Multiple Sclerosis Journal

Background: Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism.

Objectives: Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis.

Methods: Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501.

Results: HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10 ^-5). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A.

Conclusions: HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

Background: Patients with multiple sclerosis may present altered patterns of connectivity between the two brain hemispheres. To date, only transcallosal connectivity between the two primary motor cortices (M1) has been investigated functionally in patients with multiple sclerosis.

Objectives: The aim of this study was to investigate whether connectivity between the dorsal premotor cortex and the contralateral M1 was altered in patients with multiple sclerosis, and to see whether clinical progression is accompanied by exacerbated dorsal premotor cortex—M1 disconnectivity.

Methods: A twin-coil transcranial magnetic stimulation approach was used to investigate both excitatory and inhibitory interhemispheric connections between the left dorsal premotor cortex and the contralateral M1 in 18 multiple sclerosis patients without disability, in 18 multiple sclerosis patients with advanced disease and in 12 age-matched healthy subjects. To activate distinct inhibitory and facilitatory transcallosal pathways, the intensity of dorsal premotor cortex stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold).

Results: Our sample of patients with multiple sclerosis showed altered patterns of interhemispheric dorsal premotor cortex—M1 functional connectivity even in the absence of clinical deficits. Facilitatory connections originating from dorsal premotor cortex were reduced in multiple sclerosis patients with or without disability, while inhibitory dorsal premotor cortex—M1 connections were altered only in disabled patients.

Conclusions: The current study demonstrates that functional excitatory connectivity originating from non-primary motor areas is compromised in multiple sclerosis patients even in the absence of clinical disability. Clinical disease progression leads to an impairment of both excitatory and inhibitory transcallosal connections.

Background: Hypointense rims peripherally on T2-weighted MRI (rim lesions) have been associated with gadolinium ring-enhancing lesions in multiple sclerosis (MS) in pathological studies. However, little is known about their frequency, we analyzed clinical significance in a cohort of MS sufferers according to routine clinical practice.

Methods: We retrospectively reviewed all available MRI scans performed on our MS patients between 2000 and 2009. A total of 580 MRI scans from 257 patients were analyzed. The presence of rim lesions and ring enhancement was assessed and counted blind. Furthermore, the correlation between both patterns, and with clinical characteristics, was evaluated.

Results: Thirty-five rim lesions were identified and 9% (24/257) of the patients showed at least one of these lesions. Forty ring-enhancing lesions were counted and 12% (29/245) of the patients who had undergone gadolinium MRI presented at least one such lesion. Thirteen lesions co-localized both patterns (40% of the rim lesions and 33% of the ring-enhancing lesions). Rim lesions and ring-enhancing lesions were observed in patients with clinically isolated syndrome (7%, 7%), relapsing—remitting (11%, 15%) and secondary progressive (13%, 9%) but none with primary progressive MS. Presence of ring-enhancing lesions was significantly associated with a shorter time to reach EDSS (Expanded Disability Status Scale) 4.0 and 6.0 (hazard ratio 7.6, 95% confidence interval 2.3—24.6).

Conclusions: Rim lesions and ring-enhancing lesions are present in close to 10% of patients with MS, and frequently both lesions appear independently one to the other. The association of ring enhancement with worst prognosis needs to be confirmed in prospective studies.

Background: Patients with multiple sclerosis (MS) who have a favourable clinical status several years after disease onset are classified as ‘benign’. In many cases brain tissue damage does not differ between benign MS and the ‘classical’ MS forms.

Objective: To assess whether the favourable clinical course in benign MS could be explained by the presence of an efficient functional cortical reorganization.

Method: Twenty-five right-handed patients with benign MS (defined as having Expanded Disability Status Scale ≤ 3 and disease duration >15 years) underwent functional MRI during a simple motor task (right-hand tapping) to assess movement-associated brain activation. This was compared with that of 10 patients with relapsing—remitting MS and 10 normal controls. Benign MS patients also underwent conventional brain MRI and magnetization transfer imaging, which was compared with an identical examination obtained 1 year before. Quantitative structural magnetic resonance measures were baseline and changes over time in T2-lesion volume, magnetization transfer ratio in T2 lesions and normal-appearing brain and total brain volume.

Results: Movement-related activation was greater in patients with benign MS than in those with relapsing—remitting MS or normal controls, extensively involving bilateral regions of the sensorimotor network as well as basal ganglia, insula and cerebellum. Greater activation correlated with lower T2-lesion magnetization transfer ratio, and with decreasing brain volume and increasing T2 lesion volume.

Conclusions: The results suggest that bilateral brain networks, beyond those normally engaged in motor tasks, are recruited during a simple hand movement in patients with benign MS. This increased activation is probably the expression of an extensive, compensatory and tissue-damage related functional cortical reorganization. This can explain, at least in part, the favourable clinical expression of patients with benign MS.

Background: Multiple sclerosis (MS) is usually considered a ‘young persons’ disease’, typically presenting between the ages of 20 and 40. In this study we review our experience with patients diagnosed at age 60 or over, with particular emphasis on patients who continue to have evidence of active inflammation despite a later onset.

Methods: We reviewed all cases of MS diagnosed at or over age 60 in our center over a 5-year period. We identified 111 patients and recorded their clinical and imaging characteristics using prespecified variables. Analyses were performed to describe their interval to diagnosis, clinical syndromes, imaging and laboratory characteristics.

Results: At the time of diagnosis, 8% of patients had a clinically isolated syndrome, 33% were in the relapsing—remitting stage, while 23% had a secondary progressive course, and 32% were primary progressive. Eighty-eight percent of patients had a brain MRI judged ‘typical for MS’, and 32% of all patients receiving gadolinium had enhanced lesions. Forty-six percent of patients with relapsing—remitting MS or clinically isolated syndrome exhibited gadolinium enhancement. Myelitis was the most common initial clinical syndrome, and progressive myelopathy was a common but not exclusive clinical syndrome at the time of diagnosis.

Conclusions: A relapsing pattern of MS is not uncommon, even in patients diagnosed over the age of 60. Active inflammation (clinical relapses and gadolinium enhancement) occurs in a significant number of patients with MS with later diagnosis. These observations have implications for evaluation and treatment of patients with MS presenting at an older age.

Background: Extracranial venous stenosis (EVS) has recently been implicated as the primary cause of multiple sclerosis (MS).

Objective: The aim of this study was to determine the presence of EVS in MS patients.

Methods: We performed selective extracranial venography on 42 patients with early MS (EMS): clinically isolated syndrome (CIS) or relapsing—remitting MS (RRMS) of less than 5 years duration, and late MS (LMS): RRMS of more than 10 years duration. Magnetic resonance imaging (MRI) and clinical relapse data were reviewed for all patients with EVS.

Results: EVS was present in 7/29 patients with EMS and 12/13 patients with LMS, a highly significant statistical difference (p< 0.001). Only 3/42 patients (all in the LMS group) had two vessel stenoses, while the rest had only one vessel involved. EVS was seen in 1/11 patients with CIS compared with 6/18 RRMS patients of less than 5 years duration. Disease duration was greater in patients with EVS overall (p < 0.005). LMS remained an independent predictor of EVS following multivariate adjustment for gender, age at disease onset and Expanded Disability Status Scale (EDSS) (Adjusted Odds Ratio = 29 (3—298); p = 0.005]. Within the EMS group, patients with (n = 7) and without (n = 22) EVS had similar EDSS and disease duration, suggesting similar disease severity. No clear correlation could be found between site of EVS and anatomic localization of either clinical relapses or MRI gadolinium-enhancing lesions.

Conclusions: We conclude that EVS is an unlikely cause of MS since it is not present in most patients early in the disease and rarely involves more than one extracranial vein. It is likely to be a late secondary phenomenon.

Background: Bladder dysfunction is a common feature of multiple sclerosis (MS).

Objective: In this study we aimed to assess the efficacy, tolerability and safety of Sativex^® (nabiximols) as an add-on therapy in alleviating bladder symptoms in patients with MS.

Methods: We undertook a 10-week, double-blind, randomized, placebo-controlled, parallel-group trial in 135 randomized subjects with MS and overactive bladder (OAB).

Results: The primary endpoint was the reduction in daily number of urinary incontinence episodes from baseline to end of treatment (8 weeks). Other endpoints included incidence of nocturia and urgency, overall bladder condition (OBC), daytime frequency, Incontinence Quality of Life (I-QOL), Patient’s Global Impression of Change (PGIC) and volume voided. The primary endpoint showed little difference between Sativex and placebo. Four out of seven secondary endpoints were significantly in favour of Sativex: number of episodes of nocturia (adjusted mean difference -0.28, p = 0.010), OBC (-1.16, p = 0.001), number of voids/day (-0.85, p = 0.001) and PGIC (p = 0.005). Of the other endpoints, number of daytime voids was statistically significantly in favour of Sativex (-0.57, p = 0.044). The improvement in I-QOL was in favour of Sativex but did not reach statistical significance.

Conclusions: Although the primary endpoint did not reach statistical significance, we conclude that Sativex did have some impact on the symptoms of overactive bladder in patients with MS, providing evidence of some improvement in symptoms associated with bladder dysfunction in these subjects.

Background: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI-measured disease activity in relapsing—remitting MS (RRMS) patients.

Objectives: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible.

Methods: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter.

Results: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases.

Conclusions: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study.

Objective: To test the hypothesis that lower body progressive resistance training (PRT) leads to an increase of the muscle fiber cross-sectional area (CSA) and a shift in the proportion of fiber types in patients with multiple sclerosis (MS).

Methods: The present study was a two-arm, randomized controlled trial (RCT). Thirty-eight MS patients (Expanded Disability Status Scale (EDSS) 3—5.5) were randomized to a PRT group (Exercise, n = 19) or a control group (Control, n = 19). The Exercise group performed a biweekly 12-week lower body PRT program [five exercises progressing from 15RM (Repetition Maximum) towards 8RM], whereas the Control group maintained their usual daily activity level during the trial period. Muscle biopsies from vastus lateralis were taken before (pre) and after the trial (post). Thigh volume (TV) was estimated from anthropometric measurements. Isokinetic muscle strength of the knee extensors (KE) and flexors (KF) were evaluated at slow (90^°/s) and fast (180^°/s) angular velocities.

Results: In the Exercise group the mean CSA of all muscle fibers (7.9 ± 15.4% vs. -3.5 ± 9.0%, p = 0.03) and of type II muscle fibers (14.0 ± 19.4% vs. -2.6 ± 15.5%, p = 0.02) increased in comparison with the Control group. No changes occurred in the proportion of fiber types in the Exercise group. Neither was there any change in total TV. Isokinetic strength at KE180, KF90 and KF180 improved significantly after PRT when compared with the control group (10.2—21.3%, p ≤ 0.02).

Conclusions: We conclude that progressive resistance training induces a compensatory increase of muscle fiber size in patients with the central nervous system disorder, multiple sclerosis.

Background: Core stability training is popular in the management of people with multiple sclerosis (MS); however, scientific evidence to support its effectiveness is scarce.

Objective: To explore the effectiveness of core stability training on balance and mobility.

Method: A multi-centre series of eight single case studies was undertaken. Eight ambulant individuals with stable MS participated in 16 face-to-face core stability training sessions, delivered by a neurophysiotherapist, plus a daily home exercise programme. A range of outcomes were measured: 10-m timed walk, 12-item MS walking scale, timed get up and go, functional reach tests, timed single leg stance, visual analogue scales of two activities, and the Activities-specific Balance Confidence Scale.

Results: Visual analysis of trend, level and slope demonstrated improvement in five subjects (62%) in seven measures. This was confirmed by the two standard deviation band method of analysis for six measures. Analysis of group data (repeated measures within subjects analysis of variance) indicated significant improvement between baseline and intervention phases for timed walk (p = 0.019), MSWS-12 Scale (p = 0.041), forward (p = 0.015) and lateral reach (p = 0.012). In general, no further improvements were made following withdrawal of the intervention.

Conclusions: This study provides preliminary evidence of the effectiveness of an 8-week core stability training programme in improving balance and mobility in ambulant people with MS. Variations in response to intervention are evident. Assessor-blinded randomized controlled studies are required to confirm these findings and determine patient characteristics which identify those who benefit most from this intervention.

Background and Objectives: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed.

Methods: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab.

Results: At baseline, the cohort’s mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test—retest correlations were high for both SDMT (range 0.89 for weeks 0—4 to 0.96 for weeks 44—48) and MSNQ (0.82 for weeks 0—4 to 0.93 for weeks 44—48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2).

Conclusions: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Background: Patients report information deficits in the period surrounding diagnosis of multiple sclerosis (MS). We assessed the effectiveness of an add-on information aid for newly diagnosed MS patients.

Methods: We randomly assigned 120 newly diagnosed MS patients from five Italian centres to diagnosis disclosure (current practice at the centre) or current practice plus information aid (ISRCTN81072971). The information aid consisted of a personal interview with a physician using a navigable compact disc and a take-home booklet. The primary composite endpoint was score in the highest tertile of MS knowledge and satisfaction with care questionnaires. Other endpoints were safety; treatment adherence; extra contacts/consultations; switching of care centre; and changes in Hospital Anxiety and Depression Scale and Control Preference Scale scores.

Results: At 1 month, 30/60 intervention and 8/60 control patients achieved the primary endpoint (odds ratio [OR] 6.5, 95% CI 2.6—16.0; p < 0.001; number needed to treat [NNT] 3). Figures at 6 months were 26/60 intervention and 11/60 control patients (OR 3.4, 95% CI 1.5—7.8; p = 0.04; NNT 4). There were no adverse events. No significant treatment effects were seen on secondary outcomes.

Conclusion: The information aid was safe and significantly associated with attainment of the primary outcome at 1 and 6 months.

Background: Screening has frequently been proposed as a strategy for detection of depression in multiple sclerosis (MS). In a recent study, we found a minimal impact of screening, even when this was coupled with rapidly responsive and evidence-based depression care.

Methods: In order to explore the challenges involved in screening we analyzed prospective data from the Canadian Impact of MS (CIMS) database, which provides annual ratings on a self-report depression rating scale, the Center for Epidemiologic Studies Depression Rating Scale (CES-D).

Results: Approximately 30% of respondents screened positive at each visit. CES-D ratings correlated fairly strongly from year to year, Pearson’s r ranged from 0.65 to 0.73. Approximately 10% of those below the CES-D cut-point at each assessment exceeded the cut-point when rated 1 year later, but only about half of these cases had large (≥10 points) increases in their scores.

Conclusions: Screening interventions are generally oriented towards early detection, whereas the longitudinal pattern of depressive symptoms in MS appears to be characterized more prominently by a persistent burden of depressive symptoms in a substantial proportion of the population. Resources invested in screening efforts can probably be more effectively deployed in other areas, such as improved long-term clinical management.