Download Neuropathology Objectives

NEUROPATHOLOGY
Developmental Disorders & CNS Trauma
Selective Vulnerability: CELLS
Selective Vulnerability: REGIONS
Neurons – generally the most susceptible to injury
Global ischemia – excitotoxic injury to hippocampal neurons
along with selective injury to cerebellar Purkinje cells
Oligodendroglia – selectively injured in:
1) Multiple sclerosis
2) Leucodystrophies
3) Autoimmune attack: acute disseminated
encephalomyelitis (ADEM)
4) Infection: progressive multifocal
leucoencephalopathy (PML) – caused by papova
Astrocytes – generally are the most resistant to injury
Hunington disease: caudate nucleus and putamen
Parkinson disease: substantia nigra
Amyotrophic lateral sclerosis – motor neurons
1) Neuronal reaction to axonal injury (central chromatolysis)
a. Follows damage to axon
b. Margination of Nissl substance with central clearing of the cytoplasm
c. Peripheral displacement of the nucleus
2) Axonal swellings
a. Occur at axonal breakages
i. Follow closed-head trauma, with stretching and snapping of long fibers
1. Shaken baby syndrome is an example
ii. Neuronal degenerations such as primary cerebellar degenerations
iii. Vitamin E deficiency (rare)
3) Neuronal inclusions
a. Viral
i. Herpes, rabies, CMV, measles (SSPE)
b. Filaments
i. Irregular inclusions: neurofibrillary tangle (Alzheimer disease)
ii. Round inclusions: Lewy body, Pick body
1. Lewy body in Parkinson’s
2. Pick body in Pick disease
c. Neuronal “storage” diseases
4) Neuronal metabolic storage diseases
a. Glycogenoses (Pompe)
b. Sphingolipidoses (Tay-Sachs)
c. Sulfatidoses (Gaucher, Niemann-Pick)
d. Mucopolysaccharidoses (Hurler)
5) Trans-synaptic degeneration of neurons
a. Secondary degeneration of a neuron connected to a dying neuron
b. Antegrade or retrograde
c. Primarily in “dedicated” tracts in CNS
i. Dedicated means 1on1 nerve interactions (classic example would be the optic neurons)
d. Potentially reversible
6) Oligodendroglial inclusions
a. Viral
i. PML – caused by papova virus
b. Filaments
i. Glial cell inclusions (GCIs) in some non-Alzheimer neurodegenerative diseases such as corticobasal
degeneration, multiple system atrophy, and others
7) Astrocytic reactions
a. Gliosis: hypertrophy and hyperplasia with synthesis of glial filaments
b. Rosenthal fibers: swellings of processes with heat-shock proteins
c. “Alzheimer type II Glia” – seen in liver failure
d. Glial cytoplasmic inclusions
e. Elaboration of cytokines
8) Microglial reactions
a. Constitute in part the innate immune system of the brain (bone marrow derived cells)
b. CNS equivalents of macrophages
c. Respond to challenge with
i. Hypertrophy and hyperplasia
ii. Elaboration of cytokines
iii. phagocytosis
d. Also involved in synaptic remodeling
9) Ependymal reactions (cells which line the ventricles)
a. Ependymal “granulations”
b. Fusion of ependymal surfaces
c. Viral inclusions
By NEURONS
1) Central chromatolysis
2) Inclusions
3) Trans-synaptic degeneration
Patterns of reaction to disease
By AXONS
1) Swellings
By GLIA
1) Inclusions
2) Gliosis
3) Immune responses
Pathophysiology of CNS Herniation
1) Anything that increases pressure inside the skull (hydrocephalus, brain swelling, mass lesion) will compress the
brain and result in herniation
2) Types of herniation
a. Subfalcine herniation of cingulate gyrus
b. Transtentorial herniation of UNCUS
i. In extreme cases, the midbrain can be pushed against the contralateral tentorium resulting in
necrosis
1. This can create a false localizing sign with pathology on the opposite side of the body
c. Herniation of cerebellar tonsils through foramen
magnum
3) Transtentorial herniation of the Uncus
a. Herniation palsy of the 3rd cranial nerve
i. As the midbrain descends, the 3rd cranial nerve is stretched over the edge of the tentorium
ii. This results in papillary dilation on the side of the mass lesion
b. Vascular consequences:
i. As the midbrain and pons descend, the basilar artery does not follow because it is ‘tethered’ above
by the Circle of Willis
ii. The fine pontine penetrating arterioles are broken leading to pontine hemorrhage and death
4) Hydrocephalus
a. Marked dilation of the ventricular system due to obstruction of CSF flow
b. Causes of hydrocephalus
i. Occlusion of CSF flow
1. Aqueduct of Sylvius (most common area creating hydrocephalus because it is the smallest
hole)
2. Arachnoid granulations – where CSF is reabsorbed at the superior sagittal sinus
a. Can occur during meningitis
ii. Increased CSF flow (rare)
iii. Compensatory to brain atrophy
Pediatric and Perinatal Neuropathology
Causes of congenital brain malformations:
Genetics:
1) Chromosomal (6%)
2) Single gene (2%)
Environmental:
1) Nutrition – folic acid deficient
2) Disease – diabetes
3) Toxins – alcohol, smoking
4) Infections – rubella,
toxoplasmosis, CMV, syphilis
5) Radiation
Unknown (most cases**)
Embryology and Pathology of time periods
Time Period
Defects
7 days: Implantation
22-28 days: Neural
1) Anencephaly – absence of brain and cranial vault
tube formation
2) Spina bifida – bony defect in spine (most common)
a) Posterior neuropore defect – cystic, skin-covered lesion on back may contain
meningeal elements only (meningocele), or meningeal and neural elements
(myelomeningocele)
i. Myelomeningocele – absence of vertebral arches and herniation of meninges and
malformed spinal cord into cystical lesion
3) Encephalocele – brain and ventricle stick out of hole that never closed in skull
4) Arnold-Chiari Malformation – hydrocephalus, widened foramen magnum, cerebella
vermis herniation, ‘notch’ in cervical spinal cord
a) Can survive and function normally
4-8 weeks:
1) Holoprosencephaly – one large cerebral sphere instead of 2 hemispheres
Organogensis
2) Olfactory aplasia – absence of gyri recti
3) Agenesis of the corpus callosum – also has absence of cingulate gyrus
4) Dandy-Walker malformation - enlargement of the fourth ventricle, the space containing
cerebrospinal fluid between the medulla and the cerebellum, a partial or complete
absence of the cerebellar vermis – slow motor development and large heads
8 weeks-birth:
1) Agyria (no gyri) or Lissencephaly (smooth brain)
Migration of
2) Pachygria (broad or coarse gyri) neuroblasts
3) Heterotopias – the grey matter lining the lateral ventricle is abnormal
4) Polymicrogyria – note “busy” appearance of cortical gyral pattern
a) Not compatible with normal intelligence
b) The neuronal and molecular layers, but not the pia or meninges, wind up and down
forming miniature pseudogyri within the true gyri
c) Can also have Focal Polymicrogyria which is compatible with normal functioning
10 weeks: Susceptible EARLY
to destructive lesions
1) Porencephaly – basically the same as schizencephaly, except that the destructive event
has left a hole (‘pore’)
Early = 10-25 weeks
a) Note abnormal gyri that ‘radiate’ out from the lesion
Late = after 25th week
2) Schizencephaly –a destructive event (probably ischemic) has left symmetric clefts
(‘schisms’) in the brain
3) Hydrancephaly –
LATE
1) Germinal matrix hemorrhage – right next to ventricles
2) Choroid plexus hemorrhage
3) Parenchymal hemorrhage
4) Periventricular ‘leucomalacia’ – dead area in white matter
20 weeks on:
Myelination
Birth Trauma
Down Syndrome
1) Delayed myelination
a) A response to almost any chronic insult
b) No long-term sequelae
i. Myelination in the temporal lobes may be delayed until 2nd decade
1) Tearing of tentorium
2) Linear tears of white matter
3) Tears of the spinal cord and cerebellar peduncles
1) Chromosomal defect
2) Small brain
3) Reduced dendritic complexity
a) Displayed by Camera Lucida drawings
4) Premature Alzheimer changes (30s and 40s)
Other Perinatal Neuropathology
Pathology
Clinical signs
Types of diseases
Leucodystrophies
Neuronal ‘storage’ diseases
Myelin loss
Long tract signs:
1) Ataxia
2) Pyramidal signs
3) Sparing of subcortical U-fibers*
Distended neurons
Grey matter signs:
1) Developmental delay
2) Mental retardation
3) Dementia
4) Seizures
1) Metachromatic leucodystrophy
a) Myelin breakdown products stain
red-brown with cresyl violet stain
2) Krabbe’s (Globoid cell) leucodystrophy
a) Perivascular macrophages are
distended with myelin breakdown
products
3) Adrenoleucodystrophy
a) Later onset** (others occur early)
b) Peroxisome defect**
CNS Trauma & Demyelinating Diseases
Learning Objectives:
1) Define the terms concussion and contusion
a. Concussion – transient functional impairment
i. No demonstratable anatomic abnormality
ii. Amnesia for the moment of injury
b. Contusion – focal necrosis of gyral crests
i. Sparing of sulci
ii. Old lesions are depressed and yellow (hemosiderin)
2) Define “contre-coup contusion” and explain its pathogenesis
a. Contre-coup contusions
i. Coup Lesions – at the site of trauma
ii. Contre-coup – opposite the site of trauma
1. These usually result from falls from a standing position (direction of force pushes opposite
side of brain against skull)
3) Internal vs. External injury
a. Diffuse axonal injury – results from angular acceleration within skull: shaking or oblique impacts
i. Involves long axon tracts of deep white matter, corpus callosum, cerebral peduncles, & brain stem
ii. Microscopically there are axonal swellings
iii. Present in 50% of patients who develop coma after trauma
iv. May explain persistent vegetative state in absence of gross lesions*
v. In milder form may explain concussion
b. Skull fractures –
i. Damage to vessels  bleeding
ii. Damage to dura  infection
iii. Damage to brain
c. Post-traumatic syndromes
i. Post-traumatic hydrocephalus
ii. Post-traumatic dementia: “punch-drunk” syndrome (dementia pugilistica)
iii. Post-traumatic epilepsy, meningioma, infection
iv. Post-traumatic psychiatric disorders
4) Define the pathogenic, anatomic, and clinical differences between epidural and subdural hematomas
Epidural Hematoma
Pathogenesis
Always associated with skull fracture
Anatomical damage Results from tearing of middle meningeal
artery
Clinical Difference
There may be a “lucid interval” of several hours
Subdural Hematoma
Trauma may be mild, without skull fracture
Tearing of meningeal bridging veins
May become chronic
1) Evolution:
a) Lysis of clot (1 week)
b) Early organization (2 weeks)
c) Hylanized connective tissue (1-3months)
2) Often re-bleed, resulting in different stages of
organization
Most common site*
5) Describe the gross and microscopical pathology of multiple sclerosis and of other demyelinating conditions
a. Multiple sclerosis
i. A disease of young adults (20-40)
ii. Irregular, but progressive course
iii. No constant clinical picture – relapsing
iv. Chronic Autoimmune destruction of myelin
1. Lesions separated in “time and space”
v. Axonal preservation in MS
vi. Has acute and chronic pathological features
b. Acute disseminated encephalomyelitis
i. An acute, monophasic autoimmune disease with destruction of myelin
1. No repeated or chronic attacks, people get better or die
ii. May follow viral infections or vaccines
iii. Fatal in 15-20% of cases
1. Small hemorrhages begin to appear
c. Central Pontine myelinolysis
i. Formerly common in alcoholics
ii. Results from overly rapid correction of hyponatremia - IATROGENIC
6) Describe and explain the evolution of MS lesions
a. Axonal preservation occurs – if it was an infarct there would be loss of myelin and axons
b. Many of the oligodendrocytes disappear after the immune attack, but some hold on but don’t generate
myelin
i. Remyelination does occur, but the axons have very thin myelin sheaths
1. Never myelinates as good the 2nd time aroun
c. The deficient during the initial attacks is worse than afterwards because of the inflammation
i. Acutely, the attack is full of inflammatory cells, edema, cytokines causing the inflammation
ii. There is still deficit afterwards b/c of loss of myelin, but there isn’t inflammation anymore
d. Macrophages come in and strip the myelin off
e. Lesions do not appear to attack specific anatomic boundaries, it just spreads out and attacks myelin
f. Chronic lesions have sclerotic astrocytes with limited macrophages
i. Bv is sclerotic and irregular
ii. Axons begin to disappear in chronic MS
7) Compare and contrast MS and acute disseminated encephalomyelitis
8) Explain the etiology of central pontine myelinolysis, and discuss prevention of this disease
a. This is due to a metabolic problem with serum sodium concentration
b. With the rapid correction of sodium in alcoholics comes the disease
c. Metabolites need to be added slowly over a period of time to prevent the disease
Cerebrovascular Diseases
Learning Objectives:
1) Define stroke, ischemia, hypoxia, and anoxia
a. Stroke (apoplexy) –
i. A transient ischemic attack (TIA) is a temporary (<24hrs) deficit due to temporarily decreased
perfusion
ii. Caused by
1. Brain infarction 80%
2. Intracerebral hemorrhage 10%
3. Subarachnoid hemorrhage 7%
4. Misc 3%
iii. Stroke is the 3rd leading cause of death in the elderly and the most prevalent neurological disorder
b. Ischemia – decrease or lack of blood
c. Hypoxia – decrease or lack of oxygen
d. Anoxia – no oxygen
2) List the different causes of stroke and discuss their relative prevalence, their gross and histological features, and
their pathophysiology
Causes of Stroke
Prevalence
Gross features
Pathophysiology
Brain Infarction
1) Thrombic
2) Embolic
80%
Acute (week 1)– softening, blurred
grey-white margin, swelling with
midline shifts
Subacute (weeks2&3) – tissue
disintegrates, sharp demarcation of
infracted area
Chronic (weeks 4+) – cavitation,
Gliosis (firm tissue)
Thrombotic – caused by
atherosclerosis
Embolic – caused by mural thrombi,
valvular vegetations, fat emboli
Patterns of injury:
1) Focal infarction
a. Outcome is focal deficit
(classic stroke)
2) Focal patterns resulting from
intermediate degrees of global
ischemia
a. Hippocampal and cerebellar
injury
b. Laminar necrosis
c. Watershed infarction
3) Global (entire brain) infarction
a. Ischemic/hypoxic
encephalopathy (TIA or
brain death)
1) From hypertension
a. Basal ganglia (common for
hypertensive hemorrhages)
b. Pontine and cerebellar
2) From berry aneurysms
a. Massive subarachnoid
hemorrhage
3) From vascular malformations
a. Arteriovenous malformation
Thrombosis @ carotid bifurcation is
the most common
Embolism – most often from the
heart
Intracerebral hemorrhage
- Due to hypertension
10%
Bleeding into the basal ganglia,
pons, and cerebellum
b. Cavernous angioma
c. Venous malformation
Subarachnoid hemorrhage
- Due to ruptured
berry aneurysm
7%
Miscellaneous
3%
Massive, clinically significant
subarachnoid hemorrhage is
almost always due to rupture of a
berry aneurysm **
Focal subarachnoid hemorrhage is
common overlying contusions,
infarcts, infectious foci
Berry (secular) aneurysm – involves
Circle of Willis, found in 2% of
adults, etiology unknown
1) Aneurysm wall consists of
vascular intima and adventitia,
with absent smooth muscle and
elastic
2) Warning symptoms due to
leakage or nerve compression
(worst headache ever, vomiting,
loss of consciousness)
3) Sudden death (25-50%)
4) Acute vasospasm leading to
infarctions (and focal deficits)
5) Rebleeding occurs in survivors
3) Describe the different types of vascular malformation in the CNS. Differentiate them according to types of
component vessels and clinical signs and symptoms
Arteriovenous
malformation
Cavernous Angioma
Venous Angioma
Capillary
telangiectasis
Component vessels
Clinical signs
Arteries and veins
Arterial pressure blood
shunted into venous
system  veins dilate
and sclerose in response
Veins
Abnormal, dilated
veins dispersed in
brain tissue
Capillaries
Dilated, but otherwise
normal capillaries
dispersed in normal
brain tissue
Symptoms
Abnormal veins prone to
leakage, causing seizures
and massive
hemorrhages
Lesions are congenital,
but: can be silent for
many years, symptoms
typically occur in young
adults
Veins
Abnormal, dilated and
hyalinized veins
arranged compactly
with no intervening
brain tissue
Can cause
hemorrhage
DO NOT cause
hemorrhage
Virtually never causes
symptoms
NO intervening neural
parenchyma
Throughout
intervening brain
tissue, do not
generally bleed
Usually an incidental
finding on autopsy
Notes
4) Describe the pathophysiological, histological, and clinical consequences of hypertension on the brain
a. Acute hypertension – medical emergency
i. Vessels begin to die, leakage, hemorrhage
1. Pink necrosis called fibrinoid necrosis of the vessel walls
ii. Diffuse cerebral dysfunction
b. Chronic hypertension – more common
i. Cause slower changes that occur over years
ii. Atherosclerosis occurs
iii. Arteriolar changes
1. Arteriolar sclerosis
2. Pulsating of vessels
3. Microscopic hemorrhages lead to tiny cavities (lacunes)
4. Microscopic aneurysms (Charcot-Bouchard) can lead to larger hemorrhages
5) Compare and contrast Binswanger disease and Leucoairosis
a. Binswanger disease
i. White matter infarcts*
ii. Destruction of white matter
iii. Clinical deficits
iv. Rare
b. Leucoairosis
i. Periventricular signal changes on CT, MRI
ii. Pathlogical significance unkown
iii. Clinical significance unknown
iv. Common in the elderly**
v. NOT INFARCTION
Infections of the CNS
1) List the different types of organisms that infect the CNS, and the common individual organisms within each of these
groups
a. Bacteria – generally cause meningitis or abscess
i. Pneumococcus, mindingococcus, H. influenza, E. coli
ii. Signs and symptoms:
1. Headache, photophobia, irritability, stupor, stiff neck, Ketnig’s sign
iii. Usually invades hematogenously or by direct extension from otitis or sinusitis
iv. CSF changes
1. Cloudy or purulent fluid
2. Increased pressure, WBC’s, protein
3. Decreased sugar
v. Complications
1. Acute thrombosis of inflamed meningeal vessels can lead to brain infarction
2. Chronic scarring of meninges can lead to blockage of CSF flow and hydrocephalus
3. Damage to cranial nevers can lead to blindness and cranial nerve palsies
b. Viruses
i. Acute encephalitis: arbovirus, herpes simplex, CMV, rabies
ii. Subacute encephalitis: HIV, JC virus (PML), measles (SSPE)
iii. Poliomyelitis: poliovirus, West Nile
iv. Relapsing: herpes zoster
v. Viral Tropism:
1. Meninges – coxsackie, echo, mumps
2. Temporal lobes – herpes simplex
3. Dorsal ganglia – herpes zoster (varicella)
4. Motor neurons – poliovirus, West Nile
5. Cholinergic neurons – Rabies
6. Oligodendrocytes – JC virus (PML)
vi. Viral ‘aseptic’ Meningitis
1. More common than bacterial meningitis
2. Echo, coxsackie, and other enteroviruses
3. Benign: most patients recover
4. CSF – increased lymphocytes rather than neutrophils, mildly increased protein (bacterial
has increased protein), normal sugar (bacterial has decreased sugar), no bacteria
vii. Viral Encephalitis
1. More seirous than viral meningitis
a. May be:
i. Endemic – arbovirus, poliomyelitis
ii. Sporadic – herpes simplex, CMV, rabies
b. Subacute forms also exist
i. HIV encephalitis
ii. PML – from JC virus
iii. SSPE – from measles
c. Fungi – generally cause meningitis or abscess
i. Common Organisms - Candida, mucor, aspergillus, Cryptococcus
1. Meningitis – cryptococcus
2. Vascular involvement with brain infarcts – aspergillosis and mucor
3. Encephalitis with microabscesses – Candida
d. Protozoans – toxoplasmosis, amoebae
e. Metazoans – cyestericosis
f.
Prions – unique to CNS*
i. Pathology
1. Spongiform change and amyloid plaques
a. Spongiform may be in grey or white matter
b. Plaques present in some diseases
2. Almost complete lack of inflammatory response**
2) Describe the pathological and clinical features of each type of CNS infection
a. Acute Bacterial Cerebritis – transient stage leading to brain abscess
i. Can be hematogenous
1. Most often from endocarditis
2. Territory of MCA is most common site
ii. Can arise from local extension
1. Paranasal sinusitis, mastoiditis
iii. CSF findings are mild and nonspecific
1. LP may cause brain herniation (resulting form increased intercranial pressure) and death
b. Brain abscess
i. Complications
1. Mass effect with herniation
a. Subfalcine (cingulated)
b. Transtentorial (uncus)
2. Rupture into meninges with meningitis
3. Rupture into ventricle with ventriculitis
a. The fibrous capsules of abscesses are thinner on the ventricular side, facilitating
rupture inward
c. Chronic Bacterial Infections
i. Tuberculosis
1. Meningoencephalitis (most common**)
a. Exudate over the base of brain, may spread via CSF
b. Hydrocephalus from arachnoid fibrosis
c. Infarcts from endarteritis
d. AIDS patients may contract M intracellulare with limited host response
2. Tuberculoma
a. Intracerebral tuberculosis granuloma (‘gummas’)
b. May be associated with meningitis
3. Spinal epidural granuloma (TB of the spine)
a. Mainly affects thoracic and lumbar vertebra
b. May cause compression fractures
ii. Neurosyphilis
1. Occurs in 10% of untreated cases, years after primary infection
2. 3 main types involving:
a. Meninges –meningovascular syphilis (‘gummas’)
b. Cerebral cortex – causes mood alterations, often delusions of grandeur
c. Spinal cord – tabes dorsalis*
i. Degeneration of the posterior columns of spinal cord
ii. Atrophy and fibrosis of dorsal roots
iii. Neuroborreliosis (Lyme disease)
d. Arbovirus Encephalitis
i. Most common form of epidemic Encephalitis
ii. Outbreaks in late summer from airborne arthropod-borne infections
iii. WEST NILE has recently become important in US – can cause polio-like sequalae
e. West Nile virus
i. Viral illness with sequalae  fever, headache, muscle aches, swollen lymph nodes, rash
ii. Acquired via mosquito bite
iii. Possible outcomes
1. Complete recovery (>99%), death, survival with paralysis
f.
Poliovirus
i. Clinically and pathologically related to West Nile
ii. Largely eradicated by childhood vaccination programs in the 1950’s
iii. A postpolio syndrome may affect survivors decades after infection
1. Progressive weakness with muscle atrophy
2. Pathogenesis unclear
g. Herpes simplex Encephalitis
i. Usually HSV-1
ii. Severe disease, often fatal without treatment
iii. Preferentially involves area around Sylvian Fissure (temporal and frontal lobes)
iv. Necrotizing, with intranuclear inclusion bodies in both neurons and glia
h. Herpes zoster infection
i. Due to reactivation of varicella (chickenpox) virus latent in spinal or trigeminal ganglia
ii. Usually causes a painful vesicular skin infection with a distinct dermatome distribution (shingles)
iii. More rarely causes a severe demyelinating Encephalitis in Immunocompromised patients that
resembles PML
i.
Rabies
i. Transmitted by bite of a rabid animal
1. Almost ALL US cases are now due to BATS
ii. Local replication in muscle (except for bat rabies  skin fibroblasts)
iii. Trans-synaptic retrograde spread along cholinergic pathways to CNS
1. Prolonged incubation period (1-3months) means that post-exposure prophylaxis is feasible
(unique to rabies)
iv. Furious Rabies
1. Fluctuating consciousness with periods of severe agitation, hyperactivity, confusion, and
aggressiveness
2. Phobic spasms (hydrophobia)
v. Dumb or Paralytic Rabies – occurs in Immunocompromised hosts
j.
CMV ventriculoencephalitis
i. Fetal CMV: periventricular involvement with brain destruction
1. Microcephaly
2. Periventricular calcification
ii. Nuclear and cytoplasmic inclusions
iii. CMV also infects Immunocompromised adults, especially AIDS
k. HIV Encephalitis
i. CNS involved in as many as 60% of AIDS patients
1. Leads to dementia (AIDS dementia complex)
2. Vacuolar myelopathy
a. Resembles B12 deficiency
b. No virus in lesions
3. AIDS myopathy
a. May resemble inflammatory myopathy
ii. Common opportunistic CNS infections in AIDS
1. CMV Encephalitis
2. Cerebral Toxoplasmosis
3. Cryptoccocal meningitis
4. Progressive multifocal leukoencephalopathy
l.
Subacute viral infections
i. JC virus – infects Oligodendrocytes causing widespread demyelination
1. Causes PML – WHITE MATTER INVOLVEMENT
2. Primary, asymptomatic infection in most people
3. Probably reactivation of virus in immunocompromised people (AIDS)
ii. Measles Virus – infects neurons and Oligodendrocytes
1. Causes subacute sclerosing panencephalitis
2. An altered persistent virus incapable of making complete virions
3. May occur years after primary measles infection
m. Cryptococcosis
i. Most common CNS fungal infection
ii. May be spontaneous or opportunistic
1. Inhaled leading to lung infection
iii. Round organisms with thick mucoid capsule
1. Mixed India Ink stain
iv. Minimal inflammatory response
n. Aspergillosis
i. Opportunistic – patients with profound neurtropenia (especially common in bone marrow
transplant patients)
ii. Spread to brain may be: hematogenous from lungs or by direct extension from sinusitis
iii. Causes a vasculitis – invades vessel walls
o. Mucormycosis
i. Opportunistic – diabetic patients are particularly susceptible
ii. Mucor invades vessels and produces infarction
iii. May reach CNS by direct extension from nasopharynx
p. Candidiasis
i. Common complication of:
1. Indwelling catheters
2. Intensive chemotherapy and neutropenia
ii. Uncommon CNS problems with AIDS
1. AIDS patients get candida (oral thrush)
iii. Microabscesses with polys
iv. Pseudohyphae – the infective form
q. Cerebral Toxoplasmosis
i. Protozoal infection
ii. In fetuses: T in TORCH
iii. In adults with AIDS
r.
Cerebral Amebiasis
i. Acquired via the nose from swimming in warm, stagnant ponds
s. Cerebral Malaria
t. Cerebral Cysticercosis
i. Taenia solium (pork)
u. Cerebral Hydatidosis
i. Echinococcus granulosus (dog)
v. Kuru
i. “to shake with fear”
ii. Predominately a cerebellar disease
1. Ataxia and tremor
2. Dementia in terminal stages
iii. Transmitted by canabalism
iv. Caused by PRIONS (infectious protein)
w. Creutzfedlt-Jacob disease
i. Sporadic CJD (most common CJD – usually 7th decade)
ii. Familial CJD – germline PrP gene mutation (earlier onset)
iii. Iatrogenic CJD – infected grafts
iv. Variant (atypical) CJD – consumption of BSE beef
Neurodegenerative Diseases
Learning Objectives:
1) Define dementia; list the common causes of dementia
a. Dementia – a global loss of all higher mental functions
i. More than memory loss
ii. Different from mental retardation
iii. Memory loss and confusion are usually noted early
iv. Alzheimer disease is the most common cause of dementia
b. Causes of dementia:
i. Alzheimer
ii. Frontotemporal dementias (FTD(P)-17, Pick disease, Corticobasal degeneration, motor neuron
disease-type)
iii. Vascular dementia
iv. Lewy body dementia
v. Hunington disease
vi. CJD
vii. Teritary syphilis
viii. Depression
ix. Metabolic (especially hypothyroidism)
x. AIDS dementia complex
2) Distinguish dementing diseases according to etiology, pathogensis, gross and histological findings, and clinical
presentation
a. Alzheimer
i. The major clinical manifestation is dementia
1. Slowly progressive with death after 5 years
2. Late stage patients are bed-ridden and susceptible to pneumonia and sepsis
ii. Predominately a disease of AGING
1. 1% incidence at ages 60-64, rising to 40% at ages 85-89
iii. Most cases (90%) are sporadic
iv. Familial (genetic) cases have earlier onset (age 50-60 or earlier)
v. Genetics
1. Familial
a. Amyloid precursor protein (APP)
b. Presenilin 1 (14)
c. Presenilin 2 (1)
vi. Acquired Risk factors
1. Age
2. Head trauma
3. Lifestyle: smoking, obesity, diet, hypertension, cholesterol, physical inactivity
vii. Pathogenesis
1. Aβ amyloid deposition
2. Hyperphosphorylated tau protein in neurons
3. Microglial reaction to amyloid
4. Microglial toxicity to neurons: cytokines and oxidative stress
5. Vascular insufficiency
viii. Pathology
1. Aβ amyloid deposit in CORTEX (plaques)
a. Found throughout the cortex
i. Alpha-secretase necessary to properly digest amyloid into products that
can be excreted
ii. If there is a problem with alpha-secretase, then β-secretase and γ-secretase
take over and cause the amyloid to be dissociated into products that will
cause Aβ deposits
b. Contain active microglia and astrocytes, damaged nerve processes, and dying
neurons
2. Aβ amyloid deposits in vessel walls (angiopathy)
3. Neurofibrillary tangles
a. Begin to mesial temporal lobe; eventually spread throughout cortex
b. Insoluble aggregates of abnormal, Hyperphosphorylated tau protein in neurons
b. FTD(P)-17  Frontotemporal dementia with parkinsonism – chromosome 17
i. Mutations in tau gene
ii. Dementia with parkinsonian symptoms
iii. Cerebral cortical atrophy with tau-containing neurofibrillary tangles, but not Aβ plaques
iv. Degeneration of substantia nigra
c. Pick Disease
i. Vary rare cause of dementia
ii. Usually, sporadic
iii. Well recognized because of its distinct pathology
1. Striking atrophy “knife-edge” gyri
a. Severe atrophy of frontal lobes with sparring of parietal and occipital lobes
2. Numerous Pick bodies in neurons: these are round, unlike neurofibrillary tangles
d. Progressive Supranuclear Palsy
i. Onset age 50-80, death within 5-7 years
ii. Clinical picture is dominated by difficulties with eye movement, speech, and a movement disorder
resembling parkinsonism
iii. Dementia develops late in the disease
iv. Neuronal and glial tau pathology
1. Tau neurofibrillary tangles in basal ganglia and brainstem
2. Tauglial inclusions in basal ganglia and brainstem
3. Involvement of the cerebral cortex is more limited
4. There are no Aβ deposits
e. CJD
f. Tertiary syphilis
g. Depression
h. Metabolic (especially hypothyroidism)
i. AIDS dementia complex
3) Explain the role of microglia and cytokines in disease progression in Alzheimer disease
a. Microglial reaction to amyloid
b. Microglial toxicity to neurons: cytokines and oxidative stress
4) Distinguish diseases involving movement disorders according to etiology, pathogenesis, gross and histological
findings, and clinical presentation
a. Corticobasal degeneration
i. Movement disorder, often asymmetrical, and dementia
ii. Atrophy of motor cortex and of parietal cortex, also asymmetrical
iii. Pathology
1. Ballooned neurons**
2. Tau inclusions in glia and, less commonly, in neurons in affected cortex and in the
brainstem – unilaterally*
b. Motor neuron disease-type
i. Small ubiquitin-positive neuronal inclusions with no other pathology
ii. May or may not have clinical motor neuron disease
iii. May or may not be genetic (familial)
1. In familial cases some family members may have dementia, while other may have motor
neuron disease
c. Vascular dementia
i. Generally caused by numerous small strokes
ii. Clinically distinguished by a “stepwise” progression, although this is not always reliable
iii. Synergistic with Alzheimer disease: less AD pathology is required for dementia if vascular disease is
also present
d. Parkinson Disease
i. An idiopathic disease with distinctive Lewy bodies in the substantia nigra
ii. Parkinsonism – a clinical syndrome with many causes, most without Lewy bodies
1. Caused by:
a. Drugs
b. 1918 influenza
c. Multiple system atrophy**
d. Progressive supranuclear palsy**
e. Corticobasal degeneration **
iii. Parkinson’s Clinically:
1. Slowed movements and rigidity
2. Tremor
3. Preservation of higher cortical functions in most cases
4. Some patients show psychiatric changes and progressive dementia: Dementia with Lewy
bodies
iv. Etiology
1. Most cases are sporadic
2. Form familial cases, mutations have been found in genes for:
a. α-Synuclein: a presynaptic protein involved in regulation of dopamine transmission
b. Parkin: a protein involved in α-Synuclein degradation
v. Pathology
1. Degradation of dopaminergic pathways
a. Death of substantia nigra dopaminergic neurons
b. Loss of normal balance in basal ganglia circuits
2. Loss of PIGMENT in substantia nigra**
e. Lewy body dementia
i. α-Synuclein immunochemistry led to recognition of DLB as a common disorder in the 1990’s
1. DLB found in 15-25% of demented patients; many also have Alzheimer’s disease
ii. A dementing illness similar to Alzheimer disease, but often with hallucinations and fluctuation in
symptoms
iii. There are always Lewy bodies in SN, but there is not always parkinsonism
iv. Overlap with Alzheimer disease: most (60-70%) DLB cases also show Alzheimer pathology
f.
Multiple System Atrophy
i. Three formerly separate diseases, now united under the term MSA because of their common
α-Synuclein pathology
1. Striatonigral degeneration (parkinsonian symptoms)
2. Olivopontocerebellar atrophy (cerebellar dysfunction with ataxia)
3. Shy-Drager syndrome (autonomic dysfunction)
ii. The common pathology is α-Synuclein inclusions in affected areas
1. The inclusions are primarily in Oligodendrocytes
g. Huntington disease
i. Age of onset varies tremendously, but generally 30-50
ii. Autosomal dominant: Huntington on chromosome 4
iii. Large, involuntary, “dance-like” movements (chorea) are due to loss of regulation or cortical motor
neurons
iv. Later, dementia
v. The gene can now be identified in prenatal screens
1. CAG trinucleotide repeats in huntingtin gene
a. Impairs mitochondrial function and axonal transport
b. “Gain of Function” mutation
c. Anticipation occurs with CAG repeat expansion (worsening in successive
generation)
vi. Pathology
1. Degeneration of striate nuclei (caudate and putamen)
a. Loss of neurons: especially inhibitory GABA neurons
b. Leads to a disruption in excitation/inhibition balance in basal ganglia
2. Later, cortical atrophy with loss of neurons
h. Spinocerebella ataxias
i. A group of diseases (all genetic): most are dominant, some recessive
ii. Some with trinucleotide repeats
iii. Degeneration of spinal and cerebellar neurons and tracts
1. Friedreich ataxia & ataxia-telangietasia
a. Friedreich ataxia
i. Begins in childhood; death within 5 years
ii. Associated with heart disease and diabetes
iii. GAA repeats in frataxin gene
b. ataxia-telangietasia
i. Begins in early childhood; death by age 20
ii. Telangiectasias of conjunctiva, skin, and CNS
iii. Abnormal response to DNA damage*
Summary of Pathology: CELL TYPES WITH INCLUSIONS
Alzheimer disease
Pick disease
Progressive supranuclear Palsy
Corticobasal degeneration
Motor neuron disease
MND dementia
Parkinson disease
Multiple system atrophy
Summary of Pathology:
Alzheimer disease
Pick disease
Progressive supranuclear Palsy
Corticobasal degeneration
Motor neuron disease
MND dementia
Parkinson disease
Dem Lewy bodies
Multiple system atrophy
NEURONS
NEURONS
NEURONS & GLIA
NEURONA & GLIA
NEURONS
NEURONS
NEURONS
MOSTLY OLIGODENDROCYTES
DISTRIBUTION OF INCLUSIONS
CEREBRAL CORTEX & HIPPOCAMPUS
CEREBRAL CORTEX & HIPPOCAMPUS
BASAL GANGLIA & BRAINSTEM
CEREBRAL CORTEX & BRAINSTEM
SC, BRAINSTEM
CEREBRAL CORTEX & HIPPOCAMPUS
BRAINSTEM (substantia nigra)
BRAINSTEM AND CORTEX
BRAINSTEM, SPINAL CORD, AUTONOMIC
GANGLIA
Molecular pathology of inclusions
NFTs (AD, PSP)
Pick bodies
GCIs of CBD, PSP
GCIs of MSA
Lewy bodies (PD, DLB)
MND inclusions
Tau
++
++
++
Morphology of inclusions
Large, flame shaped
Large, ROUND*
Large, flame shaped or small and irregular
Small and irregular
Small, round
Small, round
Small and irregular
α-synuclein
ubiquitin
+
+
+
+
+
+
++
5) Compare and contrast the various types of lecuodystrophy
a. Leucodystrophies – diffuse degeneration of CNS white matter due to malformed myelin
b. Clinical presentation is dominated by motor signs rather than cognitive decline: spasticity, hypotonia, ataxia
c. Most have onset in early childhood; an exception is ADRENOLEUCODYSTROPHY
d. Types of Leucodystrophies:
i. Krabbe (globoid cell) lecuodystrophy
1. Deficiency in galactocerebroside β-galactosidase
2. Macrophages collect undigested cerebroside, and form multinucleated giant cells (“globoid
cells”) around blood vessels
ii. Metachromatic lecuodystrophy
1. Arylsulfatase A deficiency
a. Defective degradation of sulfatides
b. Accumulated sulfatides stain red-brown with cresyl violet
iii. ADRENOLEUCODYSTROPHY
1. Later onset (school-age childred ages 5-9) or (adult form)
2. Peroxisome defect
3. Adrenal involvement
4. Inflammation
6) Describe the clinical and pathological features of the metabolic, nutritional, and toxic disorders covered in the
lecture and in Robbins
a. Mitochondrial Diseases
i. These involve tissues with high aerobic demands: muscle, heart, retina, and brain
ii. Primarily diseases of young adults
iii. Variants include:
1. MERRF, MELAS, Kearns-Sayre syndrome
2. Leigh Disease
a. Fatal disease of early childhood
b. Caused by various mutations affecting cytochrome c oxidase
c. Resembles Wernicke-Korsakoff
b. Vitamin A deficiency: thiamine (B1)
i. May cause a peripheral neuropathy (beriberi)
ii. May cause degeneration of the mamillary bodies and brain tissue adjacent to CSF pathways that
resembles Leigh disease
iii. W-K syndrome is most commonly seen in associate with cachexia or poor nutrition: alcoholism, GI
disease, cancer, etc
c. Vitamin Deficiencies: B12
i. Degradation of both ascending and descending tracts of spinal cord: subacute combined
degeneration of the spinal cord
ii. Numbness and tingling of legs, proceeding to spastic weakness and paraplegia
iii. Folate deficiency can cause a similar syndrome
d. Metabolic disorders
i. Hypoglycemia – similar to hypoxic injury
ii. Hyperglycemia – dehydration affects brain function  rapid rehydration can cause cerebral edema
iii. Hepatic encephalopathy – hyperammonenia leads to confusion, progressing to coma
1. Can see altered astrocytes in the cerebral cortex
e. Toxic Disorders
i. Carbon monoxide – similar to hypoxic injury
1. Bilateral necrosis of globus pallidus
ii. Methanol – retinal degeneration, bilateral necrosis of putamen
iii. Ethanol – massive, acute ethanol intoxication
iv. Radiation – radionecrosis of brain is due to endothelial injury
v. Methotrexate + radiation injury
1. White matter necrosis
2. May occur months after exposure
Neoplastic Disease of the CNS
Learning Objectives:
1) List the various types of tumors that occur in the central and peripheral nervous system
a. Brain neoplasms are low frequency, but among the most common tumors in children
i. Location: Adults (70% Supratentorial) & Children (70% Infratentorial)
b. Etiology:
i. Radiation – meningiomas, sarcomas
ii. Immunosuppression - lymphoma
iii. Genetic Syndromes –
1. Neurofibromatosis (many tumor types)
2. Tuberous sclerosis (astrocytomas)
3. Von-Hippel Lindau (hemangioblastomas)
c. Special Considerations:
i. Primary malignant tumors infiltrate the brain, while metastatic malignant tumors DO NOT
ii. Limited ability to resect infiltrating tumors
iii. Clinical course is critically dependent on anatomic location of tumor
iv. Primary brain tumors do NOT metastasize outside the CNS
Brain Neoplasms
Gliomas
1) Astrocytoma
2) Ependymoma
3) Oligodendroglioma
Neuronal
1) Ganglion cell tumors
‘Primative’
1) Medulloblastoma
Others
1) Meningioma (from
arachnoid cap cells)
2) Hemangioblastoma
(unknown
histogenesis)
3) Lymphoma
4) Metastatic tumors
Age Preferences in brain neoplasms
Infants ------ Children--------------------------------------Adults---------------------------------------------------Elderly
Poorly differentiated tumors
Medulloblastoma
Pilocytic astrocytoma --------------------
Dysembryoplastic NET
Ependymoma ------------------------
Ganglion cell tumors ---------------
Oligodendroglioma 
Astrocytoma
Schwannoma
Central neurocytoma
Meningioma ------------------------------------------
Glioblastoma ------------
Lymphoma
Most common BRAIN TUMORS
In Adults:
1) Meningioma
2) Glioblastoma
3) Astrocytoma
4) Schwannoma (of C.N. VIII)
5) Lymphoma
Most common SPINAL CORD TUMORS
Of Cord:
1) Astrocytoma
2) Ependymoma
Of Nerve Roots:
1) Meningioma
2) Schwannoma
In Children:
1) Medulloblastoma
2) Pilocytic Astrocytoma
3) Ependymoma
Grading of Neural Tumors
Benign
1)
2)
3)
4)
5)
6)
7)
Low Grade
Pilocytic Astrocytoma
Meningioma
Ganglion cell tumors
Dysembryoplastic NE tumor
Central neurocytoma
Schwannoma
Neurofibroma
1) Astrocytoma
2) Oligodendroglioma
3) Ependymoma
High Grade
1)
2)
3)
4)
5)
Glioblastoma
CNS lymphoma
Medulloblastoma
Primitive NE tumor
Malignant peripheral nerve
sheath tumor
2) For each of these, describe the histogenesis, gross appearance, microscopic appearance, clinical presentation, and
degree of malignancy
a. Astrocytoma
i. Malignant (fibrillary, or diffuse) astrocytomas
1. Low grade astrocytoma (grade II), anaplastic astrocytoma (grade III), glioblastoma (grade
IV)
2. Collectively account for 80% of all adult primary brain tumors
3. Ages 30-60; higher grades at older ages
4. Low grade astrocytomas may progress to higher grade with time
5. Symptoms critically dependent on anatomic site
6. Average survival
a. Low grade astrocytoma: 5 years
b. Glioblastoma: 8-10 months
A) Low grade Astrocytoma
a. Too many astrocytes and too much pleomorphism
B) Anaplastic astrocytoma
a. Intermediate grade with intermediate prognosis
b. Pathology shows still greater cellularity and nuclear pleomorphism, plus mitotic activity
c. Anaplastic astrocytomas generally receive post-operative therapy, unlike low-grade astrocytomas
C) Glioblastoma (high grade astrocytoma)
a. May arise from dedifferentiation of lower grade astrocytoma (more common in younger patients) or..
b. May arise de novo (more common in older patients)
c. Histological features of anaplastic astrocytoma plus:
i. 2 NEW KEY features:
1. Necrosis, due to tumor outgrowing its blood supply
a. The crowded cells around the necrosis (“pseudopalisading’) are migrating away
from the ischemic focus
b. They are also expressing VEGF, which results in…
2. Proliferating “balls” of small blood vessels (microvascular proliferation) responding to
VEGF secreted by ischemic tumor cells
d. **more cellularity, more pleomorphism, plus mitotic figures**
ii. Benign (special type) astrocytomas (WHO grade I)
1. Pilocytic astrocytoma
2. Pleomorphic astrocytoma
3. Subependymal giant cell astrocytomas of tuberous sclerosis
A) Pilocytic astrocytoma
a. Usually seen in children and usually in the cerebellum
i. Midline and associated CYST may cause mass effect
b. Also occur in hypothalamus, optic nerve, brainstem
i. Can cause seizures
c. 2 key histological features: biphasic growth
i. Alternating fibrillar and loose areas
ii. ROSENTHAL fibers
B) Pleomorphic xanthoastrocytoma
a. Superficial, circumscribed, cerebral
b. Benign tumor of children and young adults
c. Striking tumor cell pleomorphism may falsely suggest a high-grade tumor
d. LIPID content (‘xantho’) is only seen in some examples
C) Subependymal giant cell astrocytoma
a. A component of tuberous sclerosis
b. Oligodendroglioma
i. 5-15% of Gliomas
ii. Tumors of adults: 4th-5th decade
iii. Cerebral hemispheres; predilection for WHITE matter
iv. Slow growth
v. Prognosis relatively good
vi. Pathology
1. Delicate branching vessels: “chicken wire pattern”
2. Microcalcifications common
3. “Fried egg” appearance
a. Sheets of uniform tumor cells, nuclei with finely granular chromatin surrounded by
clear halos
c. Neuronal Tumors
i. Ganglion cell tumors
1. Generally benign
2. Large, mature neurons may be the only feature (gangliocytoma) or may occur with a glial
component (ganglioglioma)
ii. Central Neurocytoma
1. Benign
2. Intra- or periventricular lesions
3. Composed of uniform small neurons
d. Dysembryoplastic Neuroepithelial tumor
i. A benign tumor of childhood
ii. Presents with seizures
iii. Multiple cortical nodules show diverse histological patterns
iv. A key pattern is normal neurons that “float” in a mucinous matrix between vessels lined by small
round cells (SPECIFIC GLIONEURONAL COMPONENT)
e. Atypical teratoid/rhabdoid tumor
i. Uncommon, high grade tumor of very young adults
1. -2% of childhood CNS tumors
2. 94% < 5 years of age
3. Generally in posterior fossa
ii. Histologically the tumor shows many different lines of differentiation (teratoid) as well as cells with
round accumulations of filaments (rhabdoid cells)
f.
Ependymoma
i. Seen in both children and adults
ii. Clinical features depends on location
1. Cells arranged around vessels, with thin ependymal processes directed towards vessel,
create a RIBBONED appearance
2. EM shows tiny lumens filled with microvilli and long serpentine cell junctions
iii. Slow growing
iv. Seeding of subarachnoid space in aggressive tumors
v. POOR prognosis (average survival 4 years)
vi. Locations
1. Intracranial
a. Primarily the 4th ventricle
b. Primarily the first 2 decades of life
2. Intraspinal
a. Most common location in adults
b. Most frequent intraspinal glioma**
vii. Ependymoma of 4th Ventricle
1. Disseminates through the CSF
2. Close proximity to pons and medulla makes complete resection impossible*
3. Spinal cord examples are more easily reseceted*
g. Other Ventricular Tumors
i. Subependymoma
1. Benign, small nodules on ventricular surface
a. Small, button-like projection into ventricle, composed of a special cell type, the
subependymal astrocytes
2. Origin from subependymal astrocytes (a special cell type)
3. Usually incidental findings at autopsy
ii. Choroid plexus papilloma
1. Can cause hydrocephalus in children
2. Resembles normal choroid plexus
iii. Colloid cyst of 3rd ventricle
1. “ball valve” effect with intermittent hydrocephalus (intermittent headache, loss of
consciousness)
2. Can cause sudden death
h. Poorly Differentiated Tumors (all are tumors of childhood)
1. ALL of these are known as PNETs (primitive neuroectodermal tumors)
ii. Medulloblastoma (cerebellum)
1. Most common malignant brain tumor of children
2. Solid tumor arising from cerebellar vermis
3. Highly malignant, but sensitive to radiation and chemotherapy: 5-year survival is 75%
4. Disseminates through the CSF pathways
a. Matastases to other parts of the CNS
b. “drop” metastases to cauda equine
5. “Small blue cell” neoplasm
a. Extremelycellular
b. Abundant mitosis
iii. Neuroblastoma (cerebral hemispheres)
1. Neuroblastic (primitive neuronal) differentiation
iv. Pineoblastoma (pineal region)
v. Retinoblastoma (eyes)
1. Photoreceptor differentiation
i.
Primary brain Lymphoma
i. A disease of the elderly
ii. Also a disease of immunosuppression
iii. Preference for periventicular areas
iv. Most are B-cell, large cell lymphomas
v. Tumor cells collect in perivascular spaces (perivascular cuffing, hooping)
j.
Meningioma
i. Benign tumors derived from arachnoid cells
ii. Common locations
1. Convexity meningiomas
2. Skull base meningiomas
iii. Meningiomas do not invade brain, although they may invade the overlying skull
1. May indent brain without invasion
2. Invasion of bones is common, and does not indicate malignancy
iv. Meningioma Pathology
1. Most meningiomas are ‘transitional’ types with whorls of spindled cells wrapped around
more polygonal cells
a. There is often calcifications (psammoma bodies)
2. There are numerous other histological types
k. Hemangioblastoma
i. Benign, vascular tumors of adults
ii. Most common in the cerebellum & often cystic
iii. May produce erythropoietin, causing erythrocytosis
iv. Cell of origin is unknown
v. Multiple hemangioblastomas are seen in von Hippel-Lindau syndrome
l.
1)
2)
3)
4)
Metastatic Tumors
i. Most common origins of brain mets are LUNG, BREAST, SKIN (melanoma), KIDNEY, AND GI
1. These are also the most common tumors
ii. Most frequent site is Grey-White junction in territory of MCA
iii. Mets are generally sharply demarcated (except melanoma)
m. Tumors of Nerve Roots and Peripheral Nerves
i. Schwannoma
1. 8th cranial nerve
2. Spinal nerve roots
3. Peripheral nerves
4. ALL are encapsulated lesions that do not infiltrate the parent nerve
ii. Neurofibroma
1. Spinal roots (rare)
2. Peripheral nerves
3. Almost always part of neurofibromatosis
4. DIFFUSE infiltration of the parent nerve
iii. Malignant (rare)
Schwannoma
Neurofibroma
Schwann cells
1) Schwann cells, neuritis, fibroblasts
Adjacent to nerve
2) Infiltrate nerve
Encapsulated
3) Not encapsulated
Easily resectable without nerve damage
4) Not resectable without sacrificing nerve
Review:
A)
B)
C)
D)
E)
F)
G)
Whorls
spindled cells wrapped around polygonal cells
Psammoma bodies 
laminated calcium
“Fried-egg” cells
small cells with central nuclei and clear cytoplasm
“Chicken-wire” vasculature 
branching small capillaries
Palisade 
alignment of tumor cells with each other
Pseudopalisading 
lining up of tumor cells around a central necrosis
True Rosette 
alignment of tumor cells around a central lumen or a central fibrillar area of cellular
processes
H) Pseudorosette
alignment of tumor cells around blood vessels
Pattern
Whorls, psammoma bodies
Fried-egg cells, chicken-wire vasculature
Pseudopalisades
True Palisades
Perivascular pseudorosettes
Tumor
Meningioma
Oligodendroglioma
Glioblastoma
Schwannoma
Ependymoma
3) Describe the common paraneoplastic syndromes that affect the nervous system
a. Paraneoplastic Syndromes
i. May involve central or peripheral nervous system
ii. Most common tumor: small cell carcinoma of lung
iii. Syndrome may precede clinical manifestations of malignant neoplasm
b. Types of Syndromes:
i. Lambert-Eaton myasthenic syndrome
ii. Stiff-man syndrome
iii. Retinal degeneration
iv. Limbic and brain stem encephalitis
v. Subacute cerebellar degeneration
vi. Subacute sensory neuropathy
4) Describe the clinical and pathological features of common familial tumor syndromes
a. Neurofibromatosis (von Recklinghausen disease)
i. Dominant inheritance
ii. Neurofibromatosis type 1
1. Multiple peripheral nerve neurofibromas
2. Pigmented nodules (Lisch) in iris
3. Café-au-lait spots (melanosis) in skin
4. Elephantiasis: increased connective tissue
5. Increased incidence of malignant tumors
iii. Neurofibromatosis type 2
1. Bilateral schwannomas of 8th CN
2. Increased incidence of meningiomas, gliomas
b. Tuberous Sclerosis
i. Dominant inheritance
ii. Hamartomas in brain and eyes
1. Tubers in cerebral cortex (gliotic, malformed gyri)
2. Subependymal giant cell astrocytoma
3. Retinal flial hamartoma
iii. Angiofibromas of face (adenoma sebaceum) and other areas
c. Struge-Weber disease (encephalofacial angiomatosis)
d. Von hippel-Lindau disease
i. Dominant inheritance
ii. Multiple hemangioblastomas of cerebellum, retina, and spinal cord
iii. Erythrocytosis due to erythropoietin production
iv. Systemic findings
1. Cysts in pancreas and kidneys & renal cell carcinoma & pheochromocytoma of adrenal
Diseases of Peripheral Nerves, Motor Neurons, and Muscle
Learning Objectives:
1) Distinguish the pathological features of primary axonal disease from those of primary demyelinating disease in
peripheral nerves
a. There is normally a 2:1 ratio between axonal diameter and myelin sheath thickness
b. Disease can occur with SECONDARY demyelination because of axonal degeneration or through PRIMARY
demyelination or a mix
c. Axonal Disease
i. Wallerian degeneration: when an axon is cut or damaged
1. Collagen ‘pockets’ may form when Schwann cells have lost their axons and begin to encircle
bunches of collagen fibers
ii. Distal Axonopathy or ‘dying back’ pattern: when a motor neuron is critically ill
1. Macrophage-mediated demyelination: a macrophage surrounds a myelinated axon and
begins to strip away the myelin
2. Segmental demyelination: some axons have myelin while others do not
3. Chronic demyelination and remyelination produces concentric circles of Schwann cells
around axons (“onion bulbs”)
a. These are the most common in hereditary demyelinating diseases
2) Describe the clinical features, pathological features, and etiology of Guillain Barre syndrome, chronic inflammatory
demyelinating poyradiculopathy, hereditary neuropathies, and diabetic neuropathy
a. There are INFECTIOUS causes of diseases of peripheral nerves including:
i. Leprosy
1. Lepromatous leprosy
a. Schwann cell infection, demyelination, and axonal loss
b. Preferential involvement of pain fibers leads to unnoticed limb trauma
2. Tuberculoid leprosy
a. Granulomas in small dermal nerves
b. Involvement is more focal
ii. Diphtheria
iii. Varicella-Zoster
b. Guillain Barre syndrome
i. An acute, life-threatening disease
ii. Rapidly ascending paralysis
iii. Autoimmune-mediated demyelinating disease often follows flu-like illness
1. Focal loss of myelinated axons
2. Can often be caused by campylobacter jejuni infection
iv. Respiratory support has reduced mortality
c. Chronic inflammatory demyelinating poyradiculopathy
i. A chronic, relapsing disease
1. Very sybtle lymphocytic infiltrate in CIDR
ii. Also thought to be autoimmune-mediated
iii. Treatment with corticosteroids or plasmapheresis
d. Hereditary neuropathies
i. Hereditary motor and sensory neuropathies (HMSNs)
1. A large group of disorders, formerly known as Charcot-Marie-Tooth diseases
2. Classified into 3 main groups
a. HMSN type I:
demyelinating with onion bulbs
b. HMSN type II:
neuronal
c. HMSN type III:
genetically and morphologically diverse
3. Generally mild diseases compatible with normal life span
ii. Others
e. Diabetic neuropathy
i. Very common: 50% of diabetics have neuropathy after 25 years of diabetes
ii. Sclerosis of intrafascicular arterioles (diabetic small vessel disease)
iii. Preferential involvement of small fibers, with loss of pain sensation with consequent distal limb
ulcerations
f.
Other common neuropathies
i. Uremic neuropathy
ii. Alcoholic neuropathy
iii. Amyloid neuropathy
iv. Various vitamin deficiencies
v. Long list of neurotoxic environmental toxins, especially lead and arsenic
3) Describe the clinical and pathological features of motor neuron disease (ALS) and of infantile spinal muscular
atrophy (Werdnig-Hoffman disease)
a. Amyotrophic lateral sclerosis
i. Degeneration of motor systems
1. Degeneration of corticospinal tracts
2. Death of anterior horn motor neurons
3. Atrophy of ventral nerve roots (and of muscle)
4. More subtle changes in motor cortex
ii. Clinical correlates
1. Slowly progressive, ascending paralysis
2. Preservation of sensory modalities
3. General preservation of higher cortical functions
iii. Pathogenesis of ALS
1. Proposed pathogenic factors include
a. Deficiency of Vascular Endothelial Growth Factor (VEGF)
b. Oxidative stress from free radicals
c. Excitotoxicity
d. Neurofilament disorganization & microglial inflammation
2. All of these factors might be explained by poor perfusion, with consequent generation of
free radicals and oxidative stress, leading to susceptibility to excitotoxic input and cellular
inability to maintain microfilament organization
3. Many of these factors have been implicated in other neurodegenerative diseases as well
b. Werdnig-Hoffman disease
i. Also known as Infantile Spinal Muscular Atrophy
ii. Presents as neonatal hypotonia (“floppy baby”) – which is not specific
iii. Death within first 1-2 years of life
iv. Mutation of SMN1 (Survival Motor Neuron 1) gene; mechanism of neuron death is unknown
4) Describe the clinical features and basic pathological patterns seen in:
a. Neurogenic and Neuromuscular Junction Diseases
i. Neurogenic atrophy
1. 2 types
a. Motor neuron disease
b. Peripheral neuropathies
2. Early denervation – loss of motor units leads to:
a. Small angular fibers
b. Involvement of both fiber types
3. Chronic denervation – axonal sprouting and reinnervation leads to:
a. Large motor units
b. Fiber type grouping
4. Late denervation – loss of large motor units leads to:
a. Grouped atrophy
ii. Type 2 atrophy
1. Seen with: diffuse, chronic disease, cachexia, corticosteroids
b. Myasthenia gravis
i. Autoantibodies against acetylcholine receptor
ii. Immunological destruction of neuromuscular junction
1. Simplification of postsynaptic folds and compensatory proliferation of presynaptic vesicles
iii. Rapidly fading strength (‘myasthenia’) due to depletion of synaptic acetylcholine
iv. Thymic hyperplasia or thymoma
v. Associated with other autoimmune diseases
c. Inflammatory Myopathies
Pathology
Polymyositis
Dermatomyositis
Inclusion Body Myositis
Infrafascicular inflammation
Extrafascicular inflammation;
perifascicular atrophy
Inclusions; rimmed vacuoles
Pathogenesis
Clinical
Cytotoxic T cells
Humoral
Pain
Pain & rash
Degenerative
Steroid resistant
d. Genetic Myopathies (dystrophic, congenital, and metabolic)
i. Muscular dystrophies
1. Chronic, degenerative diseases
a. Duchenne MD
i. Deficiency of DYSTROPHIN
1. ‘delta’ lesions on myofiber necrosis seen on phase-contrast micro
ii. X-linked; high mutation rate
iii. Onset age 5-6, death in late teens or early 20s
b. Becker MD
i. A milder form of Duchenne
ii. Truncated dystrophin molecule due to Multiple-of-three base deletion
c. Myotonic MD
i. A tri-nucleotide repeat disease
d. Other, rarer forms
i. Deficiency of dystrophin-associated proteins
ii. Congenital myopathies
1. Fixed, non-progressive deficits in muscle
2. Weakness at birth, structural defects
3. Many forms; most are named after their histological appearance
a. Centronuclear
b. Central core
c. Rod body
d. Etc.
iii. Metabolic myopathies
1. Glycogen storage diseases
a. Phosphorylase deficiency (McArdle disease)
i. Mild disease; onset in adulthood
ii. Exercise intolerance, later weakness
b. Phosphofructokinase deficiency
i. Like McArdle
c. Acid maltase deficiency (Pompe disease)
i. Severe neonatal disease
ii. Floppy baby
iii. Death within 1-2 years
iv. Found in lysosomes
2. Lipid storage diseases
a. Muscle Carnitine deficiency
i. A mild disease with generalized weakness
b. Carnitine palmityltransferase deficiency
i. Needed for fatty acid shuttle into the mitochondria
c. Systemic carnitine deficiency
i. A more severe disease with episodes of hepatic insufficiency and
encephalopathy
3. Mitochondrial defects
a. Abnormal mitochondria and “ragged red” fibers
b. May involve muscle, nerve, heart, retina, and/or brain; producing various
syndromes
c. Common feature is abnormal mitochondria
d. “mitochondrial myopathy” – muscle weakness due to mitochondrial dysfunction
e. Critical Illness Myopathy
i. Acute loss of myosin thick filaments
ii. Occurs commonly in patients who are critically ill and respirator-dependent, especially following
treatment with corticosteroids and with neuromuscular blocking agents
iii. Patients recover with time, assuming that their critical illness resolves
iv. Also called intensive care myopathy, thick filament myopathy, or acute quadriplegic myopathy
v. Loss of myosin filaments leads to loss of green staining on Gomori’s trichrome
Notes:
A) ‘Myopathic’ changes in muscle
a. Myofiber degeneration
i. Altered staining properties of fibers
ii. Vacuolization, macrophage invasion, etc
b. Myofiber regeneration
i. Central, enlarged nuclei
ii. Basophilia due to increased RNA content
c. Accompanying changes
i. Variation in fiber sizes
ii. Endomysial fibrosis with loss of polygonal outlines
B) Dystrophin  the abnormal protein in Duchenne and Becker dystrophies, anchors the cytoskeleton to the
extracellular matrix through several dystrophin-associated glycoproteins (DAGs)
C) Causes of neonatal hypotonia
a. POOR prognosis
i. Infantile spinal muscular atrophy (Werdnig-Hoffman disease)
ii. Acid Maltase deficiency
b. BETTER prognosis
i. Congenital myopathies
Seizures and Epilepsy
Learning Objectives:
1) Recognize common seizure types
a. Seizure – clinical event associated with an abnormal, excessive, and hypersynchronous electrical discharge
in a group of cortical neurons
b. Epilepsy – recurrent and unprovoked seizures
i. Epidemiology
1. Approximately 1% of the population suffers from epilepsy
2. About 2.5 mil patients in USA alone
3. Cumulated adjusted lifetime risk 1.3-3.1%
4. 3rd most common neurological disorder
5. Occurs with increased excitation or reduced inhibition
ii. Etiology
1. Cryptogenic (61%)
2. Trauma
3. Vascular (15%)
4. Genetic
a. Inherited channelopathies (single-gene or complex inheritance)
5. Metabolic
6. Tumor
c. ILAE classification
i. Partial Seizures
1. Simple partial seizures
a. Consciousness unimpaired
2. Complex partial seizures
a. Consciousness impaired
ii. Generalized Seizures
1. Primary generalized
a. Absence
b. JME
2. Secondary generalized
a. Lennox-Gastaut
d. Temporal lobe seizures
i. Most common form of partial seizures
ii. Aura in 20-90%
iii. Commonly arins epigastric sensation
iv. Motionless stare
v. Orofacial or limb automatisms
vi. Prominent post-ictal confusion
e. Frontal lobe seizures
i. Frequently confused with non-epileptic events
ii. May occur in clusters
iii. Aura similar to temporal lobe seizures
iv. Bizarre, stereotypical movements including thrashing, bicycling, and tonic/dystonic posturing
f.
Parietal lobe seizures
i. Sensorimotor involvement common
ii. Transient sensory symptoms
g. Occipital lobe seizures
i. Uniformed visual hallucinations including flashing lights
ii. Ictal blindness
iii. Forced version of eyes and head
h. Neonatal seizures
i. Are almost ALWAYS FOCAL
ii. Are likely to involve temporal lobe
iii. Last 2-3 minutes
iv. Migrate
v. Are associated with a wide variety of ictal morphology
1. Focal clonic
2. Focal tonic
3. myoclonic
i.
Epilepsy syndrome during 1st year of life
i. Infantile spasms
ii. Benign myoclonic epilepsy of infancy
iii. Severe myoclonic epilepsy of infancy
iv. Idiopathic or cryptogenic
v. Symptomatic
2) Identify role of various modalities in diagnosis of epilepsy
a. Imaging in Epilepsy
i. MRI superior to CT
1. MRI yield in TLE
a. Hippocampal sclerosis  57.0%
b. Foreign tissue lesion  13.5%
c. Cortlical dysplasia  10.5%
ii. Special coronal sequences through medial temporal lobe, hippocampus, and amygdale in patients
with intractable partial epilepsy
iii. FLAIR
iv. No imaging study required in idiopathic primary generalized epilepsy
b. Role of EEG in Epilepsy
i. Confirm diagnosis
1. Yield of 1st EEG for interictal abnormalities is 50-60%
2. Serial EEG increases the yield to 92%
3. Normal EEG is about 8% after serial EEGs
a. EEG abnormal in .5-3.5% of people without history of epilepsy
ii. Classify seizure type and epilepsy syndrome
iii. Guide therapy
1. Prognosis
2. Initiation of AED
3. Discontinuing AEDs
iv. Non-convulsive status epilepticus
c. Monitoring Strategies
i. Synchronized video-EEG monitoring (surface electrodes)
ii. Intracranial recording
1. Depth electrodes
2. Subdural electrodes
3) Understand the rationale for treatment of epilepsy
a. Is epilepsy a progressive disorder?
i. Short-term problems
1. Driving, work, psychosocial issues
ii. Long-term problems
1. Memory loss, depression, AED adverse effects
b. Which drug and why?
i. Seizure type
ii. Etiology and EEG
iii. Patient characteristics
iv. Conventional vs new agents
v. Cost
vi. Appropriate 1st line lagent will control seizures in 70% of patients
vii. Need to avoid sudden discontinuation of drugs as it may lead to withdrawal seizures
viii. Need to avoid side effects with slow titration and control serum levels
c. Single seizure (treat?)  70% recur into early epilepsy (monotherapy – 1st line)  20-30% recur into
chronic epilepsy (polytherapy with 1st and 2nd line drugs)  80% recur into Pharmaco-resistent epilepsy 
should now consider surgery or experimental drugs
d. Medical Intractability – inability to achieve acceptable seizures control despite adequate trials with a
sufficient number of drugs at does that are associated with no side effects or with acceptable side effects
only
e. Refractory Epilepsy
i. Medications 
40-60% seizure free
ii. Surgery 
50-80% seizure free
iii. Vagal nerve stimulator 
8-10% seizure free
iv. Ketogenic diet 
30% seizure free
4) Understand the role of medical versus surgical therapy
a. Epilepsy Surgery
i. 75,000 patients in USA with intractable epilepsy are possible surgical candidates
ii. Early surgery may prevent disabling cognitive impairment especially in children
iii. Early surgery also improves the chances of being seizure free post-op
iv. Candidates
1. Medically intractable epilepsy
2. Localized seizure focus such as mesial temporal sclerosis
3. Cortical dysplasias
4. Tumors
v. Contraindications
1. Primary generalized epilepsies
2. Progressive neurological disease
3. Medical illness
4. Psychosis
vi. Surgery Evaluation
1. Positron emission tomography (PET)
2. Ictal single photon emission tomography (SPECT)
3. WADA (memory & language)
4. f MIR
5. MRS
vii. Results of Epilepsy Surgery
1. Procedure: anterior temporal lobectomy and or amygdalohippocampectomy
2. Indication: intractable epilepsy with a mesial temporal focus
3. Seizure free: 66-68%
4. Improved: 22%
b. Vagus Nerve Stimulation
i. Indications
1. Refractory epilepsy
2. Respective surgery not an option
3. Failed respective surgery
ii. Contraindications
1. Cardiac or respiratory disease
2. Non-epileptic seizures
iii. VNS Pulse Generator & Lead
1. Pacemaker like pulse generator
2. Bipolar lead with two stimulating electrodes
3. Intermittent stimulation
a. 30 seconds on/5 minutes off
4. Mean decrease in seizure frequency 25-28%
a. 8% were seizure free
c. Discontinuing Therapy
i. Consider discontinuing AED if seizure free for 2 or more years
ii. Taper over a 6 week to 3 month period
iii. MOST RELAPSES occur in the 1st six months
iv. Remission in about 70% after 2 year seizure free period
d. Driving
i. 33% report a seizure while driving
ii. 55% had an accident while driving
Movement Disorders: diagnosis and treatment
Disorders – don’t forget that everything in lecture can be caused by drugs and can also be treated by drugs
HYPERKINETIC DISORDERS:
1) Essential Tremor/ Familial tremor
a. Disease MOST OFTEN misdiagnosed as Parkinson’s***
b. Associated with activation of muscles – will go away with relaxation
c. Postural/kinetic
d. Treatment
i. Alcohol
ii. Beta-blockers
iii. Mysoline, Klonopin,
iv. Topamax (topirimate) – one of the better new drugs
v. Thalamic deep brain stimulation
2) Huntington’s Chorea
a. Autosomal dominant/C AG repeat
i. Average age of onset of symptoms is 40-42 (after onset, life span is about 15 years)
1. Nowadays
ii. With increasing repeats, age of onset becomes younger and younger
iii. Huntington gene protein affects many pathways which makes target for treatment difficult
b. Clinical syndrome
i. Psychiatric
ii. Movement disorder
iii. Cognitive
c. Treatment – mood, anxiety, anti-psychotics
i. Antidepressants – manipulating serotonin
ii. Neuroleptics and atypical antipsychotics
iii. Monoamine depleting agents
iv. Benzodiazepines
v. Anti-epileptics for mood stabilization
3) Hemiballismus
a. Large amplitude, choreiform (one-sided, hence HEMI)
b. Subthalamic nucleus infarction
c. Usually self-limited
d. Treatment
i. Neuroleptics
ii. Monoamine depleting agents
4) Tourette’s Syndrome
a. Autosomal dominant with variable penetrance and sex dependence
b. Clinical syndrome
i. Disabling motor/vocal tics
ii. Onset before age 18
iii. Duration > 1 year
iv. Idiopathic
c. Tics may be simple or complex (copralalia)
i. Needs a vocal tic*
d. Associated features
i. OCD & ADHD
e. Treatment – YOU CAN TREAT WITHOUT GOING AFTER DOPAMINE
i. Neuroleptics
ii. Monoamine depletors
iii. Clonadine
iv. Klonopin
5) Myoclonus
a. Lightning-like interruption in normal muscle activity
i. Can be caused by many different drugs
b. Positive and/or negative
i. Positive – gain tone
ii. Negative – lose tone (will fall if you lose tone in lower extremeties)
c. Types: focal, multifocal, action, reflex, generalized
i. Acquired type the most common (often from cardiac arrests – ischemic damage to brain)
d. Treatment
i. Klonopin
ii. Mysoline
iii. Depakote
iv. Keppra – probably the best myoclonus drug
6) Dystonia
a. Involuntary contraction (e.g. writer’s cramp)
b. Types: focal, segmental, action, task-specific, generalized
c. Treatment
i. Anti-cholinergics
ii. Baclofen – central alpha-adrenergic agonist
iii. BOTOX – botulinum toxin
7) Restless Legs
a. A disorder characterized by an almost irresistible urge to move, usually associated with disagreeable leg
sensations, worse during inactivity, and often interfering with sleep
i. More common in pregnancy because of iron deficiency
ii. Very stereotyped, repetitive movement almost always– more often in older adults
b. Frequently accompanied by Periodic Leg Movements of Sleep (PLMS)
c. Syndrome
i. Creepy, crawly, tingly
ii. Like worms or bugs crawling under the skin
iii. Painful, burning, or achy
iv. Like water running over the skin
d. Secondary RLS
i. Iron-deficiency anemia
ii. Uremia (20-40% of dialysis patients)
iii. Pregnancy (up to 27%)
iv. Neurological lesions
1. Both spinal cord and peripheral nerve lesions
v. Drug-induced
1. Tricyclics, SSRI’s, lithium, dopamine blockers
e. Treatment
i. Benzodiazepines
ii. Narcotics
iii. Dopamine agonists – for people with significant problems
iv. In the past, Levodopa was given (very short-lived) – symptoms just appear earlier in the day
HYPOKINETIC DISORDERS
Tauopathies
1) CBGB
2) PSP
Parkinsonian Syndromes
Synucleinopathies
Multiple System Atrophy
Lewy Body diseases
1) SND
1) PD
2) SDS
2) PDD
3) OPCA
3) DLB
1) Classification of Parkinson Syndromes in a community
a. Idiopathic PD – 85% of PS cases
b. Vascular Parkinson’s syndrome (multiple strokes) – 3%
i. Abrupt onset, usually unilateral
ii. Step-wise or no progression
iii. Other signs – hemiparesis, aphasia, hyperreflexia
c. Drug-induced parkinsonism (DIP) – 7-9%
i. Don’t really see this anymore because we’re using atypical anti-psychotics now
d. MSA (SDS, SND, OPCD) – 2.5%
e. PSP – 1.5%
f. CBGD – 0.5%
2) Increased Mortality with Parkinsonism:
a. Untreated IPD – average life span 7-9 years
b. Treated IPD – average life span 15-20 years
i. Life-span doubled after the advent of levodopa
ii. Dementia lowers life-span
c. Parkinson’s Plus Syndrome – average life span of 7-9 years
i. Mostly untreatable with medicine (dopaminergic stimulation)
ii. Early gait and balance problems
1. Rapid progression, dysphagia, falling, older age at diagnosis, dementia
2. Death caused by: aspiration pneumonia, autonomic failure, cancer
iii. Many different areas of the brain affected
1. Shy-Drager Syndrome
a. Parkinsonism
b. Autonomic failure*
i. Drop in systolic and diastolic blood pressure
c. Urinary/sexual dysfunction
i. Persistent, involuntary partial or total bladder emptying
ii. Erectile dysfunction in males
2. Multiple system Atrophy – Striatonigral Degeneration
a. Bradykinesia – very debilitating
b. Rigidity
i. People become locked inside their bodies and cannot move voluntarily
c. Postural instability
d. Tremor (postural, resting, or both)
e. Poor or no responsiveness to levodopa
3. Progressive Supranuclear Palsy
a.
b.
c.
d.
Parkinsonism
Onset after 40, progressive
Supranuclear gaze palsy
Other
i. Dysarthria/dysphagia
ii. Falling early
4. Corticobasal Ganglionic Degeneration
a. Parkinsonism
b. Cortical signs
c. Dystonia
d. Irregular action/postural tremor
e. Myoclonus
f. Alien limb
Diseases of the Peripheral Nervous System
Learning Objectives:
1) Diseases of PNS
a. Lower Motor Neuron – LMN
i. Anterior horn cell
ii. Root
iii. Nerve
iv. Neuromuscular junction
v. Muscle
b. CNS
i. Pyramidal tract (UMN)
ii. Cerebellum – coordination
iii. Basal ganglia – muscle tone, posture
Upper Motor Neuron
1) Increased tone (spastic)
2) Brisk reflexes
3) Plantars upgoing (babinski reflex)
4) No atrophy*
5) Weakness
1)
2)
3)
4)
5)
6)
Lower Motor Neuron
Reduced tone
Absent reflexes
Downgoing
Marked atrophy*
Fasiculations
weakness
c. Muscle Diseases
i. Involve larger muscles – proximal muscles of arms and legs
ii. Difficulty going up stairs, getting up from sitting position, combing hair
iii. Deep tendon reflexes normal until late stages
d. Inherited – long history, usually years, other family members affected
e. Acquired – short history, weeks or months, other family members not affected
i. Inflammatory – polymyositis, dematomyositis
1. Polymyositis/ Dermatomyositis
a. Autoimmune disease of muscle
b. Painful or painless progressive proximal muscle weakness
c. There may be associated skin involvement with skin rash
d. The condition is then called dermatomyositis
e. Rarely cardiac muscle involved
f. Diagnosis: associated with underlying malignancy in adults > 60
i. Elevated muscle enzymes - creatine phosphokinase (CPK), aldolase
ii. Biopsy shows muscle inflammation and necrosis
iii. Very good response to corticosteroids
ii. Metabolic – endocrine disease
a. Thyroid Disease
i. Hyperthyroid myopathy
1. Middle-aged men
2. Marked wasting of muscle with weakness
3. Hypercatabolic state with muscle breakdown
4. Inflammation and infiltration of eye muscles and retroorbital
tissues can occur with proptosis and restriction of eye movements
5. Treatment of hyperthyroid state restores muscle function to
normal
ii. Hypothyroid myopathy
1. Can cause muscle weakness in children and adults
2. Muscles stiff, bulky, and weak
3. Muscle hypertrophy can occur in children
4. Thyroid hormone replacement restores muscle function to normal
b. Adrenal disease
i. Excess of steroids from overactive adrenal glands (Cushing’s syndrome) or
iatrogenic
ii. Iatrogenic cases likely with prolonged duration of therapy
iii. Fat deposition over face, abdomen with muscle weakness
iv. Treatment of adrenal over-activity or decrease in steroid dose reverses
muscle weakness
c. Parathyroid disease
2. Drugs
a. Focal myopathy
i. Pentazocine, Demerol, heroin
b. Generalized myopathy
i. Statins, procainamide, AZT, steroids, cyclosporine
c. Rhabdomyolysis
i. Cocaine, heroin, phencyclidine
3. Alcohol
4. Potassium
a. Muscle weakness can be associated with decrease or increase in serum K+
b. Muscles become weak with fall in serum K < 3Meq/L (normal 3.5-5)
i. Increased to > 7 Meq/L of K+ usually occurs in renal failure
1. High levels of K+ can cause cardiac arrest
2. Hemodialysis is needed treatment
c. Loss of potassium can be due to GI or renal causes
d. GI causes include severe diarrhea, prolonged vomiting, laxative abuse
e. Renal causes include diuretic therapy
f. Replacement of serum potassium causes dramatic improvement in weakness
iii. Toxic – drugs such as statins
iv. Infectious – trichinosis
1. Trichinosis is a parasitic infection acquired by ingestion of improperly cooked pork
2. Caused by Trichinella Spiralis
3. Larvae pass through intestinal wall into blood stream
4. Carried to muscles where they cause inflammatory reaction with pain, weakness
5. Arms and diaphragm more severely affected
6. Treated with steroids and antiparasitic drugs
2) Inherited Muscles Diseases of the PNS
a. X-linked
i. Duchenne muscular dystrophy
1. Males affected, onset in 3rd year of life
2. Proximal weakness of extremites and muscle hypertrophy
3. Respiratory and cardiac muscle involved
4. Wheelchair bound by age 10-12
5. Pathogenesis
a. Marked by elevation of CPK
b. Encoded by gene Xp21 on chromosome X
c. Carriers and affected fetus diagnosed by genetic testing
d. Muscle lacks protein called dystrophin
i. Dystrophin stabilizes muscle membrane and its absence allows calcium
mediated damage
ii. Beckers muscular dystrophy
iii. McArdles disease – inherited deficiency of the enzyme myophosphosphorylase
b.
c.
d.
e.
1. The enzyme generates glucose from glycogen in active muscle
2. With exercise enough glucose is not generated and muscle pain and cramps occur
3. With vigorous exercise, muscle breakdown may occur
Autosomal Dominant
i. Myotonic dystrophy
ii. FSHD
Autosomal Recessive
i. Limb girdle dystrophy
Types:
i. Dystrophies
ii. Metabolic muscle disease
iii. Mitochondrial diseases
1. Due to inherited defects in mitochondrial function
2. Brain and skeletal muscle especially vulnerable in these cases
3. Diseases called mitochondrial encephalomyopathies
4. Muscle weakness associated with CNS symptoms like strokes, migraines, and seizures
iv. Neuromuscular Junction Diseases
1. Myasthenia Gravis – autoimmune disease with circulating antibodies to acetylcholine
receptor
a. Majority of patients have involvement of ocular and bulbar muscles
b. Symptoms include ptosis, diplopia, dysphagia, dysarthria
c. Weakness episodic, precipitated by exertion and relieved by rest
d. Later, limb and respiratory muscles involved
e. Sensations and deep tendon reflexes normal
f. Pathogenesis:
i. Circulating Abs to AChR
ii. Ab disrupts transmission at NMJ
iii. Thymus involved inproduction of antibodies to AChR
iv. 90% of patients have abnormal thymus gland
v. 70% have hyperplasia and 20% have thymomas
g. Diagnosis:
i. Measure receptor antibody in blood
ii. Positive in 60-80% of patients
iii. Image chest for thymic enlargement
h. Treatment:
i. Cholinesterase inhibitors – prolong life of Ach at NMJ
ii. Immunosuppressive agents & possible thymectomy (for invasive tumor)
i. Drug Interactions in Myasthenia Gravis
i. Can unmask or worsen MG
ii. Do so usually by interfering with Ach release (presynaptic)
iii. May also interfere with action of Ach on the receptor (postsynaptic)
DRUGS
i. Antibiotics – gentamicin
ii. Cardiovascular drugs – beta blockers, calcium channel blockers, procainamide
iii. Psychotropic – phenothiazines
iv. Rheumatologic – d pencillamine
v. Anesthetic agents – NM blocking agents
3) Diseases of PNS
a. Polyneuropathy – symmetrical involvement of nerves in arms and legs
i. Signs and symptoms usually begin in arms and then spread to legs
ii. Distal involvement predominant – ‘glove and stocking’ distribution of deficit
iii. Deep tendon reflexes lost very early due to involvement of group 1a afferents of muscle spindle
b. Axonal Disease – involving primarily the axon:
i. Most neuropathies due to metabolic disease, toxins, deficiency states
1. Metabolic – diabetes, renal failure, hypothyroidism
2. Deficiency diseases – b12, b1, b6, niacin
3. Drugs – vincristine, cisplatin, taxol
4. Toxins – arsenic, lead
5. Connective tissue disease – lupus, rheumatoid arthritis
c. Demyelinating disease – involving the myelin sheath
i. Inflammatory - Guillain barre syndrome
ii. Infection – HIV, Lyme disease, leprosy
iii. Paraneoplastic
iv. Inherited
1. Pathogenesis:
a. Due to mutations in genes controlling peripheral myelin synthesis with formation of
defective myelin
b. Long standing complaints
c. Skeletal abnormalities like pes cavus because of muscle weakness earl in life
interferes with normal bone growth
d. Other family members affected, may have asymptomatic skeletal abnormalities
e. In some types, myelin unduly susceptible to pressure
d. Other inherited neuropathies due to excessive or abnormal deposition of proteins, lipids, etc.
i. Amyloid can be deposited in nerves and other organs like heart, kidneys – called AMYLOIDOSIS
ii. Affects smaller diameter unmyelinated fibers carry pain and temperature sensation and are part of
the ANS
iii. Patients have pain and autonomic dysfunction
iv. In Refsums disease, phytanic acid accumulation in body causes involvement of nerves, eyes, skin,
and heart
e. Mononeuropathy
i. Weakenss and sensory symptoms in distribution of a single nerve, eg. Carpal tunnel
ii. Causes:
1. Compression – median nerve at wrist (carpal tunnel syndrome), ulnar nerve at elbow,
peroneal nerve at knee
2. Trauma – laceration, blunt injury
3. Ischemia – vasculitis, diabetes
4. Infiltration – sarcoidosis
5. Infection – leprosy
f.
Root Disease - radiculopathy
i. Commonest cause is degenerative disc disease
ii. Most common at C5-6, 6-7 & L5-S1
iii. Asymptomatic involvement – one arm or leg
iv. Root pains a characteristic feature
v. Motor and sensory defect in distribution of a specific root
g. Anterior Horn Cell Disease
i. Manifestations purely MOTOR
ii. Wasting prominent
iii. Prominent fasiculations
iv. Can be acute or chronic
1. Poliomyelitis - acute
a. Viral infection of AHC
b. Virus travels by bloodstream to nervous system and localizes in AHC destroying
them, causing acute flaccid weakness
c. Eradicated by effective immunization
d. West Nile virus now more common cause of viral AHC
2. Lou Gehrigs (ALS) – chronic
a. Also called motor neuron disease
b. Degeneration of upper and lower motor neurons
c. Muscle atrophy, weakness, fasiculations, brisk reflexes, upgoing plantars
d. Also involves muscle of speech, swallowing, breathing
h. Investigations
i. Electromyography (EMG) & nerve conduction (NC) studies
ii. Nerve and muscle biopsy
iii. Muscle enzymes – creatine phosphokinase (CPK), aldolase
iv. Imaging of spine/roots – MRI
v. Laboratory tests – glucose, vitamin levels, HIV, lyme disase