Perceived neuropsychological impairment inversely related to self-reported health and employment in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients frequently report cognitive difficulties which impact daily functioning. The objective was to investigate the relationship between patient-reported cognitive impairment and depression, demographic and MS-related variables, and to clarify its impact on self-reported health measures and employment. METHOD: A large two-centre survey included the MS Neuropsychological Screening Questionnaire (MSNQ), the two-question screening tool for depression, vitality, health-related quality of life, the Health-Promoting Lifestyle Profile II and questions assessing social network satisfaction and employment status. RESULTS: Of the 751 respondents (median age 54 years, median Expanded Disability Status Scale 5, 66.2% female), two-thirds reported perceived neuropsychological impairment or depressive symptoms. Whilst depressive symptoms were related to higher MSNQ scores, the MSNQ poorly predicted depression. After correcting for confounders, higher MSNQ scores and depressive symptoms decreased vitality, health-related quality of life and health-promoting behaviours and increased the probability of being socially dissatisfied. In participants below retirement age, higher MSNQ and Expanded Disability Status Scale scores increased the probability of unemployment, whilst depression did not. CONCLUSION: The contribution of the MSNQ to self-reported health measures and its unique explanatory power regarding unemployment suggest that subjective cognitive complaints are connected to subtle, yet meaningful, neuropsychological dysfunction.

Electronic visual analogue scales for pain, fatigue, anxiety and quality of life in people with multiple sclerosis using smartphone and tablet: a reliability and feasibility study.

OBJECTIVE: To explore the reliability and feasibility of electronic visual analogue scales in people with multiple sclerosis (MS) and healthy individuals. DESIGN: Cross-sectional observational study Setting: Clinical setting Subjects: Convenience sample of 52 people with MS and 52 matched healthy controls Interventions: NA Main measures: Participants scored 15 statements assessing fatigue, pain, anxiety and quality of life on an electronic visual analogue scale (eVAS), either using a smartphone or a tablet (randomly allocated). To check for test-retest reliability, statements were administered in two separate randomly ordered groups. Subjects completed a feasibility questionnaire. RESULTS: Mean (SD) eVAS scores ranged from 35 (28.1) to 80 (22.1) in MS group, and from 57 (28.0) to 86 (13.2) in controls. Intra Class Correlations ranged from 0.73 to 0.95 in MS sample; 0.61 to 0.92 in controls. For most statements, Bland-Altman plots indicated no systematic error, but relatively large random error of the eVAS scores (exceeding 20mm). Considerable ceiling effects (i.e. better health) were found in healthy controls. Similar reliability was found among smartphone or tablet, different demographic groups and the experience-groups. CONCLUSION: Electronic visual analogue scales are reliable and useful for people with MS to register fatigue, pain, anxiety and quality of life.

Self-reported levels of education and disability progression in multiple sclerosis.

OBJECTIVES: The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). MATERIALS AND METHODS: We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. RESULTS: Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. CONCLUSIONS: Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS.

The Symbol Digit Modalities Test as sentinel test for cognitive impairment in multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is found in about half of the multiple sclerosis (MS) population and is an important contributor to employment status and social functioning. CI is encountered in all disease stages and correlates only moderately with disease duration or Expanded Disability Status Scale scores. Most present neuropsychological test batteries are time-demanding and expensive. The Symbol Digit Modalities Test (SDMT) has been suggested as a screening tool for CI in MS. In this paper, we aim to assess the performance of the SDMT in predicting the outcome of an extensive battery. METHODS: Neuropsychological test results from 359 patients were assessed in a multidisciplinary MS center (National MS Center Melsbroek, Belgium). Using receiver operating characteristic curves, the performance of the SDMT in predicting the general cognitive outcome of the extensive Neuropsychological Screening Battery for MS (NSBMS) could be assessed. The performance of the SDMT was assessed for different levels of CI and compared with other cognitive tests. Finally, useful covariates were included in a logistic regression model. RESULTS: At a specificity of 0.60 a high sensitivity (0.91) was obtained indicating the potential of the SDMT as a sentinel test for CI in MS. The SDMT outperformed the individual tests included in the NSBMS, used as benchmark. As the logistic regression model did not result in a relevant improvement, it is concluded that most clinical variables influence both the SDMT and the NSBMS in a similar way. Excluding patients with possible practice effects, an optimal cutoff of 40 was found for the SDMT. CONCLUSION: As the SDMT is an easy, low-cost and fast test, this result may help to detect CI in everyday clinical practice.

Female gender and reproductive factors affecting risk, relapses and progression in multiple sclerosis.

Multiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS.

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis.

BACKGROUND: Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). OBJECTIVE: We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. METHODS: We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan-Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment. RESULTS: 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6. CONCLUSION: The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.

Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis.

Female gender and hormones have been associated with disease activity in multiple sclerosis (MS). We investigated age at menarche, use of oral contraceptives and pregnancy in relation to progression of disability in relapsing onset and progressive onset MS. We conducted a cross-sectional survey among individuals with MS, registered by the Flemish MS Society in Belgium. A time-to-event analysis and Cox proportional hazard regression were performed with time to Expanded Disability Status Score (EDSS) of 6 (requires a cane) as outcome measure. Hazard ratios for the time from onset and the time from birth were adjusted for age at onset and immunomodulatory treatment. Data on 973 women with definite MS were collected. In the relapsing onset group, women with at least two pregnancies had a reduced risk to reach EDSS 6 compared with nulliparous women. In the progressive onset group, later age at menarche was associated with a reduced risk to reach EDSS 6, whereas oral contraceptive use was associated with a higher risk of reaching EDSS 6. Our study corroborates the association of pregnancies with a reduced progression of disability in relapsing onset MS. In progressive onset MS, a slower progression was found in women with a later onset of menarche and a more rapid progression occurred when women reported the use of oral contraceptives.

Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis.

BACKGROUND: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). OBJECTIVES: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. METHODS: We conducted a cross-sectional survey amongst individuals with MS, registered by the Flemish MS society in Belgium. A time-to-event analysis and Cox proportional-hazard regression were performed with time to Expanded Disability Status Scale (EDSS) 6 (requiring a cane or support to walk for a distance of 100 m) as outcome measure. Hazard ratios for the time from onset and from birth were adjusted for age at onset, gender and immunomodulatory treatment. RESULTS: Data of 1372 persons with definite MS were collected. In the relapsing onset group, a decreased risk for reaching EDSS 6 was found in regular consumers of alcohol, wine, coffee and fish compared with those who never consumed these substances. Cigarette smoking was associated with an enhanced risk for reaching EDSS 6. In the progressive onset group, no association with the risk of reaching EDSS 6 was found, except for the type of fish. Preference for fatty fish was associated with an increased risk to reach EDSS 6, when lean fish was taken as the reference category. CONCLUSION: Consumption of alcoholic beverages, coffee and fish were inversely associated with progression of disability in relapsing onset MS, but not in progressive onset MS. These findings allow to support the hypothesis that different mechanisms might underlie progression of disability in relapsing and progressive onset MS.

Replication of KIF21B as a susceptibility locus for multiple sclerosis.

BACKGROUND: Knowledge of genetic susceptibility to autoimmune disorders is growing exponentially. One of the messages emerging from these data is the growing overlap in genetic susceptibility to different autoimmune disorders. KIF21B is a member of the kinesin superfamily and was recently established as a susceptibility locus for inflammatory bowel disease and for multiple sclerosis. RESULTS: We here replicate the association with multiple sclerosis in a Belgian study population of 791 patients and 1098 controls. CONCLUSION: As SNPs in KIF21B increase risk for both inflammatory bowel disease and multiple sclerosis, this suggests a common pathway in the pathogenesis of these diseases.

Modifiable factors influencing relapses and disability in multiple sclerosis.

A growing body of literature indicates that the natural course of multiple sclerosis can be influenced by a number of factors. Strong evidence suggests that relapses can be triggered by infections, the postpartum period and stressful life events. Vaccinations against influenza, hepatitis B and tetanus appear to be safe. Surgery, general and epidural anaesthesia, and physical trauma are not associated with an increased risk of relapses. Factors that have been associated with a reduced relapse rate are pregnancy, exclusive breastfeeding, sunlight exposure and higher vitamin D levels. A number of medications, including hormonal fertility treatment, seem to be able to trigger relapses. Factors that may worsen progression of disability include stressful life events, radiotherapy to the head, low levels of physical activity and low vitamin D levels. Strong evidence suggests that smoking promotes disease progression, both clinically and on brain magnetic resonance imaging. There is no evidence for an increased progression of disability following childbirth in women with multiple sclerosis. Moderate alcohol intake and exercise might have a neuroprotective effect, but this needs to be confirmed.

Long-term effects of childbirth in MS.

BACKGROUND: The uncertainty about long-term effects of childbirth presents MS patients with dilemmas. METHODS: Based on clinical data of 330 female MS patients, the long-term effects of childbirth were analysed, using a cross-sectional study design. Four groups of patients were distinguished: (1) without children (n = 80), (2) with children born before MS onset (n = 170), (3) with children born after MS onset (n = 61) and (4) with children born before and after MS onset (n = 19). A time-to-event analysis and Cox proportional hazard regression were performed with time from onset to EDSS 6 and age at EDSS 6 as outcome measure. RESULTS: After a mean disease duration of 18 years, 55% had reached EDSS 6. Survival curves show a distinct shift in the time to EDSS 6 between patients with no children after MS onset and patients with children after MS onset in favour of the latter. Cox regression analysis correcting for age at onset shows that patients with children only after MS onset had a reduced risk compared with patients without children (HR 0.61; 95% CI 0.37 to 0.99, p = 0.049). Also, patients who gave birth at any point in time had a reduced risk compared with patients without children (HR 0.66; 95% CI 0.47 to 0.95, p = 0.023). A similar pattern was seen for age at EDSS 6 (HR 0.57, p = 0.027 and HR 0.68, p = 0.032 respectively) CONCLUSION: Although a bias cannot fully be excluded, these results seem to support a possible favourable long-term effect of childbirth on the course of MS.

The effect of levetiracetam on tremor severity and functionality in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) intention tremor is a disabling symptom, which is difficult to treat. OBJECTIVES: To investigate the effects of levetiracetam, an antiepileptic drug, on tremor severity and related functionality in MS. METHODS: A randomized, double-blind, placebo-controlled, cross-over study examined the effects of 6 weeks of oral levetiracetam administration (starting dose=250 mg/day, maximal dose=2000 mg/day) in 18 MS patients with disabling intention tremor. Primary outcome was Fahn's Tremor Rating Scale (FTRS) A&B. Secondary outcome measures were the nine-hole peg test, patient's opinion rated with the visual analog scale, FTRS C, and an activities of daily life questionnaire and validated tremor indexes derived during the performance of a digitized spiral drawing task and a wrist step-tracking task. Repeated measures analysis of variance and Friedman tests were applied. RESULTS: In all, 14 patients completed the trial. Maximal dose intake ranged from 1000 to most commonly 2000 mg, depending on patients' tolerance level. No significant effects of levetiracetam were found for any outcome measure. Further analyses on subgroups with different tremor severity showed no differential effects. Eight patients reported adverse events such as fatigue and stomach ache. CONCLUSIONS: Levetiracetam intake of 2000 mg/day did not affect tremor severity or functionality in patients with MS.

Proxy ratings from multiple sources: disagreement on the impact of multiple sclerosis on daily life.

BACKGROUND AND PURPOSE: The use of self-report measurements may be problematic in patients with limitations that interfere with reliable self-assessment like cognitive impairment, as may be the case in multiple sclerosis (MS). In these situations proxy respondents, such as close relatives or healthcare providers, may provide valuable information. To examine the accuracy and value of healthcare providers and close relatives to assess disease impact of MS. METHODS: MS patients, close relatives and healthcare providers completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after a rehabilitation program. Agreement between outcomes was assessed by calculating mean absolute and directional differences and intraclass correlation coefficients. RESULTS: Comparison of ratings between patients and proxy respondents revealed low levels of agreement. Close relatives appeared to significantly overestimate the disease impact of MS whereas healthcare providers tended to underestimate the disease impact of MS. CONCLUSION: Caution is advised when incorporating close relatives and healthcare providers as proxy respondents in a rehabilitation setting. However, when close relatives are consulted, one should expect a certain level of overestimation of disease impact. When consulting healthcare providers, one should expect a certain level of underestimation of disease impact.

Origin of fatigue in multiple sclerosis: review of the literature.

Fatigue is one of the most common and most disabling symptoms of multiple sclerosis (MS). Although numerous studies have tried to reveal it, no definite pathogenesis factor behind this fatigue has been identified. Fatigue may be directly related to the disease mechanisms (primary fatigue) or may be secondary to non-disease-specific factors. Primary fatigue may be the result of inflammation, demyelination, or axonal loss. A suggested functional cortical reorganization may result in a higher energy demand in certain brain areas, culminating in an increase of fatigue perception. Higher levels of some immune markers were found in patients with MS-related fatigue, whereas other studies rejected this hypothesis. There may be a disturbance in the neuroendocrine system related to fatigue, but it is not clear whether this is either the result of the interaction with immune activation or the trigger of this process. Fatigue may be secondary to sleep problems, which are frequently present in MS and in their turn result from urinary problems, spasms, pain, or anxiety. Pharmacologic treatment of MS (symptoms) may also provoke fatigue. The evidence for reduced activity as a cause of secondary fatigue in MS is inconsistent. Psychological functioning may at least play a role in the persistence of fatigue. Research did not reach consensus about the association of fatigue with clinical or demographic variables, such as age, gender, disability, type of MS, education level, and disease duration. In conclusion, it is more likely to explain fatigue from a multifactor perspective than to ascribe it to one mechanism. The current evidence on the pathogenesis of primary and secondary fatigue in MS is limited by inconsistency in defining specific aspects of the concept fatigue, by the lack of appropriate assessment tools, and by the use of heterogeneous samples. Future research should overcome these limitations and also include longitudinal designs.

Within-session practice effect on paced auditory serial addition test in multiple sclerosis.

The paced auditory serial addition test (PASAT) is increasingly used in multiple sclerosis (MS) studies. Since these studies rely on repeated assessments with relatively short inter-test intervals, practice effects can be a confounding factor. We examined intra-session PASAT practice effects in 70 relapsing remitting (RR) and 40 secondary progressive (SP) patients. The average number of correct answers increased from 39.6+/-11.7 in the first PASAT run to 43.8+/-11.4 in the second run for the RR group, and from 39.1+/-11.6 to 41.8+/-13.3 in the SP group. PASAT scores showed a consistent decrease when comparing the second half of each test to the first half for both patient groups, and for both runs. Items for which the answer was a number greater than 9 had the same discrimination ability as other test items, but were significantly more difficult. A simulation of ;single-button' responses supported the use of the simplified scoring method which is currently used in fMRI studies. Our results demonstrate a within-session PASAT practice effect in MS, as well as a fatigability effect for both patient groups.

P300 and treatment effect of modafinil on fatigue in multiple sclerosis.

To evaluate the value of visual and auditory P300 for predicting the response of multiple sclerosis-related fatigue to modafinil treatment, 33 patients were treated with 100 mg modafinil once daily for 4 weeks, following a 4-week baseline phase and an optional 8-week extension phase. The main clinical outcome parameter was a decrease in the fatigue visual analogue score (VAS) before and after 4 weeks of treatment. Patients with shorter auditory P300 latency at baseline were more likely to benefit from modafinil treatment. Auditory P300 latency predicted treatment response with a specificity of 76% and a sensitivity of 75% at a cut-off latency of 350 ms. Visual P300 latency could not be used to predict treatment response. Baseline auditory P300 latency predicted treatment response, whereas visual P300 latency did not. Clinical improvement did not correlate with changes in either visual or auditory P300.

Long-term follow up of glatiramer acetate compassionate use in Belgium.

Between June 1995 and November 1998, 228 patients with relapsing-remitting Multiple Sclerosis started treatment with glatiramer acetate (Copaxone) 20 mg once daily in the frame of a "compassionate use" protocol in 15 Belgian centers. Following an average treatment period of 5.8 years, treating neurologists were requested to fill in follow-up forms indicating neurological disability status and side effects during the previous 6 months. These data were available for 134 patients. In this group, the Expanded Disability Status Scale (EDSS) improved in 26.3% of patients. An additional 36.8% of patients remained neurologically stable. The Ambulation Index (AI) showed similar results: 12.5% of patients improved, 50% of patients remained stable, and 37.5% worsened. Only 10% of patients dropped out due to several reasons. The adverse events occurring in the period preceding the follow-up survey were non-serious and consistent with the current product information of glatiramer acetate. Among the 94 patients no longer followed-up in the compassionate program, reasons for lost to follow-up were obtained for 63; most of them (41) had stopped GA treatment or switched to another disease-modifying treatment. Overall these results are very similar to the ones reported in the extension study of the pivotal trial (Johnson et al., 2000), and indicate that patients treated with glatiramer acetate have a better outcome than expected on the basis of the natural course of the disease. Despite limitations of the study design, this report confirms the sustained efficacy of glatiramer acetate in reducing the disease progression in patients with relapsing-remitting multiple sclerosis treated in day-to-day clinical practice.

Victimization in chronic fatigue syndrome and fibromyalgia in tertiary care: a controlled study on prevalence and characteristics.

The authors studied the prevalence and characteristics of different forms of victimization in 95 patients suffering from chronic fatigue syndrome (CFS) or fibromyalgia (FM) compared with a chronic disease group, including rheumatoid arthritis (RA) and multiple sclerosis (MS) patients, and a matched healthy control group. The authors assessed prevalence rates, nature of victimization (emotional, physical, sexual), life period of occurrence, emotional impact, and relationship with the perpetrator by a self-report questionnaire on burdening experiences. CFS and FM patients showed significantly higher prevalences of emotional neglect and abuse and of physical abuse, with a considerable subgroup experiencing lifelong victimization. The family of origin and the partner were the most frequent perpetrators. With the exception of sexual abuse, victimization was more severely experienced by the CFS/FM group. No differences were found between healthy control subjects or RA/MS patients, and between CFS and FM patients. These findings support etiological hypotheses suggesting a pivotal role for chronic stress in CFS and FM and may have important therapeutic implications.

T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls.

Myelin proteins, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) are candidate autoantigens in MS. It is not clear whether MS patients show a predominant reactivity to one or several myelin antigens. We evaluated the IFN-gamma production induced by MBP and MOG and selected MBP-, MOG- and PLP-peptides in MS patients and healthy controls using the IFN-gamma ELISPOT assay. Most MS patients and healthy controls showed a heterogeneous anti-myelin T-cell reactivity. Interestingly in MS patients a positive correlation was found between the anti-MOG and anti-MBP T-cell responses. No myelin peptide was preferentially recognized among the peptides tested (MBP 84-102, 143-168, MOG 1-22, 34-56, 64-86, 74-96, PLP 41-58, 184-199, 190-209). In addition the frequency of IL2R+ MBP reactive T-cells was significantly increased in blood of MS patients as compared with healthy subjects, indicating that MBP reactive T-cells exist in an in vivo activated state in MS patients. Most of the anti-MBP T-cells were of the Th1-type because reactivity was observed in IFN-gamma but not in IL-4 ELISPOT-assays. Using Th1 (IL-12) and Th2 (IL-4) promoting conditions we observed that the cytokine secretion pattern of anti-MBP T-cells still is susceptible to alteration. Our data further indicate that precursor frequency analysis of myelin reactive T-cells by proliferation-based assays may underestimate the true frequency of myelin specific T-cells significantly.

A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis.

A double-blind clinical trial of mitoxantrone versus methylprednisolone was performed in 49 patients with relapsing, secondary multiple sclerosis. Patients were randomized to receive 13 infusions of mitoxantrone 12 mg/m2 (n = 28), or 13 infusions of 1 g of methylprednisolone (n = 21), over 32 months. Twenty-four patients completed the trial. There were no statistical differences between the two groups of patients at study entry. A significant improvement in the Expanded Disability Scale Score (EDSS) was observed in the mitoxantrone group after one year of treatment (p < 0.0022). The total number of relapses, the mean number of relapses/patient/year, and the total number of gadolinium-enhanced lesions on bi-annual MRI scans were significantly decreased in the mitoxantrone group throughout the study period. Nausea, vomiting, and alopecia were more frequent in the mitoxantrone-treated patients. Mitoxantrone has a role in the treatment of MS patients with frequent exacerbations and rapid disease progression.