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)

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.

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.