Neuropathology I

Main elements of the CNS and their basic pathologic reactions

Neurons

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

hypoxic/ischemic injury

shrinkage of the cell body, ↑eosinophilia („red cell change“), pyknosis of the nucleus

axonal injury

swelling 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 atrophy

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

accumulation of abnormal material

lysosomal disorders inclusions (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 damage gemistocytes (eccentrically expanded pink cytoplasm)

Rosenthal fibres

thick, elongated, eosinophilic protein aggregates within astrocytic processes chronic gliosis, low-grade gliomas

corpora amylacea

round, basophilic, PAS+ polyglucosan aggregates within end processes subpial, perivascular

Oligodendrocytes

small, round-shaped, dark nucleus in HE myelin formation regressive changes in

demyelinating disorders

and

leukodystrophy

Ependymal cells

cuboidal lining of the ventricular system

ependymal granulations

ependymal damage local proliferation of subependymal astrocytes

Choroid plexus

villous structure covered by cuboidal epithelium stroma contains fenestrated capillaries CSF secretion

cystic degeneration

Microglia

small elongated nucleus in HE bone marrow-derived cells

gitter cells

phagocytosis

rod cells

neurosyphilis

microglial nodules

,

neuronophagia

nodules around dying neurons

Cerebral edema, hydrocephalus and intracranial hypertension

Cerebral edema

accumulation of fluid in excess within cerebral parenchyma

Vasogenic edema

BBB disrupted (haemorrhagia, trauma, tumour) → ↑permeability of vessels → fluid shifted into intercellular spaces localized or diffuse

Cytotoxic edema

ischaemia → energy failure → disturbance of ionic gradient on cellular membrane → shift of fluid from extracellular to intracellular space usually diffuse

macro

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

micro

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

Hydrocephalus

accumulation of excessive CSF within the ventricles

Normal circulation of CSF

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

Causes

impaired 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 system ventricular dilatation proximal to the block

Communicating h.

reduced CSF resorption dilatation of the entire ventricular system

Hydrocephalus e vacuo

compensatory enlargement of the ventricled due to brain atrophy

macro

children before the closure of cranial sutures → enlargement of the head adults → 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 hypertension

headache vomiting papilloedema (ophthalmoscopy)

Three patterns of brain herniation

transtentorial (uncinate) tonsilar subfalcine (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 entry

hematogeneous spread (most common; endocarditis, bronchiectasia…) local extension from paranasal sinuses, teeth, middle ear direct implantation (trauma, lumbar puncture, ventricular drainage) via peripheral nerves (lyssa, herpetic viruses)

Acute pyogenic meningitis

leptomeninges + subarachnoid space perivascular spread into underlying brain → meningoencephalitis

Etiology

neonates: E. coli, Proteus, Streptococci group B toddlers + young children: Haemophilus influenzae adolescents: Neisseria meningitidis (meningococcus) older people: Streptococcus pneumoniae (pneumococcus), Listeria monocytogenes

Clinical presentation

fever, headache, clouding of consciousness, neck stiffnes lumbar puncture: ↑pressure, ↑↑neutrophils, ↑protein, ↓glucose

Morphology

leptomeningeal and subarachnoideal purulent exudate over the convexity of brain („pus cap“)

Complications

pyocephalus vasculitis → infarctions arachnoid adhesions → hydrocephalus

Acute viral („aseptic“) meningitis

morbilli, ECHO, Coxsackie, EBV, HSV2 clinical course less severe

macro

mild brain swelling

micro

mild lymphocytic infiltration of leptomeninges

lumbar puncture

↑lymphocytes, mild ↑protein, glucose normal

Tuberculous meningitis

Mycobacterium tuberculosis hematogeneous spread rare in developed countries children and young adults

Clinical presentation

headache, malaise, mental confusion, vomiting lumbar puncture: mononuclear cells, protein ↑↑, glucose n. or ↓

Macro

base of the brain (basilary m.) gelatinous exudate within subarachnoid space white nodules

Micro

lymphocytes, plasma cells, macrophages epithelioid granulomas with Langhans ’ giant cells caseous necrosis obliterative endarteritis (marked intimal thickening)

Complication

: arachnoid fibrosis → hydrocephalus

Brain abscess

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

Clinical presentation

focal neurological deficits signs of Intracranial hypertension

Morphology

solitary or multiple central liquefactive necrosis + purulent exudate pyogenic membrane (granulation tissue) gliosis, perifocal edema

Complications

pyocephalus herniation

Encephalitis

infection of brain parenchyma usually associated with meningitis (meningoencephalitis)

Viral encephalitis

most common form of encephalitis plenty of viral agents (measles, herpetic viruses, rabies, CMV, HIV…) common features: perivascular mononuclear infiltrates microglial nodules, neuronophagia inclusion 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

HSV1

any age, most common in children and young adults frontal and temporal lobes → alterations in mood, memory and behavior foci of necrosis and hemorrhage perivasculat inflammatory infiltrates intranuclear inclusions in both neurons and glial cells

HSV2

neonates (infection from mother during delivery) severe disseminated encephalitis

Varicella-zoster virus

immunosuppressed patients acute encephalitis with intranuclear inclusions

Rabies (lyssa)

rhabdovirus reservoirs: 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 presentation

nonspecific 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

Morphology

swelling and hyperemia of brain slight lymphocytic infiltration of leptomeninges Negri bodies – intracytoplasmatic eosinophilic inclusions (hippocampus, Purkinje cells)

Poliomyelitis acuta anterior

enterovirus eradicated in some countries (Czech rep.), common in developing countries most cases: asymptomatic or mild gastroenteritis small fraction of patients: involvement of motor gray matter damage and loss of motor neurons of spinal cord and brainstem → flaccid paralysis with muscle atrophy most severe cases: paralysis of respiratory muscles → death from asphyxia

micro:

perivascular lymphocytic infiltrates necrosis of motor neurons → neuronophagia, glial nodules

Human immunodeficiency virus

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

HIV meningoencephalitis

cause of AIDS-dementia complex HIV-infected macrophages → cytokines → neuronal damage widely distributed microglial nodules with multinucleated giant cells

HIV vacuolar myelopathy HIV polyneuropathy

Neurosyphilis

Treponema pallidum third stage, 10% of untreated patients

Tabes dorsalis

degeneration of posterior spinal columns and roots (sensory fibres) → grayish and shrunken unsteady and stamping gait loss of deep tendon reflexes very severe „lightning“ pains in lower limbs severe degeneration of large joints (Charcot joint)

Progressive paralysis (general paresis of the insane)

deterioration of personality changes in mental functions (bizzare and grandiose delusions) complete dementia brain atrophy disorganisation of the cortex (neuronal degeneration, gliosis, perivascular lymphocytic infiltrates, rod cells)

Other encephalitides

Lyme disease (borreliosis)

Borrelia burgdorferi, transmitted via tick bites see musculoskeletal pathology

Fungal encephalitis

Candida, Aspergilus, Mucor, Cryptococcus multiple abscesses, granulomas, hemorrhagic infarcts

Toxoplasmosis

Toxoplasma gondii immunosuppressed individuals, AIDS multiple foci of necrosis surrounded by mixed inflammatory infiltration tachyzoites and cyst filled by bradyzoites

Amoebic encephalitis

Naegleria: swimming pools, rapidly fatal necrotizing encephalitis Acantamoeba: chronic granulomatous meningoencephalitis

Cysticercosis

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

Slow viral infections

very long latent period

Subacute sclerosing panencephalitis

altered measles virus or aberrant T-cell response (measles or vaccination in clinical history) adolescents progressive loss of intelectual functions, motor abnormalities, dementia, death within 1 year brain atrophy, dilatation of ventricles, firm brain tissue loss of neurons, gliosis, subcortical demyelination intranuclear inclusion bodies within neurons and oligodendroglia perivascular lymphocytic infiltrations

Progressive multifocal leucoencephalopathy

JC virus (member of papovavirus group) preferential infection of oligodendrocytes → demyelination immunosupressed individuals (lymphoproliferative disorders, AIDS, immunosuppressive therapy) variable progressive neurologic symptoms multiple small gray foci throughout the brain loss of myelin staining, reduced number of axons, lipid-laden macrophages abnormal oligodendrocytes (intranuclear amphophilic inclusions), atypical astrocytes

Prion diseases

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

Creutzfeldt-Jacob disease (CJD)

rare (incidence 1 per million) in 85% sporadic, some cases familial iatrogenic infections (corneal transplants, human growth hormone preparations, brain implantation electrodes) peak incidence in 7. decade of life rapidly progressive dementia, motor dysfunction, fatal within 1 year usually no gross abnormalities or mild atrophy (due to rapid course) spongiform transformation of gray matter multiple small empty vacuoles (intracellular), loss of neurons, reactive gliosis

Variant Creutzfeldt-Jacob disease (vCJD)

UK 1995 young adults, slower clinical course exposure to bovine spongiform encephalopathy (BSE, „mad cow disease“) similar histologic picture, abundant cortical amyloid plaques

Gerstmann Sträussler-Scheinker syndrome

dementia with cerebellar ataxia often familial (autosomal dominant pattern), transmissible several mutations in PrP gene micro similar to CJD + amyloid plaques and amyloidosis of small vessels

Kuru

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