Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.

OBJECTIVE: We aimed to evaluate the effect of slow-release (SR) Fampridine on multiple outcome measures reflecting different domains, and to compare the responsiveness of the Six Spot Step Test (SSST) and the Timed 25 Foot Walk (T25FW). METHODS: For this study 108 participants were included. On day 0 they were tested with the T25FW, the SSST, the 9-Hole Peg Test (9-HPT), the 5 Times Sit-To-Stand test (5-STS) and the Symbol Digit Modalities Test (SDMT). Four weeks of treatment with SR Fampridine 10 mg BID was commenced. Participants were tested again after 26-28 days of treatment. RESULTS: Mean changes observed were: SSST -3.4±6.4 s (p<0.001), T25FW -1.2±3.7 s (p<0.001), 9-HPT -1.2±6.0 s (p<0.001), 5- STS -3.4±7.2 s (p<0.001) and SDMT 1.4±4.8 a.u. (p=0.003). Change on the SSST differed significantly from T25FW (SSST 17.0±19.6% vs. T25FW 11.2±17.1%, p=0.0013). Some 48.6% were found to have a meaningful change on the SSST compared with 25.7% on the T25FW. The response to treatment with SR Fampridine did not correlate with age, sex, Expanded Disability Status Scale and disease duration. CONCLUSION: SR Fampridine treatment has significant effects on different domains including upper and lower body and cognition. Furthermore, the SSST is more responsive to the effect of SR Fampridine than is the T25FW. ClinicalTrials.gov identifier: NCT01656148.

Patient reported outcomes in a secondary progressive MS cohort related to cognition, MRI and physical outcomes.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly being used as outcomes in secondary progressive multiple sclerosis (SPMS) trials. We examined how PROs reflect disease burden in SPMS. METHODS: In this observational prospective study, 65 SPMS patients were examined by five different PROs (Fatigue Scale Motor Cognition (FSMC), Multiple Sclerosis Impact Scale version 2 (MSIS-29v2), 36-Item Short Form Health Survey version 2 (SF-36v2), EQ-5D-5L and Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis version 2.0 (WPAI:MS)); two different rating scales, Multiple Sclerosis Impairment Scale (MSIS) and Expanded Disability Status Scale (EDSS); functional tests of mobility (Timed-25-Foot Walk (T-25FW), 6-Spot Step Test (6-SST) and (9-Hole Peg Test (9-HPT)); cognitive tests (Symbol Digital Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R)); and multimodal Magnetic Resonance Imaging (MRI). RESULTS: When the PROs were divided into physical and psychological subscores, the PRO physical subscores of FSMC, MSIS-29v2 and SF-36v2 correlated with physical rating scales (EDSS, MSIS) and physical measures of upper (9-HPT) and lower extremity function (T-25FW and 6-SST)) (p = 0.04-0.0001). 9-HPT correlated the least with physical subscores of PROs but showed the strongest correlation with activity impairment (subscore of WPAI:MS). In contrast, psychological PRO subscores of FSMC, MSIS-29v2 and SF-36v2 did not reflect the cognitive outcomes (SDMT and BVMT-R), although the cognitive scores correlated with disease burden indicated by MRI lesion volumes. The psychological PRO subscores did not correlate with fatigue, physical and MRI outcomes either. CONCLUSION: Correlation between PRO physical subscores and physical outcomes supports PROs as potentially useful clinical endpoints in SPMS. The results of this study indicate that patients with SPMS highly perceive their mobility on function of their lower extremities, while they perceive their daily activities highly dependent on function of the upper extremities. Psychological subscores of MS specific PROs may be less suitable as surrogate markers for the cognitive status and should be considered as a mental quality of life measurement independent of disease burden.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING: Teva Pharmaceutical Industries, Israel.

Methylprednisolone does not restore biological response in multiple sclerosis patients with neutralizing antibodies against interferon-ß.

BACKGROUND AND PURPOSE: Neutralizing antibodies (NAbs) appearing during treatment with Interferon-beta (IFN-beta) reduce or abolish bioactivity and therapeutic efficacy. Initial combination therapy with methylprednisolone (MP) may reduce the frequency of NAb positive patients. We hypothesized that MP treatment might also reduce NAb levels and re-establish IFN-beta bioactivity in patients already NAb+, who discontinue IFN-beta therapy. METHODS: In a 6-month open-label trial, we compared monthly high-dose pulsed MP treatment in 38 Nab positive patients with 35 NAb+, MP-untreated control patients discontinuing any therapy or switching to glatiramer acetate. All patients were NAb+ with an absent in vivo response to IFN-beta. NAbs were measured using a cytopathic effect assay and expressed as neutralizing capacity (NC) in percentage of added IFN-beta. Bioactivity was expressed as in vivo Myxovirus Resistance Protein A (MxA) mRNA induction in whole blood using real time PCR. RESULTS: At the end of study, median NAb NC was 92% in both groups. Eight patients (21%) in the MP group and four patients (11%) in the control group had regained an in vivo MxA response to IFN-beta (P = 0.35). CONCLUSIONS: Monthly pulsed MP treatment in NAb positive patients has no beneficial effect on NAb status or IFN-beta bioactivity.

Distribution-based estimates of minimum clinically important difference in cognition, arm function and lower body function after slow release-fampridine treatment of patients with multiple sclerosis.

OBJECTIVE: To provide distribution-based estimates of the minimal clinical important difference (MCID) after slow release fampridine treatment on cognition and functional capacity in people with MS (PwMS). METHOD: MCID values were determined after SR-Fampridine treatment in 105 PwMS. Testing included the Timed 25 Foot Walk (T25FW), the Symbol Digit Modalities Test (SDMT), the Six Spot Step Test (SSST), the 9-Hole-Peg-Test (9-HPT), and the 5-Time-Sit-To-Stand test (5-STS). RESULTS: MCID values: T25FW 17.8% (9.1-17.8), SDMT 17.1% (9.2-17.1), SSST 16.7% (8.5-16.7), 9-HPT 15.3% (0-15.3), and 5-STS 34.6% (16.9-34.6). CONCLUSION: This study presents distribution-based estimates of MCID values for the SSST, the 9-HPT, and the 5-STS and confirms MCID estimates for the T25FW and the SDMT.

Effect of slow release-Fampridine on muscle strength, rate of force development, functional capacity and cognitive function in an enriched population of MS patients. A randomized, double blind, placebo controlled study.

DESIGN: This study was conducted as a randomized, double blind, placebo-controlled parallel group trial preceded by open label enrichment phase. OBJECTIVES: The objectives of this study were 1) to examine the effect of SR-Fampridine treatment on muscle strength in terms of maximal voluntary contraction (MVC) and rate of force development (RFD) of the lower extremities and 2) to replicate previously published data on the effect of slow release-Fampridine (SR-Fampridine) on the functional capacity of the lower limbs, the upper limb and cognitive function, in persons with multiple sclerosis (pwMS). METHODS: Previously identified responders to SR-Fampridine were randomized to SR- Fampridine or placebo treatment for four weeks. On days 0 and 26-28 participants underwent testing by isokinetic dynamometry, Nine Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Six Spot Step Test (SSST), Timed 25 Foot Walk Test (T25FW) and 5-Times Sit-to-Stand (5-STS). RESULTS: A statistical significant effect of SR-Fampridine on MVC was demonstrated during knee extension, knee flexion and hip flexion of the weakest leg, as well as on RFD during knee extension and knee flexion of the weakest leg. Furthermore, a significant effect of SR-Fampridine on T25FW, SSST and 5-STS was demonstrated. CONCLUSION: Gold standard dynamometry assessment of muscle strength showed improved MVC and RFD in persons with MS treated with SR-Fampridine compared to placebo. Furthermore, previous findings on the effects of SR-Fampridine on functional capacity of the lower limbs were replicated. ClinicalTrials.gov identifier: NCT01656148.

MEP recruitment curves in multiple sclerosis and hereditary spastic paraplegia.

OBJECTIVE: Axons remodel at multiple levels after a single inflammatory lesion in the spinal cord, which can contribute to recovery. The primary aim of this study was to investigate whether the MEP response as function of the excitatory strength, here called recruitment curves, may be used in discriminating demyelination from compensated axonal loss. Multiple sclerosis (MS) represents both demyelination and axonal degeneration. Hereditary Spastic Paraplegia (HSP) was included as a model of pure axonal loss. METHODS: To investigate both spinal and cortical recruitment, the methods used for gradual recruitment were two different test paradigms of voluntary pre-activation and stimulus intensity. The MEP-recruitment curves were obtained by means of transcranial magnetic stimulation (TMS) in 29 MS patients, 9 patients with HSP and in 30 healthy controls. RESULTS: Saturated recruitment curves were obtained in all subject groups, muscles and paradigms and were generally found to be identical. The two groups of patients had clinical signs, CMCT changes and reduced MEP amplitude reflecting relevant cortico-spinal disorder. CONCLUSIONS: We conclude that both demyelination and axonal degeneration in the CNS leads to diminished MEP amplitudes and CMCT changes. The recruitment curves of MS and HSP was identical to controls and may not be used for diagnostic or monitoring purposes.

The diagnostic reliability of magnetically evoked motor potentials in multiple sclerosis.

In a prospective study, we evaluated the technique of magnetically evoked motor potentials (MEP) in the diagnosis of multiple sclerosis (MS). We consecutively included 68 patients with symptoms or signs compatible with a demyelinative CNS affection. We subjected all patients to CSF analysis, MRI studies of the brain and brainstem, visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), and somatosensory evoked potentials (SSEP). We then used the results to categorize the patients according to the Poser criteria of multiple sclerosis. Blinded from the results of the above investigations, one of the authors made MEP recordings from three muscles in the upper limbs and two in the lower limbs in all 68 patients. Forty patients received an MS diagnosis, and in these, MRI was positive in 88%, MEP in 83%, VEP in 67%, SSEP in 63%, and BAEP in 42%. As to the diagnosis of MS, the reliability of a prolonged central motor conduction time (CMCT) was 0.83 (0.73 to 0.93), while the reliability of a normal CMCT was 0.75 (0.61 to 0.98). The information gained by MRI was best supplemented by VEP. Of the neurophysiologic tests, the MEP was in closest agreement with the MRI with a concordance of 85%.

Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS.

OBJECTIVE: To study the association between the cortical cerebral metabolic rate of glucose (CMRglc), MRI T2-weighted total lesion area (TLA), cognitive dysfunction, and neurologic disability in MS. BACKGROUND: MRI lesion load is widely used in the clinical evaluation of the MS patient but little is known about the associated changes in cortical activation. METHODS: Twenty-three patients with clinically definite MS underwent measurements of CMRglc, TLA, motor evoked potentials (MEPs), and cognitive and neurologic disability. CMRglc was calculated using PET and 18-F-deoxyglucose and compared with nine normal control subjects. RESULTS: Reductions in CMRglc (p < 0.01) were found in the cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (Spearman rank correlation coefficient [SRCC] = -0.66, p = 0.001), and rCMRglc correlated with regional lesion load in all cerebral lobes (p < or = 0.05). Global cortical CMRglc and cognitive disability also correlated (SRCC = 0.58, p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance as well as TLA. There was no correlation between CMRglc and neurologic disability (Expanded Disability Status Scale) or MEP. CONCLUSION: Global and regional cortical CMRglc is reduced significantly in MS patients compared with normal control subjects. Furthermore, the CMRglc reductions correlate with TLA as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on cortical cerebral neural function.

Plasma exchange combined with azathioprine in multiple sclerosis using serial gadolinium-enhanced MRI to monitor disease activity: a randomized single-masked cross-over pilot study.

We enrolled 11 patients with secondary progressive MS in a randomized single-masked cross-over study of plasma exchange (PE) in combination with azathioprine 2 mg/kg. PE was performed once a week for 4 weeks and thereafter every second week for 20 weeks (14 treatments). Eight patients completed the whole trial, and three patients discontinued the trial, two during the run-in period of azathioprine treatment and one at the introduction of PE. The primary efficacy variables were the number of gadolinium-enhancing lesions and the occurrence of new enhancing lesions on serial MRI performed every 3 weeks during the PE and the control period. Secondary efficacy variables were the total MS lesion load on T2-weighted MRI, multimodal evoked potentials, and clinical neurologic ratings. No significant differences were found regarding the number of enhancing lesions or occurrence of new enhancing lesions in the two periods. Although the total MS lesion load on MRI was significantly lower (p < 0.02) and central motor conduction times decreased significantly (p < 0.05) during PE, this small study did not provide sufficient evidence for a significant beneficial effect of PE or encourage a subsequent large randomized parallel group study.

Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis.

We wanted to assess whether intravenous immunoglobulin G (IVIG) decreases disease activity on MRI in relapsing MS. Previous trials of IVIG in relapsing-remitting MS demonstrated a reduction of acute relapses, but these studies did not include MRI. We treated 26 patients in a randomized, double-blind, crossover study of IVIG 1 g/kg daily or placebo on 2 consecutive days every month during two 6-month treatment periods. The primary end point was the number of gadolinium-enhancing lesions on monthly serial MRI. Secondary efficacy variables were the occurrence of exacerbations, clinical neurologic ratings, total MS lesion load on T2-weighted MRI, and multimodal evoked potentials. Eighteen patients completed the entire trial; eight patients did not. Twenty-one patients completed the first treatment period and at least two MRI examinations in the second treatment period and were included in the intention-to-treat analysis. On serial MRI, we observed fewer enhancing lesions per patient per scan during IVIG treatment (median, 0.4; range, 0 to 9.3) than during placebo treatment (median, 1.3; range, 0.2 to 25.7; p = 0.03). During IVIG treatment, 15 patients were exacerbation free compared with only 7 on placebo (p = 0.02). The total number of exacerbations in the IVIG period was 11 and in the placebo period, 19 (not significant). None of the remaining secondary efficacy measures were significantly different between the two treatment periods. The number of adverse events, in particular eczema, was significantly higher during IVIG therapy than during placebo treatment. These results suggest that IVIG treatment is beneficial to patients with relapsing MS.

No effect of pulsed magnetic stimulation on the blood-brain barrier in rats.

The impact of transcranial pulsed magnetic stimulation on blood-brain barrier permeability was studied in rats. An integral uptake technique was used to asses the blood-brain barrier permeability to the tracers [3H]sucrose, [14C]urea, and 36Cl-. From the arterial plasma concentration-time curve-integral the permeability surface-area products were calculated. A Dantec magnetic stimulator delivering a peak magnetic field of 1.9 T with a rise-time of 160 microseconds was used for transcranial stimulation of the rats. One group of rats had about 50-60 stimulations during the 15-min infusion of the tracers while another group was exposed to 50 magnetic stimulations a day for one week. A third group comprised the controls. No differences in permeability surface-area product were found for any of the three tracers in the rats exposed to magnetic stimulation as compared with the controls. It is concluded that with regard to blood-barrier integrity, pulsed magnetic stimulation of the brain can be regarded as safe.

[Use of outcome measures in physical medicine/rheumatological rehabilitation. Results of a questionnaire study]. / Brugen af effektmål i fysiurgisk/reumatologisk rehabilitering. Resultat af en spørgeskemaundersøgelse.

BACKGROUND: As part of the EU-project ProESOR (Project for the European Standardisation of Outcome Measurement in Rehabilitation), a survey was undertaken to investigate the use of Outcome Measures (OM) within rehabilitation across Europe. This paper presents some of the Danish results of this survey. AIM: Evaluate the extent of use of OMs in rehabilitation. MATERIAL: All 37 Rheumatology/Physical Medicine and Rehabilitation departments and institutions in Denmark. METHOD: A questionnaire was mailed to the institutions. This included questions about the institution and its personnel, and nine diagnostic groups: Low back pain, multiple sclerosis, neuromuscular disorders, rheumatoid arthritis, spinal cord lesions, stroke, traumatic brain injury, hip and knee replacement, and lower limb amputees, with estimation of the number of patients treated and the extent of use of OMs. RESULTS: The majority of the departments treated more than 200 in- and out-patients per year. Patients with low back pain and rheumatoid arthritis were the largest patient groups, followed by patients with hip and knee replacement and stroke. OMs were most frequently used with rheumatoid arthritis and, to a lesser extent, patients with low back pain. Although many departments used one or more OM, several did not use any at all. For each diagnostic group more OMs were used if the patient was treated in a department specialised for patients with the particular diagnosis. More OMs were used with patients who tended to have longer inpatient stays. CONCLUSION: There is little consensus regarding which OMs should be used. We recommend that this challenge be taken up.

[Reduced metabolism in cerebral cortex correlates with MRI changes and cognitive dysfunction in patients with disseminated sclerosis]. / Reduceret cerebralt stofskifte korrelerer med MRI-forandringer og kognitiv dysfunktion hos patienter med dissemineret sklerose.

INTRODUCTION: Magnetic resonance imaging (MRI) lesion load is widely used in the clinical evaluation of patients with multiple sclerosis (MS), but little is known about the associated changes in cortical activation. For this purpose, we studied the association between the corticocerebral metabolic rate of glucose (CMRglc) and the MRI T2-weighted total lesion area (TLA). In addition, we investigated the correlation between cognitive and neurological disability and CMRglc. METHODS: Twenty-three patients with clinically definite MS underwent measurements of the CMRglc, TLA, motor-evoked potentials (MEP), and cognitive and neurological disability. CMRglc was calculated with positron emission tomography (PET) and 18-F-deoxyglucose (FDG) and compared to that of nine healthy controls. RESULTS: A reduction in CMRglc (p < 0.01) was found in cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (rho = -0.66; p = 0.001), and rCMRglc correlated with the regional lesion load in all cerebral lobes (p < or = 0.05). Global cortical CMRglc and cognitive disability were also correlated (rho = 0.58; p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance, as well as the TLA. There was no correlation between CMRglc and neurological disability (expanded disability status scale [EDSS]) or MEP. CONCLUSION: Global and regional cortical CMRglc is significantly reduced in patients with MS compared to healthy controls. The reductions in CMRglc furthermore correlate with the TLA, as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on corticocerebral neural function.

Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an MS Patient Treated with Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases. AIMS: To describe the effects of allo-HCT on the course of MS in a 49-year-old woman with longstanding progressive MS who was treated with allo-HCT for follicular lymphoma. METHODS: Non-myeloablative conditioning allo-HCT, examination for IgG oligoclonal bands and measurement of CXCL13 and matrix metalloproteinase-9 (MMP-9) concentration in the cerebrospinal fluid (CSF). RESULTS: Despite the disappearance of oligoclonal bands in CSF, disease progression and CSF inflammation was observed. CONCLUSIONS: We hypothesize that CXCL13 and MMP-9 detected in CSF may reflect ongoing, pathogenic immune activation even after the eradication of intrathecal IgG synthesis. This suggests that progressive MS may depend more on innate than on adaptive immune activation.

Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis.

BACKGROUND: It is unknown whether immunosuppression of patients who have developed interferon-beta (IFN-beta) neutralizing antibodies (NAbs) hastens disappearance of NAbs in the blood. OBJECTIVE: We wanted to test whether immunosuppression with cyclic methylprednisolone (MP) in combination with azathioprine (AZA) for 6 months accelerates recovery of IFN-beta bioactivity in patients with multiple sclerosis (MS) with abolished in-vivo myxovirus resistance protein A (MxA) mRNA response to IFN-beta. METHODS: We included 13 patients with MS with NAbs and a low IFN-beta bioavailability detected by the MxA-mRNA response in a descriptive, non-randomized trial. Another 14 NAb-positive patients with a low MxA-mRNA response served as controls. The primary outcome was the fraction of patients who regained an MxA-mRNA response to IFN-beta. NAbs were measured by means of a clinically validated cytopathic effect assay and a new reporter gene assay. The in-vivo MxA-mRNA response was measured by real-time polymerase chain reaction. RESULTS: A total of 11 patients in the treatment group completed the trial. In all, two of these 11 patients regained an in-vivo MxA-mRNA response as compared to one of 14 patients in the control group. CONCLUSION: Treatment with AZA and cyclic MP for 6 months has little or no effect on IFN-beta bioactivity in NAb-positive patients with MS.

The efficacy of multidisciplinary rehabilitation in stable multiple sclerosis patients.

OBJECTIVE: To evaluate the short-term efficacy of multidisciplinary, inpatient rehabilitation of multiple sclerosis (MS) patients. METHODS: A double-blind, randomized, parallel group design was used. The intervention group were offered comprehensive, multidisciplinary inpatient rehabilitation at the Haslev MS Hospital for an average of 35.5 days, while the control group received no treatment related to the study. All patients were examined in their homes twice with a 10-week interval. The rehabilitation of the intervention group started 2-3 weeks after the first examination and ended 2-3 weeks before the second examination. Impairment was assessed by the Multiple Sclerosis Impairment Scale and the Expanded Disability Status Scale. Disability was assessed by means of Guy's Neurological Disability Scale. Two specific scales were used to assess upper limb function and ambulation: The Nine-Hole Peg Test and timed 10-metre walking. Patients' own perception of bodily pain, bladder symptoms, spasticity, fatigue, impaired walking and transfers were recorded using visual analogue scales. Finally, quality of life was assessed using the Life Appreciation and Satisfaction Questionnaire and the Functional Assessment in Multiple Sclerosis. PATIENTS: Two hundred and thirty-three patients were screened and of those 38 were included for treatment and 52 as controls. RESULTS: We found no statistically significant differences between the two groups in any of the outcome measures. CONCLUSION: Although the study was underpowered, the negative outcome exposes the difficulties in quantitative analyses of the efficacy of multidisciplinary rehabilitation, which is liable to confounding factors such as variation in the indication for treatment, in the placebo effect, and in the reliability and responsiveness of the outcome measures.

The six spot step test: a new measurement for walking ability in multiple sclerosis.

OBJECTIVE: The primary objective of this study was to develop a quantitative test to assess ambulation in multiple sclerosis (MS) patients that is more accurate and sensitive than the Timed 25-foot walk (T25FW). For this purpose, we developed the Six Spot Step Test (SSST), which besides speed includes co-ordination and balance, to be a lower limb counterpart to the 9-Hole Peg Test (9HPT). BACKGROUND: The T25FW, which is the ambulation test of the MS Functional Composite (MSFC), reflects only the speed component of walking. The lack of sensitivity to other components of gait adds to the floor effect. METHODS AND PATIENTS: In the SSST, the patient is instructed to walk as quickly as possible from one end to the other of a rectangular field measuring 1 x 5 m, while kicking five cylinder blocks out of five circles marked on the floor. Some 151 MS patients with the Expanded Disability Status Scale (EDSS) score 0-6.5 and 64 normal controls performed the SSST and the T25FW. In addition, 41 patients performed the tests twice. RESULTS: The range of the SSST (4.7-35.1 seconds) was wider than that of the T25FW (3.5-22.6 seconds). Using control mean + 2 SD as cut off, 107 patients had abnormal SSST, while 100 patients had abnormal T25FW. The T25FW (mean) increased 2.1 seconds over the EDSS range of 0-4.0, while the SSST increased 4.9 seconds. The intra-class correlation between repeated tests (r) was 0.95 for the SSST and 0.96 for the T25FW. The correlation between the SSST and the T25FW was high (r=0.92). CONCLUSION: The SSST seems to be superior to the T25FW in terms of dynamic range, floor effect and discriminatory power. The SSST is a relevant alternative for the T25FW as the ambulation component of the MSFC.

Neutralizing antibodies hamper IFNbeta bioactivity and treatment effect on MRI in patients with MS.

We measured neutralizing antibodies (NABs) and the in vivo biologic response to interferon-beta on neopterin and beta(2)-microglobulin blood levels. All NAB-negative patients had an in vivo biologic response (full or partial), whereas all high-level positive patients had no response. High-level NAB patients had more MRI activity than NAB-negative patients (p = 0.031). Patients with a full response had less MRI activity than patients without biologic response (p = 0.032).