Onset Of Encephalitis Research Articles

Prognostic factors of subacute comprehensive encephalitis: a retrospective study.

The etiology of encephalitis is unknown in 40%-50% of cases, so a comprehensive examination of encephalitis would be significant and meaningful. The short-term outcomes in appropriately managed patients are also unknown. Short-term clinical outcomes following onset can provide clinicians with clues regarding the clinical course in the immediate future. We investigated cases of encephalitis, including viral and autoimmune encephalitis, to determine the predictable risk factors that can be assessed to determine a short-term prognosis. We studied 90 patients with encephalitis. Poor and good outcomes were defined as scores of ≥3 and ≤2 on the modified Rankin scale, respectively. Multivariate logistic regression analysis using 19 independent variables was performed. Multivariate logistic regression analysis identified cranial magnetic resonance imaging (MRI) lesions (odds ratio [OR], 3.119; 95% confidence interval [CI], 1.166-8.344; p = 0.023) and the need for mechanical ventilation (OR, 4.461; 95% CI, 1.685-11.813; p = 0.003)) as being significantly associated with poor outcomes. In 57 patients with subacute encephalitis presenting with cranial MRI lesions, bilateral lesions on cranial MRI (OR, 5.078; 95% CI, 1.516-17.007; p = 0.008) and the need for mechanical ventilation (OR, 4.461; 95% CI, 1.135-13.584; p = 0.031) were significantly associated with poor outcomes. The location of brain lesions, lateral or bilateral, on the initial MRI during the acute phase of encephalitis may be a useful predictor of the outcome during the first 2 months after encephalitis onset, even in cases of encephalitis of unknown etiology.

Criminality in patients with autoimmune encephalitis: A case series.

Despite it being an immunotherapy-responsive neurological syndrome, patients with autoimmune encephalitis (AE) frequently exhibit residual neurobehavioural features. Here, we report criminal behaviours as a serious and novel postencephalitic association. This retrospective cohort study included 301 AE patients. Five of who committed crimes underwent direct assessments and records review alongside autoantibody studies. Five of 301 patients (1.7%) with AE exhibited criminal behaviours, which included viewing child pornography (n = 3), repeated shoplifting, and conspiracy to commit murder. All five were adult males, with LGI1 autoantibodies (n = 3), CASPR2 autoantibodies, or seronegative AE. None had evidence of premorbid antisocial personality traits or psychiatric disorders. Criminal behaviours began a median of 18 months (range = 15 months-12 years) after encephalitis onset. At the time of crimes, two patients were immunotherapy-naïve, three had been administered late immunotherapies (at 5 weeks-4 months), many neurobehavioural features persisted, and new obsessive behaviours had appeared. However, cognition, seizure, and disability measures had improved, alongside reduced autoantibody levels. Criminal behaviours are a rare, novel, and stigmatizing residual neurobehavioural phenotype in AE, with significant social and legal implications. With caution towards overattribution, we suggest they occur as part of a postencephalitis limbic neurobehavioural syndrome.

Short delay to initiate plasma exchange or immunoadsorption as synergistic therapies for patients in the acute phase of anti-NMDAR encephalitis.

Combined first-line therapies have been frequently adopted for patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Plasma exchange (PE) or immunoadsorption (IA) was used as an add-on option following initial immunotherapies, including high-dose steroids and intravenous immunoglobulin (IVIG). However, whether a shorter delay of PE or IA can improve the early recovery prognosis of patients with anti-NMDAR encephalitis remains largely unknown. To compare short-term clinical improvement between patients with early and late initiation of PE or IA in anti-NMDAR encephalitis. A retrospective study was conducted for patients admitted with anti-NMDAR encephalitis between January 2015 and December 2023 (n = 29), including 21 patients who received PE or IA as synergistic therapies. The clinical prognosis was compared between the early PE/IA group and the late PE/IA group in the research. Primary outcome included changes in the Clinical Assessment Scale for Autoimmune Encephalitis (∆CASE) at 90 and 120 days after encephalitis onset. Secondary outcomes included changes in the modified Rankin scale (∆mRS) after 90 and 120 days from encephalitis onset, and the length of intensive care unit (ICU) stay for patients with severe anti-NMDAR encephalitis. The ∆CASE scores after 90 and 120 days from encephalitis onset revealed a significant difference between patients with early and late initiation of PE or IA (p ⩽ 0.05). A significant difference in the ∆mRS was also found between patients with early and late initiation of PE or IA in severe encephalitis (p ⩽ 0.05). No significant difference was found in the length of ICU admission (p = 0.101). Our findings emphasize the importance of considering PE or IA as early as feasible for patients with anti-NMDAR encephalitis, even when steroids and IVIG are in use.

The split apparent diffusion coefficient sign: A novel magnetic resonance imaging biomarker for cortical pathology with possible implications in autoimmune encephalitis.

MRI is the imaging modality of choice for assessing patients with encephalopathy. In this context, we discuss a novel biomarker, the "split ADC sign," where the cerebral cortex demonstrates restricted diffusion (high DWI signal and low ADC) and the underlying white matter demonstrates facilitated diffusion (high or low DWI signal and high ADC). We hypothesize that this sign can be used as a biomarker to suggest either acute encephalitis onset or to raise the possibility of an autoimmune etiology. A full-text radiological information system search of radiological reports was performed for all entities known to produce restricted diffusion in the cortex excluding stroke between January 2012 and June 2022. Initial MRI studies performed upon onset of clinical symptoms were screened for the split ADC sign. 25 subjects were encountered with a positive split ADC sign (15 female; median age = 57years, range 18-82). Diagnosis included six herpes simplex encephalitis, three peri-ictal MRI changes, eight PRES, two MELAS, and six autoimmune (3 anti-GABAAR, two seronegative, and one anti-Ma2/Ta). Subjects were imaged at a mean 1.8days after the onset of symptoms (range 0-8). We present a novel visual MRI biomarker, the split ADC sign, and highlight its potential usefulness in subjects with encephalopathy to suggest acute disease onset or to raise the possibility of an autoimmune etiology when location-based criteria are applied. When positive, the sign was present on the initial MRI and can therefore be used to help focus further clinical and laboratory workup.

Abstract 3 Efficacy of Foscarnet in Preventing HHV6 Encephalitis in Adult Single Cord Blood Transplantation

Abstract Introduction The risk of HHV-6 encephalitis is high in cord blood transplantation (CBT) and the prognosis after encephalitis is poor, but there is no clarity regarding effective prevention methods for HHV-6 encephalitis. Objectives We retrospectively evaluated the effect of foscarnet (FCN) in preventing HHV-6 encephalitis in CBT. Methods We included 184 patients who underwent single CBT at Kyoto University Hospital from 2005 to 2022. For those who developed HHV-6 encephalitis, we calculated cumulative steroid doses from transplantation to the date of encephalitis onset, and for those who did not develop encephalitis, we calculated them to 25 days (the median encephalitis onset). Results Median (range) age was 49 years (18-70 years); 82% used tacrolimus and MMF for GVHD prophylaxis; FCN was used prophylactically or preemptively in 141 patients (77%) to prevent HHV6 encephalitis. FCN was used in 35% of patients from day 7 post-transplant, 20% from the time of HHV-6 reactivation, and 8% after the start of steroid administration. HHV-6 encephalitis occurred in 18 (10%) of 184 patients. The median cumulative steroid dose for those receiving steroids was 4.0 mg/kg. Steroid dose (mg/kg) had a significant effect on the development of encephalitis (HR 1.09, P=0.003); pre-engraftment immune reaction had no significant effect. The ROC curve showed that the cutoff for cumulative steroid dose that best predicted the development of encephalitis was 6.5 mg/kg. FCN prophylaxis showed no significant effect in preventing HHV6 encephalitis in the high-steroid group. However, FCN prophylaxis reduced the incidence of HHV6 encephalitis in the low-steroid group with marginal significance (HR 0.22, P=0.070). Patients who developed encephalitis without HHV6 prophylaxis had a significantly lower survival rate than those who did not develop encephalitis (1yr-OS, 25% vs. 69%). However, those who developed encephalitis during HHV6 prophylaxis did not differ significantly from those who did not develop encephalitis (1yr-OS, 59% vs. 69%) (Figure). Discussion FCN prophylaxis significantly reduced the incidence of encephalitis in the low-dose steroid group, whereas prophylaxis was not effective in the high-dose steroid group. However, prophylactic administration may improve the prognosis after the onset of encephalitis.

Persistent meningitis followed by anti-NMDAR encephalitis: case series and literature review (P5-5.002)

<h3>Objective:</h3> To report the cases of two patients with persistent meningitis followed by anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and discuss the pathogenesis of the disease in conjunction with previous reports. <h3>Background:</h3> Although meningeal involvement has been reported in anti-NMDAR encephalitis, reports of persistent meningitis prior to the onset of encephalitis are rare. <h3>Design/Methods:</h3> Case series and literature review. <h3>Results:</h3> We experienced two patients with anti-NMDAR encephalitis preceded by persistent meningitis. Patient 1 presented with protracted fever, and a brain MRI revealed leptomeningitis. Although cerebrospinal fluid (CSF) cell counts spontaneously decreased from 87 to 16 cells/mm³ over 2 weeks without treatment, the symptoms and signs associated with meningitis lasted 60 days. Despite the administration of oral prednisolone, abnormal behavior and speech dysfunction occurred, leading to the diagnosis of encephalitis. After the detection of anti-NMDAR antibodies in CSF, the diagnosis of anti-NMDAR encephalitis was made, which improved after administration of intravenous methylprednisolone and plasmapheresis. Patient 2 had headache and fever for 22 days, and the CSF cell counts declined from 112 to 14 cells/mm³ over 2 weeks without treatment. The emergence of delusion, involuntary movement (tongue protrusion), and decreased level of consciousness prompted the diagnosis of encephalitis. Anti-NMDAR encephalitis was identified after the positive result of anti-NMDAR antibodies in CSF; it was successfully treated with intravenous methylprednisolone and plasmapheresis. In both cases, infectious meningitis was ruled out, suggesting a possible autoimmune mechanism. No tumors, including ovarian teratoma, were found during systemic evaluation. In previous cases, we found two patients with persistent meningitis followed by anti-NMDAR encephalitis. The findings in the four meningitis patients showed prolonged meningitis lasting from 5 to 60 days, and infectious or paraneoplastic meningitis was ruled out. <h3>Conclusions:</h3> Anti-NMDAR encephalitis should be considered a differential diagnosis of long-term persistent nonviral meningitis. <b>Disclosure:</b> Dr. Yamahara has nothing to disclose. Dr. Yoshikura has nothing to disclose. Dr. Kimura has nothing to disclose. Dr. Shimohata has nothing to disclose.

Brain MRI features of anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis secondary to central nervous system infection in adult patients.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis secondary to central nervous system (CNS) infection is a unique subtype of the autoimmune-mediated disease, of which the imaging features are unclear. To compare the brain magnetic resonance imaging (MRI) features between the anti-NMDAR encephalitis secondary to CNS infection and that without initial infection. A total of 70 adult patients with anti-NMDAR encephalitis were retrospectively enrolled (24 in the post-infection group, 46 in the non-infection-related group). Their clinical and imaging features (lesion distribution, lesion shape, enhancement pattern, brain atrophy) were reviewed and summarized. Lesion distributions were compared between the two groups on lesion probability maps. The patients with normal brain MRI scans in the post-infection group were less than those in the non-infection related group (29% vs. 63%; P = 0.0113). Among the 24 patients in the post-infection group, visible lesions were shown at the anti-NMDAR encephalitis onset in 17 patients; lesion distribution was more diffuse than the non-infection-related group, showing higher lesion peak probabilities in the bilateral hippocampus, frontal lobe, temporal lobe, insula, and cingulate. The lesions with contrast enhancement were also more common in the post-infection group than the non-infection-related group (7/13 vs. 2/10). Brain atrophy was observed in eight patients in the post-infection group and three in the non-infection-related group. Anti-NMDAR encephalitis secondary to CNS infection has its imaging features-extensive lesion distribution, leptomeningeal enhancement, early atrophy, and necrosis-that could deepen the understanding of the pathophysiology and manifestation of the autoimmune encephalitis besides the classic type.

Anti-N-methyl-D-aspartate receptor encephalitis associated with chronic myelogenous leukemia, causality or coincidence? A case report

BackgroundAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune paraneoplastic encephalitis, and is primarily associated with ovarian teratomas. Here, we report the first case of a patient diagnosed with chronic myelogenous leukemia (CML) during the recovery phase of anti-NMDAR encephalitis.Case presentationThe patient was admitted with fever, headache, and seizures. Brain MRI revealed a cerebrospinal fluid (CSF)-containing arachnoid cyst in the left temporal lobe with no other abnormal signals. EEG showed diffuse background slowing in the delta-theta range. The patient tested positive for anti-NMDAR antibodies in both the serum and CSF. One year after the onset of encephalitis, the patient was referred to the Department of Hematology for extreme leukocytosis. Karyotype analysis showed the presence of Philadelphia chromosome t(9;22)(q34;q11). Quantitative reverse transcriptase PCR analysis further identified BCR/ABL1 fusion transcripts; thus, CML was diagnosed.ConclusionsTo the best of our knowledge, this is the first case of anti-NMDAR encephalitis associated with CML. This report should alert clinicians to consider CML as a malignancy that is possibly associated with limbic encephalitis.

Bilateral Thalamic Lesions Associated With Atezolizumab-Induced Encephalitis: A Follow-up Report With Autopsy Findings.

A 72-year-old woman was clinically diagnosed with atezolizumab-induced encephalitis.1 Her clinical features were previously described1 and here we present the autopsy findings. She had been treated with atezolizumab, an immune checkpoint inhibitor (ICI), due to a metastatic non–small-cell lung cancer diagnosis. She received her final atezolizumab injection 3 weeks after encephalitis onset, and cancer therapy ceased. Although the bilateral thalamic lesions shrank after steroid pulse, IV immunoglobulin, and long-term oral steroid, the patient died of aspiration pneumonia 7 months after encephalitis onset. An autopsy revealed no evidence of cancer recurrence. Brain histologic analyses revealed lymphocytic infiltration only into the thalamus, without infection or metastasis (Figure). Both B- and T-cell infiltration was identified accompanied by neuronal loss and thalamic gliosis. The T-cell infiltration was in agreement with previous work describing ICI-induced encephalitis,2 suggesting mechanistic overlap with encephalitis/encephalopathy caused by paraneoplastic syndromes. This case also indicates that B cells contribute to the inflammatory process.

P.005 Ovarian resection in anti-NMDAr encephalitis

Background: Anti-N-methyl-D-aspartate receptor encephalitis (NMDArE) is commonly associated with ovarian teratomas, surgical resection of which can lead to significant neurologic improvement. However, the necessity of aggressive resection at the time of diagnosis is unknown; specifically, whether unilateral or bilateral oophorectomy, versus lesionectomy and partial oophorectomy (ovariotomy), is required. Methods: Eleven patients with NMDArE who underwent ovarian resection between January 1st 2012 and December 31st 2020 were retrospectively identified. Primary outcome was good one-year functional status, defined as modified Rankin Scale (mRS) score of 0-1. Results: Median age at encephalitis onset was 24 years (19–38); median delay from symptom onset to surgery was 39 days (16–129). Six patients (54.5%) had good mRS scores, unrelated to surgical resection type. Conclusions: Added clinical benefit of aggressive ovarian resection techniques at one-year follow-up was not identified in our data. Further longitudinal studies are needed to determine the indications for different surgical techniques in patients with NMDArE. Ovarian resection approaches and associated functional outcomes in patients with NMDArE

Ketogenic Diet Therapy for the Treatment of Post-encephalitic and Autoimmune-Associated Epilepsies.

Introduction: Acute Encephalitis is associated with a high risk of acute symptomatic seizures, status epilepticus, and remote symptomatic epilepsy. Ketogenic diet therapies (KDT) have been established as a feasible and safe adjunctive management of refractory- and super-refractory status epilepticus. However, the role of KDT in the chronic management of Post-encephalitic epilepsy (PE) and autoimmune-associated epilepsy (AE) is unknown. This study aims to investigate the use of KDT in patients with PE and AE.Methods: A retrospective single-center case series examining adult patients with PE and AE treated with the modified Atkins diet (MAD), a KDT commonly used by adults with drug-resistant epilepsy.Results: Ten patients with PE and AE who were treated with adjunctive MAD were included. Four patients had either confirmed or presumed viral encephalitis, five patients had seronegative AE, and one patient had GAD65 AE. The median latency between starting MAD and onset of encephalitis was 6 years (IQR: 1–10). The median duration of MAD was 10 months (IQR: 3.75–36). Three patients (30%) became seizure-free, one patient (10%) achieved 90% seizure freedom, and three patients (30%) achieved a 50–75% reduction in their baseline seizure frequency, while three patients (30%) had no significant benefit. Overall, seven patients (70%) achieved ≥50% seizure reduction.Conclusion: In addition to its established role in the treatment of RSE, KDT may be a safe and feasible option for the treatment of chronic PE and AE, particularly in those with prior history of SE. Prospective studies are warranted to explore the efficacy of KDT in management of patients with PE and AE.

Encephalitis as a neurological complication of COVID-19: A systematic review and meta-analysis of incidence, outcomes, and predictors.

Background and purposeAlthough COVID‐19 predominantly affects the respiratory system, recent studies have reported the occurrence of neurological disorders such as stroke in relation to COVID‐19 infection. Encephalitis is an inflammatory condition of the brain that has been described as a severe neurological complication of COVID‐19. Despite a growing number of reported cases, encephalitis related to COVID‐19 infection has not been adequately characterised. To address this gap, this systematic review and meta‐analysis aims to describe the incidence, clinical course, and outcomes of patients who suffer from encephalitis as a complication of COVID‐19.MethodsAll studies published between 1 November 2019 and 24 October 2020 that reported on patients who developed encephalitis as a complication of COVID‐19 were included. Only cases with radiological and/or biochemical evidence of encephalitis were included.ResultsIn this study, 610 studies were screened and 23 studies reporting findings from 129,008 patients, including 138 with encephalitis, were included. The average time from diagnosis of COVID‐19 to onset of encephalitis was 14.5 days (range = 10.8–18.2 days). The average incidence of encephalitis as a complication of COVID‐19 was 0.215% (95% confidence interval [CI] = 0.056%–0.441%). The average mortality rate of encephalitis in COVID‐19 patients was 13.4% (95% CI = 3.8%–25.9%). These patients also had deranged clinical parameters, including raised serum inflammatory markers and cerebrospinal fluid pleocytosis.ConclusionsAlthough encephalitis is an uncommon complication of COVID‐19, when present, it results in significant morbidity and mortality. Severely ill COVID‐19 patients are at higher risk of suffering from encephalitis as a complication of the infection.

Clinical characteristics and treatment outcomes of pediatric patients with postencephalitic epilepsy characterized by epileptic spasms

PurposeViral encephalitis (VE) or bacterial meningoencephalitis (BME) in early childhood may cause brain injury and neurological sequelae, including epilepsy. Postencephalitic epilepsy (PEE) characterized by epileptic spasms (ES) is a rare but serious condition; there is an urgent need to develop new methods to evaluate the characteristics of these children and select appropriate treatments. MethodsWe conducted an observational study of 20 patients (11 males, 9 females) who experienced ES after VE or BME at the Chinese PLA General Hospital. Patients were followed up for over 12 months, and outcomes were analyzed. ResultsThe median ages at the onset of encephalitis and ES were 5.5 and 11.5 months, respectively. The median age at follow-up was 35.5 months. Sixteen (80 %) patients developed drug-resistant epilepsy (DRE), including all 12 patients with VE and 4 of 8 patients with BME. Epileptiform discharges were detected on electroencephalography, including 15 patients with hypsarrhythmia and 5 without. Fifteen of the patients were treated with a 14-day intravenous infusion of adrenocorticotropic hormone (ACTH) at a dose 2.5 U/kg (≤25 U); 12 showed a short-term response but 10 experienced recurrence. Three patients received vigabatrin, and none of these patients responded to treatment. Six patients started a ketogenic diet (KD); five failed to respond and the outcome was not known in one. Four patients were treated by vagus nerve stimulation (VNS), and all showed a partial response. ConclusionChildren with PEE characterized by ES are more likely to develop DRE. The prognosis was worse for patients with VE compared to those with BME. Clarifying the efficacies of treatments involving ACTH (low-dose), KD, vigabatrin, and VNS will require further investigation.

Clinical characteristics of children and adults with anti-N-methyl-D-aspartate receptor encephalitis

ObjectivesTo investigate the clinical characteristics of children and adults with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. MethodsPatients who tested positive for the anti-NMDAR antibody (by a cell-based assay) in the cerebrospinal fluid were enrolled. They were divided into two groups based on age (<16 years or older). ResultsThree children (two males and one female) and four adults (one male and three females) were examined. The age at onset was 3.0 ± 1.41 years (range: 2–5 years) for the children and 31.8 ± 6.80 years (range: 20–36 years) for the adults. The follow-up duration was 82.7 ± 23.80 months (range: 52–110 months) for the children and 61.5 ± 12.54 months (range: 43–78 months) for the adults. Prodromal symptoms such as fever and headache were observed in three adults. Two children received influenza vaccination before the onset of encephalitis. Brain magnetic resonance imaging abnormalities were observed in three children and one adult. Basal ganglia lesions were observed in two children and one adult, and the two children showed dystonia. Two children and one adult without neoplasms experienced recurrences. The modified Rankin Scale scores at the final follow-up tended to be worse in children than in adults. ConclusionThree patients had basal ganglia lesions, and two of them showed dystonia. Dystonia with basal ganglia lesions has been rarely reported in anti-NMDAR encephalitis but should be noted as a significant symptom, which severely affects the activities of daily life.

A Systematic Review of Sodium Disorders in HHV-6 Encephalitis.

Human herpesvirus 6 (HHV-6) encephalitis has a high mortality rate. Among those who survive, ~80% develop some type of permanent neurologic disorder. Early diagnosis and treatment may help prevent long-term sequelae. There have been several case reports as well as retrospective and prospective studies associating HHV-6 encephalitis with some form of sodium imbalance, either hyponatremia or hypernatremia; however, the exact frequency post-HCT is unknown, with reports ranging from 30% to 100%. We performed a systematic review of the literature and found 34 cases of HHV-6 encephalitis reported in conjunction with sodium imbalance that documented the timing of that imbalance relative to the onset of encephalitis. Sodium imbalance occurred before or at the onset of HHV-6 encephalitis in all but 2 cases (94%). This finding supports previous suggestions that sodium imbalance can be considered an early indicator of the potential development or presence of HHV-6 encephalitis in at-risk patient populations.

Case Study on Focal Retrograde Amnesia due to Limbic Encephalitis

This case study addresses episodic memory impairment or focal retrograde amnesia related to limbic encephalitis. The patient in question was a right-handed man in his 60s who developed focal retrograde amnesia due to limbic encephalitis. An abnormal MRI signal was observed in the right medial temporal lobe. Immediately after the encephalitis onset, mental symptoms—including impaired consciousness, disorientation, hallucinations, and delusions—appeared; however, his condition improved with medical treatment. After transfer to a convalescent and rehabilitation hospital, various neuropsychological tests were conducted but no apparent functional decline was observed in intellectual function, attention, memorization, or retention. However, the patient exhibited impairments related to autobiographical memory and memory of events 4 - 5 years before the onset of limbic encephalitis. Based on these observations, the patient was considered to exhibit focal retrograde amnesia due to limbic encephalitis. Despite exhibiting retrograde amnesia, he had no difficulty in his daily life in the ward. Moreover, after discharge from hospital, smooth work reinstatement was possible. This case demonstrates that, even after exhibiting retrograde amnesia, if its duration is relatively short and physical function and other higher-order brain functions are sustained, social rehabilitation—including work reinstatement—is feasible.

Genome-based analysis of SFTSV causing severe encephalitis with brain lesions.

Encephalitis is an infrequent manifestation in the various spectrums caused by severe fever with thrombocytopenia syndrome virus (SFTSV) infection. There are few data about the possible pathogenic mechanisms of SFTSV-associated encephalitis. Here, two SFTSV-infected patients with onset of encephalitis were enrolled. The whole genome of two SFTSV strains isolated from cerebrospinal fluid (CSF) was deeply sequenced by next-generation sequencing (NGS) and phylogenetic analysis was conducted. The specific mutations of M fragment were P98L and T665S respectively. The three-dimensional structure of glycoprotein Gn which was encoded by M fragment, an important virulence factor of SFTSV, was constructed by SWISS-MODEL. There was no significant variation in glycoprotein Gn of the two isolates comparing to other strains without encephalitis. Phylogenetic trees based on the complete sequences of M segment showed the two strains were highly identical to other local strains without encephalitis. Our study demonstrates that the virulence factors of SFTSV with encephalitis are not different from those without encephalitis. SFTSV itself is a neurotropic virus.

Correlations of cytokine levels in cerebrospinal fluid and peripheral blood with outcome of HHV-6B encephalitis after hematopoietic stem cell transplantation.

Human herpesvirus (HHV)-6B encephalitis has been recognized as a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT). Little is known about the pathogenic mechanism for its progression. We retrospectively evaluated the 16 kinds of cytokines and chemokines in cerebrospinal fluid (CSF) and plasma in patients who developed HHV-6B encephalitis. Among a total of 20 patients, 12 were categorized as the poor prognosis group (died of encephalitis; n=8 and retained sequelae; n=4), and other eight patients were categorized as the good prognosis group (complete recovery; n=8). Concentrations of CSF IL-6 and IL-8 at the onset of encephalitis were significantly higher in the poor prognosis group than in the good prognosis group (median CSF IL-6, 28.27pg/mL vs 14.32pg/mL, P=.004; median CSF IL-8, 128.70pg/mL vs 59.43pg/mL, P=.043). Regarding plasma, the concentration of each cytokine at the onset of encephalitis was not significantly different between the two groups, except IL-5. However, higher levels of IL-6, IL-7, and MCP-1 and lower levels of IL-12 were observed 1week before the development of encephalitis in patients with poor prognosis (median IL-6; 464.17pg/mL vs 47.82pg/mL, P=.02; median IL-12; 1.63pg/mL vs 6.57pg/mL, P=.03). We found that one week before onset of HHV-6B encephalitis, poor prognosis patients had high plasma concentrations of IL-6, IL-7, and MCP-1 and low concentrations of IL-12. At the onset of encephalitis, high concentrations of IL-6 and IL-8 in CSF were more common in the poor prognosis group, consistent with other evidence that IL-6 can have a role in CNS disturbances. Our findings show that specific cytokine status is associated with severe brain damage in patients with HHV-6B encephalitis, demonstrate prognostic value of plasma IL-6 concentrations, and suggest evaluation of anti-cytokine therapeutics in patients with HHV-6B encephalitis.

Hyponatremia associated with human herpesvirus-6 (HHV-6) encephalitis after allogeneic hematopoietic stem cell transplantation: A presentation different from HHV-6 myelitis.

Human herpesvirus-6 (HHV-6) encephalitis and myelitis following allogeneic hematopoietic stem cell transplantation (HSCT) is frequently life-threatening. We retrospectively evaluated the clinical significance of hyponatremia in cases of HHV-6 encephalitis/myelitis. Using an institutional database and medical records, we identified and retrospectively analyzed 16 cases of HHV-6 encephalitis and/or myelitis after allogeneic HSCT. HHV-6 encephalitis and myelitis were defined as the symptoms/signs with HHV-6-DNA in the cerebrospinal fluid. Seizure and memory disorder were defined as symptoms/signs of encephalitis, and dysesthesia and vesicorectal disorder as those of myelitis. Five patients developed encephalitis with or without myelitis, and 11 patients developed myelitis alone. Hyponatremia (median 129.1mEq/L; range 125.9-130.1) was observed in all five patients with HHV-6 encephalitis at diagnosis, and values were significantly lower than those in patients with HHV-6 myelitis alone (median 137.6; range 134.0-142.2; P<0.01). In three of the five patients with encephalitis, the decrease in sodium level preceded the clinical onset of encephalitis by one or two days. These results suggest that hyponatremia may be an important manifestation of HHV-6 encephalitis, but not of myelitis, and could be a useful tool for the early prediction or diagnosis of HHV-6 encephalitis.

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis.

Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management. We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned. In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal. Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.