The lack of demonstrable HSV DNA in CSF, the lack of acute CSF signs and the lack of signs of neural and glia cells destruction indicate that a direct viral cytotoxicity is not the major pathogenic mechanism in relapse. Instead, the pronounced CSF proinflammatory immunological response and the relative lack of CSF anti-inflammatory cytokine IL-10 response suggest immunologically-mediated pathogenicity.

Background. Herpes simplex encephalitis (HSE) is a devastating disease. Methods. In Sweden, a nationwide retrospective study of the incidence, morbidity, and mortality associated with HSE during the 12-year period 1990-2001 was conducted. The national inpatient register data were used, and diagnostic data from the virus laboratories were validated.Results. In the study period, 638 patients hospitalized in Sweden received a primary diagnosis of HSE. Of these, 236 patients had a confirmed infection of the central nervous system due to herpes simplex virus type 1. This corresponds to an incidence of confirmed HSE due to herpes simplex virus type 1 of 2.2 cases per million population per year. Of the survivors, 87% were readmitted to the hospital. The most frequent diagnosis at readmission was epilepsy, which was found in 49 patients (21% of the 236 total patients; 24% of 203 survivors), with a median onset 9.3 months after the diagnosis of HSE. This corresponds to a 60-to 90-fold increase in risk, compared with that for the general population. Neuropsychiatric sequelae were evident in 45 (22%) of 203 surviving patients. The incidence of venous thromboembolism, including pulmonary embolism, was 5-14 times higher than that in the general population. Among patients with HSE due to herpes simplex virus type 1, the 1-year mortality was 14% (33 of 236 patients died), which was 8 times higher than expected.Conclusions. This is, to our knowledge, the first study to report long-term, nationwide follow-up data for patients with virologically confirmed HSE. There is considerable morbidity after HSE, with epilepsy being the most common diagnosis. This demonstrates the need for expanding our knowledge of the pathogenesis of HSE to direct more effective antiviral and antiinflammatory treatments.

The aim of this study was to investigate the incidence of influenza-related encephalitis in Sweden during 11.5 years. Studies from Japan report an increased incidence of influenza-related encephalitis/encephalopathy. Few other studies are available. We conducted a retrospective register-based study on the Swedish National Inpatient Register, which covers all Swedish hospitals. In 1987–1998, a total number of 14,250 hospitalized individuals had an influenza diagnosis (population incidence: 137 per million personyears). In-hospital mortality was 4.1%. Using three different approaches, only 21 cases of influenza-related encephalitis were found, corresponding to a rate of 1.5 per 1,000 hospitalized persons with an influenza diagnosis (population incidence 0.21 per million person-years). We conclude that encephalitis following influenza occurs rarely, or is an infrequently recognized, diagnosed or reported complication. The cases we studied in detail have all recovered without sequels.

Herpes simplex encephalitis is a devastating disease. In the early 1980s our group conducted a nationwide clinical trial of acyclovir versus vidarabine in patients with herpes simplex encephalitis in whom intrathecal herpes simplex virus (HSV) antibodies were assayed. The purpose of this study was to investigate if antibody levels and viral load correlate with outcome in herpes simplex encephalitis. We have analysed the prognostic value of HSV antibody levels in serum and cerebrospinal fluid (CSF) at the start of antiviral treatment in the 53 included patients. Frozen samples from a subset of patients were analysed with quantitative polymerase chain reaction (PCR) to assess the prognostic value of the viral load in CSF. IgG-levels in CSF at presentation were significantly higher in vidarabine-treated patients with a favourable outcome than in those treated with vidarabine but with an unfavourable outcome. The intrathecal viral load at presentation showed no correlation with outcome. However, the duration of positive HSV-PCR in CSF was longer in vidarabine-treated than in acyclovir-treated patients. These findings indicate that the B-cell response is important in the pathogenetic process of herpes simplex encephalitis. However, neither antibody levels nor viral load at presentation are useful as prognostic markers for the individual patient in this study.

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Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines—generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89–174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11–2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.