Review article
The spectrum of herpes simplex encephalitis in children

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Abstract

Clinical and basic science research carried out in recent years into herpes simplex encephalitis (HSE) have shown that the concept of a “classical” picture of HSE in children is now outdated and that our current knowledge of the disease is probably only the tip of an iceberg. Indeed, increasing evidence supports the existence of a wider range of pathophysiological mechanisms, clinical presentations and disease progressions in paediatric HSE. This paper reviews the clinical, biological and radiological data available and redefines the spectrum of HSE in children. Full understanding of the condition should improve the management of suspected cases and decrease the morbidity and the mortality associated with this disease.

Introduction

Herpes simplex encephalitis (HSE) is an infectious disease of the central nervous system (CNS) for which there is a race against the clock to provide early treatment. Indeed, the early administration of acyclovir is the only way in which the prognosis of HSE can be improved. Without treatment, HSE has a spontaneous mortality rate of 70%.1, 2 It is therefore of major importance to consider the diagnosis of HSE as early as possible.

Since the era of herpes simplex virus (HSV) DNA detection using polymerase chain reaction (PCR), studies have shown increasing evidence for the existence of a wider range of clinical presentations and disease progression in HSE in children than previously appreciated.3, 4, 5, 6, 7, 8, 9, 10, 11 Such “non-classical” clinical presentations and disease progression in children may lead to substantial delay in acyclovir administration with major consequences for outcome.

This review paper describes current knowledge of HSE in children and redefines its whole spectrum. A better knowledge of the pathophysiological mechanisms involved, the atypical initial presentations and the variations in disease progression should improve the management of suspected cases and therefore decrease the morbidity and the mortality associated with this disease.

Section snippets

Methodology

Published articles relating to HSE were identified by a search of PubMed (1965–June 2007) for articles containing the following keywords: HSV, HSE, HSV encephalitis, HSE in children and HSE relapse. Only articles published in English or French were used. Studies performed in adults, neonates or animals were only included if they provided relevant information for the purpose of this article. The references in the selected papers were also included. Articles in which the clinical details were

Epidemiology

HSE is the most common cause of sporadic encephalitis in western countries.2 Its estimated incidence in the general population is 1–4 cases per million inhabitants per year.2, 12 Large clinical series of HSE including children and adults describe a bimodal age distribution with approximately one third of the cases in the paediatric population (mainly between 6 months and 3 years of age) and one half in patients over 50 years of age.6, 11, 12, 13 HSE occur at any time of the year and there is no

Clinical presentation

The clinical hallmark of HSE is an acute encephalitic process characterised by fever, altered level of consciousness, behavioural disturbance and/or focal neurological symptoms and signs such as seizures or motor deficits.12, 13, 18, 19, 20 Meningeal signs such as neck stiffness, headache, vomiting and/or photophobia are also encountered.12, 13, 19

Atypical neurological presentations, subacute or milder forms of HSE have, however, been repeatedly reported in children.4, 5, 6, 9, 10, 15, 16, 21,

CSF and serum analyses

The cerebrospinal fluid (CSF) of patients with HSE classically contains an increased number of leukocytes with a predominance of lymphocytes and an increased protein concentration.1, 6, 12, 13, 19 Red blood cells are commonly observed and probably reflect the necrotic-haemorrhagic nature of brain lesions.6, 13, 30 In some cases, however, the CSF may be normal or contain a predominance of polymorphonuclear cells in the first days of the disease.1, 6, 12, 13, 19 Such findings may lead to

Neuroradiology and electroencephalogram studies

Cerebral imaging and electroencephalogram (EEG) bring helpful clues aiding in HSE diagnosis and should be systematically considered in each suspected case of HSE.

Two cerebral imaging techniques are commonly used in children to detect brain lesions induced by HSV: computerised tomography (CT) scanning and magnetic resonance imaging (MRI). Cerebral CT scan may be normal in the first days of the disease and later may demonstrate the presence of cerebral lesions.1, 6, 11, 15, 30, 44, 48 In the

Treatment

Two prospective randomised controlled trials have shown that acyclovir is superior to vidarabine in reducing the morbidity and the mortality of HSE.12, 68 The recommended antiviral treatment is a 10-day course of acyclovir given intravenously at a dosage of 10 mg/kg every 8 h.12, 68 In children, this regimen seems insufficient. Indeed, two studies have shown that the duration of treatment and total dosage of acyclovir given were significantly less in children with early HSE relapse than in the

Neurological outcome

Seven studies including more than 10 children with HSE treated by acyclovir addressed the neurological outcome after a first episode of HSE.15, 16, 30, 69, 79 The mortality rate observed in these paediatric studies was between 0% and 10% (see Table 1).15, 16, 30, 69, 79 The proportion of patients who fully recovered or had mild, moderate or severe neurological disabilities varied widely between studies due to differences in evaluation criteria and duration of follow-up (Table 1).15, 16, 30, 69,

Resurgence of cerebral viral replication after HSE

The resumption of cerebral viral replication occurring after a first episode of encephalitis has been repeatedly suspected in HSE relapses on the basis of the existence of new necrotic-hemorrhagic lesions distant from the initial site of encephalitis (Fig. 2), positive HSV PCR and/or increased alpha-IFN level in the CSF, reappearance of HSV IgG ITS, isolation of HSV from brain biopsy and/or clinical improvement under a new course of acyclovir treatment.7, 9, 17, 30, 69, 70, 86 In children,

Secondary immuno-inflammatory processes after HSE

Other types of neurological complications that occur in the course of HSE in children cannot be explained by the persistence or the resumption of HSV replication but rather by a secondary immune-mediated process triggered by HSV cerebral infection. Indeed, this pathophysiological mechanism has been repeatedly suspected in an acute secondary neurological deterioration which is clinically characterised by choreoathetoid movements, and supposed to be related to HSE.7, 70, 73, 79, 86, 92, 93, 94, 95

Perspectives and conclusion

The extensive clinical and basic science research performed in the last two decades on the pathophysiology of HSE and its consequences have shown that the “classical” picture of HSE in children is now outdated and that our current knowledge of HSE is probably only the tip of an iceberg.

Future advances in the understanding of HSE pathophysiology and the immunological consequences of HSV cerebral infection could lead to a better delineation of the clinical spectrum of HSE in children and to more

Acknowledgment

The authors would like to thank Dr Kate Riney (Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS Trust, London, United-Kingdom) for her helpful suggestions and advices. The authors would also like to thank Dr Marie-Anne Barthez-Carpentier (Department of Pediatric Neurology, CHRU-Tours, France) who provided the image in Fig. 3.

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