Viral Infections

Viruses: number one cause of encephalitis and meningitis

• Most cases: acute, self-limited

• Arboviruses: most common cause worldwide

U.S. incidence: 3.5 to 7.4 cases per 100,000 people per year

Specific host cell surface receptors facilitate entry

Routes: hematogenous (most common), retrograde neuronal migration (rabies/herpes)

• Transient viremia seeds muscles/reticuloendothelial system

• Secondary seeding of CNS, other organs

Infants, elderly most affected

Viral cultures: 33% to 75% are inconclusive

Meningitis: leptomeningeal infection—nuchal rigidity, headache, fever, photophobia

• Aseptic: culture negative; unknown etiology

Encephalitis: direct viral infection of parenchyma—neurologic deficits; altered consciousness, seizures

Meningoencephalitis: parenchymal, leptomeningeal infection

Encephalopathy: reversible or irreversible damage without inflammation

Myelitis: spinal cord (poliovirus)

Radiculitis: dorsal nerve roots

Neuritis: peripheral nerves

Testing

• Most cases diagnosed by PCR, ELISA serologies of CSF and serum

• Viral cultures

• CSF: moderate monocytic pleocytosis, mild/moderate protein increase, normal glucose

Most infections: self-limited; mild

High mortality: herpesviruses, some arboviruses

• Neurologic sequelae common

• Variable: based on pathogen

Antivirals: effective for certain pathogens

Cerebral edema, vascular congestion, foci of hemorrhage

Nonspecific findings

• Lymphocytic meningitis

• Perivascular lymphocytic cuffing

• Microglial nodules of brain parenchyma in encephalitis

• Destruction of neurons by activated microglia (“neuronophagia”)

• Oligodendroglial destruction can lead to demyelination

• Ependymitis

• Gliosis

Viral cytopathic effects (covered in separate chapters)

• Intranuclear inclusions (Cowdry type A: Herpes simplex, oligodendrocytic—JC virus)

• Cytoplasmic inclusions (Negri bodies; rabies)

Pathogen-specific immunohistochemistry (IHC)

Immunohistochemical markers for lymphocytes, macrophages

Other infectious encephalitides

Cerebral infarct

Seizure disorders

Carcinomatosis/paraneoplastic encephalitis

Neurosarcoidosis

Thrombotic thrombocytopenic purpura (TTP)

Most common sporadic encephalitis in the United States: two cases per million people per year

Neurotropic: likely spreads to leptomeninges via olfactory nerves

Primary infection: teens/young adults via direct contact with lesions/secretions

Herpes simplex virus (HSV-1): primarily oral lesions; 90% seroprevalence by age 50

• Latency: trigeminal ganglion; occasionally cervical ganglia

• Reactivation: occurs via anterograde axonal transport

HSV-2: primarily genital lesions; U.S. seroprevalence: 16% to 40%

• Primary cause of encephalitis in neonates

• Primary infection: up to 40%; reactivation: 8%

• Latency: sacral dorsal root ganglia

Encephalitis: acute, rapid onset with fever, altered mental status, delirium/psychiatric manifestations, seizures, neurologic deficits, smell/taste alterations, coma

• HSV-1: primary cause

Less common presentations:

• HSV-1 and -2: subacute onset; insidious encephalopathic manifestations; rarely necrotizing myelopathy

• HSV-1: brain stem encephalitis

• HSV-2: sacral myeloradiculitis; Mollaret's meningitis—recurrent, benign aseptic meningitis

CSF analysis

• Pleocytosis (lymphocytic/monocytic), red blood cells (RBCs) elevated, glucose normal/decreased

• PCR for HSV-1 and -2

• Cultures usually negative

Untreated: >70% mortality; 25% to 50% mortality with treatment

Sequelae common in survivors, even with appropriate treatment

• Seizures (most common)

• Severe neurologic deficits

• Developmental delay

Treatment: acyclovir

Pathognomonic: asymmetrical increased signal intensity of bilateral temporal lobes with focal extension to adjacent frontal lobes

Cerebral softening, congestion, and edema

Hemorrhagic necrosis of bilateral temporal lobes in asymmetrical distribution

Extension to posterior orbitofrontal, cingulate, insular cortex

Acute phase—may initially have neutrophils in subarachnoid space and brain

• Lymphohistiocytic infiltrates in leptomeninges; perivascular spaces

• Neuronophagia/microglial nodules

• Classic cytopathic effect: eosinophilic Cowdry type A intranuclear inclusions (sparse)

• Neurons and glia infected

• Progression to geographic necrosis, focal hemorrhage, marked inflammation

Chronic phase (survivors)

• Cavitary glial scar formation with atrophy, hemosiderin deposition

HSV-1 and -2 immunohistochemistry