Eculizumab for a catastrophic relapse in NMOSD: case report.

Neuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory disorders of central nervous system characterized by immune-mediated demyelination and axonal damage, predominantly affecting spinal cord and optic nerves. This case report describes a 47-year-old woman with an aggressive form of seropositive NMOSD who had previously been treated with corticosteroids, plasma exchange, and cyclophosphamide. She experienced a life-threatening relapse that did not respond to conventional treatment, but ultimately showed a positive response to eculizumab. Furthermore, we describe the role of sNfL.

Renal function's impact on serum neurofilament levels in patients with multiple sclerosis: an exploratory analysis.

BACKGROUND: sNfL, a promising biomarker for neuroaxonal damage in Multiple Sclerosis (MS), requires cautious interpretation due to several comorbidity influences. OBJECTIVES: To investigate the impact of renal function on sNfL levels in MS patients. METHODS: This retrospective study stratified patients by MS clinical phenotype, acute inflammatory activity (AIA) status-defined as relapse or gadolinium-enhancing lesions within 90 days of sample collection-renal function, assessed by estimated glomerular filtration rate (eGFR), and age (< 40 years, 40-60 years, > 60 years). Comparative analysis of sNfL levels across these groups was performed. The sNfL-eGFR relationship was examined using linear and non-linear regression models, with the best fit determined by R2 and the F estimator. RESULTS: Data from 2933 determinations across 800 patients were analyzed. Patients with renal insufficiency (RI) (eGFR < 60 mL/min/1.73 m2) and mild renal impairment (MDRF) (eGFR 60-90 mL/min/1.73 m2) showed significantly higher sNfL levels compared to those with normal renal function, a pattern also observed in age groups 40 years and older. No significant differences were found between MDRF patients and those with AIA. Among RI patients, no differences in sNfL levels were observed between relapsing-remitting and progressive MS phenotypes. A regression S-Curve model was identified as the best fit, illustrating a marked increase in sNfL levels beginning at an eGFR of approximately 75 mL/min/1.73 m2. DISCUSSION: Caution is advised when interpreting sNfL levels for monitoring MS in patients with impaired renal function.

The first reported case of drug-induced hemolytic anemia caused by dimethyl fumarate in a patient with multiple sclerosis.

BACKGROUND: Drug-induced hemolytic anemia is a rare and potentially fatal complication of drug treatment. Specific laboratory tests are crucial to confirm the diagnosis. CASE REPORT: A 38-year-old woman on treatment with dimethyl fumarate for multiple sclerosis presented with a 7-day history of weakness and fatigue. Laboratory tests revealed profound hemolytic anemia with hemoglobin levels of 4.7 g/dL (reference, 12.5-16.0), decreased haptoglobin, increased reticulocyte count, and increased indirect bilirubin. A first direct antiglobulin test was negative. The patient was started on prednisone 1 mg/kg/day, and dimethyl fumarate was withdrawn. A blood sample was drawn on Day 7 and sent to a reference laboratory. A direct antiglobulin test performed 7 days later was positive. Furthermore, an indirect antiglobulin test was positive only in the presence of the drug. RESULTS: The patient did not receive a blood transfusion, recovered clinically during the following days, and was discharged on Day 7. On Day 36, the patient's RBCs had normalized. She was changed to another disease-modifying treatment for her multiple sclerosis, and at 10-month follow-up she remained stable without any notable adverse effects. CONCLUSION: This case describes the first report of a dimethyl fumarate-induced hemolytic anemia. Laboratory results should always be interpreted within the clinical context. Specific laboratory expertise is often needed, given the complexity of the field.

Evaluating the complement C1q levels in serum and cerebrospinal fluid in multiple sclerosis patients: Could it serve as a valuable marker in clinical practice?

Immunohistochemical studies have identified complement component C1q in MS lesions. We aimed to compare serum (sC1q) and CSF (csfC1q) levels in a large cohort of MS patients (pwMS) (n = 222) with those of healthy controls (HC, n = 52), individuals with other immune (IND, n = 14), and non-immune neurological disorders (nIND, n = 15), and to analyze their correlation with other biomarkers. pwMS were divided into three series based on their origin. CSF samples were unavailable for HC. All three pwMS cohorts had lower sC1q levels compared to HC and IND. csfC1q was higher in one pwMS cohort, with a trend in another, and correlated with IgG, Free Kappa Light Chains, GFAP, and Chitinase-3 Like Protein-1 in CSF. Our findings suggest a significant role for C1q in MS pathophysiology, potentially serving as a biomarker for disease identification.

Predictive potential of serum and cerebrospinal fluid biomarkers for disease activity in treated multiple sclerosis patients.

BACKGROUND: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS). METHODS: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile. RESULTS: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35-5.4) and 2.67 (CI: 1.32-5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5-6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51-6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models. DISCUSSION: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.

Improving the efficiency of free kappa light chains as diagnostic biomarker of Multiple Sclerosis by using a novel algorithm.

BACKGROUND: Intrathecal immunoglobulin synthesis (ITS) plays a crucial role in the diagnosis of multiple sclerosis (MS). Traditionally, the gold standard method for detecting ITS has been through the analysis of oligoclonal bands (OCB). However, the paradigm has shifted with the introduction of the free kappa light chains (FKLC) method. In fact, a recent consensus recommends evaluating FKLC index (FKLCi) as the primary approach and reserving oligoclonal bands with borderline results. The objective of our study is to investigate the diagnostic efficiency of combining FKLC with other methods to predict ITS while minimizing the reliance on OCB. METHODS: A total of 192 patients were included in the study, consisting of 145 individuals diagnosed with multiple sclerosis (pwMS) and 46 with other neurological diseases (controls). Among the MS cases, 100 patients were assigned to the Training Cohort (TC), while an external Validation Cohort (VC) comprised of 45 MS patients was established. Diagnostic efficiency was assessed for FKLCi, OCB, Link index, and the Reiber formula for IgG and FKLC. Optimal cutoff values for Link index and FKLCi were also determined. The last procedure was developed for diverse algorithms using the parameters mentioned above, which included the optimal cutoffs previously obtained. The calculations were conducted independently for both the TC and the VC, as well as for a composite cohort formed by combining data from all patients (OC) RESULTS: One algorithm, named KRO, was developed based on the determination of FKLCi and Reiber Formula as the primary diagnostic parameters. For cases where the FKLCi result was mildly increased, OCB was utilized as a supplementary test. The KRO algorithm demonstrated superior diagnostic accuracy in the OC (89%), resulting in a reduction of OCB consumption by 91%. DISCUSSION: The KRO algorithm demonstrated superior sensitivity and accuracy although lower specificity and NPV compared to the use of FKLCi and OCB alone. The present research aligns with the new consensus recommendations regarding the diagnostic approach. Our findings indicate that employing a combined marker approach via KRO could prove to be a proficient screening tool for multiple sclerosis. This approach also holds the potential to address inherent limitations associated with each individual marker. However, to further validate and solidify the efficacy of our algorithm, additional studies involving larger cohorts are warranted.

Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience.

Introduction: Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS. Patients and methods: Observational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS. Results: A total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5-27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy). Conclusion: Rituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.

Escalation vs. Early Intense Therapy in Multiple Sclerosis.

The treatment strategy of multiple sclerosis (MS) is a highly controversial debate. Currently, there are up to 19 drugs approved. However, there is no clear evidence to guide fundamental decisions such as what treatment should be chosen in first place, when treatment failure or suboptimal response should be considered, or what treatment should be considered in these cases. The "escalation strategy" consists of starting treatment with drugs of low side-effect profile and low efficacy, and "escalating" to drugs of higher efficacy-with more potential side-effects-if necessary. This strategy has prevailed over the years. However, the evidence supporting this strategy is based on short-term studies, in hope that the benefits will stand in the long term. These studies usually do not consider the heterogeneity of the disease and the limited effect that relapses have on the long-term. On the other hand, "early intense therapy" strategy refers to starting treatment with drugs of higher efficacy from the beginning, despite having a less favorable side-effect profile. This approach takes advantage of the so-called "window of opportunity" in hope to maximize the clinical benefits in the long-term. At present, the debate remains open. In this review, we will critically review both strategies. We provide a summary of the current evidence for each strategy without aiming to reach a definite conclusion.

Case Report: Exacerbation of Relapses Following mRNA COVID-19 Vaccination in Multiple Sclerosis: A Case Series.

Introduction: mRNA coronavirus disease 2019 (COVID-19) vaccination has been widely used to arrest the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Rarely, autoimmune events such as relapses in patients with multiple sclerosis (MS) have been reported after vaccination. However, the possible effects of vaccination in a patient already experiencing the symptoms of a relapse represent an unusual scenario that has not been described. Patients and Methods: This is a retrospective case series of four patients from three major tertiary referral centers that received mRNA COVID-19 vaccination after starting with symptoms of acute demyelination of the central nervous system due to non-recognized MS. A detailed description of each case, including MRI studies, serum light-neurofilament levels, and cerebrospinal fluid (CSF) cytokine profile, is provided. Case Description: All patients presented exacerbation of ongoing symptoms after vaccination (range 14-112 days first dose). All patients presented MRI features suggestive of highly active MS and fulfilled McDonald 2017 criteria at the time of presentation. All patients presented high serum light-neurofilament levels and oligoclonal G bands restricted to the CSF. Higher levels of interleukin-6 in the CSF were present in the more severe cases. Discussion: We describe exacerbation of relapses after mRNA COVID-19 vaccination. We hypothesize RNA sensors such as Toll-like receptor 7 may be activated and contribute to amplify the inflammatory response during a relapse. Conclusion: Patients should seek medical attention if experiencing acute neurological symptoms, especially before vaccination. Fast diagnostic procedures and prompt treatment should be performed in these patients. Pharmacovigilance and further study are warranted to confirm causality.

Oligoclonal M bands unveil occult inflammation in multiple sclerosis.

INTRODUCTION: Recent works demonstrate that patients with multiple sclerosis (pwMS) and oligoclonal M bands (OCMB) in cerebrospinal fluid (CSF) are at higher risk of conversion to secondary progressive course, suggesting a distinct pathophysiology pathway in these patients. OBJECTIVES: To analyze the relationship of serum neurofilament light chain (s-NFL) in absence of inflammatory activity in people with multiple sclerosis (pwMS) according to the presence of OCMB versus healthy controls (HC), and the effect of aging. METHODS: Two cohorts of HC were compared to a cohort of pwMS without clinical or radiological signs of acute inflammation. Lack of inflammation was defined as the absence of relapses or gadolinium-enhancing lesions (GEL) brain in an MRI performed within three months before and after s-NFL determination. S-NFL was measured with SIMOa technology. OCMB in the cerebrospinal fluid (CSF) were analyzed with isoelectric focusing and immunoblotting. RESULTS: 254 people were studied: 124 healthy voluntary controls and 130 pwMS. Despite the absence of inflammatory activity, pwMS and OCMB showed higher levels of s-NFL compared to those without OCMB and HC (11.4 pg/mL, 8.9 pg/mL and 9.0 pg/mL, respectively). A positive and exponential correlation between age and s-NFL was observed, with highest increases among pwMS and OCMB in the CSF. DISCUSSION: In absence of overt inflammatory activity, pwMS and OCMB exhibit higher s-NFL levels, and a greater age-related increase. Thus, OCMB may portray an underlying inflammatory process not detected by conventional MRI studies and may explain the poorer prognosis of these patients.

Effectiveness of rituximab vs. ocrelizumab for the treatment of primary progressive multiple sclerosis: a real-world observational study.

INTRODUCTION: Ocrelizumab, an antiCD-20 antibody, is the only drug approved to treat patients with primary progressive multiple sclerosis (pwPPMS). Not all candidates receive this treatment due to prescription limitations. Rituximab, another antiCD-20 antibody, has been used off-label in pwPPMS before and after ocrelizumab approval. However, studies comparing effectiveness of both drugs are lacking. OBJECTIVE: To evaluate effectiveness of rituximab and ocrelizumab in pwPPMS under real-life conditions. METHODS: We conducted a multicentric observational study of pwPPMS that started ocrelizumab or rituximab according to clinical practice, with a minimum follow-up of 1 year. Data was collected prospectively and retrospectively. Primary outcome was time to confirmed disability progression at 3 months (CDW). Secondary outcome was serum neurofilament light chain levels (sNFL) at the end of follow-up. RESULTS: 95 out 111 pwPPMS fulfilled inclusion criteria and follow-up data availability: 49 (51.6%) received rituximab and 46 (48.4%) ocrelizumab. Rituximab-treated patients had significantly higher baseline EDSS, disease duration and history of previous disease-modifying treatment (DMT) than ocrelizumab-treated patients. After a mean follow-up of 18.3 months (SD 5.9), 26 patients experienced CDW (21.4%); 15 (30.6%) in the rituximab group; and 11 (23.9%) in the ocrelizumab group. Survival analysis revealed no differences in time to CDW. sNFL were measured in 60 patients and no differences between groups were found. INTERPRETATION: We provide real-world evidence of effectiveness of ocrelizumab and rituximab in pwPPMS. No differences in time to CDW were found between treatments. However, this study cannot establish equivalence of treatments and warrant clinical trial to confirm our findings.

Oligoclonal M bands and cervical spinal cord lesions predict early secondary progressive multiple sclerosis.

Objective: To determine baseline cerebrospinal fluid and magnetic resonance imaging (MRI) variables at the onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) that predict evolution to secondary progressive MS (SPMS). Methods: 276 CIS patients with a minimum follow-up of 10 years were studied. Baseline presence of oligoclonal IgG and IgM bands (OCGB and OCMB respectively); number of brain T2 lesions (B-T2L), brain gadolinium enhancement lesions (brain-GEL), cervical spinal cord T2 lesions (cSC-T2L); and fulfillment of 2017 McDonald criteria among other variables were collected. Results: 14 patients ended up with a non-MS condition. 138/276 CIS patients fulfilled 2017 McDonald criteria. Mean age was 32.4 years, 185 female. 227 received treatment, 95 as CIS. After a mean follow-up of 12 years, 36 patients developed SPMS. Conversion to SPMS was associated with OCGB (p = 0.02), OCMB (p = 0.0001); ≥ 9 B-T2L (p = 0.03), brain-GEL (p = 0.03), and cSC-T2L (p = 0.03). However, after adjusting for sex, age, BT2L, brain-GEL, SC-T2, and OCMB status, only OCMB (HR 4.4, 1.9-10.6) and cSC-T2L (HR 2.2, 1.0-6.2) suggested an independent association with risk of conversion to SPMS. Patients with both risk factors had a HR of 6.12 (2.8-12.9). Discussion: OCMB and SC-T2 lesions are potential independent predictors of conversion to SPMS.

High Levels of Cerebrospinal Fluid Kappa Free Light Chains Relate to IgM Intrathecal Synthesis and Might Have Prognostic Implications in Relapsing Multiple Sclerosis.

Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes (p < 0.0001/p < 0.05) and IgG-oligoclonal bands (OCGBs) (p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index (p = 0.049). KFLC-index was higher in patients with LMCE (p = 0.008) and correlated with CHI3L1 (p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1-147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2-7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.

Treatment of Multiple Sclerosis With Teriflunomide. Multicenter Study of Real Clinical Practice in the Valencian Community-Spain.

Introduction: We have different treatment alternatives for relapsing-remitting multiple sclerosis-RRMS-within the so-called platform drugs. It would be desirable to know the ideal drug for each patient. Real clinical practice studies provide us with data on drug efficacy in the medium and long term, safety beyond clinical trials, and can help us to know the patient profile appropriate for each therapy. Material and Methods: An observational multicenter study of real clinical practice in patients with RRMS who were treated with teriflunomide in the Valencian Community, since teriflunomide was authorized in Spain. The database created for this study collects retrospectively patients followed prospectively in the MS clinics. Objectives: To analyze the efficacy and safety of teriflunomide treatment in patients with RRMS under the conditions of real clinical practice, and to identify a patient profile responding to the treatment. Results: We obtained data from 340 patients who received at least one dose of 14 mg teriflunomide. The patients were 69.4% female to 30.6% male, had a mean age of 46.4 years, and a mean time of progression of MS of 11.5 years. The mean pre-teriflunomide relapse rate was 0.4 years, the mean EDSS scorewas 1.98, IgG Oligoclonal bands were present in the CSF of 66.2% of the patients, IgM Oligoclonal bands were present in 46.9%, and the mean number of gadolinium-enhancing lesions was 1.07 lesions per patient at the beginning of treatment. The average number of treatments previously received was 1.04, and 28.53% were naïve. After a follow-up of up to 4 years, a reduction in the annualized and cumulative annualized relapse rate was observed in the first year, in the second year, and in the third year, compared to the pre-treatment year. The EDSS scores were stabilized throughout the follow-up. Likewise, there was a reduction in gadolinium-enhancing lesions in the 1st and 2nd years compared to the pre-treatment period. Applying different generalized multiple linear regression models, we identified a profile of a responding patient to teriflunomide as a male without IgM oligoclonal bands in the CSF, a previous EDSS score of <3, and more than 5 years duration of MS.

Functional and structural changes in the visual pathway in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a heterogeneous disease with an unpredictable course. Visual pathway is a target of the disease and may reflect mechanisms that lead to disability. Structural and functional changes in the visual pathway may be studied by noninvasive techniques such as optical coherence tomography (OCT), visual evoked potentials (VEP), or B-mode transorbital sonography (TOS). OBJECTIVES: The aim is to assess changes in the visual pathway in eyes of MS patients with and without a history of optic neuritis over a 3-year period and to explore their relationship with disability. MATERIALS AND METHODS: In total, 112 eyes from 56 patients with relapsing MS were recruited: 29 with, and 83 without a history of ON (hON and nhON, respectively). Several parameters were measured by OCT, VEP, and TOS. Baseline measurements were also compared to 29 healthy controls. At 36 months, measurements were repeated in all eyes. RESULTS: At baseline, all tests showed significant differences in optic nerve structure and function in both patient cohorts in all the parameters studied, suggestive of more impairment of the visual pathway among the hON cohort. OCT showed significant differences between healthy controls and the nhON cohort. At 36 months, the nhON cohort showed significant changes by OCT, VEP, and TOS suggestive of further visual pathway impairment. OCT measurements also correlated with baseline EDSS among the nhON cohort. CONCLUSIONS: OCT is the most suitable technique and outperforms VEP and TOS to detect subclinical damage in the visual pathway. It discriminated MS patients from healthy controls and showed a progressive decline in optic nerve thickness over time among these patients.