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;95:720-732.

Serum neurofilament light chain and glial fibrillary acidic protein for predicting response to apheresis in steroid-refractory multiple sclerosis relapses.

BACKGROUND AND PURPOSE: The predictive value of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) for apheresis outcome in steroid-refractory multiple sclerosis (MS) relapse has not yet been evaluated. METHODS: We used pre- and postapheresis serum samples from 38 participants of the IAPEMS trial (clinicaltrials.gov: NCT02671682), which investigated the use of immunoadsorption versus plasma exchange for the treatment of steroid-refractory MS attacks. Response to apheresis was classified based on improvement on (i) the Expanded Disability Status Scale (EDSS), (ii) the affected functional system scores (FSS) of the EDSS, or (iii) the visual acuity for patients with optic neuritis, 4 weeks postapheresis. sNFL and sGFAP were measured by single molecule arrays. RESULTS: Preprocedural sGFAP levels could discriminate between responders and nonresponders, determined by FSS improvement (p = 0.017). In multivariate logistic regression analysis, younger age (odds ratio [OR] = 0.781, 95% confidence interval [CI] = 0.635-0.962, p = 0.020) and lower sGFAP levels (OR = 0.948, 95% CI = 0.903-0.995, p = 0.031) could predict response to apheresis in the overall cohort. We could observe a trend towards a favourable apheresis outcome with higher sNfL levels (OR = 1.413, 95% CI = 0.965-2.069, p = 0.076). Analysis of the sNfL-to-sGFAP ratio showed an OR of 1.924 (95% CI = 1.073-3.451, p = 0.028) for predicting apheresis response. The ratio showed a better predictive value than the individual parameters. Neither biomarker was affected by the number of steroid cycles preapheresis. CONCLUSIONS: Lower sGFAP levels, a higher sNfL-to-sGFAP ratio, and younger age are associated with a favourable apheresis outcome.

Quantification of blood glial fibrillary acidic protein using a second-generation microfluidic assay. Validation and comparative analysis with two established assays.

OBJECTIVES: Increased levels of glial fibrillary acidic protein (GFAP) in blood have been identified as a valuable biomarker for some neurological disorders, such as Alzheimer's disease and multiple sclerosis. However, most blood GFAP quantifications so far were performed using the same bead-based assay, and to date a routine clinical application is lacking. METHODS: In this study, we validated a novel second-generation (2nd gen) Ella assay to quantify serum GFAP. Furthermore, we compared its performance with a bead-based single molecule array (Simoa) and a homemade GFAP assay in a clinical cohort of neurological diseases, including 210 patients. RESULTS: Validation experiments resulted in an intra-assay variation of 10 %, an inter-assay of 12 %, a limit of detection of 0.9 pg/mL, a lower limit of quantification of 2.8 pg/mL, and less than 20 % variation in serum samples exposed to up to five freeze-thaw cycles, 120 h at 4 °C and room temperature. Measurement of the clinical cohort using all assays revealed the same pattern of GFAP distribution in the different diagnostic groups. Moreover, we observed a strong correlation between the 2nd gen Ella and Simoa (r=0.91 (95 % CI: 0.88-0.93), p<0.0001) and the homemade immunoassay (r=0.77 (95 % CI: 0.70-0.82), p<0.0001). CONCLUSIONS: Our results demonstrate a high reliability, precision and reproducibility of the 2nd gen Ella assay. Although a higher assay sensitivity for Simoa was observed, the new microfluidic assay might have the potential to be used for GFAP analysis in daily clinical workups due to its robustness and ease of use.

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.

CXCL13 in Cerebrospinal Fluid: Clinical Value in a Large Cross-Sectional Study.

C-X-C-motif chemokine ligand 13 (CXCL13) in cerebrospinal fluid (CSF) is increasingly used in clinical routines, although its diagnostic specificity and divergent cut-off values have been defined so far mainly for neuroborreliosis. Our aim was to evaluate the value of CSF-CXCL13 as a diagnostic and treatment response marker and its role as an activity marker in a larger disease spectrum, including neuroborreliosis and other neuroinflammatory and malignant CNS-disorders. Patients who received a diagnostic lumbar puncture (LP) (n = 1234) between July 2009 and January 2023 were included in our retrospective cross-sectional study. The diagnostic performance of CSF-CXCL13 for acute neuroborreliosis was highest at a cut-off of 428.92 pg/mL (sensitivity: 92.1%; specificity: 96.5%). In addition, CXCL13 levels in CSF were significantly elevated in multiple sclerosis with clinical (p = 0.001) and radiographic disease activity (p < 0.001). The clinical utility of CSF-CXCL13 appears to be multifaceted. CSF-CXCL13 is significantly elevated in patients with neuroborreliosis and shows a rapid and sharp decline with antibiotic therapy, but it is not specific for this disease and is also highly elevated in less common subacute neuroinfectious diseases, such as neurosyphilis and cryptococcal meningitis or in primary/secondary B-cell lymphoma.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Phelan McDermid Syndrome: Multiple Sclerosis as a Rare but Treatable Cause for Regression-A Case Report.

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. SHANK3 is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.

CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD.

OBJECTIVE: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis. METHODS: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37). RESULTS: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased. CONCLUSIONS: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.

Stress cardiomyopathy associated with the first manifestation of multiple sclerosis: a case report.

BACKGROUND: We present a case with a close temporal association of the first diagnosis of multiple sclerosis and stress cardiomyopathy. CASE PRESENTATION: A 19-year-old man experienced severe dyspnoea. The cardiac biomarkers troponin T and NT-proBNP were elevated, and transthoracic echocardiography showed basal hypokinesia. The man was diagnosed with stress cardiomyopathy after main differential diagnoses such as acute coronary syndrome, myocarditis, and pheochromocytoma were excluded. Furthermore, the patient reported vertigo and paraesthesia. Brain and spinal MRI revealed T2-hyperintense lesions with a prominent acute lesion in the pontomedullary area. Cerebrospinal fluid findings revealed a lymphocytic pleocytosis and intrathecal IgG synthesis. Serum neurofilaments were elevated. The patient was diagnosed with MS, and treatment with intravenous Methylprednisolone was initiated. The brainstem lesion due to multiple sclerosis was assumed to be the cause of stress cardiomyopathy. The patient fully recovered. CONCLUSION: Stress cardiomyopathy may be linked with the first manifestation of multiple sclerosis in the presented case since pontomedullary lesions could affect the sympathetic nervous system. This case highlights the importance of neurological history and examination in young patients with unexplained acute cardiac complaints.

Intrathecal immunoglobulin M production: A promising high-risk marker in clinically isolated syndrome patients.

Markers predicting the course of patients with clinically isolated syndrome (CIS) toward multiple sclerosis (MS) are urgently needed. We evaluated the predictive values of intrathecal immunoglobulin (Ig) G and IgM production with different methods for conversion to definite MS according to revised McDonald 2010 criteria in a cohort of 126 CIS patients. Intrathecal IgM production showed the highest likelihood ratio for the conversion of CIS patients to definite MS at 6.3, whereas it was 1.4 for oligoclonal IgG bands. We conclude that the determination of intrathecal IgM is a valuable tool to predict the disease course of patients with CIS. Ann Neurol 2018;83:1032-1036.

Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis.

Background Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (QFLC), FLC index and FLC intrathecal fraction (FLCIF). Methods κ- and λ-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. QFLC was calculated as the ratio of CSF/serum FLC concentration, the FLC index as QFLC/albumin quotient and the percentage FLCIF by comparing QFLC to a previously empirically determined, albumin quotient-dependent reference limit. Results CSF FLC concentration, QFLC, FLC index and FLCIF of both the κ- and λ-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.

Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins.

Oligoclonal Ig bands (OCBs) of the cerebrospinal fluid are a hallmark of multiple sclerosis (MS), a disabling inflammatory disease of the central nervous system (CNS). OCBs are locally produced by clonally expanded antigen-experienced B cells and therefore are believed to hold an important clue to the pathogenesis. However, their target antigens have remained unknown, mainly because it was thus far not possible to isolate distinct OCBs against a background of polyclonal antibodies. To overcome this obstacle, we copurified disulfide-linked Ig heavy and light chains from distinct OCBs for concurrent analysis by mass spectrometry and aligned patient-specific peptides to corresponding transcriptome databases. This method revealed the full-length sequences of matching chains from distinct OCBs, allowing for antigen searches using recombinant OCB antibodies. As validation, we demonstrate that an OCB antibody from a patient with an infectious CNS disorder, neuroborreliosis, recognized a Borrelia protein. Next, we produced six recombinant antibodies from four MS patients and identified three different autoantigens. All of them are conformational epitopes of ubiquitous intracellular proteins not specific to brain tissue. Our findings indicate that the B-cell response in MS is heterogeneous and partly directed against intracellular autoantigens released during tissue destruction. In addition to helping elucidate the role of B cells in MS, our approach allows the identification of target antigens of OCB antibodies in other neuroinflammatory diseases and the production of therapeutic antibodies in infectious CNS diseases.

Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: A multicenter study.

BACKGROUND: Kappa free light chains (KFLCs) have been proposed as a diagnostic biomarker in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to validate the diagnostic accuracy of intrathecal KFLC synthesis in a multicenter study. METHODS: KFLCs were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of patients with CIS (n = 60), MS (n = 60) and other neurological diseases (n = 60) from four different MS centers. The upper normal limit for intrathecal KFLC concentrations depending on blood-CSF barrier function was previously calculated in a cohort of 420 control patients. RESULTS: Diagnostic sensitivity of intrathecal KFLC synthesis, IgG synthesis according to Reiber, IgG index and oligoclonal bands (OCBs) was 95%, 72%, 73% and 93% in patients with MS and 82%, 47%, 43% and 72% in patients with CIS. Specificity of intrathecal KFLC synthesis was 95% and 98% for all other measures. CONCLUSION: These findings further support the diagnostic value of intrathecal KFLC synthesis in CIS and MS patients and demonstrate a valid, easier and rater-independent alternative to OCB detection.

Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation.

Intrathecal oligoclonal bands of the cerebrospinal fluid are considered the most important immunological biomarkers of multiple sclerosis. They typically consist of clonally expanded IgG antibodies that underwent affinity maturation during sustained stimulation by largely unknown antigens. In addition, ∼40% of patients with multiple sclerosis have oligoclonal bands that consist of expanded IgM antibodies. We investigated the molecular composition of IgM- and IgG-chains from cerebrospinal fluid of 12 patients with multiple sclerosis, seven patients with other neurological diseases, and eight healthy control subjects by high-throughput deep-sequencing and single-cell PCR. Further, we studied the expression of activation-induced cytidine deaminase, the key enzyme for affinity maturation of antibodies, in cerebrospinal fluid samples of 16 patients. From the cerebrospinal fluid of two multiple sclerosis patients we isolated single B cells and investigated the co-expression of antibody chains with activation-induced cytidine deaminase. In striking contrast to IgM-chains from peripheral blood, IgM-chains from cerebrospinal fluid of patients with multiple sclerosis or neuroborreliosis showed a high degree of somatic hypermutation. We found a high content of mutations that caused amino acid exchanges as compared to silent mutations. In addition, more mutations were found in the complementarity determining regions of the IgM-chains, which interact with yet unknown antigens, as compared to framework regions. Both observations provide evidence for antigen-driven affinity maturation. Furthermore, single B cells from the cerebrospinal fluid of patients with multiple sclerosis co-expressed somatically hypermutated IgM-chains and activation-induced cytidine deaminase, an enzyme that is crucial for somatic hypermutation and class switch recombination of antibodies and is normally expressed during activation of B cells in germinal centres. Clonal tracking of particular IgM(+) B cells allowed us to relate unmutated ancestor clones in blood to hypermutated offspring clones in CSF. Unexpectedly, however, we found no evidence for intrathecal isotype switching from IgM to IgG. Our data suggest that the intrathecal milieu sustains a germinal centre-like reaction with clonal expansion and extensive accumulation of somatic hypermutation in IgM-producing B cells.

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.

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.

Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study.

INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases - a retrospective cross-sectional study.

Introduction: The polyspecific intrathecal immune response (PSIIR), aka MRZ reaction (M = measles, R = rubella, Z = zoster, optionally Herpes simplex virus, HSV) is defined as intrathecal immunoglobulin synthesis (IIS) for two or more unrelated viruses. Although an established cerebrospinal fluid (CSF) biomarker for multiple sclerosis (MS), a chronic autoimmune-inflammatory neurological disease (CAIND) of the central nervous system (CNS) usually starting in young adulthood, the full spectrum of CAINDs with a positive PSIIR remains ill defined. Methods: In this retrospective, cross-sectional study, patients with CSF-positive oligoclonal bands (OCB) and - to enrich for non-MS diagnoses - aged ≥50 years were enrolled. Results: Of 415 with PSIIR testing results (MRZ, HSV optional), 76 were PSIIR-positive. Of these, 25 (33%) did not meet the diagnostic criteria for MS spectrum diseases (MS-S) comprising clinically or radiologically isolated syndrome (CIS/RIS) or MS. PSIIR-positive non-MS-S phenotypes were heterogenous with CNS, peripheral nerve and motor neuron involvement and often defied unequivocal diagnostic classification. A rating by neuroimmunology experts suggested non-MS CAINDs in 16/25 (64%). Long-term follow-up available in 13 always showed a chronically progressive course. Four of five responded to immunotherapy. Compared to MS-S patients, non-MS CAIND patients showed less frequent CNS regions with demyelination (25% vs. 75%) and quantitative IgG IIS (31% vs. 81%). MRZ-specific IIS did not differ between both groups, while additional HSV-specific IIS was characteristic for non-MS CAIND patients. Discussion: In conclusion, PSIIR positivity occurs frequently in non-MS-S patients ≥50 years. Although sometimes apparently coincidental, the PSIIR seems to represent a suitable biomarker for previously unnoticed chronic neurologic autoimmunities, which require further characterization.