The relationship between sleep and innate immunity.

Sleep regulates inflammatory responses, and the innate immune system affects sleep. Interleukin-1 beta, tumor necrosis factor alpha, growth hormone-releasing hormone, prolactin, and nitric oxide are somnogenic substances. Sleep deprivation, such as chronic insomnia or obstructive sleep apnea, affects cytokine production, glial function, natural killer cell activity, and inflammasome function. This review will discuss the relationship between sleep and innate immunity.

Clonal Hematopoiesis and Acute Ischemic Stroke Outcomes.

OBJECTIVE: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. METHODS: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. RESULTS: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (ß = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). INTERPRETATION: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

Lesion Detection Through MRI Postprocessing in Pathology-Proven Focal Cortical Dysplasia: Experience at a Single Institution in the Republic of Korea.

BACKGROUND AND PURPOSE: Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy, and necessitates a multimodal evaluation to ensure optimal surgical treatment. This study aimed to determine the supportive value of the morphometric analysis program (MAP) in detecting FCD using data from a single institution in Korea. METHODS: To develop a standard reference for the MAP, normal-looking MRIs by two scanners that are frequently used in this center were chosen. Patients with drug-resistant epilepsy and FCD after surgery were candidates for the analysis. The three-dimensional T1-weighted MRI scans of the patients were analyzed as test cases using the MAP. RESULTS: The MRI scans of 87 patients were included in the analysis. The radiologist detected abnormal findings correlated with FCD (RAD positive [RAD(+)]) in 34 cases (39.1%), while the MAP could detect FCD in 25.3% of cases. A combination of the MAP (MAP[+] cases) with interpretations by the radiologist increased the detection to 42.5% (37 cases). The lesion detection rate was not different according to the type of reference scanners except in one case. MAP(+)/RAD(-) presented in three cases, all of which had FCD type IIa. The detection rate was slightly higher using the same kind of scanner as a reference, but not significantly (35.0% vs. 22.4% p=0.26). CONCLUSIONS: The results of postprocessing in the MAP for detecting FCD did not depend on the type of reference scanner, and the MAP was the strongest in detecting FCD IIa. We suggested that the MAP could be widely utilized without developing institutional standards and could become an effective tool for detecting FCD lesions.

Clinicoradiologic data of familial cerebral cavernous malformation with age-related disease burden.

OBJECTIVE: Familial cerebral cavernous malformation (FCCM) is an autosomal dominant disease induced by loss-of-function mutations in three CCM genes, KRIT1, CCM2, and PDCD10. However, previous studies paid little attention to analyzing the radiologic features and age-related disease burden according to the genes. Therefore, we retrospectively reviewed the genetic tests of our center's clinical FCCM patients. METHOD: This study investigated clinical FCCM patients with multiple lesions or a family history of CCMs who underwent the FCCM gene (KRTI1, CCM2, and PDCD10) panel test. The clinical, genetic, and radiologic features were analyzed. RESULT: Among the patients (n = 34) undergoing the FCCM gene test, twenty-seven patients had CCM confirmed by brain MRI, and twenty-one patients were considered to have FCCM (cohort 1). In cohort 1, thirteen patients had mutations in the FCCM gene, but eight did not. Cohort 2 comprised cohort 1 and four family members with the same mutation as the probands. Six novel variants in CCM genes were detected (KRIT1 c.22_26del, c.815dup, c.1094_1098del, c.1147-2A>G, c.2124dup, and PDCD10 c.150 + 1dup). Cohort 1 demonstrated that brainstem lesions were mostly associated with the mutation detection in CCM genes (brainstem, lateral temporal, and parietal lesions vs. lateral temporal and parietal lesions, AUC 0.928 vs. 0.779, P = 0.0389). The radiologic severity worsened according to age in the KRIT1 group compared with the Mutation not detected group (correlation coefficient 0.75 (P < 0.001) versus 0.53 (P = 0.004)). CONCLUSION: The brainstem lesion could be the radiologic marker for FCCM with the mutation detected. The age-related disease burden regarding FCCM according to genetic information was demonstrated.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes.

BACKGROUND: We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients. METHODS: From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data. RESULTS: A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab. CONCLUSIONS: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.

Classification of white matter lesions and characteristics of small vessel disease markers.

OBJECTIVES: Radiological markers for cerebral small vessel disease (SVD) may have different biological underpinnings in their development. We attempted to categorize SVD burden by integrating white matter signal abnormalities (WMSA) features and secondary presence of lacunes, microbleeds, and enlarged perivascular spaces. METHODS: Data were acquired from 610 older adults (aged > 40 years) who underwent brain magnetic resonance imaging exam as part of a health checkup. The WMSA were classified individually by the number and size of non-contiguous lesions, distribution, and contrast. Age-detrended lacunes, microbleeds, and enlarged perivascular space were quantified to further categorize individuals. Clinical and laboratory values were compared across the individual classes. RESULTS: Class I was characterized by multiple, small, deep WMSA but a low burden of lacunes and microbleeds; class II had large periventricular WMSA and a high burden of lacunes and microbleeds; and class III had limited juxtaventricular WMSA and lacked lacunes and microbleeds. Class II was associated with older age, diabetes, and a relatively higher neutrophil-to-lymphocyte ratio. Smoking and higher uric acid levels were associated with an increased risk of class I. CONCLUSION: The heterogeneity of SVD was categorized into three classes with distinct clinical correlates. This categorization will improve our understanding of SVD pathophysiology, risk stratification, and outcome prediction. KEY POINTS: • Classification of white matter signal abnormality (WMSA) features was associated with different characteristic of lacunes, microbleeds, and enlarged perivascular space and clinical variability. • Class I was characterized by multiple, small, deep WMSA but a low burden of lacunes and microbleeds. Class II had large periventricular WMSA and a high burden of lacunes and microbleeds. Class III had limited juxtaventricular WMSA and lacked lacunes and microbleeds. • Class II was associated with older age, diabetes, and higher neutrophil-to-lymphocyte ratio. Smoking and higher uric acid levels were associated with an increased risk of class I.

Neuropsychiatric symptoms and seizure related with serum cytokine in epilepsy patients.

Neuroinflammation contributes to epileptogenesis and ictogenesis. Various signals of neuroinflammation lead to neuronal hyper-excitability. Since an interplay between epilepsy, psychiatric comorbidities and neuroinflammation has been suggested, we explored psychiatric symptoms in epilepsy patients, and the relationship with neuroinflammation. We screened epilepsy patients who were admitted for video-EEG monitoring between July 2019 and December 2020. Enrolled patients were asked to respond to neuropsychiatric questionnaires (Hospital Anxiety and Depression Scale (HADS) and Neuropsychiatric Inventory-Questionnaire (NPI-Q)) on admission. Serum cytokines (IL-1ß, IL-2, IL-6, IFN-γ, CCL2, and CCL5) were measured by ELISA on admission, and within 6 h after a seizure. We enrolled 134 patients, and 32 patients (23.9%) had seizures during monitoring. Cytokine levels did not change after seizures, but IL-2 and IL-6 increased in cases of generalized tonic-clonic seizures. The HADS-A score was lower in Q4 of CCL5 (p-value = 0.016) and anxiety was also less common in Q4 of CCL5 (p-value = 0.042). NPI-Q question 4 (depression) severity was higher in CCL2 (p-value = 0.024). This suggested that psychiatric symptoms may also be related to inflammatory processes in epilepsy patients. Further large, standardized studies are necessary to underpin the inflammatory mechanisms in epilepsy and psychiatric symptoms.

Isolated CNS involvement in eosinophilic granulomatosis with polyangiitis treated with mepolizumab: A case report.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis disease involving small-sized vessels. The literature has reported involvement of the central nervous system (CNS) in 5% cases, and isolated CNS involvement is extremely rare. Due to its rarity and scarcity of clinical data, standardized treatment of isolated CNS involvement in EGPA is unclear. Mepolizumab, an anti-interleukin-5 monoclonal antibody, was previously introduced to treat EGPA with longer remission period, more patients showing remission, and reduction in prednisolone dose of those who already taking prednisolone compared to placebo. We describe a case of isolated CNS involvement in EGPA, confirmed by brain biopsy and treated with mepolizumab, which was refractory to conventional immunotherapy.

Proportion of peripheral regulatory T cells in patients with autoimmune encephalitis.

Purpose: Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance. Any deficiency or dysfunction of the Tregs can influence the pathogenesis of autoimmune disease. This study aimed to assess the role of Tregs among patients with autoimmune encephalitis (AE) with different autoantibody types and to evaluate their association with clinical features. Methods: This was a cross-sectional observational study involving 29 patients with AE. Peripheral blood was sampled from each patient for flow cytometric analysis. Proportions of CD4+CD25+ and CD4+CD25+Foxp3+ Tregs were calculated and compared between the antibody types (synaptic, paraneoplastic, and undetermined). Associations between the proportion of Tregs and clinical features were also evaluated. Results: Five patients had synaptic autoantibodies, five had paraneoplastic autoantibodies, and the others were of an undetermined type. The proportion of CD4+CD25+ Tregs tended to be higher in those with paraneoplastic antibodies than in those with synaptic antibodies (post-hoc p = 0.028) and undetermined antibody status (post-hoc p = 0.043). A significant negative correlation was found between the proportion of Tregs and the initial modified Rankin score (r = -0.391, p = 0.036). Those who received intravenous immunoglobulin had lower proportions of Tregs than those who did not. Conclusion: The results of the present study suggest that Tregs may play different roles according to the type of AE and may be linked to disease severity.

Refractory neuro-Sweet disease successfully treated with tocilizumab and mycophenolate mofetil.

Sweet syndrome, or acute febrile neutrophilic dermatosis, is mainly a dermatologic condition presenting with erythematous plaques; however, neutrophils infiltrate multiple systems. Neuro-Sweet disease is a neurological manifestation of Sweet syndrome and a rare cause of recurrent aseptic meningoencephalitis, which needs to be distinguished from neuro-Behçet disease. Although neuro-Sweet disease generally responds well to corticosteroids, relapsing neuro-Sweet disease is not an exceptional case. Herein, we present a case of a 51-year-old male with recurrent encephalitis followed by erythematous plaques. The patient was confirmed as Sweet syndrome based on skin biopsy and showed partial response to corticosteroids. With intravenous immunoglobulin, rituximab, tocilizumab, and mycophenolate mofetil, his neurologic symptoms were fully recovered.

Teratoma Removal, Steroid, IVIG, Rituximab and Tocilizumab (T-SIRT) in Anti-NMDAR Encephalitis.

In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, we analysed the efficacy of a combined immunotherapy protocol consisting of teratoma removal, steroid, intravenous immunoglobulin (IVIG), rituximab and tocilizumab (T-SIRT). This cohort study included seventy-eight consecutive patients treated for anti-NMDAR encephalitis between Jan 2014 and Oct 2019 in a national referral hospital. Detailed 2-year disease time course was analysed using Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at every 2 weeks for 12 weeks from baseline, every month for the next 3 months and then every 3 months. Treatment regimens at each time point were categorized as SI, SIR, or SIRT with/without teratoma removal (T). Adverse events were classified according to the Common Terminology Criteria for Adverse-Events (CTCAE v5.0), where a severe adverse event was defined as an adverse event with CATAE grade 4. In a linear mixed model analysis, using the SIRT regimen was more effective than SIR or SI regimens in lowering CASE scores (P < 0.001 and P = 0.001, respectively). The presence of teratoma (P = 0.001), refractory status epilepticus (P < 0.001) and a higher CASE score at baseline (P < 0.001) predicted a higher CASE score at each time point. Completion of the (T)-SIRT regimen within 1 month of onset resulted in better 1-year improvements in CASE score (P < 0.001) and modified Rankin scale scores (P = 0.001), compared to those of using other regimens within 1 month or delaying teratoma removal for more than 1 month. Pneumonia was a frequent adverse event (52/78, 66.7%) in the whole study population and neutropenia was frequent during SIRT (11/52, 21.2%), but the regimen was well tolerated in most patients. We concluded that the early application of combined immunotherapy consisting of T-SIRT had better efficacy than was found for delayed or partial application of this combination in anti-NMDAR encephalitis.

Development of the clinical assessment scale in autoimmune encephalitis.

OBJECTIVE: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.

LGI1 expression and human brain asymmetry: insights from patients with LGI1-antibody encephalitis.

BACKGROUND: While brain asymmetry has been a fascinating issue in neuroscience, the critical mechanism remains to be elucidated. Based on some index cases with asymmetric 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) uptake in leucine-rich glioma-inactivated 1 (LGI1)-antibody encephalitis, we hypothesized LGI1 expression could be asymmetrically distributed in the human brain. METHODS: We enrolled 13 patients who were diagnosed with LGI1-antibody encephalitis between June 2012 and January 2018 at Seoul National University Hospital. Their pretreatment 18F-FDG-PET images were analyzed to find asymmetry between the left and right hemispheres. Guided by these observations, expression of LGI1 in the human hippocampus and the globus pallidus of both cerebral hemispheres was studied in nine post-mortem human brains. RESULTS: Eleven of the 13 LGI1-antibody encephalitis patients (84.6%) showed asymmetrical FDG high uptake in the hippocampus: nine (81.8%) on the left hippocampus and two (18.2%) on the right. In the basal ganglia, seven patients (53.8%) showed asymmetry: four (57.1%) on the left and three (42.9%) on the right. The asymmetry was not evident in the laterality of faciobrachial dystonic seizures, brain MRI, and EEG. When the expression of LGI1 protein was analyzed in nine post-mortem human brains by western blotting, LGI1 expression was higher on eight left globus pallidus samples (88.89%, P = 0.019) and on four left hippocampal samples (44.44%, P = 0.652), compared to their right hemisphere samples. CONCLUSIONS: Imaging parameters from patients with LGI1-antibody encephalitis and studies of LGI1 protein expression suggest that LGI1 is asymmetrically distributed in the human brain. These observations have implications for our understanding of human brain development.

Increased adverse events associated with antiepileptic drugs in anti-leucine-rich glioma-inactivated protein 1 encephalitis.

Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is a rare autoimmune condition presenting mainly as altered mental state, cognitive dysfunction, and seizure. Antiepileptic drugs (AEDs) are usually initiated to control seizures despite their limited efficacy; however, accumulating clinical experience suggests a high incidence of adverse reactions to AEDs in anti-LGI1 encephalitis. We reviewed the medical records of patients who were diagnosed with anti-LGI1 encephalitis to analyze the adverse effects of AEDs in these patients. Among the 20 patients who were treated with AEDs, 10 (50%) changed their AEDs due to adverse cutaneous drug reaction. Eight of them presented with maculopapular eruption, one with drug rash with eosinophilia and systemic symptoms syndrome, and one with eczema. Causative agents mostly consisted of aromatic AEDs. Oxcarbazepine was discontinued in two additional patients due to hyponatremia. Six patients (30%) discontinued their dose of levetiracetam because of psychiatric manifestations including irritability/aggressive behavior (four patients), insomnia (one patient), and depressive mood (one patient). Clinicians should consider adverse cutaneous drug reaction, psychiatric adverse events, and hyponatremia when selecting AEDs for the treatment of anti-LGI1 encephalitis.

Case of Rickettsia typhi-induced Brain Abscess Mimicking Brain Tumor.

Murine typhus is one of the most prevalent rickettsial infections in the world, caused by the bacterial genus Rickettsia. Though the disease manifests a relatively benign clinical course with fever, rash, and headache being the 3 classic symptoms, neurological complications may arise in patients that could become permanent. In this case study, a patient with a brain abscess caused by R typhi infection is described. Based upon the recent reemergence of arthropod-borne disease, the findings in this case are significant; R typhi can cause a brain abscess that mimics a brain tumor, which delays the diagnosis and appropriate management of the disease. Murine typhus should always be considered when performing the differential diagnosis of brain abscesses in South Korea.

Association of blood pressure variability with orthostatic intolerance symptoms.

The short-term blood pressure variability (BPV) reflects autonomic regulatory mechanisms. However, the influence of BPV in orthostatic intolerance (OI) is unknown. Herein, we assessed BPV profiles in patients with OI and determined their association with orthostatic symptoms. In this cross-sectional study, we prospectively enrolled 126 patients presenting with OI at the Seoul National University Hospital from December 2014 to August 2016. Among them, those with other neurological diseases (n = 8) and insufficient BP measurements (n = 15) were excluded. The degree of OI symptoms were measured using the self-administered orthostatic intolerance questionnaire (OIQ). All patients underwent ambulatory BP monitoring and we calculated the standard deviation and coefficient of variation as a measure of BPV. The mean age was 48.6 years and the average of the total OIQ score was 11.6. The severe OI group had higher BPV values than the mild group, although mean BP profiles did not differ significantly. Correlation analysis demonstrated that the orthostatic symptoms were positively correlated with diastolic BPV for the total and awake periods. Multiple linear regression analysis revealed that diastolic BPV (B = 0.46, p = 0.031) and current smoking (B = 4.687, p = 0.018) were independent factors for higher OI symptom scores after adjusting for covariates. The results of the current study demonstrated that a positive correlation exists between BPV and OI symptoms. Further studies are required to confirm the present findings and understand the neural mechanisms contributing to the excessive BPV in patients with OI.

The c-Abl inhibitor, nilotinib, as a potential therapeutic agent for chronic cerebellar ataxia.

Nilotinib is a potent inhibitor of tyrosine kinase BCR-ABL that penetrates the blood-brain barrier. To evaluate the effect of nilotinib in chronic cerebellar ataxia, twelve patients with chronic cerebellar ataxia nonresponsive to other treatment options (modified Rankin scale [mRS] scores: >2) and received nilotinib therapy (daily doses: 150-300mg) for >4 (range 5-16) weeks were reviewed. At follow-up, improved mRS scores were found in 7/12 (58.3%) patients and favorable mRS scores (≤2) were found in 6/12 (50.0%) patients. No severe adverse event was observed. Atrophy in the cerebellar vermis appeared to be negatively associated with favorable outcomes.

Altered Expression of the Long Noncoding RNA NEAT1 in Huntington's Disease.

Huntington's disease (HD) is a devastating neurodegenerative disease caused by cytosine-adenine-guanine trinucleotide repeat expansion in the huntingtin gene. Growing evidence supports the regulatory functions of long noncoding RNAs (lncRNAs) in the disease process, but little is known about the association between lncRNAs and neuronal death in HD. Here, we evaluated the altered expression profiles of lncRNA in HD by using microarrays. Among dysregulated lncRNAs, we focused on the upregulation of nuclear paraspeckle assembly transcript 1 (NEAT1). Quantitative PCR analysis validated increased NEAT1 levels in the R6/2 mouse brain as well as the human HD postmortem brain. To determine the biological effects of NEAT1 on neuronal survival, neuro2A cells were transfected with the NEAT1 short isoform vector and were subjected to H2O2-induced injury. Subsequently, NEAT1-transfected cells showed increased viability under oxidative stress. Our observations support the notion that NEAT1 upregulation in HD contributes to the neuroprotective mechanism against neuronal injury rather than the pathological process underlying neurodegeneration in HD.

Anti-LGI1 encephalitis is associated with unique HLA subtypes.

OBJECTIVE: Autoimmune encephalitis (AE), represented by anti-leucine-rich glioma-inactivated 1 (anti-LGI1) and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes. METHODS: We compared the HLA genotypes of 11 anti-LGI1 and 17 anti-NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans. RESULTS: Anti-LGI1 encephalitis was associated with the DRB1*07:01-DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship. INTERPRETATION: This finding suggests that most anti-LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183-192.

Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-d-aspartate receptor encephalitis.

The aim of this study was to compare serum and cerebrospinal fluid (CSF) cytokine/chemokine levels between anti-NMDAR and anti-LGI1 encephalitis patients. Samples from fourteen anti-NMDAR encephalitis patients, ten anti-LGI1 encephalitis patients, and ten controls were analyzed for the following cytokines/chemokines: IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17A, IL-23, GM-CSF, IFN-gamma, TNF-alpha, and CXCL13. Compared with controls, CSF IL-17A, IL-6 and CXCL13 were elevated in anti-NMDAR encephalitis patients (post-hoc p-values 0.002, 0.011, and 0.011, respectively) but not in anti-LGI1 encephalitis patients. In the serum, only IL-2 was increased in anti-NMDAR encephalitis. Intrathecal IL-17/IL-6 activation is a characteristic of anti-NMDAR encephalitis.