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.

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.

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.

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.

Herpes simplex virus type 2 encephalitis in a child with chronic progressive white matter lesions: A case report.

RATIONALE: This case is a rare manifestation of central nervous system infection of Herpes simplex virus (HSV)-2. Due to few studies in China, it provides a pathological basis for further diagnosis and treatment of HSV-2. PATIENT CONCERNS: We describe a patient with HSV-2 virus infection who was diagnosed with HSV-2 encephalitis in a Chinese patient. DIAGNOSIS: Based on brain biopsy and pathological findings, the patient was diagnosed with HSV-2 encephalitis. INTERVENTIONS: Hormone and antiviral therapy were given. OUTCOME: The patient eventually died. LESSONS: The diagnosis and differential diagnosis of the disease is very difficult. Its differential diagnosis include cerebrovascular disease, bacteria or fungi and other viral infection of the brain.

Herpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review.

BACKGROUND Several cases of herpes simplex virus type 1 meningoencephalitis (HSVE) have been reported in patients receiving steroids, but the exact contribution of steroids to the disorder remains unclear because other risk factors, such as chemotherapy, brain radiation, or surgery, were present in almost all cases. CASE REPORT We report the case of a 76-year-old man who developed HSVE following the administration of pulse-dose steroids. The patient had occupational asbestos exposure and a chronic interstitial lung disease of unclear etiology (sarcoidosis versus hypersensitivity pneumonitis) and was admitted for acute-on-chronic respiratory failure requiring mechanical ventilation. After a negative infectious workup and several days of antibiotics without improvement, pulse-dose steroids were administered. In the following days, the patient developed a fever and worsening encephalopathy. A lumbar puncture showed elevated nucleated cells and positive polymerase chain reaction for herpes simplex virus 1 in the cerebrospinal fluid, confirming the diagnosis of HSVE. Acyclovir treatment was initiated, but the patient later died as a result of persistent severe encephalopathy and respiratory failure with an inability to wean mechanical ventilation. CONCLUSIONS Clinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids, taking into account associated factors of immunosuppression. A high level of awareness should be especially maintained in critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway.

OBJECTIVE: To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE). METHODS: This study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non-inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA. RESULTS: Kyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non-inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups. INTERPRETATION: The results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.

Fas/FasL Contributes to HSV-1 Brain Infection and Neuroinflammation.

The Fas/FasL pathway plays a key role in immune homeostasis and immune surveillance. In the central nervous system (CNS) Fas/FasL is involved in axonal outgrowth and adult neurogenesis. However, little is known about the role of the Fas/FasL pathway in herpes encephalitis. In this study, we used a neuropathogenic clinical strain of herpes simplex virus type 1 (HSV-1) to explore infection-induced inflammation and immune responses in the mouse brain and the role of Fas/FasL in antiviral CNS immunity. HSV-1 CNS infection induced the infiltration of Fas- FasL-bearing monocytes and T cells in the brain and also to an up-regulation of Fas and FasL expression on resident astrocytes and microglia within infected sites. Upon infection, Fas- and FasL-deficient mice (lpr and gld) were partially protected from encephalitis with a decreased morbidity and mortality compared to WT mice. Fas/FasL deficiency promoted cell-mediated immunity within the CNS. Fas receptor stimulation abrogated HSV-1 induced activation and inflammatory reactions in microglia from WT mice, while lack of Fas or FasL led to a more pronounced activation of monocytes and microglia and also to an enhanced differentiation of these cells into a pro-inflammatory M1 phenotype. Furthermore, the specific immune system was more efficient in Fas- and FasL-deficient mice with significantly higher numbers of infiltrating HSV-1-specific cytotoxic T cells in the brain. Our data indicate that the Fas/FasL pathway leads to excessive neuroinflammation during HSV-1 infection, which is associated with a diminished anti-viral response and an excessive neuroinflammation.

Acute HSV and anti-NMDA encephalitis occurring as a neurosurgical complication.

We present a 24-year-old man with a 2-year history of progressive right-sided monocular vision loss with no other symptoms. An MRI showed a meningioma compressing the right optic nerve and the cavernous sinus. The tumour was partially resected. Eight days after discharge the patient was admitted with fever, a severe stabbing headache, insomnia, nausea and vomiting. A FilmArray panel and a cerebral biopsy were performed which were positive for herpes simplex virus 1 (HSV-1). An MRI of the brain showed asymmetric bilateral lesions in the frontobasal region with predominance of the right side. Acyclovir was started and continued until completing 21 days. A month after discharge, he started experiencing insomnia, trichotillomania, limb tremor, persistence of abulia, apathy and emotional lability. An HSV-1 encephalitis relapse was suspected, acyclovir and foscarnet were started. Due to the poor response to antiviral therapy CSF was tested, which was positive for anti-NMDA receptor encephalitis. A treatment course of intravenous immunoglobulin was started with a favourable outcome.

Encefalite herpética associada a mieloma múltiplo: desafio diagnóstico / Herpetic encephalitis associated with multiple myeloma: a diagnostic challenge

O mieloma múltiplo é a segunda neoplasia onco-hematológica mais comum, correspondendo a 1% das neoplasias malignas. Trata-se de uma condição subdiagnosticada, assim como a encefalite herpética. Entretanto, é comum a relação do mieloma com infecções, em decorrência do acometimento da imunidade humoral. A encefalite viral herpética tem como principal agente o vírus do herpes simples 1. O caso foi descrito baseado em um raciocínio clínico, visando contribuir para uma melhor caracterização do quadro clínico e do diagnóstico de duas entidades clínicas que possuem baixa suspeição diagnóstica e elevada morbimortalidade. Durante o curso da investigação, foram propostas variadas etiologias como responsáveis pelo rebaixamento do nível de consciência, levando a uma pesquisa de um espectro mais amplo de hipóteses diagnósticas, as quais precederam a confirmação do diagnóstico final. O quadro clínico atípico descrito apresentou obstáculos à suspeição diagnóstica correta, pois a ausência dos sinais e sintomas característicos de ambas as doenças levaram à pesquisa de um arsenal mais amplo de diagnósticos diferenciais. Assim, o atraso no diagnóstico e o início tardio do tratamento foram fatores que contribuíram para o prognóstico reservado do paciente. A associação dessas doenças é pouco descrita na literatura, de modo que mais estudos acerca do assunto se fazem necessários. (AU)

Multiple myeloma is the second most common onco-hematologic neoplasm, accounting for 1% of malignant neoplasms. As herpetic encephalitis, it is an underdiagnosed condition. However, the relation of myeloma with infections is common, due to the involvement of humoral immunity. Herpetic encephalitis has as its main etiological agent the herpes simplex virus 1. The case was described based on a clinical reasoning, aiming to contribute to a better characterization of the clinical picture and diagnosis of two entities that have low rates of diagnostic suspicion and high rates of morbidity and mortality. During the course of investigation, several etiologies were proposed as responsible for the decreased level of consciousness, leading to a search for a broader range of diagnostic hypotheses, which preceded confirmation of the final diagnosis. The atypical clinical picture described presented obstacles to the correct diagnostic suspicion, as the absence of symptoms and signs characteristic of both diseases led to the search for a broader arsenal of differential diagnoses. Thus, delayed diagnosis and late treatment were factors that contributed to the patient's reserved prognosis. The association of these diseases is poorly described in the literature, so further studies on that subject are required. (AU)

Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.

BACKGROUND: Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN). CASE PRESENTATION: We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later. CONCLUSIONS: The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.

Meningoencefalitis por herpesvirus varicelazóster como síndrome inflamatorio de reconstitución inmune. Una manifestación clínica infrecuente / VARICELLA-ZOSTER HERPESVIRUS MENINGOENCEPHALITIS AS AN INFLAMMATORY SYNDROME OF IMMUNE RECONSTITUTION. An uncommon clinical manifestation

El uso cada vez más difundido de la terapia antirretroviral de gran actividad (TARGA) en el tratamiento de los pacientes con infección por el virus de la inmunodeficiencia humana (VIH) puede dar lugar a respuestas paradojales, caracterizadas por un empeoramiento de las manifestaciones clínicas o la reactivación de ciertas infecciones oportunistas, hasta ese momento subclínicas, como el Herpes varicela-zóster (HVZ). Este cuadro clínico se conoce desde hace años como síndrome inflamatorio de reconstitución inmune (SIRI). Puede afectar a más del 30% de los pacientes seropositivos para el VIH con un tiempo de aparición promedio de 8 a 12 semanas luego del inicio o cambio de TARGA. El HZ mucocutáneo representa entre el 7% al 12% de los episodios de SIRI en estos pacientes. En este trabajo, se presenta un paciente VIH seropositivo que desarrolló un episodio de HVZ cutáneo monometamérico asociado a compromiso del sistema nervioso central bajo la forma de un síndrome meningoencefalítico

The use of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV) infection has resulted in a paradoxical response associated with the worsening of clinical symptoms of previously subclinical infections, such as herpes varicella-zoster (HVZ). This clinical picture is named as immune reconstitution inflammatory syndrome (IRIS). It may affect up to 30% of HIV-seropositive subjects within a wide range of time after the initiation or change of HAART, but mainly after 8 to 12 weeks. Mucocutaneous HZ accounts for 7%-12% of the diseases associated with HIV infection in patients with immune reconstitution from the administration of HAART. Here we present an HIV seropositive patient that developed an episode of cutaneous metameric eruption of HVZ associated with central nervous system involvement as meningoencephalitis syndrome.

[The Turning Point of Diagnostic Process for Infectious Disease of Nervous System].

Infectious diseases of the nervous system are a group of diseases; timely diagnosis and treatment for these diseases determines the effect of prognosis on life and functions. Diagnosis itself is not very difficult in cases presenting with typical symptoms. However, if mild and atypical symptoms have been present for long, the underlying disease may not be easily recognized as a neurological disease or infectious disorder, and the diagnosis may be delayed. Furthermore, neurologists may not always be able to examine patients from the first visit itself. In this chapter, I present three cases with mild and atypical initial symptoms. The first case involved a patient with tetanus, whose initial symptom was dysphagia, and the onset of trismus was the turning point for diagnosis. The second case involved a patient with herpes simplex encephalitis. Dyshydrosis and dysosmia were the initial symptoms, and the appearance of disorientation, fever, and consciousness disturbance helped in achieving the final diagnosis. The last case was of a patient with Japanese encephalitis, whose initial symptoms were fever and parkinsonism. A recent history of surgery for gastric cancer, disease onset in the summer season, and living with neighbors on pig farms was indicative of Japanese encephalitis.