INFECTIONS OF THE NERVOUS SYSTEM

Hematogenous spread via arteries: most common

Retrograde venous spread through anastomoses between veins of face and venous sinuses of skull

Direct implantation • Post-traumatic• Iatrogenic (lumbar puncture needle)

Local extension from infection in the skull or spine

Peripheral nerves - rabies and herpes zoster

Epidural and Subdural Infections

Bacterial/fungal infections, usually direct local spread

Epidural abscess, Subdural empyema

Fever, headache, neck stiffness

Treatment - complete recovery, if untreated - focal neurologic signs, lethargy, and coma

Meningitis Inflammation of lepto-meninges and CSF in subarachnoid space

Chemical meningitis: in response to a nonbacterial irritant

Infectious meningitis: • acute pyogenic (bacterial)• aseptic (viral)• chronic (tuberculous, spirochetal, or cryptococcal)

Acute Pyogenic Meningitis (Bacterial Meningitis)

In neonates: E.coli, group B streptococciIn elderly: Strep.pneumoniae, Listeria monocytogenes In adolescents/young adults: Neisseria meningitides

Signs of meningeal irritation - headache, photophobia, irritability, clouding of consciousness, and neck stiffness

Lumbar puncture: increased pressure, abundant neutrophils, elevated protein, and reduced glucose

Gram smear/ Bacterial culture

Morphology

Exudate on the surface

Engorged and prominent vessels

Meningoencephalitis: spread into brain

Microscopic examination:

Neutrophils in subarachnoid space (in severely affected cases)

around leptomeningeal blood vessels (in less severe cases)

Brain Abscesses Brain abscesses following neonatal group B streptococcus meningitis

Pus in the subarachnoid space

Aseptic Meningitis (Viral Meningitis)

Meningeal irritation, fever, and alterations of consciousness of relatively acute onset without recognizable organisms

Self-limiting, treated symptomatically

Lumbar puncture: increased lymphocytes (pleiocytosis), moderate protein elevation, normal glucose content

70% cases - enterovirus

No distinctive macroscopic / microscopic characteristics

Tuberculous Meningitis

Headache, malaise, mental confusion, and vomiting

Lumbar puncture: moderate cellularity - mononuclear cells, or a mixture of polymorphonuclear and mononuclear cells

markedly elevated protein level glucose content moderately reduced to normal

Well-circumscribed intraparenchymal mass (tuberculoma)

Chronicity causes arachnoid fibrosis - hydrocephalus

Morphology

Gelatinous /fibrinous exudate in subarachnoid space at base of brain, discrete white granules scattered over leptomeninges

Microscopic examination: Lymphocytes, plasma cells, and macrophagesGranulomas with caseous necrosis and giant cellsAcid fast bacilli

Neurosyphilis Tertiary stage in 10% of untreated cases

Paretic neurosyphilis progressive loss of mental/physical functions, mood alterations (delusions of grandeur), severe dementia

Tabes dorsalis • damage to sensory nerves in dorsal roots - locomotor ataxia• loss of pain causing skin and joint damage (Charcot joints)• lightning pains, absent deep tendon reflexes

Individuals with HIV infection are at increased risk

Morphology

Meningovascular neurosyphilisObliterative endarteritis with perivascular plasma cells and lymphocytesCerebral gummas in meninges extending into brain

Paretic neurosyphilis - loss of neurons with proliferation of microglia (rod cells) and gliosis

Tabes dorsalis - loss of axons and myelin in dorsal roots, with pallor and atrophy in dorsal columns of spinal cord

Neuroborreliosis

Borrelia burgdorferi - pathogen of Lyme disease

Neurologic symptoms are highly variable and include aseptic meningitis, facial nerve palsies, mild encephalopathy, and polyneuropathies

Brain Abscesses

Mostly bacterial infectionsDirect implantation, local extension (mastoiditis, paranasal sinusitis) or hematogenous spread (from heart, lungs, bones or after tooth extraction)

Predisposing conditions Acute bacterial endocarditis: multiple abscessesCyanotic congenital heart disease: right-to-left shunt with loss of pulmonary filtration of organismsChronic pulmonary sepsis: bronchiectasis

Clinically: progressive focal deficits, signs of raised intracranial pressure

CSF findings & Morphology

Lumbar puncture: WBC & Proteins raised Glucose content normal

Gross: lesions with central liquefactive necrosis and a surrounding FIBROUS CAPSULE

Microscopic examination: Exuberant neovascularization around necrosis Zone of reactive gliosis outside the fibrous capsule

Viral Encephalitis

Associated with meningeal inflammation – MENINGOENCEPHALITIS

Microscopy: perivascular and parenchymal mononuclear cell infiltrates, microglial nodules, and neuronophagia

Certain viruses may form inclusion bodies

Inclusion bodies : eosinophilic masses consisting of packed viral particles and products of their replication

Arboviruses Important cause of epidemic encephalitis, especially in tropical regions, high morbidity and mortality

Eastern/Western equine encephalitis and West Nile virus

Animal hosts act as reservoirs, transmitted by mosquitoes

Lumbar puncture: • Colorless, slightly elevated pressure • Neutrophilic pleiocytosis that changes to lymphocytes• Protein level is elevated, but sugar content is normal

Microscopic: Lymphocytic meningoencephalitis, multifocal gray and white matter necrosis, neuronophagia, microglial nodules

Herpes Simplex Virus Type 1

Mostly children and young adults

Symptoms: alterations in mood, memory, behavior reflect frontal/temporal involvement

Morphology :Mostly involves inferior and medial regions of temporal and orbital gyri of frontal lobes

Perivascular inflammation, Cowdry type A inclusion

Herpes Simplex Virus Type 2 Usually meningitis in adults

Disseminated severe encephalitis in neonates born by vaginal delivery to women with active primary HSV genital infections

Neonatal HSV encephalitis – the patient died four weeks after the onset of symptoms, despite treatment with Acyclovir. Necrotizing encephalitis that caused a diffuse meltdown of the brain without predilection for the frontal and temporal lobes

Varicella-Zoster Virus (Herpes Zoster)

Primary - chickenpox, then latent in dorsal root ganglia

Reactivation in adults: ShinglesPost-herpetic neuralgia

Granulomatous arteritis leads to infarcts In immunosuppressed patients causes acute encephalitis

Cytomegalovirus

Fetuses / immunosuppressed

In utero: periventricular necrosis and calcification, microcephaly

Morphology :In immunosuppressed patient - subacute encephalitis, with CMV inclusion-bearing cells

Poliovirus

Enterovirus

Infection causes subclinical/mild gastroenteritis, but in few cases flaccid paralysis with muscle wasting and hyporeflexia

Post-polio syndrome : progressive weakness with decreased muscle bulk and pain, 25-35 years after resolution of initial illness

Rabies

Severe encephalitis transmitted to humans by the bite of rabid animal

Virus ascends along peripheral nerves from wound site

Negri body

• Extraordinary CNS excitability• Violent motor responses progressing to convulsions • Hydrophobia• Alternating mania and stupor progress to coma/death

Human Immunodeficiency Virus

• Direct effects• Opportunistic infections• Tumors

Patterns of direct injury: • Aseptic HIV-1 meningitis

• HIV-1 meningoencephalitis - microglial nodules containing macrophage-derived multinucleated giant cells

• Vacuolar myelopathy resembling subacute combined degeneration (serum B12 is normal)

Progressive Multifocal Leukoencephalopathy (PML)

JC virus, a polyomavirus

Infects oligodendrocytes causes demyelination

In immunosuppressed

Patches of irregular, white matter destruction

Enlarged oligodendrocyte nuclei with ground glass appearance (chromatin replaced by viral inclusion)

Fungal Encephalitis

Candida, Mucor, Aspergillus, Cryptococcus - common

Histoplasma, Coccidioides, Blastomyces - in immunosuppressed

Candida - multiple microabscesses, with/without granuloma

Mucor - most commonly in diabetics with ketoacidosis

Aspergillus - predilection for blood vessel invasion and thrombosis (widespread septic hemorrhagic infarctions)

India Ink stain of CSF showing encapsulated yeast Mucicarmine stain of brain infected with C. neoformans

associated with AIDS

CSF - few cells, high level of protein

Mucoid encapsulated yeasts in CSF seen by INDIA INK(In tissue sections: PAS, mucicarmine, silver stains)

Fungal capsule is characteristic for Cryptococcus and forms "Soap bubble abcesses”

Cerebral Toxoplasmosis

Toxoplasma gondii

CT/MRI: multiple ring-enhancing lesions

Morphology:• Multiple abscesses • Acute lesions - necrosis

surrounded by acute/chronic inflammation and vascular proliferation

• Free tachyzoites and encysted bradyzoites

Cysticercosis

End-stage infection by Taenia solium

Cysts can be found in brain and subarachnoid space - present as mass lesion and can cause seizures

Morphology • Marked gliosis around cyst• Body wall and hooklets from mouth

parts are seen• If organism within cyst dies, intense

inflammatory infiltrate with eosinophils

Amebic meningoencephalitis - different patterns with different species

Naegleria: swimming in non-flowing warm fresh water rapidly fatal necrotizing encephalitis

Acanthamoeba: chronic granulomatous meningoencephalitis

Other protozoal infections

PRION DISEASES

Sporadic, familial, iatrogenic / variant forms of Creutzfeldt-Jakob disease (CJD)

SCRAPIE in sheep/goats, BOVINE SPONGIFORM ENCEPHALOPATHY in cattle ("mad cow" disease)

Change in PrP from native PrPc form to an abnormal configuration - PrPsc (scrapie) or PrPres (protease resistant)

PrPsc can initiate transformation of other PrPc molecules

Creutzfeldt-Jakob Disease

Rapidly progressive dementia, sporadic in 85% of cases

Iatrogenic transmission - deep implantation electrodes, contaminated preparations of human growth hormone

Clinical presentation - subtle changes in memory and behavior, rapidly progress to dementia

Periodic sharp and slow wave complexes in the EEG

Uniformly fatal, average duration of 7 months

Creutzfeldt-Jakob Disease - morphology

Microscopic examinationSPONGIFORM TRANSFORMATION of cerebral cortex and deep gray matter structures (caudate, putamen) In advanced cases - severe neuronal loss, reactive gliosis, expansion of vacuolated areas into cystlike spaces ("status spongiosus")

No inflammatory infiltrate

Immunohistochemistry: proteinase K-resistant PrPsc in tissue

Western blot (on tissue extracts after partial protease digestion)

Prion disease (CJD)

Variant CJD (vCJD)

young adults, slow progression, microscopy similar to CJD but with abundant cortical amyloid plaques

SUMMARY different routes and disease patterns

Bacterial infections - meningitis, cerebral abscesses, or chronic meningoencephalitis

Viral infections - meningitis or meningoencephalitis

HIV - directly with meningoencephalitis or opportunistic infections (toxoplasmosis, CMV) or CNS lymphoma

Prion diseases - transmitted by altered form of normal cellular protein - sporadic, transmitted, or inherited

Recommended Reading: Robbins and Cotran Pathologic Basis of Disease 8E, p1299-1309Required Reading: Robbins Basic Pathology 9E, p824 - 832