Background

Early treatment of multiple sclerosis (MS) provides significant long-term benefits. The aim of the Phase IIIb ENSEMBLE study (NCT03085810) is to evaluate the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Neurofilament light chain (NfL) is a marker of neuroaxonal injury. OCR reduced elevated NfL levels in patients with relapsing MS and primary progressive MS to those of healthy donors in the OPERA and ORATORIO studies over 96 weeks. NfL levels are assessed yearly in ENSEMBLE.

Objectives

To report 1-year NfL analyses from ENSEMBLE.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; Expanded Disability Status Scale [EDSS] score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients will receive OCR 600 mg every 24 weeks (first dose, 2×300 mg separated by 14 days) for the 192-week treatment period (maximum 8 doses). Serum NfL levels are measured via the Simoa Quanterix Advantage kit.

Results

A total of 582 patients were included in the NfL evaluation (female, 64.3%; mean [SD]: age, 32.4 [9.2] years; baseline EDSS, 1.70 [0.96]; time since MS symptom onset, 1.08 [0.84] years) with characteristics comparable with the overall population (N=678). The median serum NfL level at baseline was 13.20 pg/mL; 81.8% of patients had levels greater than healthy donors (HDs; 7.1 pg/mL). Median NfL levels at baseline in patients stratified by age, gender and EDSS score were consistent with those of the overall population. The highest median NfL levels at baseline were observed in patients with T1-weighted contrast-enhancing lesions (CELs) at screening (18.71 pg/mL; n=260) and relapses within 3 months of enrollment (14.91 pg/mL; n=217). At Week 48 the median serum NfL level was reduced to 6.35 pg/mL; 60.8% of patients had levels comparable to or lower than the HD level. Decreases in median serum NfL levels were observed, independent of the baseline demographics and disease characteristics of age, gender, EDSS score, CELs, relapses and reason for enrollment.

Conclusions

NfL levels at baseline and patterns of change over 48 weeks were in line with previous evaluations and decreased considerably after 1 year of treatment with ocrelizumab.

Background

The early detection and monitoring of cognitive and ambulatory dysfunction in multiple sclerosis (MS) may be enhanced with smartphone-adapted cognition and walking tests. Contrary to clinical measures, smartphone-based assessment allows more frequent measurements in the everyday environment, which potentially better reflects daily functioning.

Objectives

To determine the reliability, concurrent and ecological validity of self-administered smartphone-adapted Symbol Digit Modalities Test (SDMT) and Two-Minute Walking Test (2MWT).

Methods

Patients with MS were recruited. At baseline the SDMT and Timed 25-foot Walk Test (T25FW) were assessed clinically. During a 28-day follow-up, patients used the MS sherpa® app to perform the smartphone SDMT and 2MWT three times a week. The smartphone SDMT was assessed through tapping numbers corresponding to symbols on the smartphone during 90 seconds. The 2MWT measured walking distance utilizing the smartphone built-in sensors during two minutes of normal walking. Reliability of the smartphone tests were assessed by calculating intra-class correlation coefficients (ICC) between scores from week 2 and 3. Concurrent validity was addressed by calculation of correlation coefficients between the smartphone tests and their clinical counterparts. MS sherpa® also included one-item self-report scores for perceived fatigue and impact of MS on daily functioning. To assess ecological validity, the temporal association between the MS sherpa® tests and self-report scores from the everyday environment were analyzed using linear mixed models with the repeated measures as random effects.

Results

102 patients with MS were included. During the 28-day follow-up 102 patients completed a mean (± SD) of 12.1 (± 6.8) SDMTs and 74 patients completed a mean (± SD) of 8.8 (± 6.1) 2MWTs. Smartphone SDMT correlated significantly with the clinical SDMT (r = 0.607, p < 0.001) and demonstrated excellent reliability (ICC = 0.923). 2MWT was significantly correlated with T25FW (ρ = -0.352, p = 0.001) and demonstrated good reliability (ICC = 0.845). Over the 28-day period, higher 2MWT scores were related with lower perceived impact of MS on daily functioning (b = -0.005, 95% CI [-0.010, -0.001]) and higher SDMT scores were related with lower perceived fatigue (b = -0.014, 95% CI [-0.026, -0.003]).

Conclusions

Smartphone-adapted cognition and walking tests can be assessed frequently from the participants’ own environment and demonstrated validity and reliability in assessment of information processing speed and ambulatory function in MS. Support for ecological validity was found for perceived fatigue and impact on functioning in the everyday environment.

Background

Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.

Objectives

To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).

Methods

Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.

Results

Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).

Conclusions

Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.

Background

Typing behavior on a smartphone may be used as a biomarker in patients with multiple sclerosis (MS) by analyzing their keystroke dynamics (KD). The continuous acquisition of high sample rate data may provide unprecedented insights in short-term changes in important health outcomes in MS.

Objectives

To investigate the sensitivity of KD to clinically relevant change (i.e. responsiveness) in disease activity, fatigue, and clinical disability outcomes in patients with MS.

Methods

Patients with MS were recruited in this cohort study. Clinical outcomes were assessed at baseline and 3 months follow-up, including: MRI gadolinium-enhancing lesions (Gd-EL), patient-perceived fatigue, and clinical disability measures (Expanded Disability Status Scale, EDSS; Timed 25-foot Walk Test, TWT; Nine-Hole Peg Test, NHPT; Arm function in MS Questionnaire, AMSQ). Throughout the study, patients used the Neurokeys App which replaces the native keyboard with a smart-keyboard and unobtrusively collects time-stamped key press and release events in the real-world setting. Keystroke data of 14 days surrounding the clinical visits were aggregated for the analyses. The area under the receiver operating characteristics curve (AUROC) was calculated to assess responsiveness of KD in classifying anchor-based change within clinical outcomes. The minimally important change (MIC) was calculated as the mean change in KD in the lower +2 SD portion (to approximate minimal change) of patients with clinically relevant change for each clinical outcome. The MIC was compared to the smallest detectable change (SDC) to assess the capability of KD to distinguish important change from measurement error.

Results

102 patients with MS were included, of whom 94 completed follow-up. Responsiveness of KD were acceptable for change in number of MRI Gd-EL (highest AUROC = 0.73) and arm function based on the AMSQ score (highest AUROCs = 0.75). KD had excellent responsiveness to change in ambulatory function measured with TWT (highest AUROC = 0.84). EDSS and NHPT had lower AUC values than KD in classifying change in Gd-EL and AMSQ, respectively. For all keystroke features the MIC exceeded the SDC with differences ranging from 3.6 to 92.4%.

Conclusions

KD collected in patients with MS using the Neurokeys App demonstrated responsiveness to clinically relevant changes in gadolinium-enhancing lesions on MRI and clinical disability measures for arm and ambulatory function. Responsiveness of KD was higher than commonly used clinical measures in MS and sensitive enough to discriminate important change from measurement error.

Background

Myxovirus resistance protein A (MxA) is one of the proteins upregulated by interferon-beta. MxA mRNA level is often used in clinical practice to determine bioactivity of interferon-beta treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Lack of bioactivity is often due to the development of neutralizing antibodies against the drug. In 2010, we reported the association between spontaneous MxA mRNA level and clinical disease activity in multiple sclerosis (MS). Low levels of spontaneous MxA mRNA level were associated with contrast enhancing lesions (CELs) on baseline MRI, clinical relapses and a shorter time to first relapse. In the current study we assessed the long term data in the same cohort for the association between spontaneous MxA mRNA levels and clinical disease activity and disability.

Objectives

To investigate the association between spontaneous myxovirus resistance protein A (MxA) mRNA levels and disease activity in MS patients over a longer follow-up period.

Methods

Spontaneous MxA mRNA levels were determined in a previously described cohort of 116 patients diagnosed with a clinically isolated syndrome (CIS) or with a recent diagnosis of RRMS, and related to clinical scores (Expanded Disability Status Scale (EDSS), timed-25-foot walk (T25FW), 9-hole-peg test (9HPT)), and MS type over a long follow-up. MRI-imaging was performed at baseline and during follow-up to assess the development of new T2-lesions and CELs.

Results

116 patients where included in the analyses. 74 (63.8%) were female. At baseline, 67 patients (57.8%) were diagnosed with RRMS and 49 (42.2%) with a CIS. Median follow-up duration was 10.76 years (IQR 69.52-148.50 months). Median EDSS at follow-up was 3.0. Spontaneous MxA mRNA level was not associated with EDSS, T25FW and 9HPT, and MS subtype at follow-up. 89.7% of patients ever experienced MRI-activity during follow-up. Low spontaneous MxA mRNA levels were associated with the occurrence of more T2-lesions on MRI imaging during follow-up in patients with a small number of T2-lesions (<9 lesions) on baseline MRI (B=-1.595, p=0.029).

Conclusions

Baseline spontaneous MxA mRNA level is associated with the development of new T2-lesions on MRI during long-term follow-up and, if confirmed in other populations, has a potential value as a predictive biomarker for long-term inflammatory disease activity in MS.

Background

The Guy’s Neurological Disability scale (GNDS) and the Multiple Sclerosis Impact Scale (MSIS-29) are patient reported outcome measures (PROMs) which can serve as a proxy for measuring disability and impact in patients with diagnosed multiple sclerosis (pwMS). In times of increased interest for telemedicine such measures are important.

Objectives

The aim of this study was to investigate correlations between two multi-domain PROMs and often used clinical outcome measures.

Methods

248 MS patients were assessed using the GNDS, the physical part of the MSIS-29 (MSIS-phys), the Expanded Disability Status Scale (EDSS), the 9-hole peg test (9-HPT) and the Timed 25-foot walk test (T25WT) at baseline (BSL) and follow-up (FU) with a mean of 6.4 years. Cross-sectional and longitudinal correlations were studied between the overall scores and specific subcategories of the PROMs and clinical outcome measures. Additionally, the relationship between clinically significant changes in the PROMs and clinical outcomes were studied. We defined a clinically significant change of three or more points on the GDNS, eight or more points on the MSIS-phys and one point or more on an EDSS score <5.5 and one-half point or more on an EDSS score ≥5.

Results

Strong cross-sectional correlations were found between the “legs” domain of the GNDS and the pyramidal functional system (p-FS) of the EDSS (Rbsl(247)=.55, p<0.001; RFU(238)=.77, p<0.001) and the T25WT (RBSL(247)=.56, p=0.000; RFU(233)=.77, p<0.001) especially in progressive patients (PPMSbsl R(34)=.76, p<0.001; PPMSFU R(26)=.86, p<0.001, SPMSBSL R(21)=.61, P=0.003; SPMSFUR(34)=.82, p<0.001). The MSIS-phys also showed strong correlations compared to the p-FS of the EDSS RBSL(162)=.59, p<0.001; RFU(236)=.70, p<0.001) and T25WT RBSL(162)=.61, p<0.001; RFU(231)=.61, p<0.001). Only good correlations were found between the MSIS-phys and T25WT in RRMS patients (RBSL(114)=.45, p<0.001; RFU(172)=.54, p<0.001).

Longitudinal correlations for the global GNDS/MSIS-phys and EDSS/MSFC were relatively poor except for changes on the leg domain of the GNDS in relation to changes on the T25WT (R(231)=.58, p<0.001), especially in PPMS patients (R(25)=.68, p<0.001). In the majority of cases a clinically significant deterioration on the EDSS also resulted in a clinically significant worsening of the GDNS and MSIS-phys.

Conclusions

The GNDS and MSIS-phys correlate well with clinical outcome measures for physical disability. The GNDS in particular, for the lower limb function in progressive patients. PROMs are easy to apply, less-time consuming and are a more cost-effective way of capturing patients’ disability.

Background

Early treatment of multiple sclerosis (MS) has been shown to provide significant long-term benefits in terms of Expanded Disability Status Scale (EDSS) score versus delayed treatment (patients switching from placebo to active treatment). ENSEMBLE (NCT03085810) is a Phase IIIb study evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting multiple sclerosis (RRMS). Assessments of effectiveness in ENSEMBLE include composite endpoint measures, e.g. the proportion of patients with no evidence of disease activity (NEDA).

Objectives

To report ENSEMBLE 1-year interim NEDA rates.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; EDSS score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients received OCR 600 mg every 24 weeks (first dose 2×300 mg separated by 14 days) throughout the 192-week (4-year) treatment period (max 8 doses). Clinical assessments will be conducted every 24 weeks. NEDA is defined as absence of: protocol-defined relapses (PDRs), 24-week confirmed disability progression (24W-CDP), T1-weighted contrast-enhancing (CEL) and new/enlarging T2-weighted (T2w) lesions. The effects of OCR are not immediate. MRI measures were re-baselined at Week 8 (prespecified) so that the calculation of NEDA would reflect a more accurate treatment effect.

Results

A total of 678 patients (female, 64.6%) were enrolled (74.6% of patients based on the presence of reasons of both MS relapse and MRI activity) and analyzed. Baseline demographics and disease characteristics reflected a population with early-stage disease (mean [SD]: age, 32.4 [9.1] years; baseline EDSS, 1.71 [0.95]; time since RRMS diagnosis, 0.36 [0.40] years; time since MS symptom onset, 1.10 [0.84] years). At Week 48 most patients (84.8% [n/N=545/643]) reached NEDA. Most patients were free of PDR (98.1%), 24W-CDP (94.1%), CEL (94.2%; re-baselined) and new/enlarging T2w (95.2%; re-baselined) lesions. NEDA calculated without MRI re-baselining was achieved by 62.1% of patients (n/N=404/651). Safety results were consistent with prior studies.

Conclusions

In ENSEMBLE, the Year 1 NEDA rate with MRI re-baselining was high (84.8%) in patients with early-stage disease. No new safety signals were observed.

Background

Natalizumab is an effective disease-modifying therapy for relapsing remitting multiple sclerosis (RRMS). However, natalizumab trough concentrations remain high in a treatment regimen of 4-weekly infusions in 85% of patients. Previous studies showed that patients on extended interval dosing (EID) of natalizumab had comparable disease activity to standard interval dosing (SID) and a decreased risk of progressive multifocal leukoencephalopathy.

Objectives

To validate the maintenance of efficacy, measured by radiological disease activity, of personalized EID of natalizumab based on natalizumab trough concentrations. Feasibility of further extending intervals up to trough concentration of 5 μg/ml will be studied in a subgroup.

Methods

In this national multicenter prospective study (ClinicalTrials.gov Identifier: NCT04225312), 300 patients diagnosed with RRMS that received ≥ 6 consecutive natalizumab infusions will be included. Patients will be included in the main personalized EID group (aimed trough concentration 10 μg/ml), the low EID group (trough 5 μg/ml) or the SID group. Follow-up is two years with an extension phase of two years with annual MRI brain scans and 6 monthly scans for patients in the low EID group. Questionnaires will be filled in yearly by all participants.

Results

Inclusion of patients started in February 2020. Participants will be included in 22 centers in The Netherlands. So far, 69 patients were included, of whom 19 in the main EID group, showing natalizumab trough concentrations at baseline of 18.5 μg/ml (IQR 9.2 to 30.0). Current treatment intervals are 4 weeks (n=5), 5 weeks (n=5), 6 weeks (n=8) or 7 weeks (n=1). In the low EID group (n=37), natalizumab trough concentrations at baseline were 15.0 μg/ml (IQR 10.3 to 21.8). Current treatment intervals are 4 weeks (n=2), 5 weeks (n=8), 6 weeks (n=17) or 7 weeks (n=10). In the SID group (n=13), natalizumab trough concentrations at baseline were 18.0 μg/ml (IQR 14.5 to 26.0). Wearing-off symptoms were present in 33.9% of participants at baseline. No signs of radiological or clinical disease activity were present during follow-up so far.

Conclusions

Personalized extended interval dosing of natalizumab based on trough concentrations has the potential to become a safe, standardized treatment for RRMS patients using natalizumab. Final results of this study are expected in January 2024.

Background

Ocrelizumab (OCR) is an intravenously administered anti-CD20 antibody approved for relapsing and primary progressive multiple sclerosis (MS). Shortening the infusion duration to 2hrs reduces the total site stay (including mandatory pre-medication/infusion/observation) from 5.5–6hrs, to 4hrs, which may reduce patient and site staff burden.

Objectives

ENSEMBLE PLUS aims to investigate the safety and tolerability of OCR when administered over a shorter infusion time.

Methods

ENSEMBLE PLUS is a randomized, double-blind substudy to the ENSEMBLE study (NCT03085810). In ENSEMBLE, treatment-naïve patients with active, early-stage relapsing-remitting MS (18–55 years; disease duration ≤3 years; EDSS score 0–3.5) receive OCR 600mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR (600mg) administered over the approved infusion time (3.5hrs; conventional duration), was compared with a 2hr infusion (shorter duration); the infusion duration of the initial 2×300mg dose was unaffected. The frequency and severity of infusion-related reactions (IRRs) were assessed during and 24hrs post-infusion. The ENSEMBLE PLUS primary endpoint was the proportion of patients with IRRs at the first Randomized Dose.

Results

In total, 373 and 372 patients were randomized to the conventional and shorter infusion groups, respectively. At the first Randomized Dose, 99 patients (26.5%) in the conventional and 107 (28.8%) in the shorter infusion group had IRRs (difference in proportions, stratified estimates [95% CI]: 2.4% [-3.8, 8.7]); most common symptoms during the infusion were throat irritation, dysphagia and ear pruritus, whilst 24hrs post-infusion were fatigue, headache and nausea. IRRs led to infusion slowing/temporary interruption in 22 patients (5.9%) in the conventional and 39 (10.5%) in the shorter infusion group. The majority of IRRs were mild or moderate. Across all Randomized Doses, four severe (Grade 3) IRRs occurred in total, one in the conventional and three in the shorter infusion group. Overall, >99% of IRRs resolved without sequelae in both groups. No IRRs were serious, life-threatening or fatal; no IRR-related discontinuations occurred. Adverse events (AEs) and serious AEs were consistent with the known OCR safety profile.

Conclusions

Frequency and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shorter ocrelizumab infusions reduce the infusion site stay, thus may reduce patient and staff burden.

Background

Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.

Objectives

To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.

Methods

All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.

Results

Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.

Conclusions

A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.

Background

Detecting factors that influence disease variability in MS patients is crucial to provide novel insights into the etiology of the disease and guide the search for effective therapies. To study the phenotypic variability, well-defined unbiased cohort studies are necessary. The most common and arguably most important variable to be considered as a confounding factor when studying variability of disease course in MS, is age.

Objectives

To identify determinants that explain phenotypic variability in MS, while eliminating the undesirable effect of age variation between MS patients.

Methods

Project Y is an ongoing population-based cross-sectional study of all people with MS born in the Netherlands in 1966. Participants are subjected to extensive examinations of a wide array of potential determinants and outcome measures: functional and static imaging, biomarkers in body fluid, physical and cognitive measurements, and lifestyle factors early and later in life. Age and sex matched controls are included.

Results

As for July 2020, a total of 386 eligible MS patients were identified, of which 31 refused to participate and 86 patients awaiting inclusion. Thirteen patients had passed away prior to study inclusion. Between December 2017 and July 2020, 269 MS patients participated with either a full or partial data collection, together with 125 healthy controls. The total number of identified cases (386) results in a prevalence of at least 1.7/1000 in the birth year 1966.

Conclusions

The first preliminary data of our unique cohort indicate that the previously presumed prevalence of MS in the Netherlands (1/1000) is a serious underestimation of the actual prevalence.

Background

Natalizumab is a widely used treatment option for patients with relapsing-remitting multiple sclerosis (RRMS). Identifying characteristics of patients discontinuing natalizumab treatment and reasons for discontinuation could help improve clinical decision making regarding natalizumab treatment in multiple sclerosis (MS).

Objectives

To determine characteristics of RRMS patients that discontinued natalizumab treatment in a Dutch real-world cohort.

Methods

Data were collected from an ongoing observational cohort study of all natalizumab treated patients in the Amsterdam UMC. Standard clinical parameters, total number of natalizumab infusions, reasons for discontinuation and therapies the patients switched to after discontinuation of natalizumab were collected.

Results

254 patients have ever received natalizumab treatment in our cohort, of which 148 patients stopped treatment. Mean age at discontinuation of natalizumab was 40.2 years, and 65.8% was female. Patients received an average of 68 infusions. Median treatment duration with natalizumab was 4.77 years. Mean Expanded Disablity Status Scale (EDSS) was similar at the start and stop of natalizumab treatment. The majority of patients (109 in total (73.6%)) stopped natalizumab treatment solely due to JC virus (JCV) positivity. Eight patients (5.4%) discontinued due to progression of MS, 3 (2.0%) due to pregnancy, 12 (8.1%) due to an allergic reaction or antibodies, 2 (1.4%) due to side effects, 4 (2.7%) due to the patients preference for another therapy, 3 (2.0%) due to clinical stabilisation and the remaining 7 patients (4.7%) due to other reasons. Most patients switched to another type of disease modifying therapy (DMT) after natalizumab discontinuation. Patients most frequently switched to fingolimod (76 patients (51.4%)) or ocrelizumab (26 patients (17.6%)) after discontinuation of natalizumab. Fourteen patients (9.5%) did not start another DMT after natalizumab discontinuation. Thirty-nine patients (26.4%) switched a second time to a different DMT and 19 patients (12.8%) stopped DMT after an initial switch.

Conclusions

Our results suggest JCV positivity to be the most frequent reason for natalizumab discontinuation. The heterogeneity in treatment switches suggests individual treatment plans are frequently present in MS. Recognising reasons for treatment discontinuation and treatment decisions made in our patient cohort can be helpful in future clinical decision making.

Background

More than 80% of multiple sclerosis (MS) patients experience symptoms of fatigue. MS-related fatigue can only partly be explained by structural (lesions and atrophy) and functional (brain activation and conventional static functional connectivity) brain changes.

Objectives

To investigate the relationship of dynamic functional connectivity (dFC) with present and future fatigue in MS patients and compare this with commonly used clinical and MRI parameters.

Methods

In 35 relapsing-remitting MS patients (age: 42.8, female/male: 20/15, disease duration: 11 years) and 19 healthy controls (HC) (age: 41.4, female/male: 11/8), fatigue was measured using the CIS-20r questionnaire at baseline and at a 6-month follow-up. Furthermore, disability (EDSS) was assessed for patients. All subjects underwent structural MRI and resting-state functional MRI at baseline. We calculated global static functional connectivity (sFC) and assessed dynamic connectivity using a tapered sliding-window approach by calculating the summed difference (diff) and coefficient of variation (cov). Moreover, we calculated connectivity between basal ganglia and cortical regions previously associated with fatigue in MS (medial prefrontal cortex, posterior cingulate cortex, and precuneus). We performed hierarchical regression analyses with forward selection to identify the most important predictors of fatigue at baseline and follow-up.

Results

Patients were more fatigued than HCs at baseline (MS: 74.36 ± 29.33; HC: 46.72 ± 17.06; p=0.001) and follow-up (MS: 69.91 ± 27.01; HC: 45.11 ± 19.84; p=0.002). No difference in sFC was found between patients and controls. Patients had higher baseline global dFC than controls (p<0.05) but no difference in basal ganglia-cortical dFC. Basal ganglia-cortical dFC-cov added 12.5% extra explained variance (standardized β=-0.353, p=0.032) on top of EDSS (standardized β=0.380, p=0.022) to a regression model for baseline fatigue in patients (adjusted R²=0.211, p=0.011). Post-hoc analysis revealed lower basal ganglia-cortical dFC-cov in patients with severe fatigue at baseline (0.89 ± 0.06) compared to non-fatigued patients (0.93 ± 0.05; p=0.036).

Conclusions

Less dynamic connectivity between the basal ganglia and the cortex is associated with greater fatigue in MS patients, independent of disability status. These findings may reflect less efficient network reconfigurations of those connections as a potential additional neural correlate of fatigue in MS.

Background

Both upper and lower limb disability is common in multiple sclerosis (MS), but do not always occur together, suggesting partially independent underlying mechanisms. Physical disability strongly relates to brain network disturbances in MS, yet network mechanisms underlying upper and lower disability progression remain unclear.

Objectives

To investigate the relationship between upper and lower limb progression and functional sensorimotor network changes in MS.

Methods

Longitudinal data was included from a prospectively acquired cohort, with baseline data collected between 2008 and 2012 and follow-up assessments between 2014 and 2017. Participants underwent MRI and dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) tests at baseline and after 5 years. Patients were stratified into progressors (>20% decline) or non-progressors for both tests. Measures of network efficiency were calculated from resting-state functional MRI data using both static (i.e. calculated on the entire scan) and dynamic (i.e. fluctuations during the scan) approaches and compared between patient groups. Multiple logistic regression was used to identify independent predictors of upper and lower limb progression and baseline connectivity patterns.

Results

This study included 214 people with MS (age 47±11; 149 women) and 58 healthy controls (age 46±10; 31 women). Compared to respective non-progressors, upper limb progression (n=24) was related to higher dynamic efficiency of the right premotor cortex, somatosensory cortex and thalamus, while lower limb progression (n=37) was related to higher dynamic efficiency of the right supplementary motor area at baseline (p<0.05). Logistic regression showed that dynamic efficiency of the thalamus and supplementary motor area best predicted upper and lower limb progression respectively, independent of the severity of structural damage (p<0.01). Both areas displayed widespread higher dynamic connectivity in progressing compared to non-progressing patients at baseline (p<0.05).

Conclusions

Disability progression can be predicted by the severity of fluctuations (i.e. higher dynamics) in the efficiency of the sensorimotor network. The dynamic behavior of the thalamus and supplementary motor area were respectively related to upper and lower limb progression, possibly indicating different mechanisms underlying these types of progression in MS.

Background

Natalizumab is an effective disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Nine confirmed cases of PML have been reported in patients using ocrelizumab, another effective DMT for MS. In 8 cases, patients previously used natalizumab or fingolimod, likely causing PML. This phenomenon has been described as carry-over PML.

Objectives

To describe the disease course of carry-over PML after switching from natalizumab to ocrelizumab in two patients with RRMS.

Methods

Two case reports with 1 year of follow-up and retrospective longitudinal measurements of serum neurofilament light (sNfL) levels and B-cell count. Both patients provided informed consent.

Results

Regular follow-up showed no disease activity under natalizumab treatment and both patients switched to ocrelizumab following a stringent safety protocol including two additional MRI brain scans and cerebrospinal fluid (CSF) analysis. Both patients received a single infusion of 300 mg ocrelizumab before PML diagnosis. PML was diagnosed ±11 weeks (case 1) and ±13 weeks (case 2) after the last natalizumab infusion. At that time, both patients were asymptomatic. In retrospect, subtle signs suggestive of PML were already present on MRI under natalizumab treatment. One patient developed PML despite extended interval dosing of natalizumab. Both patients developed mild immune reconstitution inflammatory syndrome (IRIS) despite complete B-cell depletion. SNfL levels were 9.9 pg/ml (reference range 1-15 pg/ml) for case 1 and 16.7 pg/ml (reference range 2-18 pg/ml) for case 2 at the time of PML diagnosis and increased to 15.0 pg/ml and 36.5 pg/mL during PML-IRIS. SNfL was not elevated before radiological diagnosis of PML. PML-IRIS lesions stabilized after treatment with mefloquine and mirtazapine followed by methylprednisolone with sNfL levels of 9.0 pg/mL and 12.3 pg/mL, respectively. One patient reported no clinical symptoms and one patient only mild clinical symptoms with full recovery during the disease course of PML-IRIS. Both patients continued with ocrelizumab when B-cells started to repopulate ±10 months after the first ocrelizumab infusion.

Conclusions

The clinical course of carry-over PML was mild in both patients, suggesting that B-cell depletion did not aggravate PML-IRIS in these two patients.