Quality of life in 1000 patients with early relapsing–remitting multiple sclerosis

Background and purpose:  To examine the quality of life (QoL) in a large cohort of untreated patients with relapsing–remitting multiple sclerosis (RRMS) and to investigate the impact of intramuscular (IM) interferon beta-1a (IFNß-1a) treatment.
Methods:  Prospective, observational, open-label, multicentre study conducted in Germany. Untreated patients with RRMS who initiated treatment with IM IFNß-1a were included and followed for 12 months. QoL was measured using the EQ-5D questionnaire. Clinical response was assessed by relapse rate and disability (Expanded Disability Status Scale; EDSS).
Results:  A total of 1157 patients were included [mean age 37.6 years, median disease duration 13 months, mean relapse rate 1.7 (95%CI: 1.58–1.73), median EDSS score 2.0]. Relapse rate was reduced to 0.6 at 12 months (95%CI: 0.51–0.69, P  < 0.0001). EDSS did not change significantly. At baseline, QoL was considerably lower in MS patients compared with the general German population, but was improved after treatment initiation [utilities of EQ-5D: 0.77 (95%CI: 0.75–0.78) vs. 0.75 (95%CI: 0.74–0.76) at baseline, 95%CI for difference: 0.01–0.03, P  = 0.0046]. Higher disease activity and inability to work were negative predictors of QoL. 14.7% of patients were incapable of working for MS-related reasons.
Conclusions:  Quality of life is considerably impaired in early stages of MS. Treatment initiation with IM IFNß attenuates MS disease activity and improves QoL. Inability to work early during the disease is a major challenge for the social security systems.     

Cerebellar deficit and respiratory impairment: a strong associationin multiple sclerosis?

The aim of the study was to analyse pulmonary function and to identify reliable prognostic factors associated with respiratory abnormalities in a consecutive series of patients with multiple sclerosis (MS). Pulmonary function was evaluated by means of a battery of measures, including maximal voluntary ventilation, forced vital capacity, forced expiratory volume, in 71 consecutive patients with primary and secondary progressive MS. Respiratory impairment was common in MS patients, occurring in 63.4% of all patients, ranging from 82.9% in non‐ambulatory patients (with EDSS score >6.5) to 35.7% in ambulatory patients (with EDSS score <6). Severity of illness and cerebellar and mental impairment were significantly negatively associated with basal pulmonary function. Coordination plays an important role in determining respiratory abnormalities: respiratory abnormalities were found in 27 out of 32 patients (84.4%) with severe cerebellar impairment. The presence of severe cerebellar signs was associated with a very high risk of occurrence of respiratory impairment (O.R.=6.24; 95% C.I. 1.71–22.82). Other significant variables were severity of illness (EDSS score >6.5) (O.R.=4.71; 95% C.I. 1.42–15.66) and long disease duration (>15 years) (O.R.=3.39; 95% C.I. 1.01–11.42).     

Natural history of multiple sclerosis in a population-based cohort

Background and purpose:  We sought to identify predictive clinical factors of disability during initial course in multiple sclerosis (MS) patients.
Methods:  A total of 2871 MS patients from the LORSEP (Lorraine Multiple Sclerosis) population-based cohort were analyzed. The relationships between baseline demographic, clinical predictors and time to assignment of Expanded Disability Status Scale (EDSS) scores of 3, 4 and 6 were assessed using a Cox regression model.
Results:  Multivariate analysis showed that, for relapsing–remitting patients, a shorter time to assignment of an EDSS score of 4 was associated with an older age of onset of MS and incomplete recovery from the first relapse. Median times were not influenced by gender or the time between the first two relapses. The results also demonstrated that MS progression is independent of the initial clinical data once an EDSS score of 4 is reached rather than a score of 3 because the time from EDSS 3 to assignment of EDSS 4 were correlated with predicting variables. The data were very different for the time between assignment of scores of 4 and 6 because the median times were not influenced by any of the predicting variables.     

Efficacy of natalizumab in second line therapy of relapsing–remitting multiple sclerosis: results from a multi-center study in German speaking countries

Background:  Natalizumab has been recommended for the treatment of relapsing–remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population.
Method:  Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab ≥12 months prior to study conduction.
Results:  Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 ± 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >/= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>/= 2 relapses in the year and >/= 1 Gadolinium (Gd)+ lesion at study entry, n  = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity).
Conclusion:  Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.     

Apolipoprotein E polymorphism interacts with cigarette smoking in progression of multiple sclerosis

Background and purpose:  The influence of apolipoprotein E (ApoE) polymorphism on clinical severity of multiple sclerosis (MS) is still controversial. Cigarette smoking has been suggested to influence the progression of disability in these patients. In this study, we aimed to investigate whether an interaction of smoking with the ApoE polymorphism influences the progression of disability in MS patients.
Methods:  Smoking history from 205 female patients with MS was obtained. Clinical data collected include age at onset, disease duration, annual relapse rate, the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). ApoE polymorphism was examined in all patients and stratified according to smoking status and associations with the clinical data investigated.
Results:  There were no significant associations between cigarette smoking and any of the clinical characteristics in the whole group of patients. In women carrying the ApoE E4 isoform, smokers had a lower EDSS ( P  = 0.033) and MSSS ( P  = 0.023) in comparison with non-smokers.
Conclusion:  Our data suggest that in women with MS carrying the ApoE E4 isoform, cigarette smoking may have a protective influence on disease progression and accumulation of disability. These findings need to be confirmed by future large longitudinal studies.     

Does myasthenia gravis provide protection against cancer?

Objectives –  Reports have been made of an altered rate of extrathymic malignancies in patients with myasthenia gravis (MG). This study compared the rate of such malignancies in a group of MG patients with an optimal control group.
Materials and methods –  From the Norwegian Cause of Death Registry, we identified 249 dead MG patients (1951–2001) and a control group of 1,245 individuals (five per patient) dead in the same period, matched for sex and year of birth.
Results –  Patients with MG had a lower occurrence of malignant disease as underlying or contributing cause of death than the controls (8.8% vs 27.2%, P  < 0.001). The main difference was found for colorectal cancer, breast cancer and cancer in the upper digestive tract (esophagus and stomach).
Conclusions –  We report a significantly lower rate of extrathymic malignancies in patients with MG than in controls, and we hypothesize that MG treatment or the immunological mechanisms involved in MG may protect patients with MG from developing an extrathymic malignancy.     

Prevalence of autoimmune thyroid disorders in a Spanish multiple sclerosis cohort

The aim of the study was to determine the prevalence of thyroid autoimmune disorders in a cohort of untreated multiple sclerosis (MS) patients and compare it with a stratified sample of an adult population. We prospectively studied 93 untreated MS patients. The control group included 401 healthy subjects selected by stratified sampling in a non-iodine-deficient area. Antithyroid antibodies (ATA) (antibodies against peroxidase and thyroglobulin) were considered positive at titres ≥149 IU/ml. Antibodies were positive in 11 MS patients (11.8%; 95% CI 5.3–18.4%). This prevalence was five times higher ( P  = 0.0001) when compared with that in the control population. We found six cases with subclinical hypothyroidism (6.45%; 95% CI 11.4–1.5) in contrast to 2.24% in the control group. Comparing MS with positive and negative ATA, there was a non-significant, slightly higher frequency of low Expanded Disability Status Scale (EDSS) score in the ATA-positive group (81% vs. 73.2%). One year after start of interferon (IFN) treatment, only one patient developed subclinical thyroid dysfunction. MS patients have a higher prevalence of ATA compared with the general population. An initial ATA and thyroid-stimulating hormone (TSH) determination is recommended in all MS patients. A periodic assessment of thyroid function during IFN treatment only seems to be justified in those cases where positive ATA or dysfunction is present before treatment.     

Multiple sclerosis patients with anti-lipid oligoclonal IgM show early favourable response to immunomodulatory treatment

Background and purpose:  Interferon beta and Glatiramer acetate are safe immunomodulatory treatments (IT) for multiple sclerosis (MS), but not always effective. New drugs are available, although they show more side-effects and unknown long-term safety profile. Anti-lipid oligoclonal IgM bands (OCMB) distinguish MS patients with early aggressive course. We prospectively studied if IT are effective in these patients or if they are candidates for more aggressive drugs as first therapeutic option.
Methods:  Seventy-five clinically isolated syndrome patients were studied. OCMB and conversion to MS were assessed. Patients suffering at least two demyelinating events within 3 years were considered eligible to start IT.
Results:  Eighteen patients showed OCMB (M+) and 57 lacked them (M−). All M+ patients and only 25 M− patients were treated. The other 32 M− patients suffered less MS attacks than those required to initiate treatment. IT similarly reduced relapse rate in both treated groups ( P  < 0.0001) and reduced Expanded Disability Status Scale (EDSS) progression in M+ patients, whose EDSS score had significantly increased before treatment. EDSS did not change in M− patients during follow-up, regardless if they were treated or not.
Conclusions:  Oligoclonal IgM bands identify MS patients who are candidates for early immunomodulatory treatment as IT improves their initial aggressive disease course.     

Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study

Introduction:  Previous studies of natalizumab (Tysabri®) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity.
Patients and Methods:  We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy.
Results:  During a median observation time of 11.3 months (range 3.0–21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with ≥2 relapses or sustained increase in EDSS of ≥2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab.
Conclusions:  Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment.     

MxA protein – an interferon beta biomarker in primary progressive multiple sclerosis patients

Background and purpose:  Interferon beta (IFNβ) preparations have some effect on the progressive phase of multiple sclerosis (MS). This limited effect might be partially because of a certain number of IFNβ non-responders. Myxovirus resistance protein A (MxA) – a marker of IFNβ bioactivity – was correlated with the clinical response during an uncontrolled trial, investigating the safety of IFNβ-1b in primary progressive (PPMS) patients.
Methods:  Twenty PPMS were treated with IFNβ-1b (s.c.) for 1 year. Blood samples were taken before and 1, 2, 3, 6, 9, 12, and 15 months after treatment initiation and MxA protein levels were measured. Patients were clinically evaluated by EDSS and the more sensitive Incapacity Status Scale (ISS) and stratified in a stable and a progressing group.
Results:  Using ISS criteria, 11 patients remained stable and nine patients progressed during treatment. The mean area under the curve of log MxA levels during treatment were significantly higher in stable than in progressing patients (10.87 vs. 5.99; P  =   0.002).
Conclusion:  A good biological response to IFNβ might be associated with a better clinical effect of this drug and could be helpful in future clinical studies for early identification of treatment responders.     

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.     

High prevalence of restless legs syndrome in multiple sclerosis

Despite the fact that multiple sclerosis (MS) patients often include leg restlessness as a sensory symptom, MS is not mentioned amongst symptomatic restless legs syndrome (RLS) forms. The aim of this study was to estimate RLS prevalence in a large population of MS patients, comparing clinical and MRI findings between patients with and without RLS. Each of the 156 MS patients (100 females, 56 males, mean age 40.7 ± 10.4) enrolled in a prospective study underwent a medical history interview, a neurological examination with the assessment of the Expanded Disability Status Scale (EDSS), and a structured questionnaire to verify the presence and features of RLS. Conventional brain–spinal MRIs of 99 subjects were also evaluated and compared between patients with and without RLS. Fifty-one subjects (32.7%) (mean age 43.8 ± 12.8) met the criteria for RLS. In a few patients (8.5%), the RLS preceded clinical MS onset, whilst in the remaining cases the RLS was followed by or was simultaneous with clinical MS onset. Comparing the RLS group with the group without RLS, no significant differences were found in MS duration, gender, and referred sleep habits. The primary progressive MS course was more represented in the RLS group, which also showed a higher EDSS score. RLS is a very common finding in MS patients and should be considered amongst the symptomatic RLS forms. RLS is also associated with higher disability.     

The effects of methylprednisolone and mitoxantrone on CCL5-induced migration of lymphocytes in multiple sclerosis

Objectives –  Chemokines are involved in migration of inflammatory cells to the central nervous system (CNS) in multiple sclerosis (MS). The aim of this study was the analysis of the impact of MS treatment on CCL5-induced migration of leukocyte subpopulations.
Material and methods –  Migration of lymphocytes and monocytes from blood of MS patients treated with methylprednisolone (MP) or mitoxantrone (MTX) was analysed in a chemotaxis chamber.
Results –  CCL5-induced migration of lymphocytes from untreated MS patients was significantly increased over controls. The treatment of MS with MP and MTX reduced this chemotaxis. The plasma level of CCL5 was increased in MS patients before treatment and was also significantly decreased in the treatment of MS with MP and MTX.
Conclusions –  This observation supports the hypothesis that in MS, chemokine CCL5 may induce migration of leukocytes to the CNS and suggests that treatment of the disease with MP and MTX may reduce this migration.     

Bone mineral density in children, adolescents, and young adults with epilepsy

Purpose:   The aim of this study was to assess bone mineral density (BMD) in a large population of children, adolescents, and young adults with epilepsy alone or in association with cerebral palsy and/or mental retardation.
Methods:   Ninety-six patients were enrolled in the study. The group comprised 50 males and 46 females, aged between 3 and 25 years (mean age 11 years). The control group consisted of 63 healthy children and adolescents (23 males, 40 females), aged between 3 and 25 years (mean age 12.1 years). Patients underwent a dual-energy x-ray absorptiometry (DEXA) scan of the lumbar spine (L1–L4) and the z scores were calculated for each patient; the t score was considered for patients 18 years of age or older.
Results:   Abnormal BMD was found in 56 patients (58.3%), with values documenting osteopenia in 42 (75%) and osteoporosis in 14 (25%). A significant difference emerged between epileptic patients and the control group in BMD, z score, and body mass index (BMI) (p = <0.001). Lack of autonomous gait, severe mental retardation, long duration of antiepileptic treatment, topiramate adjunctive therapy, and less physical activity significantly correlated with abnormal BMD.
Discussion:   This study detected abnormal BMD in more than half of a large pediatric population with epilepsy with or without cerebral palsy and/or mental retardation. The clinical significance of these findings has yet to be clarified.     

Evaluation of multiple sclerosis diagnostic criteria in Suzhou, China – risk of under-diagnosis in a low prevalence area

Objective –  To evaluate the discharge diagnosis of demyelinating diseases in the central nervous system (CNS) and analyze the predictive value of the new diagnostic criteria in Suzhou, China.
Materials and methods –  We collected clinical information and data of laboratory examinations for all cases with a diagnosis of various demyelinating diseases in the CNS. All data were reviewed individually by four senior neurologists, and a diagnosis was finally given to each patient according to the McDonald criteria and the Poser criteria for multiple sclerosis (MS).
Results –  In the analysis, 176 patients with a diagnosis of demyelinating diseases in the CNS at discharge were included. In 82 patients with a diagnosis of MS at discharge, the MS diagnosis was confirmed for 74 patients according to the McDonald criteria for MS, and the positive predictive value for the discharge diagnosis of MS was 90.2% (74/82). According to the Poser criteria, 61 patients were diagnosed as MS. The consistency of the two diagnostic criteria for MS was 78.4%, based on the results of the evaluation.
Conclusions –  Under-diagnosis of MS could be one of the explanations for the low prevalence of MS in China. Compared to the Poser criteria, the McDonald criteria had a higher sensitivity for the diagnosis of MS.     

Effect of Renal Impairment on the Pharmacokinetics and Tolerability of Tiagabine

Summary: Purpose: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB).
Methods: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4–6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB · HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively.
Results: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t1/2) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 I/h, and from 6.4 to 8.4 h, respectively.
Conclusions: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.     

Alexithymia in multiple sclerosis: relationship with fatigue and depression

Objective –  The aim of this study was to investigate the prevalence of alexithymia in a sample of patients with multiple sclerosis (MS) and to further evaluate the association between alexithymia and the occurrence of common disabling MS-related symptoms such as fatigue and depression.
Methods –  Fifty-eight relapsing–remitting MS patients treated with interferon (IFN)-beta-1a underwent a complete neurological evaluation, including Expanded Disability Status Scale score assessment. Alexithymia, depressive symptoms and fatigue were assessed using the 20-item Toronto Alexithymia Scale, Beck Depression Inventory and Fatigue Severity Scale.
Results –  Prevalence of alexithymia was 13.8%, with 27.6% of patients presenting borderline alexithymia. Sixty-seven per cent of the patients complained of fatigue while 29.3% of them were depressed. Higher levels of fatigue and depression were found in alexithymic patients when compared with non-alexithymic patients. Results from logistic regressions showed that alexithymia significantly contributes to the severity of fatigue and depression.
Conclusions –  Alexithymia was associated with increased severity of fatigue and depression.     

Prevalence of migraine, tension-type headache and trigeminal neuralgia in multiple sclerosis

Background:  Prevalence rates of headache in multiple sclerosis (MS) patients varied widely in recent studies. This study aimed to investigate the 1 year prevalence of headache in MS compared with the general population.
Methods:  Population-based case–control study in Germany.
Results:  We included 491 patients with definite MS (68% female, mean age 45.3 years, 63.7% relapsing remitting MS, mean Expanded Disability Status Scale (EDSS) 3.2, 106 treated with interferon-β, 53 with glatiramer acetate, 271 untreated) and 447 age and gender matched controls. Headache was diagnosed with a validated questionnaire according to the International Headache Society Criteria. Headache prevalence was 56.2% (tension type headache 37.2%, migraine 24.6%). Headache prevalence rates did not differ from controls. Headache was not associated with disability or treatment. Trigeminal neuralgia was found in 6.3% of MS cases.
Conclusion:  Results suggest that headache in MS patients reflects comorbidity in most conditions.     

Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability

OBJECTIVE: To assess axonal damage and its contribution to disability at different stages of multiple sclerosis (MS). BACKGROUND: Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial axonal damage accompanies the inflammatory lesions of MS. However, the relation of axonal damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined. DESIGN: We performed proton magnetic resonance spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measure N-acetylaspartate (NAA, an index of axonal integrity) relative to creatine (Cr) in a large central brain volume that included mostly normal-appearing white matter on magnetic resonance imaging. RESULTS: We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically, and declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P<.001). The correlation of NAA/Cr values with EDSS score was significantly (P<.03) stronger in patients with mild disability (EDSS score <5, Spearman rank order correlation = -0.54, P<.001) than in patients with more severe disability (EDSS score >/=5, Spearman rank order correlation = -0.1, P<.9). When similar analyses were performed in patients with MS grouped for duration of disease, the subgroup with early disease duration (<5 years) also showed central brain NAA/Cr resonance intensity ratios significantly lower than healthy controls (P<.001). CONCLUSION: Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.     

Predictive value of clinical characteristics for 'benign' multiple sclerosis

We studied a cohort of 496 patients who had multiple sclerosis (MS) for at least 10 years. Ten years after disease onset, 151 had benign MS defined as an Extended Disability Status Scale (EDSS) ≤3. Between benign and non-benign patients we compared gender, age at clinical onset, relapsing–remitting or primary progressive, symptoms at onset, recovery from first relapse, time between first and second relapse, number of relapses in the first 5 years, use of immunomodulatory drugs, and EDSS scores at 2, 5 and 10 years. A multivariate regression analysis showed that a relapsing–remitting course, a low EDSS score at 5 years, and a low number of relapses in the first 5 years were predictive for benign MS at 10 years. Other factors had no additional value. Thirty-five of the 51 patients (69%) with benign MS at 10 years were still benign at 20 years. A low 10-year EDSS score was the only clinical variable associated with a benign course at 20 years. Our results suggest that within the first 5 years from onset it is not possible to predict a benign course. Disease course, EDSS score and relapse rate at 5 years are predictors for benign MS at 10 years.