Neuropathology III

Demyelinating diseases

Demyelinating diseasesloss of myelin → changed ability of axons to transmit signals → various neurological deficitswhite matter affected

Multiple sclerosismost common demyelinating disorder (1/1000 persons)any age, usually young adults, females affected twice as often as malesgeographical distribution: increase with the distance from equator, more common in northern hemisphereautoimmune disease, combination of environmental and genetic factorstransmissible agent (virus) proposed, but not identified

Clinical courserelapses (episodes of new symptoms) followed by remissions (episodes of recovery, usually not complete)gradual accumulation of neurologic deficitsmild changes in cognitive functionsretrobulbar neuritis (unilateral visual impairment): frequent initial manifestationspinal cord involvement: motor and sensory impairment, spasticity, flaccid bladderCSF findings: oligoclonal bands (↑IgG)

Morphology

Plaquesmultiple, well-circumscribed, irregularly shaped, gray-tan lesionsbeside ventricles (perivascular), optic nerves, optic chiasma, brain stem, cerebellum, spinal cord

Active plaqueongoing myelin breakdownsharp demarcationabundant macrophages (myelin debris), lymphocytes (perivascular cuffs), axons relatively preserved but reduced in number

Inactive plaqueinflammation disappeared, reactive gliosisloss 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 antigenschildrendiffuse involvement of white matterperivascular lymphoplasmacytic infiltrates and demyelinating areasheadache, lethargy, comafatal in 20%, complete recovery in remaining cases

Degenerative diseases

Degenerative diseasesunknown etiologyprogressive loss of neurons or their systemscan result in dementia and severe motor impairmentDementia: memory and cognitive impairment with preserved normal level of consciousness

Degenerative diseases of cerebral cortex

Alzheimer diseasemost common cause of dementia in the elderlyrare before 50 years of age, increasing incidence with agesporadic, 5-10% familial

Etiology and pathogenesisabnormal enzymatic cleavage of APP (amyloid precursor protein) → deposition of Aβ (β-amyloid)ApoE4 (apolipoprotein ε4) → ↑deposition of Aβdeficiency of SORL1protein → altered intracellular APP trafficking → ↑generation of Aβ

Aβ effects on neurons:altered neurotransmissiontoxicity for neurons and synapseslocal inflammatory response → neuronal injurymechanical effect on axons and dendriteshyperphosphorylation of tau protein → redistribution and aggregation → neuronal dysfunction and death

Morphologycortical atrophy (frontal, temporal, parietal lobes): widening of sulci, weight less than 1000g, hydrocephalus e vacuo (compensatory dilatation of ventricles)Neuritic (senile) plaquesextracellularcentral amyloid corespherical aggregation of dilated and tortuous neurites (dystrophic dendrites)reactive microglia and astrocytessilver impregnation, immunohistochemistryNeurofibrillary tanglesintracellularbasophilic fibrillary structures encircling or displacing nucleushyperphosphorylated tau proteinLoss of neuronsAmyloid deposition in the wall of small vesselsHirano bodies (eosinophilic rod-shaped intracellular structures)

Clinical presentationinsidious impairment of higher cognitive functionsalteration of behaviourdisorientation, memory loss, aphasia, immobilitydeath from intercurrent infection (bronchopneumonia)

Pick disease (atrophia cerebri circumscripta progressiva)

rare6th decade

Clinical presentationsimilar to Alzheimer diseasedeath within 1 to 10 years

Morphologysevere atrophy of frontal and temporal lobe („walnut appearance“)severe neuronal loss, reactive gliosisswelling of neurons, intracytoplasmatic inclusions (Pick bodies)

Degenerative diseases of extrapyramidal system

Parkinsonism (clinical syndrome)rigiditydiminished facial expression (masked facies)slowness of voluntary movementsfestinating gait (progressively shortened accelerated steps)„pill-rolling“ tremordementia in 10-15%

Causes of parkinsonismParkinson diseasepostencephalitic (encephalitis lethargica)drug-related: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, contaminant of syntethic heroin), chlorpromazine, haloperidolchronic cerebral injury in boxersischemic damage

Parkinson disease

most common cause of parkinsonismunknown etiologylate middle lifedegeneration of dopaminergic system in substantia nigra and corpus striatum

Morphologypallor of substantia nigraloss of pigmented neurons associated with gliosisremaining neurons: shrinkage, vacuolation, Lewy bodies (intracytoplasmic eosinophilic round inlusions, dense core and pale halo)

Natural historyslow progression over 10-15 years to eventual immobilitydeath from intercurrent infection (bronchopneumonia) or trauma (frequent falls)

Huntington disease

inherited autosomal dominant diseasemutation in gene located in 4p (huntingtin)degeneration of striatum (caudate nucleus and putamen)

Morphologystriking atrophy of caudate nucleus, lateral and third ventricles dilatationsevere loss of neurons in striatum, gliosis

Clinical presentationonset in the fourth and fifth decademovement disorders: chorea (involuntary jerky movements)cognitive dysfunction progressing to dementiarelentless progressive course of about 15 years, death from intercurrent infection

Degenerative diseases of motor neurons

Amyotrophic lateral sclerosislate adult lifesporadic, 5-10% familial (autosomal dominant inheritance)degeneration and loss of upper and lower motor neuronesunknown etiology

Morphologyloss 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 presentationspasticity, 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 encephalopathychronic alcoholism, excessive vomiting, malabsorption (small bowel diseases)Morphologyfoci of hemorrhae and necrosis in mammillary bodies and besides third and fourth ventriclesClinical presentationdisturbances of consciousness, abnormal eye movements, ataxiaKorsakoff syndromeshort-term memory loss, confabulationsmay be irreversiblecommon association with Wernicke encephalopathy (Wernicke-Korsakoff sy)

Vitamin B12 deficiencysubacute combined degeneration of spinal cordboth ascending and descending tracts affectedataxia, spastic weakness of lower extremities, complete paraplegia

Acquired metabolic disorders

Hypoglycemiasimilar to global hypoxiaPurkinje cell relatively spared

Hyperglycemiauncontrolled DM (ketoacidosis, hyperosmolar coma)confusion, stupor, comaglucose transported into neurons → osmotic accumulation of water

Hepatic encephalopathyliver fails to clear ammonia → changes in brain functionalteration of synaptic transmission, damage of astrocytesdepressed level of consciousness, comaflapping tremor (asterixis)

Toxins

Carbon monoxidehypoxiainjury of globus pallidusEthanolcerebral atrophy (white matter, anterior portion of cerebellar vermis)dementia, unsteady gait, nystagmusfetal alcohol syndrome: microcephaly, intellectual impairmentMethanoldegeneration of retinal ganglion cells, swelling of axons in optic disc → blindnessnecrosis of basal ganglia and deep white matterMethotrexatearachnoiditisdisseminated necrotizing leucoencephalopathy (white matter of hemispheres, brainstem and cord)Morphine, heroinischemic damage of globus pallidus and deep white matter of hemispheresLeadbrain swelling, congestion, petechial hemorrhages

Inborn metabolic errors

Neuronal storage diseasescongenital defect of lysosomal enzymesaccumulation 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 inheritancedefect of hexosamidase A → accumulation of GM2 gangliosideneurons with abundant, finely granular cytoplasmchildrencognitive impairment, blindness, seizures, death within 3-5 years

Niemann-Pick diseaseautosomal recessive inheritancedefect of sphingomyelinase → accumulation of sphingomyelinneurons with enlarged cytoplasmlipid-laden macrophages (Niemann-Pick cells) in white matter, arachnoid, choroid plexus, bone marrow, liver, spleen, lymph nodesclinical presentation at 6th month: cognitive impairment, muscle rigidity, kachexia, death within 3 years

Leucodystrophies

inherited disorders of myelin synthesis or turnoverautosomal recessive or X-linked inheritancedefects of lysosomal enzymes, mutations of myelin proteins

Morphologyatrophy of white matter, gray and translucentenlargement of ventriclesmyelin loss, lipid-laden macrophages

Clinical presentationnormal at birthprogressive 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 defectsfailure of closure or reopening

Cranioschisis totalisdefect of closure of the whole neural tubeAnencephalyabsence of brain and top of skullarea neurovasculosa on skull baseSpina bifida occultasimple agenesis of posterior vertebral archesasymptomatic, hyperpigmentation of overlying skinMeningocele, meningomyeloceleextension of malformed spinal cord tissue and meninges through defect of veretebral columnlumbosacral regionmotor and sensory deficits in lower extremitiesimpaired bowel and bladder controlpossibility of infectionEncephalocelemalformed brain tissue extends through skull defectoccipital region, posterior fossa

Forebrain malformations

Microencephalyusually associated with microcephalychromosomal abnormalities, fetal alcohol syndrome, intrauterine HIV infection

Lissencephaly (agyria)disorder of neuronal migration and diferentiation during brain developmentabsence of normal gyration (smooth surface)abnormally thick and four-layered cortex

Polymicrogyriaincreased number of irregularly formed gyri

Holoprosencephalybrain not divided into hemispheres and lobes

Posterior fossa anomalies

Arnold-Chiari (Chiari II) malformationsmall posterior fossa, cerebellar vermis extends downward through foramen magnumhydrocephalus

Chiari I malformationcerebellar tonsils extend through foramen magnumhydrocephalus, compression of medulla (cranial nerve deficits)

Dandy-Walker malformationabsent cerebellar vermis replaced by ependymal cyst

Spinal cord abnormalities

Hydromyeliadilatation of central canal

Syringomyeliafluid-filled cleft-like cavity within cordcongenital or acquired (trauma, tumour)adjacent reactive gliosis

Diseases of peripheral nerve

Reactions of peripheral nerve to injury

Axonal degenerationdamage 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 macrophagesSchwann cell proliferation → bands of Büngner (guide for regenerating axon)neural cell body: swelling, peripheral displacement of nucleus, central chromatolysis

Axonal regeneration1 week after injuryregenerating axon (axonal sprout) grows along bands of Büngner, grow rate 1-2mm per dayscar tissue between proximal and distal axonal segements → disconnection → random spread of axonal sprouts into connective tissue → traumatic (amputation) neuroma (painful nodule)

Segmental demyelinationdamage to Schwann cells or myelinloss of one or more segments of myelindisintegrating myelin engulfed by Schwann cells themselves and macrophagesremyelination: 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 transsectionWaller degeneration, axonal regeneration (microsurgery!)

Carpal tunnel syndromecompression of median nerve beneath transverse carpal ligamentEtiologyidiopathicDMpregnancyhypothyroidismrheumatoid arthritisamyloidosisClinical presentationtingling and pain in the handweaknessthenar muscle atrophy

Infective neuropathies

Leprosy (Mycobacterium leprae)Lepromatous leprosydiffuse neuropathy (sensory loss)thickened peripheral nerves (inflammatory reaction of perineurium and epineurium), numerous bacilli in fibroblasts, Schwann cells and macrophages, demyelination and axon lossTuberculoid leprosyfocal neuropathy, more benign courseepithelioid cell granulomas → thickening of nervebacilli very rare

Herpes zoster (shingles)varicella-zoster virusreactivation of latent virus in neural ganglia (immunosuppression)erythema, painful vesicles, neuralgia within one or two dermatomeinflammatory 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, menhistory of previous infection in two-thirds (usually viral)probably autoimmune processMorphologyinflammatory infitration (lymphocytes, macrophages)segmental demyelinationClinical presentationsymmetrical motor weaknessdistal muscle groups affected firstascending paralysis (respiratory failure necessitating ventilation)sometimes distal sensory loss and paresthesia

Hereditary demyelinating peripheral neuropathies

Charcot-Marie-Tooth diseaseautosomal dominant inheritancechildrendistal weakness, muscle wasting, sensory impairmentrepeated segmental demyelination and remyelination („onion bulb“)

Dejérine-Sottas diseaseautosomal recessive inheritancechildrenlimb weakness, skeletal deformities, ataxianerve conduction velocity severely reducednerves grossly enlarged (often palpable)extensive „onion bulbs“ formation, axonal loss

Tumours of peripheral nervessee Soft tissue tumours

Type 1 neurofibromatosisautosomal dominant inheritancequite 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 neurofibromatosisautosomal dominant inheritancemuch less common (1 in 40 000 – 50 000)bilateral acoustic schwannomasmultiple meningiomasgliomas