BASICS
DESCRIPTION
- Inflammation of the meninges and brain associated with clinical evidence of neurologic dysfunction
- System(s) affected: nervous
- Synonym(s): meningoencephalitis
EPIDEMIOLOGY
Incidence
3.5 to 7.4/100,000 persons/year
Prevalence
- Seasonal variation (e.g., arboviruses, enteroviruses)
- Others (e.g., herpes simplex virus [HSV]) nonseasonal
- Vaccines have altered prevalence and seasonality (e.g., mumps and measles were common in winter before routine immunization).
ETIOLOGY AND PATHOPHYSIOLOGY
- Most enter through respiratory or GI tract with subsequent hematogenous spread
- Other modes of entry include neurotropic spread (e.g., rabies) and vectors for Japanese encephalitis, dengue virus encephalitis, and tick-borne diseases.
- Specific cell lines are associated with specific symptom complexes.
- Neuronal involvement: associated with seizures
- Oligodendroglia: may cause demyelination, cortical infection, or reactive parenchymal swelling; altered levels of consciousness
- Brainstem neurons: coma, respiratory failure
- Microglia, macrophages: neurologic dysfunction
- Pathologic changes seen with postinfectious encephalomyelitis include perivascular mononuclear infiltrates.
- Most common etiologies in the United States are HSV, West Nile virus (WNV), and enteroviruses. Zika virus has gained recent attention due to an association with microcephaly. Most cases initially reported in Central and South America.
- Despite extensive evaluations, the etiologic agent is often not identified in cases of viral encephalitis.
RISK FACTORS
- Age: increased incidence in infants and elderly
- Contact with animals or insect vectors
- Impaired immune status
- Occupation (e.g., lab or animal care workers)
- Recreational activities (e.g., camping, hunting)
- Transfusion and transplantation
- Travel to endemic areas
- Recent vaccinations/unvaccinated status
GENERAL PREVENTION
- Use of mosquito repellents (DEET, picaridin) and appropriate clothing to prevent arthropod bites.
- Avoidance and prompt removal of ticks
- Elimination of mosquito-breeding sources
- Vaccination (e.g., mumps, measles, polio, rabies, Japanese encephalitis)
COMMONLY ASSOCIATED CONDITIONS
- Seizures
- Hyperthermia
- Increased intracranial pressure (ICP)
- Inappropriate antidiuretic hormone (ADH) secretion
DIAGNOSIS
- Major and minor diagnostic criteria have been proposed for probable and confirmed encephalitis of infectious or autoimmune etiology.
- Perform an epidemiologic risk factor assessment in all patients with encephalitis.
- Consider acute disseminated encephalomyelitis (ADEM) in patients with history of recent infectious illness or vaccination (1)[B].
HISTORY
- The classic encephalitis triad includes:
- Fever
- Headache
- Altered mental status
- Individual viruses are often associated with characteristic focal neurologic deficits (e.g., temporal lobe involvement in HSV).
- Assess travel, animal exposure, occupation, and vaccination status.
- General medical history should include use of immunosuppressive medications (e.g., steroids), diabetes, HIV, autoimmune disease.
PHYSICAL EXAM
- General signs
- Neurologic findings
- Altered level of consciousness
- Acute cognitive dysfunction
- Behavioral changes
- Neck stiffness
- Focal neurologic signs
- Cranial nerve palsies
- Paresthesias
- Anomic aphasia
- Inappropriate behavior
- Other
- Loss of temperature or vasomotor control
DIFFERENTIAL DIAGNOSIS
- Autoimmune (e.g., anti-N-methyl-D-aspartate [NMDA])
- Meningitis
- Intracranial space-occupying lesions
- Nonviral encephalitis (e.g., rickettsia, ehrlichiosis, Borrelia burgdorferi, Mycoplasma pneumoniae)
- Noninfectious encephalopathies (e.g., poisoning)
- Infectious encephalopathies (e.g., progressive multifocal leukoencephalopathy)
- Infectious endocarditis with CNS involvement
- Vasculitis
- Paraneoplastic syndromes
- Postinfectious encephalitis
- Postimmunization encephalitis
- ADEM
DIAGNOSTIC TESTS & INTERPRETATION
- Recommended general diagnostic studies (outside CNS) for patients suspected of having encephalitis.
- Blood cultures (1)[B]
- HIV testing (2)[C]
- Additional studies based on risk factors and clinical findings:
- Culture stool, nasopharynx, and sputum (children) (1)[B].
- Scrape active vesicles (direct fluorescent antibody testing for viral antigen).
- Tissue biopsies for culture, antigen detection, nucleic acid amplification testing, histology (1)[A]
- Serologic testing (2)[B]
- Serum and CSF IgM and IgG antibodies (test of choice for WNV)
- Serum cryptococcal antigen testing
- Acute and convalescent phase serum (helpful for the retrospective diagnosis of a specific pathogen)
- IgG in patients where encephalitis may be due to reactivation of a previously acquired infection (e.g., toxoplasmosis in HIV)
- Monospot test (Epstein-Barr virus [EBV])
Initial Tests (lab, imaging)
- Lumbar puncture (unless contraindicated) (2)[A]
- CSF pleocytosis (10 to 2,000 cells/mm3). Eosinophils may suggest helminth (can be seen with other pathogens).
- CSF glucose is normal or mildly depressed.
- CSF protein is usually mild or moderately increased.
- CSF fluid for Gram stain (bacteria) and acid-fast stain (mycobacteria)
- CSF culture for bacteria, mycobacteria, fungi
- CSF viral culture is not routinely recommended.
- Perform HSV CSF nucleic acid amplification tests (e.g., PCR) on all specimens. False negatives are common before day 2. Consider repeat in 3 to 7 days for patients with clinical presentation consistent with HSV or if temporal lobe findings on neuroimaging (1)[A].
- Enterovirus PCR based on clinical suspicion/season
- CSF PCR has high specificity for CMV.
- Influenza PCR if clinical suspicion is high (especially in the flu season and for immunocompromised patients)
- CSF testing for cryptococcal antigen is superior to India ink.
- In up to 10% of cases, CSF findings are normal.
- MRI is the imaging modality of choice and should be obtained in all cases, unless contraindicated (or diagnosis is already certain) (2)[B].
- MRI is most sensitive for HSV encephalitis when T2-weighted and fluid-attenuated inversion recovery images show temporal and limbic involvement.
- Diffusion-weighted imaging is superior to conventional MRI in encephalitis caused by HSV, enterovirus, and WNV.
- CT, with and without contrast enhancement (3)[A], is less sensitive and used only if MRI is not an option (1)[B].
Follow-Up Tests & Special Considerations
- PCR may be negative early on; repeat in 3 to 7 days if symptoms persist and suspicion is high.
- Follow-up imaging is generally not necessary.
Diagnostic Procedures/Other
- CSF culture is not routinely used to diagnose encephalitis.
- Early electroencephalogram (EEG) abnormalities are common but poorly sensitive and typically not diagnostic (4)[C].
- EEG may be useful in early herpes simplex encephalitis and (less commonly) in other herpes viruses (varicella zoster virus [VZV], EBV, human herpes virus 6 [HHV6]).
- Brain biopsy: Rarely used and not routinely recommended; consider if etiology is unknown and patient is deteriorating despite treatment (1)[B].
Test Interpretation
- Prominent perivascular meningeal inflammation
- Swelling and degenerative changes
TREATMENT
- Many patients require intensive care.
- In general, empiric therapy with acyclovir is appropriate in cases of suspected encephalitis while awaiting formal diagnosis (1)[A].
- Combine with therapy for bacterial, rickettsial, or ehrlichia infection based on clinical suspicion, risk factors, and epidemiology.
- Once etiologic agent has been identified, change to pathogen-specific therapy.
- Postexposure prophylaxis for rabies and varicella in susceptible hosts (1)[A]
GENERAL MEASURES
- Supportive therapy
- Monitoring for drug-related toxicities
MEDICATION
- No specific drug therapy is available for most types of viral encephalitis.
- HSV is an important exception: acyclovir 10 mg/kg IV q8h in adults with normal renal function
- Acyclovir is also effective against VZV encephalitis and may be used for suspected enteroviral encephalitis.
- Foscarnet IV 60 to 90 mg/kg/dose q8-12h and ganciclovir IV 5 mg/kg/dose q12h are effective against cytomegalovirus (CMV) or acyclovir-resistant HSV or HHV6.
- Appropriate antiviral therapy (i.e., oseltamivir PO, 75 mg q12h) should be started for suspected influenza infection (4)[C].
- Doxycycline PO/IV 100 mg q12h should be added to an empiric regimen when clinical setting suggests rickettsial or ehrlichia infection (1)[A].
- Corticosteroid use in viral encephalitis is controversial and not recommended as standard of practice. Steroids are important in antibody-mediated encephalitis, such as anti-NMDA disease (3)[A].
- There is insufficient evidence for the use of antiepileptic medications for the primary and secondary prevention of seizures in viral encephalitis.
ISSUES FOR REFERRAL
- Monitoring and management of ICP
- Evaluation and treatment of seizures
- Multidisciplinary team care
- Determination of empiric treatment (antimicrobial for virus, bacteria, fungi, mycobacteria, parasites)
ADDITIONAL THERAPIES
- There is limited data for most adjunctive therapies; in general, consult infectious disease specialists (e.g., interferon-α or IVIG in WNV encephalitis).
- Rabies encephalitis has been treated using induced coma with the Milwaukee protocol.
SURGERY/OTHER PROCEDURES
- No surgical treatment is routinely indicated.
- Central line placement, intubation, and other procedures as needed for support
INPATIENT CONSIDERATIONS
- Admit suspected cases for evaluation, supportive care, and treatment. Many require intensive care.
- Isolation, when indicated (e.g., rabies, influenza), otherwise standard isolation precautions
Admission Criteria/Initial Stabilization
All suspected cases of encephalitis warrant admission.
- Protect airway and provide supplemental oxygen as needed.
- Intubation and mechanical ventilatory support in severe cases
- Assess and manage circulatory status, fluids, glucose, electrolytes, and renal function (especially if on acyclovir).
IV Fluids
Assess for syndrome of inappropriate ADH hypersecretion.
Nursing
- Precautions for seizure and altered mental status
- Routine nursing care for skin care, patient comfort, monitoring, and family support
- Educate families about the importance of vaccination.
Discharge Criteria
Patients may be discharged when symptoms have resolved and hospital care is no longer needed.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Postencephalitis sequelae are primarily neurologic, and follow-up should be guided by patient's condition (e.g., anticonvulsants for seizures).
- Physical therapy may be necessary.
PATIENT EDUCATION
- DEET-containing mosquito repellents and tick removal
- Avoid outdoor activities during periods of peak mosquito activity.
- Use protective clothing.
- Adequate vector control and environmental sanitation
- Vaccination
- Prompt treatment of animal bites or bat exposure
PROGNOSIS
- Often difficult to predict. Anticipate slow, but complete, recovery from deficits in most cases.
- Outcomes are worse in elderly and infants.
- Some viruses have higher mortality (rabies, herpes B virus, untreated HSV, Eastern equine encephalitis) than others (WNV, enteroviruses).
COMPLICATIONS
Vary with age, etiologic agent, and clinical course.
In a study from 1999, on 28 children with HSV encephalitis followed over 5 years, 2 died and 10 had persistent neurodeficits.
REFERENCES
11 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):303-327.22 Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults-Association of British Neurologists and British Infection Association National Guidelines. J Infect. 2012;64(4):347-373.33 Ramos-Estebanez C, Lizarraga KJ, Merenda A. A systematic review on the role of adjunctive corticosteroids in herpes simplex virus encephalitis: is timing critical for safety and efficacy? Antivir Ther. 2014;19(2):133-139.44 Centers for Disease Control and Prevention. Neurologic complications associated with novel influenza A (H1N1) virus infection in children-Dallas, Texas, May 2009. MMWR Morb Mortal Wkly Rep. 2009;58(28):773-778.
ADDITIONAL READING
- Lahat E, Barr J, Barkai G, et al. Long term neurological outcome of herpes encephalitis. Arch Dis Child. 1999;80(1):69-71.
- Pandey S, Rathore C, Michael BD. Antiepileptic drugs for the primary and secondary prevention of seizures in viral encephalitis. Cochrane Database Syst Rev. 2014;(10):CD010247.
- Steiner I, Budka H, Chaudhuri A, et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2010;17(8):999-1009.
- 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):1114-1128.
CODES
ICD10
- A86 Unspecified viral encephalitis
- A85.2 Arthropod-borne viral encephalitis, unspecified
- A84.9 Tick-borne viral encephalitis, unspecified
- A83.9 Mosquito-borne viral encephalitis, unspecified
ICD9
- 049.9 Unspecified non-arthropod-borne viral diseases of central nervous system
- 064 Viral encephalitis transmitted by other and unspecified arthropods
- 063.9 Tick-borne viral encephalitis, unspecified
- 062.9 Mosquito-borne viral encephalitis, unspecified
SNOMED
- Viral encephalitis (disorder)
- Arbovirus encephalitis (disorder)
- Adenoviral encephalitis (disorder)
- Viral meningoencephalitis (disorder)
- West Nile encephalitis (disorder)
CLINICAL PEARLS
- All patients with suspected encephalitis must have MRI and CSF analysis (using PCR) unless otherwise contraindicated.
- Reinforce the importance of protective clothing, vector control, and vaccination to prevent viral disease.
- Empiric treatment with acyclovir is warranted in cases of suspected viral encephalitis pending formal identification of the causative organism. Most patients require hospitalization and supportive care.
- Consult appropriate subspecialty colleagues based on patient status and comorbid illnesses.