Extended Disability Status Score Research Articles

Role of Cervical Spinal Magnetic Stimulation in Improving Posture and Functional Ambulation of Patients with Relapsing Remitting Multiple Sclerosis

Balance impairment is one of the hallmarks of early MS. Proprioceptive deficit was found to be one of the main causes of this imbalance. The cervical enlargement has a strong proprioceptive system, with its projections to the reticular formation and the central pattern generators, helping in rhythmic pattern generation and alternate leg movements. Repetitive trans-spinal magnetic stimulation (rTSMS) is a noninvasive technique, which can trigger massive proprioceptive afferents. Therefore, it has the potential of improving proprioceptive deficits and motor control. Objective. To determine the effectiveness of repetitive cervical magnetic stimulation in improving functional ambulation of patients with relapsing remitting multiple sclerosis (RRMS). Design. Prospective sequential clinical trial. Setting. University and academic hospital. Participants. A total of 32 participants (N = 32) with RRMS. Interventions. Outpatient rehabilitation. The 32 patients received 10 sessions over two weeks of 20 Hz cervical spinal magnetic stimulation (SMS). Both groups were assessed at baseline, after 2 weeks, then one month later. Patients were enrolled as a control group at first and received Sham SMS, and then a wash out period of one month was done for all the patients, followed by a baseline assessment. Second, the same 32 patients rejoined as the active group, which received real magnetic stimulation. Both groups performed an intensive physical therapy program with the spinal magnetic stimulation. Main Outcome Measures. Extended Disability status score (EDSS), Timed up and Go test (TUG), Mini-Best test, dynamic posturography sensory organization composite score, and motor composite score. Results. Thirty-two RRMS patients with EDSS range from 1.5 to 6. They showed statistically significant difference between active and control groups in Mini-Best test score. We divided our patients according to EDSS into 3 subgroups: (a) mild: ≤2.5, (b) moderate: 3-5.5, and (c) severe: ≥6. Mild cases showed significant differences in EDSS score, TUG test, Mini-Best test, and dynamic posturography sensory composite scale. The effect size between the different patient subgroups was also measured and showed highly significant improvements in all measured parameters among our mild patients, indicating that this subgroup could be the best responders to cervical repetitive high-frequency magnetic stimulation. Moderate cases showed highly significant improvement in TUG score and Mini-Best test and significant change in EDSS score and the dynamic posturography sensory composite score. Severe cases showed only significant improvements in TUG, Mini-Best test, and sensory composite score. Conclusion. Cervical repetitive magnetic stimulation can help improve balance and functional ambulation and decreases the risk of falls in RRMS patients, especially in the mild, low disability cases.

Body Composition In Persons With Multiple Sclerosis Vs. Healthy Controls

Multiple Sclerosis (MS) is an autoimmune disease that attacks the myelin sheath and impedes proper conduction of action potentials through the central nervous system. As a result, persons with MS (PwMS) can experience symptoms of fatigue, muscular weakness, spasticity, and balance or gait issues. Such symptoms may reduce physical activity, negatively affecting body composition and predisposing PwMS to obesity, sarcopenia and osteoporosis. PURPOSE: The aim of the current study was to compare the body composition of PwMS and controls using DXA. METHODS: Six males and 13 females with relapsing-remitting MS and 19 Age/Sex/BMI matched healthy controls were recruited for this study. Extended disability status score (EDSS) in PwMS ranged 0 to 6 (x̄=3.1 ± 2.2). DXA scans were used to assess whole body and limb specific contents of fat, muscle and mineral content. Two-way ANOVAs (Group x Sex) with post hoc comparisons were run to assess differences across group and sex. RESULTS: Compared to male controls, MS males had a reduced whole body % lean mass (%LMWB) (60.9 ± 6.3% vs. 74.0 ± 11.0%, p=0.02), %LMARMS (66.7 ± 8.5 vs. 79.0 ± 8.6%, p=0.03), %LMLEGS (61.8 ± 6.2 vs. 75.2 ± 9.9%, p=0.02), % appendicular lean mass (aLM) (28.1 ± 5.1 vs. 35.3 ± 5.8%, p=0.03), and aLM/BMI (90.0 ± 21.10 vs. 115.8 ± 21.9, p=0.04) Similarly, the % body fat (%BF) was higher in MS males (36.7 ± 7.0%) compared to male controls (23.1 ± 11.7% and p=0.02). No between group differences were found for bone mineral content (p>0.05). When collapsed across sex, group differences disappeared in all measures except android fat mass, which was higher in PwMS (35.0 ± 16.0 kg) than controls (23.8 ± 16.3 kg, p=0.04). Interestingly, the Pearson’s r correlation between BMI and BF% was significant for the MS group (r=0.715, p<0.01) but not for the control group (r=0.347, p=0.15). EDSS scores in PwMS did not significantly correlate with any variables (p>0.05). CONCLUSIONS: Expected sex differences in body composition occurred regardless of group. MS males tended to have lower LM and higher %BF than controls, which was not seen in MS females. Significance in MS males may be explained by differences in sample size (n=6) or sex differences in MS symptom or disease progression. It is furthermore unclear to what extent individual differences in physical activity or medication may influence results.

Five year iron changes in relapsing-remitting multiple sclerosis deep gray matter compared to healthy controls

BackgroundRelapsing-Remitting MS (RRMS) Deep Grey Matter (DGM) 5 year changes were examined using MRI measures of volume, transverse relaxation rate (R2*) and quantitative magnetic susceptibility (QS). By applying Discriminative Analysis of Regional Evolution (DARE), R2* and QS changes from iron and non-iron sources were separated. Methods25 RRMS and 25 age-matched control subjects were studied at baseline and 5-year follow-up. Bulk DGM mean R2* and QS of the caudate nucleus, putamen, thalamus and globus pallidus were analyzed using mixed factorial analysis (α = 0.05) with sex as a covariate, while DARE employed non-parametric analysis to study regional changes. Regression/correlation analysis was performed with disease duration and MS Severity Score (MSSS). ResultsNo significant change in Extended Disability Status Score was found over 5 years (baseline = 2.4 ± 1.2; follow-up = 2.8 ± 1.3). Significant time effects were found for R2* in the caudate (Q = 0.000008; η2 = 0.36), putamen (Q = 0.0000007; η2 = 0.43), and globus pallidus (Q = 0.0000007; η2 = 0.43), while significant longitudinal effects were only found for QS in the putamen (Q = 0.002; η2 = 0.22). Significant bulk interaction was only found for thalamus volume (Q = 0.02; η2 = 0.20). Iron decrease was the only detected significant effect using DARE, and the highest significant DARE effect size was mean thalamus R2* iron decrease (Q = 0.002; η2 = 0.26). No significant correlations or regressions were demonstrated with clinical measures. ConclusionsThalamic atrophy was the only bulk effect that demonstrated different rates of changes over 5 years compared to age-matched controls. DARE Iron decrease in regions of the caudate, putamen, and thalamus were prominent features in stable RRMS over 5 years.

High-intensity interval ergometer training improves aerobic capacity and fatigue in patients with multiple sclerosis

Moderate endurance training leads to a significant improvement of aerobic fitness and fatigue in patients with multiple sclerosis (MS). However, the effects of high-intensity interval training (HIIT) have not systematically investigated. To determine the effects of short-term HIIT on aerobic fitness and fatigue in MS patients. Prospective monocentric, randomized, simple blinded cohort study. Participants exercised for 8 weeks on a bicycle ergometer three times weekly for 8 weeks. Forty patients with relapsing–remitting MS and an extended disability status score (EDSS) of < 3.5 participated. For 8 weeks, participants exercised three times weekly for 30 min according to two different protocols (HIIT versus moderate endurance training). Measurements were taken at baseline and after 8 weeks of training. Individual aerobic fitness (VO2peak) was assessed via a stepwise ramp protocol, fatigue by the Fatigue Severity Scale (FSS), and ambulation was measured by the Timed 25-Foot Walk Test (T25-FW). Data were analysed according to the intention-to-treat (ITT) approach. Aerobic fitness increased significantly in the HIIT group (pre: 26.7 ± 6.1, post: 29.7 ± 6.6 ml/min/kg; p < 0.04). No changes with regard to FSS and T25FW were detected in both groups. However, sub-group analysis revealed a significant decrease of fatigue in patients with elevated baseline fatigue (pre: 5.00 ± 0.7, post: 4.7 ± 1.2; p = 0.03). HIIT is a promising time-efficient approach in subjects with MS leading to rapid improvement of aerobic fitness.

Alteration of delta-6-desaturase (FADS2), secretory phospholipase-A2 (sPLA2) enzymes by Hot-nature diet with co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients

BackgroundThe effect of nutrition and dietary supplements as environmental factors has been suggested as possible factors affecting both disease risk and progression in on the course of multiple sclerosis with complex genetic-risk profiles. This study was aimed to assess regulation of surface-membrane enzymes such as Delta-6-desaturase (FADS2), secretory Phospholipase A2(sPLA2) by hemp seed and evening primrose oils as well as Hot-natured dietary intervention in relapsing remitting multiple sclerosis (RRMS) patients. Methods and materialsIn this double blind, randomized trial, 100 RRMS patients with Extended disability status score (EDSS)<6 were allocated into 3 groups: “Group A” who received co-supplemented hemp seed and evening primrose oils along with advised Hot nature diet; “Group B”, who received olive oil; “Group C”, who received the co-supplemented oils. Clinically EDSS and functional score as well as biochemical parameters [blood cells polyunsaturated fatty acid (PUFA), FADS2, sPLA2] were assessed at baseline and after 6 months. ResultsMean follow-up was 180±2.9SD days (N=65, 23 M and 42 F aged 34.25±8.07 years with disease duration 6.80±4.33 years). There was no significant difference in studies parameters at baseline. After 6 months, significant improvements in EDSS and functional score were found in the groups A and C while EDSS and pyramidal score showed significant increase in group B. Alteration of biochemical parameters showed improvement in groups A and C whereas there was worsening condition for group B after the intervention. ConclusionThe co-supplemented hemp seed and evening primrose oils with Hot nature diet can have beneficial effects in improving clinical symptoms and signs in RRMS patients which were confirmed by regulation of surface-membrane enzymes.

Retinal nerve fiber layer thickness in multiple sclerosis subtypes

Background Optical coherence tomography (OCT) is a promising tool for detecting subclinical changes in retinal nerve fiber layer (RNFL) and macular volume in multiple sclerosis (MS). Objectives The aim of the study was to assess the relationship of retinal changes in different MS subtypes with and without optic neuritis (ON) with clinical disability, duration of illness, and MRI results. Methods Twenty-four patients with relapsing-remitting subtype and 12 patients with secondary progressive subtype, of age range 16-55 years, with and without ON, and 16 age-matched and sex-matched healthy controls were enrolled in this study; in total, there were 15 male and 37 female participants. Patients were subjected to history, clinical evaluation, Extended Disability Status Score for disease severity, MRI brain with contrast, and OCT to assess the RNFL and macular volume of the optic nerve. The control group underwent OCT. Results RNFL thinning was highly correlated in both subtypes with and without ON in all field quadrants compared with the healthy controls. In addition, retinal and macular thickness inversely correlated with Extended Disability Status Score and disease duration in the progressive group than in the relapsing-remitting type. MRI with contrast inversely correlated with both macular and RNFL thickness in the progressive type. Conclusion Retinal axonal loss is more prominent in advanced stages of disease with proportionally greater thinning in eyes previously affected by clinically evident ON. In the absence of clinically evident ON, OCT is a promising potential biomarker of retinal pathology in MS subtypes.

Association of Expanded Disability Status Scale and Cytokines after Intervention with Co-supplemented Hemp Seed, Evening Primrose Oils and Hot-natured Diet in Multiple Sclerosis Patients(♦).

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Because of limited efficacy and adverse side effects, identifying novel therapeutic and protective agents is important. The aim of this study is to examine the correlations between expanded disability status scale (EDSS) and cytokines after intervention with co-supplemented hemp seed and evening primrose oils and hot-natured diet in patients with relapsing-remitting multiple sclerosis (RRMS). We studied a group of 23 patients with clinically definite RRMS, with EDSS<6 who received co-supplemented hemp seed and evening primrose oils with advising hot-natured diet. Clinically EDSS and immunological factors (plasma cytokines of IL-4, IFN-γ and IL-17) were assessed at baseline and after 6 months. Mean follow-up was 180±2.9 days (N=23, 7 Male and 16 Females aged 25.0±7.5 years with disease duration 6.26±3.9 years). After 6 months, significant improvements in extended disability status score were found in the patients in agreement with decrease cytokines of IFN-γ and IL-17 and increase cytokines of IL-4. Clinical and immunological parameters showed improvement in the patients after the intervention. Our study shows that co-supplemented hemp seed and evening primrose oils with hot-natured diet can have beneficial effects in improving clinical symptoms in relapsing remitting MS patients and significant correlation was found between EDSS and immunological findings.

Reliability and clinical significance of mobility and balance assessments in multiple sclerosis

The aim of the study was to establish the test-retest reliability, clinical significance and precision of four mobility and balance measures - the Timed 25-Foot Walk, Six-minute Walk, Timed Up and Go and the Berg Balance Scale - in individuals moderately affected by multiple sclerosis. Twenty four participants with multiple sclerosis (Extended Disability Status Score 5-6.5) were assessed on four measures of mobility and balance. The Timed 25-Foot Walk, Six-minute Walk and Timed Up and Go mobility outcome measures and the Berg Balance Scale were assessed by one assessor one week apart. Intraclass correlation coefficient (ICC) analysis was carried out to determine reliability. Minimal detectable change values were calculated to determine clinical significance; the standard error of each measurement was calculated to assess precision. All four outcome measures were found to be reliable: Timed 25-Foot Walk ICC=0.94, Six-minute Walk Test ICC=0.96, Timed Up and Go ICC=0.97 and Berg Balance Scale ICC=0.96. Minimal detectable change values were as follows: Timed 25-Foot Walk=12.6 s, Six-minute Walk Test=76.2 m, Timed Up and Go=10.6 s and Berg Balance Scale=7 points. Standard errors of measurement were as follows: Timed 25-Foot Walk=4.56 s, Six-minute Walk Test=27.48 m, Timed Up and Go=3.81 s and Berg Balance Scale=3 points. The test-retest reliability of these four outcome measures was found to be good. The calculated clinical significance and precision of these measures highlight the problems of assessing a heterogeneous clinical population.

Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) in cerebrospinal fluid (CSF) and plasma in the MS patients and the controls (other neurological non-inflammatory diseases) and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. This study involved 60 consecutive MS patients--48 patients with relapsing-remitting MS (RRMS) and 12 patients with secondary progressive MS (SPMS). The control group consisted of 20, age and sex matched, non-immunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7%) patients had relapse (RRMS), 14 (23.3%) were in remission (RRMS), while the rest of the patients, 12 (20.0%), were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS), albumin ratio and IgG index were determined in all MS patients. The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples). IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001), however plasma levels were similar. The patients in relapse (RRMS) and with progressive disease (SPMS) had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001). IL-4 CSF levels in relapse (RRMS) and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in relapse and remission (p < 0.001). The only significant correlation between cytokine level with either EDSS, or albumin ratio, or IgG index, was found between CSF TNF-alpha levels and albumin ratio in the patients with relapse (R square = 0.431, p < 0.001). According to the obtained data MS relapse was characterized by high concentrations of TNF-alpha in CSF and plasma and low concentrations of IL-4 in CSF. Remission was characterized by high concentrations of IL-4 and low concentrations of TNF-alpha both in CSF and plasma. SPMS was characterized with lower concentrations of TNF-alpha and IL-4 compared to relapse, both in CSF and plasma.

Evaluation of a home-based physiotherapy programme for those with moderate to severe multiple sclerosis: a randomized controlled pilot study

Objective: To investigate the effect of an eight-week home-based physiotherapy programme in reducing physical impairment, disability and psychological distress for people with moderate to severe multiple sclerosis (MS). Design: Pilot randomized controlled trial. Setting: Community; subjects’ homes. Subjects: Thirty people moderately to severely affected by MS (Extended Disability Status Score, EDSS, 6.5–8) were randomized to an intervention or control group. Intervention: The intervention group received twice weekly, home-based physiotherapy for eight weeks and the control group received usual care. Main measures: The following outcome measures were recorded at baseline, post-intervention (Week 8) and at follow-up (Week 16). Primary outcome measure; Multiple Sclerosis Impact Scale (MSIS29) and secondary outcome measures assessed physical impairment, MS symptoms, quality of life, mood, and disability. Results: Although the Group * Time interaction failed to reach statistical significance with MSIS29 (p = 0.925), MS – related symptom checklist (MS-RS) (p = 0.627) and for lower limb strength, right knee extension (p = 0.375) and right knee flexion (p = 0.794), there is more evidence of altered levels in the treatment group than in the control group. Conclusion: A minimum of 58 subjects per group are required to achieve a power of 80% at the 5% level of significance based on the MSIS29. A larger scale study is required.

Aspects cliniques, radiologiques, pronostiques et thérapeutiques des lésions démyélinisantes extensives

Demyelinating diseases presenting with a tumefactive demyelinating lesion (TDL) raise questions about classification, diagnosis, prognosis, and treatment. Their long-term course is not well described in literature. In a retrospective study, we describe the main characteristics of 29 patients with TDLs. In a case control study, we compared two cohorts of multiple sclerosis (MS) patients: 24 MS patients with TDL versus a reference cohort of patients with relapsing remitting MS. We compared the extended disability status score (EDSS) concerning the first demyelinating event (DE) with TDL, EDSS score at the end of follow-up and treatment intake. The objective was to discuss the prognosis and the management of TDL. In our study, the prognosis was better for patients with non-prevalent TDL (first DE without TDL) compared with patients with prevalent TDL (first DE with TDL) and was not different compared with the MS reference cohort. At the end of follow-up, there was no significant difference between patients treated with immunosuppressors after a first DE with TDL and patients with classical MS. The EDSS at the end of follow-up was statistically more severe for untreated patients after a first DE with TDL than for classical MS patients (P=0.0047). The prognosis of patients with TDL is difficult to assess because of its multifactorial nature (underlying disease and treatment impact). In our cohort, outcome of MS patients whose first severe DE involved a TDL was better when they received an early immunosuppressive treatment.

Safety and Feasibility of Autologous Bone Marrow Cellular Therapy in Relapsing-Progressive Multiple Sclerosis

In this phase I study, we assessed the safety and feasibility of intravenous, autologous bone marrow (BM) cell therapy, without immunosuppressive preconditioning, in six patients with clinically definite, relapsing-progressive multiple sclerosis (MS). Assessment of efficacy was a secondary objective and employed clinical disability rating scales, multimodal evoked potential (MMEP) recordings, and magnetic resonance imaging (MRI) scans. Cells were harvested, filtered and infused intravenously in a day-case procedure that was well tolerated by patients and was not associated with any serious adverse events (AEs). Over a period of 12 months after the therapy, clinical disability scores showed either no change (Extended Disability Status Score, EDSS) or improvement (MS impact scale-29, MSIS-29), and MMEPs showed neurophysiological improvement. MRI scans did not show any significant changes over a post-therapy period of 3 months. The lack of serious adverse effects and the suggestion of a beneficial effect in this small sample of patients with progressive disease justify conducting a larger phase II/III study to make a fuller assessment of the efficacy of mobilization of autologous BM in patients with MS.

Stem Cell Transplantation (HSCT) in Patients with Autoimmune Disease (ADs). Results of a Single Center in Brazil.

Abstract 4360Autoimmune disease (ADs) are a group of heterogeneous disease, affecting 10-12% of the population. Nowadays, more than 1300 patients worldwide have received an HSCT for ADs. Autologous HSCT trials showed that in patients with a favourable outcome, a resetting of a disregulated auto-aggressive immune system may occur, together with the ablation of auto-reactive cells. The results of Allogeneic HSCT are still unclear, due to small number and heterogeneous groups of patients and conditioning regimens. We related here the experience in the use of HSCT in ADs at the Israelita Albert Einstein Hospital during the period between 1996 to 2009. During this period 28 patients received autologous HSCT: 23 (82%) patients with multiple sclerosis (MS), 2 (7,1%) patients with Sytemic Lupus erytomatosus (SLE), one (3,5%) with Autoimmune hemolytic anemia (AIHA), one (3,5%) Antiphospholipid sydrome (AFS). and one (3,5%) with Systemic Sclerosis. The first auto HSCT was done in 1996 in one patient (female, 54 years old) with refractory AIHA, the conditioning was cyclophpsphamide/horse antilymphocyte globulin based regime (cyclophosphamide 50mg/Kg D-5 and D-4; Fludarabine 30mg/Kg D-6 to D-3, and horse globulin 15mg/Kg on Days –5, –3, –1, +1, +2, and +3). The patient was in remission for 11 years, and was salvage with rituxmab after that. Our BMT Program for MS started in 2001. A total number of 23 patients were transplanted. The condition was BEAM/horse antilymphocyte globulin in the first 8 patient, (BCNU at a dose of 300 mg/m2 on Day –7; cytarabine at a dose of 200 mg/m2 and etoposide at a dose of 200 mg/m2 from Day –6 to Day –3,melphalan at a dose of 140 mg/m2 on Day –2; and horse antilymphocyte globulin at a dose of 15 mg/kg on Days –5, –3, –1, +1, +2, and +3, together with methylprednisolone at a dose of 2 mg/kg/day.) and the remaining 15 patients received cyclophosphamide/rabbit antilymphocyte globulin based regimen (cyclophosphamide, at a dose of 50 mg/kg of body weight, used on Days –5, –4, –3 and –2, together with rabbit antimonocyte globulin at a dose of 0.5 mg/kg on Day –6 and 1 mg/kg/day on Days –5, –4, –3 and –2 followed by methylprednisolone 2 mg/kg.). The inicial extended disability status score (EDSS) median was 6,0 (5,5-7,0); 16 (70%) were female. The mediam age was 39 (27-50) years at the time of SCT and the MS subtype “Secondary Progressive” was the most common, observed in19 (82%) patient. The period of follow up was 4 years. At the BEAM group, 7 improve their neurologic score and one became stable. At the Cyclophosphamide group, 7 remaining stable, 4 improve, and 4 worse the EDSS score. At total, 19(82%) had improve/stable of their disease disability and 4 (17%) got worse. No death was observed in both groups. The two patient with SLE refractory to previews treatment received cyclophosphamide/horse antilymphocyte globulin conditioning (the same used in AIHA patient). One (male, 38 years old) is alive 9 years after SCT in clinical remission of his disease and the second one (female, 44 years old) died due therapy related mortality. The patient with AFS (male, 52 years old) had partial “remission” and died 2 years after SCT due other cause not related to transplant. The patient with SS (female, 63 years old), also received a cyclophosphamide conditioning based regimen (cyclophosphamide 50mg/Kg D-5 and D-4; Fludarabine 30mg/Kg D-6 to D-3, and rabbit antimonocyte globulin at a dose of 0.5 mg/kg on Day –6 and 1 mg/kg/day on Days –5, –4, –3 and –2 followed by methylprednisolone 2 mg/kg) and after 2 month of follow up she has improving the dermal fibrosis, but still persisting the alteration in the lung function. In Conclusion, the Autologous HSCT had a reasonable indication in a significant subset of patients that still shows an unsatisfactory response to both conventionall and new immunomodulationg agents. Our results, although in a very small number, showed a feseable treatment in that kind of patient. Long-term follow-up would be required to fully assess in therapeutic effectiveness. We believe that the development of multicentric randomized trials, is necessary, to determine the whole use of HSCT in ADs. Disclosures:No relevant conflicts of interest to declare.

Interferon Inhibitory Activity in Patients With Multiple Sclerosis

Interferon inhibitory activity (IIA) is a logical candidate for explaining neutralizing antibody-negative partial responsiveness to interferon beta in multiple sclerosis (MS), but its role has not been evaluated. To investigate the role of IIA and soluble interferon-alpha/beta receptor (sIFNR) in determining response of patients with MS to interferon beta therapy. Parallel-group, open-label study. Baird Multiple Sclerosis Center, Buffalo, NY. Patients Blood was obtained before and 24 hours after injection of interferon beta-1a from 38 anti-interferon beta neutralizing antibody-negative patients with relapsing-remitting MS and 16 untreated healthy controls. On the basis of clinical parameters of response to interferon beta therapy, the patients were divided into stable or good-responder (n = 20) and active or partial-responder (n = 18) groups. Quantitative analyses of magnetic resonance imaging were obtained; the IIA and sIFNR levels were measured using bioassay and enzyme-linked immunosorbent assay, respectively. The IIA and sIFNR levels were elevated in MS patients compared with controls (P<.001). The IIA levels were higher in active or partial responders compared with stable or good responders (P<.001); the sIFNR levels were not different between groups. The Extended Disability Status Score and T2 lesion volumes were higher in the active or partial-responder group compared with the stable or good-responder group. Interferon beta-1a did not have short-term effects on the IIA and sIFNR levels. In univariate general linear model and stepwise regression analyses, IIA levels were associated with T2 lesion volume. The levels of IIA are associated with increased MS disease activity and with responsiveness to interferon beta therapy in anti-interferon beta neutralizing antibody-negative MS patients.

Pattern reversal visual evoked potentials as a measure of visual pathway pathology in multiple sclerosis.

Pattern reversal visual evoked potentials (PRVEPs) have a well-documented role in diagnosis of multiple sclerosis (MS), but their value as a visual function surrogate remains controversial. We evaluated PRVEP in 37 patients with MS who were participating in a long-term follow-up study following a phase III trial of interferon beta-1a (Avonex). Patients were examined to determine the Kurtzke Extended Disability Status Score (EDSS), multiple sclerosis functional composite (MSFC), contrast letter acuity (CLA), and had cranial MRI scans to determine whole brain atrophy (BPF). PRVEP was evaluated for P100 latency, amplitude, and waveform morphology. Two summary scores were created: for Score A, abnormal latencies, morphologies, and amplitudes of each individual eye were added; for Score B, abnormal latencies, morphologies, and amplitude ratio between eyes was determined. Sixteen patients in this group also had PRVEP at the time they enrolled in the clinical trial, eight years previously. At the follow-up exam, over 75% of patients had abnormal PVEP parameters while visual acuity (VA) was abnormal only in 59%. Increased PRVEP latency over the eight-year period correlated with deterioration assessed by EDSS (P = 0.006), BPF (P = 0.0001), and MSFC (P = 0.0041). Score A was significantly correlated with EDSS, BPF, CLA, cognitive function, and quality of life assessed with the Sickness Impact profile. No correlation was seen with the MSFC. The results indicate that PRVEP measures MS-related pathology, and can provide not only diagnostic but also prognostic information during evaluation of MS patients.

Depression, fatigue, and health-related quality of life among people with advanced multiple sclerosis: Results from an exploratory telerehabilitation study

This study reports on secondary data, depression, fatigue and health-related quality of life (HRQOL), collected on people with advanced multiple sclerosis (MS) as part of a larger study of the impact of a telerehabilitation intervention on people with severe mobility impairment. People with spinal cord injuries (SCIs) (n=111) and the prevention of pressure sores were the primary group of interest of the project. The focus here is on data collected from people with advanced MS (n=27), who were included as an exploratory cohort, as they experience increased risk of pressure ulcer development as their level of mobility declines. The study consisted of a nine-week intervention with three randomized groups: video, telephone, and standard care. Aside from information on pressure sores, data were also collected on fatigue, depression, and HRQOL for a two-year follow-up period. For the video group HRQOL scores trended higher and fatigue and depression scores lower for 24 months. Fatigue scores were significantly lower for the video group at month six, 12, and 18. In the sample overall, fatigue symptoms were far more prominent than depressive symptoms and affected 100% higher rates of depression than women. At baseline, controlling for Extended Disability Status Score (EDSS), depression and fatigue were correlated. However, contrary to indications from previous cross-sectional studies, no consistent relationship was observed over time between the two. Telerehabilitation interventions for people with advanced MS warrant further investigation. Findings here suggest that such interventions may be beneficial, although the results need affirmation through larger samples. In addition, the higher prevalence of male depression merits serious attention.

Disease-modifying Therapies for Multiple Sclerosis.

Multiple sclerosis (MS) is likely an autoimmune disorder, although this remains unproven. Immunotherapeutic treatments have been shown to be helpful, especially in relapsing forms of the illness, but the treatments are incomplete, and many patients continue to worsen over time, even with standard therapy. Immunotherapies presently available appear to have their greatest effect when used early in the course of the illness. In relapsing-remitting multiple sclerosis (RRMS), there is overwhelming Class I data from large clinical trials that supports the use of interferon-beta-1a (IFNbeta-1a), interferon-beta-1b (IFNbeta-1b), and glatiramer acetate. Comparative data are limited, and results published in different trials support the idea that treatment outcomes with the various drugs are more similar than different. Decisions about treatment choice should be tailored to the needs of the individual patient. With the exception of a small number of patients with benign MS, all RRMS patients should be treated with one of the interferons or glatiramer acetate. There are Class I data consistent with the idea that higher dose or more frequent administration of interferon-beta (IFNbeta) is associated with better clinical outcome and reduced progression of changes on brain MRI scans. The duration of this effect is not clear, and higher dose with more frequent administration is associated with higher cost, more side effects, and greater production of interferon antibodies. Interferon antibodies possibly reduce efficacy of IFNbeta in RRMS and secondary progressive multiple sclerosis (SPMS). Clinically isolated syndromes (CIS) of demyelination in the central nervous system can be reliably diagnosed, and the risk of further episodes of demyelination is consistent with the diagnosis of RRMS stratified by use of brain MRI scans. Patients at high risk of developing RRMS after CIS achieve significant benefit after treatment with IFNbeta-1a, and initiation of therapy after CIS should be given strong consideration. There are no similar data for IFNbeta-1b or glatiramer acetate, but logic would dictate a similar response with these agents. In SPMS, there are Class I data that treatment with IFNbeta-1a or IFNbeta-1b has a significant effect on progression of brain MRI lesions, but clinical outcomes are less clearly affected. It is justifiable to treat SPMS patients with IFNbeta. Mitoxantrone may be effective in slowing progression of SPMS, and its risks are moderate. It should be used in patients with SPMS, but potential long-term risks must be discussed with the patient in detail. Results of treatment of SPMS in advanced cases (Extended Disability Status Score greater than 6.5, or restricted to wheelchair) is mostly unknown. These patients are at high risk of developing infections, especially if they use indwelling catheters, and the use of agents that induce immunosuppression may be risky. There are no effective therapies for primary progressive multiple sclerosis (PPMS). Although PPMS patients are frequently treated with one or more therapeutic agents, there is no medical justification for this now.

Gene polymorphism at position -308 of the tumor necrosis factor alpha promotor is not associated with disease progression in multiple sclerosis patients.

Tumor necrosis factor-alpha (TNFalpha) is a pluripotent proinflammatory cytokine and is thought to play an important role in the inflammatory process of multiple sclerosis (MS). A G-->A transition in the TNFalpha promotor at position -308 (TNF2 allele) has been shown to be associated with increased TNFalpha production. This study was designed to detect wether the TNF2 allele is associated with disease progression in MS. We examined the TNFalpha -308 polymorphism with an allelic discrimination PCR to detect the G-->A transition in the genomic DNA of 283 MS patients from Germany and in 72 patients with amyotrophic lateral sclerosis (ALS) and 66 with stroke from the same genetic background who served as controls. Disease severity was defined by the progression index (PI) and by progression to the important clinical landmarks of Extended Disability Status Score (EDSS) 3.5 and 6. In addition, we evaluated the TNFalpha mRNA expression in whole blood with quantitative PCR. No differences were found between the presence of the TNF2 allele in MS, ALS, or stroke patients. Among the MS patients the TNF2 allele was not associated with a certain disease course. No association was found between the accumulation of neurological deficits and progression to clinical landmarks. Although MS patients with the TNF2 allele tended to progress more rapidly from EDSS 3.5 to EDSS 6 this difference was nonsignificant (P = 0.2). Nevertheless, we observed significantly higher TNFalpha mRNA expression in blood cells of stable patients carrying the TNF2-allele in comparison to the group with the wild type (P = 0.024). To examine the effect of genetic background we examined the DNA of 60 MS patients and 20 healthy controls in a Cypriot population of Greek origin. There was a significantly lower frequency of the TNF2 allele in the Cyprus population than in Germans (P = 0.01). No significant differences were found between the frequencies of the TNF2 allele in Cypriot MS patients and controls. Although the TNF2 allele is associated with higher TNFalpha mRNA baseline levels, our data indicate that this allele appears not to contribute to MS susceptibility or severity. In addition our data demonstrate that the TNFalpha -308 polymorphism is segregated differentially in two European populations of different genetic origin.

Sleep Problems in Multiple Sclerosis

Twenty-eight consecutive patients with multiple sclerosis (MS) were clinically evaluated to determine the presence of sleep-related disorders. There were 12 males and 16 females aged between 22 and 67 with disability ranging between 1.5 and 8.5 on Kurtzke extended disability status score (EDSS). Fifteen patients (54%) reported sleep-related problems. These included difficulties initiating sleep and/or frequent awakenings due to spasms or discomfort in the legs (8 patients), difficulty in initiating or maintaining sleep (3), habitual snoring (4) and nocturia (1). All-night oximetry was performed and the tracings analysed for the number of dips in oxygen saturation (SaO2) or more than 4%. Three patients showed significant sleep-related oxygen desaturation (> 5 dips of > 4% SaO2/h). Subsequent polysomnography performed in 2 of the 3 patients with significant oxygen desaturation confirmed the presence of sleep apnoea. MRI analysis of brain stem regions showed abnormalities in 20/22 cases. The 3 patients showing nocturnal oxygen desaturation had MRI brain stem lesions, but their locations were variable and their general appearance not different from that seen in the 17 without sleep apnoea. Sleep disturbance in MS is common but poorly recognised. It is usually due to leg spasms, pain, immobility, nocturia or medication. It is much less commonly associated with nocturnal respiratory insufficiency.