Elsevier

Antiviral Research

Volume 71, Issues 2–3, September 2006, Pages 141-148
Antiviral Research

Mini-review
Herpes simplex encephalitis: Adolescents and adults

Dedicated to Prof. Erik De Clercq on the occasion of reaching the status of Emeritus-Professor at the Katholieke Universiteit Leuven in September 2006.
https://doi.org/10.1016/j.antiviral.2006.04.002Get rights and content

Abstract

Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the central nervous system despite available antiviral therapy. Children and adolescents account for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the encephalopathic, febrile patient with focal neurologic signs. However, these clinical findings are not pathognomonic because numerous other diseases in the central nervous system can mimic HSE. Neurodiagnostic evaluation can provide support for the diagnosis by the demonstration of temporal lobe edema/hemorrhage by magnetic resonance image scan and spike and slow-wave activity on electroencephalogram. In the current era, the diagnostic gold standard is the detection of herpes simplex virus (HSV) DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test and preferable to brain biopsy, false negatives can occur early after disease onset. Acyclovir is the treatment of choice and is administered at 10 mg/kg every 8 h for 21 days. Even with early administration of therapy after the disease onset, nearly two thirds of survivors have significant residual neurologic deficits. Current investigative efforts are assessing the prognostic value of quantitative PCR detection of viral DNA at the onset of therapy as well as at the completion of therapy and the contribution of prolonged antiviral therapy to improved neurologic outcome.

Introduction

Since the discussion of herpes simplex encephalitis (HSE) by the Mathewson Commission in 1926 (Mathewson Commission, 1929) and subsequent description of the histopathologic changes (Smith et al., 1941) herpes simplex virus (HSV) infection of the brain has become recognized as the most common cause of sporadic fatal encephalitis in the United States (Meyer et al., 1960). Intranuclear inclusion bodies consistent with HSV infection were demonstrated first in the brain of a neonate with encephalitis by Smith et al. (1941). Virus subsequently was isolated from brain tissue (Smith et al., 1941). The first adult case of HSE providing similar proof of viral disease (i.e. intranuclear inclusions in brain tissue and virus isolation) was described by Zarafonetis et al. (1944). The most striking pathologic findings in this patient's brain were apparent in the left temporal lobe, in which perivascular cuffs of lymphocytes and numerous small hemorrhages were found. This temporal lobe localization subsequently has been determined to be characteristic of HSE in individuals older than 3 months of age.

In the mid-1960s, Nahmias and Dowdle (1968) demonstrated two antigenic types of HSV. Viral typing allowed the demonstration that HSV-1 was responsible primarily for infections “above the belt” (including brain disease in adults), whereas HSV-2 was responsible primarily for infections “below the belt” and brain disease in neonates, although this epidemiologic paradigm has changed significantly in the 21st century as HSV-1 has become an increasingly frequent cause of genital herpes. Notably, recent studies indicate that either virus can infect the mouth or genital tract. However, essential to all observations is that HSE nonetheless is caused by HSV-1 in virtually all patients. Indeed, frank encephalitis attributed to HSV-2 has been reported only in a few cases in the world's literature (Whitley et al., 1982a, Whitley et al., 1982b).

Section snippets

Pathology and pathogenesis

The pathologic changes induced by replicating HSV include ballooning of infected cells and the appearance of chromatin within the nuclei of cells followed by degeneration of the cellular nuclei. Cells lose intact plasma membranes and form multinucleated giant cells. As host defenses are mounted, an influx of mononuclear cells can be detected in infected tissue. HSE results in acute inflammation, congestion, and/or hemorrhage, most prominently in the temporal lobes and usually asymmetrically in

Clinical presentation of HSE

HSV infections of the CNS are among the most severe of all viral infections of the human brain. Currently, HSE is estimated to occur in approximately 1 in 250,000 to 1 in 500,000 individuals per year. At the University of Alabama at Birmingham, the diagnosis of HSE was confirmed by brain biopsy in an average of 10 patients per year for an incidence of approximately 1 in 300,000 individuals, an incidence similar to those in Sweden and England (Longson, 1984, Skoldenberg et al., 1984). In the

Diagnosis

Several aspects relating to the diagnosis of HSE merit discussion particularly in relation to disease: (1) the clinical presentation with regard to the sensitivity and specificity of various clinical characteristics in children and adolescents; (2) the historical use of brain biopsy to establish the diagnosis; (3) conditions that mimic HSE; and (4) non-invasive means of diagnosis. Data from the NIAID CASG compare presentation and outcome for patients with positive brain biopsies and those with

Differential diagnosis

In a compilation of the NIAID CASG data, 193 of 432 (45%) patients undergoing brain biopsy for a focal encephalopathic process had HSE (Whitley et al., 1989). As shown in Table 2, the remaining patients were evaluated for diseases that mimic HSE (Whitley and Gnann, 2002). Thirty-eight patients had disease amenable to other forms of therapy, including brain abscess, tuberculosis, cryptococcal infection, and brain tumor. An additional 19 patients had diseases that were indirectly treatable, and

Associated neurologic syndromes

HSV obviously involves areas of the nervous system other than the brain. Primary and recurrent genital herpes have been associated with neuritis localized to one extremity or even transverse myelitis. Neuritis evident in such patients can be associated with altered sensation of the lower extremities, as can dysesthesias, shooting pain, and motor impairment.

Urinary and fecal incontinence have been reported in a few patients. An aseptic meningitis syndrome also is a common finding, frequently

Therapy

The first antiviral drug reported as efficacious therapy of HSE was idoxuridine; however, in a controlled clinical trial it proved to be both ineffective and toxic (Boston Interhospital Virus Study Group and the NIAID Sponsored Cooperative Antiviral Clinical Study, 1975). Subsequent therapeutic trials defined vidarabine as an efficacious medication for the management of biopsy-proven HSE (Whitley et al., 1977, Whitley et al., 1981); however, it has been replaced by acyclovir in the physician's

Future considerations

Several considerations are in order. First, in the management of HSE in children, adolescents, and adults, we do not have PCR evidence of disease persistence as occurs in the newborn. Stated more simply, these studies have not been performed. Such information may be important in gauging duration of therapy, as appears to be the case in the management of neonatal disease. However, definitive data remain lacking. Second, no controlled clinical trial to date has relied solely on PCR confirmation

Acknowledgements

Funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract (NO1-AI-30025, NO1-AI-65306, NO1-AI-15113, NO1-AI-62554, N01-AI-30025), the General Clinical Research Unit (RR-032), and the State of Alabama.

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