Symposium: infection (& immunity)Central nervous system herpesvirus infections
Introduction
The herpesviridae family of DNA viruses includes eight distinct viruses within three sub-families (Table 1). Herpesviridae are characterized by high rates of primary infection that are often asymptomatic or produce only mild symptoms, but with the potential for severe disease. They establish long-term latency in the host, characterized by persistence of viral genome with limited gene expression, and can reactivate to produce infectious virus in response to a variety of triggers including immunosuppression, causing subclinical infection or recurrent disease. Save for human herpesvirus 8 (HHV-8 or Kaposi's sarcoma-associated herpesvirus) all the herpesviruses cause central nervous system (CNS) disease in children, with a wide variety of clinical syndromes (Table 1).
Section snippets
Herpes simplex virus (HSV)
HSV-1 and HSV-2 primarily infect muco-epithelial cells and establish latency within ganglia of sensory neurons. They are transmitted by close contact with mucous membrane secretions. Two forms of CNS disease predominate in the young; sporadic encephalitis that is primarily caused by HSV-1 in older infants and children and encephalitis associated with neonatal HSV infection that can be caused by either HSV serotype.
Sporadic HSV encephalitis (HSE)
Herpes simplex encephalitis (HSE) is the most common worldwide cause of sporadic viral encephalitis with an incidence of 1–4 per million population per year. It occurs in a bimodal distribution with peaks between 6 months and 20 years age and the highest incidence over 50 years. In most encephalitis studies, including a recent large prospective study in the United Kingdom, HSV is the most common infectious cause of encephalitis (approximately 20%). Approximately a third of cases occur in the
Neonatal HSV CNS disease
Neonatal HSV infection is uncommon, occurring in up to 1 in 10,000 to 1 in 60,000 live births in the UK, and Australia. Disease is categorized as either ‘skin, eye, mouth’ disease (SEM), meningo-encephalitis alone or disseminated infection, with or without CNS disease. In the United States most neonatal HSV disease is caused by HSV-2, however elsewhere in the world including the UK, Australia and Canada, HSV-1 is the dominant serotype. This is consistent with recent studies showing an increased
Varicella-Zoster virus (VZV)
VZV is the cause of varicella (chicken-pox) with primary infection and herpes zoster (shingles) after reactivation. Primary VZV is transmitted by respiratory droplets as it infects muco-epithelial cells of the upper airway before causing disseminated infection. Latent VZV DNA can be found within sensory and autonomic ganglia. Shingles occurs from VZV reactivation and transport to a dermatome innervated by the related sensory neurons. VZV is associated with protean neurological manifestations
Epstein–Barr virus (EBV)
EBV is characterized by infection of and replication within lymphoid tissues and latency within memory B cells. It is primarily transmitted by close contact with mucous membrane secretions, but infection can also be acquired through blood transfusion and tissue transplantation. Up to three quarters of adults in industrialized countries are seropositive for EBV. Symptomatic primary EBV infection most commonly presents with infectious mononucleosis (IM or ‘glandular fever) in adolescence.
Cytomegalovirus (CMV)
CMV is a ubiquitous herpesvirus with wide cell tropism that establishes latency within macrophages and monocytes. It is transmitted by close contact with mucous membrane secretions, urine and breast milk and like EBV can also be transmitted through blood transfusion and tissue transplantation. Up to 40% of adolescents and 90% of adults in industrialized countries are CMV seropositive with highest prevalence in lower socioeconomic groups.
HHV-6
HHV-6 has two distinct variants; HHV-6A and HHV-6B. HHV-6A is not clearly associated with disease. HHV-6B is ubiquitous with almost all children seropositive by the age of three years. It is transmitted by close contact with oral secretions and has wide cell tropism. HHV-6 establishes latency in monocytes, macrophages and within multiple cell types of the CNS. Primary infection with HHV-6B in infants causes a non-specific febrile illness or most commonly exanthem subitum (roseola or 6th
HHV-7
HHV-7 is structurally similar to HHV-6. It is also considered ubiquitous with most children seropositive by the age of five, is transmitted by close contact with oral secretions and has a wide cell tropism. Its antigenic similarity is such that it can cause serologic cross-reactivity. Like HHV-6 it causes a non-specific febrile illness or exanthem subitum, though the latter less frequently. Primary infection has been associated with febrile seizures and encephalopathy, but this entity remains
Conclusions
Collectively, the herpesviridae family are important causes CNS disease in children, although individual syndromes (with the exception of cCMV) are rare. Key practice points are summarised in Table 2. The propensity of these viruses to establish lifelong latency and periodically reactivate makes confirmation of causative role difficult in many settings. Our understanding is most advanced for CNS HSV and VZV disease, where there are clear causal associations with each virus and CNS syndromes.
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