Childhood encephalitis in Canada in 2015

There are few conditions more devastating than severe encephalitis, in which a previously healthy child progresses, within days, from a nonspecific and apparently benign febrile illness to coma, seizure and irreversible brain injury. The current article focuses on key aspects of the etiology and management of acute and subacute childhood encephalitis beyond the neonatal period in the Canadian context. Several recent publications provide comprehensive reviews on the diagnostic approach to suspected encephalitis in both children and adults (1,2). Strictly speaking, a diagnosis of encephalitis requires proof of brain inflammation. However, in practice, the diagnosis is usually a clinical one, based on the presence of symptoms and signs including fever, headache, seizure or altered consciousness, and indirect evidence of brain inflammation such as cerebrospinal fluid (CSF) pleocytosis, elevated CSF protein level or suggestive neuroimaging abnormalities. Reduced consciousness – the hallmark of encephalopathy – is present in most cases of encephalitis, but can also be observed with other infections, such as bacterial meningitis, sepsis or malaria, and with numerous noninfectious disorders including metabolic, immunological, toxic and drug-related conditions. A case definition for encephalitis has been proposed both as an aid to diagnosis and to enable future research studies to be more comparable with one another (Table 1) (1). The incidence of encephalitis in developed countries ranges from 0.7 to 13.8 per 100,000 population (3). In a United Kingdom study, incidence rates varied from 1.5 per 100,000 overall to 2.8 per 100,000 for children and 8.7 per 100,000 for infants (4). The incidence of encephalitis due to specific pathogens is dynamic, influenced by a variety of factors including vaccination rates for diseases such as measles, mumps and varicella; geographical spread of vector-borne pathogens due to climate change or inadvertent air/ship transport, as occurred with the introduction of West Nile virus into North America; and the emergence of previously unknown zoonotic pathogens (eg, Nipah virus). Pathogenesis varies according to etiology. Classic viral encephalitis due to herpes simplex virus (HSV), enteroviruses and arboviruses is caused by direct infection of the central nervous system (CNS) and necrosis of neurons or other cells. Measles, mumps and Mycoplasma pneumoniae can cause both acute encephalitis due to direct invasion of the CNS and postinfectious immune-mediated encephalitis. Influenza and other respiratory virus-associated encephalitides may involve excessive production of proinflammatory cytokines, mitochondrial dysregulation or endothelial dysfunction (3). Acute disseminated encephalomyelitis (ADEM) is likely a consequence of autoimmunity, although the precise mechanisms are not fully understood. Development of antibodies directed against the N-methyl-D-aspartate receptor (NMDAR) is responsible for anti-NMDAR encephalitis. Post-HSV encephalitis ‘neurological relapse’ (typically characterized by choreoathetoid movements), in which HSV CSF polymerase chain reaction (PCR) testing is negative, has been attributed to the production of anti-NMDAR antibodies or, less frequently, anti-dopamine-2 receptor antibodies (5,6). A confirmed or probable etiology can be identified in 30% to 60% of acute childhood encephalitis cases. The most common infectious causes in otherwise healthy Canadian children are HSV, varicella zoster virus (VZV), Epstein Barr virus (EBV), M pneumoniae and influenza, adenovirus and other respiratory viruses (Table 2). Arboviruses endemic to North America and entero-/parechoviruses are important considerations during the summer and fall months (7-10), whereas influenza and other respiratory viruses are more typically observed during the winter months. M pneumoniae encephalitis can be observed year-round, with increased incidence coinciding with epidemic respiratory disease every three to seven years (11). Less commonly encountered pathogens include measles, mumps, rabies, Bartonella henselae, Baylisascaris procyonis and travel-related arboviruses, Rickettsia and free-living amoebae. ADEM and anti-NMDAR encephalitis are the predominant noninfectious causes of encephalitis in children, together accounting for approximately 15% to 25% of all encephalitis cases, respectively (3,12). A review of cases involving patients <30 years of age referred to the California Encephalitis Project suggested that the frequency of anti-NMDAR encephalitis was higher than any single viral etiology (12). The main causes of subacute encephalitis in children are shown in Table 3. In the immunocompromised host, herpes-group viruses (including HSV, VZV, EBV, cytomegalovirus and human herpes virus-6 [HHV-6]), enteroviruses and polyoma JC virus (progressive multifocal pediAtric infectious diseAses notes