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OBJECTIVES: To investigate the prevalence and temporal development of N-methyl-d-aspartate receptor (NMDAR) autoantibodies in relation to neurocognitive performance in patients with herpes simplex encephalitis (HSE). METHODS: This prospective observational study enrolled a total of 49 HSE patients within a randomized controlled trial of valacyclovir. Cerebrospinal fluid and serum samples were drawn in the initial stage of disease, after 2 to 3 weeks and after 3 months. Anti-NMDAR IgG was detected with HEK293 cells transfected with plasmids encoding the NMDA NR1 type glutamate receptor. A batch of neurocognitive tests, including the Mattis Dementia Rating Scale (MDRS), Glasgow Coma Scale (GCS), Reaction Level Scale (RLS85), Mini-Mental State Examination (MMSE) and National Institutes of Health (NIH) stroke scale, was performed during 24 months' follow-up. RESULTS: Anti-NMDAR IgG was detected in 12 of 49 participants. None were antibody positive in the initial stage of disease. In ten of 12 positive cases, specific antibodies were detectable only after 3 months. Notably, the development of NMDAR autoantibodies was associated with significantly impaired recovery of neurocognitive performance. After 24 months' follow-up, the median increase in MDRS total score was 1.5 vs. 10 points in antibody-positive and -negative participants (p=0.018). CONCLUSIONS: Anti-NMDAR autoimmunity is a common complication to HSE that develops within 3 months after onset of disease. The association to impaired neurocognitive recovery could have therapeutical implications, as central nervous system autoimmunity is potentially responsive to immunotherapy.

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BACKGROUND: Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis. Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications. METHODS: One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned to placebo (n = 51) or 0.5 g of valacyclovir twice daily (n = 50) for 1 year after initial treatment with 1 g of valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome was time until recurrence of meningitis. The patients were followed up for 2 years. RESULTS: The first year, no significant difference was found between the valacyclovir and placebo groups. The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.06-10.21]). One-third of the patients experienced 1-4 meningitis episodes during the study period. A considerable morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was found in both groups. CONCLUSIONS: Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could be interpreted as a rebound phenomenon.

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OBJECTIVES: To study the occurrence of relapse of herpes simplex encephalitis (HSE) and to find out whether soluble activity markers in cerebrospinal fluid (CSF) indicate direct viral or immune- mediated events. METHODS: A consecutive series of 32 adult survivors of HSE were followed to determine the incidence of clinical relapse of HSE. Four patients had neurological deterioration interpreted as relapsing HSE. Four non-relapsing HSE cases were selected as matched controls. Fifty nine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon-gamma, soluble CD8, tumour necrosis factor-alpha, and interleukin-10), amount of HSV-DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S-100-beta, and neuron specific enolase). RESULTS: Relapse of HSE was diagnosed in 3 of 26 (12 %) acyclovir-treated patients (5 episodes during 6.1 years of followup) and in 1 of 6 vidarabine-recipients. All relapses occurred from 1 to 4 months after acute HSE, except for a second relapse after 3.3 years in one patient. Computer tomography at relapses revealed few abnormalities apart from those found during the primary disease. Intravenous acyclovir and corticosteroids were given for 7-21 days in all the relapse patients. All relapse patients seemed to recover to the pre-relapse condition. HSV-DNA was demonstrated in CSF in all patients during the acute stage but not in any of 13 CSF samples taken during relapse phases. The HSV viral load during the acute stage of HSE was not higher or of longer duration in the relapsing patients than in the non-relapsing HSE controls. The levels of sCD8 were increased in nearly all CSF samples tested with peaks of sCD8 at one month of acute HSE. In all episodes of relapse, sCD8 peaks were detected during the first week at high levels. CSF levels of neuron-specific enolase, S-100 and glial fibrillary acidic protein were markedly lower at relapse than at the acute stage of HSV-1 encephalitis. CONCLUSION: 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.

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Ninety-four patients with infectious mononucleosis and symptoms < or = 7 days were randomized to treatment with oral acyclovir (800 mg 5 times/day) and prednisolone (0.7 mg/kg for the first 4 days, which was reduced by 0.1 mg/kg on consecutive days for another 6 days; n = 48), or placebo (n = 46) for 10 days. Oropharyngeal Epstein-Barr virus (EBV) shedding was significantly inhibited during the treatment period (P = .02, Mann-Whitney rank test). No significant effect was observed for duration of general illness, sore throat, weight loss, or absence from school or work. The frequency of latent EBV-infected B lymphocytes in peripheral blood and the HLA-restricted EBV-specific cellular immunity, measured 6 months after onset of disease, was not affected by treatment. Thus, acyclovir combined with prednisolone inhibited oropharyngeal EBV replication without affecting duration of clinical symptoms or development of EBV-specific cellular immunity.

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Sequential samples of serum and cerebrospinal fluid (CSF), from 9 patients with herpes simplex encephalitis (HSE), were analyzed for cytokines and soluble cytokine receptors. The response to herpes simplex virus was characterized by a vigorous compartmentalized immune response. The intrathecal response comprised three different phases: an acute stage (first week of illness), characterized by elevated CSF levels of interleukin (IL)-6 and interferon-gamma; an early convalescence stage (weeks 2-6 after onset of disease), associated with peaking levels of tumor necrosis factor-alpha and late markers of the specific T cell-mediated immune response, soluble IL-2 receptor, and soluble CD8 antigen (sCD8); and finally, a late convalescence stage, lasting months to years and associated with persistently increased levels of sCD8 in particular. These findings show the compartmentalization and kinetics of the inflammatory response in HSE and demonstrate persistence of the intrathecal inflammatory process, which may have implications for antiviral and antiinflammatory therapy.

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Neopterin and beta 2-microglobulin (beta 2M) levels were analyzed in sequential cerebrospinal fluid (CSF) and serum samples from 20 patients with herpes simplex encephalitis (HSE) and 30 patients with acute febrile encephalopathy of other cause (non-HSE). Markedly elevated acute phase CSF levels of neopterin and beta 2M were found in 19 HSE patients, but the levels were only moderately increased in most of those with non-HSE. Neopterin levels were analyzed in an additional 15 HSE patients who died within a month of the onset of neurologic symptoms and correlated with the clinical severity of the HSE. After HSE, but not after non-HSE, increased levels of neopterin and beta 2M persisted for a long time (> or = 13 years). Specific intrathecal IgG activity persisted in all but 2 HSE patients. These findings indicate that there is a vigorous acute inflammatory response and a long-term persistence of intrathecal cellular and humoral immune activity in HSE.

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A herpes simplex virus type 2 (HSV 2) etiology was sought in 93 consecutive cases of herpes simplex encephalitis (HSE) in immunocompetent post neonate patients. Antibodies to HSV 2 glycoprotein G antigen were determined by an enzyme-linked immunosorbent assay (ELISA) and HSV 2 DNA in cerebrospinal fluid (CSF) by a nested polymerase chain reaction (PCR) assay with primer pairs in the glycoprotein G gene. Evidence of HSV 2 infection was found in 6 patients; HSV 2 DNA was demonstrated in CSF and the intrathecal HSV 2 antibody response confirmed the findings. Five of the 6 patients with HSV 2 encephalitis presented a clinical picture, CSF, EEG, and CT findings characteristic of severe HSE. An atypically mild clinical course was seen in one patient. HSV 2 should be considered as an etiological agent in the viral diagnosis of HSE. With a combination of nested PCR assays for HSV 1 (primer pairs in the glycoprotein D gene) and HSV 2 in 10 microliters of CSF with no other preparation than freeze-thawing, HSV 1 or HSV 2 DNA was detected in 88 out of 93 (95%) of the first CSF specimens collected after the onset of neurological HSV disease. These findings extend and confirm previous results with PCR as a rapid and sensitive tool for early diagnosis of HSE.

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From a series of in all 93 patients with herpes simplex encephalitis (HSE), verified by biopsy and/or the demonstration of intrathecal synthesis of antibodies to the virus, cerebrospinal fluid (CSF) and serum samples were analysed and compared with samples from 80 patients with non-HSE, i.e. acute encephalitis of non-HSV origin (approximately 50% with other known aetiology, 50% of unknown origin) treated on the suspicion of HSE but in whom no signs of intrathecal HSV antibody synthesis were found, and samples from an additional 42 patients with other verified or suspected diseases of the CNS. To improve the early non-invasive diagnosis of HSE, a HSV IgG capture enzyme linked immunosorbent assay (ELISA) was developed to demonstrate intrathecal synthesis of antibodies to the virus and the results were compared to those of the indirect ELISA. The capture ELISA was found to be advantageous in detecting the early antibody response and yielded more clear-cut results. No correction for damage to the blood-CSF barrier was needed and the method was therefore less labour-intensive than the indirect ELISA. Furthermore, a polymerase chain reaction (PCR) assay, with two "nested" primers pairs selected in the glycoprotein D gene of HSV-1, was developed for the amplification of HSV DNA in CSF. The method was found to be a rapid and non-invasive means of diagnosing HSE in a very early stage of the disease; it was highly sensitive and specific. With a combination of nested PCR assays for HSV-1 and HSV-2 (primers in the glycoprotein G gene) in 10 microliters of CSF, HSV DNA was detected in CSF from 88 out of 93 patients (95%) with HSE. Evidence of HSV-2 aetiology was found in 6 of 93 consecutive cases of HSE in immunocompetent patients by type-specific assays for the demonstration of HSV-2 DNA (primers in the gG gene) and HSV-2 antibodies (to gG2 antigen) in the CSF. Five of the 6 patients with HSV-2 encephalitis exhibited a clinical picture of severe HSE indistinguishable from that of "classical" HSV-1 encephalitis. The combined use of PCR for the detection of HSV DNA in the CSF and the demonstration of intrathecal synthesis of antibodies to the virus will yield a reliable diagnosis and is now the method of choice for the diagnosis of HSE.(ABSTRACT TRUNCATED AT 400 WORDS)

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The ability of serum C-reactive protein (S-CRP) to differentiate between acute bacterial and viral meningitis was evaluated in 235 patients, both children and adults. The patients underwent lumbar puncture due to suspected central nervous system (CNS) infection. In patients with bacterial meningitis, 7/60 (12%) had S-CRP concentrations below 50 mg/l. Of these patients, 4 were children below 6 years of age, all with symptoms of meningitis for less than 12 h before admission and 3 adults of whom 1 had symptoms of meningitis for less than 12 h. In patients with viral meningitis, 15/146 (10%) had S-CRP concentrations above 50 mg/l. Only 3 children below 6 years of age with viral meningitis had S-CRP concentration above 20 mg/l, but none exceeded 50 mg/l. An S-CRP value above 50 mg/l in patients with CSF pleocytosis usually indicates bacterial etiology. However, S-CRP values above 50 mg/l may occasionally be seen in viral meningitis. In children younger than 6 years of age a discriminatory level for S-CRP of 20 mg/l can be used to distinguish between bacterial and viral meningitis, but for older patients a discriminatory level of 50 mg/l is more appropriate. If the duration of the illness is less than 12 h, S-CRP concentrations below the discriminatory levels are of limited diagnostic value.

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With the aim of improving early diagnosis of herpes simplex encephalitis a polymerase chain reaction (PCR) assay with two "nested" primer pairs was developed for the amplification of herpes simplex virus DNA in cerebrospinal fluid (CSF). Southern blotting was used to confirm the specificity of the amplification. The assay was applied to 151 CSF samples from 43 consecutive patients with herpes simplex encephalitis verified by the finding of herpes simplex virus/viral antigen in a brain biopsy sample or at necropsy (13) and/or intrathecal production of IgG antibody to the virus (40). As controls, 87 CSF samples from 60 patients with acute febrile focal encephalopathy (initially suspected to be herpes simplex encephalitis but excluded by the absence of intrathecal antibody synthesis) were tested. PCR detected herpes simplex virus DNA in 42 of the 43 patients with proven herpes simplex encephalitis; all but 1 were positive in the first CSF sample taken. The 1 PCR-negative patient had been treated with acyclovir from 20 h after the onset of symptoms. All the control subjects were PCR negative, as were 270 internal contamination controls. The PCR result remained positive in samples drawn up to 27 days after the onset of neurological symptoms. This method is a rapid and non-invasive means to diagnose herpes simplex encephalitis; it is highly sensitive and specific.

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The kinetics of appearance and specificity of HIV-1 neutralizing antibodies was studied in four individuals. HIV-1 was isolated during symptomatic primary HIV-1 infection and repeatedly thereafter, and tested against autologous sera collected in parallel. Our patients developed isolate-specific low-titer neutralizing antibodies within 2-4 weeks, and the titers to the first isolates increased with time. We documented the emergence of virus variants with reduced sensitivity to neutralization by autologous, but not heterologous, sera in three patients. These virus variants were not, however, resistant to neutralization per se, since they were readily neutralized by the positive control serum. Our patients did not develop antibodies capable of neutralizing the new virus variants during the observation period. This suggests either a failure of the immune system to respond to the new virus variants or a mechanism by which the virus evades detection by the immune system. The emergence of neutralization-resistant virus variants was not directly correlated with disease progression since two patients have remained asymptomatic after the emergence of such virus variants. It is, however, likely that the emergence of virus variants which the patient fails to neutralize in the long run contributes to disease progression.

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We wish to report a 76-year-old woman with 2 episodes of meningitis related to the intake of trimethoprim. On both occasions the patient demonstrated encephalitic symptoms and a pathological electroencephalogram with cerebral function disturbances. A similar case with encephalitic symptoms due to trimethoprim has not been reported earlier.

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