Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

Discontinuation of first-line disease-modifying therapy in relapse onset multiple sclerosis.

BACKGROUND: It is not known if and when first-line disease modifying therapy (DMT) can safely be discontinued in relapse onset multiple sclerosis (MS) patients. OBJECTIVES: To investigate the characteristics of patients who discontinued first-line DMT, and the occurrence of clinical and radiological inflammatory disease activity after discontinuation. METHODS: We collected clinical and MRI parameters from patients with relapse onset MS in the MS Center Amsterdam and Rijnstate Hospital Arnhem who discontinued first-line DMT with no intention of restarting or switching treatment. RESULTS: In total, 130 patients were included in the analyses. After discontinuation, 78 patients (60%) experienced disease activity. Sixty-three patients (48.5%) showed MRI activity after DMT discontinuation, 40 patients (30.8%) experienced relapse(s), and 29 patients (22.3%) restarted DMT. Higher age at DMT discontinuation was associated with a lower risk of MRI activity (45 -55 vs. <45 years: OR 0.301, p = 0.007, >55 vs. <45 years, OR: 0.296, p = 0.044), and with a lower risk of relapse(s) after discontinuation (45-55 vs. <45 years: OR=0.495, p = 0.106, >55 vs. <45 years: OR=0.081, p = 0.020). CONCLUSION: Higher age at first-line DMT discontinuation is associated with lower risk and severity of radiological disease activity in MS, and a lower risk of relapse(s) after discontinuation.

Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon ß-1a.

OBJECTIVE: Evaluate the effect of subcutaneous interferon ß-1a (sc IFN ß-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). METHODS: Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN ß-1a 44 µg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. RESULTS: In patients not converting to CDMS, sc IFN ß-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P < 0.001 and P = 0.005) and new T1 iso-intense lesions (P < 0.001 and P = 0.002) after 24 months; only sc IFN ß-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P < 0.001). PVVC findings in patients treated with sc IFN ß-1a suggested pseudo-atrophy that was ~ fivefold greater versus placebo in the first year of treatment (placebo 1.11%; qw 4.28%; tiw 6.76%; P < 001); similar findings were apparent for non-converting patients. CONCLUSIONS: In patients with an FCDE, treatment with sc IFN ß-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

The prevalence of internuclear ophthalmoparesis in a population-based cohort of individuals with multiple sclerosis.

BACKGROUND: Internuclear ophthalmoparesis (INO) occurs in 15-52% of individuals with multiple sclerosis (MS) and is reliably detected by infrared oculography. Methods for diagnosing INO with infrared oculography and the association between INO and MS characteristics need confirmation. We aimed to describe INO prevalence and the clinical characteristics of individuals with MS and INO in a population-based cohort of individuals with MS born in the year 1966 (Project Y). METHODS: Previously described thresholds for the versional dysconjugacy index (VDI), assessed with standardized infrared oculography, were used to detect INO in participants of project Y. Clinical characteristics, visual functioning and complaints were compared between individuals with MS with INO and individuals with MS without INO. RESULTS: Two-hundred-twenty individuals with MS and 110 healthy controls were included. VDI values exceeding the threshold for INO presented in 53 (24%) individuals with MS and 19 controls (13%). INO was associated with male sex, greater disability, worse cognition and worse arm function in individuals with MS. There was no association with disease duration, visual functioning or complaints. CONCLUSIONS: INO is prevalent among individuals with MS aged fifty-three and related to clinical characteristics of MS. INO was more frequently detected in healthy controls than previous studies, implying that oculography based diagnosis of INO requires further refinement.

Cross-sectional and longitudinal correlations between the Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and other outcome measures in multiple sclerosis.

BACKGROUND: The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) is the first validated disease specific patient-reported outcome measure (PROM) designed to assess upper extremity function in patients with multiple sclerosis (MS). OBJECTIVE: To determine correlations between the AMSQ and established physician- and performance based outcome measures. METHODS: In a cross-sectional cohort of 533 patients correlations between the AMSQ and the Expanded Disability Status Scale (EDSS), its functional systems, the 9-Hole Peg Test (9-HPT) and the Timed-25 Foot Walk (T25FW) were determined. Subgroup analyses were performed as well. Also, correlations were determined in 110 of 533 patients with available longitudinal data. RESULTS: Strongest correlations were found in the cross-sectional cohort between the AMSQ and the EDSS (ß 0.60, p<.001), the 9-HPT dominant hand (ß 0.52, p<.001) and 9-HPT non-dominant hand (ß 0.46, p<.001), the Pyramidal (ß 0.57 p<.001) and the Cerebellar functional system (ß 0.54, p<.001) of the EDSS. CONCLUSION: The moderate correlations between the AMSQ and several established physician- and performance based outcome measures underline that the AMSQ, an easily at long-distance administrable PROM, could be considered as a reliable outcome measure for the monitoring of MS in daily practice. Additional research is needed to support these findings.

The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) who are treated with monoclonal antibodies frequently report an increase of MS-related symptoms prior to the next dose known as the wearing-off phenomenon. The objective of this study was to assess the prevalence and predicting factors of the wearing-off phenomenon in patients with MS using ocrelizumab. METHODS: This was a prospective cohort study in patients with MS receiving ocrelizumab ≥1 year. Most participants received B-cell guided personalized extended interval dosing to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Participants completed questionnaires during ocrelizumab infusion and 2 weeks thereafter. Demographics, clinical and radiological characteristics, CD19 B-cell counts, and serum neurofilament light (sNfL) levels were collected. Data were analyzed using logistic regression analyses. RESULTS: Seventy-one (61%) out of 117 participants reported the wearing-off phenomenon during ocrelizumab treatment. The most frequently reported symptoms were fatigue, cognitive disability and sensory symptoms. Wearing-off symptoms started < 1 week (11%), 1-4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion. Fifty participants (43%) reported a current wearing-off phenomenon at the first questionnaire. Higher body mass index (threshold BMI ≥ 25) increased the odds of reporting a current wearing-off phenomenon (OR 2.70, 95% CI 1.26 to 5.80, p = .011). Infusion interval, EDSS score, MRI disease activity, clinical relapses, CD19 B-cell counts, and sNfL levels were no predictors. Disappearance of the wearing-off phenomenon occurred in the first week after ocrelizumab infusion in most participants. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Reporting the wearing-off phenomenon did not influence treatment satisfaction. Forty of 109 participants (37%) reported post-infusion symptoms, such as fatigue, flu-like symptoms or walking difficulties. These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks. CONCLUSIONS: The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab. Only BMI was identified as a predicting factor. The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts. The wearing-off phenomenon of ocrelizumab therefore does not seem to reflect suboptimal control of MS disease activity.

Retinal inter-eye difference and atrophy progression in multiple sclerosis diagnostics.

BACKGROUND: The visual system could be included in the diagnostic criteria for multiple sclerosis (MS) to demonstrate dissemination in space (DIS) and dissemination in time (DIT). OBJECTIVE: To investigate the diagnostic value of retinal asymmetry in MS. METHODS: A prospective, longitudinal study in individuals with MS (n=151) and healthy controls (n=27). Optical coherence tomography (OCT) was performed at 0, 2 and 4 years. Macular ganglion cell and inner plexiform layer (mGCIPL) thickness was determined as well as measures for retinal asymmetry: the inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD). Receiver operator characteristics curves were plotted and the area under the curve (AUC) was calculated for group comparisons of the mGCIPL, IEPD, IEAD and atrophy rates. RESULTS: The diagnostic accuracy of both the IEPD and IEAD for differentiating bilateral and unilateral MS optic neuritis was high and stable over time (AUCs 0.88-0.93). The IEPD slightly outperformed the IEAD. Atrophy rates showed low discriminatory abilities for differentiating MS from controls (AUC 0.49-0.58). CONCLUSION: The inter-eye differences of the mGCIPL have value for demonstration of DIS but in individuals with longstanding MS not for DIT. This may be considered as a test to detect DIS in future diagnostic criteria. Validation in a large prospective study in people presenting with symptoms suggestive of MS is required.

Impaired saccadic eye movements in multiple sclerosis are related to altered functional connectivity of the oculomotor brain network.

BACKGROUND: Impaired eye movements in multiple sclerosis (MS) are common and could represent a non-invasive and accurate measure of (dys)functioning of interconnected areas within the complex brain network. The aim of this study was to test whether altered saccadic eye movements are related to changes in functional connectivity (FC) in patients with MS. METHODS: Cross-sectional eye movement (pro-saccades and anti-saccades) and magnetoencephalography (MEG) data from the Amsterdam MS cohort were included from 176 MS patients and 33 healthy controls. FC was calculated between all regions of the Brainnetome atlas in six conventional frequency bands. Cognitive function and disability were evaluated by previously validated measures. The relationships between saccadic parameters and both FC and clinical scores in MS patients were analysed using multivariate linear regression models. RESULTS: In MS pro- and anti-saccades were abnormal compared to healthy controls A relationship of saccadic eye movements was found with FC of the oculomotor network, which was stronger for regional than global FC. In general, abnormal eye movements were related to higher delta and theta FC but lower beta FC. Strongest associations were found for pro-saccadic latency and FC of the precuneus (beta band ß = -0.23, p = .006), peak velocity and FC of the parietal eye field (theta band ß = -0.25, p = .005) and gain and FC of the inferior frontal eye field (theta band ß = -0.25, p = .003). Pro-saccadic latency was also strongly associated with disability scores and cognitive dysfunction. CONCLUSIONS: Impaired saccadic eye movements were related to functional connectivity of the oculomotor network and clinical performance in MS. This study also showed that, in addition to global network connectivity, studying regional changes in MEG studies could yield stronger correlations.

The use of multi-domain patient reported outcome measures for detecting clinical disease progression in multiple sclerosis.

OBJECTIVE: Patient reported outcome measures (PROMs) are especially relevant in times of increased interest in telehealth but little is known about their relation to functional disability measures. METHODS: We assessed 248 people with MS at baseline and at > = 5-years follow-up. We investigated cross-sectional and longitudinal correlations between changes in the Guy's Neurological disability scale (GNDS), and the physical part of the Multiple Sclerosis Impact Scale (MSIS-29) and the Expanded Disability Status Scale (EDSS), 9-hole peg test (9-HPT) and timed 25-foot walk (T25FW). RESULTS: The strongest cross-sectional correlations were found between the GNDS and EDSS in the complete cohort (r = 0.66, p <.001, n = 248) as well as in progressive patients (r = 0.72, p <.001, n = 35), and the GNDS and T25FW in progressive MS (r = 0.64, p <.001, n = 34). Longitudinal correlations were poor except for changes on the leg domain of the GNDS in relation to T25FW changes in progressive MS (r = 0.68, p <.001, n = 26). In the majority of cases a clinically significant deterioration on the EDSS also resulted in a clinically significant worsening of the GDNS and MSIS. CONCLUSION: Both PROMs correlate well with physical disability outcomes, and seem suitable for detecting changes in lower limb function in progressive MS. The GNDS has a higher agreement with EDSS progression than the MSIS-physical.

Saccadic delay in multiple sclerosis: A quantitative description.

In multiple sclerosis (MS), eye movement disorders are common and can be quantified with infrared video-oculography. A well-known abnormality is internuclear ophthalmoplegia (INO). This study aims to describe saccadic abnormalities beyond INO and investigate their clinical relevance. A validated standardized infrared oculography protocol, DEMoNS, was used for quantifying saccadic eye movements in three different tasks in MS patients and healthy controls. The relationship between the saccadic parameters and disease characteristics was investigated. Furthermore, the association between saccadic parameters and visual functioning was analysed using logistic regression models, adjusted for possible confounders. This cross-sectional study included 218 subjects with MS and 58 healthy controls. The latency of all saccades was longer in MS patients than in healthy controls. This saccadic delay was larger in subjects with a longer disease duration and more disabled subjects. Furthermore, it was significantly related to presence of a lower vision-related quality of life. This study provided a comprehensive overview of performance of MS patients in different saccadic tasks, compared to healthy controls. Saccadic delay in MS patients was present in all saccadic tasks and was related to advancing disease and visual functioning in daily life.

Objective quantification of vitreous haze on optical coherence tomography scans: no evidence for relationship between uveitis and inflammation in multiple sclerosis.

BACKGROUND AND PURPOSE: The occurrence of intermediate uveitis, which is characterized by the presence of vitreous haze (VH), in patients with multiple sclerosis (MS) may be a sign of coexistent inflammatory central nervous system (CNS) disease activity. Using an automated algorithm to quantify VH on optical coherence tomography (OCT) scans, the aim was to investigate whether VH in MS patients is associated with signs of inflammatory CNS disease activity. METHODS: Vitreous haze was quantified on OCT macular volume scans of 290 MS patients and 85 healthy controls (HCs). The relationship between VH and clinical, retinal OCT and magnetic resonance imaging parameters of inflammatory disease activity was investigated using generalized estimating equations. RESULTS: Mean VH scores did not differ between patients and HCs (P = 0.629). Six patients (2.1%) showed values higher than the highest of the controls by HCs. VH scores did not differ between the different disease types or between eyes with and without a history of optic neuritis (P = 0.132). VH was not associated with inner nuclear layer volume on OCT (P = 0.233), cerebral T2 lesion load on magnetic resonance imaging (P = 0.416) or the development of new relapses (P = 0.205). CONCLUSION: In this study, OCT-based automated VH estimation did not detect increased vitreous inflammation in MS patients compared to HCs and did not find an association with CNS inflammatory burden.

Responder rates to fampridine differ between clinical subgroups of MS patients and patient reported outcome influences treatment decision making.

BACKGROUND: Fampridine is an effective treatment to improve ambulation for some multiple sclerosis (MS) patients. Remarkable discrepancies exist between responder rates in clinical trials and the proportion of patients continuing treatment in clinical practice. This may be related to clinical phenotypes of MS patients, and the influence of patient reported outcome (PRO) on treatment decision making. OBJECTIVE: To analyse responder rates to fampridine on ambulation and upper extremity function (UEF) and the influence on treatment decision making in different clinical subgroups in a real-world setting. METHODS: MS patients with ambulatory impairment treated with fampridine were included. Patients were subdivided based on disease duration, clinical phenotype, Expanded Disability Status Scale (EDSS), baseline walking speed, and presence of UEF impairment. Ambulatory response was assessed with the Timed 25-Foot Walk (T25FW, responder defined as ≥20% improvement) and with the MS Walking Scale (MSWS, responder defined as ≥8 points improvement) as a PRO. For patients also reporting impaired UEF, the Arm Function in MS Questionnaire (AMSQ, responder defined as ≥15 improvement) was the PRO of choice. Decision on treatment continuation was based on improvement of T25FW, MSWS and the clinicians' overall impression for improvement. RESULTS: In total 344 patients were included of which 75.3% continued treatment. More patients with a relapsing clinical phenotype continued treatment vs patients with a progressive phenotype (83.6 vs 68.6%, p < 0.01). A positive linear trend was found between severity of walking disability, as determined by baseline walking speed, and T25FW response (p < 0.01), while there was an inverse linear association between walking disability and MSWS response (p = 0.03). However, the proportion of patients continuing treatment was similar between subgroups of baseline walking speed. Impaired UEF was reported by 183 (66.5%) patients, of which 64 (39.3%) were AMSQ responders. Patients responding on AMSQ compared to non-responders, were also more frequently MSWS responders (82.8 vs 65.3%, p = 0.02), while response on T25FW was similar, and continued treatment more often (85.9 vs 70.7%, p = 0.04). This suggests an influence of PRO on treatment decision making. CONCLUSION: Responder rates and treatment continuation of fampridine differed between clinical subgroups of MS. PROs influenced treatment decision making of fampridine in clinical practice, particularly in patients with mild ambulatory impairment or those reporting UEF impairment. To some extent, these findings explain discrepancies found between clinical trials and clinical practice, and support the importance of subgroup analyses and incorporation of PROs in clinical trials. For clinical practice, using PROs to assess patients experience in conjunction with performance measures helps in treatment decision making.

Validation of mean upper cervical cord area (MUCCA) measurement techniques in multiple sclerosis (MS): High reproducibility and robustness to lesions, but large software and scanner effects.

INTRODUCTION: Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking. METHODS: Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations. RESULTS: In dataset A, MUCCA differed between MR machines (p < 0.001) and methods (p < 0.001) used, but not between scan sessions. With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreement = 0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistency = 0.981 and 0.976, respectively). Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SI ≥ 0.921), with a significant main effect of method (p < 0.001), but not of MR machine or subject group. In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (p > 0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962). CONCLUSION: Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.

Long-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab.

BACKGROUND: Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited. OBJECTIVE: To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab. METHODS: Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab. RESULTS: EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6-6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00-1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06-2.72, p = 0.028). CONCLUSION: The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.

Saccadic fatigability in the oculomotor system.

BACKGROUND: Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS), but challenging to quantify. This prospective study investigated if repeated saccadic eye movements enable measurement of oculomotor fatigability and can reflect on perceived fatigue in MS. METHODS: A standardized infrared oculography protocol (DEMoNS) was used for quantifying saccades in MS patients and healthy controls which included a first and a repeated pro-saccadic task (FPT and RPT). Saccadic peak velocity, latency, gain, area under the curve (AUC) and peak velocity divided by amplitude (Pv/Am) were calculated in both tasks. Perception based fatigue was assessed using the Checklist Individual Strength and the Neurological Fatigue Index (NFI). Linear regression models were used for assessing the relation between saccadic parameters and perceived fatigue. RESULTS: This study included 181 MS patients and 58 healthy controls subjects. From FPT to RPT, there were significant changes in saccadic parameters. Latency of both tasks was significantly related to NFI summary score (FPT: ß = 0.022, p = .049, RPT: ß 0.023, p = .021). These relationships were weakened after adjustment for Expanded Disability Status score (p > .05). There was however no significant group difference in changes in saccadic parameters. CONCLUSIONS: This study presents an objective and reproducible method for measuring saccadic fatigability. Saccadic fatigability was found to be of limited use in MS, and should be tested in conditions affecting ocular muscles or the neuromuscular junction.

Diagnosing and quantifying a common deficit in multiple sclerosis: Internuclear ophthalmoplegia.

OBJECTIVE: We present an objective and quantitative approach for diagnosing internuclear ophthalmoplegia (INO) in multiple sclerosis (MS). METHODS: A validated standardized infrared oculography protocol (DEMoNS [Demonstrate Eye Movement Networks with Saccades]) was used for quantifying prosaccades in patients with MS and healthy controls (HCs). The versional dysconjugacy index (VDI) was calculated, which describes the ratio between the abducting and adducting eye. The VDI was determined for peak velocity, peak acceleration, peak velocity divided by amplitude, and area under the curve (AUC) of the saccadic trajectory. We calculated the diagnostic accuracy for the several VDI parameters by a receiver operating characteristic analysis comparing HCs and patients with MS. The National Eye Institute Visual Function Questionnaire-25 was used to investigate vision-related quality of life of MS patients with INO. RESULTS: Two hundred ten patients with MS and 58 HCs were included. The highest diagnostic accuracy was achieved by the VDI AUC of 15° horizontal prosaccades. Based on a combined VDI AUC and peak velocity divided by amplitude detection, the prevalence of an INO in MS calculated to 34%. In the INO group, 35.2% of the patients with MS reported any complaints of double vision, compared to 18.4% in the non-INO group (p = 0.010). MS patients with an INO had a lower overall vision-related quality of life (median 89.9, interquartile range 12.8) compared to patients without an INO (median 91.8, interquartile range 9.3, p = 0.011). CONCLUSIONS: This study provides an accurate quantitative and clinically relevant definition of an INO in MS. This infrared oculography-based INO standard will require prospective validation. The high prevalence of INO in MS provides an anatomically well described and accurately quantifiable model for treatment trials in MS.

High work absence around time of diagnosis of multiple sclerosis is associated with fatigue and relapse rate.

BACKGROUND: Multiple sclerosis (MS) is associated with high rates of disability pension and work absence. Little is known about work absence in early MS. The objectives of this study were (1) to assess the prevalence of work absence shortly after MS diagnosis, (2) to explore health-related quality of life (HRQoL) and disease impact in relation to work absence and (3) to investigate demographic and clinical factors that may be associated with high work absence. METHODS: Patients with relapsing remitting (RRMS) or primary progressive MS (PPMS) were included shortly after MS diagnosis. We collected data on work absence due to MS in the year prior to inclusion, disability (Expanded Disability Status Scale), relapse rate, fatigue (Neurological Fatigue Index), health-related quality of life (HRQoL, 36-Item Short Form Survey) and disease impact (Multiple Sclerosis Impact Scale). For analysis, patients were divided in 2 groups: low work absence (<1 month) and high work absence (≥1 month). Data was analyzed using backward logistic regression techniques. RESULTS: In total, 90 MS patients participated (80 RRMS, 10 PPMS, mean age = 39.3 years, median disease duration since diagnosis = 0.5 year). Work absence in the year prior to inclusion was reported by 66 patients (73.3%). High work absence of ≥ 1 month was reported by 41 patients (45.6%). Disability, gender, age, disease duration and education did not differ between groups. Patients with high work absence reported a lower HRQoL and higher disease impact compared to patients with low work absence. Backward regression analysis showed that high work absence is associated with being single/not married, fatigue and relapses. The strongest association was found for fatigue (highest fatigue vs. lowest fatigue level: OR total group = 7.8, RRMS = 15.8). In RRMS patients the second-strongest association was relapse rate (≥2 relapses in the past year vs. no relapses: OR 11.1). CONCLUSION: Prevalence of work absence is high in early MS. Patients with high work absence report a lower HRQoL and a higher disease impact. High work absence is associated with being single/not married, fatigue and relapses. Interventions aimed at fatigue and prevention of relapses may help maintain employment in early MS.

Predicting clinical progression in multiple sclerosis after 6 and 12 years.

BACKGROUND AND PURPOSE: To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures. METHODS: A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow-up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. RESULTS: Higher 6-year EDSS score was predicted by early EDSS score and whole-brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2  = 0.56). Predictors for 12-year EDSS score included larger EDSS score changes and higher T1-hypointense lesion volumes (adjusted R2  = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole-brain atrophy (adjusted R2  = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1-hypointense lesion volumes (adjusted R2  = 0.14). CONCLUSIONS: Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

Acid sphingomyelinase: No potential as a biomarker for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) lacks reliable biomarkers that reflect disease activity. Recent evidence suggests that an altered sphingolipid metabolism is associated with MS pathogenesis. OBJECTIVE: To explore acid sphingomyelinase (ASM) activity and altered sphingolipid metabolism as potential biomarkers in serum of MS patients, to predict active and progressive disease, and response to disease modifying therapy (DMT). METHODS: Levels of serum ASM activity were longitudinally analyzed in 40 clinically isolated syndrome, 64 relapsing remitting (RR) and 10 primary progressive MS patients, and 22 healthy controls (HC). ASM activity and sphingolipid levels were measured in a different sample of 61 RRMS patients using DMT. RESULTS: A significant difference in ASM activity levels was observed between MS patients and HC (p < 0.001). There was no correlation between ASM activity levels and disease activity, progression or response to DMT. Ceramide (Cer)-C16:0 , Cer-C24:0 and sphingomyelin (SM)-C20:0, SM-C22:0, SM-C24:0 and SM-C24:1 showed a significant increase during fingolimod use. CONCLUSION: Although higher levels in MS patients were found, ASM activity levels do not show potential as a biomarker for predicting disease activity, progression or response to DMT. Two ceramides and four types of sphingomyelin require further investigation as potential markers for treatment response.

A standardized protocol for quantification of saccadic eye movements: DEMoNS.

OBJECTIVE: Quantitative saccadic testing is a non-invasive method of evaluating the neural networks involved in the control of eye movements. The aim of this study is to provide a standardized and reproducible protocol for infrared oculography measurements of eye movements and analysis, which can be applied for various diseases in a multicenter setting. METHODS: Development of a protocol to Demonstrate Eye Movement Networks with Saccades (DEMoNS) using infrared oculography. Automated analysis methods were used to calculate parameters describing the characteristics of the saccadic eye movements. The two measurements of the subjects were compared with descriptive and reproducibility statistics. RESULTS: Infrared oculography measurements of all subjects were performed using the DEMoNS protocol and various saccadic parameters were calculated automatically from 28 subjects. Saccadic parameters such as: peak velocity, latency and saccade pair ratios showed excellent reproducibility (intra-class correlation coefficients > 0.9). Parameters describing performance of more complex tasks showed moderate to good reproducibility (intra-class correlation coefficients 0.63-0.78). CONCLUSIONS: This study provides a standardized and transparent protocol for measuring and analyzing saccadic eye movements in a multicenter setting. The DEMoNS protocol details outcome measures for treatment trial which are of excellent reproducibility. The DEMoNS protocol can be applied to the study of saccadic eye movements in various neurodegenerative and motor diseases.