Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management.

This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab - most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings.

Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis.

OBJECTIVES: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS. METHODS: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated. RESULTS: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30th-], 2.11 [20th-], and 2.8 [10th percentile], P = 0.007, 0.012 and 0.005, respectively). CONCLUSIONS: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback.

Weaning and extubation failure in myasthenic crisis: a multicenter analysis.

Myasthenic crisis (MC) requiring mechanical ventilation is a serious complication of myasthenia gravis (MG). Here we analyze the frequency and risk factors of weaning- and extubation failure as well as its impact on the clinical course in a large cohort. We performed a retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015. Weaning failure (WF) was defined as negative spontaneous breathing trial, primary tracheostomy, or extubation failure (EF) (reintubation or death). WF occurred in 138 episodes (64.2%). Older Age (p = 0.039), multiple comorbidities (≥ 3) (p = 0.007, OR = 4.04), late-onset MG (p = 0.004, OR = 2.84), complications like atelectasis (p = 0.008, OR = 3.40), pneumonia (p < 0.0001, OR = 3.45), cardio-pulmonary resuscitation (p = 0.005, OR = 5.00) and sepsis (p = 0.02, OR = 2.57) were associated with WF. WF occurred often in patients treated with intravenous immungloblins (IVIG) (p = 0.002, OR = 2.53), whereas WF was less often under first-line therapy with plasma exchange or immunoadsorption (p = 0.07, OR = 0.57). EF was observed in 58 of 135 episodes (43.0%) after first extubation attempt and was related with prolonged mechanical ventilation, intensive care unit stay and hospital stay (p ≤ 0.0001 for all). Extubation success was most likely in a time window for extubation between day 7 and 12 after intubation (p = 0.06, OR = 2.12). We conclude that WF and EF occur very often in MC and are associated with poor outcome. Older age, multiple comorbidities and development of cardiac and pulmonary complications are associated with a higher risk of WF and EF. Our data suggest that WF occurs less frequently under first-line plasma exchange/immunoadsorption compared with first-line use of IVIG.

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

OBJECTIVE: Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state-of-the-art clinical settings and trials applying combined outcome parameters. METHODS: Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed-25-foot walk test (T25FW), and nine-hole-peg-test (9HPT)). RESULTS: 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7-61.2], 135 female, median follow-up: 29.3 months [17.9-40.9]) were included. NfL (age-) and GFAP (age- and sex-) adjusted Z scores were higher in pwPMS compared to HC (p < 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits (n = 169). GFAP Z score >3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12-5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21-6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53-12.13], p = 0.006). INTERPRETATION: Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non-active pwPMS with particularly high progression risk.

Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG- /MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG- /MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG- /MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024.

Inner Retinal Layer Changes Reflect Changes in Ambulation Score in Patients with Primary Progressive Multiple Sclerosis.

The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker of disease progression exist only for PwMS with a relapsing-remitting course (RRMS) so far. In contrast, longitudinal data of retinal layers in patients with primary-progressive MS (PPMS) are inconsistent, and the association of OCT parameters with ambulatory performance in PwMS has rarely been investigated. We aimed to investigate the relative annual rates of change in retinal layers in PwMS (RRMS and PPMS) compared with healthy controls (HC) using OCT and to evaluate their association with ambulatoryfunctionalscore (AS) worsening in PPMS. A retrospective analysis of a longitudinal OCT dataset of the retinal layers of PwMS and HC from two MS centers in Germany was performed. Walking ability was measured over a standardized distance of 500 m, and changes during the observation period were categorized using the AS and the expanded disability status scale (EDSS). 61 HC with 121 eyes and 119 PwMS (PPMS: 57 patients with 108 eyes; RRMS: 62 patients with 114 eyes) were included. The median follow-up time for PwMS was 3 years. The relative annual change of pRNFL (peripapillary retinal nerve fiber layer) and INL (inner nuclear layer) was significantly different in PwMS compared with HC. RRMS and PPMS subgroups did not differ in the annual atrophy rates. In patients with PPMS, worsening of the AS was significantly associated with increased thinning of the TMV (total macular volume), GCIP (ganglion cell and inner plexiform layer), and ONPL (outer nuclear and outer plexiform layer) (all p-value < 0.05, r > 0.30). For every -0.1% decrease in the TMV, GCIP, and ONPL, the risk of a deterioration in the AS increased by 31% (hazard ratio (HR): 1.309), 11% (HR: 1.112), and 16% (HR: 1.161), respectively. In addition, worsening EDSS in PPMS was significantly associated with the relative annual atrophy rates of pRNFL, TMV, and GCIP (all p-value < 0.05). Disability progression in PPMS can be measured using OCT, and increasing annual atrophy rates of the inner retinal layers are associated with worsening ambulation. OCT is a robust and side-effect-free imaging tool, making it suitable for routine monitoring of PwMS.

International Delphi Consensus on the Management of AQP4-IgG+ NMOSD: Recommendations for Eculizumab, Inebilizumab, and Satralizumab.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab. METHODS: We recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%). RESULTS: The Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps. DISCUSSION: An established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis.

The term 'neuromyelitis optica spectrum disorders' (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options.

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Long-term Efficacy of Satralizumab in AQP4-IgG-Seropositive Neuromyelitis Optica Spectrum Disorder From SAkuraSky and SAkuraStar.

BACKGROUND AND OBJECTIVES: Satralizumab, an interleukin 6 receptor inhibitor, reduced the risk of protocol-defined relapse (PDR) vs placebo in 2 independent, double-blind studies in patients with neuromyelitis optica spectrum disorder (NMOSD). We assessed the long-term efficacy of satralizumab in patients with aquaporin-4-immunoglobulin G (IgG)-seropositive (AQP4-IgG+) NMOSD. METHODS: Following the double-blind periods of SAkuraSky (satralizumab + baseline immunosuppressive treatment [IST]) and SAkuraStar (satralizumab monotherapy), patients could enter the open-label extension (OLE, satralizumab 120 mg Q4W ± IST). This analysis included all AQP4-IgG+ patients who received ≥1 dose of satralizumab in the double-blind and/or OLE periods, from patients' first dose to the data cutoff (February 22, 2021). PDR in the OLE period was determined by the investigator without external adjudication. We evaluated time to first investigator-reported PDR (iPDR), severe iPDR (≥2 point increase in the Expanded Disability Status Scale [EDSS] score), and sustained EDSS worsening (EDSS score increase of ≥2, ≥1, or ≥0.5 points for patients with baseline scores of 0, 1-5, or ≥5.5, respectively, confirmed ≥24 weeks post-initial worsening), plus the annualized iPDR rate (ARR). RESULTS: Forty-six of 55 AQP4-IgG+ patients (84%) in SAkuraSky and 57/64 patients in SAkuraStar (89%) continued from the double-blind periods into the OLEs. In total, 111 AQP4-IgG+ patients received ≥1 dose of satralizumab in the double-blind and/or OLE periods and were included in these analyses (SAkuraSky: 49; SAkuraStar: 62). The median (range) duration of satralizumab exposure was 4.4 (0.1-7.0) years in SAkuraSky and 4.0 (0.1-6.0) years in SAkuraStar, with a combined 440.1 patient-years of treatment. Seventy-one of 111 patients (64%) received satralizumab for ≥192 weeks (3.7 years). At this time point, 71% (SAkuraSky) and 73% (SAkuraStar) of satralizumab-treated patients were free from iPDR, 91% (SAkuraSky) and 90% (SAkuraStar) were free from severe iPDR, and 90% (SAkuraSky) and 86% (SAkuraStar) had no sustained EDSS worsening. The overall adjusted ARR (95% CI) was 0.12 (0.08-0.18) in SAkuraSky and 0.08 (0.05-0.13) in SAkuraStar and remained stable over time. DISCUSSION: These long-term results from the OLE periods of the SAkura studies demonstrate the continued efficacy of satralizumab over more than 3.5 years of treatment. High proportions of patients remained free from relapse, severe relapse, or worsening disease, with a consistently low ARR. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov registration numbers: NCT02028884 (SAkuraSky) and NCT02073279 (SAkuraStar). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that satralizumab reduces the risk of relapse in patients with AQP4-IgG+ NMOSD beyond the first 96 weeks of treatment.

Immunoadsorption as maintenance therapy for refractory neuromyelitis optica spectrum disorder.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing autoimmune disease of the central nervous system, affecting mainly optic nerves and spinal cord. NMOSD pathophysiology is associated with anti-aquaporin-4 (AQP4) immunoglobulin G (IgG) autoantibodies. Rapid extracorporeal elimination of autoantibodies with apheresis techniques, such as immunoadsorption (IA), was proven to be an effective treatment of NMOSD attacks. Data on the long-term use of IA to prevent attacks or progression of NMOSD are lacking. Objectives: The aim of this study was to evaluate efficacy and safety of maintenance IA for preventing recurrence of NMOSD attacks in patients refractory to other immunotherapies. Design: Case study. Methods: Retrospective analysis of two female patients with severe NMOSD refractory to conventional immunotherapies was performed. Both patients had responded to tryptophan IA (Tr-IA) as attack therapy and subsequently were treated with biweekly maintenance Tr-IA. Results: Patient 1 (AQP4-IgG seropositive, age 42 years) had 1.38 attacks of optic neuritis per year within 10.1 years before commencing regular Tr-IA. With maintenance Tr-IA for 3.1 years, one mild attack occurred, which was responsive to steroid pulse therapy. Expanded Disability Status Scale (EDSS) was stable at 5.0. Visual function score of the last eye improved from 3 to 1. Patient 2 (AQP4-IgG seronegative, age 43 years) experienced 1.7 attacks per year, mainly acute myelitis and optic neuritis, during the period of 10.0 years before the start of Tr-IA. During regular Tr-IA treatment, no further NMOSD attack occurred. The patient was clinically stable without any additional immunosuppressive treatment for 5.3 years. EDSS improved from 6.0 to 5.0, and the ambulation score from 7 to 1. Tolerability of Tr-IA was good in both patients. No serious adverse events occurred during long-term clinical trajectories. Conclusion: Tr-IA was well tolerated as maintenance treatment and resulted in clinical stabilization of two patients with highly active NMOSD, who were refractory to standard drug therapy.

Humoral COVID-19 vaccine response in patients with NMOSD/MOGAD during anti-IL-6 receptor therapy compared to other immunotherapies.

BACKGROUND: Data on the humoral vaccine response in patients on anti-interleukin-6 (IL-6) receptor therapy remain scarce. OBJECTIVE: The main objective of our study was to investigate the humoral response after vaccination against SARS-CoV-2 in neuromyelitis optica spectrum disorder (NMOSD)/myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) patients treated with anti-IL-6 receptor therapy. Secondarily, we analyzed relapse activity timely associated with vaccination. METHODS: In this retrospective cross-sectional multicenter study, we included 15 healthy controls and 48 adult NMOSD/MOGAD patients without previous COVID-19 infection. SARS-CoV-2 spike protein antibody titers during anti-IL-6 receptor therapy were compared to anti-CD20 antibody therapy, oral immunosuppressants, and to nonimmunosuppressed individuals. RESULTS: We observed 100% seroconversion in the anti-IL-6 receptor treatment group. Titers of SARS-CoV-2 spike protein antibodies were lower compared to healthy controls (720 vs 2500 binding antibody units (BAU)/mL, p = 0.004), but higher than in the anti-CD20 (720 vs 0.4 BAU/mL, p < 0.001) and comparable to the oral immunosuppressant group (720 vs 795 BAU/mL, p = 1.0). We found no association between mRNA-based vaccines and relapse activity in patients with or without immunotherapy. CONCLUSIONS: Despite being lower than in healthy controls, the humoral vaccine response during anti-IL-6 receptor therapy was evident in all patients and substantially stronger compared to anti-CD20 treatment. No relevant disease activity occurred after mRNA vaccination against SARS-CoV-2.

Effects of the COVID-19 Pandemic on Patients With NMO Spectrum Disorders and MOG-Antibody-Associated Diseases: COPANMO(G)-Study.

BACKGROUND AND OBJECTIVES: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). METHODS: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database. RESULTS: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3). DISCUSSION: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease.

Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Experiences of persons with multiple sclerosis with rehabilitation-a qualitative interview study.

BACKGROUND: Managing multiple sclerosis (MS) includes different treatment approaches. Rehabilitation is a key strategy in MS for improving functioning, activity and participation. As part of a larger study on overall patient experiences with different treatment approaches, this study aims to give an overview of different patients' experiences and perspectives on inpatient rehabilitation in MS. METHODS: We conducted problem-centered interviews in 50 persons with MS in Germany, of whom most had relapsing-remitting MS. We used the maximum variation sampling method during recruitment. Data were analyzed thematically. RESULTS: As a result of the analysis, three major themes were identified: 1) factors contributing to the decision-making concerning rehabilitation, 2) experience with the rehabilitation setting, 3) benefits of rehabilitation treatments. The treating physicians' attitude had a major impact on the decision to either opt for rehabilitation or not. Setting goals prior to rehabilitation was given a high priority. Exchanging experiences with other persons with MS presented a major benefit from rehabilitation while for some being separated from regular daily life resulted in a more ambiguous attitude ranging from appreciation of escaping daily hassles to substantial behavioral change management. CONCLUSION: Patients reported various experiences in the process of decision-making with regard to rehabilitation. Physicians´ advice, goal setting and the selection of the most suitable rehabilitation clinic were considered most relevant.

Experiences of persons with Multiple Sclerosis with lifestyle adjustment-A qualitative interview study.

BACKGROUND: Persons with Multiple Sclerosis (pwMS) follow individual strategies to cope with this highly heterogeneous disease. As surveys show, lifestyle habits play an important role in pwMS. However, little is known about individual experiences of pwMS with different lifestyle adjustment strategies. OBJECTIVE: This study aims to describe and understand individual experiences of pwMS with lifestyle adjustments. METHODS: Semi-structured interviews were conducted with 50 pwMS in Germany. Criteria for inclusion were age ≥ 18 years and a diagnosis of relapsing-remitting Multiple Sclerosis. Data were analyzed inductively and deductively according to a six-step thematic analysis. RESULTS: The three main themes for experience-based lifestyle adjustments were: 1) nutrition and supplements, 2) exercise and physical activity, and 3) stress management. Influencing factors on the decision-making process such as active disease management, information and advice, desire for mental health and social support, and the wish for self-determination were identified. Impacts of starting or maintaining lifestyle habits included, for example, MS-specific, general, and mental health benefits, the development of coping strategies, social support, and barriers that led to a termination of lifestyle adjustments. CONCLUSION: This study provides a rich and nuanced amount of experiences of pwMS with lifestyle adjustments and leads to three important conclusions: 1) Further research is warranted to better describe the perceived effects of lifestyle habits on MS symptoms and progression, in particular with regard to nutrition and stress reduction; 2) patient education in MS should include the available evidence on lifestyle management and 3) patients need to be actively supported in changing their lifestyle behavior.

Development and evaluation of a website with patients experiences of multiple sclerosis: a mixed methods study.

BACKGROUND: A variety of management options (e.g., disease-modifying therapy, lifestyle interventions, rehabilitation) are available for persons with relapsing-remitting multiple sclerosis (MS). Besides coping with the diagnosis, persons with MS have to make complex decisions, e.g., regarding disease-modifying therapies. In addition to factual information, reports of patient experiences may support other patients in their decision-making. Therefore, we developed a website presenting patient experiences illustrated by video, audio and text files. This study aimed to test the acceptability and usability of a website with patient experiences with MS. METHODS: A mixed-methods approach was applied. A total of 69 participants visited the German "Patient Experiences with MS (PExMS)" website and among them, 50 persons with MS and 6 experts completed an online survey. In total, 18 participants took part in telephone interviews or focus groups. Data from the survey were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. RESULTS: Both quantitative and qualitative responses suggest that the PExMS website was viewed positively by patients and experts. 94% of persons with MS agreed that the information was comprehensible and reliable. 54% felt encouraged to share their health problems with others after having studied the website. 74% claimed to use the website if they had to make a decision regarding their health. Qualitative responses deduced from the website fell into 5 key themes: (1) web design, appearance, and functionality, (2) content, (3) usability, (4) satisfaction, and (5) loyalty. The search for persons of similar age and with comparable experiences was a major driving force to navigate the website. The material on the website was perceived as diverse, covering both positive and negative experiences in daily living with MS. All participants greatly appreciated having access to other people's experiences online and judged the material on the website as particularly helpful in decision-making for disease-modifying therapies. CONCLUSIONS: The findings suggest that the PExMS website might have the potential to be a useful source of audio-visual information for persons with MS. Given the lack of websites available to patients with experiential information, health care professionals may be encouraged to routinely inform patients about this website at regular appointments.

Seronegative myasthenic crisis: a multicenter analysis.

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Seronegative patients represent around 10-15% of MG, but data on outcome of seronegative MCs are lacking. We performed a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody-positive MG (AChR-MG) or seronegative MG between 2006 and 2015 in a retrospective German multicenter study. We identified 15 seronegative MG patients with 17 MCs and 142 AChR-MG with 159 MCs. Seronegative MCs were younger (54.3 ± 14.5 vs 66.5 ± 16.3 years; p = 0.0037), had a higher rate of thymus hyperplasia (29.4% vs 3.1%; p = 0.0009), and were more likely to be female (58.8% vs 37.7%; p = 0.12) compared to AChR-MCs. Time between diagnosis of MG and MC was significantly longer in seronegative patients (8.2 ± 7.6 vs 3.1 ± 4.4 years; p < 0.0001). We found no differences in duration of mechanical ventilation (16.2 ± 15.8 vs 16.5 ± 15.9 days; p = 0.94) and length of stay at intensive care unit (17.6 ± 15.2 vs 17.8 ± 15.4 days; p = 0.96), or in-hospital mortality (11.8% vs. 10.1%; p = 0.69). We conclude that MC in seronegative MG affects younger patients after a longer period of disease, but that crisis treatment efficacy and outcome do not differ compared to AChR-MCs.