Oral Dimethyl Fumarate in Children With Multiple Sclerosis: A Dual-Center Study

BackgroundFirst-line injectable therapies for multiple sclerosis in children may be ineffective or not well-tolerated. There is therefore an urgent need to explore oral medications for pediatric multiple sclerosis. We review our dual-center experience with oral dimethyl fumarate.MethodsThis study was a retrospective review of children 18 years of age or less with multiple sclerosis treated with dimethyl fumarate at Yale University and the University of Colorado. Clinical, demographic, and magnetic resonance imaging parameters were analyzed.ResultsWe identified 13 children treated with oral dimethyl fumarate for a median of 15.0 months (range, 1 to 25). Dimethyl fumarate was utilized as first-line therapy in five children (38%). Ten children (77%) tolerated dose escalation to the usual adult dose of 240 mg twice daily. Nine children had ≥12 months of follow-up on treatment. Eight of nine (89%) displayed stabilized or reduced relapse rates and disability scores on treatment. Nine children underwent brain magnetic resonance imaging performed after 12 or more months of therapy. New T2 lesions were observed in three children (33%), one of whom had been nonadherent to treatment. Common side effects included facial flushing (8/13, 62%), gastrointestinal discomfort (7/13, 54%), rash (3/13, 23%), and malaise (2/13, 15%). Three children (23%) discontinued treatment because of side effects. No patients displayed laboratory abnormalities including lymphopenia or abnormal liver transaminases. There were no reported infections.ConclusionsOral dimethyl fumarate appears to be safe and generally well tolerated in children with multiple sclerosis. Formal clinical trials to evaluate efficacy are ongoing.     

维生素D_3添加治疗复发型多发性硬化的临床随机对照研究

目的采用临床随机对照研究维生素D3添加治疗复发型多发性硬化(MS)患者的临床疗效和安全性。方法缓解复发型MS患者72例,随机分成维生素D3组(甲泼尼龙+维生素D3治疗)和激素组(甲泼尼龙治疗,为对照),每组36例,维生素D3组在激素治疗基础上添加骨化三醇胶丸口服。治疗前后记录症状、体征,评定扩展残疾状态评分(EDSS)分值,治疗后随访2年。疗效评定考核指标采用MS年复发次数,复发间隔时间,EDSS评分下降值。结果治疗前维生素D3组年龄、病程、复发次数、EDSS数值与激素组比较,差异无统计学意义(P0.05);治疗后第6、12个月EDSS数值与激素组比较,差异也无统计学意义(P0.05)。治疗后第24个月,维生素D3组与激素组比较EDSS数值(P0.05)、年复发次数(P0.05)、复发间隔时间(P0.01),差异有统计学意义。结论维生素D3添加治疗能减少MS的复发次数、延长复发间歇时间、延缓残疾进展速度。     

Evaluation of response of multiple sclerosis (MS) relapse to oral high-dose methylprednisolone: usefulness of MS functional composite and Expanded Disability Status Scale

To compare the usefulness of multiple sclerosis functional composite (MSFC) to the Expanded Disability Status Scale (EDSS) in assessing functional changes related to relapse. A prospective 12-week follow-up study after relapse was conducted among 14 multiple sclerosis (MS) patients treated with oral high-dose (1 g) methylprednisolone for 3 days. MSFC and the EDSS were assessed on day 0, before treatment and, 1, 4 and 12 weeks afterwards. In relapses, EDSS (2.5 ± 1.2 to 3.8 ± 1.0) and z-score of the MSFC (0.15 ± 0.58 to −0.59 ± 0.70) worsened. After 1 week of treatment, the EDSS improved (3.3 ± 1.2; P  =   0.002) while the MSFC did not change significantly. At week 4, EDSS improvement was maximal (2.8 ± 1.3; P  =   0.001). At week 12, EDSS remained stable whereas z-score continued improving (0.26 ± 0.74). z-9peg-hole-test was the most sensitive subtest. There was correlation between baseline values of both scales (−0.620, P  <   0.05) and between changes due to relapse (−0.535, P  <   0.05). 78.5% of patients had improved at week 4 (35.7% at week 1). There were no serious adverse effects. MSFC and the EDSS were sensitive to changes due to relapses, although the dynamics for restoring baseline function were different. Our data support the usefulness of both scales in clinical trials, providing complementary information about outcome of MS patients with relapses.     

Determination of ventricular diameters in multiple sclerosis patients with transcranial sonography (TCS)

Abstract.Context: Brain atrophy is an indicator of diffuse brain pathology that appears even in the early stages of multiple sclerosis (MS). Magnetic resonance imaging (MRI) techniques used in clinical trials suggest a correlation between ventricular enlargement and axonal pathology and clinical disability in MS.Objective: To evaluate by transcranial sonography (TCS) and MRI ventricular diameters in order to assess prospectively the development of brain atrophy in MS.Setting: MS outpatient clinic of a university hospital.Patients and Methods: 38 MS patients (27 females, 11 males) were followed up for 2 years. Ventricular diameters (third ventricle, right and left lateral ventricle) were determined by TCS at baseline, 12 and 24 months and correlated with clinical disability (Expanded Disability Status Scale, EDSS), and the Multiple Sclerosis Functional Composite Score (MSFC). MRI was performed at study entry and after two years.Main outcome measure: Correlation of ventricular diameters measured by TCS and MRI with assessment of clinical disability in MS patients at baseline and after two years.Results: TCS and MRI measurements especially of third ventricle diameter matched closely at study entry and after two years (r = 0.9; p < 0.0001). At all time points the width of the third ventricle was significantly correlated with clinical disability (EDSS: r = 0.6, p < 0.01; MSFC: r = –0.6, p < 0.02). In the follow-up over 2 years there was an increase of the width of the third ventricle in comparison with study entry (p < 0.002). Increase of third ventricular width at study entry was associated with higher EDSS levels after 2 years (p = 0.01).Conclusion: Assessment of ventricular diameters by TCS is a reliable tool with which to monitor brain atrophy in the longitudinal follow-up of MS patients. Because TCS is a simple, inexpensive, non-invasive and generally available bedside-test it may be used in clinical practice as well as in therapeutic trials to assess brain atrophy.(died unexpectedly 05. 08. 2003)     

Increased disability and MRI lesions after discontinuation of IFN-beta-1a in secondary progressive MS

OBJECTIVE: To examine neurological and magnetic resonance imaging (MRI) changes following discontinuation of interferon (IFN)-beta-1a treatment in secondary progressive multiple sclerosis (SPMS). METHODS: The study involved 21 SPMS patients who received subcutaneous (s.c.) IFN-beta-1a 44 microg three times weekly (t.i.w.) for 12 months and were thereafter followed up without treatment for a further 12 months. The number of relapses, disability on the Expanded Disability Status Scale (EDSS) and MRI were recorded at baseline, at 12 months of IFN-beta-1a 44 microg t.i.w. and 1 year after discontinuation of treatment. RESULTS: During the 12-month treatment EDSS score and volumes of brain T2- and T1-weighted lesions remained without significant progression, but at 12 months after treatment discontinuation both EDSS score and the volumes of cerebral lesions increased significantly. Cerebrospinal fluid fraction increased significantly both during the treatment and during follow-up. CONCLUSIONS: Discontinuation of IFN-beta-1a 44 microg t.i.w. in SPMS may be associated with an increase in neurological disability and brain lesions on MRI.     

The epidemiology of multiple sclerosis in Europe

Multiple sclerosis (MS) is a chronic and potentially highly disabling disorder with considerable social impact and economic consequences. It is the major cause of non-traumatic disability in young adults. The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multidisciplinary health care. Available MS epidemiological estimates are aimed at providing a measure of the disease burden in Europe. The total estimated prevalence rate of MS for the past three decades is 83 per 100 000 with higher rates in northern countries and a female:male ratio around 2.0. Prevalence rates are higher for women for all countries considered. The highest prevalence rates have been estimated for the age group 35–64 years for both sexes and for all countries. The estimated European mean annual MS incidence rate is 4.3 cases per 100 000. The mean distribution by disease course and by disability is also reported. Despite the wealth of epidemiological data on MS, comparing epidemiological indices among European countries is a hard task and often leads only to approximate estimates. This represents a major methodological concern when evaluating the MS burden in Europe and when implementing specific cost-of-illness studies.     

多发性硬化患者抑郁的研究

目的研究多发性硬化(MS)患者抑郁的发生率、特点及其相关因素。方法通过汉密尔顿抑郁量表(Hamilton depression，HAMD)了解作者医院32例MS患者的抑郁状况，进而以扩展残疾状况评分(expanded disability status scale，EDSS)评估其神经功能缺损程度，并与其他神经免疫性疾病患者、非免疫性中枢神经系统疾病患者和健康者各30名进行比较；同时分析MS患者年龄、性别、病程、EDSS评分与患者抑郁的相关性。结果MS患者抑郁的发生率为43．6％，明显高于各对照组；患者神经功能缺损程度与抑郁呈正相关；MS患者年龄、性别、病程与抑郁无明显相关。结论MS患者抑郁发生率很高，应引起临床关注；抑郁的发生可能与其中枢神经系统病灶及免疫学异常有关。     

Altered serotonin uptake kinetics in multiple sclerosis

Summary Platelet serotonin uptake was studied in 20 patients with multiple sclerosis (MS) in acute relapse and in 20 age-and sex-matched controls. While there was no difference in the maximum velocity of the uptake, Michaelis constants were significantly higher and correlated positively with the Disability Status Scale score. The results suggest a competitive block of the serotonin uptake sites in platelets of MS patients.     

Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese

Background

Clinical outcome of Chinese relapsing remitting multiple sclerosis (RRMS) patients is uncertain.

Aim

To study the long-term clinical outcome of Chinese RRMS patients.

Method

RRMS patients with duration of 10 years or longer followed up in our hospital is retrospectively studied.

Results

61 RRMS patients (75% female) were studied. Their mean symptom onset age was 25.9 years and mean duration was 20.6 years (range 10-33); 36% patients had received β-interferon and 30% azathioprine. Their mean EDSS scores were 3.3 (range 1-7) and 4.7 (range 1-8) at 10 years and latest follow-up (mean duration 20.6 years) respectively. At 10 years, 30% patients had EDSS score ≤2, 34% EDSS 2.5-3.5, 20% EDSS 4.0-5.5 and 16% ≥6; 18% developed SPMS. At latest follow-up, 15% patients had EDSS ≤2, 20% EDSS 2.5-3.5, 19% EDSS 4.0-5.5 and 46% ≥6.0; 53% developed SPMS. The median time from symptom onset to EDSS 6 was 22 years. No differences were detected in demographic characteristics, presenting neurological features, number of attacks in first 2 years, neuroradiological findings and disease modifying therapies between patients with EDSS <6 and ≥6 at ten years. EDSS scores at 10 years and latest follow-up were similar for patients who had received β-interferon and those who had not.

Conclusion

Hong Kong Chinese RRMS patients may have worse long-term clinical outcome than Caucasian patients.     

A comparison of two neurologic scoring instruments for multiple sclerosis

We examined the degree of association between two neurologic impairment scales, the Extended Disability Status Scale (EDSS) and the Scripps Neurologic Rating Scale (SNRS), with data from a randomized, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of cladribine as treatment for chronic progressive multiple sclerosis (MS). We found that the EDSS and SNRS were not strongly correlated within individual patients, contrary to expectation; moreover, in 9 of the 48 evaluable patients, the directions of their changes from baseline values were not mutually consistent. The scales were differentially sensitive to clinical changes over time, with the EDSS indicating a more abrupt, and the SNRS a more gradual, change in the clinical course of disease. The validity of different impairment scales, and their sensitivity to detect clinical changes, should be formally assessed in future clinical trials using these scales as outcome measures.     

Changes in LORETA and conventional patterns of P600 after steroid treatment in multiple sclerosis patients

OBJECTIVE: The P600 component of event-related potentials (ERPs) reflecting the 'rule-governed sequence of information processing', has been associated with multiple sclerosis (MS)-related cognition. The present study aimed at examining the effects of methylprednisolone treatment in MS patients on cognition as reflected by the low-resolution brain electromagnetic tomography (LORETA) of the P600 as well as its conventional constituents (amplitudes and latencies) recorded during a working memory (WM) test. METHOD: A paired LORETA comparison was performed in the P600 component of ERPs elicited during a (WM) test in 18 MS patients suffering from the relapsing-remitting form, before and after 1 week treatment with methylprednisolone. The P600 component was also evaluated in 16 healthy controls matched to the patients on age and educational level. RESULTS: When pre- and post-treatment recordings of LORETA were compared all patients as a group showed significantly different patterns of current density activation located at right frontal lobe. The treatment was accompanied by an increase of the amplitude of P600 at the right frontoparietal area. In the post-treatment phase the patients exhibited significant improvement of the memory performance as compared to themselves before treatment. As a result both the P600 amplitudes and memory performance at post-treatment were closer to those exhibited by normal controls. CONCLUSION: These findings support the notion that steroid treatment in relapsing-remitting MS patients, may exert a beneficial effect in 'rule-governed sequence of information processing'.     

Associations of the Expanded Disability Status Scale with anxiety and depression in multiple sclerosis outpatients

OBJECTIVES: We evaluated cross-sectionally the associations of depression and anxiety with age, sex, duration of illness, educational level, degree of disability and treatment with interferon-beta in outpatients with relapsing-remitting multiple sclerosis (RRMS) during a clinically stable phase of their illness. MATERIALS AND METHODS: The depression status scored on the Beck Depression Inventory (BDI), the symptoms of anxiety assessed using the State Trait Anxiety Inventory (STAI) and the level of disability measured by the Expanded Disability Status Scale (EDSS) were quantified in 86 consecutive RRMS patients. RESULTS: Linear regression analyses indicated that EDSS was independently (P < 0.001) associated with BDI and STAI and accounted for 15.7% and 18.5% of the variance in BDI and STAI respectively. The former association retained its statistical significance in multiple regression models adjusting for demographic and clinical characteristics. CONCLUSIONS: Disability status is an independent but moderate determinant of depression and anxiety in MS patients.     

Quality of life in patients with multiple sclerosis: the impact of fatigue and depression

Quality of Life (QOL) is impaired in multiple sclerosis (MS) in part due to physical disability. MS-associated fatigue (MSF) and depression (MSD) are common and treatable features of MS, which could also impact on QOL, independent of physical disability. We prospectively studied 60 consecutive patients with MS. QOL was assessed using Multiple Sclerosis Quality of Life (MSQOL)-54. Group differences in QOL scores were assessed after adjusting for Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS) and Hamilton Depression Inventory scores. MS patients were grouped into relapsing-remitting (RR) or secondary-progressive (SP), MSF (FSS> or =5) or MS-nonfatigue (MSNF) (FSS< or =4), and MSD or MS-nondepression (MSND). After accounting for disability and depression, fatigue was associated with impaired QOL with respect to health perception (p=0.03) and limitations due to physical dysfunction (p=0.008). After accounting for disability and fatigue, depression was associated with lower QOL with respect to health perception (p=0.02), sexual dysfunction (p=0.03), health distress (p=0.03), mental health (p=0.006), overall QOL (p=0.006), emotional dysfunction (p=0.04), and limitations due to emotional dysfunction (p=0.03). This study demonstrates that fatigue and depression are independently associated with impaired QOL in MS, after accounting for physical disability, suggesting that their recognition and treatment can potentially improve QOL.     

Cardiovascular dysfunction in multiple sclerosis

Cardiovascular dysfunction (CD) in multiple sclerosis (MS) is related to involvement of reflex pathways in the brainstem. The battery of CD tests was applied to a group of 40 healthy subjects and 40 patients with MS, divided in 2 subgroups according to the expanded disability status scale (EDSS). The tests included: 1) postural blood pressure changes, 2) postural heart rate changes, 3) heart rate changes on inspiration/forced expiration and 4) ECG R-R interval measurement on the Valsalva maneuver. Both groups were subjected to the functional independence scale (FIM). Imaging studies were reviewed and autonomic dysfunction at other levels was explored. The results showed a statistically significant difference (P < 0.05) in all tests when comparing patients to controls. Tests 1 and 4 had the highest significance, with findings of more severe involvement in patients with a higher EDSS and lower FIM. A correlation was also found between CD and brainstem lesions on MRI (P < 0.01). A significant number of MS patients had evidence of CD. Test 1 may be considered a simple marker, in daily clinical practice, to detect subclinical CD. Subclinical CD is a cause of disability in this group of patients.