Neuropathology III

1. Neuropathology III

2. Demyelinating diseases

3. 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)

4. 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)

5. 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

6. Degenerative diseases

7. 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

8. 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

9. 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)

10. 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)

11. 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

12. 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)

13. 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

14. 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)

15. Acquired metabolic and toxic disorders

16. 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

17. 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)

18. 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

19. Inborn metabolic errors

20. 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

21. 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)

22. Malformations and developmental disorders

23. 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

24. 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

25. 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

26. Spinal cord abnormalities Hydromyelia dilatation of central canal Syringomyelia fluid-filled cleft-like cavity within cord congenital or acquired (trauma, tumour) adjacent reactive gliosis

27. Diseases of peripheral nerve

28. 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 1-2mm per day scar tissue between proximal and distal axonal segements → disconnection → random spread of axonal sprouts into connective tissue → traumatic (amputation) neuroma (painful nodule)

29. 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“)

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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