Huanyu Meng

Anti-Seizure-Related 6 Homolog Like 2 (Sez6l2) encephalitis is a rare autoimmune disorder characterized by cerebellar ataxia and cognitive impairment. The 13 previously reported cases included in our systematic analysis focus on adults, leaving gaps in pediatric demographics, longitudinal multimodal imaging markers, and effective management of refractory cases. This study aimed to expand the clinical spectrum, evaluate multimodal imaging in localizing neuroinflammation/monitoring response, and assess the efficacy of combined first- and second-line immunotherapy. We analyzed a longitudinal cohort of five Sez6l2-antibody-positive patients (aged 15–72 years) alongside a systematic review (N = 18). Clinical severity (mRS, CASE, MMSE, MoCA), structural MRI, and ¹⁸F-DPA714 PET/MRI mapped neuroinflammation and monitored therapeutic response. Our cohort features the first documented adolescent case. All five patients presented with ataxia and cognitive deficits. While MRI revealed cerebellar atrophy in three patients, ¹⁸F-DPA714 PET/MRI detected microglial activation in the cerebellum (n = 4) and bilateral mesial temporal lobes (n = 1), mapping precisely to clinical phenotypes. Longitudinally, clinical improvement paralleled a 7%–8% reduction in cerebellar tracer uptake in Case 1. Patients receiving combined first- and second-line immunotherapy (efgartigimod, ofatumumab; n = 3) achieved pronounced cognitive and psychiatric recovery. Conversely, first-line therapy alone yielded limited efficacy in the 66-year-old patient with established atrophy, while the adolescent showed more favorable responsiveness. The systematic review (N = 18) confirmed universal ataxia (100%), frequent cognitive impairment (72%), and significant residual disability (median mRS 4). This study expands the demographic spectrum of Sez6l2 encephalitis to adolescents and provides cohort-based evidence for multimodal imaging in localizing neuroinflammation/monitoring response, highlighting combined immunosuppressants as possible new therapeutic options.

Background: Anti-vimentin IgG-associated autoimmune encephalitis (AE) is a recently described autoimmune astrocytopathy characterised by relapsing-remitting cerebellar ataxia, brainstem involvement and pyramidal tract lesions. Nevertheless, several key aspects remain poorly elucidated, including the full clinical phenotypic spectrum (particularly peripheral nervous system (PNS) involvement), the interpretation of serological discrepancies and long-term management outcomes. Additionally, the imaging evidence for neuroinflammation and the evidence regarding evolution following treatment remain insufficient. Case presentation: We reported a man in his late 40s who developed a core triad of cerebellar ataxia, pyramidal signs and peripheral neuropathy. Conventional MRI was unremarkable, but cerebrospinal fluid analysis revealed anti-vimentin IgG positivity (titre 1:10) with type III oligoclonal bands while serum was negative. ¹⁸ F-DPA714 positron emission tomography/MRI showed elevated tracer uptake in the mesial temporal lobe, frontal lobe and brainstem, correlating with clinical signs. After intravenous immunoglobulin induction and ofatumumab maintenance therapy, the patient showed clinical improvement (modified Rankin Scale from 2 to 1) at 3-month follow-up, paralleled by reduced tracer uptake. Conclusions: This first reported middle-aged male case expands the demographic and phenotypic spectrum of anti-vimentin IgG-associated AE to include PNS involvement. This case highlights the diagnostic value of antibody detection and advanced imaging modalities in atypical presentations of anti-vimentin IgG-associated AE.

Purpose Autoimmune encephalitis (AE) refers to a group of rare autoimmune diseases affecting the central nervous system. New research shows that it can trigger neurodegenerative changes, especially brain atrophy. This atrophy has multiple causes, which worsen the prognosis. Thus, future studies need to focus on the early identification of AE patients at risk of brain atrophy and early interventions to prevent this complication. This review covers epidemiology, risk factors, clinical symptoms, pathophysiological mechanisms, and immunosuppressive therapy and summarizes current progress in understanding AE-related brain atrophy. Latest findings AE patients with brain atrophy often have anti-N-Methyl-D-Aspartate Receptor (NMDAR), anti-Leucine-Rich Glioma-Inactivated 1 (LGI1), anti-glutamic acid decarboxylase 65 kDa Isoform (GAD65) antibodies, and other antibodies in serum and cerebrospinal fluid; however, seronegative patients may also have atrophy. The temporal lobe, cerebellum, and brainstem most often show reduced volume, causing ataxia, memory decline, and cognitive and motor impairments. The risk factors include patient age, antibody types, and early cognitive impairments as non-modifiable factors. Timely treatment, the duration of status epilepticus, cumulative disease burden, nutritional status, and concomitant medications are modifiable risk factors. The mechanisms of AE-related brain atrophy include metabolic disturbances and immune-mediated pathology. Glucocorticoids and intravenous immunoglobulin (IVIG) may reduce atrophy but do not restore brain volume. Some novel treatments are under investigation; however, no current clinical trials specifically target brain atrophy. Summary Previous research has facilitated the understanding of the clinical presentation, mechanisms, and treatment of brain atrophy. Some studies suggest that children with AE can also experience brain atrophy, and subsequent follow-ups revealed brain dysplasia. However, the data primarily originate from studies with small-sized adult samples, and studies concerning children are lacking. Large-sample, multi-age stratified cohort studies are needed to explore early identification using neuroimaging biomarkers, new mechanisms, and novel therapeutic approaches to improve patient prognosis.

Objective This study investigated the efficacy of ofatumumab (OFA) combined with corticosteroids in autoimmune encephalitis (AE) patients refractory to conventional treatment. Methods Eighteen AE patients admitted to Ruijin Hospital between June 2022 and September 2023 received four subcutaneous 20-mg OFA injections at 0, 1, 6, and 12 weeks combined with standard corticosteroid therapy. Results Clinical symptoms, modified Rankin scale (mRS) scores, Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores, serum immunoglobulin (Ig) levels (IgG and IgM), and peripheral blood CD20 + B cell levels were documented before OFA administration and at 1, 2, 6, 12, and 24 weeks post-treatment. OFA treatment significantly improved psychiatric symptoms (P = 0.025), cognitive dysfunction (P = 0.008), and seizure frequency (P = 0.014). The mRS and CASE scores improved after two injections in patients with anti-NMDAR encephalitis (P = 0.041), but not in patients with anti-LGI1 encephalitis (P > 0.05). The mRS scores significantly improved at 12 weeks post-treatment in antibody-negative encephalitis. Blood CD20 + B cell levels dropped to zero after an average of 2.5 injections. No significant changes could be observed in serum IgG and IgM levels (P > 0.05). Seven patients had mild fever or pulmonary infections post-treatment. Conclusion This study suggests that OFA is a safe and effective treatment for a subset of AE patients, particularly in cases of anti-NMDAR encephalitis, though further research is needed on long-term outcomes and recurrence.

Objective: Anti-dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis is a rare autoimmune encephalitis, and clinical and experimental information regarding this disease is limited. We conducted this study to comprehensively describe the clinical characteristics, ancillary test results, neuroimaging results, and treatment response in a group of Chinese patients with anti-DPPX encephalitis for better understanding this disease.Methods: We recruited 14 patients who tested positive for anti-DPPX antibodies in the serum and/or cerebrospinal fluid from 11 medical centers between March 2021 and June 2023. This retrospective study evaluated data on symptoms, autoantibody test, auxiliary examinations, treatments, and outcomes.Results: The average age at diagnosis was 45.93 ± 4.62 years (range: 11–72 years), and 9 of the 14 patients were males. The main symptoms included cognitive impairment (50.0%, 7/14), central nervous system hyperexcitability (42.9%, 6/14), gastrointestinal dysfunction (35.7%, 5/14), and psychiatric disorders (35.7%, 5/14). Notably, we discovered specific findings on ¹⁸F-fluorodeoxyglucose positron-emission tomography (PET)/magnetic resonance imaging in two patients. Co-existing autoantibodies were identified in two patients. Parainfection was identified in four patients. One patient had other autoimmune diseases, and one had tumor. Eleven patients received immunotherapy and most patients improved at discharge. Surprisingly, three male patients but no female patients relapsed during the 6 months of follow-up.Conclusion: The development and outcome of anti-DPPX encephalitis are variable. Male patients were predominant in our cohort. The most common symptoms were the classical triad of prodromal gastrointestinal dysfunction, cognitive and mental disorders, and central nervous system hyperexcitability. Infections, immune dysregulation, and tumors may be important etiologies. Long-term monitoring of disease development should be done in male patients. Overall, our results highlight novel clinical characteristics of anti-DPPX encephalitis.

Paraneoplastic amyotrophic lateral sclerosis (ALS) is a rare and special type of ALS. The pathogenesis, clinical presentation, treatment and prognosis remain poorly understood. We herein presented three cases of paraneoplastic ALS. In case 1, we first reported an ALS patient with the positive serum antibodies against both Sry-like high mobility group box 1 (SOX1) and glutamic acid decarboxylase 65 (GAD65). However, immunotherapy did not improve his neurological symptoms. We also reported two ALS patients with renal clear cell carcinoma and chronic myelogenous leukemia. No positive paraneoplastic antibodies were detected in either the serum or the cerebrospinal fluid of the two patients, and their clinical symptoms progressed slowly after tumor treatment. The three cases enriched the existing case pool of this rare disorder. In addition, we have comprehensively reviewed the literature of paraneoplastic ALS. The clinical features, treatment effect and prognosis were summarized to broaden our understanding of paraneoplastic ALS.

Immune checkpoint inhibitors (ICIs) are being used in patients with various advanced malignancies, and patient outcomes have improved considerably. Although ICIs can effectively treat tumors, 30–60% of patients experience immune-related adverse events (irAEs). Autoimmune encephalitis (AE) is a rare irAE that has become a novel topic in neuroimmunology and has received increasing attention in recent years. Herein, we report a rare case of GAD65-antibody–associated AE after metastatic small cell lung cancer treatment with pembrolizumab. The patient received IVIg therapy for AE and continuous pembrolizumab therapy without suspension of tumor treatment. At 1 year follow-up, both the patient’s AE symptoms and tumors were stable. We consider that the treatment of ICI-associated AE should be more individualized with prudent decision-making and should balance the tumor progression and AE treatment. In addition, we have also comprehensively reviewed the literature of ICI-associated AE, and summarized the clinical features, treatment, and prognosis of AE caused by ICI, thus broadening our understanding of the neurological complications caused by ICI.

Helios is important for functional and phenotype stability of regulatory T cells (Tregs). However, the role of Helios in autoimmune diseases and its regulation remains unclear. This study aimed to investigate the role of Helios+ Tregs in myasthenia gravis (MG) and glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) in the modulation of Helios. Multicolor flow cytometry was performed to analyze Helios+ Tregs in peripheral blood from MG patients and healthy donors (HDs). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of soluble GITRL/GITR in plasma. Tregs were isolated via magnetic separation and treated with recombinant GITRL and GITR-Fc. Membrane GITRL on Tregs and expression of Helios and other markers (FOXP3, CD25, CD39, CTLA-4, PD-L1 and IL-10) involved in immunosuppressive activity were determined by flow cytometry. Both Helios+ Tregs and soluble GITR were decreased in generalized MG (GMG) patients (n = 14), compared with HDs (n = 14) and ocular MG (OMG) patients (n = 16). Helios+ Tregs possessed greater immunosuppressive capacity compared to Helios− Tregs. Further analysis indicates soluble GITR was negatively correlated with quantitative MG score and promoted Helios expression and enhanced function of Tregs independently of membrane GITRL. This work demonstrates abnormal changes in Helios+ Tregs and soluble GITR in MG, as well as direct regulation of Helios by GITR in the context of Tregs. This work provides new insight into the role of GITR in the regulatory pathway of Helios and pathogenesis of MG.