Charlotte Schubert

Cerebral malaria (CM) is a potentially lethal complication of Plasmodium falciparum infection characterized by blood-brain barrier disruption and brain hemorrhage. Although immune-mediated endothelial damage is central to CM pathology, the mechanisms linking cytotoxic immune responses to endothelial injury remain unclear. Here, we show that CD8 ⁺ T cells induce receptor-interacting serine/threonine-protein kinase 1 (RIPK1)–regulated cell death of brain endothelial cells in mouse CM, while RIPK1 phosphorylation is increased in brain endothelial cells in human CM. Using magnetic resonance imaging, three-dimensional tissue-cleared brain imaging, cross-species pathology, endothelial translatomics, immunocerebrovascular interactomics, and genetic association testing, we identify a CD8 ⁺ T cell–dependent, RIPK1-centered mouse endothelial cell death program. Combined RIPK1 and caspase inhibition protected cross-presenting endothelial cells from CD8 ⁺ T cell–mediated death in vitro. In vivo, brain endothelial-specific genetic inactivation or systemic pharmacological inhibition of RIPK1 kinase activity prolonged survival in mouse CM without altering parasitemia. These findings support RIPK1 inhibition as a promising therapeutic strategy to counter CD8 ⁺ T cell–induced endothelial death in CM.

Background: The therapeutic landscape of generalised myasthenia gravis (gMG) has evolved substantially with the approval of targeted immunotherapies, including complement C5 inhibitors (C5‐I) and neonatal Fc receptor inhibitors (FcRn‐I). While pivotal trials have demonstrated marked efficacy in defined subgroups, real‐world experience reveals more heterogeneous outcomes and raises questions about optimal patient selection, therapy sequencing and integration into clinical practice. In Germany and Austria, early access following regulatory approval has facilitated clinical experience over recent years. This expert opinion paper aims to combine current evidence with clinical experience to guide the use of C5‐I and FcRn‐I in everyday care. Methods: A panel of 18 neurologists from Germany and Austria, including two paediatric neurologists, evaluated study data and real‐world experiences. Through structured discussion and a consensus process, they developed evidence‐ and experience‐based recommendations on integrating targeted immunotherapies into existing treatment algorithms. Results: The panel provides practical recommendations for managing (highly) active gMG in adults, focusing on C5‐I (eculizumab, ravulizumab, zilucoplan) and FcRn‐I (efgartigimod, rozanolixizumab). The statements cover initiation criteria, sequencing and switching within and between drug classes and transitions to intensified immunomodulatory therapies (rituximab, apheresis, intravenous or subcutaneous immunoglobulin), as well as special considerations for juvenile MG. Conclusions: This expert statement provides a practice‐oriented framework integrating current evidence and clinical experience to support individualised therapeutic decision‐making in gMG.

ObjectivesLipoprotein receptor-related protein 4 antibody-positive myasthenia gravis (LRP4-Ab-positive MG) is a rare serologic subgroup with poorly defined clinical phenotype. This study investigat...

Disability trajectories in aquaporin-4 immunoglobulin G-seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are primarily driven by attack-related damage. Confirmed disability worsening (CDW) independent of attacks has been described but occurs infrequently in AQP4-IgG+ NMOSD and MOGAD. Confirmed disability improvement (CDI) has not been evaluated in large cohorts. We determined the frequency of CDI and CDW independent of attacks and identified clinical factors associated with these outcomes in AQP4-IgG+ NMOSD and MOGAD. This retrospective, multicenter cohort study analyzed data from the German Neuromyelitis Optica Study Group (NEMOS) registry. Adult patients with AQP4-IgG+ NMOSD or MOGAD and longitudinal Expanded Disability Status Scale (EDSS) assessments were included. EDSS episodes were defined as periods with ≥3 EDSS assessments without attacks, obtained ≥90 days after attack. CDW and CDI were defined as sustained EDSS increase or decrease (≥1.5 for baseline EDSS 0; ≥1.0 for EDSS 1.0-5.5; ≥0.5 for EDSS ≥6.0) confirmed after at least 6 months. The primary outcomes were annualized CDI and CDW rates. Risk factors were assessed using multivariable Anderson-Gill regression models. A total of 338 EDSS episodes of 307 patients (n: 202/105, median age at EDSS change: 56/41 years, 88/49% female, both p < 0.001; AQP4-IgG+ NMOSD/MOGAD) were included. Adjusted annualized CDI and CDW rates did not differ between AQP4-IgG+ NMOSD (CDI: 0.083, 95% CI 0.029-0.233; CDW: 0.025, 95% CI 0.007-0.092) and MOGAD (CDI: 0.057, 95% CI 0.012-0.277; CDW: 0.036, 95% CI 0.002-0.513). In AQP4-IgG+ NMOSD, a lower number of prior attacks was associated with higher CDI rates (hazard ratio [HR] 0.89, 95% CI 0.82-0.97). Younger age was associated with increased CDI rates in both AQP4-IgG+ NMOSD and MOGAD (HR 0.96, 95% CI 0.94-0.99, for both). CDI and CDW independent of attacks, although rare, occur in AQP4-IgG+ NMOSD and MOGAD. The association between fewer prior attacks and higher CDI rates in AQP4-IgG+ NMOSD underscores the importance of early attack prevention. Limitations include the retrospective design, and the limited number of CDI and CDW events.

Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) act as key signalling molecules in the central nervous system (CNS) and regulate neuroinflammatory responses through purinergic receptors. Although astrocytes and neurons undergo profound changes in signalling and metabolism during inflammation, the contribution of specific purinergic pathways to inflammation-induced neurodegeneration remains unclear. Here we show that the ADP/ATP-activated Gq-coupled receptor P2Y ₁ drives astrocyte-mediated neurotoxicity in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Using plasma membrane-targeted luciferase reporter mice, we demonstrate that extracellular ATP levels are increased during acute EAE. This was accompanied by elevated astrocytic P2ry1 expression, which is also observed in inflammatory MS lesions. In vivo, pharmacological inhibition or astrocyte-specific deletion of P2Y ₁ reduced disease severity, astrocytosis, and neuronal loss, whereas neuron-specific deletion exerted only modest effects. Mechanistically, astrocytic P2Y ₁ signalling promoted cytokine-induced ERK activation, inflammatory gene expression, and metabolic reprogramming in vitro. In contrast to supernatants from stimulated P2Y ₁ -deficient astrocyte culture, supernatants derived from stimulated P2Y ₁ -proficient astrocytes reduced neuronal viability, demonstrating neurotoxic effects mediated by astrocyte-derived factors. In contrast, neuronal P2Y ₁ signalling primarily contributed to oxidative stress and mitochondrial dysfunction. Together, these findings identify astrocytic P2Y ₁ as a key regulator of neuroinflammatory damage and a potential therapeutic target.

Introduction: Generalized myasthenia gravis (gMG) may progress to life‐threatening myasthenic crises (MC) requiring mechanical ventilation. Standard therapy includes intravenous immunoglobulins (IVIg), plasmapheresis (PLEX), immunoadsorption (IA), and high‐dose corticosteroids. This study aimed to evaluate the real‐world effectiveness of complement‐inhibitors (C5‐I) in patients refractory to the standard treatment of MC (termed therapy‐refractory MC). Methods: This multicentre, retrospective study included patients with acetylcholine‐receptor‐antibody positive (AChR‐ab+) gMG experiencing MC or severe exacerbations (MGFA IVb/V) treated with eculizumab or ravulizumab in the intensive or intermediate care unit (ICU/IMC). The primary outcome was the proportion of patients discharged from ICU/IMC within six weeks after C5‐I initiation (German Clinical Trials Registry; DRKS00032104). Results: Among 17 identified cases, seven had thymoma‐associated MG (TAMG) and 10 had late‐onset MG; median age was 77 years. Five patients required non‐invasive and 12 invasive ventilation; nine underwent tracheotomy. Therapies included IVIg, PLEX, IA, and corticosteroids. Rituximab was added in two cases. Twelve patients received eculizumab and five ravulizumab. Median hospitalization before C5‐I initiation was 32 days (IQR 22–50) and median ICU‐stay was 17 days (IQR 4.5–35) thereafter. Fourteen patients (82%) reached the primary outcome. Two patients died due to bacterial sepsis; no meningococcal infection was observed. Conclusion: In MC or severe exacerbations insufficiently responsive to standard treatment with IVIg and PLEX/IA, add‐on C5‐I therapy may represent an effective therapeutic approach. Importantly, TAMG, a subtype typically excluded from interventional trials yet often requiring more intensive therapy, also demonstrated clinical improvement. These findings warrant further systematic evaluation of C5‐I as adjunctive therapy for AChR‐ab+ therapy‐refractory MC.

Background: Myasthenia gravis (MG) is an autoimmune disease with an onset age distribution in women, which peaks within the reproductive age range, leading to a potential interference with pregnancy. In this systematic review, we aim to assess the impact of pregnancy on the course of MG during pregnancy and postpartum period and to identify potential risk factors influencing the postpartum course. Methods: A systematic literature search was conducted in the two databases PubMed and Epistemonikos on the topic “Myasthenia gravis and pregnancy” in October 2025. We included cohort studies and case series with at least 5 cases, reporting the clinical course of MG in women during pregnancy or postpartum period. Quality assessment was performed using the Critical Appraisal Skills Programme (CASP) tool for cohort studies. Results: In total, 34 studies were included, covering 3720 pregnancies in women with MG. Of 842 pregnancies worsening myasthenic symptoms was reported in 30% of pregnancies most frequently in the first trimester. Postpartum exacerbations were observed in 27% of the cases. However, incidence of worsening and scoring systems differed vastly. Preterm birth was reported at a rate of 9%. Vaginal delivery and cesarean section were performed in 68% and 32% respectively. Of 1530 infants, 9% developed neonatal myasthenia gravis. Conclusion: This review confirms that symptom worsening is most common in the first trimester or postpartum. Women with MG were more likely to require cesarean section or operative vaginal delivery compared to general population data. However, the studies’ quality varied widely. Prospective studies are needed to better identify risk factors for complicative course during pregnancy and postpartum period.

Introduction: Rituximab is effective and widely used as long‐term treatment in aquaporin‐4‐IgG‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). However, infections remain a significant concern during rituximab treatment. Methods: We conducted a retrospective multicenter cohort study within the NMO Study Group (NEMOS) in Germany, analyzing demographic and clinical data from people with AQP4‐IgG+ NMOSD receiving rituximab or azathioprine by retrospective chart, and compared infection occurrence and severity. For rituximab‐treated patients, we collected laboratory data (blood lymphocytes, B‐cell counts, serum IgG, IgM, and IgA levels), assessed risk factors for infections, and determined the probability of infection within a 3‐month window before and after the laboratory assessment. Results: In 92/170 rituximab and in 12/33 azathioprine treatment episodes, one or more infections were documented. Rituximab and azathioprine showed comparable types and risk of infection (HR = 1.24, 95% CI: 0.68–2.25). Rituximab‐treated individuals older than 60 years had a higher risk of infection (HR = 1.62, 95% CI: 1.02–2.57). Hypogammaglobulinemia (IgG < 6.0 g/L: OR = 2.27, 95% CI: 1.15–4.48; IgM < 0.3 g/L: OR = 2.08, 95% CI: 1.05–4.09) predicted infections and the occurrence of both low IgG and IgM serum levels further increased the risk of infection (OR = 2.77, 95% CI: 1.10–6.98) during rituximab treatment. Low IgG and IgA serum levels as well as lymphopenia predicted infection‐related hospitalizations. Conclusion: Age > 60 years and immunoglobulin serum levels during rituximab treatment may serve as predictors for infection and help to individualize treatment decisions in NMOSD.

Objective: This study aimed to compare the detection rates and inter-rater agreements of the sagittal T2w-TSE and sagittal short tau inversion recovery (STIR) sequence versus the axial T2w-TSE sequence with full spinal cord coverage in identifying spinal cord lesions in patients with suspected demyelinating diseases and diagnosed multiple sclerosis (MS). Methods: 104 patients were prospectively enrolled in this study and underwent MRI, including a sagittal T2w-TSE and STIR sequence, as well as an axial T2w-TSE sequence with full spinal cord coverage. Two experienced neuroradiologists, blinded to clinical parameters, independently evaluated the scans in separate sessions. After blinded readings, raters re-evaluated all sequences to assess if lesions could be retrospectively identified in other sequences. Results: Spinal cord lesions were found in 81 patients. The highest inter-rater reliability was observed for the sagittal T2w-TSE sequence (κ = 0.73, 95%-CI 0.66–0.79), followed by the axial T2w-TSE (κ = 0.71, 95%-CI 0.63–0.79) and the sagittal STIR sequence (κ = 0.65, 95%-CI 0.58–0.73). The axial T2w-TSE sequence demonstrated superior lesion detection rates, identifying significantly more lesions ( n = 361) compared to the STIR ( n = 293) and T2w-TSE sagittal ( n = 224) sequence ( p < 0.001). Conclusion: Axial T2w-TSE sequences with full spinal cord coverage provide superior lesion detection compared to sagittal sequences and should be included in standard MRI protocols for MS patients. They may accelerate meeting MRI criteria for MS, improve monitoring of disease progression, and enhance prediction of future disability.