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Background and Objectives Recognition of autoimmune encephalitis (AIE) can be difficult as typical radiological or cerebrospinal fluid abnormalities may be lacking. We investigated the yield of comprehensive diagnostic testing for anti‐neuronal antibodies in patients suspected of encephalitis in an acute setting. Methods In a prospective multicenter cohort, we included patients suspected of encephalitis in whom a lumbar puncture was performed. We retrospectively selected patients from this cohort in whom no infectious cause was identified and an autoimmune CNS disease was considered. Immunohistochemistry was performed on the CSF samples as an index test to screen for anti‐neuronal antibodies, and confirmatory cell‐based assays were performed. Results Between 2017 and 2021, 723 episodes were included in 707 patients. The median age was 55 years, and 347 (48%) of the episodes occurred in women. In 59 of 723 episodes (8%), a clinical diagnosis of autoimmune CNS disease was made. Twenty‐three (3%) of them fulfilled the diagnostic criteria for possible AIE, and 9 (1%) had antibody‐positive AIE (five anti‐NMDAR encephalitis, two anti‐LGi1 encephalitis, one anti‐Ma2 encephalitis and anti‐CV2 encephalitis). Extensive antibody testing identified no additional anti‐neuronal antibodies in the remaining 47 episodes. Discussion In a cohort of patients with a suspected encephalitis presenting in an acute setting, the incidence of possible AIE was low, and in only one‐third of possible AIE episodes an anti‐neuronal antibody was detected. Anti‐neuronal antibody testing beyond what was done in the clinical setting did not yield additional cases of antibody‐positive AIE. In a retrospective analysis of suspected autoimmune encephalitis (AIE) cases from a prospective cohort including patients with an acute presentation, nine cases of antibody‐positive AIE were identified during hospitalization. Extensive additional anti‐neuronal antibody testing did not yield additional cases of antibody‐positive AIE.

Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001). Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

Background Encephalitis originates from diverse autoimmune and infectious etiologies. Diagnostic challenges arise due to the spectrum of presentation and the frequent absence of specific biomarkers. This study aimed to comprehensively characterize and differentiate autoimmune encephalitis (AE) from infectious encephalitis (IE) in adults, and disentangle clinical, paraclinical, and therapeutic differences. Methods A cohort study spanning 10 years was conducted across three Austrian tertiary care hospitals. Inclusion criteria comprised adults with probable or definite encephalitis. Demographics, clinical features, technical findings, treatment modalities, and outcomes were collected from the electronic patient files. A follow-up was performed via telephone interviews and clinical visits. Results Of 149 patients, 17% had AE, 73% IE, and 10% encephalitis of unknown etiology. Significant differences between AE and IE included the prevalence of acute symptomatic seizures (AE: 85% vs. IE: 20%, p  < 0.001), fever (8% vs. 72%, p  < 0.001), headache (15% vs. 61%, p  < 0.001), and focal neurological deficits (56% vs. 23%, p  = 0.004), respectively. Paraclinical differences comprised lower CSF pleocytosis in AE compared to IE (median 6 cells/µl vs. 125 cells/µl, p  < 0.001). Epileptic discharges on EEG and MRI lesions were more prevalent in AE than IE (50% vs. 14%, p  < 0.001; 50% vs. 28%, p  = 0.037). The modified Rankin Scale scores at discharge and last follow-up (median duration 2304 days, IQR 1433–3274) indicated favorable outcomes in both groups. Conclusion This comprehensive analysis provides insights into the epidemiology, clinical, paraclinical, and therapeutic aspects and the outcomes of AE and IE in adults. We developed a diagnostic tool that facilitates early differentiation between AE and IE, aiding in timely therapeutic decision-making.

Infectious encephalitis is a serious global health problem linked to high rates of mortality and morbidity. However, clinical and laboratory factors that impact neurological outcomes following infectious encephalitis remain poorly understood. Accordingly, we undertook a systematic review and meta-analysis of clinical and laboratory factors influencing neurological outcomes following infectious encephalitis. We searched MEDLINE and EMBASE from inception to 25th September 2023 for observational studies that reported on neurological outcomes at discharge or at ≥ 6 months. We assessed the prognostic value of a priori selected clinical and laboratory-based features by estimating pooled risk ratios (RRs) through a random-effects meta-analysis. The I statistic was used to assess heterogeneity. This study is registered with PROSPERO (CRD42023485045). There were several key findings. First, immunocompromised status, status epilepticus, and Glasgow coma scale of < 8 during initial admission were significantly associated with poor neurological outcomes both at discharge and ≥ 6 months after infectious encephalitis onset. Second, CSF leucocytosis [RR: 0.83 95% CI: 0.69-0.98, p = 0.03, n = 5, I  = 0%] conferred better neurological outcomes while elevated CSF protein [RR: 1.25 95% CI: 1.07-1.46, p = 0.006, n = 7, I  = 0%] was linked to worse neurological outcomes at discharge. Third, there was no significant association between adjunct steroid therapy and neurological outcomes at discharge and ≥ 6 months. This is the first systematic review and meta-analysis to investigate prognostic factors linked to neurological outcomes following infectious encephalitis. The results highlight the prognostic value of a range of easily accessible clinical and laboratory parameters.

Balamuthia mandrillaris is a rare, free-living amoeba (FLA) that causes granulomatous amoebic encephalitis, a disease with close to 90% mortality. The geographical ranges of many FLA are expanding, potentially increasing human exposure to B. mandrillaris . Here, we report a case of a 58-year-old woman with progressive neurological symptoms, ultimately diagnosed postmortem with B. mandrillaris encephalitis through plasma metagenomic next-generation sequencing (mNGS) despite negative results on both cerebrospinal fluid (CSF) mNGS and CSF PCR testing. Histologic analysis and real-time PCR (qPCR) studies on postmortem brain tissue confirmed B. mandrillaris infection with significant vascular clustering of trophozoites. Retrospective analysis of CSF mNGS data demonstrated subthreshold reads for B. mandrillaris , emphasizing the challenges of interpreting low-level pathogen signals. A systematic review of 159 published B. mandrillaris cases revealed only two reports of B. mandrillaris diagnosed using plasma mNGS, both of which also had diagnostic CSF studies. This case demonstrates the diagnostic challenges of B. mandrillaris infections, highlights its vascular tropism, and suggests that plasma mNGS may warrant evaluation as a diagnostic tool for B. mandrillaris .

Background. The spectrum of neurologic disease attributable to Mycoplasma pneumoniae in children is incompletely understood in part because of limitations of microbiologic diagnostic methods. Our objective was to characterize the neurologic complications of M. pneumoniae in children using stringent diagnostic criteria. Methods. All children admitted to the Hospital for Sick Children over a 16-year period with acute neurologic manifestations and polymerase chain reaction (PCR)–confirmed M. pneumoniae infection were eligible for inclusion. Cases were categorized as definite, probable, or possible according to strength of evidence implicating M. pneumoniae. Children with underlying noninfectious neurologic conditions or an alternative infectious cause were excluded. Results. A total of 365 children had M. pneumoniae detected in the cerebrospinal fluid (CSF) or respiratory tract by PCR, 42 (11.5%) of whom had neurologic disease attributable to M. pneumoniae. The most common clinical syndromes were encephalitis (52%), acute disseminated encephalomyelitis (12%), transverse myelitis (12%), and cerebellar ataxia (10%). Two distinct disease patterns were observed, one with a prolonged prodrome (≥7 days), respiratory manifestations, an immunoglobulin M (IgM) response in peripheral blood, and detection of M. pneumoniae in the respiratory tract, but not the CSF, and one with a brief (<7 days) or no prodrome, less frequent respiratory manifestations and IgM response, and detection of M. pneumoniae in the CSF, but not the respiratory tract. Conclusions. Our findings support the hypothesis of two separate pathogenetic mechanisms for M. pneumoniae–associated neurologic disease, one related to direct infection of the central nervous system and one indirect, likely immunologically mediated.

Background Recognizing patients with encephalitis may be challenging. The cardinal symptom, encephalopathy, has a wide array of differential diagnoses. In this prospective study we aimed to explore the etiology of encephalitis and to assess the diagnostic accuracy of symptoms and clinical findings in patients with encephalitis in an encephalopathic population. Methods Patients with acute onset of encephalopathy ( n  = 136) were prospectively enrolled from January 2014–December 2015 at Oslo University Hospital, Ullevaal. Clinical and biochemical characteristics of patients who met the case definition of encephalitis were compared to patients with encephalopathy of other causes. Results Among 136 patients with encephalopathy, 19 (14%) met the case-definition of encephalitis. For 117 patients other causes of encephalopathy were found, infection outside the CNS was the most common differential diagnosis. Etiology of encephalitis was confirmed in 53% (4 bacterial, 4 viral, 1 parasitic, and 1 autoimmune). Personality change, nausea, fever, focal neurology, recent travel history, and low inflammation markers were significantly more abundant in patients with encephalitis, but the diagnostic accuracy for individual parameters were low (area under the curve (AUC) < 0.7). The combination of fever (OR = 6.6, 95% CI, 1.6–28), nausea (OR = 8.9, 95% CI, 1.7–46) and a normal level of ESR (erythrocyte sedimentation rate < 17 mm/hr, OR = 6.9, 95% CI, 1.5–33) was significant in multivariate analysis with an AUC (area under the curve) of 0.85 (95% CI, 0.76–0.94). Moderately increased pleocytosis in CSF (5-100 × 10 6 /L) further increased the diagnostic accuracy of this combination, AUC 0.90 (95% CI, 0.81–0.98). Conclusions There is a wide diversity in differential diagnoses in patients with encephalopathy, and no single symptom or finding can be used to predict encephalitis with high accuracy in this group. The combination of fever, nausea and a low ESR in an encephalopathic population, increased the diagnostic accuracy of encephalitis compared to solitary parameters. The triad could be a useful clinical tool for early diagnosis of encephalitis, and these patients should be considered for further diagnostics such as lumbar puncture (LP).

Abstract Background Encephalitis is caused by infection, immune mediated diseases, or primary inflammatory diseases. Of all the causative infectious pathogens, 90% are viruses or bacteria. Granulomatous amoebic encephalitis (GAE), caused by Balamuthia mandrillaris, is a rare but life-threatening disease. Diagnosis and therapy are frequently delayed due to the lack of specific clinical manifestations. Method A healthy 2 year old Chinese male patient initially presented with a nearly 2 month history of irregular fever. We present this case of granulomatous amoebic encephalitis caused by B. mandrillaris. Next generation sequencing of the patient’s cerebrospinal fluid (CSF) was performed to identify an infectious agent. Result The results of next generation sequencing of the CSF showed that most of the mapped reads belonged to Balamuthia mandrillaris. Conclusion Next generation sequencing (NGS) is an unbiased and rapid diagnostic tool. The NGS method can be used for the rapid identification of causative pathogens. The NGS method should be widely applied in clinical practice and help clinicians provide direction for the diagnosis of diseases, especially for rare and difficult cases.

Background and objectives: Tick-borne encephalitis virus (TBEV) infections have been the cause of threatening outbreaks for many years. Apart from several physical and chemical methods to prevent tick bites, active vaccination of people highly exposed to infection is still the most important strategy of prevention. However, in some subjects, the lack of or low response to TBEV antigens is observed. The aim of the current study was to assess the prevalence of seronegative rate for anti-TBEV antibodies and the risk factors for waning immunity. Materials and Methods: 2315 at least primary vaccinated subjects from the high risk group for TBEV infections participated in this study. A commercial enzyme-linked immunosorbent assay (ELISA) test was used for the assessment of anti-TBEV IgG serum level. Results: Data showed that 86.2% of subjects who underwent vaccination were positive for anti-TBEV antibodies within 5 years. As much as 13.8% of subjects that underwent primary or primary and booster vaccination were barely protected after vaccination. Women and subjects under 60 years underwent more effective protection but sex and older age was not a risk factor for being a subject of waning immunity. A logistic regression showed that both a longer time since the vaccination and a lower number of booster doses constantly increased the chance of lost anti-TBEV antibodies. Conclusions: This study demonstrates that the vaccination schedule should be reevaluated. The extension of the interval of booster immunization is risky and all subjects should be surrounded by care consisting of more frequent monitoring of serum antibodies by personalized schedule to adjust the frequency of subsequent doses of booster vaccination.