• HSV-1
• HSV-2
• VZV
• CMV
• EBV (seldom affects CNS directly, but could be important in pathogenesis of primary CNS lymphoma in immunocompromised)

dsDNA linear with envelope

• pathogenesis
  • CNS primary infection
  • reactivation from trigeminal ganglion
• targets
  • medial temporal lobe
  • limbic regions
• histopathology
  • necrotizing, hemorrhagic infection
  • intranuclear viral inclusions in neurons and glia

• adults
  • pathogenesis- retrograde spread to CNS from sacral DRG (latency established after genital infection)
  • nature of infection
    • healthy adult- aseptic meningitis
    • immunocompromised- necrotizing encephalitis
• neonates
  • pathogenesis- acquire via passage through vaginal canal with primary HSV-2 infection OR transplacentally
  • nature of infection- necrotizing encephalitis

• pathogenesis
  • childhood viral exanthem with latency established in DRG or trigeminal ganglia
  • viral reactivation after many years with anterograde axonal transport to skin in dermatome distribution
  • with primary infection or reactivation VZV may travel retrograde to spinal cord/brain, especially in immunosuppressed
    • myeloradiculitis
    • encephalitis
    • CNS vascular infection
• histopathology- intranuclear inclusions in neurons and glia

• nature of infection
  • intrauterine infection
    • targets periventricular regions with severe necrosis leading to:
      • periventricular calcification
      • microcephaly
      • CNS malformation
  • infection in immunosuppressed
    • encephalitis
    • retinitis
    • myeloradiculitis
• histopathology- cellular enlargement with prominent intranuclear (w/ or w/o cytoplasmic) inclusions in neurons, glia, endothelial cells

• epidemiology
  • endemic in birds, small mammals
  • important causes of epidemic viral encephalitis
• transmission
  • via insects to horses and humans as incidental hosts
    • vectors: mosquitos (MOST COMMON) and ticks (RARE)
  • incidence of human encephalitis coincides with season of vector activity (ex: mosquito is summer through early fall)
• nomenclature reflects geographic distribution, insect vector, or incidental host

• birds are normal reservoir
• may cause meningoencephalitis when transmitted by mosquitoes to human as incidental host
  • transmitted human to human by blood transfusion, organ donation

• classification- enterovirus
• pathogenesis
  1. infect gut
  2. spread to blood
     • few strains can invade CNS from blood, based on neurovirulence
  3. produce aseptic meningitis picture with or without acute myelitis
  4. myelitis will result in virus targeting motor neurons of spinal cord (ant. horn cells) and brainstem
     • flaccid areflexic paralysis (MAJOR CLINICAL MANIFESTATION)
     • resp. muscle involvement fatal
• vaccination has reduced incidence worldwide

• epidemiology- virus endemic in small animals
  • dogs, bats, wild animals
• pathogenesis
  1. transmitted to human by bite of infected animal
  2. virus inoculates at bite site
  3. travel retrograde through axons of PNS to reach CNS (time of disease onset reflects bite distance from CNS)
  4. lead to fulminant encephalitis
• histopathology- Negri bodies
  • neuronal cytoplasmic inclusions
  • round or oval, pink
  • seen best in Purkinje cells, hippocampal pyramidal neurons

1. early onset measles infection (less than 2 yrs old)
2. nonproductive (no viral replication) CNS latency of altered measles virus after primary infection
3. onset of progressive behavior, cognitive, motor disturbances months to years after initial measles infectionm
4. encephalitis with widespread neuronal and white matter destruction
   • intranuclear inclusions in neurons, oligodendrocytes

1. reactivation of latent JC polymovirus infection acquired earlier in life during period of immunocompromise
   • primary infection asymptomatic
   • latent in lymphocytes, kidney
2. infecting glia or reactivation
   • oligodendrocyte involvement leads to myelin loss
   • astrocyte involvement leads to enlarged bizarre astrocyte nuclei
3. progressive neurologic syndrome due to CNS white matter destruction
   • multiple foci of secondary demyelination in cerebral, cerebellar, brainstem white matter
   • viral inranuclear inclusions in oligodendrocyte nuclei

• early/seroconversion- aseptic meningitis
• late- subacute meningoencephalitis
  • direct HIV infection of cerebral microglia and macrophages lead to multinucleated giant cells
    • w/ or w/o infection of astrocytes, endothelial cells
  • neurons destroyed by cytokines, BBB failure
  • clinical dementia, motor disturbances, seizures

• direct- more so in peds
• opportunistic- more so in adults

• infections
  • parasites- Toxoplasmosis
  • viral- CMV, PML
  • fungal- cryptococcus
  • bacterial- M TB, MAC
• malignacy- primary CNS lymphoma

• structure- unicellular organism btw virus and bacteria
  • possess cell walls, antibiotic sensitive (like bacteria)
  • live and reproduce only inside host cells (like viruses)
• pathogenesis
  1. spread by insect vectors (ticks, lice, mites)
  2. infect CNS vascular endothelium leading to:
     • vasculitis
     • hemorrhage
     • thrombosis
     • infarction
• CNS rickettsial infections
  • rocky mountain spotted fever (spread via tick)
  • typhus (spread via human body louse)

• chronic meningitis: Cryptococcus
• septic vasculitis: Aspergillus, Mucor
• parenchymal invasion: Candida, Cryptococcus

• common organisms- Candida, Aspergillus, Mucor, Cryptococcus
• pathogenesis (associated with immunocompromise)
  1. hematogenous dissemination/local extension of extracranial (pulmonary, sinonasal) infection to CNS
  2. inflammatory response granulomatous or minimal dependent on immune status of host and infecting organism (ex: cryptococcus may elicit little inflam. response to large organism burden)

• malaria
• amebiasis
• trypanosomiasis
• toxoplasmosis

• host- cat (sexual stage of reproduction)
• pathogenesis (humans are intermediate host)
  1. acquire disease from food tainted by several oocyst containing cat feces
  2. GI cysts digestion and liberation of tachyzoites
  3. tachyzoites infect GI macrophages
  4. hematogenous and lymphatic dissemination of tachyzoites
  5. CNS infection

• cysticercosis, echinococcosis
• neurocysticercosis
  • larvae of Tenia solium (pork tapeworm encyst in human CNS)
  • human (definitive host) ingest eggs ment for pig (intermediate host)
    • human functions as dead end intermediate host

• intrauterine/neonatal
  • transplacental passage of tachyzoites during primary maternal infection
  • fetal meningoencephalitis
    • targets subpial and subventricular regions
    • widespread gray and white matter destruction
    • diffuse brain calcification, hydrocephalus, CNS malformation
• immunosuppressed
  • abscess (MOST COMMON lession of brain in AIDS)
    • ring enhancing cerebral abscesses at gray/white cortical junction, deep gray matter
      • w/ or w/o meningitis, vasculitis, retinitis
  • microscopy- free tachyzoites and encysted bradyzoites

1. normal neuronal protein PrP^C is converted from alpha helix isoform to beta pleated sheet PrP^SC
   • single aberrant PrP^SC molecule serves as template for conversion of other PrP^C molecules (cascade)
2. PrP^SC resistant to normal cellular degredation mechanisms and normal techniques of sterilization and tissue fixation (these proteins do not have nucleic acid)
3. PrP^SC accumulates in brain tissue
4. neuronal cell bodies and axons acquire vacuoles (spongiform change)

• arise spontaneously
  • inheritied AA substitution in polypeptide sequence predispose to abnormal folding
  • sporadic and inherited forms
• introduce in surgery, ingestion, organ transplantation (infectious forms of prion disease)

• prognosis- fatal in less than a year
• presentation
  • rapidly progressive (wks to months) dementia
  • myoclonic jerks (rapidly alternating contraction and relaxation)
• histopathology
  • widespread neuronal loss, gliosis, spongiform change in brain gray matter
  • no inflammatory response

• Gerstmannn Straussler Scheinker syndrome (GSS)
• fatal familial insomnia

• scrapie (sheep)
• bovine spongiform encephalopathy (BSE)
  • cows
  • crossing of species barrier (sheep to cows via scrapie contaminated cow feed)

• kuru- human to human via canabalism
• variant CJD- BSE cross species barrier of infected cattle to humans by ingesting BSE infected beef