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A. Definitions navigator

  1. Encephalitis refers to inflammation of the parenchymal central nervous system (CNS)
  2. Clinical and/or pathologic evidence of cerebrum, brainstem, cerebellum by inflammation
  3. May or may not involve inflammation of the meninges (which is meningitis)
  4. Most forms of encephalitis are caused by viruses
    1. Primary viral encephalitis
    2. Postinfectious or parainfectious
    3. Slow viral infections
  5. Wide variety of non-viral causes, especially in immunocompromised patients

B. Symptoms of Encephalitis [24]navigator

  1. Clinical Hallmarks of Acute Encephalitis
    1. Fever
    2. Headache
    3. Altered mental status (confusion, lethargy, drowsiness, stupor)
    4. Common: disorientation, behavioral and speech disturbances
    5. Specific for encephalitis: focal neurologic signs, hemiparesis, or seizures
    6. Meningitis does not include altered sensorium or focal neurologic signs
  2. Systemic symptoms are common: myalgia, malaise, fever, rash
    1. Often occurs with upper respiratory infections
    2. Nausea and vomiting are common
  3. Meningismus (neck stiffness) occurs with meningeal irritation
    1. Meningitis
    2. Meningoencephalitis
  4. Acute psychosis may be coincident with encephalitis, particular with herpesviruses

C. Pathogenesis navigator

  1. Access of viruses to CNS occurs by hematogenous or neuronal routes
  2. Hematogenous Spread
    1. Most common
    2. Usually leads to altered blood-brain barrier
    3. Capillary and endothelial inflammation of cortical vessels often found
    4. Grey matter or grey-white junction typically affected
    5. Perivascular lymphocytic infiltration (passive or active viral transfer)
  3. Nervous System Spread
    1. Less common, but usual route for herpes simplex virus (HSV)
    2. Olfactory tract may be major route into CNS
    3. Rabies may also invade CNS along neuronal routes
  4. Once virus has infected CNS, histological changes occur
    1. Astrocytosis and gliosis
    2. Cowdry Type A intranuclear inclusions found in herpesvirus infection
    3. Negri bodies found in rabies virus infection
  5. Acute Disseminated Encephalomyelitis (ADEM) [20]
    1. Associated with postviral or post-vaccination in ~55% of cases
    2. Remainder of cases are idiopathic
    3. Symptoms: encephalopathy, hemiparesis, seizures, visual dysfunction, acute psychosis
    4. Ataxia, dysarthria, cranial-nerve palsies, myelopathy also observed
    5. Evolves over period of days to weeks in most cases
    6. Cerebrospinal fluid slightly meningitic
    7. Usually has dramatic response to very high dose glucocorticoids
    8. Methylprednisolone IV 1000mg qd x 3 days, 500mg qd x 3 days, 250mg qd x 3 days
    9. Then oral prednisone is given in slow taper following symptoms
    10. Long term residual deficits may occur

D. Selected Viral Agentsnavigator

  1. Arboviruses (most common causes in USA)
    1. Insect (arthropod)-borne viruses
    2. Dengue Fever (<5% of cases of CNS infection) [13]
    3. Large number of arthropod (mainly mosquito and tick) borne viruses implicated [1]
    4. St. Louis Encaphlitis flavivirus sometimes considered in this group (see below)
  2. Togaviruses (summer and fall)
    1. alphaviruses are most common in USA (see below):
    2. Eastern Equine Encephalitis Virus (EEEV) [3]
    3. Western Equine Encephalitis Virus (WEEV)
    4. Venezualen Equine Encephalitis Virus (VEEV)
  3. Picornaviruses
    1. Enteroviruses most common in summer and fall
    2. Poliomyelitis is best known
    3. Enterovirus 71 (caused hand-foot-mouth disease with neurologic sequellae)
    4. Can cause a flaccid paralysis similar to poliovirus and flaviviruses such as WNV [30]
  4. Paramyxovirus (winter months)
    1. Uncommon causes include Hendra virus, Nipah virus [11]
    2. Nipah Virus Encephalitis reported among pig farmers in Malasia [14]
    3. Nipah infection presented mainly with fever, headache, dizziness and vomiting
    4. Brain stem dysfunction also occurs with Nipah infection
    5. Nipah symptoms include hypertension, tachycardia, myoclonus, hypotonia, areflexia
  5. Herpesviruses [2]
    1. HSV-1 - most common cause of nonepidemic sporadic encephalitis
    2. HSV-1 also causes benign recurrent lymphocytic meningitis
    3. Non-typable herpesviruses and HSV-2 are often found
    4. Epstein-Barr Virus (EBV) infection is not uncommon
  6. Flaviviruses [4]
    1. Japenese Encephalitis Virus
    2. West Nile Virus (see below)
    3. St. Louis Encephalitis virus (see below)
    4. Murray Valley Encaphalitis
    5. Dengue Viruses
    6. Yellow Fever Virus
    7. Kunjin Virus and Kunjin-like (New York isolate) virus [12]
    8. Tick-borne encephalitis (see below)
  7. Japanese Encephalitis Virus [5]
    1. Endemic flavivirus found in Southeast Asia
    2. ~50,000 cases per year in Asia, mainly in children
    3. Can cause severe meningoencephalomyelitis
    4. Common cause of acute flaccid paralysis mimicing poliomyelitis in Vietnam
    5. Efficacy of single dose SA 14-14-2 vaccine is >99% [18]
    6. High dose interferon alpha 2a 10 MU/m2 daily x 7 days did not improve outcomes [21]
    7. JE-VAX is licensed in USA, Canada, Australia: formalin-inactivated mouse-brain derived
    8. Protective efficacy ~90% in children in Thailand but anaphylaxis occurs in ~0.5%
    9. Novel, purified inactivated JEV vaccine propagated in monkey (Vero) cells has improved tolerability compared with mouse brain-derived vaccine [26]
  8. Tick-borne encephalitis [33]
    1. Due to a flavivirus, tick-brone encephalitis virus
    2. Ticks: Ixodes
    3. Western Europe to Eastern Japan; patchy endemic foci
    4. Causes acute meningoencephalitis with or without myelitis
    5. Morbidity is age depdent, with highest in adults
    6. About 30% of patients have longlasting sequelae, including cognitive dysfunction
    7. Serology is used for diagnosis, but no specific therapies available
  9. Bunyavirus: La Crosse Encephalitis (see below)
  10. Rabiesvirus
  11. Measles Virus [22]
    1. Frank encephalitis occurs 1 per 1000 children infected
    2. Distinct from SSPE, an inflammatory response to infection (1 per 100,000 infections)
    3. Others measles CNS Disease includes APME and measles inclusion body encephalitis (MIBE)
  12. Immunocompromised Patients - HIV encephalitis, CMV encephalitis, others
  13. Influenza [7]
    1. Acute necrotizing encephalopathy is a very uncommon severe complication of influenza
    2. Vasogenic and cytotoxic edema in the brain
    3. Leukocytosis in periphery
    4. Cerebrospinal fluid may show no cells and unremarkable chemistry
    5. Severe encephalopathic picture requiring intensive care
    6. Treatment with oseltamivir and methylprednisolone
  14. JC Polyomavirus (see below)

E. Most Common Encephalitides in USA [1]navigator

  1. Western Equine (WEEV)
    1. West, midwest USA
    2. Affects infants and >50 year olds
    3. Mortality: moderate in infants, low in others
    4. Seizures not uncommon
  2. Eastern Equine (EEEV) [3,24]
    1. East, Gulf Coast, Southern USA
    2. Togavirus infects both children and adults
    3. ~1% of viral encaphlitiis in US
    4. Incubation period >1 week
    5. Prodrome of fever, headache, influenza-like symptoms
    6. Seizures and focal neurological (including cranial nerve) signs common
    7. Once neurological symptoms occur, deterioration is rapid
    8. Peripheral blood leukocytosis and hyponatremia
    9. Focal changes in basal ganglia and thalamus on MRI
    10. Mortality >30%
  3. Venezualen (VEEV)
    1. South America, Southern USA
    2. Adults
    3. Mortality: rare
    4. Myalgia and pharyngitis common
  4. West Nile Virus (see below)
  5. St. Louis [24]
    1. Central, west, southern USA
    2. Transmission between birds and mosquitos
    3. >50 year olds
    4. Mortality: 20%
    5. Nausea, vomiting, stupor, irritability
  6. La Crosse [15]
    1. Central, eastern USA
    2. Children
    3. Mortality: 10-15%
    4. Seizures, paralysis, focal weakness, vomiting, disorientation
    5. Aseptic meningitis (13%), hyponatremia (21%), increased intracranial pressure (13%)
    6. May be mistaken for herpes simplex encephalitis
    7. Diagnosis by specific serology
  7. Powassan Virus [24]
    1. Northeastern USA
    2. Tick-borne virus infects woodchucks and skunks
    3. Mortality 10-15%

F. West Nile Virus (WNV) [4,12,16,17,19]navigator

  1. Single stranded RNA flavirvirus
  2. Transmission
    1. Mainly transmitted by mosquitos
    2. Maternal-fetal, blood transfusion, lactation, organ donor [23] reported
    3. Can be transmitted through red blood cell, platelet, fresh frozen plasma [8]
    4. Routine detection of WNV RNA in blood donations has essentially eradicated transmission through blood products in USA [31,32]
  3. Causes disease in humans and birds, including fatilities
  4. Found in East Coast USA, Africa, Middle East, Europe
    1. In USA, as of April 15, 2003, 4156 cases in 39 states with documented infections [23]
    2. 2866 cases in USA in 2003 with 246 deaths
    3. Thousands of symptomless and symptomatic cases reported mainly in adults
    4. Age is most important risk factor for neurological disease and death
    5. Age >74 years and presence of diabetes mellitus were each 5X risks for death
  5. Most cases include mild symptoms lasting 3-5 days
    1. Fatigue, muscle weakness (>50%), fever (>90%), nausea, vomiting, confusion [24]
    2. <1% with severe neurological disease: acute flacid paralysis, meningitis, encephalitis
    3. Movement disorders most common neurologic symptom: tremor, myoclonus, parkinsonism [9]
    4. Unusual irreversible poliomyelitis-like syndrome with flaccid paralysis [4,9,30]
    5. Other flaviviruses and enteroviruses can cause this poliomyelitis syndrome
  6. Diagnosis
    1. WNV specific IgM levels in serum and/or cerebrospinal fluid (CSF)
    2. CSF also shows leukocytosis, elevated protein, normal glucose
    3. MRI findings can be suggestive with basal ganglia, thalamus often involved [30]
  7. Treatment
    1. Mainly supportive care
    2. HIgh dose interferon alpha2b and/or human immunoglobulin with high titer anti-WNV Abs promising therapies based on animal models [17]
    3. New drugs and a vaccine are being developed
  8. Prevention by elimination of mosquito breeding sites and use of insect repellent

G. Progressive Multifocal Leukoencephalopathy (PML) [27,28]navigator

  1. Caused by JC Virus [27]
    1. JC polyomavirus is a relative of the simian virus SV40
    2. JC virus antibodies (evidence of presence of agent) in 60-80% of adults
    3. Immunosuppression appears necessary for pathogenesis of JC Virus
    4. Virus normally remains quiescent in kidney and lymphoid organs of immunocompetent
    5. In normal persons, virus may be found in urine
    6. With immunosuppression, hematogenous dissemination occurs and CNS infection possible
    7. Normally, lymphocytes (probably CD8+) suppress virus
  2. Rare progressive demyelinative disorder
  3. Usually occurs as late complication of severe (cellular) immunodeficiency
    1. Most common in late stage HIV infection
    2. Also occurs in leukemia (CLL), Hodgkin's disease
    3. Reported in organ transplant patients
    4. Increased risk with treatment with natalizumab (Tysabri®), an alpha4 integrin blocker which disrupts lymphocyte trafficking used in Crohn's disease and multiple sclerosis [27]
    5. May be found with systemic lupus, sarcoidosis, immunosuppression
  4. No known treatment at the present time; cytarabine did not alter course [29]
  5. Withdrawal of immunosuppression may lead to some improvement

H. Differential Diagnosis of Encephalitis [2]navigator

  1. Bacterial
    1. Early meningitis
    2. Brain abscess
    3. Subdural empyema
    4. Mycobacteria (mainly tuberculosis)
    5. Mycoplasma
    6. Spirochete - syphilis, Lyme Disese
    7. Nocardia
    8. Listeria
    9. Meningococcus
  2. Fungi: Cryptococcus, Coccidioides, Histoplasma, Candida, Mucormyces
  3. Rickettsia: rocky mountain spotted fever
  4. Protozoa: ameba, malaria, toxoplasma
  5. Medications: salicylates, barbiturates, heavy metals, intravenous gammaglobulin
  6. Systemic Disease
    1. Sarcoidosis
    2. Hyperglobulinemia
    3. Vasculitis
    4. Endocarditis embolization
    5. Systemic lupus erythematosus (SLE)
  7. Neoplastic Encephalitis: carcinomatous meningitis
  8. Post-vaccination Encaphlitis: autoimmune response (serum sickness reaction)
  9. Gullain-Barre Syndrome
  10. Other
    1. Helminthic infections - rare in USA
    2. Subdural hematoma
    3. Adrenal leukodystrophy

I. Diagnosisnavigator

  1. Routine laboratory tests are usually not helpful
  2. Cerebrospinal Fluid (CSF) Analysis
    1. High protein with normal or slightly low glucose
    2. White Cells: typically with lymphocyte (mononuclear) predominance
    3. Significant red blood cells (with xanthochromia) may be seen in herpetic encephalitis [2]
    4. Normal CSF may be found in 3-5% of patients with encephalitis
    5. Polymerase chain reaction (PCR) detection of viral DNA/RNA in CSF
    6. Viral cultures, with or without PCR-based DNA analyses, are most specific
  3. PCR is essential for specific and rapid diagnosis and should be increasingly used
  4. CT or MRI of head are usually not helpful
    1. Should be reserved for seziures or focal signs
    2. MRI may show early hemorrhage in herpes encephalitis
  5. Electroencephalogram (EEG) may show diffuse slow wave activity
  6. Serology
    1. Acute and convalescent viral titers are useful for diagnosis and epidemiology
    2. Requires convalescent titers for confirmation
    3. For many viruses, 4 fold increase in viral titer above control levels is considered diagnositic

J. Treatment navigator

  1. Supportive and symptomatic therapy is mainstay
    1. Intubation for airway protection in patients with altered consciousness
    2. Anticonvulsants (eg. diazepam, phenytoin) for seizures
    3. Antihyperthermia measures (particularly with WEEV)
  2. If herpes simplex virus (HSV) infection is suspected, antiviral therapy must be started
    1. High dose intravenous acyclovir (10mg/kg iv q8°) for moderate and severe cases
    2. Oral acyclovir should not be used for initial encephalitis treatment
  3. Varicella zoster infection may also be treated with acyclovir or newer agents
  4. Intravenous fluids and anti-nausea agents should be given in severe cases
  5. HIV encephalitis has responded to high dose zidovudine (ZDV)
  6. Specific therapy for non-viral pathogens

K. Complicationsnavigator

  1. Severe CNS Sequellae
    1. HSV-1
    2. Eastern Equine Encephalitis [3]
    3. Japanese Encephalitis
    4. St. Louis Encephalitis
    5. Measles Encephalitis and SSPE (see below)
    6. JC Virus - PML (often fatal)
  2. Mild Disease
    1. California Encephalitis
    2. Western Equine Encephalitis

L. Types of Slow Virus CNS Infectionsnavigator

  1. Inflammatory
    1. Subacute sclerosing panencephalitis (SSPE)
    2. Progressive multifocal leukoencephalopathy (PML)
    3. Progressive rubella encephalitis
    4. Tropical spastic paraparesis - HTLV-1 associated myelopathy
    5. HIV Encephalopathy
    6. Persistent infection in immunodeficient patients
  2. Spongiform Encephalopathies [10]
    1. Vacuolation of nervous tissue with variable neurological findings, always fatal
    2. Strongly associated with proteinacious infectious particles called "Prions"
    3. Creutzfeld-Jacob Disease, Gerstmann-Straussler-Scheinker Disease, Familial Insomnia
    4. "Mad Cow Disease" (bovine spongioform encephalopathy) variant CJD transmitted to humans in Britain

M. Subacute Sclerosing Panencephalitis (SSPE) [6]navigator

  1. Progressive fatal encephalitis with dementia
    1. Typically in children and adolescents (80% under 11 years old)
    2. Ratio of males to females is 3-5 to 1
    3. SSPE occurs in 1-10 cases per 100,000 persons with measles infection
  2. Measles or measles related virus is responsible
    1. Risk is 16X increased when measles occurs at <2 years old versus >5 years old
    2. Incubation period is usually less than one decade
    3. Measles infections occur at 1-10 cases per 100,000
  3. Pathogenesis and Pathology
    1. Measles infection through receptor CD46, found on neurons and inflammatory cells
    2. CD46 is a complement regulatory protein
    3. Persistent measles genome is found systemically in patients with SSPE
    4. Neurofibrillary tangles - cells involved often contain measles virus genome
    5. Frank encephalitis with perivascular CD4+ T cells
    6. B lymphocytes found in parenchymal inflammatory infiltrates
    7. Alterations in measles virus proteins M, H and F have been found
  4. Symptoms and signs
    1. Insidious mental deterioration
    2. Myoclonus
    3. Ophthalmologic symptoms: macular color changes, optic atrophy, papilledema, retinitis, retinal vasculitis, pigmentary disturbances [25]
    4. Progression to cortical blindness often occurs
    5. Motor symptoms
    6. Distinct from frank measles encephalitis, which is acute and more common
  5. CSF Analysis
    1. Gamma-globulin level is elevated
    2. Anti-measles Ab titers increased (ratio for CSF to serum antibody ~1:5)
    3. Otherwise, the CSF is normal
  6. Elevated measles antibody levels in blood but anti-matrix (M) protein Ab are absent
  7. Treatment
    1. Experimental therapies are under investigation
    2. Orally administered Inosiplex (isoprinosine) and intraventricular interferon alpha 2b

References navigator

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