fibrosis |
| Dystrophin gene,
basically no protein expressed at all |
|
| Becker = same gene,
less common, less severe
| Diminished or
abnormal dystrophin expression |
|
| Emery-Dreyfuss =
mutation distinct from dystrophin gene
| Elbow and ankle
contractures |
|
|
| Autosomal
| Limb-Girdle muscular
dystrophy
| Dominant or
recessive, mutations of proteins that interact with dystrophin |
|
| Myotonic dystrophy
| Dominant,
anticipation (trinucleotide repeat) |
| Cataracts, frontal
balding, gonadal atrophy, cardiomyopathy, decreased IgG |
| Myotonia = sustained
involuntary contraction of a group of muscles |
| Muscle spindle
changes |
|
| Fascioscapulohumeral
MD
| Dominant, face, neck
and shoulder girdle |
| Inflammatory
infiltrate of muscle |
|
| Oculopharyngeal MD
| Dominant, mid-adult
life, rimmed vacuoles in type 1 fibers |
|
| Congenital MD
| Recessive, neonatal
hypotonia, respiratory insufficiency |
| Merosin positive or
negative, endomysial fibrosis and variable fiber size |
|
|
Ion Channel Myopathies
| Hypokalemic,
hyperkalemic, and normokalemic periodic paralysis
| Muscle Na+ channel,
PAS-positive vacuoles, dilation of sarcoplasmic reticulum |
|
| Myotonia congenita
| Stress, fatigue makes
it worse |
| Muscle Cl- channel |
|
| Paramyotonia congenita
| Childhood disorder,
same Na+ channel as hyperkalemic periodic paralysis |
|
| Malignant hyperpyrexia
| Dramatic
hypermetabolic state with anesthesia, halothane, succinylcholine (autosomal
dom.) |
|
Congenital Myopathies
| Central core disease
| Affects type 1 fibers,
may develop malignant hyperthermia |
|
| Nemaline myopathy
| Proximal muscles
worst, aggregates of a-actinin (Z-band material) |
|
| Centronuclear myopathy
| Extraocular and facial
muscles, lots of centrally located nuclei, usually just type 1 fibers |
|
Myopathies Associated With Inborn Errors of Metabolism
| Lipid myopathies
| Carnitine deficiency
|
| Carnitine palmitoyl
transferase deficiency = rhabdomyolysis after prolonged exercise, myoglobin
in urine, renal failure |
|
| Mitochondrial myopathies
| External
ophthalmoplegia, ragged red fibers on trichrome stain, “parking lot”
inclusions |
| Can be autosomal or
maternally inherited |
|
Toxic Myopathies
| Thyrotoxic = proximal
weakness, periodic paralysis, hypokalemia |
| Alcohol = rhabdomyolysis
with myoglobin in urine, may lead to renal failure |
| Steroids = proximal
weakness, no relation to steroid level |
Inflammatory Myopathies
| Infectious myositis |
| Non-infections
inflammatory muscle disease |
| Systemic inflammatory
diseases |
Neuromuscular Junction
Myasthenia Gravis
| Immune-mediated injury
of Ach receptors, easy fatigability, ptosis, diplopia |
| Diffuse type 2 muscle
atrophy |
| Junctional folds
abolished at neuromuscular junction |
| Antibodies to AchR in
85-90% of patients. Plasmaphersis can treat. |
| 15% have other
autoimmune dz, thyroid, RA, SLE, collagen-vascular disorders |
| Thymic hyperplasia =
65-75%, thymoma in 15% |
Lambert-Eaton Myasthenic Syndrome
| Paraneoplastic disorder
of NMF |
| 60% small cell CA of
lung |
| Contractions increase
(NOT DECREASE) with repeated stimuli |
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
| Loss of LMN and UMN |
| Men > 50, auto. dom.,
superoxide dismutase gene |
Bulbospinal Atrophy
| ALS with predominantly
bulbar manifestations |
| Motor cranial nerves
damaged, except those that control extraocular muscles |
| Death from respiratory
complications |
Parkinson’s Disease
Parkinsonism
| Diminished facial
expression, stooped posture, bradykinesia, small steps, rigidity, pill-rolling
tremor |
Idiopathic Parkinson’s Disease
| Pallor of substantia
nigra and locus ceruleus (loss of catecholaminergic neurons) |
| Gliosis |
| Lewy bodies (contain a-synuclein)
in remaining neurons |
Progressive Supranuclear Palsy
| Loss of vertical gaze,
truncal rigidity, dementia |
| Neuronal loss,
neurofibrillary tangles in basal ganglia and other areas |
Corticobasal Degeneration
| Ballooned neurons in
motor cortex |
| Loss of pigmented
neurons in striatum |
Multiple System Atrophies
| Striatonigral
degeneration
| Like Parkinson’s, but
resistant to L-DOPA therapy, no Lewy bodies |
|
| Olivopontocerebellar
atrophy
| Shrinkage of pons,
loss of Purkinje cells, degeneration of inferior olives |
|
| Shy-Drager Syndrome
| Parkinsonism and
autonomic system failure |
| Loss of sympathetic
neurons in IML |
|
Huntington’s Disease
Huntington’s Disease
| Autosomal dominant |
| Chorea at first, maybe
parkinsonism (bradykinesia, ridigity, dementia) late in disease |
| Atrophy of caudate and
putamen |
| Medium-sized spiny
neurons |
| Neurons that contain
nitric oxide synthase and cholinesterase are spared |
Huntingtin Gene
| Chromosome 4 |
| Trinucleotide repeat,
polyglutamine tract |
Ataxia
Spinocerebellar ataxias (SCA)
| Autosomal dominant,
unstable expansions of CAG repeats |
Friedrich ataxia
| Autosomal recessive,
male preponderance |
| Dz manifests around 11
years of age |
| Gait ataxia, dysarthria,
depressed reflexes, Babinski sign, sensory loss |
| Pes cavus, scoliosis,
diabetes, cardiac arrhythmias, myocarditis |
| GAA repeat |
| Pathology
| Fiber loss and gliosis
in posterior columns, corticospinal, and spinocerebellar tracts |
| Neuronal loss in
Clarke’s column, VIII, X, and XII cranial nerve nuclei, dentate nucleus,
Purkinje cells and DRG cells |
| Peripheral neuropathy |
|
Ataxia-Telangiectasia
| Autosomal recessive |
| Cerebellar dysfunction
and recurrent infections |
| Conjunctival
telangienctasias |
| Pathology
| Loss of Purkinje and
granule cells |
| Absence of thymus |
| Hypoplastic gonads |
| Lymphoid malignancy |
|
CNS Infections
Meningitis
| Bacterial meningitis |
o
Neonates = E. coli and group B
strep
o
Infants and children = H.
influenza
o
Adolescents and young adults = N.
meningitides
o
Elderly = Strep pneumo and L.
monocytogenes
·
Meningeal irritation with
headache, photophobia, confusion, neck stiffness
·
Purulent CSF with increased
pressure, elevated protein, and reduced glucose
·
Leptomeningeal fibrosis and
hydrocephalus may occur
·
Viral meningitis
o
Enteroviruses (echovirus,
Coxsackie, poliovirus)
o
Usually self-limited
o
Meningeal irritation and CSF
lymphocytic pleocytosis
o
Moderate protein elevation
o
Normal CSF glucose
Brain Abscess and Subdural Empyema
| Bacterial endocarditis,
cyanotic heart disease, chronic pulmonary sepsis predispose |
| Strep and staph usually |
| Thrombophelebitis =
venous occlusion and infarction of brain |
| Focal deficits with
ICP |
| CSF pressure, cell
count, protein increased with normal glucose |
| Herniation |
Chronic Meningoencephalitis
| Tuberculous Meningitis
| Headache, malaise,
confusion, vomiting |
| CSF pleocytosis of
mono’s, increased protein |
| Arachnoid fibrosis,
hydrocephalus, obliterative endarteritis |
| MAC in AIDS patients |
| Subarachnoid space has
fibrinous exudates with granulomas at base of brain, encasing cranial nerves |
|
| Neurosyphilis
| Meningovascular
neurosyphilis
| Obliterative
endarteritis |
|
| Paretic neurosyphilis
| Brain invasion by
spirochetes |
| Neuronal loss and
proliferation of microglia (rod cells) |
|
| Tabes dorsalis
| Spirochete damage to
sensory nerves in dorsal roots and loss of axons and myelin in dorsal
columns |
| Impaired joint
position sense |
| Locomotor ataxia,
Charcot joints |
|
|
| Lyme Disease
| Spirochete Borrelia
burgdorferi transmitted by Ixodes tixk |
| Aseptic meningitis,
encephalopathy, and polyneuropathies |
| Proliferation of
microglia |
|
Viral Encephalitis
| Arthropod-borne viral
encephalitis
| Epidemics (Eastern and
Western Equine, St. Louis, California) |
| Animal hosts and
mosquito or tick vectors |
| Seizures, confusion,
delirium, stupor, coma |
|
| HSV-1 encephalitis
| Any age group, but
most common in children and young adults |
| Hemorrhagic,
necrotizing lesions of temporal lobes |
| Cowdry intranuclear
viral inclusion bodies in neurons and glia |
|
| HSV-2 encephalitis
| Generalized severe
encephalitis in neonates |
|
| VZV encephalitis
| Granulomatous
arteritis and necrotizing encephalitis in immunocompromised |
|
| CMV encephalitis
| Periventricular
necrosis and calcification in HIV |
| Subacute with
microglial nodules |
|
| Poliomyelitis
| Lower motor neurons
attacked with muscle wasting |
| Flaccid paralysis,
death from paralysis of respiratory muscles, myocarditis |
| Usually just anterior
horn damaged |
| Post-polio syndrome 30
years later = progressive weakness and pain |
|
| Rabies
| Can occur with
exposure to bats even without a bite |
| Ascends to CNS along
peripheral nerves |
| Excitability,
hydrophobia and flaccid paralysis |
| Negri bodies in
hippocampal pyramidal and Purkinje cells |
| Usually no
inflammation |
|
| HIV
| HIV-1 aseptic
meningitis
| Within 1-2 weeks of
seroconversion in 10%, myelin loss in hemispheres |
|
| HIV-1 encephalitis
| HIV-related
cognitive/motor complex |
| Microglial nodules
with giant cells, myelin damage, and gliosis |
|
| Vacuolar myelopathy
| 20-30% of AIDS
patients at autopsy |
| Destruction of
posterior and lateral columns, resembles subacute combined degen. |
| Similar to HTLV-1
myelopathy |
|
| Cranial and peripheral
neuropathies
| CIDP |
| Zidovudine-related
acute toxic reversible myopathy with ragged red fiers and myoglobinuria |
|
|
| Progressive Multifocal
Leukoencephalopathy
| JC virus infects
oligodendrocytes |
| Immunosuppressed
patients |
| Patches of
demyelination, oligodendrocyte nuclei with viral inclusions |
|
| Subacute Sclerosing
Panencephalitis
| Measles virus |
| Persistent but
nonproductive infection of CNS by altered measles virus |
| Gliosis and myelin
degeneration |
| Neurofibrillary
tangles |
|
Fungal and Parasitic Infections
| Chronic meningitis = C.
neoformans even in immunocompetent patients |
| Vasculitis = Mucor and
Aspergillus |
| Parenchymal invasion =
Candida and Cryptococcus |
| Protozoans
| Toxoplasma gondii
| AIDS |
| Multiple
ring-enhancing lesions |
| Cerebritis and
calcified lesions in fetus of infected mother |
|
| Malaria (Plasmodium) |
| Amebiasis |
| Trypanosomiasis |
|
| Rickettsia
| Typhus |
| Rocky Mountain Spotted
Fever |
|
| Metazoa
| Cysticercosis
|
| Echinococcosis |
|
Multiple Sclerosis and
Demyelinating Diseases
Multiple Sclerosis
| Cellular immunity
against myelin components |
| MZ twin concordance =
25% |
| Plaques are gray
discolorations of white matter occurring especially around ventricles |
| Inactive plaques show
gliosis and remain unmyelinated |
| Variants
| Neuromyelitis optica (Devic
disease) in Asians |
| Acute multiple
sclerosis |
|
Acute Disseminated Encephalomyelitis
| Acute, post-viral, PMNs,
perivenous demyelination |
Acute Hemorrhagic Leukoencephalitis
| Hemorrhagic necrosis of
gray and white matter. May by post-viral. |
Central Pontine Myelinolysis
| Too rapid correction of
hyponatremia |
Cerebrovascular Disease
Hypoxia, Ischemia, and Infarction
| Watershed areas, esp.
between anterior and middle cerebral artery distribution |
| 12-24 hours = red
neurons |
| Susceptible regions
| Pyramidal neurons of
hippocampus |
| Purkinkje cells of
cerebellar cx |
| Pyramidal neurons in
neocortex |
|
| Healing by gliosis |
| Infarction
| Thrombosis
| Carotids or basilar
system, astherosclerosis |
|
| Embolism
| Intracerebral
arteries (MCA), from cardiac mural thrombi from cardiac infarcts, etc. |
|
|
Nontraumatic Intracranial Hemorrhage
| Intraparenchymal
| Hypertensive
| Putamen, thalamus,
cerebellar hemispheres |
| Arteriolar injury
from microaneurysms |
|
| Lobar
| Amyloid angiopathy
or hemorrhagic diatheses |
| Hematoma reabsorbed
over months |
|
|
| Subarachnoid
| Rupture of berry
aneurysm
| Most often in
anterior circulation |
| Sporadic or
associated with autosomal dominant polycystic kidney disease |
| Hypertension and
collagen disorders predispose |
|
10mm have 50% risk of bleeding per year |
| Rupture with
straining at stool or sexual orgasm |
| Arterial vasospasm |
|
|
| Vascular Malformations
| Arteriovenous
malformations
| Most often in MCA
territory |
| 2 men : 1 women |
| 10-30 years of age,
presenting as seizure disorder or hemorrhage |
|
| Cavernous hemangiomas
| Distended, loose
vascular channels with thin collagen walls in cerebellum, pons, and
subcortical regions |
|
| Capillary
telangiectasia
| Foci of dilated,
thin-walled vascular channels over normal brain parenchyma |
| Most often occur in
pons |
|
|
Hypertensive Cerebrovascular Disease
| Lacunar infarcts
(caudate, thalamus, pons) |
| Acute hypertensive
encephalopathy
| Confusion, vomiting,
convulsions |
| Autopsy = edematous
brain with petechiae and necrosis of arterioles |
|
Alzheimer’s Disease and Dementia
Alzheimer Disease
| Most cases are sporadic
(5-10% familial) |
| Trisomy 21 who survive
over 45 years |
| E4 allele of
apolipoprotein E (chromosome 19) assoc. with increased risk of AD |
| Morphology
| Narrowed gyri, widened
sulci |
| Hydrocephalus ex vacuo |
| Neuritic plaques
| Central amyloid core
(amyloid B-peptide derived from APP) surrounded by microglia and reactive
astrocytes in hippocampus, amygdala, and neocortex |
| Neurofibrillary
tangles = helical filaments in entorhinal cx, hippocampus, amygdala, basal
forebrain, raphe nuclei. Contain hyerphosphorylated tau, MAP2, ubiquitin,
and AB. |
| Amyloid angiopathy =
vascular deposition of AB |
|
|
| Pick Disease
| Much rarer than AD |
| Dementia with frontal
signs |
| Ballooned neurons
rather than plaques and tangles |
|
Transmissible Spongiform Encephalopathies
| CJD
| Rapidly progressive
dementia |
| Mostly sporadic, may
be familial |
| Iatrogenic
transmission |
| Fatal usually within 7
months |
|
| Variant CJD (UK)
| Disease affected young
adults |
| Behavioral disorders
early in disease |
| Neurologic sybdrome
progressed more slowly |
|
| GSS
| Inherited mutation of
PRNP gene |
| Chronic cerebellar
ataxia and progressive dementia |
|
| FFI
| No spongiform
pathology |
| Neuronal loss and
reactive gliosis in ventral and dorsomedial thalamus |
| Neuronal loss of
inferior olivary nucleus |
|
| Kuru plaques
| Deposits of PrP, which
occur in cerebellum of patients with GSS |
| Present in abundance
in cerebral cx of variant CJD |
|
|
