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Neuropathology III
Demyelinating diseases
Demyelinating diseases
loss of myelin → changed ability of axons to transmit signals → various
neurological deficits
white matter affected
Multiple sclerosis
most common demyelinating disorder (1/1000 persons)
any age, usually young adults, females affected twice as often as males
geographical distribution: increase with the distance from equator, more
common in northern hemisphere
autoimmune disease, combination of environmental and genetic factors
transmissible agent (virus) proposed, but not identified
Clinical course
relapses (episodes of new symptoms) followed by remissions (episodes of
recovery, usually not complete)
gradual accumulation of neurologic deficits
mild changes in cognitive functions
retrobulbar neuritis (unilateral visual impairment): frequent initial manifestation
spinal cord involvement: motor and sensory impairment, spasticity, flaccid
bladder
CSF findings: oligoclonal bands (↑IgG)
Morphology
Plaques
multiple, well-circumscribed, irregularly shaped, gray-tan lesions
beside ventricles (perivascular), optic nerves, optic chiasma, brain stem,
cerebellum, spinal cord
Active plaque
ongoing myelin breakdown
sharp demarcation
abundant macrophages (myelin debris), lymphocytes (perivascular cuffs), axons
relatively preserved but reduced in number
Inactive plaque
inflammation disappeared, reactive gliosis
loss of myelin stain (luxol blue)
Acute disseminated encephalomyelitis
immune-mediated demyelination after variety of systemic infectious diseases
(measles, varicella, rubeola, influenza, parotitis, scarlet fever)
cross-reaction with myelin antigens
children
diffuse involvement of white matter
perivascular lymphoplasmacytic infiltrates and demyelinating areas
headache, lethargy, coma
fatal in 20%, complete recovery in remaining cases
Degenerative diseases
Degenerative diseases
unknown etiology
progressive loss of neurons or their systems
can result in dementia and severe motor impairment
Dementia: memory and cognitive impairment with preserved normal level of
consciousness
Degenerative diseases of cerebral cortex
Alzheimer disease
most common cause of dementia in the elderly
rare before 50 years of age, increasing incidence with age
sporadic, 5-10% familial
Etiology and pathogenesis
abnormal enzymatic cleavage of APP (amyloid precursor protein) → deposition of
Aβ (β-amyloid)
ApoE4 (apolipoprotein ε4) → ↑deposition of Aβ
deficiency of SORL1protein → altered intracellular APP trafficking → ↑generation of
Aβ
Aβ effects on neurons:
altered neurotransmission
toxicity for neurons and synapses
local inflammatory response → neuronal injury
mechanical effect on axons and dendrites
hyperphosphorylation of tau protein → redistribution and aggregation → neuronal
dysfunction and death
Morphology
cortical atrophy (frontal, temporal, parietal lobes): widening of sulci, weight less
than 1000g, hydrocephalus e vacuo (compensatory dilatation of ventricles)
Neuritic (senile) plaques
extracellular
central amyloid core
spherical aggregation of dilated and tortuous neurites (dystrophic dendrites)
reactive microglia and astrocytes
silver impregnation, immunohistochemistry
Neurofibrillary tangles
intracellular
basophilic fibrillary structures encircling or displacing nucleus
hyperphosphorylated tau protein
Loss of neurons
Amyloid deposition in the wall of small vessels
Hirano bodies (eosinophilic rod-shaped intracellular structures)
Clinical presentation
insidious impairment of higher cognitive functions
alteration of behaviour
disorientation, memory loss, aphasia, immobility
death from intercurrent infection (bronchopneumonia)
Pick disease (atrophia cerebri circumscripta
progressiva)
rare
6th decade
Clinical presentation
similar to Alzheimer disease
death within 1 to 10 years
Morphology
severe atrophy of frontal and temporal lobe („walnut appearance“)
severe neuronal loss, reactive gliosis
swelling of neurons, intracytoplasmatic inclusions (Pick bodies)
Degenerative diseases of extrapyramidal system
Parkinsonism (clinical syndrome)
rigidity
diminished facial expression (masked facies)
slowness of voluntary movements
festinating gait (progressively shortened accelerated steps)
„pill-rolling“ tremor
dementia in 10-15%
Causes of parkinsonism
Parkinson disease
postencephalitic (encephalitis lethargica)
drug-related: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, contaminant
of syntethic heroin), chlorpromazine, haloperidol
chronic cerebral injury in boxers
ischemic damage
Parkinson disease
most common cause of parkinsonism
unknown etiology
late middle life
degeneration of dopaminergic system in substantia nigra and corpus striatum
Morphology
pallor of substantia nigra
loss of pigmented neurons associated with gliosis
remaining neurons: shrinkage, vacuolation, Lewy bodies (intracytoplasmic
eosinophilic round inlusions, dense core and pale halo)
Natural history
slow progression over 10-15 years to eventual immobility
death from intercurrent infection (bronchopneumonia) or trauma (frequent falls)
Huntington disease
inherited autosomal dominant disease
mutation in gene located in 4p (huntingtin)
degeneration of striatum (caudate nucleus and putamen)
Morphology
striking atrophy of caudate nucleus, lateral and third ventricles dilatation
severe loss of neurons in striatum, gliosis
Clinical presentation
onset in the fourth and fifth decade
movement disorders: chorea (involuntary jerky movements)
cognitive dysfunction progressing to dementia
relentless progressive course of about 15 years, death from intercurrent infection
Degenerative diseases of motor neurons
Amyotrophic lateral sclerosis
late adult life
sporadic, 5-10% familial (autosomal dominant inheritance)
degeneration and loss of upper and lower motor neurones
unknown etiology
Morphology
loss of motor neurons in precentral gyrus → atrophy of descending corticospinal
tracts (lateral portion of spinal cord) → loss of motor neurons in anterior horns of
spinal cord → loss of myelinated fibers of anterior roots → neurogenic atrophy of
skeletal muscles („amyotrophy“)
Clinical presentation
spasticity, hyperreflexia, abnormal plantar reflex (loss of upper motor neurons)
weakness, later atrophy and fasciculations (twitching) of muscles (loss of lower
motor neurons)
Acquired metabolic and toxic disorders
Vitamin deficiencies
Thiamine (B1)
Wernicke encephalopathy
chronic alcoholism, excessive vomiting, malabsorption (small bowel diseases)
Morphology
foci of hemorrhae and necrosis in mammillary bodies and besides third and fourth
ventricles
Clinical presentation
disturbances of consciousness, abnormal eye movements, ataxia
Korsakoff syndrome
short-term memory loss, confabulations
may be irreversible
common association with Wernicke encephalopathy (Wernicke-Korsakoff sy)
Vitamin B12 deficiency
subacute combined degeneration of spinal cord
both ascending and descending tracts affected
ataxia, spastic weakness of lower extremities, complete paraplegia
Acquired metabolic disorders
Hypoglycemia
similar to global hypoxia
Purkinje cell relatively spared
Hyperglycemia
uncontrolled DM (ketoacidosis, hyperosmolar coma)
confusion, stupor, coma
glucose transported into neurons → osmotic accumulation of water
Hepatic encephalopathy
liver fails to clear ammonia → changes in brain function
alteration of synaptic transmission, damage of astrocytes
depressed level of consciousness, coma
flapping tremor (asterixis)
Toxins
Carbon monoxide
hypoxia
injury of globus pallidus
Ethanol
cerebral atrophy (white matter, anterior portion of cerebellar vermis)
dementia, unsteady gait, nystagmus
fetal alcohol syndrome: microcephaly, intellectual impairment
Methanol
degeneration of retinal ganglion cells, swelling of axons in optic disc → blindness
necrosis of basal ganglia and deep white matter
Methotrexate
arachnoiditis
disseminated necrotizing leucoencephalopathy (white matter of hemispheres,
brainstem and cord)
Morphine, heroin
ischemic damage of globus pallidus and deep white matter of hemispheres
Lead
brain swelling, congestion, petechial hemorrhages
Inborn metabolic errors
Neuronal storage diseases
congenital defect of lysosomal enzymes
accumulation of intermediary metabolite within neurons (and sometimes glia) →
enlargement of cytoplasm, subsequent loss (brain atrophy) and reactive gliosis
GM2 gangliosidosis (Tay-Sachs disease)
autosomal recessive inheritance
defect of hexosamidase A → accumulation of GM2 ganglioside
neurons with abundant, finely granular cytoplasm
children
cognitive impairment, blindness, seizures, death within 3-5 years
Niemann-Pick disease
autosomal recessive inheritance
defect of sphingomyelinase → accumulation of sphingomyelin
neurons with enlarged cytoplasm
lipid-laden macrophages (Niemann-Pick cells) in white matter, arachnoid, choroid
plexus, bone marrow, liver, spleen, lymph nodes
clinical presentation at 6th month: cognitive impairment, muscle rigidity, kachexia,
death within 3 years
Leucodystrophies
inherited disorders of myelin synthesis or turnover
autosomal recessive or X-linked inheritance
defects of lysosomal enzymes, mutations of myelin proteins
Morphology
atrophy of white matter, gray and translucent
enlargement of ventricles
myelin loss, lipid-laden macrophages
Clinical presentation
normal at birth
progressive impairment of motor functions, spasticity, hypotonia
Several types:
metachromatic leucodystrophy (defect of arylsulphatase A)
Krabbe disease (defect of galactocerebroside-β-galactosidase)
adrenoleucodystrophy (peroxisomal defects)
Malformations and developmental disorders
Neural tube defects
failure of closure or reopening
Cranioschisis totalis
defect of closure of the whole neural tube
Anencephaly
absence of brain and top of skull
area neurovasculosa on skull base
Spina bifida occulta
simple agenesis of posterior vertebral arches
asymptomatic, hyperpigmentation of overlying skin
Meningocele, meningomyelocele
extension of malformed spinal cord tissue and meninges through defect of
veretebral column
lumbosacral region
motor and sensory deficits in lower extremities
impaired bowel and bladder control
possibility of infection
Encephalocele
malformed brain tissue extends through skull defect
occipital region, posterior fossa
Forebrain malformations
Microencephaly
usually associated with microcephaly
chromosomal abnormalities, fetal alcohol syndrome, intrauterine HIV infection
Lissencephaly (agyria)
disorder of neuronal migration and diferentiation during brain development
absence of normal gyration (smooth surface)
abnormally thick and four-layered cortex
Polymicrogyria
increased number of irregularly formed gyri
Holoprosencephaly
brain not divided into hemispheres and lobes
Posterior fossa anomalies
Arnold-Chiari (Chiari II) malformation
small posterior fossa, cerebellar vermis extends downward through foramen
magnum
hydrocephalus
Chiari I malformation
cerebellar tonsils extend through foramen magnum
hydrocephalus, compression of medulla (cranial nerve deficits)
Dandy-Walker malformation
absent cerebellar vermis replaced by ependymal cyst
Spinal cord abnormalities
Hydromyelia
dilatation of central canal
Syringomyelia
fluid-filled cleft-like cavity within cord
congenital or acquired (trauma, tumour)
adjacent reactive gliosis
Diseases of peripheral nerve
Reactions of peripheral nerve to injury
Axonal degeneration
damage to the neurone (neuronopathy) or axon (axonopathy)
axonal segment distal to the injury: fragmentation of axon, retraction of myelin
sheats (Waller degeneration)
engulfment of axonal debris and myelin globules by Schwann cells and
macrophages
Schwann cell proliferation → bands of Büngner (guide for regenerating axon)
neural cell body: swelling, peripheral displacement of nucleus, central
chromatolysis
Axonal regeneration
1 week after injury
regenerating axon (axonal sprout) grows along bands of Büngner, grow rate 12mm per day
scar tissue between proximal and distal axonal segements → disconnection →
random spread of axonal sprouts into connective tissue → traumatic (amputation)
neuroma (painful nodule)
Segmental demyelination
damage to Schwann cells or myelin
loss of one or more segments of myelin
disintegrating myelin engulfed by Schwann cells themselves and macrophages
remyelination: proliferation of Schwann cells, movement along denuded segment,
formation of new internodes (shorter, variation in length)
repeated episodes of demyelination and remyelination: Schwann cells arranged
aroun the axon in whorled pattern („onion bulbs“)
Mechanical injury
Traumatic transsection
Waller degeneration, axonal regeneration (microsurgery!)
Carpal tunnel syndrome
compression of median nerve beneath transverse carpal ligament
Etiology
idiopathic
DM
pregnancy
hypothyroidism
rheumatoid arthritis
amyloidosis
Clinical presentation
tingling and pain in the hand
weakness
thenar muscle atrophy
Infective neuropathies
Leprosy (Mycobacterium leprae)
Lepromatous leprosy
diffuse neuropathy (sensory loss)
thickened peripheral nerves (inflammatory reaction of perineurium and epineurium),
numerous bacilli in fibroblasts, Schwann cells and macrophages, demyelination and
axon loss
Tuberculoid leprosy
focal neuropathy, more benign course
epithelioid cell granulomas → thickening of nerve
bacilli very rare
Herpes zoster (shingles)
varicella-zoster virus
reactivation of latent virus in neural ganglia (immunosuppression)
erythema, painful vesicles, neuralgia within one or two dermatome
inflammatory infiltrate within ganglia and sensory nerves
Metabolic neuropathies
Diabetic: especially lower extremities, paresthesia, segmental demyelination
Uraemic: symmetrical distal sensorimotor neuropathy, combined axonal
degeneration and segmental demyelination
Paraneoplastic: lung carcinoma, sensorimotor neuropathy, subacute sensory
neuropathy
Toxic neuropathies
acrylamide, hexacarbons (organic solvents), organophosphorus compounds, drugs
(isoniazid, vincristine, nitrofurantoin, amiodarone)
variable sensorimotor neuropathies
Immune-mediated neuropathies
Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré
syndrome)
20-50 years, men
history of previous infection in two-thirds (usually viral)
probably autoimmune process
Morphology
inflammatory infitration (lymphocytes, macrophages)
segmental demyelination
Clinical presentation
symmetrical motor weakness
distal muscle groups affected first
ascending paralysis (respiratory failure necessitating ventilation)
sometimes distal sensory loss and paresthesia
Hereditary demyelinating peripheral neuropathies
Charcot-Marie-Tooth disease
autosomal dominant inheritance
children
distal weakness, muscle wasting, sensory impairment
repeated segmental demyelination and remyelination („onion bulb“)
Dejérine-Sottas disease
autosomal recessive inheritance
children
limb weakness, skeletal deformities, ataxia
nerve conduction velocity severely reduced
nerves grossly enlarged (often palpable)
extensive „onion bulbs“ formation, axonal loss
Tumours of peripheral nerves
see Soft tissue tumours
Type 1 neurofibromatosis
autosomal dominant inheritance
quite common (1 in 3000)
multiple neurofibromas (solitary and plexiform)
pigmented nodules of iris (Lisch nodules)
cutaneous hyperpigmentations (café-au-lait spots)
higher rate of malignant transformation of neurofibromas than in general population
Type 2 neurofibromatosis
autosomal dominant inheritance
much less common (1 in 40 000 – 50 000)
bilateral acoustic schwannomas
multiple meningiomas
gliomas