Viral and Prion Infections

• Viruses
• Types
• DNA – can be enveloped (with circular (pox) or linear (herpes) DNA), or unenveloped (with circular (JC/SV40) or linear (adenovirus) DNA)
• RNA – all have envelope except picornavirus (polio, echo, cocksackie); can be + sense (togavirus, retrovirus, flavivirus) or - sense (paramyxovirus, orthomyxovirus, rhabdovirus, bunyavirus, arenavirus)
• Aseptic meningitis – 70% caused by enterovirus (also caused by syphilis, Cryptococcus, TB, lymphoma, etc.); fever/headache/nuchal rigidity without focal signs or encephalitis; CSF has lymphocytes
• Encephalitis – can be epidemic (arbovirus) or sporadic (HSV, CMV, papovavirus, toxo, aspergillus, listeria)
• Arbovirus – perivascular mononuclear infiltrate – togavirus, bunyavirus, flavivirus, reovirus; causes Eastern (70% mortality, late summer); Western (less severe); Venezuelan (mild); La Cross (causes meningitis as well); St. Louis (summer, birds); Japanese (most common worldwide, 50% mortality)
• Herpes – shielded from host immune system by blood brain barrier; usually transmitted through peripheral nerve (rarely hematogenous) or olfactory mucosa in children
• causes meningitis, encephalitis, myelitis, keratitis, hemorrhagic temporal lobe encephalitis
• HSV2 – diffuse encephalitis in neonates
• Virus appears as Cowdry type A inclusions in first few days of infection – intranuclear, eosinophilic with halo (type B have no halo and look like ground glass)

§ necrotizing encephalitis

• Ramsey-Hunt syndrome – infection of V1 with lesions on cornea
• Herpes Simplex Encephalitis
• The most common form of non-epidemic acute encephalitis
• Incidence is 2.3/million persons per year
• Biphasic peak is between 5-30 years and >50 years
• 95% of cases are caused by HSV Type I
• Access to the CNS is non-hematogenous
• Penetration occurs at mucocutaneous sites (i.e., lip, olfactory) and retrograde transport occurs within sensory nerve transmitting virus to the CNS
• Location is typically temporofrontal and limbic
• History: Malaise, fever, headache, behavioral changes progress to major neurologic manifestations (seizures, hemiparesis, dysphasia, and altered LOC)
• Diagnosis:
• LP shows lymphocytic pleocytosis with normal glucose, marginally elevated protein
• EEG shows disorganized and slow background rhythm with periodic lateralized epileptiform discharges primarily in the temporofrontal region
• MRI shows edema and hemorrhage in temporofrontal region
• Brain biopsy shows characteristic pathology
• Treatment: Acyclovir
• Outcome: 30% mortality in treated, 80% mortality in untreated
• CMV – found in all body fluids; most often causes intrauterine infection (microcephaly, microphthalmia, hydrocephalus, chorioretinitis); can also cause necrotizing encephalomyelitis in AIDS
• Rasmussen’s encephalitis – seizures (complex partial status) with unilateral atrophy; possibly CMV or antibodies to glutamate receptors

§ periventricular calcification

§ necrotizing epenymitis

§ large nuclear inclusion with halo (Chowdry A)

§ may have cytoplasmic inclusions

• Varicella – shingles; 70% involves T5-9, 15% involves CN V1; Ramsey-Hunt involves geniculate ganglion
• Causes encephalitis, myelitis, angiitis
• Located in dorsal root ganglion
• Rabies – through peripheral nerve; 1-3 months incubation; causes encephalitis or paralytic (GBS-like) prodrome; 100% mortality in 2-25 days
• affects limbic lobe
• negri bodies – intracytoplasmic inclusions (ribonucleoprotein) in purkinje cells, brainstem, hippocampus

§ cytoplasmic inclusion bodies

§ Negri bodies often in Purkinje cells

• inflammation in brainstem
• Enterovirus – picornavirus
• Polio – 7-21 day incubation, 10% have viremia, most are subclinical nonparalytic, involves anterior horn cells and brainstem nuclei; no viruses in CSF; causes perivascular mononuclear infiltrate; most from vaccine (1 in 2.5 million)
• Cocksackie or echovirus – meningitis, polymyositis; can be cultured from CSF; associated with humoral immune deficiency
• West Nile

§ non-necrotizing encephalitis

§ severe muscle weakness with meningoencephalitis

§ predilection for brainstem, thalamus, spinal cord

• Mumps – causes meningitis in 10% (25% viral encephalitis before vaccine)
• Measles – rash; encephalomyelitis in 1%
• If infected before 2 years can get SSPE (childhood behavioral changes followed by myoclonus, seizures, weakness, death in 1-3 years); perivascular lymphocytes in gray and white matter with neuronophagia and demyelination; intranuclear and intracytoplasmic inclusions in neurons and glia; 2-3/sec EEG pattern
• Progressive Multifocal Leukoencephalopathy (PML) – caused by JC virus (papovavirus) – white matter hypodensities with no enhancement; spares cortex; minimal cellularity; CSF normal
• Multifocal disease of white matter seen in the immunocompromised
• Most cases are caused by the JC virus (a polynoma virus belonging to the papova group)

§ lesions in white matter

§ multiple confluent lesions with preference for gray-white junction

§ vasculitis-like inflammation

§ spherical cell with no cytoplasm

§ giant, bizarre astrocytes (may be multinucleated)

• Symptoms: Progressive change in mental status, dementia, language dysfunction, visual defects, weakness, and ataxia
• Diagnosis: MRI shows asymmetrical multifocal white matter lesions without mass effect or enhancement
• Treatment: No known treatment for the disease
• Outcome: Course over 6 months to one year
• HTLV1 – retrovirus causing tropical spastic paraparesis without sensory deficit (anterior/lateral column)
• HIV (HTLV2)
• AIDS-dementia complex – 80% of AIDS patients; dementia, behavioral changes, motor deficits
• Congenital – atrophy, hydrocephalus, microcephaly, facial dysmorphism, calcification of basal ganglia
• Encephalitis – microglial nodules in white matter, focal demyelination with neuronal loss, reactive astrocytes, calcified basal ganglia, multinucleated giant cells
• AIDS myelitis – vacuolization of lower thoracic spinal cord – mostly anterior and lateral

§ brought to brain by monocytes

§ activated monocytes release cytokines and induce apoptosis

§ microglial nodules with multinucleated cells

§ pallor of myelin

• Prion Disease
• includes kuru, CJD (with myoclonus, extrapyramidal symptoms, visual deterioration), Gerstmann-Straussler syndrome (ataxia/hyperreflexia without myoclonus); 1.5-2/sec EEG reaction to painful stimuli
• spongiform degeneration
• Jakob-Creutzfeldt Disease (CJD)
• Symptoms:  Rapidly progressive dementia often associated with myoclonus
• Incidence in 1/million person per year
• Usually presents in the 6^th decade with slight female predominance
• 5-10% of cases is familial
• Etiology:  A proteinaceous infectious particle (prion) which is an abnormal isoform of a normal cellular protein has the capacity to transform the normal protein into the abnormal isoform, resulting in cell death
• Diagnosis:
• LP generally normal (occasional mild protein elevation)
• EEG shows generalized slowing or more characteristically pseudoperiodic sharp wave activity
• Brain biopsy shows diagnostic spongiform cortical degeneration with reactive astrocytosis/gliosis
• Treatment:  There is no known treatment for this disease
• Outcome:  Mean duration of illness is approximately 7-8 months
• Kuru – cerebellar-predominant disease
• Scrappie – in sheep
• normal proteins with abnormal configuration; abnormal protein is not digested by protease
• variant CJD is earlier onset, affects cerebellum and cortex, psychotic presentation (not myoclonus), kuru-like body outside of cerebellum (plaques)