Clinical characteristics and outcomes of patients with Herpes Simplex Encephalitis in Vietnam: a retrospective study.

BACKGROUND: Herpes simplex encephalitis (HSE) is an important central nervous infection with severe neurological sequelae. The aim of this study was to describe clinical characteristic and outcomes of patients with HSE in Vietnam. METHODS: This was a retrospective study of 66 patients with herpes simplex encephalitis who admitted to the National Hospital for Tropical Diseases, Hanoi, Vietnam from 2018 to 2021. The detection of herpes simplex virus (HSV) in cerebrospinal fluid was made by the real-time PCR assay. We reported the clinical manifestation on admission and evaluated clinical outcomes at the hospital discharge by modified Rankin Scale (mRS). Multivariate logistic regression analysis was used to analyze the independent risk factors of severe outcomes. RESULTS: Of the 66 patients with laboratory confirmed HSE, the median age was 53 years (IQR 38-60) and 44 patients (69.7%) were male. The most common manifestations included fever (100%), followed by the consciousness disorder (95.5%). Other neurological manifestation were seizures (36.4%), memory disorders (31.8%), language disorders (19.7%) and behavioral disorders (13.6%). Conventional magnetic resonance imaging (MRI) showed 93.8% patients with temporal lobe lesions, followed by abnormalities in insula (50%), frontal lobe (34.4%) and 48.4% of patients had bilateral lesions. At discharge, 19 patients (28.8%) completely recovered, 15 patients (22.7%) had mild sequelae, 28 patients (42.4%) had moderate to severe sequelae. Severe neurological sequelae were memory disorders (55.8%), movement disorders (53.5%), language disorders (30.2%). Multivariate logistic regression analysis showed that Glasgow score decrement at admission, seizures, and time duration from onset of symptoms to the start of Acyclovir treatment > 4 days were independent factors associated with severe outcomes in HSE patients. CONCLUSION: Glasgow score decrement, seizures and delay treatment with Acyclovir were associated with the poor outcome of patients with HSE.

Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.

BACKGROUND AND OBJECTIVES: Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for ∼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. METHODS: We used the US Medicaid Analytic eXtract data between 2007 and 2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age and sex-matched adult cases of HSVE with a sufficient enrollment period (12 months before HSVE diagnosis) to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson Comorbidity Index, and non-autoimmune comorbidities. RESULTS: Incidence of HSVE was ∼3.01 per 105 person-years among adults. A total of 951 HSVE cases and 95,100 age and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong (adjusted odds ratio (OR) 2.6; 95% CI 2.2-3.2). The association of HSVE and immunomodulating medications had an OR of 2.2 (CI 1.9-2.6), also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: OR 2.3 (CI 1.9-2.7) for autoimmune disease and 2.0 (CI 1.7-2.3) for immunosuppressive and immunomodulatory medications. DISCUSSION: In a large, national population, HSVE is strongly associated with preexisting autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date.

An Observational Study on Pattern of Empirical Acyclovir Therapy in Children With Acute Encephalitis From Northern India.

OBJECTIVES: To identify the prevalence of herpes simplex encephalitis (HSE), factors influencing the duration of empirical acyclovir and frequency of acute kidney injury (AKI) in children with acute encephalitis syndrome (AES). DESIGN: Prospective observational study. SETTING: Pediatric Emergency Department and PICU of a tertiary hospital in Northern India. PATIENTS: All consecutive, eligible children between 1 month and 12 years old presenting with AES, defined as altered consciousness for greater than 24 hours (including lethargy, irritability, or a change in personality) and two or more of the following signs: 1) fever (temperature ≥ 38°C) during the current illness, 2) seizures or focal neurological signs, 3) cerebrospinal fluid (CSF) pleocytosis, 4) electroencephalogram, and/or 5) neuroimaging suggesting encephalitis, who received at least one dose of acyclovir. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 101 children screened, 83 were enrolled. The median (interquartile range [IQR]) age was 3 years (1-6 yr). Thirty-one children (37.3%) were diagnosed with AES, of which four were labeled as probable HSE (three based on MRI brain, one based on serology). Scrub typhus, dengue, Japanese encephalitis, and mumps were the other infective causes. The median (IQR) duration of acyclovir therapy was 72 hours (24-264 hr); 21 children (25.3%) received acyclovir for less than 24 hours and 11 (13.3%) for greater than or equal to 14 days. New-onset AKI was seen in 18 children (21.7%) but was mostly transient. Death ( n = 8, 9.6%) and discontinuation of care due to futility or other reasons ( n = 15, 18%) were noted in 23 children (28%). Factors associated with duration of acyclovir greater than 7 days, on univariable analysis, were lower modified Glasgow Coma Score at admission, requirement of invasive ventilation, invasive intracranial pressure monitoring, and CSF pleocytosis (5-500 cells). On multivariable analysis, only CSF pleocytosis of 5-500 cells was associated with duration of acyclovir greater than 7 days. CONCLUSIONS: Given the low prevalence of HSE, and the risk of AKI, this study sensitizes the need to review our practice on initiation and stopping of empirical acyclovir in children with acute encephalitis.

Epidemiology and long-term neurological sequelae of childhood herpes simplex CNS infection.

AIM: Herpes simplex CNS infection is a rare but important cause of neurological disability. Long term outcomes after HSV CNS infection in Australia have not yet been fully described. We sought to provide a comprehensive review of HSV CNS infection in children using a retrospective 13-year evaluation of statewide laboratory and clinical records and a parent survey conducted at least one year after the initial infection. METHODS: All positive PCR HSV 1 and 2 results from cerebrospinal fluid (CSF) or brain tissue were obtained from Queensland pathology providers for children aged 0-16 years between 1 January 2005 and 31 December 2017. Clinical data were obtained from patient records and longer-term outcomes via parent survey at least 1 year after initial infection. RESULTS: Forty-three children were identified over the 13-year period, 17 (39.5%) neonates and 26 (60.4%) non-neonates. The annual incidence for HSV CNS infection in Queensland children aged ≤16 years was 0.3/100 000 (95% confidence intervals (CIs): 0.2-0.4) with neonates at highest risk (incidence 2.5/100 000 live births, 95% CI: 1.5-3.9). HSV 1 was the predominant serotype in both neonates and non-neonates (9/17, 52.9% neonates and 19/26, 73.1% non-neonates). Seven (16.3%) children died, five (5/17, 29.4% neonates), directly attributable to HSV CNS infection (all neonates). Twenty-five (58.1%) had neurological morbidity at discharge (9/17 neonates (52.9%) vs. 16/26 (61.5%) non-neonates) and 20/27 (74.1%) reported long-term neurological morbidity at follow-up (5/9 neonates (55.6%) vs. 15/18 non-neonates (83.3%)). Seven children (two neonates and four non-neonates) with long-term neurological sequelae had no neurological morbidity identified at discharge. CONCLUSION: Significant long-term neurologic sequelae were seen in children with HSV CNS infection even in children with no neurological disability identified at discharge from hospital. Careful neurodevelopmental follow-up of all children is recommended.

Herpes Simplex Virus Encephalitis With Initial Negative Polymerase Chain Reaction in the Cerebrospinal Fluid: Prevalence, Associated Factors, and Clinical Impact.

OBJECTIVES: To describe the prevalence, associated factors, and clinical impact of an initial negative herpes simplex virus (HSV) polymerase chain reaction (PCR) in critically ill patients with PCR-proven HSV encephalitis. DESIGN: Retrospective multicenter study from 2007 to 2017. SETTING: Forty-seven French ICUs. PATIENTS: Critically ill patients admitted to the ICU with possible/probable acute encephalitis and a positive cerebrospinal fluid (CSF) PCR for HSV. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 273 patients with a median Glasgow Coma Scale score of 9 (6-12) at ICU admission. CSF HSV PCR was negative in 11 cases (4%), exclusively in lumbar punctures (LPs) performed less than 4 days after symptoms onset. Patients with an initial negative PCR presented with more frequent focal neurologic signs (4/11 [36.4%] vs 35/256 [13.7%]; p = 0.04) and lower CSF leukocytosis (4 cells/mm3 [3-25 cells/mm3] vs 52 cells/mm3 [12-160 cells/mm3]; p < 0.01). An initial negative PCR was associated with an increased delay between LP and acyclovir treatment (3 d [2-7 ] vs 0 d [0-0 d]; p < 0.01) and was independently associated with a poor neurologic outcome at hospital discharge (modified Rankin Scale score ≥ 4) (adjusted odds ratio, 9.89; 95% CI, 1.18-82.78). CONCLUSIONS: In severe herpes simplex encephalitis, initial negative CSF HSV PCR occurred in 4% of cases and was independently associated with worse neurologic outcome at hospital discharge. In these patients, a systematic multimodal diagnostic approach including early brain MRI and EEG will help clinicians avoid delayed acyclovir initiation or early inappropriate discontinuation.

US Hospitalizations and 60-Day Readmission Rates Associated With Herpes Simplex Virus Encephalitis: Analysis of All Cause Readmissions and Encephalopathy Associated Readmissions.

BACKGROUND: Herpes simplex encephalitis (HSE) is the most common cause of encephalitis hospitalizations. We sought to describe and analyze features associated with all cause readmissions and encephalopathy associated readmissions amongst HSE cases. METHODS: HSE hospitalizations and 60-day rehospitalizations were assessed in a retrospective cohort using linked hospitalizations from the Healthcare Utilization Project (HCUP) National Readmission Database (NRD) from 2010 through 2017. Risk factors for all-cause readmissions and encephalopathy associated readmissions were assessed with a weighted logistic regression model. RESULTS: There were 10 272 HSE cases in the US between 2010 and 2017, resulting in a national rate of 4.95 per 100 000 hospitalizations. A total of 23.7% were readmitted at least once within 60-days. Patients that were readmitted were older (mean age 62.4 vs 57.9, P < .001), had a greater number of procedures at the index hospitalization (adjusted odds ratio [aOR] 1.03, P < .001) and have a higher Charlson comorbidity score (aOR 1.11, P < .001). Among those readmitted, 465 (16.5%) had an encephalopathy related diagnosis. Over 8 years, the rate of encephalopathy associated readmissions increased from 0.12 to 0.20. Encephalopathy specific readmissions were found to be associated with greater age (mean age 65.9 vs 61.7, P = .004) and findings of cerebral edema at index hospitalization (aOR 2.16, P < .001). CONCLUSIONS: HSE readmissions are relatively common, particularly among older and sicker individuals. However, early signs and symptoms of neurological disease at index were correlated with encephalopathic specific readmissions.

Assessment of Magnetic Resonance Imaging Changes and Functional Outcomes Among Adults With Severe Herpes Simplex Encephalitis.

Importance: Current guidelines recommend brain magnetic resonance imaging (MRI) for clinical management of patients with severe herpes simplex encephalitis (HSE). However, the prognostic value of brain imaging has not been demonstrated in this setting. Objective: To investigate the association between early brain MRI data and functional outcomes of patients with HSE at 90 days after intensive care unit (ICU) admission. Design, Setting, and Participants: This multicenter cohort study was conducted in 34 ICUs in France from 2007 to 2019 and recruited all patients who received a clinical diagnosis of encephalitis and exhibited cerebrospinal fluid positivity for herpes simplex virus DNA in the polymerase chain reaction analysis. Data analysis was performed from January to April 2020. Exposures: All patients underwent a standard brain MRI during the first 30 days after ICU admission. Main Outcomes and Measures: MRI acquisitions were analyzed by radiologists blinded to patients' outcomes, using a predefined score. Multivariable logistic regression and supervised hierarchical classifiers methods were used to identify factors associated with poor outcome at 90 days, defined by a score of 3 to 6 (indicating moderate-to-severe disability or death) on the Modified Rankin Scale. Results: Overall, 138 patients (median [interquartile range {IQR}] age, 62.6 [54.0-72.0] years; 75 men [54.3%]) with an admission median (IQR) Glasgow Coma Scale score of 9 (6-12) were studied. The median (IQR) delay between ICU admission and MRI was 1 (1-7) days. At 90 days, 95 patients (68.8%) had a poor outcome, including 16 deaths (11.6%). The presence of fluid-attenuated inversion recovery MRI signal abnormalities in more than 3 brain lobes (odds ratio [OR], 25.71; 95% CI, 1.21-554.42), age older than 60 years (OR, 7.62; 95% CI, 2.02-28.91), and the presence of diffusion-weighted MRI signal abnormalities in the left thalamus (OR, 6.90; 95% CI, 1.12-43.00) were independently associated with poor outcome. Machine learning models identified bilateral diffusion abnormalities as an additional factor associated with poor outcome (34 of 39 patients [87.2%] with bilateral abnormalities had poor outcomes) and confirmed the functional burden of left thalamic lesions, particularly in older patients (all 11 patients aged >60 years had left thalamic lesions). Conclusions and Relevance: These findings suggest that in adult patients with HSE requiring ICU admission, extensive MRI changes in the brain are independently associated with poor functional outcome at 90 days. Thalamic diffusion signal changes were frequently observed and were associated with poor prognosis, mainly in older patients.

Pediatric N-Methyl-d-Aspartate (NMDA) Receptor Encephalitis, With and Without Herpes Encephalitis.

OBJECTIVE: To compare clinical, diagnostic, management, and outcome factors in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and a history of herpes simplex encephalitis (HSE) to children with NMDAR encephalitis without a history of HSE. METHODS: All patients with anti-NMDAR antibodies in cerebrospinal fluid treated at our institution between 2012 and 2019 were identified and divided into those with a history of HSE (HSE+NMDAR group) and those without a history of HSE (NMDAR-only group). Demographic data, clinical characteristics, immunotherapy, and outcome data were collected on all patients and compared between the 2 groups. RESULTS: Seventeen patients were identified with anti-NMDAR antibodies in cerebrospinal fluid, 6 of whom had a history of HSE. Mean age in the HSE+NMDAR cohort was significantly younger in the HSE+NMDAR cohort, as 5 of the 6 patients were infants. Of HSE+NMDAR patients, 50% had behavioral symptoms, 67% had movement disorders, and 100% had seizures at disease nadir. In the NMDAR-only group, 100% had behavioral symptoms, 73% had movement disorders, and 73% had seizures at nadir. HSE+NMDAR patients received a median of 1 immunotherapy, compared to a median of 4.5 immunotherapies in the NMDAR-only group. CONCLUSION: Behavioral symptoms were more common in NMDAR-only patients, whereas seizures were more common in HSE+NMDAR patients. Both groups had significant disability at disease nadir, with more improvement in disability over time in the NMDAR-only group. HSE+NMDAR patients received fewer immunotherapies than NMDAR-only patients. Outcomes of infants with HSE appear to primarily reflect sequelae from HSE.

Epilepsy after brain infection in adults: A register-based population-wide study.

OBJECTIVE: To describe risk and risk factors of epilepsy after hospitalization for brain infection in adults in Sweden. METHODS: This was a matched retrospective cohort study based on the comprehensive National Patient and Cause of Death Registers. All individuals age >18 without prior epilepsy who received inpatient care in 2000-2010 for a brain infection were included, with 3 age- and sex-matched unexposed controls per exposed individual (n = 12,101 exposed and 36,228 controls). Kaplan-Meier risks of epilepsy after different brain infections were calculated and risk factors identified by Cox regression. Patients were followed until the end of 2017. RESULTS: The 10-year risk of epilepsy was 5.9% (95% confidence interval [CI] 5.5-6.3) in cases and 1.2% (95% CI 1.0-1.4) in controls: 1.7% (95% CI 0.7-2.7) after tick-borne encephalitis, 4.1% (95% CI 3.3-4.9) after bacterial meningitis, 26.0% (95% CI 21.5-30.5) after herpes simplex virus encephalitis, and 30.2% (95% CI 27.1-33.3) after brain abscess. In Cox regression, seizure during the index admission and mechanical ventilation were epilepsy risk factors. CONCLUSIONS: Epilepsy is common after several types of brain infections in adults. The type of infection, its severity, and propensity to cause seizures in the acute phase influence the risk of subsequent epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in adults, brain infection is associated with an increased risk of subsequent epilepsy.

Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity.

Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/ß immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.

Functional outcomes in adult patients with herpes simplex encephalitis admitted to the ICU: a multicenter cohort study.

PURPOSE: We aimed to study the association of body temperature and other admission factors with outcomes of herpes simplex encephalitis (HSE) adult patients requiring ICU admission. METHODS: We conducted a retrospective multicenter study on patients diagnosed with HSE in 47 ICUs in France, between 2007 and 2017. Fever was defined as a body temperature higher or equal to 38.3 °C. Multivariate logistic regression analysis was used to identify factors associated with poor outcome at 90 days, defined by a score of 3-6 (indicating moderate-to-severe disability or death) on the modified Rankin scale. RESULTS: Overall, 259 patients with a score on the Glasgow coma scale of 9 (6-12) and a body temperature of 38.7 (38.1-39.2) °C at admission were studied. At 90 days, 185 (71%) patients had a poor outcome, including 44 (17%) deaths. After adjusting for age, fever (OR = 2.21; 95% CI 1.18-4.16), mechanical ventilation (OR = 2.21; 95% CI 1.21-4.03), and MRI brain lesions > 3 lobes (OR = 3.04; 95% CI 1.35-6.81) were independently associated with poor outcome. By contrast, a direct ICU admission, as compared to initial admission to the hospital wards (i.e., indirect ICU admission), was protective (OR = 0.52; 95% CI 0.28-0.95). Sensitivity analyses performed after adjustment for functional status before admission and reason for ICU admission yielded similar results. CONCLUSIONS: In HSE adult patients requiring ICU admission, several admission factors are associated with an increased risk of poor functional outcome. The identification of potentially modifiable factors, namely, elevated admission body temperature and indirect ICU admission, provides an opportunity for testing further intervention strategies.

Acute retinal necrosis following herpes simplex encephalitis: a nationwide survey in Japan.

PURPOSE: Acute retinal necrosis (ARN) is a severe necrotizing retinitis caused by varicella-zoster virus or herpes simplex virus (HSV) that often results in blindness. Occasionally, HSV-caused ARN develops after herpes simplex encephalitis (HSE). It remains unknown, however, when and how often ARN develops after HSE. To investigate the actual conditions of patients with ARN following HSE and the interval period between the prior HSE and the onset of ARN, a retrospective nationwide survey of the Japanese population was performed. STUDY DESIGN: Retrospective. METHODS: Questionnaires were sent out to the neurology and ophthalmology departments of teaching hospitals in Japan. They inquired about HSE patients in neurology departments and ARN patients diagnosed with HSV in ophthalmology departments. The proportion of the HSV-ARN patients with a history of HSE and their interval periods were obtained from the questionnaires returned by the ophthalmology departments. RESULTS: Neurology departments of 324 hospitals responded to the questionnaires (response proportion: 40.9%), and 53 HSE cases were reported. Ophthalmology departments of 535 hospitals responded the questionnaires (response proportion: 54.3%), and 67 HSV-ARN cases were reported. Among the 67 HSV-ARN cases, 16 (23.9%) had histories of prior HSE. Although the interval periods from the prior HSE to the onset of HSV-ARN varied among cases, nearly half developed HSV-ARN within 2 years. CONCLUSIONS: This nationwide survey of the Japanese population showed that HSV-ARN develops after HSE in higher frequency within 2 years. Neurologists and ophthalmologists should be aware that HSE survivors have a risk of contracting HSV-ARN.

Hyponatremia Is Predictive of HSV-1 Encephalitis among Patients with Viral Encephalitis.

Encephalitis is an inflammatory process involving the brain parenchyma associated with neurologic dysfunction. The main causes of infectious encephalitis are viruses, including Herpes simplex virus type 1 (HSV-1). As the mortality rate of HSV-1 encephalitis could be reduced with early acyclovir treatment, it is imperative to distinguish HSV-1 encephalitis from other type of viral encephalitis as early as possible. However, sophisticated methods for definitive diagnosis of HSV-1 encephalitis are not readily available. We aimed to explore distinctive clinical and laboratory features of HSV-1 encephalitis. All of the adult patients with viral encephalitis hospitalized between 2011-2017 were enrolled, including 16 patients with HSV-1 encephalitis and 51 patients non-HSV-1 viral encephalitis. Determination of viruses in cerebrospinal fluid was performed by PCR tests. Female sex, hyponatremia, and abnormalities in MRI were independently associated with HSV-1 encephalitis (p < 0.05 for each). In particular, hyponatremia (< 135 mEq/L) was found in nine patients with HSV-1 encephalitis (56.3%) and 10 patients with non-HSV-1 viral encephalitis (19.6%) (p = 0.005). As serum sodium is determined easily and quickly in clinical practice, the presence of hyponatremia among patients with viral encephalitis could be helpful for the early diagnosis of HSV-1 encephalitis before cerebrospinal fluid PCR results were available. Moreover, the presence of positive finding in MRI could further support the diagnosis. This is the first study that compared the serum sodium levels among patients between HSV-1 and non-HSV-1 viral encephalitis. We thus propose the diagnostic value of hyponatremia for HSV-1 encephalitis.

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

BACKGROUND: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). INTERPRETATION: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy. FUNDING: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Caracterização etiológica, epidemiológica e clínico-patológica da meningoencefalite por herpesvírus bovino em bovinos no Estado de Goiás / Etiological, epidemiological, clinical and pathological characterization of meningoencephalitis in cattle by bovine herpesvirus in the State of Goiás, Brazil

Foram estudados 26 casos de meningoencefalite por herpesvírus bovino (BoHV) diagnosticados entre 2010-2016, no Estado de Goiás (GO). A doença acometeu principalmente bovinos jovens, entre 60 dias a 18 meses de idade. Não houve associação entre os casos e o sexo dos bovinos e a sazonalidade. A doença foi observada em todas as cinco Mesorregiões do Estado, com uma frequência maior nas Mesorregiões Sul e Centro. Os sinais clínicos mais frequentemente observados incluíram cegueira, incoordenação, sialorreia e ataxia. As principais alterações macroscópicas observadas incluíram congestão com tumefação e achatamento das circunvoluções, amolecimento e amarelamento do córtex telencefálico e focos de hemorragia. Em cinco encéfalos, não foram observadas alterações macroscópicas e em quatro as alterações não foram informadas. As principais alterações histológicas ocorreram no córtex telencefálico, principalmente o córtex frontal e parietal, mas em alguns casos, lesões de menor intensidade foram também observadas no tálamo, núcleos basais, mesencéfalo, ponte, bulbo, cerebelo e hipocampo. Todos os casos apresentaram meningoencefalite linfoplasmocítica e corpúsculos de inclusão intranucleares basofílicos em astrócitos e, eventualmente, em neurônios. Outras lesões frequentes incluíram necrose neuronal laminar segmentar (neurônio vermelho), espongiose, tumefação do núcleo das células endoteliais, gliose focal ou difusa, hipertrofia de astrócitos, infiltração por células gitter, congestão e hemorragia. Lesões menos comuns incluíram astrócitos Alzheimer tipo II, lesão residual e neuronofagia. A necrose neuronal e o edema (espongiose) foram mais acentuados nas camadas granular externa, molecular, de células piramidais e granular interna dos telencéfalos. Tanto os giros quanto os sulcos foram afetados igualmente. Dos 26 casos, o DNA de BoHV-5 foi amplificado em dois (7,69%) casos, enquanto que o de BoHV-1 foi identificado em um caso (3,84%). Nos casos positivos para BoHV-5 foram usadas amostras fixadas em formol a 10% e incluídas em parafina e amostras congeladas foram utilizadas no caso positivo para BoHV-1.(AU)

Twenty six cases of bovine herpetic meningoencephalitis diagnosed from 2010-2016 in Goiás state, Brazil, were studied. Affected cattle were mainly 60-day to 18-month-old. There was no association of the disease with sex and seasonality. The disease was found in all five mesoregions with a higher prevalence in southern and central state of Goiás. Clinical signs more frequently observed included blindness, incoordination, circling, excessive salivation, and ataxia. Main gross findings in the brain were congestion with swelling and flattening of gyri, softening and yellow discoloration of cerebral cortex and hemorrhagic foci. In five cases no gross changes were observed in the brain and in four cases there is no information. The main histopathological changes were in the cortex of telencephalic lobes, especially the frontal and parietal; however less prominent and less frequently found lesions occurred in the thalamus, basal nuclei, midbrain, pons, medulla oblongata, cerebellum, and hippocampus. All cases presented lymphoplasmocytic meningoencephalitis and intranuclear basophilic inclusion bodies in astrocytes, less commonly in neurons. Other frequent lesions included segmental laminar neuronal necrosis (red neurons), spongiosis, swollen vascular endothelial nuclei, gliosis (focal and diffuse), hypertrophy of astrocytes, infiltration of gitter cells, congestion, and hemorrhage. Lesions less frequently observed were Alzheimer type II astrocytes, residual lesion and neuronophagia. The most frequently affected cortical layers by neuronal necrosis and edema were external and internal granular, molecular, and pyramidal cell layers. Gyri and sulci were equally affected. Of the 26 cases, in 2 (7.69%) the DNA of BoHV-5 was amplified with samples fixed in 10% formalin and paraffin-embedded. DNA of BoHV-1 was identified in another case (3.84%) where, positive to BoHV-1, fresh samples were used.(AU)

Infectious meningitis and encephalitis in adults in Denmark: a prospective nationwide observational cohort study (DASGIB).

OBJECTIVES: To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark. METHODS: Nationwide prospective observational study of all cases of proven community-acquired infectious meningitis and encephalitis in adults treated in all infectious diseases departments in Denmark from 1 January 2015 to 30 June 2016. We included data on symptoms, aetiology, treatment and outcome assessed by the Glasgow Outcome Scale (GOS) 30 days after discharge. GOS 1-4 was categorized as unfavourable outcome. RESULTS: During 18 months of observation, we identified 252 cases of viral meningitis (3.6/100 000/year), 214 cases of bacterial meningitis (3.1/100 000/year) and 96 cases of infectious encephalitis (1.4/100 000/year). In bacterial meningitis, Streptococcus pneumoniae was the most frequent infectious agent (n = 101) followed by Staphylococcus aureus (n = 24) and ß-haemolytic streptococci (n = 14). Meningococcal meningitis was rare (n = 11). In encephalitis, herpes simplex virus type 1 was most common (n = 37) followed by varicella zoster virus (n = 20), whereas varicella zoster virus (n = 61) was most common in viral meningitis followed by enterovirus (n = 50) and herpes simplex virus type 2 (n = 46). Case fatality and unfavourable outcome occurred in 31/214 (15%) and 96/214 (45%) with bacterial meningitis and in 5/96 (5%) and 55/89 (62%) with encephalitis. For viral meningitis, unfavourable outcome occurred in 41/252 (17%). CONCLUSIONS: The epidemiology and clinical presentation of the examined central nervous system infections differed considerably and bacterial meningitis was more frequent than previously estimated. Overall prognosis remains poor for bacterial meningitis and encephalitis. Prospective nationwide clinical databases of central nervous system infections may be superior to epidemiological monitoring based on notifications or laboratory systems.

[Clinical, epidemiological, and etiological studies of adult aseptic meningitis: a report of 12 cases of herpes simplex meningitis, and a comparison with cases of herpes simplex encephalitis].

We treated 437 cases of adult aseptic meningitis and 12 cases (including 2 recurrent patients; age, 31.8 ± 8.9 years; 7 females) of herpes simplex meningitis from 2004 to 2016. The incidence rate of adult herpes simplex meningitis in the cases with aseptic meningitis was 2.7%. One patient was admitted during treatment of genital herpes, but no association was observed between genital herpes and herpes simplex meningitis in the other cases. The diagnoses were confirmed in all cases as the cerebrospinal fluid (CSF) was positive for herpes simplex virus (HSV)-DNA. For diagnosis confirmation, the DNA test was useful after 2-7 days following initial disease onset. Among other types of aseptic meningitis, the patients with herpes simplex meningitis showed relatively high white blood cell counts and relatively high CSF protein and high CSF cell counts. CSF cells showed mononuclear cell dominance from the initial stage of the disease. During same period, we also experienced 12 cases of herpes simplex encephalitis and 21 cases of non-hepatic acute limbic encephalitis. Notably, the patients with herpes simplex meningitis were younger and their CSF protein and cells counts were higher than those of the patients with herpes simplex encephalitis.

Varicela y herpes zóster: retos para la salud pública / Varicella and herpes zoster: challenges for public health

Resumen: Objetivo: Evaluar el comportamiento epidemiológico de la varicela y el herpes zoster (HZ) para determinar políticas de salud y disminuir prevalencia y complicaciones. Material y métodos: La frecuencia de casos se estimó con datos del Sistema Único de Información para la Vigilancia Epidemiológica (SUIVE), periodo 2000-2013; para los egresos hospitalarios de varicela y HZ, se utilizaron datos del Sistema Nacional de Información en Salud (Sinais). Resultados: El promedio de casos de varicela anual fue 296 733, 57% menores de 9 años, la mayoría de marzo a mayo; de 2004 a 2012 los egresos hospitalarios de varicela fueron 17 398, de ellos 4.6% presentó meningoecefalitis, 2.5% neumonía y 18% otras complicaciones. Por herpes zoster 7 042 egresos, más afectados de 65 años o más, 1.3:1 la relación mujer:hombre. Las complicaciones: neuralgia (11%), afección ocular (7%), meningoencefalitis (5.4%), enfermedad diseminada (2.8%) y otras (5.4%); estancia hospitalaria entre 6.4 a 13.3 días. Conclusiones: Los datos coinciden con los de la literatura de otros países. Se discute el papel de la vacunación en la prevención de la infección en niños y adultos.

Abstract: Objective: To evaluate the epidemiological behavior of varicella and herpes zoster (HZ) to determine the need of health policies to diminish prevalence and avoid complications. Materials and methods: To assess frequency, we analyzed data from the National Information System for Epidemiological Surveillance (SUIVE) from 2000 to 2013; to assess the discharge data of varicella and HZ, we evaluated information from the National System of health information (Sinais). Results: The average annual cases of chickenpox were 296 733, 57% mostly children under 9 years, most of them from March to May. From 2004 to 2012 hospital discharge of varicella were 17 398, of which 4.6% had meningoecephalitis, 2.5% pneumonia and 18% other complications. For herpes zoster 7 042 discharges, mostly affected were patients 65 years or older, 1.3:1 the woman-man relationship. Main complications were: neuralgia (11%), eye involvement (7%), meningoencephalitis (5.4%), disseminated disease (2.8%) and others (5.4%); hospital stay was between 6.4 and 13.3 days. Conclusions: Data is consistent with that of the literature in other countries. The role of vaccination to prevent infection in children and adults is discussed.

Burden of herpes simplex virus encephalitis in the United States.

Herpes simplex virus encephalitis (HSVE) is a disease of public health concern, but its burden on the healthcare of United States has not been adequately assessed recently. We aimed to define the incidence, complications and outcomes of HSVE in the recent decade by analyzing data from a nationally representative database. Healthcare Cost and Utilization Project databases were utilized to identify patients with primary discharge diagnosis of HSVE. Annual hospitalization rate was estimated and several preselected inpatient complications were identified. Regression analyses were used to identify mortality predictors. Key epidemiological factors were compared with those from other countries. Total 4871 patients of HSVE were included in our study. The annual hospitalization rate was 10.3 ± 2.2 cases/million in neonates, 2.4 ± 0.3 cases/million in children and 6.4 ± 0.4 cases/million in adults. Median age was 57 years and male:female incidence ratio was 1:1. Rates of some central nervous system complications were seizures (38.4%), status epilepticus (5.5%), acute respiratory failure (20.1%), ischemic stroke (5.6%) and intracranial hemorrhage (2.7%), all of which were significantly associated with mortality. In-hospital mortality in neonates, children and adults were 6.9, 1.2 and 7.7%, respectively. HSVE still remains a potentially lethal infectious disease with high morbidity and mortality. Most recent epidemiological data in this study may help understanding this public health disease, and the patient outcome data may have prognostic significance.