OVERVIEW: What every practitioner needs to know

Are you sure your patient has encephalitis? What should you expect to find?

  • Encephalitis is diffuse inflammation of brain parenchyma, usually due to infection with a virus.
  • It is classified as primary if it is a direct result of infection (the neurons are infected and virus often can be recovered) or postinfection, which is likely autoimmune (following vaccination or a viral illness, which may have been subclinical so the patient does not recall it. In this form, the neurons are spared and virus is not recovered).
  • A severe form of postinfectious encephalitis is acute disseminated encephalomyelitis (ADEM), which is more common in adolescents and children than adults.
  • In most cases of encephalitis, the causative infectious agent is not identified.
  • If an agent is identified, common causes in the United States are West Nile virus (WNV), herpes simplex, and enteroviruses. However, many viruses can cause encephalitis, including other herpes viruses (cytomegalovirus [CMV], Epstein-Barr, varicella), other arboviruses (including Eastern equine, Western equine, St. Louis encephalitis, Japanese B encephalitis), measles, mumps, rubella, rabies, and HIV.
  • Nonviral causes can include bacteria (including Borrelia burgdorferi, Coxiella burnetii, Rickettsia rickettsii, Erlichia chaffeensis, Listeria monocytogenes, Mycobacterium tuberculosis) as well as parasites (Toxoplasma gondii, Trypanosoma brucei, Plasmodium falciparum) and fungi (Histoplasma capsulatum, Coccidioides species, Cryptococcus neoformans).
  • Patients or their families may report that the patient initially had a nonspecific viral prodrome, but this history may be absent.
  • Symptoms then progress to fever, headache and altered mental status.
  • Altered mental status, with or without localized neurologic abnormalities, is the hallmark of encephalitis, in contrast to aseptic meningitis where cerebral function is largely intact. There is a broad range of possible manifestations of altered mental status including personality changes, irritability lethargy, stupor, or coma.
  • Classic symptoms in herpes simplex (HSV) encephalitis include personality changes and psychiatric complaints, but these are not pathognomonic.
  • If the cerebellum is affected, cranial nerve dysfunction, ataxia and abnormal muscle tone (hypotonia or myoclonus) may be present.
  • Seizures occur in encephalitis in as many as 40-50% of patients.
  • Very rarely chorea or dystonia can occur.
  • Encephalitis and meningitis may exist together; one clinical presentation may predominate, or findings of both may be present (meningoencephalitis).
  • Altered mental status is the key physical finding.
  • Nuchal rigidity is present when encephalitis and meningitis are both present (meningoencephalitis).
  • Localized neurologic abnormalities, including cranial nerve palsies, seizures, hemiparesis, hypotonia or myoclonus, can be seen.
  • A flaccid paralysis may be seen in WNV infection, mimicking or poliomyelitis.
  • A rash may be seen with WNV (maculopapular) or varicella (vesicular) encephalitis but is often absent.
  • Rabies encephalitis may be accompanied by hydrophobia and agitation.
  • A vesicular rash may accompany varicella encephalitis; however, this may be absent. Therefore, a normal skin exam does not exclude this as a possible cause of encephalitis.
  • Parotitis in an unimmunized patient with encephalitis should increase suspicion for mumps.

How did the patient develop encephalitis? What was the primary source from which the infection spread?

  • In primary infectious encephalitis, the cause of disease is inflammation of the brain parenchyma caused by direct infection with viruses or other organisms.
  • In these cases, infection was transmitted by various methods, depending on the particular organism. For example, mosquitoes for WNV, and contact with infectious lesions for herpes simplex. Please refer to the chapters on individual microorganisms for full details.
  • In postinfectious encephalitis, the mechanism of disease is autoimmune, following a preceding viral infection.

Which individuals are of greater risk of developing encephalitis?

Immunocompromised individuals, including those with HIV/AIDS, are at higher risk for encephalitis due to T. gondii, Coccidioides species, C. neoformans, H. capsulatum, CMV, and M. tuberculosis, among others.

A history of travel may increase suspicion for causes such as Japanese encephalitis virus, Nipah virus, Gnathostoma (South-East and Far East Asia), rabies, P. falciparum(South Asia),T. brucei rhodesiense, T. brucei gambiense, rabies (Africa),rabies, Eastern equine encephalitis virus, Western equine encephalitis virus,Venezuelan equine encephalitis virus, B. bacilliformis(South America), and tick-borne encephalitis virus(Russia).

Seasonal variation is important, as the cases caused by mosquitoes (including WNV, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis, La Crosse virus), ticks (Powassan virus, tick-borne encephalitis virus, B. burgdorferi, E. chaffeensis, R. rickettsii) and enteroviruses largely occur in the spring and summer.

Continue Reading

Unimmunized patients are at greater risk for encephalitis due to measles, mumps, rubella, varicella, influenza, Japanese encephalitis, and polio.

A history of animal bite increases concern for rabies encephalitis, particularly if it occurred while traveling to regions where domestic animals are not routinely vaccinated.

Individuals who spend time outdoors for work or recreation are at increased risk for mosquito or tick-borne causes. Water exposure can be a risk for Naegleria fowleri.

Beware: there are other diseases that can mimic encephalitis:

  • Noninfectious entities that can mimic encephalitis include autoimmune disease, paraneoplastic syndromes accompanying malignancy, status epilepticus, acute hemorrhage, and toxins.
  • Metabolic encephalopathy caused by end-stage liver or renal disease can also resemble encephalitis
  • Please also see the discussion above of acute disseminated encephalomyelitis (ADEM), which occurs after vaccination or a viral infection, primarily in children and adolescents.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis
  • The complete blood test (CBC) results may be variable, depending on the causative agent, but in general do not help identify a specific etiology.
  • Serology can be helpful, primarily if cerebrospinal fluid (CSF) studies are inconclusive.
  • CSF analyses are the mainstay of diagnosis. However, it is important to remember that in greater than 60% of encephalitis cases, no definitive causative agent is identified.
  • Standard evaluation of the CSF (cell count and differential, glucose, protein) reflects inflammation of the central nervous system (CNS). This is true whether the patient has primarily encephalitis, meningitis or a combination of both. The findings with viral encephalitis are very similar to those for viral meningitis. However, there can be overlap of laboratory values for viral and bacterial encephalitis, or meningitis (see Table I. Cerebrospinal fluid findings in meningitis).
  • The presence of red blood cells in the CSF (in the absence of a traumatic lumbar puncture) may support HSV encephalitis.
Table I.
Cerebrospinal fluid findings in meningitis

Results that confirm the diagnosis
  • Polymerase chain reaction (PCR) of the CSF has become increasingly used clinically. Many laboratories can perform this testing to assess for the presence of herpes simplex and enteroviruses.
  • CSF culture is negative in viral meningitis, but should be sent to evaluate for less common causes including bacterial, fungal and M. tuberculosis encephalitis.
  • CSF serology is diagnostic if positive.
  • Serum serology can be a helpful primarily if CSF studies are inconclusive. Because acute and convalescent sera in paired specimens are the most helpful when assessing for antibody increases, it is important to collect a specimen during the early stage at presentation, and then again 3-4 weeks later.
  • If an acute specimen was not collected for comparison, there may still be benefit to sending the convalescent specimen and it may still suggest a diagnosis. A single serum specimen is sufficient to diagnose WNV virus, mumps, and St. Louis encephalitis virus.
  • Culture or biopsy from other sites can strongly suggest the diagnosis in the setting of encephalitis. PCR or cultures of vesicles can identify HSV, and nuchal biopsy can diagnose rabies infection.
  • Brain biopsy is reserved for cases in which all other causes are inconclusive.
  • Electroencephalogram (EEG) does not confirm the diagnosis, but temporal lobe activity may be consistent with herpes simplex encephalitis, and it can also be used to evaluate for status epilepticus which may mimic encephalitis.

What imaging studies will be helpful in making or excluding the diagnosis of encephalitis?

  • Brain MRI is more sensitive than CT for identifying parenchymal gray or white matter lesions, and should be performed to exclude tumor, abscess, hemorrhage or other intracranial disease that can mimic encephalitis.
  • Temporal lobe lesions on imaging are consistent with HSV encephalitis.
  • MRI and CT can evaluate for hydrocephalus, which is much more common with the non-viral causes of encephalitis.
  • MRI $$$, CT $$ ($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Depending on the level of suspicion for infectious versus non-infectious causes, consultation with neurology and/or infectious diseases specialists will likely be helpful.

1. Anti-infective agents

Choice of treatment varies widely based on suspected or confirmed etiologic agent. Please see Table II for treatment options.

Table II.
Treatment options and adjunctive therapies for specific organisms.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

HSV encephalitis is one of the few causes of viral encephalitis where treatment is available with acyclovir. It causes significant morbidity and mortality even with prompt treatment; however, without treatment, it is uniformly fatal. For all patients with encephalitis, begin prompt empiric treatment with acyclovir 10mg/kg IV every 8 hours while awaiting results of diagnostic tests. If negative, discontinue. If a positive CSF PCR, treat with acyclovir x 21 days.

2. Next list other key therapeutic modalities.

Most clinicians attempt to monitor intracranial pressure (ICP) when performing lumbar puncture and will attempt to decrease elevated ICP using standard techniques. However, there are no prospective clinical trial data to suggest that this impacts morbidity or mortality.

See notes section of Table II for other adjunctive therapies for specific organisms.

What complications could arise as a consequence of encephalitis?

What should you tell the family about the patient’s prognosis?

  • The most predictive factor for prognosis in patients with encephalitis is the severity of disease.
  • In patients with focal, limited seizure activity, for instance, recovery was much more likely than for patients who presented with diffuse, global and prolonged seizures, or edema.
  • In the majority of cases, an etiologic agent is never identified.
  • Herpes and varicella zoster are among the few viral causes of encephalitis for which prompt treatment has been shown to decrease morbidity and mortality, but even appropriate intervention does not uniformly prevent all sequelae in these patients.

Add what-if scenarios here:

  • As has been stated before in this chapter, have a low threshold to start IV acyclovir to cover herpes viruses. In patients with encephalitis, it is reasonable to empirically cover for bacterial causes and herpes viruses while awaiting CSF analysis and microbiology results.
  • If an etiologic agent is not immediately apparent after routine evaluation, seek infectious diseases consultation.
  • In many cases, supportive treatment is all that is available.
  • Specimens of CSF and sera may need to be sent to state or CDC laboratories for further testing, but these often are not completed quickly enough to guide clinical management.

How can encephalitis be prevented?

  • Varicella, measles, mumps, and influenza can be prevented with vaccine.
  • HIV encephalitis is decreased in patients on highly active antiretroviral therapy (HAART).
  • Malaria can be prevented with avoidance of mosquito bites and with antibiotic pre-exposure prophylaxis.
  • Other zoonotic infections are prevented by avoiding the vector (e.g. mosquitoes for arboviruses, and ticks for B. burgdorferi, R. rickettsii, and E. chaffeensis).

WHAT’S THE EVIDENCE for specific management and treatment recommendations?


Glaser, CA, Honarmand, S, Anderson, LJ, Schnurr, DP, Forghani, B, Cossen, CK, Schuster, FL, Christie, LJ, Tureen, JH. “Beyond viruses: clinical profiles and etiologies associated with encephalitis”. Clin Infect Dis. vol. 43. 2006 Dec 15. pp. 1565-77. (Epidemiology of encephalitis cases from California 1998-2005.)

Clinical guidelines

Tunkel, AR, Glaser, CA, Bloch, KC, Sejvar, JJ, Marra, CM, Roos, KL, Hartman, BJ, Kaplan, SL, Scheld, WM, Whitley, RJ. “The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America”. Clin Infect Dis.. vol. 47. 2008 Aug 1. pp. 303-27. (Very thorough review of epidemiology, diagnostic testing and treatment.)

Solomon, T, Michael, BD, Smith, PE, Sanderson, F, Davies, NW, Hart, IJ, Holland, M, Easton, A, Buckley, C, Kneen, R, Beeching, NJ. “On behalf of the National Encephalitis Guidelines Development and Stakeholder Groups: Management of suspected viral encephalitis in adults – Association of British Neurologists and British Infection Association National Guidelines”. J Infect.. vol. 64. 2012 Apr. pp. 347-373.

Sonneville, R, Klein, IF, Wolff, M. “Update on investigation and management of postinfectious encephalitis”. Curr Opin Neurol. vol. 23. 2010 Jun. pp. 300-4.


Ambrose, HE, Granerod, J, Clewley, JP, Davies, NW, Keir, G, Cunningham, R, Zuckerman, M, Mutton, KJ, Ward, KN, Ijaz, S, Crowcroft, NS, Brown, DW. “UK Aetiology of Encephalitis Study Group: Diagnostic strategy used to establish etiologies of encephalitis in a prospective cohort of patients in England”. J Clin Microbiol. vol. 49. 2011 Oct. pp. 3576-83. (Describes developing algorithm for evaluating encephalitis cases in the U.K.)