Neuropathology I

Main elements of the CNS and their basic pathologic reactions

Neuronsmarked variations in size and shape (Purkinje cell, granular cell)cell body + processes (axon and dendrites)Nissl substance (GER) – proteosynthesis

hypoxic/ischemic injuryshrinkage of the cell body, ↑eosinophilia („red cell change“), pyknosis of the nucleus

axonal injuryswelling and rounding of the neuronal body, central chromatolysis (disappearance of the Nissl substance)axonal spheroids (disruption of axonal transport), Waller degeneration distally from the site of injury

neuronal atrophyshrinkage of the neuronal body, ↑basophilia, thickened and tortuous („corkscrew“) dendritesneurodegenerative diseases, trans-synaptic degeneration

accumulation of abnormal materiallysosomal disordersinclusions (viral, neurodegenerative diseases)

Astrocytes

oval-shaped pale nucleus, numerous processes (invisible in HE)supporting and metabolic function

gliosis (hypertrophy and hyperplasia)repair of brain tissue damagegemistocytes (eccentrically expanded pink cytoplasm)

Rosenthal fibresthick, elongated, eosinophilic protein aggregates within astrocytic processeschronic gliosis, low-grade gliomas

corpora amylacearound, basophilic, PAS+ polyglucosan aggregates within end processessubpial, perivascular

Oligodendrocytes

small, round-shaped, dark nucleus in HEmyelin formationregressive changes in demyelinating disorders and leukodystrophy

Ependymal cells

cuboidal lining of the ventricular system

ependymal granulationsependymal damagelocal proliferation of subependymal astrocytes

Choroid plexus

villous structure covered by cuboidal epitheliumstroma contains fenestrated capillariesCSF secretion

cystic degeneration

Microglia

small elongated nucleus in HEbone marrow-derived cells

gitter cellsphagocytosis

rod cellsneurosyphilis

microglial nodules, neuronophagianodules around dying neurons

Cerebral edema, hydrocephalus and intracranial hypertension

Cerebral edemaaccumulation of fluid in excess within cerebral parenchyma

Vasogenic edemaBBB disrupted (haemorrhagia, trauma, tumour) → ↑permeability of vessels → fluid shifted into intercellular spaceslocalized or diffuse

Cytotoxic edemaischaemia → energy failure → disturbance of ionic gradient on cellular membrane → shift of fluid from extracellular to intracellular spaceusually diffuse

macrodiffuse or localized brain swelling, brain softer than normal, flattened gyri, ventricular system compressed

microvacuolation, red cell change, loss of myelin staining, enlargement of extracellular spaces

Hydrocephalusaccumulation of excessive CSF within the ventricles

Normal circulation of CSFproduced by choroid plexus → circulation through ventricular system → exit to subarachnoideal space (foramina Luschka and Magendie) → resorbed by arachnoid granulations

Causesimpaired flow of CSF (subarachnoideal scarring after meningitis or hematoma, block of ventricular system by tumour or blood clot, congenital malformations)↓resorption of CSF (hypoplasia or damage of arachnoideal granulations)↑secretion of CSF (choroid plexus tumours)

Noncommunicating h.CSF flow block within ventricular systemventricular dilatation proximal to the block

Communicating h.reduced CSF resorptiondilatation of the entire ventricular system

Hydrocephalus e vacuocompensatory enlargement of the ventricled due to brain atrophy

macrochildren before the closure of cranial sutures → enlargement of the headadults → dilatation of the ventricular system, intracranial hypertension

Intracranial hypertension

brain enclosed within rigid container (skull)↑volume of intracranial contents (edema, hydrocephalus, tumour, haemorrhage, abscess…) → ↑intracranial pressure → displacement of brain tissue across dural barriers or through openings (herniation), decrease of blood perfusion (global ischaemia)

General clinical features of intracranial hypertensionheadachevomitingpapilloedema (ophthalmoscopy)

Three patterns of brain herniationtranstentorial (uncinate)tonsilarsubfalcine (cingulate)

Transtentorial (uncinate) herniation

medial aspect of temporal lobe compressed against margin of tentorium

damage of III. cranial nerve → pupillary dilation and impairment of ocular movements on the side of the lesion

compression of posterior cerebral artery → ischemia of occipital lobe (including primary visual cortex)

tearing of penetrating vessels → Duret’s hemorage of midbrain and pons

Tonsilar herniation

cerebelar tonsils into foramen magnum

brainstem compresion → damage of respiratory and cardiac centres of medulla

Subfalcine (cingulate) herniation

cingulate gyrus under the edge of falx

compression of anterior cerebral artery → infarction

Infections

Infections

Possible routes of entryhematogeneous spread (most common; endocarditis, bronchiectasia…)local extension from paranasal sinuses, teeth, middle eardirect implantation (trauma, lumbar puncture, ventricular drainage)via peripheral nerves (lyssa, herpetic viruses)

Acute pyogenic meningitisleptomeninges + subarachnoid spaceperivascular spread into underlying brain → meningoencephalitisEtiologyneonates: E. coli, Proteus, Streptococci group Btoddlers + young children: Haemophilus influenzaeadolescents: Neisseria meningitidis (meningococcus)older people: Streptococcus pneumoniae (pneumococcus), Listeria monocytogenesClinical presentationfever, headache, clouding of consciousness, neck stiffneslumbar puncture: ↑pressure, ↑↑neutrophils, ↑protein, ↓glucoseMorphologyleptomeningeal and subarachnoideal purulent exudate over the convexity of brain („pus cap“)Complicationspyocephalusvasculitis → infarctionsarachnoid adhesions → hydrocephalus

Acute viral („aseptic“) meningitis

morbilli, ECHO, Coxsackie, EBV, HSV2

clinical course less severe

macromild brain swelling

micromild lymphocytic infiltration of leptomeninges

lumbar puncture↑lymphocytes, mild ↑protein, glucose normal

Tuberculous meningitisMycobacterium tuberculosishematogeneous spreadrare in developed countries children and young adults

Clinical presentationheadache, malaise, mental confusion, vomitinglumbar puncture: mononuclear cells, protein ↑↑, glucose n. or ↓

Macrobase of the brain (basilary m.)gelatinous exudate within subarachnoid spacewhite nodules

Microlymphocytes, plasma cells, macrophagesepithelioid granulomas with Langhans’ giant cellscaseous necrosisobliterative endarteritis (marked intimal thickening)

Complication: arachnoid fibrosis → hydrocephalus

Brain abscess

acute focal suppurative infectionbacterial infection (Staphylococci, Streptococci)hematogeneous spread (endocarditis, bronchiectasia, osteomyelitis)local extension (sinusitis, middle ear - mastoiditis)direct implantation (trauma)

Clinical presentationfocal neurological deficitssigns of Intracranial hypertension

Morphologysolitary or multiple central liquefactive necrosis + purulent exudatepyogenic membrane (granulation tissue)gliosis, perifocal edema

Complicationspyocephalusherniation

Encephalitisinfection of brain parenchymausually associated with meningitis (meningoencephalitis)

Viral encephalitismost common form of encephalitisplenty of viral agents (measles, herpetic viruses, rabies, CMV, HIV…)common features:

perivascular mononuclear infiltratesmicroglial nodules, neuronophagiainclusion bodies

Tick encephalitis

arboviruses (arthropod borne)

several forms (central european, russian, St. Louis fever, …)

transmitted by tick bites, disease reservoirs – animals (rodents)

perivascular monocelular infiltrates, lymphocytic meningitis

severe cases: focal gray and white matter necroses, individual neuronal necrosis followed by neuronophagia and glial nodules → neurologic deficits (paresis)

Herpetic encephalitis

HSV1any age, most common in children and young adultsfrontal and temporal lobes → alterations in mood, memory and behaviorfoci of necrosis and hemorrhageperivasculat inflammatory infiltratesintranuclear inclusions in both neurons and glial cells

HSV2neonates (infection from mother during delivery)severe disseminated encephalitis

Varicella-zoster virusimmunosuppressed patientsacute encephalitis with intranuclear inclusions

Rabies (lyssa)rhabdovirusreservoirs: various animals (dogs, foxes, bats)transmission by bite of a rabid animal (saliva)virus enters CNS by ascending along peripheral nerves → incubation period up to 9 months

Clinical presentationnonspecific symptoms (malaise, fever, headache)severe CNS excitability (even slight touch → convulsions)hydrophobia (painful pharyngeal contracture after swallowing or even looking at water)death from respiratory center failure

Morphologyswelling and hyperemia of brainslight lymphocytic infiltration of leptomeningesNegri bodies – intracytoplasmatic eosinophilic inclusions (hippocampus, Purkinje cells)

Poliomyelitis acuta anterior

enteroviruseradicated in some countries (Czech rep.), common in developing countriesmost cases: asymptomatic or mild gastroenteritissmall fraction of patients: involvement of motor gray matter

damage and loss of motor neurons of spinal cord and brainstem → flaccid paralysis with muscle atrophymost severe cases: paralysis of respiratory muscles → death from asphyxia

micro:perivascular lymphocytic infiltratesnecrosis of motor neurons → neuronophagia, glial nodules

Human immunodeficiency virus

60% of patients with AIDS develop neurologic dysfunctionseither direct effect of HIV or secondary involvement by opportunistic infections (toxoplasma, cryptococcus, HSV1, HSV2, VZV, CMV, …)

HIV meningoencephalitiscause of AIDS-dementia complexHIV-infected macrophages → cytokines → neuronal damagewidely distributed microglial nodules with multinucleated giant cells

HIV vacuolar myelopathy

HIV polyneuropathy

NeurosyphilisTreponema pallidumthird stage, 10% of untreated patients

Tabes dorsalisdegeneration of posterior spinal columns and roots (sensory fibres) → grayish and shrunkenunsteady and stamping gaitloss of deep tendon reflexesvery severe „lightning“ pains in lower limbssevere degeneration of large joints (Charcot joint)

Progressive paralysis (general paresis of the insane)deterioration of personalitychanges in mental functions (bizzare and grandiose delusions)complete dementiabrain atrophydisorganisation of the cortex (neuronal degeneration, gliosis, perivascular lymphocytic infiltrates, rod cells)

Other encephalitides

Lyme disease (borreliosis)Borrelia burgdorferi, transmitted via tick bitessee musculoskeletal pathology

Fungal encephalitisCandida, Aspergilus, Mucor, Cryptococcusmultiple abscesses, granulomas, hemorrhagic infarcts

ToxoplasmosisToxoplasma gondiiimmunosuppressed individuals, AIDSmultiple foci of necrosis surrounded by mixed inflammatory infiltrationtachyzoites and cyst filled by bradyzoites

Amoebic encephalitisNaegleria: swimming pools, rapidly fatal necrotizing encephalitisAcantamoeba: chronic granulomatous meningoencephalitis

Cysticercosisencysted larvae of tapeworm (Taenia solium)intracranial hypertension (mass effect), seizures

Slow viral infectionsvery long latent period

Subacute sclerosing panencephalitisaltered measles virus or aberrant T-cell response (measles or vaccination in clinical history)adolescentsprogressive loss of intelectual functions, motor abnormalities, dementia, death within 1 yearbrain atrophy, dilatation of ventricles, firm brain tissueloss of neurons, gliosis, subcortical demyelinationintranuclear inclusion bodies within neurons and oligodendrogliaperivascular lymphocytic infiltrations

Progressive multifocal leucoencephalopathyJC virus (member of papovavirus group)preferential infection of oligodendrocytes → demyelinationimmunosupressed individuals (lymphoproliferative disorders, AIDS, immunosuppressive therapy)variable progressive neurologic symptomsmultiple small gray foci throughout the brainloss of myelin staining, reduced number of axons, lipid-laden macrophagesabnormal oligodendrocytes (intranuclear amphophilic inclusions), atypical astrocytes

Prion diseases

abnormal forms of normal cellular protein (prion protein, PrP; prion = proteinaceous infection)abnormal PrP – „knotted“ conformationability of abnormal PrP to initiate comparable conformation changes of other PrP molecules → transmissible diseasesspontaneous conformation change → sporadic formsmutation of gene encoding PrP → higher rate of conformation changes → familial formsaccumulation of abnormal PrP → cell injury (cytoplasmic vacuoles, neuronal cell death

Creutzfeldt-Jacob disease (CJD)rare (incidence 1 per million)in 85% sporadic, some cases familialiatrogenic infections (corneal transplants, human growth hormone preparations, brain implantation electrodes)peak incidence in 7. decade of liferapidly progressive dementia, motor dysfunction, fatal within 1 yearusually no gross abnormalities or mild atrophy (due to rapid course) spongiform transformation of gray mattermultiple small empty vacuoles (intracellular), loss of neurons, reactive gliosis

Variant Creutzfeldt-Jacob disease (vCJD)UK 1995young adults, slower clinical courseexposure to bovine spongiform encephalopathy (BSE, „mad cow disease“)similar histologic picture, abundant cortical amyloid plaques

Gerstmann-Sträussler-Scheinker syndromedementia with cerebellar ataxiaoften familial (autosomal dominant pattern), transmissibleseveral mutations in PrP genemicro similar to CJD + amyloid plaques and amyloidosis of small vessels

Kuruendemic to highlands of New Guinea (Fore tribe)ritual canibalismcerebellar ataxia, progressive motor dysfunction, severe tremor (kuru = shivering)death usually within 1 year