Version May 2024
INTRODUCTION — Encephalitis is inflammation of the brain parenchyma, manifest by neurologic dysfunction (eg, altered mental status, behavior, or personality; motor or sensory deficits; speech or movement disorders; seizure) and evidence of central nervous system inflammation (eg, cerebrospinal fluid pleocytosis and/or findings consistent with encephalitis on neuroimaging or electroencephalogram).
The pathogenesis, epidemiology, and etiology of viral encephalitis in children and adolescents will be discussed here. The clinical manifestations, differential diagnosis, evaluation, treatment, and prevention of viral encephalitis in children and adolescents as well as viral encephalitis in adults are discussed separately. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis" and "Acute viral encephalitis in children: Treatment and prevention" and "Viral encephalitis in adults".)
TERMINOLOGY — Central nervous system (CNS) infections are described according to the site of infection:
●Encephalitis – Encephalitis is defined as inflammation of the brain parenchyma and is manifested by signs of neurologic dysfunction. Characteristic clinical features include altered mental status (decreased level of consciousness, lethargy, personality change, unusual behavior), seizures, and/or focal neurologic signs, often accompanied by fever, headache, nausea, and vomiting [1]. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Clinical features'.)
●Meningitis – Meningitis is inflammation of the meninges and is typically manifested by fever, headache, nausea, vomiting, photophobia, and stiff neck. (See "Viral meningitis in children: Clinical features and diagnosis", section on 'Clinical features'.)
●Rhombencephalitis – Rhombencephalitis, or brainstem encephalitis, is characterized by myoclonic jerks, tremor, ataxia, cranial nerve involvement, autonomic instability, respiratory abnormalities, shock, and coma.
●Myelitis – Myelitis is inflammation of the spinal cord and is characterized by weakness, paralysis, bowel and/or bladder dysfunction, and changes in tone and reflexes. (See "Disorders affecting the spinal cord", section on 'Acute viral myelitis'.)
●Radiculitis – Radiculitis is inflammation of the nerve roots and is characterized by weakness, shooting pain, dysesthesia, and diminished reflexes.
Some viruses cause less discrete manifestations CNS infection and are described with broader terms:
●Meningoencephalitis – Meningoencephalitis refers to CNS infection manifesting signs and symptoms consistent with inflammation of the meninges and brain parenchyma.
●Encephalomyelitis – Encephalomyelitis refers to CNS infection manifesting signs and symptoms consistent with inflammation of the brain parenchyma and spinal cord.
Abnormal brain function distinguishes encephalitis from meningitis. The distinction between these entities is frequently blurred due to both presenting concurrently; however, it is important to try to determine the presence of encephalitis because the likely causes may differ somewhat (table 1).
●Encephalopathy – Encephalopathy is a disruption of brain function in the absence of a direct inflammatory process in brain parenchyma (eg, caused by metabolic disturbance, hypoxia, ischemia, drugs, intoxications, organ dysfunction, systemic infection). This is discussed separately. (See "Acute toxic-metabolic encephalopathy in children" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
PATHOGENESIS — There are two main ways in which viruses cause neurologic manifestations:
●They can directly invade central nervous system (CNS), as in acute viral encephalitis. In such cases, the virus can be cultured from the brain or evidence of the virus can be found on histologic examination. Direct invasion may occur as an extension of viral meningitis, secondary to viremia, or via retrograde spread through the peripheral nerves (eg, rabies, herpes simplex virus [HSV]) [2,3].
The innate immune system and, in particular, the pattern recognition receptor, toll-like receptor 3 (TLR3), plays a key role in protecting the CNS from infection with HSV type 1. Patients with autosomal recessive and autosomal dominant TLR3 deficiency and deficiency in signaling pathways downstream of TLR3 have been found to be predisposed to HSV type 1 encephalitis [4]. (See "Herpes simplex virus type 1 encephalitis", section on 'Host susceptibility'.)
●Viruses also can trigger postinfectious encephalitis by provoking an autoimmune response (eg, anti-N-methyl-D-aspartate encephalitis, acute disseminated encephalomyelitis). In postinfectious encephalitis, a virus cannot be detected or recovered from the brain, but there is often history of illness two to four weeks prior to the onset of symptoms and signs. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)
It can be difficult to differentiate viral encephalitis from postinfectious and autoimmune encephalitis without neuroimaging and antibody testing. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Antibody testing'.)
EPIDEMIOLOGY — Reported annual incidence rates for childhood encephalitis range from 4 to 10 cases per 100,000 per year [5-12]. The incidence is highest among infants <1 year. In a study based on data from the Pediatric Health Information System database that included >7000 pediatric admissions for encephalitis during the years 2004 to 2013, the median age was nine years [13]. In this cohort, 40 percent of children were admitted to the pediatric intensive care unit and the median length of hospital stay was 16 days.
In temperate regions, seasonal variation in rates of childhood encephalitis occur [10]. This is largely driven by endemic circulation of enteroviruses and some arboviruses, which peak in the late summer to fall. (See "Arthropod-borne encephalitides" and "Enterovirus and parechovirus infections: Epidemiology and pathogenesis", section on 'Epidemiology'.)
The number of encephalitis cases declined following introduction of vaccines against poliovirus, measles, mumps, and varicella viruses. However, some regions saw increasing numbers of cases in the late 1990s to 2010s [10]. This may be partially due to increasing use of immunosuppressive therapies and to better sensitivity and greater availability of some of the diagnostic modalities used to diagnose encephalitis (eg, polymerase chain reaction tests and magnetic resonance imaging).
ETIOLOGY
Overview — Among infectious causes of encephalitis, viruses are the most frequently identified etiology [14]. Bacteria, fungi, and parasites also cause encephalitis but less commonly than viruses (table 2). In many cases of encephalitis, the etiology remains unknown, despite extensive diagnostic testing [14-17].
In a prospective multicenter study of 526 children ≤14 years old who underwent evaluation for suspected encephalitis from 2013 to 2016, 55 percent of cases met criteria for the diagnosis of acute encephalitis [18]. Of these cases, 57 percent were due to confirmed or probable infectious causes, 25 percent were immune mediated (ie, acute disseminated encephalomyelitis or autoimmune encephalitis), and 17 percent were due to unknown causes. Among infectious encephalitis, the leading causes were enteroviruses (10 percent), parechovirus (10 percent), influenza (6 percent), herpes simplex virus (HSV; 6 percent), and Mycoplasma pneumoniae (6 percent). In the patients who did not meet diagnostic criteria for acute encephalitis, other diagnoses included bacterial or viral meningitis, tuberculous meningitis, disseminated neonatal HSV, acute cerebellar ataxia, stroke, structural brain disease, epilepsy, genetic/metabolic disorders, Guillain-Barré syndrome, psychiatric disorders, medication side effect/overdose, and other miscellaneous forms of encephalopathy.
In other prospective series of pediatric encephalitis, confirmed or probable infectious etiologies were identified in approximately 40 to 60 percent of cases and possible infectious etiologies in approximately 25 percent [8,16,17,19].
Viral pathogens — A wide variety of viruses can cause encephalitis (table 2). Among those most commonly isolated are enteroviruses (eg, echoviruses, coxsackieviruses A and B, and the numbered enteroviruses), parechoviruses, HSV type 1 and 2, other Herpesviridae (eg, Epstein-Barr virus [EBV], varicella-zoster virus, cytomegalovirus, human herpesvirus 6), influenza, and arboviruses (eg, La Crosse virus, West Nile virus [WNV], and other arboviruses).
Less common viral causes of encephalitis include Nipah virus, rabies virus, and Japanese encephalitis virus, depending on geographic locale (table 3). (See "Nipah, Hendra, and other henipaviruses" and "Clinical manifestations and diagnosis of rabies".)
Enteroviruses and parechoviruses — Nonpolio enteroviruses (eg, echoviruses, coxsackieviruses A and B, and the numbered enteroviruses) and human parechoviruses (particularly type A3) are a major cause of encephalitis in children, accounting for 10 to 20 percent of cases in published series [8,16,20,21]. Enteroviruses have a clear seasonality, with 78 percent of cases in the United States occurring from June through October [22]. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis".)
Herpes simplex virus — Approximately 5 percent of cases of childhood encephalitis are caused by HSV [21,23]. Clinical features of HSV encephalitis include [23]:
●Cerebrospinal fluid (CSF) pleocytosis (94 percent)
●Elevated CSF protein (50 percent)
●Electroencephalographic changes (94 percent)
●Imaging abnormalities (88 percent)
HSV type 1 encephalitis occurs in all age groups [24]. It is the most common confirmed cause of sporadic fatal encephalitis [25], with an incidence of approximately 2.2 cases per 1 million population per year [25,26].
HSV type 2 is the predominant cause of neonatal HSV infection, although this varies geographically. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)
Other herpesviruses — In addition to HSV types 1 and 2, other herpesviruses are common causes of encephalitis in children. These include:
●EBV – In a prospective registry of 216 cases of childhood encephalitis from a single institution (1994 to 2003), EBV was identified as the cause in 6 percent [27]. In other pediatric series, EBV was reported in only 2 to 3 percent of patients [8,16,17,21]. Encephalitis caused by EBV most commonly presents with neurologic manifestations; it does not typically follow an infectious mononucleosis-like illness. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)
●Cytomegalovirus. (See "Overview of cytomegalovirus infections in children".)
●Human herpesvirus 6, particularly in immunocompromised children. (See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment".)
●Varicella-zoster virus – Varicella-zoster virus was previously a relatively common cause of childhood encephalitis, but it has declined considerably with routine vaccination [7]. (See "Clinical features of varicella-zoster virus infection: Chickenpox", section on 'Encephalitis'.)
Arboviruses
●La Crosse encephalitis – Among the arboviruses, La Crosse virus is the most common cause of central nervous system (CNS) infection in children in North America. La Crosse encephalitis virus has been reported in more than one-half of states. La Crosse virus has a clear seasonal occurrence (July through September).
La Crosse encephalitis is most common in children five to nine years old [28,29]. It usually presents with mild meningoencephalitis, but subsequent neurologic deterioration may occur. Approximately 50 percent of children present with seizures. The electroencephalogram may show focal activity. (See "Arthropod-borne encephalitides", section on 'La Crosse encephalitis virus'.)
●WNV – WNV, mainly transmitted by mosquito bites, is found across the United States. WNV CNS disease occurs in <1 percent of infected persons, mainly adults [30-32]. WNV encephalitis occurs in children but is rare. (See "Epidemiology and pathogenesis of West Nile virus infection" and "Clinical manifestations and diagnosis of West Nile virus infection".)
●Other arboviruses – Other arboviral causes of encephalitis must be considered in specific geographic locations (eg, Colorado tick fever virus in the western United States and Japanese encephalitis virus in Asia) (table 4). (See "Arthropod-borne encephalitides".)
Influenza virus — Influenza virus is a recognized cause of viral encephalitis [33,34]. In a prospective registry of 311 cases of childhood encephalitis from a single institution (1994 to 2005), influenza was identified as the etiology in approximately 5 percent (the same proportion as HSV) [33,34]. The majority of cases occur in children <5 years old. The pathogenesis of influenza-associated CNS disease in unknown. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Central nervous system'.)
Other viruses — Respiratory viruses and other viruses are identified in approximately 5 percent of childhood encephalitis cases [8,16,21,35-37].
●Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children")
●Human metapneumovirus (see "Human metapneumovirus infections")
●Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")
●Parainfluenza virus (see "Parainfluenza viruses in children")
●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see "COVID-19: Clinical manifestations and diagnosis in children")
●Parvovirus B19 (see "Clinical manifestations and diagnosis of parvovirus B19 infection")
●Measles, mumps, and rubella – Measles, mumps, and rubella encephalitis are rare in countries that vaccinate against these diseases [24] (see "Measles, mumps, and rubella immunization in infants, children, and adolescents")
Nonviral pathogens — Important nonviral pathogens in childhood encephalitis that are discussed in detail separately include (table 2):
●M. pneumonia (see "Mycoplasma pneumoniae infection in children")
●Chlamydia (Chlamydophila) pneumonia
●Borrelia burgdorferi (Lyme disease) (see "Lyme disease: Clinical manifestations in children", section on 'Neurologic manifestations' and "Nervous system Lyme disease", section on 'Lyme encephalomyelitis')
●Bartonella henselae (cat scratch disease) (see "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease")
●Listeria monocytogenes (see "Clinical manifestations and diagnosis of Listeria monocytogenes infection", section on 'Central nervous system infection')
●Mycobacterium tuberculosis (see "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis" and "Central nervous system tuberculosis: An overview")
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Basics topics (see "Patient education: Encephalitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Encephalitis is inflammation of the brain parenchyma, manifest by neurologic dysfunction (eg, altered mental status, behavior, or personality; motor or sensory deficits; speech or movement disorders; seizure) and evidence of central nervous system inflammation (eg, cerebrospinal fluid pleocytosis and/or findings consistent with encephalitis on neuroimaging or electroencephalogram). (See 'Terminology' above.)
Encephalitis may occur due to an acute viral infection or as a postinfectious complication. (See 'Pathogenesis' above.)
●Incidence – Reported annual incidence rates for childhood encephalitis range from 4 to 10 cases per 100,000 per year. The incidence is highest among infants <1 year old. (See 'Epidemiology' above.)
●Etiology – In many cases of encephalitis, the etiology remains unknown despite extensive evaluation. Viruses are the most commonly identified infectious causes of encephalitis. The most frequently isolated viral pathogens include (table 2) (see 'Viral pathogens' above):
•Enteroviruses (eg, echoviruses, coxsackieviruses A and B, and the numbered enteroviruses) (see 'Enteroviruses and parechoviruses' above)
•Parechoviruses (see 'Enteroviruses and parechoviruses' above)
•Herpes simplex virus (HSV) type 1 and 2 (see 'Herpes simplex virus' above)
•Other Herpesviridae (eg, Epstein-Barr virus [EBV], varicella-zoster virus, cytomegalovirus, human herpesvirus 6) (see 'Other herpesviruses' above)
•Influenza (see 'Influenza virus' above)
•Arboviruses (eg, La Crosse virus, West Nile virus [WNV], and other arboviruses) (see 'Arboviruses' above)
Other infectious causes include bacteria, fungi, and parasites (table 2). (See 'Nonviral pathogens' above.)
The list of potential infectious pathogens may be narrowed according to clinical clues (table 1), location (or travel history) (table 3), and exposure to arthropod vectors (table 4). (See 'Etiology' above and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Krogstad, MD, who contributed to earlier versions of this topic review.
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