ABSTRACT
Spread of herpes simplex virus 1 (HSV1) from the periphery to the central nervous system (CNS) can lead to extensive infection and pathological inflammation in the brain, causing herpes simplex encephalitis (HSE). It has been shown that microglia, the CNS-resident macrophages, are involved in early sensing of HSV1 and induction of antiviral responses. In addition, infiltration of peripheral immune cells may contribute to the control of viral infection. In this study, we tested the effect of microglia depletion in a mouse model of HSE. Increased viral titers and increased disease severity were observed in microglia-depleted mice. The effect of microglia depletion was more pronounced in wild-type than in cGas-/- mice, revealing that this immune sensor contributes to the antiviral activity of microglia. Importantly, microglia depletion led to reduced production of type I interferon (IFN), proinflammatory cytokines, and chemokines at early time points after viral entry into the CNS. In line with this, in vitro experiments on murine primary CNS cells demonstrated microglial presence to be essential for IFN RNA induction, and control of HSV1 replication. However, the effect of microglia depletion on the expression of IFNs, and inflammatory cytokines was restricted to the early time point of HSV1 entry into the CNS. There was no major alteration of infiltration of CD45-positive cells in microglia-depleted mice. Collectively, our data demonstrate a key role for microglia in controlling HSV1 replication early after viral entry into the CNS and highlight the importance of a prompt antiviral innate response to reduce the risk of HSE development. IMPORTANCE One of the most devastating and acute neurological conditions is encephalitis, i.e., inflammation of brain tissue. Herpes simplex virus 1 (HSV1) is a highly prevalent pathogen in humans, and the most frequent cause of viral sporadic encephalitis called herpes simplex encephalitis (HSE). HSV1 can infect peripheral neurons and reach the central nervous system (CNS) of humans, where it can be detected by brain resident cells and infiltrating immune cells, leading to protective and damaging immune responses. In this study, we investigated the effects of microglia depletion, the main brain-resident immune cell type. For this purpose, we used a mouse model of HSE. We found that viral levels increased, and disease symptoms worsened in microglia-depleted mice. In addition, mice lacking a major sensor of viral DNA, cGAS, manifested a more pronounced disease than wild-type mice, highlighting the importance of this immune sensor in the activity of microglia. Microglia depletion led to reduced production of many known antiviral factors, most notably type I interferon (IFN). The importance of microglia in the early control of HSV1 spread and the generation of antiviral responses is further demonstrated by experiments on murine mixed glial cell cultures. Interestingly, mice with microglia depletion exhibited an unaltered activation of antiviral responses and recruitment of immune cells from the periphery at later time points of infection, but this did not prevent the development of the disease. Overall, the data highlight the importance of rapid activation of the host defense, with microglia playing a critical role in controlling HSV1 infection, which eventually prevents damage to neurons and brain tissue.
Subject(s)
Encephalitis, Herpes Simplex , Herpesvirus 1, Human , Immunity , Interferon Type I , Microglia , Virus Internalization , Animals , Brain/immunology , Brain/virology , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Encephalitis, Herpes Simplex/immunology , Encephalitis, Herpes Simplex/physiopathology , Herpesvirus 1, Human/metabolism , Immunity/immunology , Inflammation/pathology , Interferon Type I/metabolism , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/virology , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolismABSTRACT
Herpes simplex virus 1 (HSV-1) is responsible for herpes simplex virus encephalitis (HSE), associated with a 70% mortality rate in the absence of treatment. Despite intravenous treatment with acyclovir, mortality remains significant, highlighting the need for new anti-herpetic agents. Herein, we describe a novel neurovirulent recombinant HSV-1 (rHSV-1), expressing the fluorescent tdTomato and Gaussia luciferase (Gluc) enzyme, generated by the Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) (CRISPR-Cas9) system. The Gluc activity measured in the cell culture supernatant was correlated (P = 0.0001) with infectious particles, allowing in vitro monitoring of viral replication kinetics. A significant correlation was also found between brain viral titers and Gluc activity in plasma (R2 = 0.8510, P < 0.0001) collected from BALB/c mice infected intranasally with rHSV-1. Furthermore, evaluation of valacyclovir (VACV) treatment of HSE could also be performed by analyzing Gluc activity in mouse plasma samples. Finally, it was also possible to study rHSV-1 dissemination and additionally to estimate brain viral titers by in vivo imaging system (IVIS). The new rHSV-1 with reporter proteins is not only as a powerful tool for in vitro and in vivo antiviral screening, but can also be used for studying different aspects of HSE pathogenesis.
Subject(s)
Encephalitis, Herpes Simplex/physiopathology , Herpesvirus 1, Human/isolation & purification , Animals , Antiviral Agents/therapeutic use , Base Sequence , Blood-Brain Barrier , Brain/virology , Chlorocebus aethiops , Encephalitis, Herpes Simplex/drug therapy , Encephalitis, Herpes Simplex/virology , Genes, Reporter , Genes, Viral , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/physiology , Luminescence , Mice , Mice, Inbred BALB C , Multiplex Polymerase Chain Reaction/methods , Valacyclovir/therapeutic use , Vero Cells , Viral Load , Virus Replication/geneticsABSTRACT
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.
Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis/diagnosis , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/etiology , Encephalitis, Herpes Simplex/complications , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/physiopathology , Case-Control Studies , Causality , Child , Child, Preschool , Encephalitis, Herpes Simplex/epidemiology , Encephalitis, Herpes Simplex/physiopathology , Female , Humans , Immunologic Factors/therapeutic use , Infant , Male , N-Methylaspartate , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical dataABSTRACT
INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.
Subject(s)
DNA, Viral/cerebrospinal fluid , Epstein-Barr Virus Infections/physiopathology , Herpesvirus 4, Human/genetics , Immunocompetence , Infectious Encephalitis/physiopathology , Meningitis/physiopathology , Adult , Aged , Coinfection , Cytomegalovirus Infections/cerebrospinal fluid , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/physiopathology , Encephalitis, Herpes Simplex/cerebrospinal fluid , Encephalitis, Herpes Simplex/complications , Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Viral/cerebrospinal fluid , Encephalitis, Viral/complications , Encephalitis, Viral/physiopathology , Enterococcus faecalis , Epstein-Barr Virus Infections/cerebrospinal fluid , Epstein-Barr Virus Infections/complications , Female , Gram-Positive Bacterial Infections/cerebrospinal fluid , Gram-Positive Bacterial Infections/complications , Gram-Positive Bacterial Infections/physiopathology , Guillain-Barre Syndrome/cerebrospinal fluid , Guillain-Barre Syndrome/complications , Guillain-Barre Syndrome/physiopathology , Humans , Infectious Encephalitis/cerebrospinal fluid , Infectious Encephalitis/complications , Infectious Encephalitis/microbiology , Intensive Care Units , Intracranial Hypotension/cerebrospinal fluid , Intracranial Hypotension/complications , Intracranial Hypotension/physiopathology , Male , Meningitis/cerebrospinal fluid , Meningitis/complications , Meningitis/microbiology , Meningitis, Pneumococcal/cerebrospinal fluid , Meningitis, Pneumococcal/complications , Meningitis, Pneumococcal/physiopathology , Meningitis, Viral/cerebrospinal fluid , Meningitis, Viral/complications , Meningitis, Viral/physiopathology , Middle Aged , Optic Neuritis/cerebrospinal fluid , Optic Neuritis/complications , Optic Neuritis/physiopathology , Streptococcal Infections/cerebrospinal fluid , Streptococcal Infections/complications , Streptococcal Infections/physiopathology , Streptococcus pneumoniae , Varicella Zoster Virus Infection/cerebrospinal fluid , Varicella Zoster Virus Infection/complicationsABSTRACT
Objective. Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic fatal encephalitis worldwide and remains a devastating disease despite antiviral therapy. EEG can be an important tool in the diagnosis of HSE, and we propose that it can be used to monitor the progression of the disease in patients with treatment refractory HSE. Methods. This is a case report of a patient with HSE who was monitored on continuous EEG (CEEG) throughout course of her disease. Results. A 62-year-old woman with no history of neurologic disease, who presented with generalized weakness and lethargy for 2 weeks, and rapidly deteriorated with encephalopathy, fever, and seizures. Lumbar puncture demonstrated elevated protein and white blood cells with positive herpes simplex virus (HSV) DNA. CEEG initially showed right-sided lateralized periodic discharges and focal seizures/status epilepticus with shifting predominance, and then later progressed to be more focal on the left, and then progressed to demonstrating more generalized findings. Magnetic resonance imaging obtained 3 times confirmed what CEEG heralded with evolution from prior studies which were concordant with CEEG, suggesting disease spread. Significance. We report the case of a patient with HSE who was monitored on CEEG and propose that CEEG can be used as a marker for progression of disease and thus may prompt escalation in therapy. While imaging studies may confirm spread of disease, using CEEG may prevent the delay of treatment and lead to more rapid therapy in cases of refractory HSE.
Subject(s)
Brain/physiopathology , Electroencephalography , Encephalitis, Herpes Simplex/physiopathology , Seizures/physiopathology , Biomarkers/analysis , Disease Progression , Electroencephalography/methods , Encephalitis, Herpes Simplex/diagnosis , Female , Humans , Longitudinal Studies , Magnetic Resonance Imaging/methods , Middle Aged , Tomography, X-Ray Computed/methodsABSTRACT
Cognitive and memory impairment are related to cholinergic dysfunction and are important complications of viral encephalitis, In view of paucity of studies on cholinergic dysfunction in encephalitis, this study has been undertaken. We report acetyl choline esterase (AChE) and muscurinic 2 (M2) receptor levels in herpes simplex encephalitis (HSE) and Japanese encephalitis (JE) patients, and correlate these with cognitive functions and MRI findings. Patients with JE and HSE were evaluated for consciousness, neurological and MRI findings, plasma AChE and M2 receptor levels on admission and after one year. Twenty-nine patients with JE and 23 with HSE were included. Admission AChE levels in JE (48.32⯱â¯5.36â¯nmol/min/ml) and HSE (41.92⯱â¯5.12â¯nmol/min/ml) were significantly lower compared with controls (70.50⯱â¯8.30â¯nmol/min/ml). M2 receptor levels were also low in JE (4.52⯱â¯0.56â¯ng/ml) and HSE (4.35⯱â¯0.57â¯ng/ml) compared with controls (7.95⯱â¯0.41â¯ng/ml). In JE, AChE activity (râ¯=â¯0.43, pâ¯=â¯0.02) and M2 receptor levels (râ¯=â¯0.43, pâ¯=â¯0.02) correlated with caudate involvement, and AChE activity (râ¯=â¯0.76, pâ¯=â¯0.03) with Mini Mental State Examination ( MMSE) score. In HSE, M2 receptor levels (râ¯=â¯0.53, pâ¯=â¯0.03) correlated with MMSE. The levels of AChE and M2 receptors increased at one year compared to the baseline, which was greater in JE than in HSE. Both AChE and M2 receptors were reduced in JE and HSE and correlated with cognition at one year. Recovery of these biomarkers was more in JE than HSE.
Subject(s)
Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Japanese/physiopathology , Receptors, Cell Surface/metabolism , Acetylcholine , Acetylcholinesterase , Adolescent , Adult , Aged , Brain/physiopathology , Child , Cholinergic Agents , Encephalitis, Viral/physiopathology , Female , Humans , India/epidemiology , Magnetic Resonance Imaging , Male , Middle Aged , Receptor, Muscarinic M2/analysis , Receptor, Muscarinic M2/metabolism , Receptors, Cell Surface/analysis , Receptors, Cholinergic/analysis , Receptors, Cholinergic/metabolismSubject(s)
Acyclovir/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Encephalitis, Herpes Simplex/complications , Encephalitis, Herpes Simplex/drug therapy , Magnetic Resonance Imaging , Prednisolone/therapeutic use , Retinal Detachment/drug therapy , Retinal Detachment/virology , Spinal Puncture , Aged , Confusion , Encephalitis, Herpes Simplex/diagnosis , Encephalitis, Herpes Simplex/physiopathology , Fever , Humans , Male , Nausea , Treatment Outcome , VitrectomyABSTRACT
BACKGROUND: Herpes simplex virus (HSV) encephalitis is a life-threatening infection of the brain, which has significant physical, cognitive and social consequences for survivors. Despite increasing recognition of the long-term effects of encephalitis, research and policy remains largely focused on its acute management, meaning there is little understanding of the difficulties people face after discharge from acute care. This paper aims to chart the problems and challenges which people encounter when they return home after treatment for HSV encephalitis. METHODS: The paper reports on data from 30 narrative interviews with 45 people affected by HSV encephalitis and their significant others. The study was conducted as part of the ENCEPH-UK programme grant on Understanding and Improving the Outcome of Encephalitis. RESULTS: The findings show the diverse challenges which are experienced by people after treatment for HSV encephalitis. We first chart how peoples' everyday lives are fragmented following their discharge from hospital. Second, we document the social consequences which result from the longer-term effects of encephalitis. Finally, we show how the above struggles are exacerbated by the lack of support systems for the post-acute effects of encephalitis, and describe how people are consequently forced to devise their own care routines and strategies for managing their problems. CONCLUSION: The paper argues that in order to improve long-term outcomes in encephalitis, it is vital that we develop pathways of support for the condition beyond the acute hospital setting. We conclude by making recommendations to enhance communication and care for the post-acute consequences of encephalitis, to ensure those affected are fully supported through the chronic effects of this devastating disease.
Subject(s)
Activities of Daily Living , Brain/physiopathology , Encephalitis, Herpes Simplex/physiopathology , Survivors/psychology , Adolescent , Adult , Child , Child, Preschool , Communication , Female , Healthcare Disparities , Humans , Interviews as Topic , Male , Middle Aged , Patient Discharge , Qualitative Research , Young AdultABSTRACT
Herpes simplex encephalitis (HSE) is associated with significant mortality and morbidity. As a consequence of HSE, up to 75% of infected individuals die or experience irreversible neurological damage. While the pathogenesis of the disease is unknown, it is traditionally hypothesized that the viral infection occurs by neuronal transmission directly from peripheral sites. Non-neuronal modes of infection have generally been overlooked as the brain is protected by the blood-brain-barrier (BBB). The BBB poses an effective barrier to pathogens as well as to drugs such as chemotherapies. In the pursuit to deliver chemotherapeutic agents to the brain, several studies demonstrated that phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may increase the permeability of the BBB enabling successful delivery of chemotherapeutic agents to the brain. In this communication, we report a case of HSE infection in a 62-year-old man, which we suspect was facilitated by the use of sildenafil during a primary genital herpes simple virus (HSV) infection. Due to large number of patients treated with PDE5 inhibitors for erectile dysfunction and the high incidence of genital HSV infection in the general population, a larger study should examine the potential risk of developing HSE in patients treated with PDE5 inhibitors.
Subject(s)
Encephalitis, Herpes Simplex/chemically induced , Herpes Genitalis/drug therapy , Sildenafil Citrate/adverse effects , Blood-Brain Barrier/physiopathology , Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Herpes Simplex/virology , Herpes Genitalis/physiopathology , Herpes Genitalis/virology , Humans , Male , Middle Aged , Permeability , Sildenafil Citrate/administration & dosageABSTRACT
Herpes simplex virus (HSV) encephalitis can manifest with different clinical presentations, including acute monophasic illness and biphasic chronic granulomatous HSV encephalitis. Chronic encephalitis is much less common, and very rare late relapses are associated with intractable epilepsy and progressive neurological deficits with or without evidence of HSV in the cerebrospinal fluid. The authors report on an 8-year-old girl with a history of treated HSV-1 encephalitis when she was 13 months of age and focal epilepsy when she was 2 years old. Although free of clinical seizures, when she was 5, she experienced behavioral and academic dysfunction, which was later attributed to electrographic focal seizures and worsening electroencephalography (EEG) findings with electrical status epilepticus during slow-wave sleep (ESES). Following a right temporal lobectomy, chronic granulomatous encephalitis was diagnosed. The patient's clinical course improved with the resolution of seizures and EEG abnormalities.
Subject(s)
Drug Resistant Epilepsy/etiology , Drug Resistant Epilepsy/surgery , Encephalitis, Herpes Simplex/complications , Herpesvirus 1, Human , Anterior Temporal Lobectomy , Brain/diagnostic imaging , Brain/pathology , Brain/physiopathology , Brain/surgery , Child , Drug Resistant Epilepsy/diagnostic imaging , Drug Resistant Epilepsy/physiopathology , Encephalitis, Herpes Simplex/diagnostic imaging , Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Herpes Simplex/surgery , Female , HumansABSTRACT
AIM: To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD: We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%). RESULTS: Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and significantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo). INTERPRETATION: Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence.
Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis/physiopathology , Encephalitis, Herpes Simplex/physiopathology , Mental Disorders/physiopathology , Movement Disorders/physiopathology , Simplexvirus/pathogenicity , Adult , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/complications , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/etiology , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/microbiology , Child , Encephalitis, Herpes Simplex/complications , Female , Humans , Mental Disorders/etiology , Movement Disorders/etiologyABSTRACT
OBJECTIVES: To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. METHODS: The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. RESULTS: Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. CONCLUSIONS: This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis.
Subject(s)
Brain Edema/diagnostic imaging , Encephalitis, Herpes Simplex/diagnostic imaging , Magnetic Resonance Imaging , Temporal Lobe/diagnostic imaging , Acyclovir/administration & dosage , Adrenal Cortex Hormones/administration & dosage , Adult , Brain Edema/drug therapy , Brain Edema/physiopathology , Brain Edema/virology , Encephalitis, Herpes Simplex/drug therapy , Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Herpes Simplex/virology , Female , Humans , Male , Middle Aged , Neuroimaging/methods , Simplexvirus/pathogenicity , Temporal Lobe/physiopathology , Temporal Lobe/virology , Treatment OutcomeSubject(s)
Encephalitis, Herpes Simplex/diagnosis , Gait Disorders, Neurologic/physiopathology , Memory Disorders/physiopathology , Temporal Lobe/diagnostic imaging , Aftercare , Aged , Brain/diagnostic imaging , Confusion/etiology , Encephalitis, Herpes Simplex/cerebrospinal fluid , Encephalitis, Herpes Simplex/complications , Encephalitis, Herpes Simplex/physiopathology , Fever/etiology , Gait Disorders, Neurologic/etiology , Humans , Hyponatremia/etiology , Magnetic Resonance Imaging , Male , Memory Disorders/etiology , Spinal PunctureABSTRACT
BACKGROUND: Herpes simplex encephalitis (HSE) occurs without regional and seasonal predilections. HSE is important to differentiate from arboviral encephalitis in endemic areas because of therapeutic potential of HSE. This study evaluates clinical features, MRI and laboratory findings which may help in differentiating HSE from Japanese encephalitis (JE). METHODS: Confirmed patients with JE and HSE in last 10years were included. The presenting clinical symptoms including demographic information, seizure, behavioral abnormality, focal weakness and movement disorders were noted. Cranial MRI was done and location and nature of signal alteration were noted. Electroencephalography (EEG), cerebrospinal fluid (CSF), blood counts and serum chemistry were done. Outcome was measured by modified Rankin Scale (mRS). Death, functional outcome and neurological sequelae were noted at 3, 6 and 12months follow up, and compared between HSE and JE. Outcome was categorized as poor (mRS;>2) and good (mRS≤2). RESULTS: 97 patients with JE and 40 HSE were included. JE patients were younger than HSE and occurred in post monsoon period whereas HSE occurred throughout the year. Seizure (86% vs 40%) and behavioral abnormality (48% vs 10%) were commoner in HSE; whereas movement disorders (76% vs 0%) and focal reflex loss (42% vs 10%) were commoner in JE. CSF findings and laboratory parameters were similar in both the groups. Thalamic involvement in JE and temporal involvement in HSE were specific markers of respective encephalitis. Delta slowing on EEG was more frequent in JE than HSE. 20% JE and 30% HSE died in the hospital, and at 1year follow up JE patients showed better outcome compared to HSE (48% vs 24%). Memory loss (72% vs 22%) was the predominant sequelae in HSE. CONCLUSION: Seizure and behavioral abnormality are common features in HSE whereas focal reflex loss is commoner in JE. In a patient with acute encephalitis, thalamic lesion suggests JE and temporal lobe involvement HSE. Long term outcome in JE is better compared to HSE.
Subject(s)
Encephalitis, Herpes Simplex/diagnosis , Encephalitis, Japanese/diagnosis , Adolescent , Adult , Age Factors , Aged , Biomarkers/cerebrospinal fluid , Brain/diagnostic imaging , Brain/physiopathology , Child , Child, Preschool , Diagnosis, Differential , Electroencephalography , Encephalitis, Herpes Simplex/mortality , Encephalitis, Herpes Simplex/physiopathology , Encephalitis, Herpes Simplex/therapy , Encephalitis, Japanese/mortality , Encephalitis, Japanese/physiopathology , Encephalitis, Japanese/therapy , Female , Follow-Up Studies , Humans , Infant , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Herpes simplex virus encephalitis (HSE) is a significant cause of morbidity and mortality. Neurologic sequelae are common even after early initiation of acyclovir treatment. The host immune response during HSE can also lead to brain damage. There are an increasing number of reports favoring steroid use in HSE. OBJECTIVES: We aimed to compare the prognosis of children with HSE with and without steroid therapy. STUDY DESIGN: We retrospectively screened our hospital archive from 2009 to 2014 for patients diagnosed with HSE with a positive result for herpes simplex virus polymerase chain reaction in cerebrospinal fluid. Patients ≥1 month and ≤18 years at diagnosis were included in the study. Clinical outcomes in terms of cognitive function, motor function, electroencephalographic findings, seizure frequency, and radiologic findings were compared in patients who received adjuvant steroid therapy with those who did not. RESULTS: Six patients (1 boy, 5 girls; aged 4 months to 10 years) were included. Overall symptom duration before hospital admission was ≤5days. Patients received acyclovir treatment for 21-28days. Three received steroid therapy early during the disease and three patients did not. No adverse effects related to steroids were observed. Follow-up duration was 6 months to 5 years. All patients had radiologic sequelae of encephalitis. Cognition, motor function, and seizure control were better in patients who received steroid therapy. CONCLUSIONS: Adjuvant steroid therapy seems to be effective in decreasing morbidity in children with HSE but the radiologic sequelae were the same in both groups.
Subject(s)
Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , Brain/diagnostic imaging , Encephalitis, Herpes Simplex/drug therapy , Acyclovir/pharmacology , Antiviral Agents/pharmacology , Brain/drug effects , Cerebrospinal Fluid/virology , Child , Child, Preschool , Cognition/drug effects , Encephalitis, Herpes Simplex/diagnostic imaging , Encephalitis, Herpes Simplex/physiopathology , Female , Humans , Infant , Male , Retrospective Studies , Simplexvirus/genetics , Simplexvirus/isolation & purification , Treatment OutcomeABSTRACT
Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.
Subject(s)
Encephalitis, Herpes Simplex/diagnosis , Encephalitis, Herpes Simplex/drug therapy , Encephalitis, Herpes Simplex/physiopathology , Herpesvirus 1, Human/physiology , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Antiviral Agents/therapeutic use , Brain/diagnostic imaging , Brain/physiology , Brain/physiopathology , Brain/virology , Edema/virology , Encephalitis, Herpes Simplex/complications , Female , Humans , Seizures/virology , Treatment OutcomeABSTRACT
No disponible
Subject(s)
Humans , Female , Pregnancy , Adult , Encephalitis, Herpes Simplex/complications , Encephalitis, Herpes Simplex/diagnosis , Encephalitis, Herpes Simplex/therapy , Acyclovir/therapeutic use , Tocolysis/methods , Betamethasone/therapeutic use , Pregnancy Complications/epidemiology , Pregnancy Complications/prevention & control , Encephalitis, Herpes Simplex/physiopathology , Cerebrospinal Fluid/cytology , Electroencephalography/methods , Polymerase Chain Reaction/methodsABSTRACT
Herpes simplex virus (HSV) encephalitis is associated with a high risk of mortality and sequelae, and early diagnosis and treatment in the emergency department are necessary. However, most patients present with non-specific febrile, acute neurologic impairment; this may lead clinicians to overlook the diagnosis of HSV encephalitis. We aimed to identify which data collected in the first hours in a medical setting were associated with the diagnosis of HSV encephalitis. We conducted a multicenter retrospective case-control study in four French public hospitals from 2007 to 2013. The cases were the adult patients who received a confirmed diagnosis of HSV encephalitis. The controls were all the patients who attended the emergency department of Grenoble hospital with a febrile acute neurologic impairment, without HSV detection by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF), in 2012 and 2013. A multivariable logistic model was elaborated to estimate factors significantly associated with HSV encephalitis. Finally, an HSV probability score was derived from the logistic model. We identified 36 cases and 103 controls. Factors independently associated with HSV encephalitis were the absence of past neurological history (odds ratio [OR] 6.25 [95 % confidence interval (CI): 2.22-16.7]), the occurrence of seizure (OR 8.09 [95 % CI: 2.73-23.94]), a systolic blood pressure ≥140 mmHg (OR 5.11 [95 % CI: 1.77-14.77]), and a C-reactive protein <10 mg/L (OR 9.27 [95 % CI: 2.98-28.88]). An HSV probability score was calculated summing the value attributed to each independent factor. HSV encephalitis diagnosis may benefit from the use of this score based upon some easily accessible data. However, diagnostic evocation and probabilistic treatment must remain the rule.