Diagnosis and Therapy of Infectious Encephalitis in Children: A Ten-Years Retrospective Study.

BACKGROUND: Infectious encephalitis represents a rare but potentially severe clinical condition. However, limited international data are available in pediatric age. METHODS: We conducted a retrospective study to review (a) the clinical presentation; (b) laboratory, radiology, and neurophysiology findings; (c) the correlations between these exams and outcome; and (d) the therapy performed. RESULTS: Fifty-six patients were enrolled [22 female (39.6%), mean age 4.7 years, IQR 0.7-8.7 years], 19.6% presented neurologic sequelae. HSV was the single most frequently isolated pathogen (19.6%), although in most cases, the etiology remained undefined. 41.1% children presented prodromal before the development of neurologic signs. Fever was the most frequent constitutional symptom (83.9% of cases). Cerebrospinal fluid was normal in 48.5% of cases and electroencephalograpy in 24.5% cases. Brain computed tomography scans was normal in 33 (91.7%) cases, while cerebral magnetic resonance imaging (MRI) showed pathologic findings in 62.5% of cases. MRI was the only parameter associated with neurologic sequalae [P = 0.01; OR, 8.1 (95% CI: 1.52-42.84)]. CONCLUSIONS: Pediatric encephalitis is a heterogeneous entity with nonspecific clinical and laboratory findings, with undefined etiologies in most times. MRI can play a primary role, both on a diagnostic and prognostic point-of-view, and its role should be implemented and made more accessible. Further studies are needed to define the exact role and timing of steroids.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

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.

[Multifocal encephalitis as a neurological manifestation of COVID-19 infection]. / Encefalitis multifocal como manifestación neurológica de la infección por COVID-19.

TITLE: Encefalitis multifocal como manifestación neurológica de la infección por COVID-19.

Minimal Cerebrospinal Fluid Concentration of Miltefosine despite Therapeutic Plasma Levels during the Treatment of Amebic Encephalitis.

Miltefosine is an alkylphosphocholine compound that is used primarily for treatment of leishmaniasis and demonstrates in vitro and in vivo antiamebic activity against Acanthamoeba species. Recommendations for treatment of amebic encephalitis generally include miltefosine therapy. Data indicate that treatment with an amebicidal concentration of at least 16 µg/ml of miltefosine is required for most Acanthamoeba species. Although there is a high level of mortality associated with amebic encephalitis, a paucity of data regarding miltefosine levels in plasma and cerebrospinal fluid in vivo exists in the literature. We found that despite aggressive dosing (oral miltefosine 50 mg every 6 h) and therapeutic plasma levels, the miltefosine concentration in cerebrospinal fluid was negligible in a patient with AIDS and Acanthamoeba encephalitis.

Diagnostic accuracy of a commercial multiplex PCR for the diagnosis of meningitis and encephalitis in an Italian general hospital.

Infectious meningitis and encephalitis are potentially life-threatening conditions caused mostly by bacterial and viral agents. Rapid diagnosis and prompt treatment are associated with a more favorable outcome. In recent years nucleic acid amplification tests have been developed to speed detection and identification of pathogens directly from cerebrospinal fluid (CSF). The aim of this study was to compare the diagnostic accuracy of a commercially available multiplex PCR assay for etiological diagnosis of infectious meningitis directly from CSF samples with culture. A secondary endpoint was to look for a possible screening threshold based on main CSF indices and urgent blood test results, to define CSF samples with low pre-test probability of PCR and/or culture-positive result. We performed a secondary analysis of results of CSF samples already processed as part of routine clinical care from February 2016 to December 2018. In all, 109 CSF samples were included in the study and a total of 14 bacteria were identified by either PCR, culture or both methods, along with nine samples positive for viruses. The comparison of PCR results with culture showed no significant difference: 7/109 (6.4%) vs 13/109 (11.9%) respectively, p=0.07. After exclusion of the isolates not detectable by the multiplex PCR panel, the diagnostic accuracy was: 100% (95% confidence interval (CI): 54.1% to 100%) sensitivity; 98.9% (95% CI: 93.5% to 99.9%) specificity; 85.7% (95% CI: 42% to 99.2%) positive predictive value; 100% (95% CI: 95.1% to 100%) negative predictive value; 96 (95% CI: 13.6 to 674.6) LR+; Zero LR-; Cohen's kappa: 0.918, p<0.0001. CSF protein value ≤ 28 mg/dl and CSF glucose/blood glucose ratio ≥0.78 were associated with both PCR-negative result for bacteria or viruses and culture-negative result. The multiplex PCR evaluated in this study showed a very good diagnostic performance compared to culture, and the thresholds found can be a useful tool to best choose which samples to test.

Ratio of Alpha 2-Macroglobulin Levels in Cerebrospinal Fluid and Serum: An Expression of Neuroinflammation in Acute Disseminated Encephalomyelitis.

BACKGROUND: Acute encephalitis and encephalopathy are life-threatening diseases in children. However, no laboratory examinations are performed for their early diagnosis and treatment. Alpha 2-macroglobulin (α2M) is a blood glycoprotein that increases during the early stages of inflammation. In the present study, we investigated the role of α2M levels in acute encephalitis and encephalopathy. METHODS: We analyzed the cerebrospinal fluid and serum samples from patients with acute disseminated encephalomyelitis, infection-related acute encephalopathy, febrile status epilepticus, and febrile seizure simplex type. Samples were collected from the pediatric department of hospitals throughout the Fukushima Prefecture between January 1, 1999, and May 31, 2012. RESULTS: α2M levels in the cerebrospinal fluid were 4.7 (3.8-8.4) µg/mL for acute disseminated encephalomyelitis, 2.1 (1.1-2.3) µg/mL for infection-related acute encephalopathy, 1.1 (0.9-6.4) µg/mL for febrile status epilepticus, and 1.0 (0.8-1.1) µg/mL for febrile seizure simplex type. α2M levels in patients with acute disseminated encephalomyelitis were significantly higher than those in patients with infection-related acute encephalopathy and febrile seizure simplex type (P = 0.019 and P = 0.002, respectively). The ratio of α2M level in the cerebrospinal fluid to that in the serum in patients with acute disseminated encephalomyelitis was significantly higher than the ratio in patients with febrile status epilepticus (P = 0.04). In patients with acute disseminated encephalomyelitis, α2M levels in the cerebrospinal fluid decreased with treatment. CONCLUSIONS: Our results suggest that α2M levels in the cerebrospinal fluid reflect the neuroinflammatory status of patients with acute disseminated encephalomyelitis.

An Improved Specimen Handling Procedure for Pathogen Detection of the Cerebrospinal Fluid by Microscope.

BACKGROUND: In order to increase the detection rate of pathogenic microorganisms in CSF, an improved specimen handling procedure (ISHP) was created. METHODS: This study enrolled encephalitis and control groups, both groups were handled with traditional specimen handling procedure (TSHP) and ISHP. Glutaraldehyde was added to the ISHP. Observed items included: total protein, glucose, chloride, adenosine deaminase, lactate dehydrogenase, sediment, cell and pathogen, Pandy's test. RESULTS: Sediment test of CSF: There was 1 specimen in 10 control specimens tested by TSHP in which Pandy's test was positive; there were 2 specimens tested by ISHP which could see sediment by eye. There was no statistical difference between those two methods (p = 1.000, Table 1). Ten specimens in 23 of the encephalitis group processed by TSHP were positive with Pandy's test; 23 specimens processed by ISHP could all see sediments by eye (Figure 1). There was a statistical difference between the two methods (p = 0.000, Table 1). Pathogen test of CSF: no pathogen was found in the control group processed by TSHP and ISHP. No pathogen was found in the encephalitis group specimens processed by TSHP. Pathogen tests were positive in 7 encephalitis specimens processed by ISHP (p = 0.009, Table 1), which were confirmed as Rickettsia spp. by Gimenze stain (Figure 1B), IFA (Figure 2). CONCLUSIONS: The results revealed that ISHP contributes to the separation of cells, pathogens (such as Rickettsia), and proteins.

Evaluation of the FilmArray™ Meningitis/Encephalitis panel with focus on bacteria and Cryptococcus spp.

PURPOSE: Molecular methods provide fast and accurate detection of both bacteria and viruses in the cerebrospinal fluid (CSF) causing infection in the central nervous system (CNS). In the present study we evaluated the bacterial detection performance of the fully automated FilmArray™ Meningitis/Encephalitis (ME) panel (bioMérieux) by comparing it with culture and multiplexed in-house PCR. METHODS: Three sample types were analysed; Contrived samples with known bacterial/fungal concentration (n = 29), clinical samples from patients with verified cause of CNS infection (n = 17) and external quality assessment (EQA) samples (n = 11). Another six samples were purposely prepared with multiple targets to evaluate multiplex capacity. RESULTS: The FilmArray™ had a slightly higher limit of detection for Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes and Streptococcus agalactiae compared to in-house PCR methods but performed equal or better when compared to culture. The FilmArray™ ME panel detected the expected pathogen in 17 of 17 clinical samples and yielded detection of three additional viruses of which one was confirmed with comparator techniques. All but one of the EQA samples were correctly detected. CONCLUSIONS: The results of this study are promising and the FilmArray™ ME panel could add to the diagnostic algorithm in CNS-infections. However, the limit of detection for the important pathogens N. meningitidis and S. pneumoniae could be improved.

Brainstem encephalitis. A diagnostic dilemma.

Brainstem encephalitis (BE) is a rare, severe, and potentially life-threatening inflammation of the central nervous system. Brainstem encephalitis has multiple etiologies, which vary in treatment and outcomes. The current literature is generally focused on the infectious causes of BE, while little is known about the other entities, including cases with inconclusive diagnoses. Additionally, the outcomes of BE are not well documented. We present a case of an 18-year-old male who presented with progressive symptoms of brainstem involvement. His clinical investigations, including cerebrospinal fluid (CSF) analysis, were normal; magnetic resonance imaging (MRI) of the brain showed an enhancing medullary lesion, while tissue biopsy yielded no specific diagnosis. Multiple empirical treatments to address possible autoimmune and infectious processes were started with no significant improvement. He continued to deteriorate over a period of 12 weeks. Thereafter, following intensive supportive and rehabilitative care, he started to show slow signs of improvement.

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis.

OBJECTIVE: To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis. METHODS: We performed a population-based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age- and sex-adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded. RESULTS: The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995-2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person-years, respectively (p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis (p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person-years (1995-2005) to 1.2/100,000 person-years (2006-2015; p = 0.02), attributable to increased detection of autoantibody-positive cases. The incidence (2.8 vs 0.7/100,000 person-years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine-rich glioma-inactivated protein 1, 0.7/100,000; collapsin response-mediator protein 5, 0.7/100,000; N-methyl-D-aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000. INTERPRETATION: This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166-177.

Clinical and cerebrospinal fluid findings contribute to the early differentiation between infectious and noninfectious encephalitis.

Early recognition and prompt specific treatment are crucial factors influencing the outcome of patients with acute encephalitis. The aim of this study was to determine the main causes of acute encephalitis in our population and to find predictors that may lead to specific diagnosis. Adult patients admitted to our hospital with suspected diagnosis of encephalitis in the period 2006-2013 were included. One hundred and five medical records were analyzed. Eighty-two patients with infectious encephalitis were identified (78% of total cases), 53 (65%) men and 29 (35%) women, mean age 47.8 years. The most common microorganisms identified were: HSV-1 (11%), VZV (10%), HSV-2 (5%) and EBV (5%). Twenty-three patients (22% of the series) had non-infectious encephalitis. Headache (p < 0.0001) and fever (p = 0.008) were more frequent in encephalitis of infectious origin. Protein levels and white blood cell counts in the cerebrospinal fluid were significantly higher in patients affected by infectious encephalitis than in those affected by noninfectious encephalitis (OR 95% CI 12.3 [2.9-51.7] and OR 95% CI 7.4 [2-27], respectively). Identifying specific causal agents of acute encephalitis remains a major challenge. Cerebrospinal fluid markers, as well as specific clinical findings, may however contribute to initial differentiation between infectious and noninfectious causes.

Clinical and cerebrospinal fluid findings contribute to the early differentiation between infectious and noninfectious encephalitis

Early recognition and prompt specific treatment are crucial factors influencing the outcome of patients with acute encephalitis. The aim of this study was to determine the main causes of acute encephalitis in our population and to find predictors that may lead to specific diagnosis. Adult patients admitted to our hospital with suspected diagnosis of encephalitis in the period 2006-2013 were included. One hundred and five medical records were analyzed. Eighty-two patients with infectious encephalitis were identified (78% of total cases), 53 (65%) men and 29 (35%) women, mean age 47.8 years. The most common microorganisms identified were: HSV-1 (11%), VZV (10%), HSV-2 (5%) and EBV (5%). Twenty-three patients (22% of the series) had non-infectious encephalitis. Headache (p < 0.0001) and fever (p = 0.008) were more frequent in encephalitis of infectious origin. Protein levels and white blood cell counts in the cerebrospinal fluid were significantly higher in patients affected by infectious encephalitis than in those affected by noninfectious encephalitis (OR 95% CI 12.3 [2.9-51.7] and OR 95% CI 7.4 [2-27], respectively). Identifying specific causal agents of acute encephalitis remains a major challenge. Cerebrospinal fluid markers, as well as specific clinical findings, may however contribute to initial differentiation between infectious and noninfectious causes.

El reconocimiento temprano y la instauración del tratamiento adecuado son dos elementos de gran relevancia en el pronóstico de las encefalitis agudas. El objetivo del presente trabajo es determinar las principales causas de encefalitis aguda en nuestro medio, así como buscar predictores que permitan orientar a un diagnóstico determinado. Se revisaron de manera retrospectiva las historias clínicas de todos los pacientes adultos que consultaron en nuestro centro entre 2006 y 2013 con el diagnóstico presuntivo de encefalitis. Ciento cinco pacientes fueron finalmente incluidos en nuestro estudio. Se identificaron 82 pacientes con encefalitis de origen infeccioso (78%), 53 (65%) fueron hombres y 29 (35%) mujeres, con una edad promedio de 47.8 años. Los agentes infecciosos más frecuentes fueron virus: HSV-1 12 (11%), VZV 11 (10%), HSV-2 5 (5%) y EBV 5 (5%). Se diagnosticó encefalitis no infecciosa en 23 (22%) pacientes. La cefalea (p < 0.0001) y la fiebre (p = 0.008) fueron más frecuentes en las encefalitis de origen infeccioso. Además, los niveles de proteínas y células en el LCR fueron significativamente mayores en los casos de etiología infecciosa que en los de etiología no infecciosa (OR 12.3 95%CI [2.9-51.7] y OR 7.4 95%CI [2-27], respectivamente). La identificación de la etiología específica de las encefalitis agudas continúa siendo un gran desafío y en la mayoría de los casos no se identifica el agente causal. Determinados marcadores en el LCR pueden contribuir a la identificación inicial de las encefalitis de etiología infecciosa versus no infecciosa.

Infectious encephalitis: Management without etiological diagnosis 48hours after onset.

INTRODUCTION: The etiological diagnosis of infectious encephalitis is often not established 48hours after onset. We aimed to review existing literature data before providing management guidelines. METHOD: We performed a literature search on PubMed using filters such as "since 01/01/2000", "human", "adults", "English or French", and "clinical trial/review/guidelines". We also used the Mesh search terms "encephalitis/therapy" and "encephalitis/diagnosis". RESULTS: With Mesh search terms "encephalitis/therapy" and "encephalitis/diagnosis", we retrieved 223 and 258 articles, respectively. With search terms "encephalitis and corticosteroid", we identified 38 articles, and with "encephalitis and doxycycline" without the above-mentioned filters we identified 85 articles. A total of 210 articles were included in the analysis. DISCUSSION: Etiological investigations must focus on recent travels, animal exposures, age, immunodeficiency, neurological damage characteristics, and potential extra-neurological signs. The interest of a diagnosis of encephalitis for which there is no specific treatment is also to discontinue any empirical treatments initially prescribed. Physicians must consider and search for autoimmune encephalitis.

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.

Elevated levels of cerebrospinal fluid S100B are associated with brain injury and unfavorable outcomes in children with central nervous system infections.

PURPOSE: This work aimed to assess whether elevated levels of cerebrospinal fluid (CSF) S100B are associated with brain injury and unfavorable outcomes at discharge in children with central nervous system (CNS) infections. METHODS: CSF S100B and associated clinical parameters were retrospectively analyzed in 83 children with CNS infections and 88 children without neurological pathology served as controls. Children with CNS infections were divided into an infectious encephalitis group and an infectious meningitis group based on whether cerebral parenchyma was involved, and CSF S100B levels in different age subgroups between the two groups were compared. The predictive value of CSF S100B in children with infectious encephalitis was evaluated by multivariate logistic regression analysis, and the discriminative power was investigated by receiver operating characteristic (ROC) analysis. RESULTS: CSF S100B levels in the infectious encephalitis group were significantly higher than the infectious meningitis and the control group at each age range. CSF S100B ≥ 0.96 µg/L had 62.9% sensitivity and 76.2% specificity for diagnosing cerebral parenchyma injury in children with CNS infections. Increased CSF S100B levels were proven to be an independent predictor of unfavorable outcomes in children with infectious encephalitis and the optimal cut-off value (1.77 µg/L of CSF S100B) for predicting unfavorable outcomes in children with infectious encephalitis showed 61.1% sensitivity and 96.2% specificity. CONCLUSIONS: This study has demonstrated that elevated levels of CSF S100B are associated with brain injury and could be used as an independent predictor of clinically unfavorable outcomes at discharge in children with CNS infections.

Febrile infection-related epilepsy syndrome treated with anakinra.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945.

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.