Vitamin D, HLA-DRB1 and Epstein-Barr virus antibody levels in a prospective cohort of multiple sclerosis patients.

BACKGROUND AND PURPOSE: Our objective was to study the association between serum levels of anti Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody and 25-hydroxyvitamin D (25(OH)D) in a prospective cohort of patients with relapsing-remitting multiple sclerosis. METHOD: The study comprised 90 patients with relapsing-remitting multiple sclerosis, all participants in a randomized clinical trial of ω-3 fatty acids (the OFAMS study). Repeated, paired measurements of serum 25(OH)D and serum EBNA-1 immunoglobulin G (IgG) levels were obtained at baseline and every 6 months for 24 months. The association between serum EBNA-1 IgG and serum 25(OH)D levels was analysed using generalized linear models for hierarchical data. RESULTS: There was a significant variation in EBNA-1 IgG antibody level between sampling months (Fdf 11 = 1.8, P = 0.043, one-way anova). There was a negative association between EBNA-1 IgG and 25(OH)D [B = -0.230, 95% confidence interval (CI) (-0.440, -0.023), P = 0.030] and a positive association between EBNA-1 IgG and HLA-DRB1*15 positive status [B = 94.7, 95% CI (2.423, 186.9), P = 0.044]. The association between 25(OH)D and EBNA-1 IgG remained significant after adjusting for the patient's age, gender, HLA-DRB1*15, retinol levels and interferon ß-1a treatment. CONCLUSION: Our study demonstrates monthly differences in EBNA-1 IgG levels and an association between EBNA-1 IgG, 25(OH)D levels and HLA-DRB1*15. These results indicate that EBNA-1 IgG serum levels are affected by genetic and environmental factors that also modulate multiple sclerosis risk.

Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.

BACKGROUND: The evidence base in cognitive rehabilitation in multiple sclerosis (MS) is still sparse. OBJECTIVE: The aim of the study was to investigate the effects of cognitive rehabilitation on cognitive and executive coping, psychological well-being and psychological aspects of health-related quality of life (HRQoL) in patients with MS. METHODS: One hundred and twenty patients with cognitive complaints, taking part in a 4-week multidisciplinary rehabilitation, were randomized to an intervention group (n = 60) and a control group (n = 60). Both groups underwent neuropsychological assessment with subsequent feedback and took part in general multidisciplinary MS rehabilitation. Additionally, the intervention group participated in cognitive group sessions as well as individual sessions. The main focus was to formulate Goal Attainment Scaling goals for coping with cognitive challenges. For 3 months past rehabilitation, the intervention group received biweekly telephone follow-up, focusing on goal attainment. RESULTS: Executive functioning improved significantly from baseline to four and 7 months in both groups. Improvements in psychological well-being and psychological aspects of HRQoL occurred only in the intervention group. CONCLUSION: Multicomponent cognitive rehabilitation administered within the context of multidisciplinary rehabilitation can improve psychological well-being and psychological aspects of HRQoL.

WT1 and interferon-ß-vitamin D association in MS: a longitudinal study.

BACKGROUND: It has been suggested that polymorphisms in the WT1 gene modulate the effect of IFN-ß treatment in multiple sclerosis (MS) through regulation of the relationship between IFN-ß and vitamin D. OBJECTIVE: To examine whether WT1 modulates the relationship between IFN-ß and vitamin D in a longitudinal study with repeated assessment of vitamin D before and after initiation of IFN-ß. METHODS: In a prospective study of 85 patients with relapsing remitting MS, 25-hydroxyvitamin D was measured at month 0, 1, 3, 6, 7, 9, 12, 18 and 24. None of the patients used any immunomodulatory treatment at inclusion, and all started IFN-ß treatment at month 6. RESULTS: The mean concentrations of seasonally adjusted 25-hydroxyvitamin increased slightly (3.1 ± 1.2 nmol/l, P = 0.008) after initiation of IFN-ß. The association between IFN-ß treatment and 25-hydroxyvitamin D was similar in patients carrying any of the two alleles in the WT1 SNPs (rs10767935 and rs5030244) recently reported to modulate this relationship. CONCLUSIONS: In this prospective study with repeated measurements of 25-hydroxyvitamin D before and during treatment with IFN-ß, we did not find that genetic variation in WT1 plays any role in regulating the relationship between IFN-ß and serum 25-hydroxyvitamin D.

Predictors of executive complaints and executive deficits in multiple sclerosis.

OBJECTIVES: To investigate executive complaints and objective executive deficits and their relations to both depression and neurological function in multiple sclerosis (MS). MATERIALS AND METHODS: One hundred and twenty MS patients participating in multidisciplinary rehabilitation underwent assessment with the Expanded Disability Status Scale (EDSS), neuropsychological tests of executive function, self-report measures of executive function (BRIEF-A), and depression (BDI-II). RESULTS: Multivariate regression analysis showed that moderate depression and above (BDI-II > 20) significantly predicted a high degree of subjective executive complaints. Multivariate regression analysis showed that EDSS scores above 4.3 significantly predicted executive cognitive deficit, measured by neuropsychological tests. CONCLUSION: Among the study variables, depression was the strongest predictor of executive complaints. A high degree of neurological disability was the strongest predictor for executive deficit, measured by neuropsychological tests.

Modelling and prediction of 25-hydroxyvitamin D levels in Norwegian relapsing-remitting multiple sclerosis patients.

BACKGROUND/AIM: 25-Hydroxyvitamin D (25(OH)D) levels are suggested to influence the susceptibility and risk of disease progression in multiple sclerosis (MS). Seasonal fluctuation of 25(OH)D levels may differ in magnitude between individuals. The purpose of this paper was to model the seasonal fluctuation of vitamin D in Norwegian MS patients and to examine to which extent one single 25(OH)D measurement predicts the level at other time points throughout the year. METHODS: During December 2004 and July 2008, 762 serum samples were collected from 92 Norwegian relapsing-remitting MS patients. Time series analysis and multivariate modelling techniques were used to model seasonal fluctuations and intra- and inter-individual variations in 25(OH)D values. RESULTS: Most patients reached their lowest 25(OH)D level in March/April and the highest in July/August. There were substantial intra-individual variations in the extent of seasonal fluctuation, with 36.6% of explainable variation in seasonally adjusted 25(OH)D levels (on a logarithmic scale) attributable to the patient level. The remaining 63.4% could be accounted for by sources of inter-individual variation. Both the total and inter-individual variabilities were lowest in February, and the prediction interval in this month was up to 26% narrower compared to other months. The prediction intervals would be at least 21% wider with only one observation available per patient. CONCLUSIONS: The seasonal fluctuations of 25(OH)D levels in Norwegian relapsing-remitting MS patients are subject to pronounced intra- and inter-individual variation. The most representative measurements of 25(OH)D levels are taken in February.

Validation of the multiple sclerosis international quality of life (MusiQoL) questionnaire in Norwegian patients.

OBJECTIVES: To assess the validity and reliability of the multidimensional, self-administered Multiple Sclerosis International Quality of Life (MusiQoL) questionnaire, previously validated in a large international sample, in Norwegian patients. PATIENTS AND METHODS: Patients with different types and severities of multiple sclerosis (MS) were recruited from a single MS centre in Norway. All patients completed the MusiQoL and Short Form-36 (SF-36) QoL questionnaires at baseline and a mean of 21 (SD 7) days later. A neurologist collected sociodemographic, MS history and outcome data. Construct validity, internal consistency, reproducibility and external consistency were tested. RESULTS: One hundred and four patients were evaluated. Construct validity was confirmed in terms of satisfactory item internal consistency correlations in eight of nine MusiQoL dimensions (Spearman's correlation: 0.34-0.79) and scaling success of item discriminant validity (75.0-100%). All dimensions of the MusiQoL questionnaire exhibited satisfactory internal consistency (Cronbach's alpha: 0.44-0.87) and reproducibility (intraclass correlation coefficients: 0.36-0.86). External validity testing showed that the global MusiQoL score correlated significantly with all but one individual SF-36 dimension score (Spearman's correlation: 0.29-0.56). CONCLUSIONS: These results demonstrate that the Norwegian-language version of the MusiQoL questionnaire is a valid and reliable instrument for assessing health-related QoL in Norwegian patients with MS.

Fatigue in multiple sclerosis: associations with health-related quality of life and physical performance.

BACKGROUND AND PURPOSE: fatigue is a common, but still one of the least understood symptoms in multiple sclerosis (MS). We aimed to investigate whether fatigue was associated with demographic-, clinical-, health-related quality of life (HRQoL)- and physical performance variables, and whether change in fatigue after treatment was associated with changes in HRQoL and physical performance. METHODS: sixty patients were included for inpatient physiotherapy. Fifty-six patients completed the study and were available for analysis. Fatigue (Fatigue Severity Scale; FSS), HRQoL (Multiple Sclerosis Impact Scale; MSIS-29) and physical performance (walking ability and balance) were assessed at screening, baseline, after treatment and at follow-up after 3 and 6 months. We analysed possible associations between fatigue and other variables at baseline by regression models, and between change in fatigue versus changes in both HRQoL and physical performance variables after physiotherapy by correlation analysis. RESULTS: fatigue at baseline was associated with HRQoL (explained 21.9% of variance), but not with the physical performance tests. Change in fatigue was correlated with change in HRQoL, but not with changes in physical performance. All measures were improved after treatment (P ≤ 0.001). While improvements in fatigue and HRQoL were lost at follow-up, improvements in physical performance tests were maintained for at least 6 months (P ≤ 0.05). CONCLUSIONS: fatigue was associated with HRQoL at baseline. Improvement in fatigue seemed to be related to other factors than improvement in physical performance. A broader strategy including both physical and psychological dimensions seems to be needed to improve fatigue over the long-term.

The influence of warm versus cold climate on the effect of physiotherapy in multiple sclerosis.

OBJECTIVE: To compare the effect of inpatient physiotherapy in a warm versus cold climate in short- and long-term perspectives. METHODS: Sixty multiple sclerosis (MS) patients with gait problems, without heat intolerance, were included in a randomized cross-over study of 4-week inpatient physiotherapy in warm (Spain) and cold (Norway) climate. The primary outcome, 6-min walk test (6MWT), and secondary physical performance and self-reported measures were scored at screening, baseline, after treatment and at 3 and 6 months of follow-up. Treatment effects were analysed by mixed models. RESULTS: After treatment, the mean walking distance had increased by 70 m in Spain and 49 m in Norway (P = 0.060). Improvement in favour of warm climate was demonstrated at 6 months of follow-up, 43 m (Spain) compared to 20 m (Norway) (P = 0.048). The patients reported less exertion after walking (6MWT) in favour of treatment in Spain at all time points (P < 0.05). No significant differences in change were detected for the other physical performance measures. Most self-reported measures showed more improvement after treatment in Spain, but these improvements were not sustained at follow-up. CONCLUSION: The results indicate that MS patients without heat intolerance have additional benefits from physiotherapy in a warm climate.

Fatigue in Parkinson's disease: a short update.

This article provides a short update on fatigue in Parkinson's disease (PD), focusing on measurements, prevalence, associated factors, pathophysiology and treatment. As long as there is no universally accepted definition of fatigue the definition used has to be stated. Different aspects of fatigue, namely physical-, mental- and chronic fatigue will be discussed. The many questionnaires used to assess fatigue measure different aspects of fatigue, making comparisons between studies difficult. Examples of uni- and multidimensional self-report questionnaires are given. In PD patients, the wide range of prevalence of fatigue (37-56%) is largely because of varying definitions of fatigue and populations tested. Without understanding the pathophysiology of subjective fatigue, the development of effective therapies is a challenge.

Pain in Parkinson's disease: Prevalence and characteristics.

Parkinson's disease is a chronic, progressive, incurable neurodegenerative disease. As the disease progresses, motor disturbances and non-motor symptoms represent considerable illness burdens. Symptom relief is the goal for the treatment. Pain is frequently observed in patients with Parkinson's disease, but its prevalence, characteristics and associations with Parkinson's disease are poorly documented. These were investigated in 176 home-living PD patients. They underwent a neurological examination and a structured interview for registration of pain characteristics in addition to responding to standardised questionnaires. Pain was reported by 146 (83%) patients. Compared to the general population, the Parkinson's disease patients experienced significantly more pain as measured by SF-36 Bodily Pain Scale. The average pain during the last 24h measured by the Brief Pain Inventory was 2.85. Fifty-three percent of the patients reported one, 24% reported two and 5% reported three pain types. Musculoskeletal pain was reported by 70%, dystonic pain by 40%, radicular-neuropathic pain by 20% and central neuropathic pain by 10%. Thirty-four percent were on analgesic medication. Pain was not associated with age, disease duration or severity of the disease; female gender was the only significant predictor of pain. Pain is frequent and disabling, independent of demographic and clinical variables except for female gender, and is significantly more common in Parkinson's patients compared to the general population. A minority of the Parkinson's disease patients with pain received analgesic medication. The findings call for improved attention to assessment and treatment of pain in the follow-up of Parkinson's disease patients.

Depression and anxiety amongst multiple sclerosis patients.

The aim of this study was to investigate the prevalence of symptoms of depression and anxiety amongst multiple sclerosis (MS) patients, and the associations with demographic and clinical characteristics. The current treatment for depression and anxiety was also evaluated amongst the MS patients. A total of 140 MS patients from Eastern Norway underwent neuropsychiatric and clinical examinations, with registration of symptoms of depression and anxiety (Hopkins Symptom Checklist-25), as well as information about any help seeking for depression were obtained. A total of 31.4% patients reported symptoms of depression, whilst 19.3% reported anxiety; both symptoms were significantly higher than that amongst the general population (P < 0.001). Fatigue and younger age at onset were significantly associated with symptoms of depression, whilst fatigue and pain, lower Expanded Disability Status Scale score and younger age at onset were associated with symptoms of anxiety. The proportion of reported treatment of depression was 15.9% and for anxiety 11.1%. Of untreated patients with symptoms, 18.2% expressed the need for treatment. A greater focus on depression and anxiety amongst MS patients is needed to establish the appropriate treatment for patients suffering from MS.

Quality of life among young patients with ischaemic stroke compared with patients with multiple sclerosis.

OBJECTIVES: We aimed to evaluate the quality of life among young ischaemic stroke (IS) patients at long-term follow-up by comparing them with multiple sclerosis (MS) patients with secondary progressive course. The mean age at stroke onset was 41.6 years. METHODS: Nottingham Health Profile scores were obtained from 191 IS patients 6 years (mean) after the index stroke, from 337 MS patients 5 years (mean) after the onset of the secondary progressive course and from 216 controls. RESULTS: The mean age of IS patients was 47.8 years and MS patients 44.5 years at follow-up. The MS patients as a group had worse subscores than the IS patients. When adjusting for physical mobility, complaints of fatigue (P = 0.012) were more frequent among MS patients, whereas pain (P < 0.001) and sleep (P = 0.007) disturbances were more frequent among IS patients. CONCLUSION: The comparison of IS and MS patients highlights the importance of pain and sleep disturbances among IS patients when adjusting for physical mobility.

Health-related quality of life in secondary progressive multiple sclerosis.

Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta1a (IFN-beta1a), 22 mug subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS.

IL-10 promoter haplotype influence on interferon treatment response in multiple sclerosis.

The level of interleukin-10 (IL-10) expression is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 gene, which constitute three haplotypes, GCC, ATA, and ACC. The ATA (a non-GCC) haplotype, which is associated with low IL-10 expression, has been shown to improve interferon (IFN) treatment response in hepatitis C. We analysed the distribution of IL-10 promoter haplotype combinations to determine whether they could influence initial IFN treatment response in 63 patients with relapsing-remitting multiple sclerosis (MS). The patients were grouped into non-GCC or GCC haplotypes, and the clinical and magnetic resonance imaging (MRI) disease activity was compared in the two groups. During the first 6 months of treatment, MS patients with non-GCC haplotypes experienced fewer new MRI T1-contrast enhancing lesions [0.77+/-0.36 (SEM)] than patients with the GCC haplotype (2.45+/-0.57) (P=0.05, Mann-Whitney U test). No differences were detected on clinical disease activity. The results suggest an influence of IL-10 promoter polymorphisms on IFN treatment response in MS.

Pain and sensory complaints in multiple sclerosis.

Pain is a frequent and disabling symptom among multiple sclerosis (MS) patients. The importance of this problem was investigated in a hospital based MS population. A total of 142 MS patients underwent neurological examination and a structured interview for registration of pain and sensory symptoms. One-hundred and five patients reported sensory and/or pain symptoms. Pain was reported by 93 patients and was most frequently located in the limbs and lumbar region. The presence of pain was independent of gender, age at onset and examination, disability, disease course and duration. The most frequently reported characteristics of the symptoms were paresthesia, neuralgia and deep muscular aching. About 40% of the patients reported that the symptoms had important influence on daily activities. Only one-third of the patients were treated for their pain. Pain is a frequent and disabling symptom, independent of demographic and clinical variables in MS patients. The low frequency of treatment for these symptoms indicates a need for improved attention to this problem.

The effect of tolcapone on the pharmacokinetics of benserazide.

This study investigated the potential interaction between tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, and the decarboxylase inhibitor, benserazide. In an open-labelled six-week study, patients with Parkinson's disease (PD), treated with levodopa/benserazide, were given tolcapone at 200 mg t.i.d. Blood samples for analysis of benserazide, its main active metabolite, trihydroxybenzylhydrazine, levodopa and 3-O- methyldopa (3-OMD) were collected immediately before and repeatedly after the first drug intake of the day at baseline and after 1-2 and 6 weeks of treatment. Furthermore, animal experiments were performed to determine the levels of benserazide and trihydroxybenzylhydrazine at doses for which safety had previously been established. It was shown that tolcapone can cause an increase in benserazide plasma concentrations and that this effect is dependent on the benserazide dose. When tolcapone was combined with 25 mg benserazide the elevation was small. Although the increase was more pronounced when tolcapone was combined with 50 mg benserazide, the levels were still substantially lower than concentrations causing toxicity in animals. The safety margin derived from this study, together with the absence of any organic toxic effects in clinical trials, show that the observed interaction between tolcapone and benserazide does not represent a safety concern for PD patients treated with this combination.

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

BACKGROUND: More than 50% of patients with Parkinson's disease develop motor response fluctuations (the 'wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa. OBJECTIVES: The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone. METHODS: In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. RESULTS: After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (p < 0.01 vs. placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (p < 0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (p < 0.05), "on" time increased by 21.3% (p < 0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (p < 0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhoea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100 mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea. CONCLUSION: Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy.

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

BACKGROUND: More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa. OBJECTIVES: The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone. METHODS: In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. RESULTS: After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P

The HLA-DQ(alpha 1*0102, beta 1*0602) heterodimer may confer susceptibility to multiple sclerosis in the absence of the HLA-DR(alpha 1*01, beta 1*1501) heterodimer.

The frequencies of DR2, DQ6-related DRB1, DQA1, DQB1 haplotypes were compared in 181 multiple sclerosis patients and 294 controls in Norway. All individuals carried either DR2 or DQ6, i.e., the DQ(alpha 1*0102, beta 1*0602) heterodimer. The DR(alpha 1*01, beta 1*1501) and the DQ(alpha 1*0102, beta 1*0602) heterodimers were carried by 171 of the patients (94%) and 289 (98%) of the controls. Seven of the patients and one of the controls carried the DQ(alpha 1*0102, beta 1*0603) heterodimer together with the DR(alpha 1*01, beta 1*1501) heterodimer. Two patients carried the DQ(alpha 1*0102, beta 1*0602) heterodimer in the absence of the DR( alpha 1*01, beta 1*1501) heterodimer. The DR(alpha 1*01, beta 1*1501) heterodimer was not observed in the absence of the DQ(alpha 1*0102, beta 1*0602) heterodimer or the DQ(alpha 1*0102, beta 1*0603) heterodimer, neither in the patients nor in the controls. Our findings indicate that the genes encoding the DQ(alpha 1*0102, beta 1*0602) heterodimer may confer susceptibility to developing multiple sclerosis in the absence of the DRB1*1501 allele.