Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.

Adjunctive Intravenous Immunoglobulin and Glucocorticoid Therapy in Severe Herpes Simplex Encephalitis with Excellent Outcome Begs for Larger Trials Evaluating Immunomodulatory Therapy.

BACKGROUND Despite the preponderance of evidence of immune-driven pathophysiology of disease in herpes simplex virus-1 (HSV-1) encephalitis, current treatment paradigms do not officially recommend adjunctive immunomodulatory therapy in addition to acyclovir. This may in part explain the poor long-term outcomes in patients with severe HSV encephalitis. This report is of a 21-year-old man presenting with a 4-day history of nausea, headache, and fever and a diagnosis of HSV-1 encephalitis. CASE REPORT We describe the case of a young male with clinically and radiographically severe HSV-1 encephalitis diagnosed by PCR of cerebrospinal fluid (CSF), who demonstrated immediate improvement upon treatment with intravenous immunoglobulin (IVIG, 0.5 g/kg daily ×3 days) in addition to acyclovir and dexamethasone therapy. Acyclovir therapy was extended beyond 21 days due to persistently positive HSV-1 CSF PCR. He developed N-methyl-D-aspartate (NMDA) receptor antibodies at 6 weeks, but his long-term outcome far exceeded expectations. While some of his neurological deficits appear to be permanent, he is living a normal life. CONCLUSIONS Overwhelming evidence demonstrates that brain injury due to HSV encephalitis is driven by immune reactions stimulated by HSV rather than HSV itself. Nevertheless, use of immunomodulatory therapy such as glucocorticoids and IVIG are left to the discretion of individual clinicians rather than being recommended in treatment guidelines, which instead recommend acyclovir therapy. The present case highlights the potential role of immunomodulatory therapy with IVIG in HSV encephalitis and the importance of early diagnosis and treatment.

Unmasking bipolarity in recurrent depressive disorder following herpes simplex virus triggered n-methyl-D-aspartate encephalitis.

OBJECTIVE: Herpes simplex virus (HSV) infection triggered n-methyl-D-aspartate (NMDA) encephalitis can lead to varied neuropsychiatric manifestations, including movement disorders and manic symptoms. HSV is known to affect the same brain regions as in secondary mania. METHOD: We present a 35-year-old female diagnosed with recurrent depressive disorder (RDD) who developed NMDA encephalitis triggered by HSV infection. RESULT: HSV-triggered NMDA encephalitis led to a manic switch in a woman with RDD on antidepressants, along with the new onset of dyskinetic movements. CONCLUSION: A neurological insult predisposed our patient to the variable effects of antidepressant drugs.

Encefalitis autoinmune posherpética. Caso clínico pediátrico / Autoimmune post-herpes simplex encephalitis. A pediatric clinical case report

La encefalitis por virus herpes simple (VHS) es una causa frecuente de encefalitis grave y potencialmente fatal. La encefalitis autoinmune posherpética (EAPH) afecta a un porcentaje de los pacientes que han presentado encefalitis herpética (EH) y se caracteriza por la aparición de nuevos síntomas neurológico/psiquiátricos, y/o por el empeoramiento de los déficits adquiridos durante la infección viral dentro de un lapso temporal predecible. Se produce por un mecanismo no relacionado con el VHS, sino por fenómenos autoinmunes, y es susceptible de tratamiento con inmunomoduladores. Se presenta el caso de un varón de 5 años de edad con EAPH que requirió tratamiento inmunomodulador, de primera y segunda línea, con buena evolución y remisión de los síntomas.

Herpes simplex virus (HSV) encephalitis is a common cause of severe and potentially fatal encephalitis. Autoimmune post-herpes simplex encephalitis (AIPHSE) affects a percentage of patients who developed herpes simplex encephalitis (HSE) and is characterized by the onset of new neurological/psychiatric symptoms and/or worsening of deficits acquired during the herpes infection within a predictable time frame. It is caused by a mechanism not related to HSV, but by autoimmune conditions, and is susceptible to treatment with immunomodulators. Here we describe the case of a 5-year-old boy with AIPHSE who required first- and second-line immunomodulatory treatment, with an adequate course and remission of symptoms.

Herpes Simplex Virus Encephalitis after Recovery from Coronavirus Disease 2019: A Rare Case Report.

An 85-year-old woman was diagnosed with coronavirus disease 2019 (COVID-19). The patient was treated with dexamethasone, and the infection was cured. She later developed a low-grade fever and fell unconscious. Positivity for herpes simplex virus deoxyribonucleic acid polymerase chain reaction (HSV-DNA PCR) was detected in the cerebrospinal fluid, so she was diagnosed with HSV encephalitis. The patient was treated with antiviral drugs and recovered from the HSV encephalitis. This case suggests that, in patients with COVID-19 and disorders of consciousness, the possibility of HSV encephalitis should be considered along with COVID-19 encephalitis.

Anti-NMDAR encephalitis secondary to acute necrotizing encephalopathy caused by herpes simplex virus infection in infants: Case series.

BACKGROUND: To describe the clinical characteristics of anti-NMDAR encephalitis secondary to acute necrotizing encephalopathy caused by herpes simplex virus encephalitis in infants, and aid in its early recognition, diagnosis and treatment. CASE PRESENTATION: A total of 4 infants were included; all presented with fever, seizures, and progressive disturbances of consciousness and were diagnosed with herpes simplex virus (HSV-1) encephalitis. Cerebrospinal fluid (CSF) protein levels progressively increased, and the head MRI showed necrotizing encephalopathy. There was no significant improvement or recurrence after treatment with acyclovir, dexamethasone, or immunoglobulins. CSF reexamination at 3 weeks to 3 months showed positive anti-NMDAR IgG antibodies and gradual improvement after high-dose methylprednisolone therapy. CONCLUSION: Infants with ANE associated with HSV can develop secondary anti-NMDAR encephalitis, recognition of which is critical to ensure the appropriate institution of immunotherapy after active CNS infection has been ruled out.

Metagenomic search of viral coinfections in herpes simplex encephalitis patients.

Little is known about concomitant central nervous system (CNS) infections by more than one virus. Current diagnostics are based on molecular tests for particular pathogens making it difficult to identify multi-viral infections. In the present study, we applied DNA- and RNA-based next-generation sequencing metagenomics (mNGS) to detect viruses in cerebrospinal fluids from 20 patients with herpes simplex encephalitis. Coinfection was detected in one patient: sequences in cerebrospinal fluids matched enterovirus A (2.660 reads; 4% of recovered genome) and enterovirus B (1.571 reads; 13% of recovered genome). Subsequent PCR combined with serotyping allowed to identify human echovirus 6, a representative of enterovirus B. Several other mNGS hits (human pegivirus, Merkel cell polyomavirus, human papillomavirus type 5) were not considered to represent a genuine signal as they could not be confirmed by specific RT-PCR/PCR. HSV DNA, while being detectable by PCR in every patient, was detected by mNGS in only one. In conclusion, contaminations and false signals may complicate mNGS interpretation; however, the method can be useful in diagnostics of viral coinfections in CNS, particularly in the case of rare pathogens.

State of the Art: Acute Encephalitis.

Encephalitis is a devastating neurologic disease often complicated by prolonged neurologic deficits. Best practices for the management of adult patients include universal testing for a core group of etiologies, including herpes simplex virus (HSV)-1, varicella zoster virus (VZV), enteroviruses, West Nile virus, and anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis. Empiric acyclovir therapy should be started at presentation and in selected cases continued until a second HSV-1 polymerase chain reaction test is negative. Acyclovir dose can be increased for VZV encephalitis. Supportive care is necessary for other viral etiologies. Patients in whom no cause for encephalitis is identified represent a particular challenge. Management includes repeat brain magnetic resonance imaging, imaging for occult malignancy, and empiric immunomodulatory treatment for autoimmune conditions. Next-generation sequencing (NGS) or brain biopsy should be considered. The rapid pace of discovery regarding autoimmune encephalitis and the development of advanced molecular tests such as NGS have improved diagnosis and outcomes. Research priorities include development of novel therapeutics.

Contactin-associated protein-2 and anti-aquaporin-4 antibody positive autoimmune encephalitis secondary to herpes simplex encephalitis: A case report.

RATIONALE: Recurrent herpes simplex encephalitis (HSE) can easily induce autoimmune encephalitis (AE). However, there are few reports of anti-contactin-associated protein-2 (CASPR2)-related encephalitis, especially with positive anti-aquaporin 4 (AQP4) antibodies. PATIENT CONCERNS: A 14-year-old boy was admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University for "headache, dizziness, and fever for four days" with positive anti-CASPR2 and anti-AQP4 antibodies in the cerebrospinal fluid. DIAGNOSES: Cranial MRI showed lesions in the right hippocampus, amygdala, and insular lobe, with local sulcus enhancement in the right insular, temporal, and frontal lobes. The fluid-attenuated inversion recovery was significantly enhanced. Human herpes virus type I was detected by cerebrospinal fluid metagenomic testing. The patient was diagnosed with AE secondary to HSE, with positive anti-CASPR2 and anti-AQP4 antibodies. INTERVENTIONS: After 2 weeks of immunoglobulin and methylprednisolone immunomodulatory therapy, acyclovir antivirus, mannitol dehydration, reducing intracranial pressure, and other symptomatic support therapy. OUTCOMES: The patient's symptoms significantly improved, with no complaints of discomfort, and he was discharged for observation. The patient was followed up a month after discharge and had no complaints of discomfort. LESSONS: CASPR2 and anti-aquaporin-4 antibody-positive AE have not been reported to be positive. This case will raise awareness of CASPR2 and anti-aquaporin-4 antibody-positive AE secondary to HSE, strengthen diagnostic capacities, and provide advice to treat it.

Comparison of two assays to diagnose herpes simplex virus in patients with central nervous system infections.

BACKGROUND: Multiplex PCR panels are frequently used for detecting the diagnosis of central nervous system infection, but have demonstrated lower sensitivity for herpes simplex virus (HSV) compared to targeted PCRs. Providers in our institution frequently order both multiplex (BioFire Meningitis/Encephalitis Panel (MEP)) and targeted HSV PCR (Diasorin Simplexa HSV-1/2 Direct), allowing comparison of assay performance in practice and a unique clinical characterization of patients with concordant positive or discordant results. METHODS: We retrospectively analyzed all HSV testing performed using the two assays simultaneously in a large multi-center institution between 12/10/2018 and 6/6/2022. We described and compared laboratory, diagnostic and therapeutic data between patients with positive results on both assays with patients with discordant results. RESULTS: 1,387 patients were tested with both assays, of which 25 were positive on at least one assay. Eleven (44%) had discordant results; 9 were targeted-PCR-positive/MEP-negative and 2 were targeted-PCR-negative/MEP-positive. Compared with patients with concordant positive results, discordant targeted PCR-positive/MEP-negative patients had a higher PCR cycle threshold value (i.e., >35) and milder illness characterized by lower CSF WBC counts (4 vs 152; p = 0.032), fewer MRI abnormalities (37.5% vs. 87.5%; p = 0.039), HSV meningoencephalitis as primary discharge diagnosis (33% vs. 100%; p<0.0001) and were more often treated with oral medication or none at all. CONCLUSIONS: Patients with discordant targeted PCR-positive/MEP-negative results represent a population with milder clinical disease. These findings will help clinicians and laboratorians determine when both targeted HSV and multiplex assays should be performed simultaneously and identify patients for whom a multiplex PCR may suffice, despite lower assay sensitivity.

Outcomes of HSV-1 encephalitis infection in glioblastoma: An integrated systematic analysis.

INTRODUCTION: Herpes Simplex Virus-1 (HSV-1) is a neurotropic DNA virus with neural latency and stereotypic viral encephalitis. It has been reported to conceal underlying glioblastoma (GBM) due to similar radiographic imaging and clinical presentation. Limited data exist on the co-occurrence of GBM and HSV-1. To better describe the pathophysiology of HSV-1 superinfections in GBM, we performed a comprehensive review of GBM cases with superimposed HSV-1. METHODS: A comprehensive literature search of six electronic databases with apriori search criteria was performed to identify eligible cases of GBM with HSV-1. Relevant clinic-radiographic data were collected, Kaplan-Meier estimates, Fisher's exact test, and logistic regression analyses were used. RESULTS: We identified 20 cases of HSE in GBM with an overall survival (OS) of 8.0 months. The median age of presentation was 63 years (range: 24-78 years) and the median interval between GBM or HSE diagnosis was 2 months (range: 0.05-25 months). HSE diagnosis before GBM diagnosis was a predictor for improved survival (HR: 0.06; 95% CI: [0.01-0.54]; p < 0.01). There is a significant reduction in OS in patients with concomitant HSE and GBM compared to the cancer genome atlas (TCGA) cohort (median OS: 8 months vs. 14.2 months; p < 0.05). Finally, HSV does not directly infect GBM cells but indirectly activates a local immune response in the tumor microenvironment. CONCLUSIONS: Superimposed HSE in GBM may contribute to a significant reduction in OS compared to uninfected controls, potentially activating proto-oncogenes during active infection and latency. Preoperative HSE may induce an antiviral immune response, which may serve as a positive prognostic factor. Prompt antiviral treatment upon co-occurrence is necessary.

HSV-1 Encephalitis Presenting with Diplopia: Effects of Infection or Autoimmunity?

This report describes a case in which diplopia was developed as a finding of postinfectious anti- N -methyl- d -aspartate receptor encephalitis. Infectious encephalitis, especially herpes simplex virus, is essential as it is one of the triggers of autoimmune encephalitis. Even if the cases present unexpected clinical findings, we should be vigilant in terms of autoimmune processes, such as diplopia seen in our case.

A case of herpes simplex virus induced peripheral neuropathy and encephalitis with positive GM3 and CASPR2 antibody.

BACKGROUND: We reported on a case involving an older patient with HSV-1 encephalitis who simultaneously experienced the onset of peripheral nerve symptoms associated with the presence of anti-GM3 immunoglobulin G (IgG). CASE PRESENTATION: A 77-year-old male was admitted to hospital with high fever, weakness of both lower limbs, and an unstable gait. A CSF test revealed a strikingly increased protein level (1,002 mg/L, normative values: 150-450 mg/L) and MRI revealed hyper-signal lesions in the right temporal lobe, right hippocampus, right insula, and right cingulate gyrus. The CSF was positive for HSV PCR (HSV-1,17870). In addition, the serum samples were positive for CASPR2 antibodies (antibody titer: 1/10) and anti-GM3 immunoglobulin G (IgG) (+). The patient was diagnosed with HSV-1-induced peripheral nerve symptoms that were associated with encephalitis and the presence of anti-GM3 IgG and anti-CASPR2 antibodies. The patient had received included intravenous immunoglobulin, intravenous acyclovir, and corticosteroids therapy. At the one-year follow-up examination, he had regained the necessary skills associated with daily life. CONCLUSIONS: Herpes simplex virus infection often induces encephalitis, and reaction to the virus may trigger an autoimmune response. Early diagnosis and treatment can avoid the progression of the disease to include autoimmune encephalitis.

Autoimmune post-herpes simplex encephalitis. A pediatric clinical case report. / Encefalitis autoinmune posherpética. Caso clínico pediátrico.

Herpes simplex virus (HSV) encephalitis is a common cause of severe and potentially fatal encephalitis. Autoimmune post-herpes simplex encephalitis (AIPHSE) affects a percentage of patients who developed herpes simplex encephalitis (HSE) and is characterized by the onset of new neurological/psychiatric symptoms and/or worsening of deficits acquired during the herpes infection within a predictable time frame. It is caused by a mechanism not related to HSV, but by autoimmune conditions, and is susceptible to treatment with immunomodulators. Here we describe the case of a 5-year-old boy with AIPHSE who required first- and second-line immunomodulatory treatment, with an adequate course and remission of symptoms.

La encefalitis por virus herpes simple (VHS) es una causa frecuente de encefalitis grave y potencialmente fatal. La encefalitis autoinmune posherpética (EAPH) afecta a un porcentaje de los pacientes que han presentado encefalitis herpética (EH) y se caracteriza por la aparición de nuevos síntomas neurológico/psiquiátricos, y/o por el empeoramiento de los déficits adquiridos durante la infección viral dentro de un lapso temporal predecible. Se produce por un mecanismo no relacionado con el VHS, sino por fenómenos autoinmunes, y es susceptible de tratamiento con inmunomoduladores. Se presenta el caso de un varón de 5 años de edad con EAPH que requirió tratamiento inmunomodulador, de primera y segunda línea, con buena evolución y remisión de los síntomas.

When herpes simplex virus encephalitis meets antiviral innate immunity.

Herpes simplex virus (HSV) is the most common pathogen of infectious encephalitis, accounting for nearly half of the confirmed cases of encephalitis. Its clinical symptoms are often atypical. HSV PCR in cerebrospinal fluid is helpful for diagnosis, and the prognosis is usually satisfactory after regular antiviral treatment. Interestingly, some patients with recurrent encephalitis have little antiviral effect. HSV PCR in cerebrospinal fluid is negative, but glucocorticoid has a significant effect after treatment. Specific antibodies, such as the NMDA receptor antibody, the GABA receptor antibody, and even some unknown antibodies, can be isolated from cerebrospinal fluid, proving that the immune system contributes to recurrent encephalitis, but the specific mechanism is still unclear. Based on recent studies, we attempt to summarize the relationship between herpes simplex encephalitis and innate immunity, providing more clues for researchers to explore this field further.

Surgical Management in Herpes Simplex Encephalitis: Illustrative Case Report and Systematic Review of the Literature.

BACKGROUND: Herpes simplex virus (HSV) is a common cause of viral encephalitis and can result in refractory seizures. Although HSV encephalitis (HSVE) is treated primarily with acyclovir, surgery can play a role in medically intractable cases. OBJECTIVE: To systematically review cases describing surgery for the treatment of severe HSVE. We also present an illustrative case of anterior temporal lobectomy (ATL) for refractory status epilepticus in a patient with unilateral HSVE. This case demonstrates one clinical context in which surgery can be a useful adjunct. METHODS: We performed a systematic review using PubMed and Google Scholar, including case reports and series describing surgical interventions for HSVE. Clinical data were extracted from 54 publications that incorporated 67 patient cases. RESULTS: Surgical decompression occurred at a wide range of times after the onset of illness, although most patients were operated on 4 or more days after HSVE symptoms began. Numerous reports indicated that decompressive craniectomy, temporal lobectomy, and hematoma removal could treat intractably elevated intracranial pressure because of HSVE with favorable long-term outcomes. We describe an additional case in which a 52-year-old woman with HSVE developed refractory right temporal lobe seizures. After ATL, the seizures resolved with significant clinical improvement. CONCLUSION: Surgical treatment can be a useful adjunct for treatment of HSVE. There is substantial variability in the timing of surgical decompression in patients with HSVE, which can be necessary up to approximately 3 weeks after illness onset. ATL should be considered for refractory status epilepticus in HSVE with a unilateral seizure focus.

Empirical intravenous aciclovir therapy in a suspected case of acute encephalitis.

Herpes simplex encephalitis is the most common cause of sporadic viral encephalitis worldwide but presents as a diagnostic challenge at many settings due to its non-specific symptoms, which can be easily mistaken for systemic infection or metabolic encephalopathy. It has diverse range of presentations from fever, altered sensorium, nausea, vomiting, meningismus to seizures, neurological deficits and coma in advanced stages. It is associated with significant morbidity and mortality if treatment is delayed or inadequate. We here discuss a case of Herpes simplex virus (HSV) encephalitis which rapidly progressed to result in irreversible neurological insult due to delayed diagnosis and treatment.

Autoimmune Encephalitis with Autoantibodies to NMDAR1 following Herpes Encephalitis in Children and Adolescents.

Herpes simplex virus (HSV) type 1 is a frequent pathogen causing infectious encephalitis (HSVE). Early treatment with intravenous acyclovir has led to a significant decrease in mortality. However, especially in children, deterioration during or after HSVE may occur without any evidence of HSV reactivation or improvement following repeated antiviral therapy. Here, we report 15 patients (age range 3 months to 15 years) who suffered from autoimmune encephalitis with autoantibodies to NMDAR1 following Herpes encephalitis, presenting with movement abnormalities (young children) or neuropsychiatric symptoms (older children) as major complaints, respectively. The diagnosis was based on positive cerebrospinal fluid (CSF) and/or serum anti-NMDAR-antibodies with two children showing only positive CSF antibody findings. The time lag between first symptoms and diagnosis of autoimmune encephalitis was significantly longer than between first symptoms and diagnosis of HSVE (p <0.01). All patients improved during immunosuppressive treatment, during which plasmapheresis or rituximab treatments were applied in 11 patients, irrespective of their age. Despite immunotherapy, no patients relapsed with HSVE. Early diagnosis and treatment of autoimmune encephalitis after HSVE may be associated with a better outcome so that high clinical awareness and routine testing for anti-NMDAR-antibodies after HSVE seems advisable. If autoimmune encephalitis is suspected, antibody testing should also be performed on CSF if negative in serum.