ENCEPHALITIS, VIRAL

ENCEPHALITIS, VIRAL - Mary Cataletto, MD
BASICS
DESCRIPTION
• Acute brain inflammation caused by viral invasion or by a viral-mediated inflammatory response in the brain following an acute, systemic infection
• May be accompanied by meningeal, spinal cord, or peripheral nerve involvement
• Most cases are rare complications of common systemic viral infections.
• Post-viral encephalitis usually occurs via immune-mediated mechanisms and has onset 2-12 days after the primary viral infection.
• System(s) Affected: Nervous
• Synonym(s): Meningoencephalitis
GENERAL PREVENTION
• Use of appropriate insect repellants, protective clothing, and avoidance and removal of ticks
• Human vaccines are available for Yellow fever and Japanese encephalitis virus
• West Nile Virus (WNV): Vaccine available for horses
EPIDEMIOLOGY
• Predominant age: Age extremes at highest risk, especially for herpes simplex encephalitis
- WNV encephalitis found to have age-related susceptibility with advanced age.
• Predominant sex: Male = Female
Incidence
• Uncommon in US: 117 cases reported to Centers for Disease Control and Prevention (CDC) in 2000; estimated 20,000 cases per year overall, most of which are mild
• Herpes simplex virus encephalitis (most common) estimated incidence is 1 in 250,000 per year
Prevalence
• Seasonal variation
• Arthropod-borne diseases (e.g., arboviruses) are predominantly spring and summer
• Enteroviruses peak in late summer, early fall (most common cause of viral meningitis in the US and responsible for up to 20% of viral encephalitis)
• Mumps and varicella prevalent in spring
• Most others (e.g., herpes simplex virus) are not seasonal.
RISK FACTORS
• Many agents produce more severe disease in newborns and the elderly
• Travel to endemic areas; contact with animals
• Exposure to vectors (e.g., culicine mosquitoes)
• Poor hygiene (principal mode of transmission of enteroviruses is fecal-oral, although respiratory transmission is important for some enteroviruses)
• HIV infection
• Immunosuppression
ALERT
Geriatric Considerations
May be at risk for severe disease
Pediatric Considerations
• Enteroviruses are a major cause of encephalitis in children (e.g., Coxsackieviruses A2, 4-7, 9, 10, 16 and B1-5; echoviruses 1-9, 11-25,27,30  33 and enterovirus 71
• Newborns are at higher risk for severe herpes simplex virus and enteroviral CNS disease.
• Pediatric cases of WNV CNS infection are uncommon.
• Children are more commonly symptomatic from arboviral infection than are adults.
Pregnancy Considerations
• Risk of herpes simplex virus infection in an infant delivered vaginally to a mother with a primary genital infection is ~40%; drops to 3-5% in reactivation genital lesions
• Enteroviruses may be transmitted transplacentally to fetus; cause of neonatal disease if mother infected just prior to delivery
• Intrauterine transmission of WNV is suspect. The CDC is collecting data.
ETIOLOGY
• Epidemic
- Arboviruses (e.g., St. Louis encephalitis, Japanese encephalitis, eastern equine encephalitis, western equine encephalitis, Venezuelan equine encephalitis, West Nile fever) most important cause of severe encephalitis worldwide
- Enteroviruses (most commonly Coxsackie B viruses, but also includes poliovirus, echovirus)
- Nipah virus
- Mumps
- Varicella-zoster
- Influenza
- Human T-lymphotropic virus type III (HTLV-III)
• Endemic
- Herpes simplex virus types 1 and 2
- Epstein-Barr virus
- Varicella-zoster virus
- Adenovirus
- Rabies
- Dengue
- Benign lymphocytic choriomeningitis V
- Infectious mononucleosis
- California encephalitis virus
- St. Louis encephalitis virus
- Russian spring-summer encephalitis
- Murray Valley encephalitis
- Lacrosse encephalitis
- Powassan encephalitis


DIAGNOSIS
SIGNS AND SYMPTOMS
• Nonspecific symptoms (e.g., malaise, skin rash, fever, myalgia) may precede neurologic symptoms.
• Mental status changes/confusion
• Meningeal involvement is signified by stiff neck and headache.
• Photophobia, lethargy progressing to coma, seizures, and focal neurologic deficits may be observed.
• Progression is variable; may be rapid or follow a more indolent course
• Temporal lobe involvement by herpes simplex leads to temporal lobe seizures, aphasia, and anosmia.
• Presence of postural or kinetic tremors, myoclonus, and weakness is not common in most encephalitis. Presence of these symptoms should raise concern about the possibility of WNV, St. Louis encephalitis, and Japanese encephalitis.
TESTS
• Electroencephalographic findings are usually abnormal, with slowing or epileptiform activity present. Temporal lobe abnormalities, particularly periodic lateralized epileptic form discharges, should suggest a diagnosis of herpes simplex virus encephalitis.
• Most viral encephalitis cases have specific diagnosis made by measurement of acute and convalescent (2-3 weeks) serum antibody concentrations for the specific pathogen. A 4-fold change in titer is suggestive of the diagnosis.
• Cerebrospinal fluid (CSF) antibody index can be used to ascertain specific CNS production of antibody against the infecting agent: Serum and CSF IgG antibody and serum and CSF albumin concentrations are determined. Infection may be suggested by a higher specific antibody: Albumin ratio in CSF than in serum.
• Antigen detection in CSF by polymerase chain reaction has been useful in cases of herpes simplex virus and enteroviral disease, but is available only in some centers.
• Enteroviruses may be recovered from CSF viral culture in ~60% of cases, but most other viral agents are present in quantities too low to be detected by these techniques.
• CSF WNV IgM antibodies are diagnositic of WNV CNS infection. Negative results during the 1st 72 hours do not eliminate the diagnosis. Most patients (>90%) with WNV CNS infection will be positive by day 8. IgM antibody response may persist postinfection.
Lab
• Standard laboratory studies (e.g., CBC, serum chemistries) are usually normal or nonspecifically abnormal.
• CSF examination is essential
- WBC count is usually increased (10-2,000 cells/mm3) but may be normal, especially in immunocompromised host; neutrophils predominate early, then a shift to mononuclear cells is seen
- RBC count usually normal (more likely elevated in herpes simplex infections)
- Protein may be normal or mildly elevated.
- Glucose may be normal or mildly decreased.
- Enzyme-linked immunosorbent assay detection of IgM is helpful retrospectively to determine the causative agent.
- Polymerase chain reaction to amplify viral DNA is the diagnostic choice for herpes simplex virus (particularly in neonatal cases), cytomegalovirus, human herpesvirus 6, and enterovirus infections. Availability is limited.
• Drugs that may alter lab results: Steroid therapy may mask CSF inflammatory findings.
• Disorders that may alter lab results: Immunocompromised patients may have normal CSF findings.
Imaging
• Imaging studies (e.g., CT scan, MRI, brain scan) may be normal early; later, nonspecific abnormalities are seen (Exception: Herpes simplex encephalitis)
• Temporal lobe pathology suggests the diagnosis of herpes simplex virus
• MRI more sensitive than CT in viral encephalidities May increase yield by T2 weighted imaging and FLAIR sequences.
• Single-proton emmission CT, may be considered in cases where MRI is normal, EEG is nondiagnostic, and HSE is still strongly suspected.
Diagnostic Procedures/Surgery
Brain biopsy, coupled with immunohistochemistry, may be useful in certain cases, particularly to identify treatable causes.
Pathological Findings
• Varies according to etiology
• Usually have prominent perivascular inflammation
• Swelling and degenerative changes of neural elements
• Negri bodies may be seen in brain, conjunctiva, and skin from the base of the neck in rabies patients
DIFFERENTIAL DIAGNOSIS
• Bacterial infection
• Rickettsial infection
• Spirochetal infection
• Other infectious agents
- Naegleria, Acanthamoeba
• Intracranial hemorrhage
• Intracranial tumor
• Trauma
• Thromboembolism
• Systemic lupus erythematosus
• Toxic ingestion
• Hypoglycemia
TREATMENT
GENERAL MEASURES
• Appropriate health care: Inpatient with symptomatic and supportive therapy as needed
• Maintenance of adequate respiratory and circulatory support
• Control cerebral edema if necessary (hyperventilation, osmotic diuresis).
• Anticonvulsant as needed
• Monitor for syndrome of inappropriate antidiuretic hormone secretion.
• Prevent bed sores.
Diet
• As indicated by clinical condition
• May need fluid restriction for syndrome of inappropriate antidiuretic hormone secretion or cerebral edema
Activity
As indicated by clinical condition
MEDICATION (DRUGS)
First Line
Specific antiviral therapy is not available for many of the etiologic agents described. However consideration should be given to the following antiviral agents when the causative organism is identified (when available, consultation with an infectious disease specialist is recommended):
• Acyclovir for herpes simplex encephalitis (NB resistance may be seen in immunocompromised hosts)
• Pleconaril (Picovir) for enteroviral encephalitis
• Amantadine or Rimantidine for Influenza A:
- Oseltamivir for Influenza B
• Foscarnet (Foscavir) is an effective option in patients with acyclovir resistant herpes simplex virus.
• Vidarabine (adenine arabinoside) for acyclovir-resistant herpes simplex virus; has been used in combination with acyclovir
FOLLOW-UP
PROGNOSIS
• Generally difficult to predict; somewhat based on infecting agent (e.g., herpes simplex virus-2, severe; varicella, mild) and age
• WNV encephalitis (based on 2002 and 2003 epidemics) overall mortality 12-15% but up to 35% in patients >65 years old.
• With disseminated neonatal herpes simplex virus, early antiviral therapy reduces mortality rate to 60% (85% without therapy), but subsequent neurologic impairment is ~40%.
• With CNS neonatal herpes simplex virus disease only, mortality is ~15% (50% without therapy). Unfortunately, antiviral therapy has had no impact on the morbidity of survivors; 65% have neurologic impairment.
COMPLICATIONS
• Varies with etiologic agent
• Herpes simplex virus encephalitis has the highest morbidity and mortality of the the common viral encephalitides (untreated mortality, 70%; 5% of survivors have normal neurologic function).
PATIENT MONITORING
Intracranial pressure monitoring may be needed for severe cases.
REFERENCES
1. Feigin R, Cherry I, Textbook of pediatric infectious diseases, 5th ed., Saunders; 2004.
2. Griffin DE, Johnson RT. Encephalitis, myelitis, and neuritis. In: Mandell GL, et al, eds. Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone; 1995.
3. Hinson VK, Tyou WR. Update on viral encephalitis. Curr Opin Neurol. 2001;14:369-374.
4. Read SJ. Laboratory diagnosis of common viral infections of the central nervous system by using a single multiplex PCR screening assay. J Clin Microbiol. 1999;37:1352-1355.
5. Redington J, Tyler KL. Viral infections of the nervous system. Arch Neurol. 2002;59:712.
6. Romero JR, Newland JG. Viral meningitis and encephalitis: Traditional and emerging viral agents. Sem Ped Inf Dis. 2003;14:72-82.
7. Tyler, KL. West Nile Infection in the United States. Arch Neurol 2004;61:1190-1195.
8. Whitley RJ. Viral encephalitis. New Engl J Med. 1990;323:242.
9. Whitley RJ. Viral encephalitis. Pediatr Rev. 1999;20:192-198.
ADDITIONAL READING
Interim guidelines for the evaluation of infants born to mothers infected with West Nile Virus during pregnancy, MMWR. 2004;53:154-157