Definitions and Epidemiology
Encephalitis is defined as inflammation of the brain tissue, infectious or otherwise, causing alterations in cerebral function. The patient with encephalitis often presents with fever, headache, altered mental status, behavioral changes, focal neurological signs, and seizures. Meningoencephalitis describes the clinical entity in which the inflammation extends to the subarachnoid spaces and meninges. When the spinal cord is involved in the inflammatory process, then the term "encephalomyelitis" is used. Noninfectious encephalitis is an antibody-mediated inflammation of the brain parenchyma, which may be triggered by immune response to a viral illness or tumor.
Estimating the true incidence of encephalitis is difficult, as most cases are not reported to local health departments. The most accurate estimates are those concerning the subset of arthropod-borne viral, or arboviral, encephalitides due to tracking efforts at the Centers for Disease Control (CDC), which estimates between 250 to 3000 cases occurring annually.36 The California Encephalitis Project documented all hospitalized cases of encephalitis in California from 1991 to 1999 and found 35 to 50 cases per 100,000 people annually. Encephalitis occurred in the highest numbers in infants, followed by the elderly. A specific cause was reported in approximately 45% of the 13,939 cases; HSV accounted for 14% of all cases while arboviral disease was identified in fewer than 1% of the cases (West Nile Virus had not yet become established in California).34
Due to the protection of the blood–brain barrier (BBB), the lack of a lymphatic system and the absence of major histocompatibility complexes (antigen-presenting cells), the brain was historically considered an immunologically isolated organ without the same vulnerabilities to infectious agents or immune responses as other body systems. It is increasingly apparent that the BBB is a far more dynamic entity than previously thought.
The BBB is made of capillary endothelial cells, astrocytes, and pericytes with unique properties not seen in other organ systems. These anatomic differences include narrow tight junctions, lack of fenestrations, decreased transport, and a continuous basement membrane. Electrically, the surfaces of these cells are negatively charged, and therefore repel proteins and other negatively charged molecules. Specific areas within the CNS differ in their levels of BBB permeability. For example, the choroid plexus endothelium has fenestrations, allowing free entry of immune cells to the CSF. The ependymal lining of the ventricles lacks tight junctions, which permits drainage of CNS antigens into the CSF.
The definitive diagnosis of encephalitis requires brain tissue, which yields a diagnosis by microscopic evaluation for inclusion bodies, isolation of the causative agent from brain tissue cultures, or detection of the infectious agent by in situ polymerase chain reaction (PCR). Detection of a serologic response or identification of the infectious agent in the CSF or other body fluids allows a presumptive diagnosis. The California Encephalitis Project reported a definitive diagnosis (brain tissue diagnosis) in 30% of cases, while a presumed diagnosis (serum, urine, or stool) was found in 12%.38 Other sources report diagnostic rates of 50%.39
While isolating virus from CSF and other body fluid cultures is helpful for definitive diagnosis, this process is cumbersome and prone to contamination. PCR testing, which detects tiny portions of the DNA in the CSF, allows diagnoses to be made more quickly and reliably. Detecting antibodies for serologic testing is limited by even small doses of immunoglobulin therapy, and because it often requires both infected samples and convalescent samples, may take weeks to confirm.
All viruses affecting the central nervous system (CNS) produce similar pathologic features, including inflammation and neuronal death. Thus, most viral CNS infections appear on neuroimaging as an increase in water content of the affected tissue. On CT scan this increased water content is manifest as patchy hypodensities, and on MRI as hypointense signal on T1 and hyperintense signal on T2 and FLAIR (fluid-attenuated inversion recovery).
When imaged early in its course, viral encephalitis may first appear on MRI as restricted diffusion on diffusion-weighted imaging (Figure 16-4). Thus, acute DWI changes may be more sensitive to abnormalities than conventional T1 or T2 imaging sequences40-42 in early imaging. Later in the disease process, MRI often shows confluent areas of T2 hyperintensities involving white and gray matter, which may exert a variable amount of mass effect. When present, these hyperintensities enhance diffusely with gadolinium. While these findings fail to differentiate viral infections from one another, the asymmetry and the involvement of both white and gray matter structures help to differentiate viral encephalitis from primary metabolic/ toxic disorders or parainfectious disorders, such as acute disseminated encephalomyelitis (ADEM; Figure 16-5).
MRI of viral encephalitis in a 7-year-old male presenting with sudden-onset status epilepticus. (A) Hyperintensity in the splenium of the corpus callosum (white arrow) on axial FLAIR MRI. (B) Restriction of water diffusion demonstrated on apparent diffusion coefficient (ADC) maps of the diffusion weight imaging (DWI) examination (black arrow). (Reproduced with permission from Shah S. Pediatric Practice: Infectious Disease. New York: McGraw-Hill; 2009: Figure 17-1.)
Areas of inflammation (arrowheads) consistent with acute disseminated encephalomyelitis (ADEM) in a 9-year-old male presenting with lethargy, irritability, and left hemi-ataxia. (A) Inflammatory lesion in the left cerebellar peduncle. (B) Subcortical inflammatory white matter lesion in the right temporal lobe. (C) Prominent lesion in the splenium of the corpus callosum. (D) Multiple bilateral subcortical inflammatory white matter lesions. (Reproduced with permission from Shah S. Pediatric Practice: Infectious Disease. New York: McGraw-Hill; 2009: Figure 17-2.)
Though these general features apply to most viral encephalitides, certain infections show characteristic tropisms that are helpful in the differential diagnosis. Herpes simplex virus (HSV) encephalitis has been associated with hemorrhagic inflammation, frequently bilateral, of the medial temporal lobe, sylvian fissure, and orbital-frontal cortex (Figure 16-6).
14-year-old male presenting with coma and status epilepticus, diagnosed with HSV encephalitis. (A) Axial flair demonstrating medial temporal (hippocampus) and orbitofrontal (arrow) involvement. (B) Axial flair demonstrating bilateral sylvian fissure (arrows) involvement. (C) Coronal flair demonstrating orbitofrontal and interhemispheric involvement. (D) Diffusion weighted imaging (b = 1000) demonstrating infarction (cytotoxic edema) of the right temporal lobe. (Reproduced with permission from Shah S. Pediatric Practice: Infectious Disease. New York: McGraw-Hill; 2009: Figure 17-3.)
In neonates, the areas of inflammation are seldom as well defined as in older children or adults, and manifest as loss of distinction of the gray–white interface on T2-weighted imaging. Echo gradient imaging reveals a hemorrhagic component corresponding to infarction on diffusion-weighted imaging in the acute phase of the disease (5 to 7 days from insult).
Varicella-zoster virus (VZV) is an infrequent cause of encephalitis, but must be considered as a possible cause in those patients at risk either from immunocompromise or from direct inoculation via lumbar puncture. VZV is a common pathogen in other CNS infections such as transverse myelitis and cerebellitis and has been associated with transient arteriopathy of childhood and stroke.43,44
Electroencephalogram (EEG) must be considered early in the evaluation of patients with viral encephalitis, as subclinical seizures are a treatable cause of altered mental status. EEG may also disclose other nonspecific abnormalities including focal slowing or focal epileptiform discharges. Acute destructive lesions can produce periodic lateralized epileptiform discharges (PLEDS), usually in temporal leads. PLEDS are considered nonspecific but are highly suggestive of HSV encephalitis.45
CSF profiles in viral encephalitis typically show mildly elevated WBC counts, with a lymphocytic predominance and, later in the course, mildly elevated protein. Elevated RBC counts and xanthochromia reflect the necrotizing nature of HSV infection; however, early in the disease CSF findings can be normal. PCR is the most common method used for CSF analysis, although PCR specificity may be as low as 94%, with 98% sensitivity,46 between 72 hours and 2 weeks of symptom onset. For this reason, patients may require repeat testing (Table 16-8).
Table 16–8. Acute Disseminated Encephalomyelitis Versus Viral Encephalitis ||Download (.pdf)
Table 16–8. Acute Disseminated Encephalomyelitis Versus Viral Encephalitis
|Age||Children >> Adults||Any|
|Spinal cord/cerebellum involvement||±||–|
|CSF||Lymphocytic pleocytosis||Lymphocytic pleocytosis|
|± Elevated protein||Elevated protein|
|Normal glucose||± Normal glucose|
|Negative cultures||± Negative cultures|
|+ Elevated oligoclonal bands and myelin basic protein||– Oligoclonal bands|
|– Myelin basic protein|
|Serum||± Leucocytosis||+++ Leucocytosis|
|MRI||Multiple areas of white matter hyperintensity||Focal areas (1 or 2) of white or gray matter hyperintensity|
|Often in deep brain structures (basal ganglia, brainstem, cerebellum, spinal cord) and optic nerves||Unilateral/bilateral|
The etiology of infectious viral encephalitis has changed significantly with the advent of widespread immunizations (Tables 16-9 and 16-10). The most common causes of viral encephalitis 30 years ago were measles, mumps, rubella, and varicella, which now rarely cause neurological disease. HSV is thought to be the most common diagnosable and treatable cause of viral encephalitis in both the United States and United Kingdom, with arboviruses, varicella zoster virus, Epstein-Barr virus (EBV), mumps, measles, and enteroviruses following in prevalence. A Finnish study published in 2001 found VZV to be the most common cause of diagnosed viral encephalitis, meningitis, and myelitis (29% of all confirmed agents), with HSV, enteroviruses, and influenza A making up the majority of other confirmed etiologic agents.47 Even within this population, however, an etiologic agent was not identified in 60% of cases. In U.S. National Hospital Discharge Data, the pathogenic species was found in only 40% of cases.48 According to the California Encephalitis Project, up to 70% of cases of encephalitis remain idiopathic.37
Table 16–9. Viral Encephalitides ||Download (.pdf)
Table 16–9. Viral Encephalitides
|Double-stranded DNA viruses||Adenovirus|
|Herpes simplex virus 1 and 2|
|Human herpesvirus 6 and 7|
|Single stranded DNA virus||Parvovirus|
|Arboviruses (single-stranded RNA viruses)||California (La Crosse) virus|
|Eastern equine virus|
|St. Louis encepalitis|
|West Nile virus|
|Western equine virus|
|Colorado tick fever|
|Enterovirus (single-stranded RNA viruses)||Poliovirus|
|Other RNA viruses||Hepatitis A influenza|
|Respiratory syncytial virus|
|Transmitted via mammals||Rabies|
|Equine morbillivirus (Hendra)|
Table 16–10. Nonviral Causes of Encephalitis ||Download (.pdf)
Table 16–10. Nonviral Causes of Encephalitis
|Coxiella burnetti (Q fever)|
|Human African trypanosomiasis|
|Postimmunization encephalitis||Smallpox vaccine|
Postinfectious encephalitis, or acute disseminated encephalomyelitis (ADEM), is the most common white matter disease in children49 and is usually seen days to weeks after mild viral illness or immunizations. The presumed cause of ADEM is thought to be antibodies to the offending virus cross-reacting with myelin surface proteins. The inflammation results in widespread monophasic demyelination, with a full recovery expected in the majority of pediatric cases. ADEM differs from viral encephalitis in the location of lesions on imaging: ADEM has a predilection for the cerebellum and optic nerves, which is unusual for encephalitis. Spinal cord inflammation may be noted in both, but is more frequent in ADEM than in viral encephalomyelitis. Clinical progression to coma occurs more rapidly and more commonly in ADEM than in viral encephalitis.45
CSF profiles in ADEM and viral encephalitis are similar and typically show elevated WBC counts with a lymphocytic predominance. To distinguish the two entities a thorough history of prodromal illnesses must be combined with MRI findings as well as negative CSF, blood, nasopharyngeal swab, urine serology, and cultures (Table 16-8). ADEM is treated with immunomodulation using high-dose intravenous glucocorticoids or pooled intravenous immune globulin (IVIG). The precise mechanism of action of these latter therapies is unknown.
Paraneoplastic encephalitis typically involves the limbic area with a fulminant and progressive course. The pathophysiology is thought to involve antibodies formed against a neoplasm that cross-react to brain tissue antigens. Thus paraneoplastic disorders can be diagnosed by identifying pathologic antibodies in the CSF. Paraneoplastic disorders are rare in children, but should be considered in the differential diagnosis, as they can resemble HSV encephalitis. Ospoclonus-myoclonus, or the "syndrome of dancing eyes and dancing feet," is perhaps the most common paraneoplastic disorder and is associated with neuroblastoma, which is invariably low grade. Opsoclonus refers to unusual and exaggerated eye movements that can be elicited on visual tracking. Myoclonus is rapid, jerky, involuntary movements of the limbs or trunk.
Clinical Presentation and Management
Because the etiologic agent remains unknown in most cases of viral encephalitis, management is limited to symptomatic treatment. Tests to consider in the initial evaluation of the child with encephalitis are summarized in Table 16-11, while key clinical features of the viral encephalitides are summarized in Table 16-12. Even for diagnosable entities, very few treatment options exist. HSV and VZV should be treated with acyclovir, while cytomegalovirus (CMV) can be treated with ganciclovir (Table 16-13). In immunocompromised patients, aggressive treatment with antibiotics and antivirals is important until treatable causes of encephalitis/meningitis are ruled out.
Table 16–11. Laboratory Diagnosis of Viral Encephalitides ||Download (.pdf)
Table 16–11. Laboratory Diagnosis of Viral Encephalitides
|Virus||PCR CSF||PCR Serum||Serology: CSF||Serology: Serum||Culture: Pharynx||Culture: Rectum||Culture: Blood||Culture: CSF||Other|
|HSV 1 & 2||+++||+||±||–||–||–||–||Intranuclear|
|Measles virus||+||–||+ IgG||+ IgG||+||–||+||–||Urine|
|Rabies virus||+||–||+++||+++||–||–||–||+||Negri bodies|
Table 16–12. Key Features of the Viral Encephalitides ||Download (.pdf)
Table 16–12. Key Features of the Viral Encephalitides
|Virus||Key Clinical or Epidemiologic Features|
|HSV||Common cause of encephalitis.|
|Predilection for temporal lobes, sylvian fissure, orbital-frontal cortex. Associated with periodic lateralizing epileptiform disharges on EEG, vesicles on the skin, focal seizures, hemiparesis, aphasia and cranial neuropathies.|
|HHV-6||Rarely causes encephalitis.|
|Typically occurs in infants and small children, and has a focal onset.|
|VZV||Uncommon cause of encephalitis.|
|Typically occurs in children. Usually associated with vesicular rash, headache, vomiting, altered mental status, and seizures. Can also cause ischemic or hemorrhagic infarcts.|
|EBV||Rarely causes encephalitis.|
|Often associated with rash or mononucleosis.|
|CMV||Rarely causes encephalitis.|
|More common in immunocompromised patients.|
|EV||Common cause of CNS infection, but rarely causes encephalitis.|
|Often associated with pharyngitis, gastroenteritis, and rash.|
|Arboviruses||Most common causes of worldwide encephalitis.|
|WNV||Associated with headache, vomiting, diarrhea, abdominal pain, and rash. Presents with seizures, flaccid paralysis, cranial neuropathies.|
|EEE||Rare cause of encephalitis, but children are most affected.|
|Presents with sudden high fever, seizures, and altered mental status.|
|SLE||Rarely causes encephalitis.|
|Presents with headache.|
|La Crosse||Rare cause of encephalitis, but occurs most commonly in children.|
|Associated with upper respiratory illness, abdominal pain, and seizures.|
|Influenza||Rarely causes encephalitis in the United States.|
|Presents with a prodrome of myalgias and fever, progresses to cause seizure.|
|Rabies||Rare in developed countries, but common throughout the world.|
|Encephalitic||Presents with anxiety, hydrophobia, aerophobia, hypersalivation, and seizures.|
|Paralytic||Presents with progressive peripheral nerve paralysis|
|Measles||Rarely causes encephalitis, more commonly causes SSPE.|
|SSPE occurs months to years after measles infection and presents with progressive dementia, myoclonus, seizures, and ataxia.|
|Mumps||Rarely causes encephalitis.|
|Presents with fever, headache, and a typically mild course.|
|Post infectious encephalomyelitis: occurs 7-10 days after mumps infection and is more severe. Symptoms include seizure, hemiparesis, and altered mental status.|
Table 16–13. Antiviral Therapy ||Download (.pdf)
Table 16–13. Antiviral Therapy
|Antiviral Agent||Indication||Drug-Related Complications|
|Amantadine||Influenza A||Declining effectiveness, anticholinergic effects|
|Cidofovir||CMV retinitis, acyclovir-resistant herpes||Nephrotoxic|
|Foscarnet||Herpes viruses: CMV (including CMV retinitis), herpes simplex viruses||Hypocalcemia, renal failure|
|Ganciclovir||CMV||Aplastic anemia, phlebitis, nephrotoxic, teratogenesis,|
|Oseltamivira||Influenza A and B||Stevens-Johnson syndrome, hepatitis|
|Ribavarin||Influenza A and B, West Nile virus Research ongoing in hepatitis B/C, polio, measles, smallpox||Nephrotoxic, teratogenesis|
The development of novel antiviral agents has lagged due to the research emphasis on immunization. As the majority of cases lack an isolated causative agent, the value of developing specific antiviral drugs is questionable. The use of immunomodulatory therapy, such as steroids, to treat encephalitis is compelling; however, the relative rarity of cases makes a single-center study difficult if not impossible. Acyclovir, supportive care, and rehabilitative therapies remain the only treatments at this time for viral encephalitis.
Herpes Simplex Virus 1 and 2
Herpes simplex virus (HSV) 1 and 2 are double-stranded DNA viruses that remain dormant in human host neurons. The clinical features distinguishing HSV 1 and 2 are few, and thus it is not clinically useful to discriminate between them.
One-third of patients with HSV encephalitis are less than 20 years of age and the majority have no prior existing conditions.50 About half of all patients with HSV encephalitis report a viral prodrome prior to the onset of neurological symptoms, with symptoms of upper respiratory and gastrointestinal illness being the most commonly reported. Neonates who acquire HSV develop CNS infection in over 50% of cases. Infection typically occurs at the time of birth (85%), but can also occur transplacentally (5%) or in the postpartum period (10%).45 Symptoms of HSV infection in neonates range from subtle (skin vesicles) to fulminant (fever, seizures, obtundation).
HSV infects peripheral sensory neurons and then spreads to the CNS by retrograde axonal transport. The patient invariably experiences fever, headache, and altered mental status. Focal seizures at the time of presentation are common (75% of patients), while hemiparesis (45%), aphasia (75%), and cranial neuropathies are also seen. Infections can rapidly progress to involve greater areas of brain tissue.45
In the last 20 to 30 years, with the advent of acyclovir, there have been significant declines in the mortality and morbidity associated with HSV encephalitis. Prior to the use of acyclovir, approximately 70% of patients with HSV encephalitis died; this has decreased to 19% since the widespread use of acyclovir.38 Neurological outcomes have also improved, and long-term studies demonstrate a normal outcome in 38%, moderate impairment in 9%, and severe impairment in 53%.38,50 Outcomes were most improved in younger age-groups and in patients with shorter latency to treatment.38 The typical dose of acyclovir is 30 mg/kg/d IV, divided every 8 hours for 14 to 21 days in children; and 60 mg/kg/d IV divided every 8 hours for 21 days in neonates.
Human Herpesvirus 6 (Hhv-6)
Human herpesvirus 6 (HHV-6), also known as roseola, usually infects children during infancy, with two-thirds of children seroconverting by 1 year.51 HHV-6 encephalitis is usually focal, and thus can be confused with HSV encephalitis. Viral invasion of the CNS is a common event during primary infection, as demonstrated by the high rate of febrile seizures. It typically causes high fever, with frank encephalitis occurring only rarely.52 The incidence of HHV-6 encephalitis is unknown.
Varicella Zoster Virus (VZV)
Prior to widespread vaccination campaigns, 4 million cases of primary varicella zoster virus (VZV; chickenpox) occurred annually. Rates of serious infection-related morbidity and mortality were highest in children under 10 years of age, accounting for 60% of hospitalizations and 40% of deaths.53 Direct infection of the CNS during a primary VZV infection is rare, but meningoencephalitis may occur by invasion of the vascular endothelium,54 leading to primary VZV encephalitis. Occurring mostly in the pediatric population, this small-vessel vasculopathy presents with headache, fever, vomiting, altered mental status, seizure, and focal deficits. Encephalitis may also complicate reactivation of VZV (zoster or shingles), usually in elderly populations. This encephalitis, by contrast, is due to a large-vessel vasculopathy, with acute focal deficits developing weeks to months after the clinical infection. MRI findings include ischemic or hemorrhagic infarcts in the cortex and subcortical gray and white matter.
The diagnosis of VZV encephalitis is made via CSF PCR for VZV or serology for VZV specific IgM in the CSF. Treatment in children is acyclovir IV 60 mg/kg/d, divided every 8 hours for 14 days.
Epstein– Barr virus (EBV) causes severe encephalitis in fewer than 1% of infected patients.54 More often, EBV causes aseptic meningitis, cerebellitis, myelitis, or ADEM with a benign course and full recovery from the infection expected. The diagnosis of EBV is made by measuring acute and convalescent serum IgM antibodies to the EBV capsid antigen. A CSF PCR test is available, but sensitivity and specificity of this test are unknown.
Congenitally acquired cytomegalovirus (CMV) causes severe and permanent brain injury, but encephalitis due to CMV is relatively uncommon except in the immunocompromised child.39 Serious CMV infections in the immunocompromised are treated with ganciclovir.
The enterovirus (EV) family—including polioviruses, coxsackie viruses A and B, and echoviruses—are collectively the leading viral cause of CNS disease in children in the United States, particularly affecting neonates and immunocompromised hosts.45 Outbreaks of EV generally occur in late summer and early fall and are often associated with pharyngitis, gastrointestinal symptoms, or rash and desquamation of the hands, feet, and mouth (herpangina). Encephalitis, meningoencephalitis, cerebellitis, and a polio-like syndrome are most often seen with EV serotypes 70 and 71, but can occur with any virus in this family.45 The viruses can be cultured directly from the CSF, but diagnosis is usually made by CSF EV PCR, which has 96% to 100% sensitivity and >99% specificity.51 Current treatment is symptomatic and supportive, while drug trials are ongoing.
Arboviruses are the most commonly identified cause of severe encephalitis worldwide.39 Single-stranded RNA viruses, they are usually transmitted to humans via mosquito or tick vectors, although transmission has also been reported following blood product transfusion, organ transplantation, needle sticks, transplacentally and via breast milk. Arboviruses have complex life-cycles involving birds and other mammals, with humans being dead-end hosts. After entering the bloodstream, they reach the CNS via endothelial cell infection. The infection in the brain is diffuse, and thus the sequelae are nonfocal, including altered mental status, vomiting, and fever. PCR testing has not been developed for routine use, as its sensitivity in arboviruses is poor. Evaluation of virus-specific IgM from CSF or blood is the most widely used diagnostic method.
Prior to 1999 there were no reported West Nile virus (WNV) cases in the Western Hemisphere. In 2006, a total of 4256 infected individuals were reported, with 1449 cases of confirmed West Nile meningitis/encephalitis, including 165 fatalities.55 Roughly 80% of infected individuals experience no symptoms, while 20% have mild flu-like symptoms of fever, headache, vomiting, diarrhea, abdominal pain, myalgia, and rash.56 Neuroinvasive disease typically includes seizures, altered mental status, meningoencephalitis, acute flaccid paralysis, cranial neuropathies, movement disorders, and optic neuritis.45,57 In patients with neuroinvasive disease, 15% progress to coma.57 The proportion of each presenting symptom varies with location and timing within the season. WNV meningitis and encephalitis occur more commonly in adults and are uncommon in children.
Diagnosis of neuroinvasive disease is made by CSF serology. WNV IgM is detectable in more than 90% of infected individuals 1 week after symptom onset. IgM-related immunity may persist for more than 1.5 years, complicating the diagnosis of acute disease. The presence of anti-WNV IgG peaks at 4 weeks after infection and persists throughout life. Currently the treatment of WNV is supportive, though current clinical trials include passive immunization, interferon alpha, and ribavirin. Overall, mortality from WNV is roughly 2% to 14%, with encephalitis-specific mortality estimated at 12% to 24%.45,57 In the United States, donor blood is screened for WNV.
Eastern Equine Encephalitis
Like WNV, eastern equine encephalitis (EEE) can cause severe disease, with 30% mortality and 30% serious neurological sequelae in survivors.58 It is an uncommon cause of illness in North America, with only 95 cases reported between 1995 and 2005.59 The presentation is both sudden and fulminant, with high fever, seizures, and rapid deterioration of mental status. Young children are most severely affected and have the highest rate of neurological sequelae in recovery.
ST. Louis Encephalitis Virus
St. Louis encephalitis (SLE) virus is more common than EEE and, according to the CDC, carries a risk of serious neurological morbidity in 10% of patients and of mortality in 5%. From 1964 to 2005, there were 4478 cases in the United States, with an annual average of 128 cases.60 While the disease is widespread throughout North America, there is a higher risk of encephalitis and serious neurological infection in low-income areas, as well as with the elderly.61 Most individuals infected with SLE are asymptomatic, but when symptoms are present they range from simple headache to severe encephalitis.
California (La Crosse) Virus
La Crosse virus is less frequent than EEE or SLE in the United States and causes a milder form of encephalitis. Between 1964 and 2005 there were 3375 cases reported to the CDC, ranging from 41 to 167 per year.62 Most cases are asymptomatic or result in mild illness, with rare neurological sequelae and very rare mortality (<1%).63 It is overwhelmingly a childhood disease, with over 90% of cases occurring in children under 16 years. When symptoms occur, the presentation is a sudden onset of fever, headache, upper respiratory illness, abdominal pain, and seizures.
Influenza types A and B are common causes of illness, but rarely cause neurological complications in the United States. Influenza has been associated with Reye syndrome, encephalitis, transverse myelitis, acute necrotizing encephalopathy, Guillain-Barré syndrome, and seizures. The data regarding serious neurological sequelae differ by geography and strain. Japanese data shows that roughly 100 children die annually from influenza encephalitis.64 Similarily, the mortality rates in influenza encephalopathy in Japan are as high as 25% to 37%.65,66 A recent study suggests the prevalence of influenza encephalitis in the United States is considerably lower; this single-center, retrospective chart review found only 842 laboratory-confirmed cases of influenza A and B in children from 2000 to 2004. Of those patients, 72 children experienced influenza-related neurological complications, but the authors found no cases of influenza encephalitis or influenza-related mortality.67 The neurological complications consisted of seizures (78%), acute encephalopathy (11%), cerebral infarction after hypotension (5%), postinfectious influenza encephalopathy (3%), and aseptic meningitis (3%).67 From 2003 to 2004, of the 153 deaths in children from influenza reported to state health departments, 16% were associated with altered mental status and 6% were associated with encephalopathy.68 Treatment for influenza is primarily supportive, although rimantadine and oseltamivir have been used for CNS infections.
While relatively rare in the United States, rabies is an important cause of serious neurological illness and death. There were only 36 laboratory-confirmed cases in the United States from 1990 to 2001,69 with half of those cases occurring in children and adolescents.39 Worldwide, however, roughly 55,000 deaths occur due to rabies each year.70 It is generally spread to humans by infected animal bites, although documented cases of rabies with no history or evidence of an animal bite exist. The virus spreads through retrograde axonal transport, causing progressive changes in mental status, seizures, cranial neuropathies, dysphagia, and paresis. Two forms of CNS rabies exist: one causes encephalitis, with seizures and fever, and eventually progresses to paralysis; the other begins with paralysis of the peripheral nerves and is associated with fever, but not seizures. The paralytic form differs from Guillan-Barré syndrome by the association with fever, and the lack of sensory deficits. Once these symptoms occur, the disease almost invariably induces cardiopulmonary failure and death, in 5 to 7 days. Diagnosis is typically made at autopsy via serologic or PCR testing of brain tissue, and histologic examination of the tissue may demonstrate Negri bodies. Viral culture may be used as a confirmatory technique. The most sensitive (100%) noninvasive antemortem diagnostic test is PCR analysis looking for rabies RNA in the saliva of the patient, with the next most sensitive (67%) test being antigen testing of hair follicles obtained by nuchal skin biopsy.71 Additional tests include antibody testing of CSF and serum, and antigen testing of a touch impression from the cornea.
There is no treatment available for rabies after symptom onset, but presymptomatic post exposure vaccine combined with immunoglobulin administration is highly effective if given within 24 hours after exposure,72 and may be effective for up to 72 hours after exposure, in some cases. The only case of survival documented after symptom onset occurred in a 15-year-old girl who was placed into chemical coma with ketamine, midazolam, and barbiturates. High-dose ribavirin (33 mg/kg/load plus 64 mg/kg/d) and amantidine (200 mg/kg/d) were administered for 1 week. Five months after hospitalization she had dysarthria, buccolingual choreoathetosis, intermittent dystonia, and ballismus, but was able to attend high school part-time. No formal neurocognitive testing was reported at that time.73 As of April 2007, she planned to graduate from high school and to attend college. Her persistent neurological deficits include numbness on her thumb, in the area of the bite, abnormal tone in her left arm, and a widened running gait.73 Further attempts to utilize this treatment strategy have failed.74
Measles is rare in the post vaccine era and progresses to encephalitis in only 0.74 per1000 cases.39 Its more common neurological syndrome, subacute sclerosing panencephalitis (SSPE), occurs in older children and adults months to years after a primary measles infection. This clinical syndrome presents with dementia, myoclonus, ataxia, epilepsy, and motor function decline, and progresses slowly to death. The clinical features have been divided into four stages (the Jabour stages)
|IA||Behavioral, cognitive, and personality changes.|
|IIA||Mental deterioration, myoclonic spasms (periodic, generalized, frequently causing drop spells).|
|IIB||Apraxias, agnosias, language difficulties, spasticity. Ambulation with assistance.|
|IIIA||Less speech, visual difficulties, myoclonic spasms frequent, ± seizures.|
|IIIB||No spontaneous speech, poor comprehension, blind, myoclonic spasms, bedridden, dysphagia, EEG w/ background delta, chorea, ballismus.|
|IV||No myoclonus, EEG low voltage with no periodic slow-wave complexes, vegetative state.75|
SSPE findings on EEG include high-voltage (300-1500 μV) and repetitive polyphasic sharp and slow-wave complexes of 0.5- to 2-second duration recurring every 4 to 15 seconds. Rarely, the complexes can occur at intervals of 1 to 5 minutes, with the intercomplex interval shortening as the disease progresses.
Treatment for SSPE is predominantly symptomatic. Intrathecal interferon alpha initially showed promise in a case report by inducing remission for 7 to 8 years, but this initial success was followed by a severe neurocognitive decline.76
While most cases of mumps occur in areas of the world where routine childhood vaccinations do not occur, epidemics have also been seen in vaccinated populations. In the first 10 months of 2006, there were 5783 cases of mumps reported, with a median age of 22.77 According to the CDC, 50% to 60% of cases of mumps show a CSF pleocytosis, despite encephalitis occurring in less than 2 per 100,000 cases.48 Mumps occurs more often in the spring and has a low mortality rate. Patients with mumps encephalitis present with mild, nonfocal symptoms of fever and headache. Diagnosis is made by CSF and serum serology with culture of the nasopharynx, CSF, urine, and saliva.
A postinfectious encephalomyelitis due to mumps may also occur, usually 7 to 10 days after infection. These patients exhibit more severe symptoms such as seizure, hemiparesis, and altered mental status. This variant carries a higher mortality rate of 10%.45
Nipah and Hendra viruses are both in the family Paramyxoviridae. The Nipah virus was identified in 1999 as the cause of a large outbreak of encephalitis among pig farmers in Malaysia and Singapore. The natural reservoir for Nipah virus is still under investigation, but preliminary data implicate bats of the genus Pteropus in Malaysia. In Malaysia and Singapore, humans were infected with Nipah virus through close contact with infected pigs. The Hendra virus, first isolated in 1994, is related but not identical to the Nipah virus. It is predominantly known to cause fatal respiratory infections in horses and humans, but a solitary case of adult encephalitis has been reported.
Expected outcomes vary significantly with the etiology of the viral encephalitis, but certain generalizations can be made. Young infants usually have more severe disease and therefore more significant sequelae. One study examining the prognostic indicators in 462 cases of pediatric encephalitis (including HSV, VZV, enterovirus, respiratory virus, measles, mumps, rubella, and M.pneumoniae etiologies) found mortality five times greater in infants compared to older children, and found that patients with significantly altered mental status had 4 times the risk of death.79 The majority of survivors experience seizures or cognitive and focal neurological deficits, negatively affecting their quality of life. The economic impact of encephalitis is difficult to calculate, as survivors typically require intensive supportive services and, as a group, have decreased independence as adults. Overwhelmingly, the longitudinal data on outcomes in encephalitis have focused on herpes encephalitis before the advent of acyclovir. The most recent longitudinal study examined the rehabilitation of 8 patients, including 1 child, diagnosed with encephalitis from 1990 to 1997. The study focused only on the rehabilitation scores of the patients, without mention of seizure incidence, cognitive or physical impairment, or quality of life.80 Clearly more investigation into the outcomes of children with viral encephalitis is required before conclusions can be drawn regarding prognosis.