PATHOGENS

• The list is not comprehensive.
• Viruses:
  • Herpes Simplex virus (HSV, most common sporadic form in the U.S.)
  • CMV, VZV and EBV
  • HHV-6: especially following hematopoietic stem cell transplantations.
  • 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.
      • For details on seasonal outbreaks in the U.S., see relevant viruses on the CDC website.
    • Powassan virus (a member of tick-borne encephalitis flaviviruses): seen in New England, Upper Midwest U.S., Canada, and Asia. Two lineages:
      • Lineage 1 (Powassan): Ixodes cookei vector
      • Lineage 2 (Deer tick virus): Ixodes scapularis vector
  • Chikungunya virus
  • Enterovirus (more commonly causes meningitis), poliovirus
  • Japanese encephalitis virus: seen in SE Asia, Japan, Korea, N. Australia
  • Murray Valley encephalitis virus: Australia
  • Rabies
  • Tick-borne encephalitis virus: central Europe through Eurasia
  • Adenovirus
  • Parvovirus B19
  • Hendra virus, Nipah virus: Australia, SE Asia
  • Other less common viral etiologies include:
    • Influenza
      • In children, it may cause acute necrotizing encephalopathy (ANE) or diffuse cerebral edema.
        • Most ANE cases are reported in SE Asia.
    • Rabies
    • Cache Valley virus
      • Mosquito vector, in the U.S., Canada, Caribbean
        • 10 reported cases, CDC performs diagnostics.
    • Human herpesvirus-6
      • In immunocompromised or children < 2 years.
    • Human parechoviruses
      
      • The leading cause of aseptic meningoencephalitis, typically in infants < 3 months.
    • B virus (post-monkey bite)
    • Acute HIV infection: may occasionally present with encephalitis.
      • Possible especially in immune-suppressed
        • EBV
        • CMV
        • VZV
      • Below may also cause post-infectious CNS disease
        
        • Mumps
        • Measles
        • Rubella
• Bacteria:
  • Anaplasma phagocytophilum: vector same as for Lyme disease, the deer tick Ixodes scapularis
  • Bartonella species: B. bacilliformis, B. henselae
    • Predominantly in children.
  • 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
  • Rickettsia rickettsii (RMSF):
    • The dog tick is the most common vector.
  • T. pallidum (syphilis)
  • Tropheryma whipplei (Whipple disease)
• Parasites: may cause granulomatous meningoencephalitis.
  
  • Amoebic encephalitis is most commonly caused by Naegleria fowleri or Acanthamoeba species.
  • Baylisascaris procyonis
  • Balamuthia mandrillaris
  • Gnathostomiasis
  • Plasmodium falciparum
  • Taenia solium
  • Toxoplasma gondii
  • Trypanosomiasis (T. brucei rhodesiense, T. brucei gambiense)
• Fungi: among the leading causes
  
  • Coccidioides species
  • Cryptococcus neoformans
  • Histoplasma capsulatum
• Immunosuppressed patients
  • HIV/AIDS:T. gondii, Cryptococcus, histoplasmosis, coccidiomycosis, M. tuberculosis, CMV, JCV.
  • Solid organ or stem cell transplant: T. gondii, Cryptococcus, coccidiomycosis, histoplasmosis, HSV, VZV, EBV, CMV, HHV-6, WNV, Leptospirosis, Acanthamoeba, Balamuthia madrillaris,

CLINICAL

• Fever, cognitive deficits, focal neurologic signs (often rapidly progressive), and/or seizures 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)[2].
    • The gold standard is brain biopsy, which is rarely performed, hence the clinical definition above.
    • Encephalopathy: this is not encephalitis but rather altered mental status or other cognitive impairments with or without brain inflammation. The term is often used when brain inflammation is 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)[2].
• In the U.S., annual cases are ~5/100,000 populations [1990-2017].
  • Age matters with some organisms.
    • HSV may occur at any age but is most commonly seen at < 1 year and > 65 years.
    • Enterovirus is most common < 1 year of age.
    • WNV is seen among immunocompetent individuals > 50 years.
• 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, and 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 Table Table 1: Possible etiologic agents of encephalitis based on epidemiology and risk factors[20]. and Table Table 2: Possible etiologic agents of encephalitis based on clinical findings[20]. for a more comprehensive list and section below for additional epidemiological clues.
  • Autoimmune encephalitis: multiple causes
    • In one large series, N-methyl-D-aspartate receptor encephalitis was identified as the leading cause of encephalitis (more than HSV, VZV, and WNV).[14]
    • Many other antibody-mediated causes of encephalitis exist, reviewed by Dalmau NEJM 2018[6].
      • Anti-LGI1, anti-CASPR2, anti-AMPAR, anti-GABA-A-R, anti-GABA-B-R, anti-GlyR, anti-mGluR5
      • Acute demyelinating encephalomyelitis (ADEM), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)
      • SLE, Behcet’s, sarcoidosis
      • Checkpoint inhibitor-related or CAR-T-cell therapy
      • Cerebral amyloid angiopathy
      • Post-infectious conditions
  • Note: < 50% of cases identified with specific etiology.
    • Encephalitis is unlikely as an active explanation if both MRI (with contrast) and CSF profiles are normal.

DIAGNOSIS

• Suggested core testing.[1] If other specific concerns are raised by history or exam as above, see the module for testing suggestions.
  • Imaging and neurodiagnostic testing:
    • MRI w/ contrast may be normal in many cases early on.
      • It may show temporal lobe changes (in HSV) or more diffuse involvement.
    • CXR
    • An EEG is abnormal in many cases of HSV encephalitis with characteristic temporal lobe spikes.
      • It 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 cultures (viral cx of limited value), or serology (based on suspected agents: IgM, acute/convalescent IgG or CSF antibodies).
      • CSF
        • HSV PCR should be performed on all pts with encephalitis. If negative, repeat w/i 3-7d in pts with compatible findings if another diagnosis is secured.
          • Note: A negative PCR test is not absolute evidence that a certain infection is not extant.
        • VZV PCR
        • EBV PCR
        • WNV IgM, IgG
        • VDRL
        • Cryptococcal antigen
        • Autoimmune N-methyl-D-aspartate receptor encephalitis in one large series was identified as the leading cause of encephalitis (4x >HSV, VZV, WNV)[14].
        • Oligoclonal bands
        • IgG index
      • Serum/blood
        • Blood cultures
        • Syphilis testing
        • Mycoplasma pneumoniae IgG
        • WNV IgM (seasonal)
        • EBV capsid IgM, IgG
        • HIV 4th generation antibody
        • Anti-NMDAR antibodies
      • Other
        • Multiplex respiratory panel
        • Enterovirus PCR (stool or rectal swab)
• Other modalities (non-core)
  • Next-generation sequencing may pick up additional cases not identified by conventional testing. In one series, it detected a pathogen in 16% of cases, with > 50% also detected by conventional testing[4].
    • However, it is less sensitive to many pathogens, e.g., serology is best for WNV.
• • Brain biopsy:
    • Consider brain biopsy in patients with continued deterioration despite acyclovir.
    • Yield is low (< 15%), though may be higher in immunosuppressed patients.
      • A biopsy is often pursued later in the disease course and may partly explain the lower yield in many case series.
• Many cases are without known etiology despite extensive testing.

TREATMENT

FOLLOW UP

• The relapse rate of HSV encephalitis is ~5% or more, with this occurring more in pediatric populations. Negative HSV PCR in CSF portends better outcomes and less relapse--especially in neonates.

OTHER INFORMATION

• HSV early treatment correlates with better outcomes.
  • Clues: fever, seizure, mental status or personality changes, focal neurological deficits, temporal lobe involvement on MRI. ALWAYS start empiric acyclovir while awaiting test results.
  • CSF showing RBCs and elevated protein (HSV meningitis).
  • No HSV skin lesions were seen in the majority.
• Suspected or proven HSV: use acyclovir IV. If the dx studies are negative, a brain biopsy is suspicious.

Pathogen Specific Therapy

Basis for recommendation

1. Bloch KC, Glaser C, Gaston D, et al. State of the Art: Acute Encephalitis. Clin Infect Dis. 2023;77(5):e14-e33.  [PMID:37485952]

   Comment: A comprehensive review from an ID perspective also focuses on the range of infections. For example, it is benign, mainly in children (e.g., La Crosse), to devastating (rabies, ~100% mortality). Diagnosis and management were discussed, along with when to proceed to brain biopsy or NGS testing. The review excludes causes in children < 6 months of age.
   

2. 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 the definition of encephalitis as well as suggested diagnostic algorithm.
   

References

3. Britton PN, Dale RC, Blyth CC, et al. Causes and Clinical Features of Childhood Encephalitis: A Multicenter, Prospective Cohort Study. Clin Infect Dis. 2019.  [PMID:31549170]

   Comment: Study of 287 children in Australia found the following causes of encephalitis in confirmed cases: 57% (95% confidence interval [CI], 52%-63%) had infectious causes, 10% enterovirus, 10% parechovirus, 8% bacterial meningoencephalitis, 6% influenza, 6% herpes simplex virus (HSV), and 6% Mycoplasma pneumoniae; 25% (95% CI, 20%-30%) had immune-mediated encephalitis, 18% acute disseminated encephalomyelitis, and 6% anti-N-methyl-d-aspartate receptor encephalitis; and 17% (95% CI, 13%-21%) had an unknown cause.
   

4. Wilson MR, Sample HA, Zorn KC, et al. Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis. N Engl J Med. 2019;380(24):2327-2340.  [PMID:31189036]

   Comment: One-year study of 204 pediatric and adult patients with 58 infections in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) unidentified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.
   

5. Ruzek D, Avšič Županc T, Borde J, et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res. 2019;164:23-51.  [PMID:30710567]

   Comment: A flavivirus that is transmitted by ticks in Europe, Russia and Asia that in countries where the infection is common strategies include the use of a protective vaccine, specific anti-TBEV immunoglobulin for post-exposure prophylaxis (available only in Russia). Unfortunately, uptake of the vaccine is relatively low.
   

6. Dalmau J, Graus F. Antibody-Mediated Encephalitis. N Engl J Med. 2018;378(9):840-851.  [PMID:29490181]

   Comment: Helpful review with NMDAR among the most frequently encountered cause of antibody-mediated encephalitis. Many others are listed along with there associations (see Table 1 in this article).
   

7. Backman R, Foy R, Diggle PJ, et al. A pragmatic cluster randomised controlled trial of a tailored intervention to improve the initial management of suspected encephalitis. PLoS One. 2018;13(12):e0202257.  [PMID:30521521]

   Comment: 24 hospitals in the United Kingdom had the implementation of protocols regarding encephalitis occluding lumbar puncture within 12 hours and instituting acyclovir within 6 hours. The interventions had no benefit obvious compared to control; however, both hospitals added 8.5% improvement compared to preintervention suggesting some spillover of educational aspects
   

8. Stahl JP, Azouvi P, Bruneel F, et al. Guidelines on the management of infectious encephalitis in adults. Med Mal Infect. 2017;47(3):179-194.  [PMID:28412044]

   Comment: Guidelines from France, that offer fairly specific management recommendations regarding testing and treatment (lots of "ifs, then."
   

9. 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.
   

10. 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.
    

11. 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.
    

12. 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 the local health department.
    

13. 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.
    

14. 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.
    Rating: Important
    

15. 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.
    

16. 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: An 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.
    

17. 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.
    

18. 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 the concern of rabies.
    Rating: Important
    

19. 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: A longitudinal cohort of 156 pts. Most recovered both mental and physical function by 1 year after infection onset. The 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.
    

20. 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: This is the first comprehensive guideline ever published for encephalitis. The document has extensive information that helps the clinician regarding signs, symptoms, epidemiological risks and diagnostic approaches. It still retains much useful information despite its age. See Bloch’s 2023 article for an updated perspective.
    

21. 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.
    

22. 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 the current 95%) and had a good side effect profile.
    

23. 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.
    

24. 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.
    

25. 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.
    

26. 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.
    

27. 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.
    

28. 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.
    

29. 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.
    

30. 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.
    

31. 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.