Absent anti-N-methyl-D-aspartate receptor NR1a antibodies in herpes simplex virus encephalitis and varicella zoster virus infections.

PURPOSE: A 2012 report and subsequent case series described anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients during the acute phase and relapse of herpes simplex virus 1 (HSV1) encephalitis (HSV1E). However, the prevalence of this phenomenon is unknown and systematic studies on other viral infections of the nervous system are missing. MATERIALS AND METHODS: We retrospectively analyzed serial cerebrospinal fluid (CSF) and serum samples of consecutive patients treated for neurological HSV1, HSV2 and varicella zoster virus (VZV) infections in our tertiary care university hospital between 2003 and 2013 for the presence of antibodies directed against the NR1a subunit of the NMDAR using indirect immunofluorescence. RESULTS: In total, 88 patients with the following infections were identified through an electronic database search: HSV1 (24 with encephalitis), HSV2 (6 with meningitis, 3 with encephalitis and 1 with myelitis), or VZV (3 with meningitis, 33 with encephalitis, 17 with radiculitis and 1 with myelitis). Two patients with HSV1E and HSV2E, respectively, experienced a clinical relapse. Clinical follow-up was for up to 85 months, and repetitive serum and CSF analyses for up to 43 months. However, at no time did any of the 88 patients exhibit anti-NMDAR NR1a antibodies. CONCLUSIONS: In this study, we did not detect anti-NMDAR NR1a antibodies in serial CSF and serum samples of HSV1E patients or patients with other viral infections (HSV2 and VZV). However, the presence of antibodies directed against other epitopes of the NMDAR and other neuronal cell surface antigens cannot be excluded, necessitating further studies.

The Interleukin-1 Balance During Encephalitis Is Associated With Clinical Severity, Blood-Brain Barrier Permeability, Neuroimaging Changes, and Disease Outcome.

BACKGROUND: Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood. METHODS: We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging-based temporal lobe volume. RESULTS: Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P= .004). Among patients infected with HSV, the ratio of CSF IL-1ß to IL-1RA was associated with a worse outcome (P= .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%;P= .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P= .012) and a positive correlation with serum IL-1α level (P= .0003) and CSF IL-1ß level (P= .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P= .007) and CSF specimens from all patients (P= .016); the IL-10 level correlated inversely with BBB permeability (P= .005). CONCLUSIONS: A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.

Meningoencefalitis herpética: ¿cuándo sospecharla? / Herpetic meningoencephalitis: a review

La encefalitis herpética (EH) secundaria a la infección por el virus de herpes simple 1 (VHS1) es la causa conocida más frecuente a nivel mundial de infección viral fatal del sistema nervioso central (SNC). La agresividad de su curso clínico y la morbilidad asociada a su desarrollo obligan a todo médico generalista a mantener una alta sospecha clínica para lograr su diagnóstico. Ciertas manifestaciones clínicas como la fiebre asociada a alteraciones en el sensorio o a alteraciones en el comportamiento de un paciente o a ambas posibilidades se presentan en un porcentaje superior al 90% de los casos confirmados. La solicitud en el líquido cefalorraquídeo (LCR) de la reacción en cadena de la polimerasa (PCR) para el VHS1 es el estudio complementario de laboratorio que posee la mayor sensibilidad y especificidad para confirmar el diagnóstico de EH. A su vez, la resonancia nuclear magnética (RNM) es el estudio de imagen que posee mayor sensibilidad y especificidad para el diagnóstico de la enfermedad. La EH secundaria al VHS1 es, de las infecciones virales que afectan el SNC, la única que posee tratamiento específico. La instauración temprana de tratamiento con aciclovir disminuye la mortalidad asociada al desarrollo de la enfermedad de un 70% y sin tratamiento, hasta un 10-20%. El objetivo principal de esta revisión es señalar las diversas situaciones clínicas en las cuales se debe sospechar la EH así como guiar la correcta utilización de los estudios complementarios e instaurar de manera temprana el tratamiento para reducir al máximo la morbimortalidad. (AU)

The herpes simplex virus type 1 (HSV1) encephalitis (EH) is the most common known cause of sporadic fatal encephalitis worldwide. The fatal consequences in the development of this disease and the morbidity related to it, should alert general practitioner to be always aware of its possible diagnosis. Clinical features such as fever associated with altered mental status or disturbances in the level of consciousness are present in more than 90% of confirmed cases. The analysis of the polymerase chain reaction (PCR) for HSV1 in central nervous system (CNS) fluid is the laboratory study of choice for establishing the diagnosis with the best sensitivity and specificity. Moreover, magnetic resonance image (MRI) is the most sensitive and specific imaging study for the detection of this entity. The VHS1 EH is one of the few treatable viral infection of the central nervous system to date. Hence, early administration of adequate antiviral therapy with Acyclovir remains paramount. The early administration of empiric therapy can decrease the mortality rate from 70% without treatment to 10-20% in confirmed cases. We sought to describe the disease's clinical features, and to further discuss the accurate use of diagnostic tools and treatment strategies in order to reduce the high related morbi-mortality. (AU)

N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse.

Herpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial.

Herpes simplex virus encephalitis is a trigger of brain autoimmunity.

In 5 prospectively diagnosed patients with relapsing post-herpes simplex encephalitis (HSE), N-methyl-D-aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p=0.004; cerebrospinal fluid, p=0.04). The 3 retrospectively identified NMDAR antibody-positive patients also had evidence of relapsing post-HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor.

BACKGROUND: Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR). METHODS: We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea. RESULTS: The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers. CONCLUSIONS: These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.

Varicella zoster virus meningoencephalitis accompanied by rhabdomyolysis without skin eruption.

We report a case of a 38-year-old man with a Varicella zoster virus (VZV) reactivation who manifested meningoencephalitis accompanied by rhabdomyolysis without a skin eruption. During the acute phase, VZV DNA was detected in serum and cerebrospinal fluid (CSF) by the polymerase chain reaction (PCR). After 16 days, all symptoms and signs resolved, and follow-up PCR studies revealed negative conversion of VZV in the serum and CSF. We discuss the possible underlying mechanism of VZV reactivation in our patient. This is the first case report of VZV reactivation meningoencephalitis accompanied by rhabdomyolysis without skin eruption demonstrated by viral DNA in the serum and CSF.

N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis.

OBJECTIVE: To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE). METHODS: Retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients' serum was studied in cultures of primary mouse hippocampal neurons. RESULTS: N-Methyl-D-aspartate receptor (NMDAR) antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons. INTERPRETATION: Some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy. .

Valacyclovir for herpes simplex encephalitis.

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.

HLA-DRB1*01 allele and low plasma immunoglobulin G1 concentration may predispose to herpes-associated recurrent lymphocytic meningitis.

Recurrent lymphocytic meningitis (RLM) is a rare illness caused mostly by herpes simplex virus type 2 (HSV-2). Predisposing factors are not known. Deficiencies in immunoglobulin (Ig) G subclasses 1 (IgG1) and 3 (IgG3) and complement protein C4 are associated with susceptibility to and persistence of bacterial and viral infections. Selected HLA and mannose-binding lectin (MBL) alleles have previously been associated with recurrent genital herpes or herpetic meningitis. We assessed the frequencies of low IgG1 and IgG3, their allotypes (Gm), and HLA-A*, -B*, -DRB1*, and MBL2 alleles, as well as deficiencies in C4A and C4B genes, as potential predisposing factors for HSV-2-associated RLM. The level of IgG1 was lower (p = 0.009) and the frequency of low IgG1 was higher (p < 0.001) in patients than in controls. Furthermore, the risk for a new meningitis episode was increased in patients with low IgG1 (incident ratio 2.05). HLA-DRB1*01 (p = 0.009) and -B*27 (p = 0.050) were more common among patients than controls. We conclude that HLA-DRB1*01 and -B*27 alleles and low plasma IgG1 levels may be significant risk factors for RLM.

Serum S-100B protein levels in patients with herpes simplex encephalitis and tick-borne encephalitis--a marker of CNS damage during the initial stage of disease.

BACKGROUND AND PURPOSE: This study was mainly aimed at the comparative analysis of serum S-100B protein in patients with herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). S-100B protein is an established biochemical marker of astroglial damage in central nervous system (CNS) injury. METHODS: Serum levels of S-100B were measured using a commercial immunolumino-metric assay (LIA). RESULTS: Patients with HSE (n = 17) had significantly higher levels of S-100B with median 0.351 microg/l (range 0.017-0.636) compared to patients with TBE (n = 15), who had 0.04 microg/l (range 0.001-0.542) (p < 0.001), as well as controls (n = 17) 0.054 (range 0.004-0.214) (p < 0.001). 11/17 patients with HSE had serum S-100B levels above 0.2 microg/l, in contrast to 1/15 patients with TBE and 1/17 of the control patients. The patients with HSE with serum levels below 0.2 microg/l had a mean 3.2 days disease duration, while patients with levels above 0.2 microg/l had 6 days disease duration. CONCLUSIONS: The serum levels of S-100B in the acute stage of disease were significantly higher in patients with HSE than in patients with TBE or controls. A role for the use of serum S-100B in monitoring CNS damage during initial stage of disease in HSE is suggested.

Widespread unilateral pain associated with herpes simplex virus infections.

UNLABELLED: We describe a patient group with unexplained widespread pain on one side of the body and pain exacerbations during active labial or genital herpes and during herpetic central nervous system infections. The patients had no visible lesion of the central nervous system on magnetic resonance imaging or abnormality in electrophysiological studies. To understand the nature of the pain and its possible relation to herpes simplex virus (HSV) infections, a clinical neurological examination was performed and quantitative sensory testing and skin biopsies were assessed in 17 patients. The levels of serum total immunoglobulins and IgG subclasses and the frequencies of the immune response genes at the IGH@, HLA-A, -B, -DRB1, C4A, and C4B loci were analyzed in the patients and in control subjects. The patients manifested a uniform clinical syndrome with unilateral pain that was best described as neuropathic and that was exacerbated by HSV reactivations. Low plasma IgG3 concentrations, the presence of either low plasma IgG1 or IgG3 or both, and high anti-HSV-2-IgG titers were more common in the patients than in the control subjects, which rendered the patients more vulnerable to HSV recurrences. PERSPECTIVE: We suggest that low immunoglobulin subclass levels and certain MHC alleles render the patients susceptible to recurring HSV infections. HSV reactivations and the accompanying inflammatory process cause dysfunction of the central nervous system that manifests as neuropathic pain. Studies using functional brain imaging are needed to clarify this syndrome.

West Nile encephalitis mimicking herpes encephalitis.

A male with a febrile illness, altered consciousness, and seizures was diagnosed with meningoencephalitis. The suspected etiology was herpes simplex virus on the basis of a focal seizure at presentation, and he was treated with acyclovir until this pathogen was excluded. The patient made a complete recovery. Because of a West Nile fever epidemic in Israel at the time, serology tests for West Nile virus were performed; results were positive. This case highlights the diagnostic problems in West Nile fever. The literature is discussed in brief.

Steroid therapy in an infant with human herpesvirus 6 encephalopathy.

We describe a 10-month-old girl who developed convulsive status during febrile illness. Human herpesvirus 6 DNA was detected in both the serum and the cerebrospinal fluid by polymerase chain reaction. Interleukin-6 was increased in the serum. The patient improved after a commencement of steroids pulse therapy. This case suggests that proinflammatory cytokines are responsible for the pathogenesis of the encephalopathy.

Drug-induced hypersensitivity syndrome due to mexiletine associated with human herpes virus 6 and cytomegalovirus reactivation.

A 66-year-old man developed a fever of 38 degrees C and generalized pruritic rash about one month after mexiletine hydrochloride administration for ventricular tachycardia. The rash appeared as edematous erythema and papules with purpura on the lower extremities. Liver dysfunction, leukocytosis, and atypical lymphocytes were also present. Elevated antibody titer against human herpes virus 6 (HHV-6) was detected during the course of the disease (1:20 -> 1:640). The patient was diagnosed as having drug-induced hypersensitivity syndrome (DIHS) due to mexiletine. Discontinuation of the mexiletine administration and systemic corticosteroid treatment led to a temporary improvement, but tapering the corticosteroid dose twice led to recrudescence. Simultaneous with the recrudescence, elevated antibody titers against HHV-6 and cytomegalovirus were detected, as well as viral DNA in the blood, suggesting that these two viruses may have been involved in the recrudescence. The patient died of myocarditis, most likely related to cytomegalovirus. Our case indicates that, in addition to HHV-6, other herpes viruses such as cytomegalovirus can be reactivated in DIHS and may modify the clinical disease activity.

[Herpes encephalitis at children]. / Opryszczkowe zapalenie mózgu u dzieci.

Significant mortality, high incidences of complications and permanent neurological sequel are still noted in patients suffering fro herpetic encephalitis. They result mainly from delayed diagnosis and treatment of the specific cause. The aim of our paper was the analysis o a clinical course of patients with Herpes simplex encephalitis. From 1999 to 2001 7 patients aged 2 weeks to 15 years, treated in Children' Neurology Department of Silesian School of Medicine, were diagnosed to have herpetic encephalitis. Fever, headache, vomiting, as well as alteration of consciousness, all typical for neuroinfection were main clinical symptoms present on admission. Three children presented with respiratory distress requiring admission to Intensive Care Unit. On examination "cold sores" were found in 2 patients, in remaining 5 the history of exposition to herpes labialis was obtained. On neurological examination we found either right or left hemiparesis in all patients, motor aphasia in 2 and left sided central facial nerve palsy in 1. Lumbar puncture revealed lymphocytosis in 5 patients. Anti-HSV type IgG an IgM antibodies were found in serum of all 6 patients, while only in 2 of them were detected in cerebrospinal fluid (CSF). These were the 2 most severely ill children. In 2 patients DNA HSV using PCR (polymerase chain reaction) method was found in CSF and in serum. Magnetic resonance imaging (MRI) of the head confirmed diagnosis. Although herpetic encephalitis is an uncommon, sporadic disease, the diagnosis should be considered in any child with neuroinfection and early treatment started before laboratory confirmation.