Background and purpose
Susac syndrome (SuS) is a rare, autoimmune, neurological disease characterized by a clinical triad of branch retinal artery occlusion, sensorineural hearing loss and ...encephalopathy. Neuropsychological functioning in SuS is little researched and the prevalence, nature, and evolution over time of cognitive deficits in SuS remain unclear. This study aimed to better understand the long‐term neuropsychological outcomes of patients with SuS.
Methods
Thirteen patients with SuS (mean SD age 39.5 11.1 years) were enrolled at the Ghent University Hospital by their treating neurologist. The cognitive functioning and emotional well‐being of each patient was evaluated by means of a thorough neuropsychological test battery at baseline and after 2 years. Follow‐up testing after 2 years was performed in 11 patients (mean SD age 42.2 11.5 years).
Results
Patients showed normal neuropsychological test results at a group level, both at baseline and follow‐up testing. Significant improvements over time were found for information processing speed, verbal recognition, and semantic and phonological fluency. Individual test results showed interindividual variability at baseline, with most impairments being in attention, executive functioning and language, which improved after a 2‐year period. In addition, patients reported significantly lower mental and physical well‐being, both at baseline and follow‐up testing.
Conclusions
Our results suggest that neuropsychological dysfunction in SuS is limited at a group level and improves over time. Nonetheless, individual test results reveal interindividual variability, making cognitive screening essential. Furthermore, a high psycho‐emotional burden of the disease was reported, for which screening and follow‐up are necessary.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and purpose
Alemtuzumab, a monoclonal CD52 antibody, is a high‐efficacy disease‐modifying‐therapy in relapsing‐remitting multiple sclerosis (RRMS). Recently, intracerebral hemorrhage (ICH) ...was reported as a possible treatment‐related adverse event. Arterial hypertension during infusion was suggested as a potential cause, although platelet or endothelial dysfunction may also contribute. This study aimed to screen for occult hemorrhagic cerebral lesions after alemtuzumab treatment and to further elucidate risk factors.
Methods
We included 30 RRMS patients who received alemtuzumab treatment at Ghent University Hospital or Sint‐Jan Bruges Hospital. Retrospective data concerning vital signs, adverse effects and thrombocyte levels during treatment were collected. The occurrence of occult intracranial hemorrhagic lesions was assessed by magnetic resonance imaging with susceptibility‐weighted imaging (SWI).
Results
The mean (standard deviation SD) systolic blood pressure (SBP) during the morning, afternoon and evening was 120 (3.38) mmHg during first administration and 114 (4.40) mmHg during second administration (N = 13). There was no significant increase in SBP when comparing morning, afternoon and evening per day, nor was there a significant difference in daily mean SBP between consecutive administration days. Thrombocyte count during treatment cycles ranged between 107 × 109/L and 398 × 109/L, with a mean (SD) absolute reduction of 59.3 × 109/L (50.65) or a mean (SD) relative reduction of 25.0 (12.84)% (N = 20). No patient had ICH, nor did SWI show any cerebral microbleeds or other hemorrhagic lesions post‐treatment (N = 23).
Conclusions
In our patient population, alemtuzumab treatment was not associated with arterial hypertension, ICH or occult microbleeds. Possible differences in administration regimen (ambulatory vs. in‐hospital setting) and patient population (cardiovascular risk) might explain an increased risk in different populations.
Arterial hypertension and intracerebral hemorrhages were recently reported as adverse events in alemtuzumab‐treated multiple sclerosis patients. In our cohort, retrospective analysis did not show a significant increase in systolic blood pressure during alemtuzumab infusions. Magnetic resonance imaging with susceptibility‐weighted imaging (SWI) sequences did not show any signs of hemorrhage or (occult) microbleeds post‐treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cerebrospinal fluid (CSF) kappa free light chain (κFLC) measures gained increasing interest as diagnostic markers in multiple sclerosis (MS). However, the lack of studies comparing assay-dependent ...diagnostic cutoff values hinders their use in clinical practice. Additionally, the optimal κFLC parameter for identifying MS remains a subject of ongoing debate.
The aim of this study was to compare same-sample diagnostic accuracies of the κFLC index, κIgG index, CSF κFLC/IgG ratio, and isolated CSF κFLC (iCSF-κFLC) between two reference centers using different methods.
Paired serum and CSF samples were analyzed for κFLC and albumin concentrations by Freelite
-Optilite (Sint-Jan Bruges hospital) and N Latex
-BNII (Ghent University hospital). Diagnostic performance to differentiate MS from controls was assessed using ROC curve analysis.
A total of 263 participants were included (MS,
= 80). Optimal diagnostic cutoff values for the κFLC index (Freelite
-Optilite: 7.7; N Latex
-BNII: 4.71), κIgG index (Freelite
-Optilite: 14.15, N Latex
-BNII: 12.19), and CSF κFLC/IgG ratio (Freelite
-Optilite: 2.27; N Latex
-BNII: 1.44) differed between the two methods. Sensitivities related to optimal cutoff values were 89.9% (Freelite
-Optilite) versus 94.6% (N Latex
-BNII) for the κFLC index, 91% (Freelite
-Optilite) versus 92.2% (N Latex
-BNII) for the κIgG index, and 81.3% (Freelite
-Optilite) versus 91.4% (N Latex
-BNII) for the CSF κFLC/IgG ratio. However, for iCSF-κFLC, optimal diagnostic cutoff values (0.36 mg/L) and related specificities (81.8%) were identical with a related diagnostic sensitivity of 89.9% for Freelite
-Optilite and 90.5% for N Latex
-BNII. The diagnostic performance of the κFLC index area under the curve (AUC) Freelite
-Optilite: 0.924; N Latex
-BNII: 0.962 and κIgG index (AUC Freelite
-Optilite: 0.929; N Latex
-BNII: 0.961) was superior compared to CSF oligoclonal bands (AUC: 0.898, sensitivity: 83.8%, specificity: 95.9%).
The κFLC index and the κIgG index seem to be excellent markers for identifying MS, irrespective of the method used for κFLC quantification. Based on the AUC, they appear to be the measures of choice. For all measures, optimal cutoff values differed between methods except for iCSF-κFLC. iCSF-κFLC might therefore serve as a method-independent, more cost-efficient, initial screening measure for MS. These findings are particularly relevant for clinical practice given the potential future implementation of intrathecal κFLC synthesis in MS diagnostic criteria and for future multicentre studies pooling data on κFLC measures.
Background:
Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab.
Objective:
To determine ...predictors of relapse and disability progression when switching from another DMT to ocrelizumab.
Methods:
Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1–2 months or 2–6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP).
Results:
After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57–11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2–6 m compared to <1 m: HR = 9.57, 95% CI = 1.92–47.64, p = 0.006).
Conclusion:
The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background and purpose
This study assessed the effect of patient characteristics on the response to disease‐modifying therapy (DMT) in multiple sclerosis (MS).
Methods
We extracted data from 61,810 ...patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow‐up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12‐month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics.
Results
Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio HR = 0.52, 95% confidence interval CI = 0.45–0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41–0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09–1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity.
Conclusions
DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Susac syndrome (SuS) is a rare immune-mediated endotheliopathy that affects the brain, retina and inner ear and is characterised by the variable clinical triad of encephalopathy, visual and ...vestibulocochlear dysfunction. Here, we present clinical and paraclinical data of 19 SuS patients followed at Ghent University Hospital and highlight some atypical clinical and novel radiological findings. Our findings suggest that spinal involvement expands the clinical phenotype of SuS. We further introduce dark blood sequences as a more sensitive technique to detect radiological disease activity in SuS. Our data add to the current understanding of the diagnosis, monitoring and treatment of SuS.
•Susac syndrome (SuS) is an auto-immune endotheliopathy that affects the brain, retina and inner ear.•Spinal cord involvement may be underdiagnosed, warranting active screening for spinal symptoms.•Dark blood sequences might be more sensitive in detecting radiological disease activity in SuS.•Increasing insights in SuS pathophysiology may lead to more targeted therapy in the near future.•The complexity, rarity and unpredictable nature of SuS warrants follow up in dedicated SuS units.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy.
This was a retrospective cohort study from 2 large observational MS ...registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation.
A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80).
The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod).
This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
IMPORTANCE: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit ...the risk of severe relapses. OBJECTIVES: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. DESIGN, SETTING, AND PARTICIPANTS: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. EXPOSURES: Dimethyl fumarate, fingolimod, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. RESULTS: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean SD age, 41.3 10.6 years; 990 female 71%) switched to dimethyl fumarate (138 9.9%), fingolimod (823 59.4%), or ocrelizumab (425 30.7%) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. CONCLUSION AND RELEVANCE: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.
•Despite current treatment options, disability progression cannot always be halted in MS.•A healthy lifestyle may be crucial in increasing brain reserve and delaying disability in MS.•Blood pressure, ...weight and measures for physical activity and cognitive reserve showed associations with the multiple sclerosis severity score.
To determine the association between lifestyle risk factors with 1/ the Multiple Sclerosis Severity Score (MSSS) and 2/ ongoing subclinical brain damage in non-active MS patients on high-efficacy treatment.
Cross-sectional study in persons with Multiple Sclerosis (PwMS) investigating lifestyle factors including cognitive reserve (CR), physical activity (PA), smoking status, alcohol use, dietary habits, body mass index (BMI), blood pressure (BP) and cholesterol ratio. Data were collected through validated questionnaires, clinical and laboratory examination. Serum Neurofilament light chain (sNfL) levels were used as a proxy for ongoing brain damage in a subgroup of persons with non-active MS on high-efficacy treatment. Multiple regression analysis (MRA) models explored the relationship between lifestyle factors with the MSSS score and sNfL.
351 PwMS were included (43.04 ± 11.77 years, 69.8% female). Higher CR and PA were associated with a lower MSSS; overweight or obesity and higher systolic BP with a higher MSSS. The MRA model explained 22.2% of the variance for MSSS (R².255, adjusted R².222). Higher BMI and BP were related to lower sNfL. Twenty-3% (R².279, adjusted R².230) of the variance was explained in the MRA model for sNfL.
Our study suggests an association between a ‘brain healthy lifestyle’ with disability progression in MS. A cognitive and physical active lifestyle alongside a normal body weight and blood pressure may help to prevent future disability in MS. Longitudinal and interventional research is necessary to gain insight in the causal pathway of these risk factors in preventing disability progression in MS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study ...was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS.
This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS.
The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9).
In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.
