Marie B. D'hooghe

Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression

Accumulating evidence indicates an immunosuppressive role for CD4+CD25+ regulatory T cells (Tregs) in autoimmune diseases. Although an impaired Treg function in patients with relapsing‐remitting multiple sclerosis (RR‐MS) has been reported recently, no information is available so far about Treg function in the progressive stage of the disease. In the present study, the phenotypic and functional characteristics of CD4+CD25+ T cells isolated from the peripheral blood of patients with RR‐MS and secondary progressive multiple sclerosis (SP‐MS) were investigated. No significant quantitative or phenotypic abnormalities in CD4+CD25+ T cells from RR‐ and SP‐MS patients were detected. However, whereas a reduced suppressor function of CD4+CD25+ T cells toward proliferation and interferon‐γ production of CD4+CD25– responder T cells was found in RR‐MS patients, SP‐MS patients showed a normal Treg function. The suppressive capacity of MS‐derived CD4+CD25+ T cells was correlated with disease duration but not with age, indicating that Treg function is more affected in the early phase of the disease process. Consistently with the suppressive capacity, CD4+CD25+ T cells from SP‐MS patients showed normal levels of FOXP3 mRNA in contrast to RR‐MS patients that had a reduced FOXP3 expression. These data are the first to demonstrate differences in function and FOXP3 expression of CD4+CD25+ T cells from patients with RR‐ and SP‐MS.

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 (nu200a=u200a80), (2) with children born before MS onset (nu200a=u200a170), (3) with children born after MS onset (nu200a=u200a61) and (4) with children born before and after MS onset (nu200a=u200a19). 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, pu200a=u200a0.049). 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, pu200a=u200a0.023). A similar pattern was seen for age at EDSS 6 (HR 0.57, pu200a=u200a0.027 and HR 0.68, pu200a=u200a0.032 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.

A rapid screening tool for fatigue impact in multiple sclerosis

BackgroundFatigue is a common complaint in multiple sclerosis (MS) and often interferes with daily functioning. Both clinicians and researchers may need to detect high levels of fatigue impact using a time and effort efficient tool. This study evaluates the psychometric properties of a rapid screening instrument for fatigue impact in multiple sclerosis.MethodsThree visual analogue scales (VAS) for assessing the impact of fatigue were developed. Sixty two subjects with definite MS (mean age 52 +/- 10.5 years; 29 women) and 24 healthy controls (mean age 52 +/- 14 years; 13 women) completed all VAS scales (range 0–100), the Fatigue Severity Scale (FSS) (range 7–63), the Modified Fatigue Impact Scale (MFIS) (range 0–84) and the Guys Neurological Disability Scale (GNDS) (range 0–5). All tests were repeated with an interval of maximum three days.To evaluate the reproducibility, intraclass correlations (ICC) were calculated, based on one-way analysis of variance for repeated measurements. Validity was considered by means of correlation coefficients. ROC analysis was used to determine the accuracy of the VAS scales.ResultsThe ICC of the VAS scales ranged from 0.68 to 0.69. VAS scales showed low to moderate correlation with FSS, MFIS and GNDS (Kendalls tau 0.23–0.45) and were not related with physical or cognitive performance, or with depression. All VAS scales were able to discriminate between subjects with MS and controls. Twenty five subjects with MS had a Fatigue Severity Scale score of 36 or more and were classified into the fatigue group. ROC analysis showed that VAS_1 is most useful to classify subjects in the fatigue group. A cut-off value of VAS_1 of 59 displayed 76% sensitivity and 72% specificity. When using the MFIS score of 40 or more to classify the groups, VAS_1 remained the strongest tool, with 81% sensitivity and 77% specificity at a cut-off value of 59.ConclusionThe VAS for the impact of fatigue on daily life (VAS_1) is a moderately reliable, though valid and useful tool to screen rapidly for fatigue impact in multiple sclerosis. A cut-off value of 59 satisfactorily classifies individuals having severe fatigue with a high impact on daily life. In clinical practice, a more comprehensive assessment of fatigue and the impact on daily life is recommended.

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

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.

Measuring activity patterns using actigraphy in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease resulting in impairments in motor and mental performance and restrictions in activities. Self‐report instruments are commonly used to measure activity patterns; alternatively, actigraphs can be placed on several parts of the body. The aims of this study were to evaluate the superiority and specificity of actigraph placement (wrist vs. ankle) in subjects with MS and healthy controls and explore the relationship between self‐report and objective activity patterns. A total of 19 subjects with definite MS and 10 healthy volunteers wore actigraphs on the non‐dominant wrist and ankle for three days while they kept a log to register performed activities every. 5 h. Wrist and ankle actigraphs produced similar activity patterns during the most active hours (09∶00–20∶30 h) (ANOVA, time×location interaction: F=.901, df=23, p=.597) in individuals with MS and healthy controls (between subjects factor F=3.275, p=.083). Wrist placement of the actigraphs was better tolerated than ankle placement. Wrist actigraph data corresponded to a higher degree with self‐reported activities of the upper limbs in the early afternoon, whereas ankle data seem to reflect better whole body movements in the later afternoon/early evening. Overall, actigraph data correlated moderately with self‐reported activity (r=.57 for ankle and r=.59 for wrist). The regression model revealed that self‐reported activities explained 44% of the variance in ankle and 50% of wrist data. Wrist and ankle actigraphs produce similar activity patterns in subjects with MS and in healthy controls; however, the placement of actigraphs on the wrist is better tolerated. Ankle actigraphs reflect general movement but underestimate upper body activity. Subjective registration of activity level partly matches with objective actigraph measurement. A combination of both objective and subjective activity registration is recommended to evaluate the physical activity pattern of subjects with MS.

Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon \beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial

Anti-inflammatory drugs are effective on relapses, but neuroprotective agents to prevent disability are still unavailable. Uric acid has neuroprotective effects in experimental models including encephalomyelitis and appears to be involved in multiple sclerosis. Oral administration of inosine, a precursor of uric acid, increases serum uric acid levels and is well tolerated. Our objective was to test the possibility that a combination therapy associating an anti-inflammatory drug (interferon β) and an endogenous neuroprotective molecule (uric acid) would be more effective than interferon β alone on the accumulation of disability. Patients with relapsing—remitting multiple sclerosis on interferon β for at least 6 months were randomized to interferon β + inosine or interferon β + placebo for 2 years. The dose of inosine was adjusted to maintain serum uric acid levels in the range of asymptomatic hyperuricaemia (≤10 mg/dl). The primary end points were percentage of patients with progression of disability and time to sustained progression (Kaplan—Meier analysis). The combination of interferon β and inosine was safe and well tolerated but did not provide any additional benefit on accumulation of disability compared with interferon β alone. We conclude that endogenous neuroprotective mechanisms recently identified in multiple sclerosis are complex and uric acid does not reflect the entire story.

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.

Cerebral hypoperfusion: a new pathophysiologic concept in multiple sclerosis?

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.

Graph theoretical analysis indicates cognitive impairment in MS stems from neural disconnection.

Background The mechanisms underlying cognitive impairment in MS are still poorly understood. However, due to the specific pathology of MS, one can expect alterations in connectivity leading to physical and cognitive impairment. Aim In this study we aimed at assessing connectivity differences in EEG between cognitively impaired (CI) and cognitively preserved (CP) MS patients. We also investigated the influence of the measures used to construct networks. Methods We included 308 MS patients and divided them into two groups based on their cognitive score. Graph theoretical network analyses were conducted based on networks constructed using different connectivity measures, i.e. correlation, correlation in the frequency domain, coherence, partial correlation, the phase lag index and the imaginary part of coherency. The most commonly encountered network parameters were calculated and compared between the two groups using Wilcoxons rank test. Clustering coefficients and path lengths were normalized to a randomized mean clustering coefficient and path length for each patient. False discovery rate was used to correct for the multiple comparisons and Cohens d effect sizes are reported. Results Coherence analysis suggests that theta and delta connectivity is significantly smaller in cognitively impaired patients. Small-worldness differences are found in networks based on correlation, theta and delta coherence and correlation in the frequency domain. Modularity was related to age but not to cognition. Conclusion Cognitive deterioration in MS is a symptom that seems to be caused by neural disconnections, probably the white matter tracts connecting both hemispheres, and leads to a wide range in network differences which can be assessed by applying GTA to EEG data. In the future, these results may lead to cheaper and more objective assessments of cognitive impairment in MS.

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.