History

Rabies encephalitis was recognized in ancient times in Europe and Asia. In ad 100, Celsus noted the relationship of animal rabies to human disease. “Sleeping sickness” associated with epidemic influenza was noted early in the 18th century. For the past 100 years, epizootics of encephalitis in equine animals have been observed in the United States, and, in 1933, St. Louis encephalitis virus was isolated from the brains of humans dying of epidemic encephalitis. Meningoencephalitis was recognized at the beginning of the 20th century as a complication of mumps. Nonpolio enteroviruses have been known for the past 60 years to be a cause of encephalitis; during the same period, more than 400 zoonotic arthropod-borne viruses have been discovered. Of these, 100 or more cause encephalitis in humans. In countries where vaccines are widely available there has been a decline in vaccine-preventable neurologic complications from measles, mumps, and rubella. However, there has been a continually expanding list of emerging or reemerging pathogens, including Balamuthia mandrillaris, Baylisascaris procyonis, human parechoviruses, Nipah virus, Chandipura virus, and Zika virus. Moreover, there has been expansion of certain agents into geographic regions. West Nile virus, for instance, has expanded its geographic range from Africa to North and South America, Europe, the Middle East, western Asia, and Australia. Japanese encephalitis virus has spread into India, Nepal, and northern Australia. Chikungunya is the most recent example of a striking geographic virus expansion, with outbreaks in the Indian Ocean and subsequent spread to India and Europe, and then to the Caribbean, Central, and South and North America. Simultaneously the neurologic complications from Chikungunya appear to be increasing as well.

Etiology

The many causes of encephalitis include both infectious and noninfectious entities. The infectious causes include viruses, bacteria, fungi, and parasites. Etiologic agents of acute encephalitis, meningoencephalitis, or illnesses that clinically resemble encephalopathy are listed in Table 36.1 . Many of the infectious agents or diseases are discussed more fully and are referenced more completely elsewhere in this book.

Despite extensive testing and evaluation, the causes of many cases of encephalitis remain unexplained in recent prospective studies. During the first 7 years of the California Encephalitis Project, 1570 patients were identified who met the case definition of having encephalitis (immunocompetent patients older than 6 months of age hospitalized with at least 24 hours of encephalopathy and one or more of the following characteristics: fever, seizure, focal neurologic findings, or electroencephalographic [EEG] or neuroimaging findings consistent with encephalitis). A confirmed or probable agent was identified in only 251 (16%) cases; of these agents, 69% were viral, 20% were bacterial, 3% were prion, 3% were parasitic, and 1% were fungal. An additional 13% had a possible cause identified, and a noninfectious cause was identified in 8% of cases. In 2007 the California Encephalitis Project (CEP) began to test for anti– N -methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a recently identified noninfectious cause of encephalitis. Within the CEP cohort, cases of anti-NMDAR encephalitis were identified more frequently than any viral etiology, including herpes simplex virus type 1, West Nile virus, and varicella zoster virus. Overall the Centers for Disease Control and Prevention Emerging Infections Program Encephalitis Project, which represents the largest cohort of patients with encephalitis studied to date (>5000), has identified a confirmed or probable cause of encephalitis in approximately one-third of cases studied. Similar percentages of “unknown” causes have been seen in studies across the globe, such as in Australia from 1990 to 2007, with 69.8% unknown, and in England from 1989 to 1998, with 60% unknown.

Epidemiology

Because of the diversity of the infectious disease agents causing encephalitis, the incidence, geographic distribution, age distribution, and seasonality vary tremendously. The specific epidemiology of each infectious agent or disease is presented in detail in the respective chapters of this book; only a brief overview is presented here.

Accurate information on the overall incidence of encephalitis is lacking owing to the vast number of agents and the imprecise case definition. Nevertheless incidence rates for encephalitis range from 1.5 to 8.8 per 100,000 population. In the United States, a study of hospital discharge data from 1988 through 1997 determined a rate of 7.3 encephalitis hospitalizations per 100,000. The incidence of ADEM (a form of postinfectious encephalitis) is estimated to account for 10% to 15% of encephalitis overall, with specific ADEM incidence numbers estimated to be 0.4 to 0.8 per 100,000.

Although encephalitis per se does not appear to follow a seasonal pattern, specific pathogens, particularly arthropod-borne viruses, do have well-defined temporal patterns. Encephalitis caused by arboviruses can sometimes occur in localized outbreaks, and epidemics or sporadic cases may be seen. In temperate areas, most cases occur in summer and fall. The occurrence of human infection and disease is influenced by the abundance of mosquito vectors and natural reservoir in animals. Although enteroviral disease, including aseptic meningitis, occurs in epidemics, severe encephalitis caused by these agents usually is a sporadic event. Influenza-associated encephalopathy has been described sporadically, but, when it occurs, it follows a seasonal pattern with illnesses occurring primarily during the winter months in temperate climates. Sporadic cases of encephalitis occur in any season. Epidemiologic considerations that must be reviewed in a search for the causative agent include geographic area; climatic conditions; animal, water, food, soil, and personal exposures; and host factors.

For most viral agents, the incubation periods range from a few days to a few weeks. Rabies is an important exception to this. Although the incubation for rabies is typically 20 to 60 days, it can be up to 7 years. Additionally, measles, which can cause an acute form of encephalitis, also can cause an indolent, slowly progressive form of encephalitis, termed subacute sclerosing panencephalitis, that can manifest years after the original infection.

Pathogenesis

Because encephalitis has multiple causes, the lack of a unified pathogenesis is not surprising. *

* References .

In many viral encephalitides, such as those caused by arboviruses, mumps, and enteroviruses, the CNS infection occurs after a primary viral infection elsewhere in the body. Generally the infectious agents, whether from ingestion, as in enteroviral infections, or from the bite of a mosquito, as in an arboviral infection, enter the lymphatic system. In the lymphatics, viral multiplication occurs, which results in seeding of the bloodstream and infection of other organs in the body. Viral multiplication occurs at these secondary infection sites; extensive secondary viremia occurs, and then the CNS becomes infected. The reason certain viruses are more “neurotropic” than others is not well known. One hypothesis is that the small size of arboviruses allows them to escape clearance of the reticuloendothelial system. Arboviruses may enter the CNS via the cerebral capillaries with vascular endothelial cell infection. Indeed, recent studies have found that hypertension and diabetes are risk factors for the development of West Nile virus neuroinvasive disease. Actual involvement of nervous tissue may result from growth across or passive diffusion through brain capillaries or centripetal axonal transport of virus from the olfactory neuroepithelium to the olfactory bulb.

Infection of the brain also may occur through the peripheral nerves. This retrograde spread of virus is important in encephalitis caused by herpes simplex virus, poliovirus, and rabies virus. In the case of rabies, after the virus is introduced through the skin, usually via a bite, the rabies virus replicates in skeletal muscle and travels to the CNS via the peripheral nerves. Rabies is unique among viral diseases with respect to incubation period. In some cases of prolonged incubation periods the virus likely remains close to the viral entry site. Once the virus has spread to the brain via peripheral nerves, rabies virus disseminates throughout the CNS. Another mechanism organisms use to gain entry to the CNS is exemplified by free-living amoebae such as N. fowleri ; these organisms enter transnasally, pass through the cribriform plate, and invade the frontal lobes of the brain.

Postinfectious or parainfectious encephalitis is an acute demyelinating disease of the brain in which the findings suggest an autoimmune process. Usually little evidence of an active infectious process is present when symptoms occur. Viral or other agents probably invaded the CNS initially and then were cleared but were a trigger for the subsequent development of disease. An immune (T-cell) response to myelin basic protein occurs.

Pathology

The classic findings in viral encephalitis include perivascular mononuclear cell inflammation, neuronal destruction, neuronophagia, and microglial nodules, with most of the abnormalities seen in the gray matter of the brain. Tissue sections of the brain generally reveal meningeal congestion and mononuclear infiltration, perivascular cuffs of lymphocytes and plasma cells, some perivascular tissue necrosis with myelin breakdown, neuronal disruption in various stages (including ultimately neuronophagia), and endothelial proliferation or necrosis. The severity and the extent of observed lesions vary with the infectious agent and with the degree of reaction of the host. The cerebral cortex, especially the temporal lobe, often is affected severely by herpes simplex virus, and arboviruses tend to affect the entire brain. Intranuclear inclusions are suggestive of a member of the Herpesviridae. Rabies has a predilection for the basal structures; involvement of the spinal cord, nerve roots, and peripheral nerves varies. Negri bodies, if identified, are pathognomonic for rabies. Although rabies has one of the highest fatality rates of any infectious disease, brain tissue shows relatively benign neuropathologic changes without evidence of neuronal death. In contrast, Naegleria causes marked hemorrhagic necrosis, especially in the olfactory bulbs and cerebral cortex. The pathologic process seen in patients with herpes simplex encephalitis is also characterized by a hemorrhagic necrosis but in different locations (i.e., the temporal and frontal lobes).

In contrast to acute viral encephalitis where gray matter is predominantly affected, the white matter is most affected in postinfectious encephalitis. A marked degree of demyelination with preservation of neurons and their axons is considered to be predominantly postinfectious or parainfectious (autoimmune) encephalitis.

Finally some infectious agents such as Mycobacterium tuberculosis and fungi can cause encephalitis-like symptoms without parenchymal involvement. For example, tuberculosis can lead to hydrocephalus and cranial nerve palsies. Other agents, such as varicella-zoster virus and coccidioidomycosis, can cause vasculitis resulting in infarctions in the brain with resultant focal neurologic deficits mimicking encephalitis.

Clinical Manifestations

The clinical findings in encephalitis are determined by the severity of involvement and anatomic localization of the affected portions of the nervous system, the inherent pathogenicity of the offending agent, and the immune and other reactive mechanisms of the patient (“host factors”). Evidence of brain parenchymal involvement is the hallmark of encephalitis. Children with encephalitis may show evidence of diffuse disease, such as behavioral or personality changes; decreased consciousness; and generalized seizures or localized changes, such as focal seizures, hemiparesis, movement disorders, cranial nerve defects, and ataxia. Some children may seem to be mildly affected initially only to lapse into coma and sudden death. In others, the illness is ushered in by high fever, violent convulsions interspersed with bizarre movements, and hallucinations alternating with brief periods of clarity, and the children emerge with relatively few sequelae.

Specific forms of encephalitis or complicating manifestations of encephalitis include Guillain-Barré syndrome and related syndromes, acute transverse myelitis, acute hemiplegia, brainstem encephalitis, and acute cerebellar ataxia. Acute cerebellar ataxia is characterized by an abrupt onset of truncal ataxia resulting in varying degrees of gait disturbance and balance abnormalities. Children with this illness have tremulousness of the head and trunk when in the upright position and of the extremities when attempting to move them against gravity. The duration of illness varies from 3 to 4 days to several weeks. Acute cerebellar ataxia often follows chickenpox or other viral illnesses. In one study, 3% were related to immunization. Approximately 90% of patients recovered completely from the ataxia, but 20% had transient behavioral or intellectual disturbances. Five percent had persistent learning problems.

Most commonly, the initial manifestations resemble an undifferentiated acute systemic illness with fever, headache, or, in infants, screaming spells, abdominal distress, nausea, and vomiting. Signs of an associated mild nasopharyngitis may suggest a respiratory tract infection. As the temperature increases, new findings direct attention to the nervous system: mental dullness eventuating in stupor; bizarre movements; convulsions; nuchal rigidity, often not as pronounced as in purely meningitic illness; and focal neurologic signs, which may be stationary, progress, or fluctuate. Loss of bowel and bladder control and unprovoked emotional outbursts may occur.

A wide range of severity of clinical manifestations exists even with the same etiologic agent. Nevertheless some organisms show tropism for a specific area of the brain and consequently specific clinical characteristics are appreciated. Arboviruses often can cause diffuse brain involvement with global impairment, whereas herpes simplex virus type 1 almost universally involves the temporal lobe. The classic features of herpes simplex encephalitis include fever, altered level of consciousness, dysphagia, focal motor seizures, and hemiparesis; almost all adults with this disease exhibit these features. Children, however, may have atypical features and can have extratemporal lobe involvement. One study identified up to one-fourth of children with atypical features, such as ataxia, decreased visual acuity, or tonic-clonic seizures. Primary varicella infection is often associated with cerebellar inflammation, and patients present with ataxia and nystagmus and may or may not have cognitive impairment. Individuals with Epstein-Barr virus encephalitis can sometimes have micropsia, macropsia, and/or size distortion, called “Alice in Wonderland” syndrome. The occurrence of seizures is variable depending on the pathogen. In Bartonella encephalopathy, generalized seizures are common, whereas they are unusual in West Nile virus infection. Individuals with rabies often have rapidly progressive encephalitis. Paresthesia at or near the bite site is unique to rabies. Most (approximately 80%) patients with rabies have the “furious” form, characterized by agitation, hydrophobia, delirium, and seizures. Patients with the “paralytic” form (approximately 20%) have ascending paralysis, followed by confusion and coma. Although these two forms are described, it is not unusual for patients to have features of both.

Brainstem encephalitis is a rare disorder, but it is important because clinical signs appear similar to those of a brainstem glioma. The differentiation is important because treatment is radically different. The differentiation is made by the time of onset of symptoms and by the course. Brainstem glioma usually has slowly progressive symptoms developing over the course of several weeks or months. Brainstem encephalitis evolves over 1 to 7 days. Both disorders may be associated with radiographic evidence of brainstem enlargement. Brainstem encephalitis resolves after 1 to 4 weeks, whereas a tumor continues to progress until radiation therapy is given.

Most cases of brainstem encephalitis seem to be postinfectious and are similar to postinfectious cerebellar ataxia, Miller-Fisher syndrome, or Guillain-Barré syndrome. The conditions often overlap. In postinfectious cases, the onset of brainstem encephalitis begins 1 to 3 weeks after a nonspecific viral infection. Brainstem encephalitis has been reported to occur, however, as a result of specific, identifiable, and some treatable infectious agents, including herpes simplex virus, varicella zoster virus, cytomegalovirus, enterovirus 71, West Nile virus, M. pneumoniae, L. monocytogenes, Propionibacterium acnes, and Campylobacter jejuni.

Some patients with a typical clinical picture of brainstem encephalitis have had anti-GQ1b antibodies in the serum, which may represent a subgroup of postinfectious brainstem encephalitis cases. Brainstem encephalitis may arise in HIV-infected patients and may be due to a treatable cause, such as herpes simplex encephalitis. In an enterovirus outbreak in Taiwan, the most common neurologic complication was rhombencephalitis, and a 14% mortality rate was reported.

Patients with noninfectious anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis typically display psychiatric symptoms, seizures, cognitive dysfunction, orofacial dyskinesias, and autonomic instability. Notably, the behavioral characteristics of a patient with anti-NMDAR encephalitis may resemble that of rabies. Patients with autoimmune limbic encephalitis also present with psychiatric symptoms and seizures in addition to rapidly progressive short-term memory deficits.

Differential Diagnosis

The evaluation of a patient with an acute CNS illness (encephalopathy) must be considered carefully, and the sequence of tests should be dictated by the specific circumstances of the individual patient. Several disease processes may have presentations similar to infectious causes.

The differential diagnosis of acute encephalopathy includes the following:

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  Anti-NMDAR encephalitis has recently been found to be one of the leading causes of noninfectious encephalitis in children

  
  
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  Acute demyelinating disorders, including ADEM, acute multiple sclerosis, and acute hemorrhagic leukoencephalitis

  
  
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  Other postinfectious diseases, including Guillain-Barré syndrome (including Miller-Fisher variant), brainstem encephalitis, and acute cerebellar ataxia

  
  
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  Status epilepticus, especially nonconvulsive status epilepticus, such as complex-partial status or absence status

  
  
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  Metabolic diseases, such as hypoglycemia, uremic encephalopathy, hepatic encephalopathy, and rare genetic inborn errors of metabolism, including disorders of glucose or ammonia metabolism

  
  
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  Toxic disorders, such as drug ingestion or Reye syndrome

  
  
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  Mass lesions, such as tumor or abscess

  
  
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  Subarachnoid hemorrhage from arteriovenous malformation or aneurysm

  
  
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  Embolic lesions caused by bacterial endocarditis

  
  
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  Acute confusional migraine

Evaluation of a Patient With Encephalopathy or Possible Encephalitis

Although many cases of encephalitis remain without a cause, and many of the causes are not treatable per se, a thorough diagnostic evaluation is important. For example, the identification of a specific cause may be helpful for prognosis, lead to the discontinuation of unnecessary antimicrobial therapy, and be useful for potential prophylaxis of contacts and initiation of public health interventions. Obtaining a careful history and performing a physical and neurologic examination are essential in all patients who have a history consistent with encephalitis. The differential diagnosis previously presented indicates that encephalitis is only one of many disorders that can manifest as an acute or subacute picture of encephalopathy. Although the diagnosis of encephalitis may be determined best with a lumbar puncture and evaluation of the CSF, lumbar puncture may be contraindicated in some disorders and, if performed inappropriately, may lead to serious complications and even death. A child who has a cerebellar tumor with acute obstruction of the fourth ventricle may have a decreasing level of consciousness caused by the rapidly increasing intracranial pressure. Nuchal rigidity may be present. The family may not have recognized the more subtle changes in cerebellar functions for the months before the acute obstruction developed and may give a history of acute encephalopathy. In that case, a lumbar puncture could result in herniation through the foramen magnum. It is essential that the patient be assessed for the possibility of increased intracranial pressure and the potential for herniation.

The patient’s history should be reviewed carefully, questioning specifically for symptoms of neurologic problems that manifested in the days or weeks before the acute disorder occurred. The physical examination must be performed with special attention given to focal neurologic abnormalities, cerebellar signs, and evidence of increased intracranial pressure. Conducting a careful funduscopic examination is important but may be impossible in an agitated patient or young child. The presence of papilledema indicates that neuroimaging should be performed before doing the lumbar puncture. If spontaneous venous pulsations are noted on funduscopic examination, intracranial pressure is not increased and the lumbar puncture can be done without imaging.

In addition to a lumbar puncture, neuroimaging and obtaining an EEG can help in determining the cause of the encephalopathy and the most appropriate course of therapy. Results of the history and physical examination provide a guide to the most appropriate first test to perform, but generally neuroimaging is the most likely to be helpful. The exception would be a child in nonconvulsive status epilepticus. The history may suggest encephalitis as the most likely diagnosis, but, in some patients, nonconvulsive status epilepticus may be clinically indistinguishable from encephalitis.

Diagnosis

A meticulous history is essential, including exposure in the previous 3 to 4 weeks of illness onset; sick contacts; exposure to mosquitoes, ticks, and animals; recent vacations or picnics or other outdoor activities; awareness of illness in animals in the patient’s environment; recent travel from the home area; recent injections of any kind; and the possibility of accidental exposure to heavy metals, pesticides, or other questionable substances. The CSF must be examined carefully to exclude other disorders that respond to specific therapy. Smears for bacteria, appropriate rapid antigen-identification tests, and cultures of the CSF are mandatory; the history and clinical findings may indicate the need for acid-fast stain and culture of the sediment for mycobacteria. Although often not done because of inconvenience, opening CSF pressures should be measured. Molecular testing has advanced the diagnostics for encephalitis overall, but there are a number of important limitations of molecular diagnostics (both false-positive and false-negative findings). In particular, it is important to understand that a positive polymerase chain reaction (PCR) test in the CSF does not necessarily equate with disease and vice versa. Additionally, there is still a very important role for culture and serologic assays for the diagnosis of encephalitis. Recommended test types and “pitfalls” in testing are outlined in Table 36.1 . A diagnostic algorithm is presented in Box 36.2 .

Box 36.2

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