Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood

Childhood herpes simplex virus-1 (HSV-1) encephalitis (HSE) may result from single-gene inborn errors of TLR3 immunity. TLR3-dependent induction of IFN-α/β or IFN-λ is crucial for protective immunity against primary HSV-1 infection in the central nervous system (CNS). We describe here two unrelated children with HSE carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal-dominant (AD) trait but by different mechanisms: haplotype insufficiency (D50A) or negative dominance (G159A). A defect in polyinosinic-polycytidylic acid-induced TLR3 responses can be detected in fibroblasts heterozygous for G159A but not for D50A TBK1. Nevertheless, viral replication and cell death rates caused by two TLR3-dependent viruses (HSV-1 and vesicular stomatitis virus) were high in fibroblasts from both patients, and particularly so in G159A TBK1 fibroblasts. These phenotypes were rescued equally well by IFN-α2b. Moreover, the IFN responses to the TLR3-independent agonists and viruses tested were maintained in both patients' peripheral blood mononuclear cells and fibroblasts. The narrow, partial cellular phenotype thus accounts for the clinical phenotype of these patients being limited to HSE. These data identify AD partial TBK1 deficiency as a new genetic etiology of childhood HSE, indicating that TBK1 is essential for the TLR3- and IFN-dependent control of HSV-1 in the CNS.     

Psychosis and herpes simplex encephalitis

We have reported an unusual presentation of herpes simplex encephalitis in a patient with a 3 1/2-year history of a schizo-affective disorder. In the month immediately before diagnosis, the patient lost contact with reality and became violent. After successful treatment with antipsychotic medication, he had agitation and disorientation, as well as fever and cerebrospinal fluid pleocytosis. There were no focal neurologic findings. When a low-density lesion in the right temporal lobe was defined by computerized axial tomography, brain biopsy and culture isolated herpes simplex virus type 1. After therapy with vidarabine, the patient regained independence in simple daily activities. This case stresses the possibility of herpes simplex encephalitis in patients with an acute mental change.     

Valacyclovir for herpes simplex encephalitis

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.     

Voxel-based morphometry of herpes simplex encephalitis

Voxel-based morphometry (VBM) is a powerful tool for analyzing changes in gray or white matter density of the brain. By using an automated segmentation procedure and standardized parametric statistics it avoids biases inherent in operator-dependent morphological operations (J. Ashburner and K. J. Friston, 2000, NeuroImage 11, 805-821). Since its introduction in 1995, VBM has been used to examine anatomical changes in a variety of diseases associated with neurologic and psychiatric dysfunction. Given the power of this technique for discerning subtle anatomical changes, we wanted to assess its performance on brains with gross structural abnormalities. Such results could have implications regarding the difficulties to be faced when examining other types of distorted brains (e.g., brains with changes due to degenerative disease). This report describes the use of VBM for examining individual and group changes in gray matter concentration in five patients who had recovered from herpes simplex encephalitis (HSE) compared with age- and sex-matched controls. Because HSE tends to affect a specific set of brain regions we thought that this would (1) provide an opportunity to assess the anatomical face validity of VBM, (2) allow us to assess the problems of this technique when used on distorted brains, and (3) provide an in vivo demonstration of the gray matter changes due to HSE. We found that, despite problems in normalizing and segmenting these severely distorted brains, VBM was able to identify correctly a number of the regional gray matter abnormalities in HSE. The results, while consistent with the well-known histopathology of the disease, also demonstrate potential difficulties with this method.     

Atypical manifestations of herpes simplex encephalitis

The diagnosis of herpes simplex encephalitis is readily considered in patients with focal findings on neurologic and radiologic examinations. In the two patients we have described, the diagnosis was delayed because clinical findings were attributed to other medical conditions, and radiologic studies were nondiagnostic. A high index of suspicion and repeated neuroradiologic tests are recommended in patients with unexplained encephalitis.     

Transient global amnesia secondary to herpes simplex viral encephalitis

Sir, A 39-year-old company director had been under recent financialstress. On the day of hospital admission, he had been at hisdesk for an hour without complaint. Colleagues witnessed himsuddenly becoming distressed, and, although he was not directlyspoken to, he left the office and drove three miles home. Onarrival, his     

MELAS误诊为单纯疱疹病毒性脑炎一例

线粒体脑肌病伴高乳酸血症和卒中样发作（MELAS）是母系遗传性线粒体疾病,临床表现多样,易与单纯疱疹病毒性脑炎（HSE）混淆。该文报道1例初诊时误诊为HSE的MELAS患者,该例患者因反复发热、头痛、肢体抽搐1个月,再发头痛1周就诊,入院时初步疑诊为HSE,予以抗病毒治疗无效,进一步行血液和尿液基因检测确诊为MELAS。MELAS可与不典型的HSE表现相似,应谨慎鉴别。脑脊液和（或）血清乳酸升高和基底节钙化有助于诊断MELAS,MELAS的线粒体DNA突变可通过血液和尿液基因检测,而不需要采用肌肉活组织检查这样的有创检查。     

Evoked potentials in severe herpes simplex encephalitis

Diagnostic and prognostic value of evoked potentials (EP) were studied in 5 patients with severe herpes simplex encephalitis (HSE). Latency of the third negative cortical N70 peak, elicited by median nerve stimulation, was prolonged in 3 survivors with Glasgow coma score of 6 (115 vs 71 ms in controls,p<0.05), but normal after improvement of the acute disease, N70 right to left interhemisphere difference was increased initially in the 4 survivors (26 vs 3 ms in controls,p<0.05) indicating focal brain involvement, a crucial finding in HSE. The first cortical N 20 peak was preserved in all survivors even during deep coma where evaluation of brain function is difficult. Auditory brainstem EP were normal in all patients and useful to exclude brainstem death. In severe HSE, somatosensory long-latency EP are an effective monitor of the level of impaired consciousness and can detect brain focal signs. Short-latency N20 components may be predictive of the outcome.The study was supported by the Fonds zur Förderung der wissenschaftlichen Forschung P7382M     

Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity

Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-β and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient's fibroblasts with HSV-1, the impairment of IFN-β and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient's peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14(+) and/or CD16(+) monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.     

Parechovirus-A3 encephalitis presenting with focal seizure mimicking herpes simplex virus infection

BackgroundFebrile neonates and young infants presenting with seizure require immediate evaluation and treatment. Herein we experienced two young infants with parechovirus-A3 (PeV-A3) encephalitis, initially presented with focal seizure suspecting herpes simplex virus (HSV) encephalitis.CasesWe have experienced 2 infantile cases, initially presented with focal seizure. At presentation, HSV encephalitis was strongly suspected and empiric acyclovir therapy was started; however, serum and/or cerebrospinal fluid (CSF) PCR for HSV were negative. Instead, serum and/or CSF PCR for parechovirus-A was positive. PeV-A3 infection was confirmed by genetic sequence analyses. Both cases required multiple anticonvulsant therapy and intensive care for intractable seizure. Diffusion-weighted imaging of brain magnetic resonance imaging (MRI) showed distinct findings; high-intensity lesions in the gray matter of parietal and occipital lobes in Case 1, and bilateral decreased diffusion of the deep white matter and corpus callosum in Case 2. We have followed two cases more than four years; Case 1 developed epilepsy, has been on an anticonvulsant to control her seizure. Case 2 has significant neurodevelopmental delay, unable to stand or communicate with language.ConclusionsPeV-A3 encephalitis needs to be in differential diagnosis when neonates and young infants present with focal seizure, mimicking HSV encephalitis. Special attention may be necessary in patients with PeV-A3 encephalitis given it could present with intractable seizure with high morbidity in a long-term.     

单纯疱疹病毒性脑炎8例病例分析

目的探讨单纯疱疹病毒性脑炎(HSE)的临床表现、辅助检查、诊断及治疗,提高HSE的早期诊断和治愈率。方法回顾8例HSE患者的临床表现,脑电图、影像学、脑脊液检查结果及治疗,并结合相关文献进行分析。结果 HSE患者均急性或亚急性起病,主要临床表现为发热、头痛、意识及精神障碍。头颅MRI、脑电图检查有利于早期诊断。脑脊液HSV-1 IgM抗体阳性及PCR DNA检测发现该病毒DNA可确诊。结论通过HSE的临床特点,结合脑电图、脑脊液及影像学检查,对HSE作出早期诊断,尽早使用抗病毒治疗是改善预后的关键。     

Frontal impairment and confabulation after herpes simplex encephalitis: A case report

We describe the rehabilitation training of a 53-year-old woman with severe confabulatory and dysexecutive syndrome, as well as memory impairment, after herpes simplex encephalitis (HSE). Secondary narcolepsy was also present. Neuropsychologic deficits were detailed through an extensive examination, and specific techniques were used to improve performances in each defective cognitive domain. Improvement of vigilance and attention was reached through appropriate and timed periods of rest, along with attentional tasks of growing difficulty. Different external aids were used to reduce temporal disorientation, to contrast confabulation and inertia, and to overcome memory deficits in everyday life. Their independent use by the patient was implemented through cues that were progressively reduced. Treatment also focused on planning, categorization, and topographic orientation. The patient's family gave constant support during rehabilitation and provided informal training after discharge. The patient was able to regain independence in everyday life at home.     

Long-term outcome of severe herpes simplex encephalitis: a population-based observational study

IntroductionHerpes simplex encephalitis (HSE) is a rare disease with a poor prognosis. No recent evaluation of hospital incidence, acute mortality and morbidity is available. In particular, decompressive craniectomy has rarely been proposed in cases of life-threatening HSE with temporal herniation, in the absence of evidence. This study aimed to assess the hospital incidence and mortality of HSE, and to evaluate the characteristics, management, the potential value of decompressive craniectomy and the outcome of patients with HSE admitted to intensive care units (ICUs).MethodsEpidemiological study: we used the hospital medical and administrative discharge database to identify hospital stays, deaths and ICU admissions relating to HSE in 39 hospitals, from 2010 to 2013. Retrospective monocentric cohort: all patients with HSE admitted to the ICU of the university hospital during the study were included. The use of decompressive craniectomy and long-term outcome were analyzed. The initial brain images were analyzed blind to outcome.ResultsThe hospital incidence of HSE was 1.2/100,000 inhabitants per year, 32 % of the patients were admitted to ICUs and 17 % were mechanically ventilated. Hospital mortality was 5.5 % overall, but was as high as 11.9 % in ICUs. In the monocentric cohort, 87 % of the patients were still alive after one year but half of them had moderate to severe disability. Three patients had a high intracranial pressure (ICP) with brain herniation and eventually underwent decompressive hemicraniectomy. The one-year outcome of these patients did not seem to be different from that of the other patients. It was not possible to predict brain herniation reliably from the initial brain images.ConclusionsHSE appears to be more frequent than historically reported. The high incidence we observed probably reflects improvements in diagnostic performance (routine use of PCR). Mortality during the acute phase and long-term disability appear to be stable. High ICP and brain herniation are rare, but must be monitored carefully, as initial brain imaging is not useful for identifying high-risk patients. Decompressive craniectomy may be a useful salvage procedure in cases of intractable high ICP.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1046-y) contains supplementary material, which is available to authorized users.     

脑电图对单纯疱疹病毒性脑炎的早期诊断和预后评价

目的 探讨单纯疱疹病毒性脑炎(HSE)的脑电图构型和预后的关系。方法回顾性分析26例HSE患者的脑电图，并与CT、MRI和临床结局进行对照。结果CT、MRI和脑电图异常率分别为53．8％、66．7％和92．3％。异常脑电图构型：弥漫性慢波16例，额颞区慢波5例，周期波5例。结论脑电图检查有助于HSE的早期诊断和预后评价。     

Carbamazepine as therapy for psychiatric sequelae of herpes simplex encephalitis

We have presented a case of herpes simplex encephalitis that is interesting in that seizure activity was detected in mesial temporal structures, without manifestations of seizure activity except for severe emotional lability with explosive emotional outbursts. Response to carbamazepine (Tegretol) included marked reduction in EEG-detected seizure activity and in the frequency of emotional outbursts, extending to one year after treatment.     

小儿单纯疱疹病毒性脑炎13例临床分析

目的：探讨阿昔洛韦(ACV)与大剂量静脉丙种球蛋白(HDIVIG)联合治疗单纯疱疹病毒性脑炎(HSVE)的疗效。方法：对确诊HSEl3例进行回顾性临床分析，用HDIVIG治疗者，剂量200mg／kg／d，连用3～5天。结果：平均住院天数明显缩短，临床症状和体征消失快，疗程短，于发病2周内使用效果最好，对病程超过2周且头颅CT有低密度灶者疗效欠佳。