Encephalitis

Identifying the specific cause is key to effective management

Kathleen M. Gutierrez, MD; Charles G. Prober, MD

VOL 103 / NO 3 / MARCH 1998 / POSTGRADUATE MEDICINE

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This is the second of three articles on CNS Infections

Preview: Encephalitis affects persons in all age-groups and can result from a myriad of infectious and noninfectious causes. Depending on the cause, the outcome may be benign or in some cases fatal. So where do you start in the process of paring down the diagnostic possibilities? Drs Gutierrez and Prober describe the key clinical features of this potentially life-threatening disease and recommend a comprehensive approach to diagnostic evaluation.

Encephalitis is an acute inflammatory process that affects brain tissue and is almost always accompanied by inflammation of the adjacent meninges. The disease is most commonly caused by viral infection. Encephalitis resulting from viral infection manifests as either acute viral encephalitis or postinfectious encephalomyelitis. Acute viral encephalitis is caused by direct viral infection of neural cells with associated perivascular inflammation and destruction of gray matter. Postinfectious encephalomyelitis follows infection with various viral or bacterial agents; the primary pathologic finding is demyelination of white matter.

In the United States, the annual incidence of encephalitis is about 1 in 200,000. Children, the elderly, and immunocompromised persons are most commonly affected (1). Acute encephalitis is more common in the first year of life; in contrast, postinfectious encephalomyelitis is rare in infancy. According to the Centers for Disease Control and Prevention (CDC) (2), 717 cases of primary infectious encephalitis and 143 cases of post-infectious encephalomyelitis were reported in 1994; these numbers likely underestimate the true incidence of disease. Encephalitis was deleted from the list of nationally notifiable diseases in 1995.

Viral causes

More than 100 different viruses can cause acute encephalitis (table 1). In the United States, the most frequently reported causes are enteroviruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and arthropod-borne viruses (arboviruses). Before widespread use of live measles, mumps, and rubella virus vaccine (M-M-R II), mumps virus was also a common source of aseptic meningitis and encephalitis.

Table 1. Common viral causes of acute encephalitis in the United States
Cause	Characteristics of infection
MORE COMMON
Enteroviruses	Common in summer and fall
Herpes simplex virus types 1 and 2	Common year-round; focal neurologic findings
Arboviruses California serogroup (predominantly La Crosse strain) St Louis encephalitis Western equine encephalitis Eastern equine encephalitis	Common in summer and fall; transmitted by mosquito bite or tick bite (Powassan encephalitis)
LESS COMMON
Adenoviruses	Occurs year-round; respiratory prodrome
Coltivirus (Colorado tick fever)	Occurs in spring and summer in western states; transmitted by tick bite
Cytomegalovirus&	Affects primarily immunosuppressed persons
Epstein-Barr virus	Occurs year-round; adenopathy, splenomegaly
HIV	Occurs year-round; dementia
Human herpesvirus 6	Occurs year-round
Influenza A and B	Occurs in winter
Lymphocytic choriomeningitis virus	Occurs in fall and winter; transmitted by rodents; parotitis, orchitis
Measles	Occurs in winter and spring; exanthem
Mumps	Occurs in winter and spring; parotitis, orchitis
Rabies	Occurs year-round
Rubella	Occurs in winter and spring; rash, lymphadenopathy
Varicella	Chickenpox or herpes zoster

Enteroviruses
Enteroviruses are the most common agents in central nervous system (CNS) infection, causing aseptic meningitis in most cases. Patients with abnormal neurologic findings indicating parenchymal involvement are said to have meningoencephalitis or encephalitis. The nonpolio serotypes most often associated with CNS infection include echoviruses 7, 9, 11, and 30; coxsackievirus B5; and enterovirus 71 (3).

Most patients with enteroviral CNS infection have mild, generalized disease that resolves without sequelae. However, focal infections and severe, even fatal cases have been reported (3,4). Infection with enterovirus 71 may result in a paralytic illness that resembles polio. Chronic, unremitting enteroviral meningoencephalitis occurs in patients who lack humoral immunity (5).

Herpes simplex viruses
HSV-1 and HSV-2 cause encephalitis in about 1 in 250,000 to 500,000 persons every year in the United States (6). HSV-2 encephalitis occurs primarily in neonates. Neonatal infection is acquired perinatally, and symptoms (eg, fever, lethargy, irritability, seizures) appear within the first month of life. Neonatal HSV encephalitis is a diffuse process, and generalized encephalomalacia may result. Despite therapy with intravenous acyclovir (Zovirax), the majority of surviving infants have substantial neurologic sequelae.

HSV encephalitis in older children and adults usually is caused by HSV-1. Encephalitis may result from reactivation of latent HSV-1 in the trigeminal ganglion or from primary infection. Initial signs and symptoms include fever, headache, and changes in behavior. Subsequently, focal seizures, hemiparesis, cranial nerve deficits, and visual field abnormalities may occur. A score of less than 6 on the Glasgow Coma Scale, age greater than 30 years, and presence of encephalitis for more than 4 days before initiation of therapy are predictive of severe sequelae or death (7). Most survivors of HSV encephalitis have neurologic sequelae ranging from impaired new learning to severe motor and sensory deficits, aphasia, and amnestic syndrome. Encephalitis may recur despite appropriate antiviral therapy.

Arboviruses
Arboviruses are RNA viruses transmitted to vertebrate hosts by hematophagous arthropods, such as mosquitoes and ticks. Such viruses cause about 10% of all reported cases of sporadic encephalitis but may account for up to 50% of all cases in epidemic years. The four most common arboviral encephalitides in the United States are the California encephalitis serogroup, St Louis equine encephalitis, western equine encephalitis, and eastern equine encephalitis. Rare causes of arboviral encephalitis include Venezuelan equine encephalitis, Colorado tick fever, and Cache Valley, Powassan, and Jamestown Canyon viruses (8).

California encephalitis is the most commonly reported arboviral infection in the United States. Seventy-six cases were reported in 1994 (9). Most cases are caused by the La Crosse strain and occur in the midwestern and eastern United States. La Crosse virus is transmitted by the tree-hole mosquito, and its principal vertebrate hosts are eastern chipmunks, gray squirrels, and red foxes. Although all age-groups may be infected, 90% of symptomatic cases occur in children. La Crosse encephalitis is rarely fatal. Residual seizure disorders are reported in about 10% of patients and persistent abnormalities on electroencephalography (EEG) in up to 70%.

Cases of St Louis encephalitis are widespread throughout the United States, occurring periodically in focal outbreaks. As many as 2,000 cases are reported in years during large outbreaks and as few as 20 cases in other years (9). Clinical disease occurs most often in children and the elderly. It is most severe in the elderly, among whom the mortality rate is 20% (9). Permanent neurologic deficits are uncommon, although emotional disturbances may persist.

Western equine encephalitis is prevalent in the western United States and Canada. Disease is most severe in infants and young children. Seizures occur in 90% of affected infants, and permanent neurologic sequelae develop in 50% (10).

Eastern equine encephalitis is the most severe of the arboviral encephalitides seen in the United States; cases most often occur in the Atlantic and Gulf coast regions (11). Although few cases are reported annually, the infection-to-illness ratio is high. The mortality rate during epidemics approaches 70%, and survivors usually have significant neurologic sequelae.

Other diagnostic considerations

Differential diagnosis of encephalitis encompasses a large number of viruses as well as nonviral pathogens and noninfectious causes (table 2).

Table 2. Nonviral and noninfectious causes of encephalitis

Bacterial Bartonella henselae Bartonella quintana Borrelia burgdorferi Brucella species Leptospira interrogans Listeria monocytogenes Mycobacterium tuberculosis Mycoplasma pneumoniae Rickettsia rickettsii Treponema pallidum Brain abscess or subdural empyema Partially treated bacterial meningitis Protozoal Naegleria fowleri Acanthamoeba species Cysticercosis Echinococcus species Plasmodium falciparum Trypanosoma species Fungal Blastomycosis Coccidioidomycosis Cryptococcosis Histoplasmosis Noninfectious Central nervous system hemorrhage Collagen vascular disease Exposure to certain toxins or drugs Inborn errors of metabolism Malignant disease

Although human rabies is rare in the United States, it always should be considered in patients presenting with unexplained, rapidly progressive encephalitis. In recent cases reported to the CDC, patients had no history of animal bite or contact with bats (12). Post-exposure rabies prophylaxis (in conjunction with recommendations of state and local health departments) should be offered to contacts of rabies-infected patients.

HIV may be the primary cause of encephalitis in persons with AIDS (13). However, opportunistic infections also must be considered (table 3).

Table 3. Infectious causes of encephalitis in immunocompromised patients

Viral Enterovirus* Cytomegalovirus Human herpesvirus 6 Herpes simplex virus types 1 and 2 JC virus** Measles Rubella Varicella Protozoal Amebic meningoencephalitis Toxoplasmosis Fungal Cryptococcus neoformans Coccidioidomycosis Blastomycosis Histoplasmosis Aspergillus species Candida species *Cause of chronic meningoencephalitis in patients with humoral immunodeficiency. **Cause of progressive multifocal leukoencephalopathy in patients with HIV infection.

Patients with bacterial infection of the CNS usually appear more acutely ill than those with viral infection. However, meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b may be insidious in onset. CNS infection caused by less virulent bacteria, such as Mycobacterium tuberculosis, Treponema pallidum, Borrelia burgdorferi, Bartonella henselae (cat-scratch disease) (14), and Bartonella quintana (15), also may be clinically indolent. Parameningeal bacterial infections (eg, brain abscess, subdural empyema) may have features similar to those of viral CNS infections.

Other sources of encephalitis include noninfectious disorders such as metabolic derangement (eg, hypoglycemia, electrolyte disturbances, uremia, hepatic encephalopathy, inborn errors of metabolism), malignant disease, collagen vascular disease, and intracranial hemorrhage. Exposure to certain drugs or toxins may also cause encephalitis.

Postinfectious encephalomyelitis

Postinfectious encephalomyelitis, also known as acute disseminated encephalomyelitis, is characterized by perivenular inflammation and demyelination of brain tissue. In this disorder, peripheral blood lymphocytes react against myelin basic protein. Before widespread vaccination, postinfectious encephalomyelitis most commonly occurred after smallpox and measles infections. In recent years, the disease has been associated with various viral and bacterial infections (16,17). Patients may have a history of an exanthem or a nonspecific respiratory or gastrointestinal illness 1 to 3 weeks before onset of neurologic symptoms. Acute cerebellar ataxia is a form of acute postinfectious encephalomyelitis following varicella infection.

Clinical manifestations
Onset of encephalitis usually is acute, but signs and symptoms of CNS involvement often are preceded by a nonspecific, acute febrile illness. Presenting symptoms in adults and older children are headache and malaise; infants typically are irritable and lethargic. Fever, nausea, vomiting, neck pain, and photophobia are common. Alteration of level of consciousness ranges from mild lethargy and confusion to coma. Generalized or focal neurologic abnormalities may be stationary, progressive, or fluctuating. Seizures are common, and unprovoked emotional bursts and loss of bowel and bladder control may occur. Clinical signs and symptoms of postinfectious encephalomyelitis may resemble those of acute viral encephalitis.

Diagnosis
An approach to diagnosis of encephalitis is presented in table 4. In the absence of focal neurologic findings and evidence of a space-occupying lesion, lumbar puncture should be performed. Examination of cerebrospinal fluid (CSF) in a patient with viral CNS infection reveals a normal or elevated opening pressure. A moderate elevation in white cell count (up to several hundred per cubic millimeter) is typical. Polymorphonuclear cells may predominate early in the illness but are replaced by mononuclear cells within hours. Other typical CSF findings include a normal or elevated protein level and a normal glucose level. A routine Gram stain should also be obtained. In addition, CSF should be cultured for bacteria, viruses, fungi, and mycobacteria. An India ink capsule stain of CSF sediment should be performed when cryptococcal infection is suspected. Naegleria fowleri or Acanthamoeba species may be detected by examination of a wet mount of centrifuged CSF and can be cultured on nonnutrient agar layered with enteric bacteria. Immunofluorescent tests to determine species of amebae are available through the CDC (18). Oligoclonal bands are sometimes present in the CSF of patients with postinfectious encephalomyelitis.

Table 4. Diagnostic evaluation of encephalitis
History taking
Recent illness Exposure to ill contacts Place of residence (rural, urban) Occupation (eg, agriculture, work involving exposure to toxic chemicals)	Animal exposure Tick or mosquito bite Recent travel Medications (taken by patient or other family members)
Physical examination
Laboratory studies
CEREBROSPINAL FLUID Opening pressure Gram's stain Complete blood cell count and differential Measurement of glucose and protein levels Bacterial, mycobacterial, viral, and fungal cultures India ink capsule stain Wet mount (for amebae) Stain for acid-fast bacilli Testing to consider: Antibody to arbovirus Polymerase chain reaction for herpes simplex virus and enterovirus Antibody to specific pathogens Cryptococcal antigen VDRL CULTURE Viral cultures of nasopharynx, rectum, urine, and blood (buffy coat) Blood culture for bacteria	SERUM TESTING Sample of acute-phase serum for testing later Testing to consider: Mycoplasma pneumoniae Borrelia burgdorferi Bartonella species Arboviruses Coccidioides immitis Cysticercosis Brucella species Leptospira interrogans VDRL/RPR for syphilis Cryptococcal antigen HIV antibody Toxicology screen Metabolic screen of blood and urine Measurement of electrolyte, glucose, ammonia, and pH levels
Neurodiagnostic testing
Magnetic resonance imaging with contrast Electroencephalography Brain biopsy (when indicated)

HSV may be isolated from CSF in up to 50% of cases of neonatal HSV infection but is rarely found in specimens obtained from older children and adults with HSV encephalitis. Vesicular, conjunctival, nasopharyngeal, urine, and rectal cultures may be positive for HSV in neonates with HSV encephalitis. Viral cultures of CSF are positive in 50% to 70% of patients with enteroviral meningitis but in a smaller percentage of those with encephalitis. Viral cultures from the nasopharynx and rectum are helpful in selected cases if the results are positive. In rare cases, arboviruses are isolated from blood during the acute phase of illness.

Serologic testing during the acute and convalescent phases of illness is of little immediate value in the diagnosis of HSV or enteroviral encephalitis. In contrast, the presence of arbovirus-specific IgM in spinal fluid is diagnostic of arboviral encephalitis. A fourfold change in specific IgG antibody also is diagnostic. More information regarding diagnosis of arboviral infection may be obtained from the CDC.* Serologic testing may be indicated under certain epidemiologic circumstances (eg, encephalitis caused by infection with HIV, B burgdorferi, Epstein-Barr virus, or Mycoplasma pneumoniae).

Polymerase chain reaction (PCR) is being more widely used to detect viral DNA or RNA in CSF (19). This method has been reported to have greater than 95% sensitivity and 100% specificity for HSV DNA in patients with biopsy-proven HSV encephalitis (6). PCR techniques show excellent specificity and sensitivity in the diagnosis of enteroviral meningitis, and use in diagnosis of encephalitis appears promising (3).

Magnetic resonance imaging (MRI) and computed tomography (CT) can provide useful information in the evaluation of encephalitis (20). MRI is the more sensitive test. Changes in acute infectious encephalitis include edema and abnormalities of the basal ganglia, cortex, and gray-white matter junction. An MRI scan may be normal early in the course of HSV encephalitis, but within days focal edema and hemorrhage usually are evident. Eastern equine encephalitis produces focal abnormalities involving the basal ganglia and thalami (11). MRI findings with other arboviral encephalitides are less well characterized. Abnormalities seen in patients with postinfectious encephalomyelitis include areas of demyelination (often symmetric) of spinal cord, white matter, and basal ganglia (21). Use of gadolinium enhances the sensitivity of MRI for detecting vasculitic lesions and brain abscess. CT is superior for detecting intracranial calcifications.

EEG is a useful complementary test for diagnosis of encephalitis. In patients with HSV encephalitis, EEG may reveal focal unilateral or bilateral periodic discharges localized in the temporal lobes.

Brain biopsy is the definitive test for diagnosis of acute encephalitis. Biopsy should be considered in cases in which the diagnosis is uncertain and response to therapy is poor (22).

Treatment

Until a bacterial cause of CNS inflammation is excluded, parenteral antibiotics should be given. Treatment with a third-generation cephalosporin, such as cefotaxime sodium (Claforan) or ceftriaxone sodium (Rocephin), is recommended. Vancomycin (Lyphocin, Vancocin, Vancoled) should be added in geographic areas where strains of S pneumoniae resistant to penicillin and cephalosporins have been reported.

Empirical therapy with intravenous acyclovir should be initiated when HSV encephalitis is suspected. The recommended dosage is 30 mg/kg per day in three divided doses for 14 to 21 days. Relapse may occur, and retreatment should be considered.

Arboviral and enteroviral encephalitis is treated with symptomatic and supportive care. Patients with headache should rest in a quiet, dark environment and take analgesics. Narcotic therapy may be needed for pain relief; however, medication-induced changes in level of consciousness should be avoided.

Treatment of postinfectious encephalomyelitis is supportive. Anecdotal reports suggest that corticosteroid treatment may be effective.

Complications

Complications of severe encephalitis include seizures, increased intracranial pressure, and respiratory decompensation. Patients should be monitored closely in facilities with appropriate resources for management of these serious adverse events. Inappropriate secretion of antidiuretic hormone is common; therefore, frequent monitoring of electrolyte concentrations is indicated.

Prognosis

Supportive care and rehabilitation are important after the patient recovers. Because some sequelae of encephalitis may be subtle, neurodevelopmental and audiologic evaluations should be part of routine follow-up.

Most patients completely recover from viral encephalitis; however, prognosis depends on the cause and severity of the illness and the patient's age. If the clinical illness is severe and substantial parenchymal involvement is evident, prognosis is poor. Potential deficits include intellectual, motor, psychiatric, epi-leptic, visual, and auditory abnormalities. Severe sequelae should be anticipated in patients with eastern equine encephalitis or infection caused by HSV-1 or HSV-2.

Summary

Acute viral encephalitis and postinfectious encephalomyelitis affect both children and adults. Enteroviruses, HSV types 1 and 2, and arboviruses are the most common causes of encephalitis in the United States; however, the differential diagnosis is broad. History taking and physical examination can provide clues to the cause, but the diagnosis is usually established on the basis of CSF analysis, viral culture, MRI, and serologic testing, when indicated. In the future, PCR techniques may enhance rapidity of diagnosis.

Until the specific cause is identified, empirical therapy should be given. Because complications can be severe, all patients with encephalitis should be monitored in a facility capable of providing supportive intensive care. Long-term follow-up is important to detect sequelae, particularly in patients with eastern equine or HSV encephalitis.

temp table grounds

*Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases, Rampart Rd, Colorado State University Foothills Research Campus, PO Box 2087, Fort Collins, CO 80522 (970-221-6400).

References

0. Koskiniemi M, Rautonen J, Lehtokoski-Lehtiniemi E, et al. Epidemiology of encephalitis in children: a 20-year survey. Ann Neurol 1991;29(5):492-7
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3. Modlin JF, Dagan R, Berlin LE, et al. Focal encephalitis with enterovirus infections. Pediatrics 1991;88(4):841-5
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11. Centers for Disease Control and Prevention. Human rabies--Montana and Washington, 1997. MMWR 1997;46(33):770-4
12. Simpson DM, Tagliati M. Neurologic manifestations of HIV infection. Ann Intern Med 1994;121(10):769-85 [Erratum, Ann Intern Med 1995;122(4):317]
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16. Byington CL. An encephalitic syndrome in a seven year old. Pediatr Infect Dis J 1995;14(6):550-1, 553-5
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19. Shaw DW, Cohen WA. Viral infections of the CNS in children: imaging features. AJR Am J Roentgenol 1993;160(1):125-33
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Dr Gutierrez is clinical instructor and staff physician, division of pediatric infectious disease, Stanford University School of Medicine, Stanford, California. Dr Prober is professor of pediatrics, medicine, microbiology, and immunology and associate chairman, department of pediatrics, Stanford University School of Medicine. Correspondence: Kathleen M. Gutierrez, MD, Division of Infectious Diseases, Department of Pediatrics, Stanford University Medical Center, 300 Pasteur Dr, Room G312, Stanford, CA 94305. E-mail: md.gutka@lpch.stanford.edu.

Symposium Index

• INTRODUCTION by Andrew E. Simor, MD, FRCPC
• BACTERIAL MENINGITIS IN CHILDREN AND ADULTS: Changes in community-acquired disease may affect patient care by Elizabeth J. Phillips, MD, FRCPC, Andrew E. Simor, MD, FRCPC
• ENCEPHALITIS: Identifying the specific cause is key to effective management by Kathleen M. Gutierrez, MD, Charles G. Prober, MD
• NEUROLOGIC MANIFESTATIONS OF HIV INFECTION: Using imaging studies and antiviral therapy effectively by Anita R. Rachlis, MD, FRCPC, MEd

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