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- List is not comprehensive.
- Herpes Simplex virus (HSV, most common sporadic form in U.S.)
- CMV, VZV and EBV
- HHV-6: especially following hematopoietic stem cell transplanations.
- Common arboviruses causing encephalitis in the U.S.:
- Most common: West Nile virus
- Others seen with fluctuating frequencies: St. Louis encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, La Crosse encephalitis virus, Colorado tick fever.
- Powassan virus (member of tick-borne encephalitis flaviviruses): seen in New England, Upper Midwest U.S., Canada, Asia. Two lineages:
- Lineage 1 (Powassan): Ixodes cookei vector
- Lineage 2 (Deer tick virus): Ixodes scapularis vector
- Chikungunya virus
- Enterovirus (more commonly causes meningitis), polio virus
- Japanese encephalitis virus: seen in SE Asia, Japan, Korea, N. Australia
- Murray Valley encephalitis virus: Australia
- Tick-borne encephalitis virus: central Europe through Eurasia
- Parvovirus B19
- Hendra virus, Nipah virus: Australia, SE Asia
- Other less common viral etiologies include:
- Anaplasma phagocytophilum: vector same as Lyme disease, the deer tick Ixodes scapularis
- Bartonella species: B. bacilliformis, B. henselae
- Borrelia burgdorferi
- Borrelia miyamotoi: see Borrelia species module
- Possibly B. mayonii
- Coxiella burnetii (Q fever)
- Ehrlichia chaffeensis: transmitted by the Lone Star tick (Amblyomma americanum).
- Listeria monocytogenes
- Mycobacterium tuberculosis
- Mycoplasma pneumoniae: more common in children, controversial cause
- Rickettsia rickettsii (RMSF): Dog tick is the most common vector
- T. pallidum (syphilis)
- Tropheryma whipplei (Whipple disease)
- Parasites: may cause a granulomatous meningoencephalitis.
- Amoebic encephalitis most commonly caused by Naegleria fowleri or Acanthamoeba species.
- Baylisascaris procyonis
- Balamuthia mandrillaris
- Fungi: among leading causes
- Fever, cognitive deficits, focal neurologic signs (often rapidly progressive), and/or seizures of preceded by nonspecific/flu-like prodrome.
- Encephalitis (2013 International Encephalitis Consortium): defined as brain inflammation associated with neurologic dysfunction (see Diagnostic Criteria for Encephalitis and Encephalopathy of Presumed Infectious or Autoimmune Etiology table).
- Gold standard: brain biopsy, but rarely performed hence clinical definition above.
- Encephalopathy: altered mental status or other cognitive impairments with or without brain inflammation. Term often used when inflammation of brain not suspected, e.g., toxic-metabolic encephalopathy or Bartonella systemic infection without evidence of invasive CNS process.
- See Diagnostic Criteria for Encephalitis and Encephalopathy of Presumed Infectious or Autoimmune Etiology table).
- Encephalitis (2013 International Encephalitis Consortium): defined as brain inflammation associated with neurologic dysfunction (see Diagnostic Criteria for Encephalitis and Encephalopathy of Presumed Infectious or Autoimmune Etiology table).
- Review travel, sexual contact, tick/insect hx.
- Obtain hx looking for epidemiological risks including: geography, exposure to vectors, time of year, travel hx, animal contact, recent vaccines, occupational exposure (especially lab workers).
- PE: meningeal signs (meningoencephalitis), abnormal mental status with ataxia, hemiparesis, aphasia, cranial nerve involvement and psychosis possible.
- Ddx: among most common--arboviruses (summer-fall), HSV (most common sporadic cause), enterovirus (summer-fall), toxic/metabolic explanations, CNS vasculitis, paraneoplastic syndromes, post-infectious or post-immunization encephalitis/encephalomyelitis (e.g., ADEM).
- See pathogens list and tables for more comprehensive list and more section below for additional epidemiological clues.
- Autoimmune N-methyl-D-aspartate receptor encephalitis in one large series was identified as the leading cause of encephalitis (more than HSV,VZV, WNV).
- Note: < 50% of cases identified with specific etiology.
Table 1: Possible etiologic agents of encephalitis based on epidemiology and risk factors.
Epidemiology or risk factor
Possible infectious agent(s)
Infants and children
West Nile virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus, Japanese encephalitis virus, Cryptococcus neoformans (bird droppings), rabies virus.
Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Hendra virus
Old World primates
Eastern equine encephalitis virus (South America), Venezuelan equine encephalitis virus, tick-borne encephalitis virus, Powassan virus (woodchucks), La Crosse virus (chipmunks and squirrels), Bartonella quintana
Sheep and goats
Japanese encephalitis virus, Nipah virus
Varicella zoster virus, cytomegalovirus, human herpesvirus 6, West Nile virus, HIV, JC virus, L. monocytogenes, Mycobacterium tuberculosis, C. neoformans, Coccidioides species, Histoplasma capsulatum, T. gondii
Raw or partially cooked meat
Raw meat, fish, or reptiles
Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus, Japanese encephalitis virus, West Nile virus, La Crosse virus, Plasmodium falciparum
Exposure to animals
Exposure to horses
Exposure to Old World primates
Physicians and health care workers
Herpes simplex virus (neonatal), varicella zoster virus, Venezuelan equine encephalitis virus (rare), poliovirus, nonpolio enteroviruses, measles virus, Nipah virus, mumps virus, rubella virus, Epstein-Barr virus, human herpesvirus 6, B virus, West Nile virus (transfusion, transplantation, breast feeding), HIV, rabies virus (transplantation), influenza virus, M. pneumoniae, M. tuberculosis, T. pallidum
Acute disseminated encephalomyelitis
All agents transmitted by mosquitoes and ticks (see above)
HIV, T. pallidum
Enteroviruses, Naegleria fowleri
Late summer/early fall
All agents transmitted by mosquitoes and ticks (see above), enteroviruses
Transfusion and transplantation
Cytomegalovirus, Epstein-Barr virus, West Nile virus, HIV, tick-borne encephalitis virus, rabies virus, iatrogenic CJD, T. pallidum, A. phagocytophilum, R. rickettsii, C. neoformans, Coccidioides species, H. capsulatum, T. gondii
Murray Valley encephalitis virus, Japanese encephalitis virus, Hendra virus
West Nile virus, tick-borne encephalitis virus, A. phagocytophilum, B. burgdorferi
West Nile virus, P. falciparum
Tick-borne encephalitis virus
Rabies virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus, R. rickettsii, B. bacilliformis (Andes mountains), P. falciparum, T. solium
Southeast Asia, China, Pacific Rim
Japanese encephalitis virus, tick-borne encephalitis virus, Nipah virus, P. falciparum, Gnanthostoma species, T. solium
Table 2: Possible etiologic agents of encephalitis based on clinical findings.
Possible infectious agent
HIV, Epstein-Barr virus, cytomegalovirus, measles virus, rubella virus, West Nile virus, Treponema pallidum, Bartonella henselae and other Bartonella species, Mycobacterium tuberculosis, Toxoplasma gondii, Trypanosoma brucei gambiense
Varicella zoster virus, B virus, human herpesvirus 6, West Nile virus, rubella virus, some enteroviruses, HIV, Rickettsia rickettsii, Mycoplasma pneumoniae, Borrelia burgdorferi, T. pallidum, Ehrlichia chaffeensis, Anaplasma phagocytophilum
Respiratory tract findings
St. Louis encephalitis virus (early)
Cranial nerve abnormalities
T. whipplei (oculomasticatory)
Parkinsonism (bradykinesia, masked facies, cogwheel rigidity, postural instability)
Poliomyelitis-like flaccid paralysis
- MRI may be normal in many cases early on. May show temporal lobe changes (in HSV) or more diffuse involvement.
- EEG abnl in many cases of HSV encephalitis with characteristic temporal lobe spikes. Should be performed in all pts to rule out non-convulsive seizure activity.
- Lab: obtain CSF if safe to do so, usually w/ mononuclear cells and increased protein; CSF PCRs, CSF culture (viral cx of limited value), or serology (based on suspected agents: IgM, acute/convalescent IgG or CSF antibodies).
- HSV PCR should be performed on all pts with encephalitis. If negative, repeat w/i 3-7d in pts with compatible findings if not other diagnosis secured.
- Note: negative PCR test is not absolute evidence that the certain infection is not extant.
- Autoimmune N-methyl-D-aspartate receptor encephalitis in one large series was identified as the leading cause of encephalitis (4x >HSV,VZV,WNV).
- Consider brain biopsy in pts with continued deterioration despite acyclovir.
- Many cases without known etiology despite extensive testing.
Diagnostic Alogrithm for Initial Evaluation in Adults:
Diagnostic Algorithm for Children:
- If infectious diagnosis not rapidly achieved, consider obtaining anti-NMDAR antibody testing as it is a leading cause of encephalitis.
General recommendations, empiric therapy
- Important to consider treatable causes and use empiric therapy.
- Start acyclovir 10mg/kg q8h in all pts with suspected encephalitis give leading treatable cause.
- Doxycycline (200mg load then 100mg q12h) should be also considered in anyone with potential tick exposure that may transmit Rocky Mt Spotted fever, other rickettsial infections, Ehrlichia or Lyme disease.
- Supportive care is all that can be done for most pts.
- Many cases of encephalitis without an identifiable cause or due to a virus without known therapy.
Viral encephalitis, treatable causes
- HSV: acyclovir 10mg/kg IV q8h x 14-21d.
- In neonates: 20mg/kg IV q8h x 21d.
- If good response not seen, f/u LP and treat until HSV PCR negative.
- VZV: acyclovir 10-15mg/kg IV q8h x 10-14d. Alternative: ganciclovir.
- CMV: ganciclovir 5 mg/kg IV q12h x 14-21 days; then 5mg/kg IV every day for maintenance .
- B virus: ganciclovir 5 mg/kg IV twice daily or acyclovir 15 mg/kg IV q8h x > 14d or until all CNS sx resolve, then acyclovir 800 mg PO 5 times daily or valacyclovir 1 g PO three times a day indefinitely. See B virus module for details.
- HHV-6: case reports suggest ganciclovir or foscarnet may help. Follow CMV recommendations.
- Listeria: ampicillin 2mg IV q4h + gentamicin 5mg/kg/d IV divided q8h x 3-6 weeks.
- Alternative: TMP/SMX 15mg/kg/d IV divided q6h x 3-6 weeks.
- Pyrimethamine 100-200mg orally once (loading dose), then 50-100mg PO every day + sulfadiazine 4-8 g PO every day + folinic acid 10mg PO every day x minimum 6 weeks.
- Pyrimethamine 100-200mg PO once (loading dose), then 50-100mg PO every day + clindamycin 900mg IV q6h + folinic acid 10mg PO every day x minimum 6 weeks.
- Autoimmune encephalitis: often a probable rather than a definitive diagnosis.
- Acute disseminated encephalomyelitis: neurology consultation, high-dose corticosteroids recommended. Plasma exchange or IV IgG could be considered.
- Anti-NMDAR encephalitis: antibody-mediated process directed against extracellular epitopes of NR1subunit epitope of NMDA receptor.
- May occur as a paraneoplastic–driven process, especially ovarian teratoma.
- Approximately 75% rate seen following tumor removal, or if non-tumor related, use of corticosteroids, immunoglobulin, plasmapheresis, rituximab or cyclophosphamide.
- Tick-borne encephalitis virus: flavivirus infection seen in Western Europe through Eurasia.
- Serology to diagnose. No effective treatment known.
- Commercial vaccine available in Europe, thought to be >95% effective.
- Japanese encephalitis virus: vaccine available, recommended for people living in rural, rice-growing parts of Asia or who are traveling to such regions with extended stay and for laboratory workers at risk for exposure.
Selected Drug Comments
Always indicated in suspected encephalitis cases until HSV comfortably ruled-out by PCR study or good alternative diagnostic explanation.
Meropenem and imipenem have been shown to be bactericidal for listeria and may be considered as alternatives when ampicillin, penicillin, and trimethoprim/sulfamethoxazole are not tolerated. These drugs are virtually untested clinically; however, meropenem appears to have less potential to lower the seizure threshold and is thus the favored carbapenem for treating CNS infections.
Use should be considered for any pts with potential risk for tick-borne infections such as RMSF, other rickettsial infections including ehrlichia.
- HSV is critical to treat rapidly.
- Suspected or proven HSV: use acyclovir IV. If dx studies negative, may need brain bx if suspicious.
Pathogen Specific Therapy
Human immunodeficiency virus
St Louis encephalitis virus
Albendazole + diethylcarbamazine
Albendazole + corticosteroids
Basis for recommendation
- Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57(8):1114-28. [PMID:23861361]
Comment: Helpful guidance that sets priorities including definition of encephalitis as well as suggested diagnostic algorithm.
- Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47(3):303-27. [PMID:18582201]
Comment: First comprehensive guideline ever published for encephalitis. Document has extensive information that helps the clinician regarding signs, symptoms, epidemiological risks and diagnostic approaches.
- Ziai WC, Lewin JJ. Advances in the management of central nervous system infections in the ICU. Crit Care Clin. 2006;22(4):661-94; abstract viii-ix. [PMID:17239749]
Comment: Includes strategies in critically ill patients that may require ICU monitoring.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016. [PMID:26906964]
Comment: More than a primer on an often competing diagnosis under consideration.
- Dalton HR, Kamar N, van Eijk JJ, et al. Hepatitis E virus and neurological injury. Nat Rev Neurol. 2016;12(2):77-85. [PMID:26711839]
Comment: Hepatitis E has been increasingly described as causing a range of neurological problems including Guillain−Barré syndrome (GBS), neuralgic amyotrophy, and encephalitis and/or myelitis. --albeit uncommonly.
- Gnann JW, Sköldenberg B, Hart J, et al. Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy. Clin Infect Dis. 2015;61(5):683-91. [PMID:25956891]
Comment: Extra valacyclovir beyond standard IV therapy for 90d appeared to offer no benefit in this RCT of 87 pts.
- Wormser GP, Pritt B. Update and Commentary on Four Emerging Tick-Borne Infections: Ehrlichia muris-like Agent, Borrelia miyamotoi, Deer Tick Virus, Heartland Virus, and Whether Ticks Play a Role in Transmission of Bartonella henselae. Infect Dis Clin North Am. 2015;29(2):371-81. [PMID:25999230]
Comment: Powassan/Deer Tick virus is probably under-recognized. Testing usually needs to be coordinated on CSF or serum through local heatlh department.
- Patel H, Sander B, Nelder MP. Long-term sequelae of West Nile virus-related illness: a systematic review. Lancet Infect Dis. 2015;15(8):951-9. [PMID:26163373]
Comment: Search for relevant literature yielded 67 studies with findings of muscle weakness, memory loss, and difficulties with activities of daily living among the most common physical, cognitive, and functional sequelae, respectively/ Increased risks of significant sequelae were seen in older men with underlying illnesses such as cardiovascular disease or cancer.
- Gable MS, Sheriff H, Dalmau J, et al. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7):899-904. [PMID:22281844]
Comment: In the California Encephalitis Project study, anti-NMDAR encephalitis proved to be the cause of encephalitis that was 4x more frequent then other causes often diagnosed by infectious diseases physician such as herpes simplex virus, West Nile virus were varicella zoster virus.
- McJunkin JE, Nahata MC, De Los Reyes EC, et al. Safety and pharmacokinetics of ribavirin for the treatment of la crosse encephalitis. Pediatr Infect Dis J. 2011;30(10):860-5. [PMID:21544005]
Comment: Phase I and IIa studies have interesting PK/PD information regarding ribavirin; however, this available data does not suggest benefit and treatment of lacrosse encephalitis.
- Pouplin T, Pouplin JN, Van Toi P, et al. Valacyclovir for herpes simplex encephalitis. Antimicrob Agents Chemother. 2011;55(7):3624-6. [PMID:21576427]
Comment: Interesting study that suggests high-dose valacyclovir (1000 mg three times daily) achieves suitable CSF levels and may be an option in resource limited countries where parenteral acyclovir here may not be feasible.
- Granerod J, Tam CC, Crowcroft NS, et al. Challenge of the unknown. A systematic review of acute encephalitis in non-outbreak situations. Neurology. 2010;75(10):924-32. [PMID:20820004]
Comment: Authors examine literature and suggest that many cases of encephalitis without defined etiology may have an explanation (infectious or auto-immune) and therefore continued efforts are needed to understand causes.
- Gable MS, Gavali S, Radner A, et al. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis. 2009;28(12):1421-9. [PMID:19718525]
Comment: NMDA (N-methyl-D-aspartate) receptor antibody encephalitis is an autoimmune disorder that can present acutely and be confused with viral meningitis. CSF pleocytosis and elevated protein levels exist for both the autoimmune and the infectious categories.
This entity primarily afflicts children, teens, or young adults often with very prominent psychiatric features. Some may have autonomic dysfunction leading to concern of rabies.
- Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet. 2008;371(9627):1861-71. [PMID:18514730]
Comment: Comprehensive review of a problem of tick-borne encephalitis that is mostly due to flavivirus infections seen in Western Europe extending through Eurasia to Japan. As no effective treatment is known, prevention through immunization is the best strategy.
- Loeb M, Hanna S, Nicolle L, et al. Prognosis after West Nile virus infection. Ann Intern Med. 2008;149(4):232-41. [PMID:18711153]
Comment: Longitudinal cohort of 156 pts. Most recovered both mental and physical function by 1 year after infection onset. Presence of comorbid conditions was associated with a slower recovery. Depression, fatigue and mood issues did not seem to persist longer in the group with more severe, neuroinvasive disease.
- Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis. 2007;44(12):1617-24. [PMID:17516407]
Comment: Subset of WNV encephalitis patients have unresolved neurological sequelae.
- Tauber E, Kollaritsch H, Korinek M, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet. 2007;370(9602):1847-53. [PMID:18061060]
Comment: Trial looking at a next generation inactivated JEV vaccine that avoids the issues known to the currently licensed, mouse-brain-derived vaccine. The new vaccine provided 98% seroconversion (compared to current 95%) and had a good side effect profile.
- Solomon T. Flavivirus encephalitis. N Engl J Med. 2004;351(4):370-8. [PMID:15269317]
Comment: Comprehensive review on the subject including latest diagnostics.
- Petersen LR, Marfin AA, Gubler DJ. West Nile virus. JAMA. 2003;290(4):524-8. [PMID:12876096]
Comment: Comprehensive update on the newly seen North American infection. Includes information on encephalitic, meningoencephalitic and ascending paralysis style presentations. Diagnostics discussed.
- Domingues RB, Tsanaclis AM, Pannuti CS, et al. Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis. 1997;25(1):86-91. [PMID:9243040]
Comment: Study investigating the spectrum of illness associated with herpes simplex infection, as established by PCR assay. Atypical cases were found, including brainstem encephalitis, chronic encephalitis, and milder forms of encephalitis that were poorly appreciated in the era in which brain biopsy was necessary for diagnosis.
- Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis. 1995;20(2):414-20. [PMID:7742450]
Comment: Recent review of pathogenesis and diagnostic and therapeutic strategies. Normal function is established in only 38% of patients treated with acyclovir. Glasgow coma score <6, age >30, and encephalitis >4 days duration are poor prognostic factors. 5-10% of patients relapse after a 10-14 day course of therapy.
- Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1995;171(4):857-63. [PMID:7706811]
Comment: Study establishing PCR detection of HSV DNA as the standard for diagnosis of herpes simplex encephalitis.
- Poscher ME. Successful treatment of varicella zoster virus meningoencephalitis in patients with AIDS: report of four cases and review. AIDS. 1994;8(8):1115-7. [PMID:7986408]
Comment: While the outcome of VZV meningoencephalitis in immunocompetent patients is generally favorable, reports indicate patients with HIV infection may have worse outcomes. These 4 patients appeared to benefit from IV acyclovir or ganciclovir given for 10-14 days.
- Armstrong RW, Fung PC. Brainstem encephalitis (rhombencephalitis) due to Listeria monocytogenes: case report and review. Clin Infect Dis. 1993;16(5):689-702. [PMID:8507761]
Comment: Review of the literature available for this rare manifestation of listerial infection. Early treatment with ampicillin or penicillin was associated with > 70% survival. Limited data available for alternative therapies, although trimethoprim/sulfamethoxazole was used successfully.
- Whitley RJ, Cobbs CG, Alford CA, et al. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA. 1989;262(2):234-9. [PMID:2544743]
Comment: Study of 432 patients who underwent brain biopsy for presumed HSV encephalitis. 45% had HSV, but 9% (16% of those without HSV) had other treatable etiologies. In cases in which the diagnosis cannot be made non-invasively, the yield for brain biopsy would appear to outweigh the risks, particularly in immunocompromised patients.
- VanLandingham KE, Marsteller HB, Ross GW, et al. Relapse of herpes simplex encephalitis after conventional acyclovir therapy. JAMA. 1988;259(7):1051-3. [PMID:3339802]
Comment: Basis of the recommendations for treatment courses of 14-21 days with IV acyclovir.
- Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med. 1986;314(3):144-9. [PMID:3001520]
Comment: One of two controlled trials showing a beneficial effect of acyclovir over vidarabine on mortality.
- Hardy WD, Daar ES, Sokolov RT, et al. Acute neurologic deterioration in a young man. Rev Infect Dis. 1991;13(4):745-50. [PMID:1925293]
Comment: Presentation and discussion of acute encephalopathy associated with acute HIV infection (seroconversion). This form of encephalopathy may be severe but typically has onset and resolution within one week. It is surely under recognized. The diagnosis may require viral load testing, as serological testing may be negative or indeterminate.
- CDC; Update: West Nile virus encephalitis--New York, 1999; MMWR Morb Mortal Wkly Rep; Vol. 48; pp. 944;
Comment: Update on the outbreak of arboviral encephalitis that affected 56 patients, with 7 deaths. This was the North American debut for this flavivirus, which is transmitted within the avian population.
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