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.

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 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.

Ocrelizumab after natalizumab in JC-virus positive relapsing remitting multiple sclerosis patients.

Ocrelizumab is often used as an alternative therapy in natalizumab-treated MS patients at risk for progressive multifocal leukoencephalopathy (PML). Our objective was to assess efficacy and safety of JC-virus positive patients switching (either directly or indirectly) from natalizumab to ocrelizumab. Forty-two patients were included from an observational cohort (median follow-up 21 months). No evidence of disease activity was found in 83% of direct switchers and 50% of indirect switchers. Two direct switchers were diagnosed with carry-over PML. Our data support a direct switch for adequate disease suppression, although carry-over PML illustrates the dilemma when choosing between a direct or indirect switch.

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.

Motor evoked potential: a reliable and objective measure to document the functional consequences of multiple sclerosis? Relation to disability and MRI.

OBJECTIVE: In an attempt to analyze whether MEP can serve as a valid measure for evaluating neurological dysfunction in multiple sclerosis (MS), we related MEP to clinical and MRI measures. METHODS: Transcranial magnetic stimulation was applied in 52 MS patients to determine the central motor conduction time (CMCT) to the extremities. We calculated Z-scores for each CMCT (Zcmct) corrected for height. All patients underwent two clinical measurements and a MRI scan, of which T1 and T2 brain lesion volumes, brain volume, spinal cord volume and the number of T2 spinal cord lesions were derived. RESULTS: The clinical measurements correlated significantly with various Zcmct (Spearman correlation coefficients ranged from 0.29 to 0.53; p<0.05). The number of spinal cord lesions, brain T1 and T2 lesion volume and spinal cord volume correlated with various Zcmct (r=0.31-0.53; p<0.05). Linear regression analysis revealed that the clinical measurements were explained by Zcmct left leg and T1 lesion volume (adjusted R(2)=0.38). For one clinical measurement the number of spinal cord lesions was also included (adjusted R(2)=0.43). CONCLUSION: We found a relation between MEP, brain and spinal cord MRI measures, and two clinical measures. Moreover, a model for explaining disability in MS revealed that MEP measures provide information in addition to MRI measures. SIGNIFICANCE: This study suggests that MEP is a measure that might adequately reflect pathology and neurological dysfunction in MS.

Long-term clinical outcome of primary progressive MS: predictive value of clinical and MRI data.

The authors sought to identify clinical and MRI predictors of outcome in primary progressive multiple sclerosis (PPMS). Clinical and MRI assessments were performed at baseline and 2 and 5 years (clinical only). At baseline, disease duration, expanded disability status scale (EDSS) and brain volume predicted outcome. Adding short-term change variables, baseline EDSS, changes in T2* lesion load and cord area, and number of new lesions were predictive. Clinical and MRI variables predict long-term outcome in PPMS.

A longitudinal study of cognition in primary progressive multiple sclerosis.

There are few longitudinal studies of cognition in patients with multiple sclerosis, and the results of these studies remain inconclusive. No serial neuropsychological data of an exclusively primary progressive series are available. Cross-sectional analyses have revealed significant correlations between cognition and magnetic resonance imaging (MRI) parameters in primary progressive multiple sclerosis (PPMS). This study investigated cognitive and MRI change in 99 PPMS patients from five European centres for 2 years. They were assessed at 12 month intervals using the Brief Repeatable Battery, a reasoning test, and a measure of depression. The MRI parameters of T1 hypointensity load, T2 lesion load, and partial brain volume were also calculated at each time point. There were no significant differences between the mean cognitive scores of the patients at year 0 and year 2. However, one-third of the patients demonstrated absolute cognitive decline on individual test scores. Results indicated that initial cognitive status on entry into the study was a good predictor of cognitive ability at 2 years. There was only a small number of significant correlations between changes in cognition and changes on MRI, notably T1 hypointensity load with the two attentional tasks (r = -0.266, P = 0.017; r = -0.303, P = 0.012). It is probable that multiple factors underlie this weak relation between the cognitive and MRI measures.

Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS.

OBJECTIVE: To investigate the cognitive skills of patients with relapsing remitting multiple sclerosis (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) relative to healthy control subjects and to assess whether there is heterogeneity in the type of cognitive disabilities demonstrated by patients with different MS phenotypes. METHODS: RRMS patients (n = 108), SPMS patients (n = 71), PPMS patients (n = 55), and healthy control subjects (n = 67) underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological Tests. RESULTS: Relative to controls, cognitive performance of RRMS patients was deficient when tasks required higher-order working memory (WM) processes (Word List Generation, 10/36 Spatial Recall Test, Symbol Digit Modalities Test). PPMS and SPMS patients performed poorer than control subjects on all tasks. SPMS patients performed more poorly than PPMS patients when tasks required higher-order WM processes, except when speed of information processing played a relatively important role (Symbol Digit Modalities Test, Paced Auditory Serial Addition Test). Whereas RRMS patients generally performed better than the progressive subtypes, they showed relatively poor verbal fluency. CONCLUSION: MS patients with different disease courses have different cognitive profiles.

Patients with multiple sclerosis prefer early diagnosis.

The new diagnostic criteria for multiple sclerosis (MS) allow for a definite diagnosis in earlier stages of the disease. Yet, clinicians may hesitate to pursue a diagnosis of multiple sclerosis at the presentation of first symptoms because they consider an early diagnosis of limited benefit to patients. It is unknown whether patients themselves prefer to be informed in an early phase. We studied satisfaction with the timing of diagnosis in patients recently diagnosed with MS and found that 75% was satisfied, 24% favoured an earlier, and only 6% a later disclosure of the diagnosis. Patients who preferred an earlier diagnosis had a significantly longer interval between their first visit to the neurologist and the disclosure of diagnosis (P < 0.001). The probability that the patient was satisfied with the timing of diagnosis did not substantially decrease in the months following the first visit to the neurologist, leaving ample opportunity for a thorough evaluation of the early clinical course. We conclude that patients with MS prefer an early diagnosis.

The patient's perception of a (reliable) change in the Multiple Sclerosis Functional Composite.

OBJECTIVE: To prospectively characterize the relation between two-year changes in functional impairment as measured by the Multiple Sclerosis Functional Composite (MSFC) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS). METHODS: One hundred and eighty-eight patients with multiple sclerosis (MS) were recruited at our outpatient clinic. Impairment and disability were assessed using the MSFC and GNDS at baseline and follow-up. Longitudinal correlations were studied between changes in MSFC and GNDS and their corresponding components. We also studied changes in GNDS in relation to what can be classified as a reliable change in MSFC; for example, 20% change in each MSFC component or a change of 0.5 in total MSFC score. In addition, we studied the change in total number of GNDS subcategories with a score of 3 or higher in relation to the predefined MSFC changes, these subcategories being indicative of the requirement for help by another person. RESULTS: Despite good cross-sectional correlations between MSFC and GNDS, no significant correlation was found between longitudinal changes in MSFC and GNDS. Analysing the change in GNDS in relation to the predefined MSFC changes shows that GNDS changes are nicely rank ordered when more stringent definitions of reliable change were applied. In addition, analysing the number of GNDS subcategories scored 3 or higher indicate that there is a profile of worsening on the MSFC being associated with increase in the amount of help required from others. CONCLUSION: Our longitudinal data suggest that a reliable change is associated with a likewise change in patient perceived disability, the smallest reliable change being identified by at least 20% change in each MSFC component.

[Alpha]B-crystallin genotype has impact on the multiple sclerosis phenotype.

BACKGROUND: Both multiple sclerosis (MS) susceptibility and MS clinical phenotype are in part genetically determined. [Alpha]B-crystallin is a candidate autoantigen in MS, and there are three polymorphisms in the promoter region of the encoding gene (CRYAB): at positions -C249G, -C650G, and -A652G. METHODS: These polymorphisms were studied in sporadic cases of MS, assessing disease susceptibility, clinical phenotype, and MRI appearance. RESULTS: The CRYAB polymorphisms influenced susceptibility as well as disease expression in MS. CONCLUSION: Carriers of the rare allele CRYAB-650*C had an increased likelihood of a noninflammatory, neurodegenerative phenotype characterized by a relatively rapid, primary progressive clinical disease course.

Anxiety and depression influence the relation between disability status and quality of life in multiple sclerosis.

Disability status, depression and anxiety are important determinants of quality of life (QoL) in patients with multiple sclerosis (MS). We investigated whether anxiety and depression influence the relation between disability status and QoL in our cohort of recently diagnosed patients. Disability status [Expanded Disability Status Scale (EDSS)], anxiety and depression [Hospital Anxiety and Depression Scale (HADS)], and QoL (SF-36) were prospectively obtained in 101 MS patients. The relation between EDSS and SF-36 scales was examined using regression analyses, without and with adjustment for anxiety and depression. Interaction effects were investigated by comparing the relation between EDSS and QoL in patients with high and low anxiety and depression. In the unadjusted analyses, EDSS was significantly related to all SF-36 physical and mental health scales. After adjustment for anxiety and depression, EDSS was significantly related only to the SF-36 physical functioning, role-physical functioning and bodily pain scales. The relation between EDSS and these SF-36 scales was consistently higher in patients with more symptoms of anxiety or depression, suggesting that anxiety and depression strengthened the association of EDSS in these SF-36 physical health scales. After adjustment for anxiety and depression, EDSS was not significantly related to the SF-36 mental health scales and the general health scale. This finding is compatible with the hypothesis that anxiety and depression are intermediate factors in the association of EDSS with these SF-36 scales. Screening for symptoms of anxiety and depression is recommended in studies that use QoL as an outcome measure of treatment or intervention efficacy.

The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study.

Progressive axonal loss is the most likely pathologic correlate of irreversible neurologic impairment in primary progressive multiple sclerosis. In a run-in versus treatment trial, we show that the neuroprotective agent riluzole seems to reduce the rate of cervical cord atrophy and the development of hypointense T1 brain lesions on magnetic resonance imaging.

Chemokine receptor expression on T cells is related to new lesion development in multiple sclerosis.

The expression of chemokine receptors CCR5 and CXCR3 on CD4 and CD8 positive T cells in blood, measured by flow cytometry, was studied in 124 patients with different clinical subtypes of multiple sclerosis (MS) and 22 healthy controls. In a subgroup of patients (n=69) from whom MRI was available, chemokine receptor expression was correlated to the annualised changes in T1 and T2 lesion load. It was found that CCR5 and CXCR3 on both cell types might have impact on annualised increase in T2 lesion load, but not on T1 lesion load. Our results suggest that chemokines may play a more important role in the development of new lesions in MS than in the long-term outcome of those lesions.

Multiple sclerosis functional composite: impact of reference population and interpretation of changes.

The Multiple sclerosis functional composite (MSFC) has been recommended as a clinical outcome measure to be used in future MS trials. A specific characteristic of the MSFC is that it is defined as a measure of impairment relative to a reference population. Using different reference populations affects actual MSFC scores. If the selection of a reference population also has an effect on sensitivity to change of the MSFC, comparison of data from clinical trials will be almost impossible when different reference populations are used We studied the effect of the selection of a reference population on the outcome of a trial by simulating 343 intervention trials and comparing results obtained by using three different reference populations: two previously published MS patient populations and a healthy population. Scores of the healthy population were collected in the first part of the study. The effects of sex, age and education level on test scores of healthy subjects were studied as well. In the healthy controls, sex, age and education level had a different impact on individual test scores of MSFC components and overall MSFC score. Our study shows that, with the use of the MSFC, the selection of different reference populations does not affect the trial statistics and significance, but it does affect comparability of results between different trials, and complicates the dinical interpretation of any observed change.

Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue.

INTRODUCTION: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy extent and severity of lesions or damage of whole brain issue (WBT). METHODS: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). RESULTS: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coeffcient beta = 0.59, p < 0.001 for WBT and beta = -0.19, p < 0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient beta = 0.43, p < 0.001 for T1LV and beta =-0.38, p < 0.001 for WBT). CONCLUSION: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VP) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.

The FAS-670 polymorphism influences susceptibility to multiple sclerosis.

Several studies have reported a defective Fas function in patients with multiple sclerosis (MS). We were interested whether this could result from a genetically altered Fas regulation. We examined the FAS-670 polymorphism in 382 patients with MS and 206 controls, and found that the carriership of allele FAS-670*G was significantly less frequent in patients than in controls. We found no association between the carriership of FAS-670*G and clinical features. For a subgroup of patients, longitudinal MRI data were available. We observed similar brain and lesion volumes in carriers and noncarriers of FAS-670*G. These data suggest that FAS-670*G decreases the risk of developing MS, but does not affect the course of disease.

Two-year follow-up study of primary and transitional progressive multiple sclerosis.

This study documents changes in clinical and magnetic resonance imaging (MRI) characteristics in a large cohort of patients with primary and transitional progressive multiple sclerosis (PP and TPMS) over 2 years. Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two. Of the 190 patients recruited clinical data were available on 125 patients (66%, five centres) and MRI data were available on 113 patients (59%, four centres) at 2 years. Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased. In PPMS significantly higher lesion loads were found in those who presented with non-cord syndromes when compared to cord presentation and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant cord atrophy was only seen in those with a cord presentation. Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.