Multiple Sclerosis Journal

Background: The association of human leukocyte antigen (HLA) genes and multiple sclerosis (MS) has been extensively investigated in Caucasians, but less so in Oriental races such as Chinese.

Objectives: To review studies on association of HLA class II alleles with MS in the Chinese population.

Methods: An extensive search for published studies up to June 2010 was performed in the electronic databases. The meta-analysis facilities in the NCSS statistical package were utilized to analyze the findings in these studies. The odds ratios (ORs) of HLA-DR allele distributions in MS were analyzed against controls.

Results: Eleven case-control studies were identified: nine genotyping and two serotyping studies. Six genotyping studies were suitable for HLA-DRB1 allele meta-analysis, which showed that HLA-DRB1*15 was associated with risk of MS in the combined group (308 cases and 407 controls; OR 1.39) while the HLA-DRB1*09 and HLA-DRB1*0901 alleles were protective. When the equivalent serotypes in these six studies were combined with the results from the two serotyping studies (431 cases and 652 controls) for a meta-analysis of HLA-DR serotypes, HLA-DR2 was a risk factor (OR 1.63) and HLA-DR9 was strongly protective in the combined group (OR 0.64).

Conclusions: Although limited data are available, our meta-analysis suggests that HLA-DR2/DRB1*15 are also associated with risk of MS in the Chinese population but less strongly so than in Western MS populations, whereas HLA-DR9 alleles appear to confer resistance in this population.

Background: During the third trimester of pregnancy multiple sclerosis (MS) disease activity is reduced. It is not fully understood which factors mediate this disease amelioration.

Objective: To study alterations of the monocyte transcriptome during pregnancy in MS patients, using a genomewide approach to identify differentially regulated genes.

Methods: Women with MS and healthy controls were longitudinally studied, including a visit before pregnancy.

Results: RNA-microarray analysis was performed in six patients. We found a significant increase of CD64 (Fc gamma receptor 1a, FcgR1a) during the third trimester compared with baseline, confirmed by RT-PCR in a group of ten patients. Analysis with Ingenuity software was performed using all genes expression of which was altered at least 1.5-fold in at least five out of six patients. Major networks that were altered during MS pregnancy were: cell-to-cell signalling and interaction, immune response, and cell signalling. From the genes selected for Ingenuity analysis, seven additional candidate genes, selected for their biological interest, were tested using RT-PCR in ten patients with MS and nine controls. We found an increased expression of JAK2 and STAT1 directly postpartum in patients with MS and in controls.

Conclusion: The increased CD64 expression during pregnancy is indicative of enhanced innate immune functions.

Background: Staphylococcus aureus may produce superantigens that can non-specifically activate CD4⁺ cells to potentially target the myelin basic protein.

Objective: This study examined the association between individuals with multiple sclerosis (MS) and colonization with S. aureus harbouring superantigens.

Methods: Nasal swabs were collected from non-MS subjects and patients with MS who had not experienced a relapse in the past six months (MS stable group) and who had suffered a relapse within 30 days of study recruitment (MS exacerbation group). S. aureus was isolated from the anterior nares of participants following standard procedures and staphylococcal superantigen genes (sea, seb, and tsst-1) were detected using standard laboratory PCR techniques.

Results: The study enrolled 204 patients, 80 in the non-MS and MS stable groups and 44 patients in the MS exacerbation group. Overall, 27.0% of patients were colonized with S. aureus with no significant differences identified between study groups. Amongst individuals colonized with S. aureus, the prevalence of sea was significantly greater in the MS exacerbation versus non-MS study group (p < 0.05; odds ratio 7.9; 95% confidence interval 1.2–49.5).

Conclusions: The ability to rapidly screen patients for the presence of S. aureus producing sea may serve as a useful marker of a potential MS exacerbation.

Background: Multiple sclerosis (MS) is an autoimmune disease resulting in inflammation and demyelination of neurones in the central nervous system (CNS). The first sign of MS is often monosymptomatic optic neuritis (MON). Cerebrospinal fluid from a patient with MS analysed by electrophoresis often shows a split to form so called oligoclonal bands (OCBs). OCBs consist of proteins from activated lymphocytes and plasma cell clones.

Objectives: The aim of this study was to review the published literature on OCBs in MON patients and perform a meta-analysis of the studies in order to assess the utility of OCB determination in patients with MON in the prediction of their risk of MS.

Methods: Review and meta-analysis of the results of 10 published studies.

Results: OCBs as a predictive test had a sensitivity of 73–100% (mean 88.5%), a specificity of 41–90% (mean 57%) and OR-values between 2.75 and 171 (mean 34.2). The areal under the summary receiver operator characteristic (ROC) curve was 0.89 (unweighted) and 0.82 (weighted). The studies showed large heterogeneity in the diagnostic accuracy.

Conclusion: This literature-based meta-analysis provides evidence that OCBs may have a high predictive value for the development of MS in patients with MON. Standardization of laboratory methods and diagnostic criteria would help bring out the full clinical potential of the test. To elucidate the predictive value of OCBs versus MRI, we recommend that a similar meta-analysis of studies of MRI in MON be performed.

Background: The default-mode network (DMN) has been increasingly recognized as relevant to cognitive status.

Objectives: To explore DMN changes in patients with relapsing–remitting (RR) multiple sclerosis (MS) and to relate these to the cognitive status.

Methods: Eighteen cognitively impaired (CI) and eighteen cognitively preserved (CP) RRMS patients and eighteen healthy controls (HCs), matched for age, sex and education, underwent neuropsychological evaluation and anatomical and resting-state functional MRI (rs-fMRI). DMN functional connectivity was evaluated from rs-fMRI data via independent component analysis. T2 lesion load (LL) was computed by a semi-automatic method and global and local atrophy was estimated by SIENAX and SPM8 voxel-based morphometry analyses from 3D-T1 images.

Results: When the whole group of RRMS patients was compared with HCs, DMN connectivity was significantly weaker in the anterior cingulate cortex, whereas it was significantly weaker in the core but stronger at the periphery of the posterior cingulate cortex. These findings were more evident in CP than CI patients. Observed DMN changes did not correlate with global atrophy or T2-LL, but were locally associated with regional grey matter loss.

Conclusion: Relapsing–remitting multiple sclerosis patients show a consistent dysfunction of DMN at the level of the anterior node. DMN distribution changes in the posterior node may reflect a possible compensatory effect on cognitive performance.

Background: Women with multiple sclerosis (MS) are advised to discontinue interferon-beta therapy before trying to conceive. Unplanned pregnancies occur and risks related to exposure remain unclear.

Methods: To determine pregnancy outcomes following interferon-beta therapy, we examined pregnancies from a global drug safety database containing individual case safety reports received in the post-marketing setting and safety data from clinical trials of subcutaneous interferon beta-1a in MS.

Results: One thousand and twenty-two cases of exposure to subcutaneous interferon beta-1a during pregnancy were retrieved; 679 had a documented outcome. In cases for which exposure duration was available (n = 231), mean time of foetal exposure to subcutaneous interferon beta-1a before treatment discontinuation was 28 days; most pregnancies (199/231; 86.1%) were exposed for ≤45 days. To avoid bias, only outcomes for prospective data (n = 425) in pregnancies exposed to interferon beta-1a in utero were analysed further. Of these, 324 (76.2%) resulted in normal live births and four (0.9%) in live births with congenital anomalies (3 [0.7%] were ‘major’). Four (0.9%) pregnancies resulted in stillbirths (1 [0.2%] with foetal defects). There were 5 (1.2%) ectopic pregnancies, 49 (11.5%) spontaneous abortions and 39 (9.2%) elective terminations. Most pregnancies exposed to subcutaneous interferon beta-1a in utero were associated with normal live births. The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population.

Conclusions: These data should be taken into account when considering options for women with MS who become pregnant or who are planning pregnancy while on treatment with subcutaneous interferon beta-1a.

Background: Risks that are potentially associated with long-term therapies should be assessed.

Objective: The present analyses were performed to determine the risk of malignancy in patients with multiple sclerosis (MS) receiving subcutaneous (sc) interferon (IFN) beta-1a, using pooled safety data from key clinical trials and data from the Merck Serono Global Drug Safety database.

Methods: The standard Medical Dictionary for Regulatory Activities query “malignancies” was used to retrieve relevant cases from each data set. The incidence of malignancies per 1000 patient-years was calculated using the pooled safety data from clinical trials. The reporting rates of malignancy types were calculated for the post-marketing setting based on sales volume. Malignancies were grouped by organ localization and classified as medically confirmed or not medically confirmed according to the source of each report. The number of reported cases of each type was compared with the expected number in the general population.

Results: Analysis of pooled safety data from 12 key clinical trials did not show an increased incidence of malignancy per 1000 patient-years with sc IFN beta-1a (4.0; 95% confidence interval (CI): 2.9–5.5) compared with placebo (6.4; 95% CI: 3.3–11.2). Analysis of the database shows that among the medically confirmed cases, reported to expected ratios ranged from 1 : 6 to 1 : 18 for solid tumours and from 1 : 2 to 1 : 9 for lymphohaematopoietic tumours.

Conclusion: Safety data from both clinical trial and post-marketing settings suggest that treatment with sc IFN beta-1a does not increase the risk of malignancy in patients with MS.

Background: Acute disseminated encephalomyelitis (ADEM) affects children more frequently than adults. Current studies investigating ADEM in different age groups are difficult to compare.

Objective: To investigate whether the clinical presentation, outcome and disease course of ADEM differ between adults and children.

Methods: Disease characteristics of 25 adults and 92 children suffering from ADEM between 1988 and 2008 were compared.

Results: The most common presenting symptoms of ADEM in both groups were pyramidal signs and encephalopathy. Ataxia occurred more frequently in children (p = 0.002). In general, MRI showed ill-defined and large white matter lesions in both groups, whereas periventricular lesions were more prevalent in adults (p = 0.001). In adults, duration of hospitalization was longer (p = 0.002) and intensive care unit (ICU) admission was more frequently required (p = 0.043). Three adults (12%) and one child (1%) died (p = 0.030). Fewer adults had complete motor recovery after their first clinical event (p < 0.001). In 73 patients follow-up time was ≥ 2 years and most of these patients remained monophasic. Although relapses after ADEM can occur, only one adult (5%) and five children (6%) converted to MS.

Conclusions: The clinical presentations in children and adults share similarities, but the disease course and outcome of ADEM is more severe in adults with respect to hospitalization, ICU admission, recovery and mortality.

Background: Children with multiple sclerosis (MS) can suffer significant cognitive deficits. This study investigates the sensitivity and validity in pediatric MS of two visual processing tests borrowed from the adult literature, the Brief Visuospatial Memory Test-Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT).

Objective: To test the hypothesis that visual processing is disproportionately impacted in pediatric MS by comparing performance with that of healthy controls on the BVMTR and SDMT.

Methods: We studied 88 participants (43 MS, 45 controls) using a neuropsychological assessment battery including measures of intelligence, language, visual memory, and processing speed. Patients and demographically matched controls were compared to determine which tests are most sensitive in pediatric MS.

Results: Statistically significant differences were found between the MS and control groups on BVMTR Total Learning (t (84) = 4.04, p < 0.001, d = 0.87), BVMTR Delayed Recall (t (84) = 4.45, p < 0.001, d = 0.96), and SDMT (t (38) = 2.19, p = 0.035, d = 0.69). No significant differences were found between groups on confrontation naming or general intellectual ability. Validity coefficients exploring correlation between BVMTR, SDMT, and disease characteristics were consistent with the adult literature.

Conclusions: This study found that BVMTR and SDMT may be useful in assessing children and adolescents with MS.

Background: Cognitive impairment is frequent in multiple sclerosis (MS) and lacks effective treatment. Cognitive rehabilitation is widely applied in neurorehabilitation settings. Functional magnetic resonance imaging (fMRI) may help in investigating changes in brain activity and provide a tool to assess the efficacy of rehabilitation.

Aim: To investigate the effect on brain activity as measured by fMRI of a cognitive rehabilitation programme in patients with MS and cognitive impairment.

Method: Fifteen patients with MS and cognitive impairment and five healthy subjects were recruited. Neuropsychological assessments were performed in patients with MS at study entry and after rehabilitation to assess cognitive changes. fMRI scans were performed at week −5 (baseline), week 0 (immediately before rehabilitation) and week 5 (immediately after rehabilitation). The fMRI paradigm was the Paced Auditory Serial Addition Test (PASAT). The cognitive rehabilitation programme was composed of 15 computer-aided drill and practice sessions and five non-computer-aided cognitive stimulation group sessions (over 5 weeks). Strict guidelines ensured comparability of all rehabilitation interventions.

Results: Patients had increased brain fMRI activity after rehabilitation in several cerebellar areas when compared with healthy subjects. After rehabilitation, patients had significantly improved their performance on the backward version of the Digit Span Test (p = 0.007) and on a composite score of neuropsychological outcomes (p = 0.009).

Conclusion: The results of the present study indicate that this cognitive rehabilitation programme increases brain activity in the cerebellum of cognitively impaired patients with MS. The role of fMRI in the assessment of neurorehabilitation schemes warrants further investigation.

Background: Resistance training studies in multiple sclerosis (MS) often use short intervention periods. Furthermore, training efficiency could be optimized by unilateral training and/or electrical stimulation.

Objective: To examine the effect(s) of unilateral long-term (20 weeks) standardized resistance training with and without simultaneous electro-stimulation on leg muscle strength and overall functional mobility.

Methods: A randomized controlled trial involving 36 persons with MS. At baseline (PRE) and after 10 (MID) and 20 (POST) weeks of standardized (ACSM) light to moderately intense unilateral leg resistance training (RES_O, n = 11) only or resistance training with simultaneous electro-stimulation (RES_E, n = 11, 100 Hz, biphasic symmetrical wave, 400 µs), maximal isometric strength of the knee extensors and flexors (45°, 90° knee angle) and dynamic (60–180°/s) knee-extensor strength was measured and compared with a control group (CON, n = 14). Functional mobility was evaluated using the Timed Get Up and Go, Timed 25 Foot Walk, Two-Minute Walk Test, Functional Reach and Rivermead Mobility Index.

Results: Maximal isometric knee extensor (90°, MID: +10 ± 3%, POST: +10 ± 4%) in RES_O and knee flexor (45°, POST: +7 ± 4%; 90°, POST: +9 ± 5%) in RES_E strength increased (p < 0.05) compared with CON but RES_O and RES_E did not differ. Also, impaired legs responded positively to resistance training (unilateral leg strength analysis) and functional reaching increased significantly in RES_O (+18%) compared with CON. Dynamic muscle strength and the remaining functional mobility tests did not change.

Conclusion: Long-term light to moderately intense resistance training improves muscle strength in persons with MS but simultaneous electro-stimulation does not further improve training outcome.

Background: Patient-reported quality of life (QOL) is an outcome measure in clinical trials in multiple sclerosis (MS), but translated QOL instruments may affect the actual comparability of data.

Objectives: We aimed to investigate possible differences in QOL in MS between cultures and countries. We employed the Functional Assessment of Multiple Sclerosis (FAMS) Version 4 questionnaire, which is a state-of-the-art QOL instrument.

Methods: Some 484 MS patients from Austria (145), Germany (144), and Poland (195) aged 20–60 years, and stratified for sex and disease severity as measured by the Expanded Disability Status Scale (EDSS) score completed the respective FAMS translation and a socio-demographic questionnaire.

Results: Analysis of variance and post-hoc Scheffé-test showed that 64% of the FAMS items were answered significantly differently (p < 0.001) between the three countries. A multivariate regression analysis including all the available disease-related and socio-demographic variables revealed the factors age, EDSS score, employment, social contacts, MS course, and country to be significant predictors of both the total FAMS score and the score for items answered differently between the three countries.

Conclusions: Differences exist in the QOL of MS patients from Austria, Germany, and Poland which seem to lie beyond the impact of disease severity. They appear to be related to culture or other country-specific factors, as country was an independent predictor of differently answered items of the FAMS and thus also of the whole FAMS. QOL instruments should consider this aspect to faithfully reflect subjective information such as patient-reported benefit of treatment in multinational clinical trials.

Parental consanguinity (PC) may be a risk factor for familial multiple sclerosis (FMS) throughout inbred communities. The objective of this report was to estimate prevalence of FMS and rate of PC among FMS versus non-FMS patients. All Saudi MS patients were identified from our registry. The history of PC was analyzed as a case-control study. In total 141 MS patients were identified. Of these, 30 (21%) reported having at least one affected relative, 37.6% reported PC and 16% presented first-degree PC. In addition, FMS patients were more likely than non-FMS patients to report PC. In conclusion, FMS is prevalent among Saudi MS patients. MS patients with a history of PC were more likely to have FMS, suggesting a potential role of consanguinity.

The consequences of interruption of natalizumab treatment are incompletely known. The objective was to assess the confirmed annualized relapse rates for patients preceding initiation, during and following suspension of natalizumab therapy. A chart review was conducted and data were analyzed using the Generalized Estimating Equations. During natalizumab therapy the confirmed annualized relapse rate was 0.08, compared to 0.52 (p = 0.0003) during the prior 12 months and to 0.35 (p = 0.0032) during the following 3 to 24 months. Similar results were found when confirmed and unconfirmed were analyzed. To conclude, following cessation of natalizumab therapy disease activity rapidly returned to pre-natalizumab levels.

We report a 55-year-old male patient with secondary progressive multiple sclerosis who developed an acute febrile syndrome with fever, neutrophilia and tender erythematous plaques and papules on his upper extremities after his fifth mitoxantrone infusion. Infectious, haematological and rheumatological diseases were ruled out, but skin biopsy showed neutrophilic infiltrations in the dermis consistent with Sweet’s syndrome. Treatment with oral corticosteroids led to prompt improvement of systemic and cutaneous symptoms. To our knowledge, this is the first report of a patient with Sweet’s syndrome after mitoxantrone therapy. Clinicians should be aware of Sweet’s syndrome in patients with otherwise unexplained acute febrile illness and erythematous skin rash in association with mitoxantrone therapy. Skin biopsy helped to exclude other diseases and confirmed Sweet’s syndrome.

Paraneoplastic cerebellar degeneration (PCD) is a rare non-metastatic complication of cancer mediated by T lymphocytes and auto-antibodies directed against Purkinje cells of the cerebellum. We report a patient with relapsing–remitting multiple sclerosis who developed a progressive cerebellar syndrome with dysarthria, ataxic gait and vertigo mimicking development of secondary progressive multiple sclerosis but caused by anti-Yo antibody positive PCD associated with ovarian cancer, presenting an unusual diagnostic challenge.