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

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

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

Clinical disability in multiple sclerosis (MS) is insufficiently explained by structural damage as measured with standard magnetic resonance imaging (MRI) measures. More advanced measures of brain network atrophy and functional network changes might better explain symptoms and clinical deterioration.

Objectives

To investigate the relevance of functional network alterations in addition to network atrophy for explaining physical disability in MS.

Methods

In this cross-sectional study 143 MS patients and 36 healthy control participants underwent resting-state magnetoencephalography (MEG) and structural MRI. Functional connectivity between regions was estimated using the phase lag index, from which the minimum spanning tree (MST) was constructed, representing the backbone of the functional network. The topology of the MST was described using the so-called tree hierarchy (MST-Th). Gray matter (GM) volume was calculated within literature-based resting-state network maps (i.e. visual, sensorimotor, dorsal attention, ventral attention, limbic, fronto-parietal, default mode, deep gray matter, and cerebellar networks). Physical disability was quantified with the Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (9HPT) and Timed 25-Foot Walk Test (TWT). Network atrophy and topology were compared between groups and related to disability.

Results

Atrophy was apparent in all resting-state networks. All volumes correlated positively (p<.001) with EDSS and 9HPT: Spearman’s ρ between .289 and .567, highest correlations for sensorimotor, default mode, fronto-parietal and dorsal attention networks. EDSS correlated negatively with MST-Th in the lower alpha band (α1) (p < 0.008), while 9HPT correlated negatively with MST-Th in the upper and lower alpha, gamma, delta and theta bands (p <0.05), indicating a less efficient network relating to worse disability. TWT was related to atrophy in all networks, but not network topology. Together, MST-Th-α1, age, cerebellar and fronto-parietal atrophy explained 36% of EDSS variance, while 19% of 9HPT variance was explained by deep GM atrophy and MST-Th-α1. Lesion volume had no added significant effect on variance.

Conclusions

These results suggest that more advanced measures of network atrophy and functional network topology can explain a significant degree of disability variance in MS. In addition, mobility scores were not related to network changes, which could imply different underlying pathological substrates compared to those that underlie upper limb dexterity.

Background

Eye movement is controlled by a widespread network of cortical and subcortical areas, the oculomotor brain network, thus accurate measurement of these movements could represent a non-invasive method to reflect (dys)functioning of these interconnected areas. This is especially relevant for diseases in which network disruption is known to represent a key pathological feature, as in multiple sclerosis (MS).

Objectives

To investigate the association between saccadic eye movements and functional connectivity of the oculomotor brain network in patients with MS.

Methods

Subjects were included from the prospective Amsterdam MS cohort. A validated standardized infrared oculography protocol (DEMoNS) was used for quantifying pro-saccades and anti-saccades (reflexive and voluntary saccadic eye movements, respectively). After resting-state magnetoencephalography (MEG) measurement, data pre-processing and beamforming of the MEG data to source space, 73 oculomotor regions of the Brainnetome atlas were included based on previous literature (i.e. the FOcuS atlas). The phase lag index (PLI) was used as a measure of functional connectivity (FC) between all regions within the oculomotor network (and it’s subnetworks) for the six conventional frequency bands. The relationship between saccadic parameters and mean FC was analyzed using multivariate linear regression models adjusted for sex, age and disease type. Effect size modification by sex was additionally investigated.

Results

The 183 included patients with MS showed altered saccadic eye movements compared to the 58 included healthy controls. Regarding pro-saccades, worse saccadic eye movement performance was mainly related to a higher FC in theta and gamma bands and a lower connectivity in alpha and beta bands. Strongest relations with FC were found for peak velocity and the parietal eye field (theta band, β -2.1 E-4, p=0.006), gain and the precuneus (gamma band, β -1.3 E-4, p=0.003) and gain and the inferior frontal eye field (theta band, β -21.0 E-4, p<0.001). For anti-saccades, the strongest associations were found between the proportion of errors and the thalamus (beta band, β 8.0 E-4, p=0.006) and error of the final eye position and the precuneus (theta band, β -6.2 E-4, p=0.004). For female MS patients the proportion of errors was also strongly related to the supplementary eye field (gamma band, β 6.4 E-4, p=0.003) and for male patients the latency of a correct response to the cingulate eye field (delta band, β 5.3 E-4, p=0.006).

Conclusions

Saccadic eye movements were related to altered functional connectivity of fronto-parietal brain regions and the thalamus in patients with MS. Furthermore, there was evidence for a relevant sex difference in patterns of functional damage of the oculomotor brain network. This network approach provides an additional backing for the future use of eye movement measurement as an easy applicable tool for monitoring or predicting the disease 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.