Scripps Neurological Rating Scale Research Articles

Dynamic disability measures decrease the clinico-radiological gap in people with severely affected multiple sclerosis

BackgroundExpanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS). ObjetiveTo explore the relationship between disability measures and MRI outcomes in severely-affected pwMS. MethodsPwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained. ResultsGreatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not. ConclusionGranular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS.

Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis

BackgroundMultiple sclerosis (MS) is a progressively debilitating neurological condition in which the immune system abnormally erodes the myelin sheath insulating the nerves. Mesenchymal stem cells (MSC) have been used in the last decade to safely treat certain immune and inflammatory conditions.MethodsA safety and feasibility study was completed on the use of umbilical cord MSC (UCMSC) as a treatment for MS. In this 1-year study, consenting subjects received seven intravenous infusions of 20 × 106 UCMSC over 7 days. Efficacy was assessed at baseline, 1 month and 1 year after treatment, including magnetic resonance imaging (MRI) scans, Kurtzke Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale, Nine-Hole Peg Test, 25-Foot Walk Test, and RAND Short Form-36 quality of life questionnaire.ResultsTwenty subjects were enrolled in this study. No serious adverse events were reported. Of the mild AEs denoted as possibly related to treatment, most were headache or fatigue. Symptom improvements were most notable 1 month after treatment. Improvements were seen in EDSS scores (p < 0.03), as well as in bladder, bowel, and sexual dysfunction (p < 0.01), in non-dominant hand average scores (p < 0.01), in walk times (p < 0.02) and general perspective of a positive health change and improved quality of life. MRI scans of the brain and the cervical spinal cord showed inactive lesions in 15/18 (83.3%) subjects after 1 year.ConclusionsTreatment with UCMSC intravenous infusions for subjects with MS is safe, and potential therapeutic benefits should be further investigated.Trial registration ClinicalTrials.gov NCT02034188. Registered Jan 13, 2014. https://clinicaltrials.gov/ct2/show/NCT02034188

Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment.

Therapeutic advance in progressive multiple sclerosis (MS) has been very slow. Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively acquired candidate outcomes in the real-world situation of progressive MS trials to select and validate the best-performing outcome. The 1-year pre-treatment period of adaptively designed IPPoMS (ClinicalTrials.gov #NCT00950248) and RIVITaLISe (ClinicalTrials.gov #NCT01212094) Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing 8 clinical, 1 electrophysiological, 1 optical coherence tomography, 7 MRI volumetric, 9 quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over 1 year (Δ) in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR) and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning techniques, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and 9 hole peg test. CombiWISE outperformed all clinical scales (Δ = 9.10%; p = 0.0003) and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR, and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS patients and in a cross-sectional cohort of 303 untreated subjects. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with a standard error of 0.10. The novel validated clinical outcome, CombiWISE, outperforms the current broadly utilized MRI brain atrophy outcome and more than doubles sensitivity in detecting clinical deterioration in progressive MS in comparison to the scale traditionally used for regulatory approval, EDSS.

Novel composite MRI scale correlates highly with disability in multiple sclerosis patients

Understanding genotype–phenotype relationships or development/validation of biomarkers requires large multicenter cohorts integrated by universal quantification of crucial phenotypical traits, such as central nervous system (CNS) tissue destruction. We hypothesized that mathematical modeling-guided combination of biologically meaningful, semi-quantitative MRI elements characterized by high signal-to-noise ratio will provide such reliable, universal tool for measuring CNS tissue destruction. We retrospectively graded 15 elements in MRI scans performed in 419 untreated subjects with or without neurological diseases, while being blinded to their prospectively acquired clinical scores. We then used 305 subjects for disability-guided mathematical modeling to select and combine MRI elements that had non-redundant contributions to clinical disability, resulting in Combinatorial MRI Scale (COMRIS). We validated our model on the remaining 114 independent subjects. COMRIS requires 5–10min per scan on average to compute and demonstrates highly significant (p<0.0001) and validation-consistent Spearman correlation coefficients (0.75, 0.76, and 0.65) for the expanded disability status scale (EDSS), Scripps neurological rating scale (SNRS), and symbol digit modality test (SDMT) measures of neurological disability, respectively. Because COMRIS is not greatly influenced by MRI scanners or protocols and can be computed even in the presence of some motion artifacts, it does not require censoring out patients and it provides comparable results across different cohorts. As such, it represents a broadly available clinical and research tool that can facilitate multicenter research studies and comparative analyses across patient cohorts and research projects.

Neurocognitive functions and brain atrophy after proven neuroborreliosis: a case-control study.

BackgroundPatients often report neurocognitive difficulties after neuroborreliosis (NB). The frequency and extent of cognitive problems in European patients have been studied incompletely.MethodsSixty patients received a neurological and neuropsychological work-up 6 months or longer after treatment for proven NB. Quality of life, psychiatric symptom load, and brain atrophy were measured. All results were compared with a group of 30 healthy control persons adapted for age, gender and education being serologically negative for Borrelia burgdorferi senso latu. A cognitive sum score and a global sum score including cognitive, psychological results and quality of life data was calculated for both groups.ResultsPatients after NB showed a lower (i.e. more impaired) score on the Scripps Neurological rating scale (SNRS), but the observed neurological deficits were generally mild (mean ± SD: 97.1 ± 4.7 vs. 99.1 ± 2.4, p = 0.02). The mean neuropsychological domain results of the NB group were all within the normal range. However, a lower performance was found for the frontal executive function z-values (mean ± SD –0.29 ± 0.60 vs. 0.09 ± 0.60; p = 0.0059) of NB patients. Comparing the global sum score (mean ± SD 11.3 ± 4.2 NB vs. 14.3 ± 2.9 control, p = 0.001) and the cognitive sum score of the NB group with those of the control group (mean ± SD -0.15 ± 0.42 NB vs. 0.08 ± 0.31 control, p = 0.0079), both differences were statistically different. The frequencies of impaired global sum scores and those of the pathological cognitive sum scores (p = 0.07) did not differ statistically. No significant differences were found for health-related quality of life (hrQoL), sleep, psychiatric symptom load, or brain atrophy.ConclusionThe mean cognitive functions of patients after proven NB were in the normal range. However, we were able to demonstrate a lower performance for the domain of frontal executive functions, for the mean cognitive sum score and the global sum score as a sign of subtle but measurable sequelae of neuroborreliosis. Brain atrophy is not a common consequence of neuroborreliosis.

Sub-millimeter imaging of brain-free water for rapid volume assessment in atrophic brains

IntroductionCerebral atrophy occurs in healthy aging, and in disease processes such as multiple sclerosis (MS), it correlates with disability accumulation. Imaging measurements of brain atrophy are commonly based on tissue segmentation, which is susceptible to classification errors and inconsistencies. High-resolution imaging techniques with strong contrast between brain parenchyma and cerebrospinal fluid (CSF) might allow fully automated, rapid, threshold-based determination of the free water in the brain. We hypothesized that total brain-free-water (BFW) volume and BFW volume expressed as a normalized fraction of the intracranial volume (“BFW fraction”), determined from heavily T2-weighted images, would be useful surrogates for cerebral atrophy and therefore would correlate with clinical measures of disability in MS. MethodsWhole brains of 83 MS cases and 7 healthy volunteers were imaged with a 4.7-min, heavily T2-weighted sequence on a 3T MRI scanner, acquiring 650-μm isotropic voxels. MS cases were clinically assessed on the Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale (SNRS), Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), and 25-Foot Timed Walk. Twelve of the MS cases were rescanned within an average of 1.8months to assess reproducibility. Automated calculations of BFW volume and BFW fraction were correlated with clinical measures of disability upon adjusting for age and sex. Results were compared to data from T1-based approaches (SIENAX and Lesion-TOADS). Results and discussionBFW volume was automatically derived from heavily T2-weighted images with no need for separate skull stripping. BFW volume and fraction had mean scan–rescan coefficients of variation of 1.5% and 1.9%, respectively, similar to the T1-based approaches tested here. BFW fraction more strongly correlated with clinical measures than T1-derived results. Among those clinical measures, modality-specific disability scores, such as SDMT and 9HPT, were more strongly associated with BFW fraction than composite measures, such as EDSS and SNRS. ConclusionThe BFW method robustly estimates cerebral atrophy in an automated, fast, and reliable manner, and as such may prove a useful addition to imaging protocols for clinical practice and trials.

Intrathecal effects of daclizumab treatment of multiple sclerosis

We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon-β and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system. Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF. The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56(bright) NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment. The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period.

At 50, the Journal Looks Back… and Ahead

<b>Objective: </b> There is only limited evidence from adequately controlled clinical trials to support high-dose methylprednisolone therapy for attacks of multiple sclerosis (MS) and none supporting oral administration. We assessed the effect of oral high-dose methylprednisolone therapy in attacks of MS. <b>Methods: </b> Twenty-five patients with an attack of MS lasting less than 4 weeks were randomized to placebo treatment. Twenty-six patients received oral methylprednisolone (500 mg once a day for 5 days with a 10-day tapering period). The patients received scores on the Scripps Neurological Rating Scale (NRS) and Kurtzke Expanded Disability Status Scale. The symptoms were scored on a visual analog scale (VAS) before treatment and after 1, 3, and 8 weeks of treatment. Primary efficacy measures were NRS and VAS scores in the first 3 weeks and changes in NRS score and answers to an efficacy questionnaire administered after 8 weeks of treatment. <b>Results: </b> Changes in NRS scores among methylprednisolone- and placebo-treated patients differed significantly in the first 3 weeks and after 8 weeks(<i>p</i> = 0.005 and <i>p</i> = 0.0007). VAS scores the first 3 weeks and treatment efficacy after 8 weeks also favored a beneficial effect of methylprednisolone treatment (<i>p</i> = 0.02 and <i>p</i> = 0.05). After 1, 3, and 8 weeks, 4%, 24%, and 32% in the placebo group and 31%, 54%, and 65% in the methylprednisolone group had improved one point on the Expanded Disability Status Scale score (all <i>p</i> &lt; 0.05). No serious adverse events were seen. <b>Conclusion: </b> Oral high-dose methylprednisolone is recommended for managing attacks of MS.

A Preliminary Result of Treatment of Neuromyelitis Optica With Autologous Peripheral Hematopoietic Stem Cell Transplantation

Autologous peripheral hematopoietic stem cell transplantation (APHSCT) was performed to treat a patient with neuromyelitis optica. We observed that the patient achieved clinical remission after APHSCT during 12 months of follow-up. The patient improved on the expanded disability status scale neurologic assessment and the Scripps neurologic rating scale worksheet scores on follow-up examination compared with baseline. The MRI abnormalities on T1WI and T2WI improved. The postpartum maternal blood helper T (CD3+CD4+ T cell) and the CD4+/CD8+ ratio were decreased, and the cytotoxic T (CD3+CD8+ T) cell increased. This shows that APHSCT in this patient with neuromyelitis optica appears to reduce the frequency of attacks with improvement in disability. However, a larger study with more patients and a longer follow-up would be required to assess the encouraging preliminary results.

A Short-Term, Multidisciplinary, Intensive Inpatient Neurorehabilitation Program for Multiple Sclerosis Patients with Moderate Disability: A Pilot Study

Intensive inpatient neurorehabilitation may be an effective form of intervention for people with multiple sclerosis (MS) to supplement treatment with disease-modifying agents. The primary objective of this study was to evaluate the tolerability and safety of a personalized, one-on-one, short-term, intensive inpatient neurorehabilitation program for MS patients with moderate disability. Thirty MS patients (diagnosed using Polman criteria) with moderate disability as indicated by Expanded Disability Status Scale (EDSS) score of 5.0 to 6.5 were enrolled in a 4-week intensive inpatient neurorehabilitation program. The primary outcome measures were tolerability and safety. Secondary outcome measures were impairment, disability/activity, handicap/participation, fatigue, and quality of life. The results showed good tolerability, with only three patients (10%) developing transitory neuromuscular fatigue; and safety, with adverse events observed in only six patients (20%). Significant improvement was found in impairment and disability/activity as measured by the Scripps Neurological Rating Scale (P = .000) and the EDSS (P = .001), respectively. The Multiple Sclerosis Quality of Life–54 showed improvement in physical (P = .008) and mental health (P = .026), and the Fatigue Impact Scale showed improvement in fatigue (17 patients) (P = .005). This pilot study demonstrated good tolerability and safety of the short-term inpatient intensive neurorehabilitation program. Impairment, disability/activity, quality of life, and fatigue were improved at the completion of the program. Sustained improvement remains to be determined in future clinical trials.

Severe steroid-resistant post-infectious encephalomyelitis

Based on their presumed immuno-mediated etiology, post-infectious CNS disorders are commonly treated with high-dose steroids. Factors influencing treatment effectiveness, possible alternative options for steroid-resistant cases, and their outcome profiles, remain unclear. We here describe the clinical features, the prognosis and the efficacy of i. v. immunoglobulins (IVIg) in a series of severe ADEM refractory to steroids. We performed an inception cohort study on inpatients of the Neurologic and Infectious Disease Clinics, consecutively admitted over eight years, with a minimum two-year follow-up. Nineteen patients affected by classic and site-restricted ADEM were treated with IVIg after steroid failure. Five other patients received IVIg as first-line treatment due to steroids contraindications: although not included in the analysis, they were monitored for anecdotal comparison. Steroids were administered as IV 6-methylprednisolone (6-MP) 500/1000 mg daily until a maximum dose of 6-8 g; IVIg were administered at 0.4 g/kg/day for 5 days. The outcome was assessed by the Scripps Neurological Rating Scale (SNRS) score with determined periodicity. We observed that steroid-resistant patients showed high prevalence of PNS damage (89%) and myelitis (95 %). Other features were old age, severe disability at onset, and moderate to severe blood-brain-barrier (BBB) damage on CSF. In 10/19 patients (53 %) IVIg were effective, the clinical improvement beginning within the end of the five-day cycle,without relapses. Prominent effects of IVIg were detectable on motor dysfunction. Milder onset disability (p = 0.013) and lower CSF albumin (p = 0.006) were the predictors of IVIg response. Among steroid-free patients, 3/5 were responsive to IVIg. We conclude that IVIg can be useful in a portion of patients with severe steroid-resistant ADEM and prominent motor dysfunction. Unsolved issues regard the usefulness of IVIg in less selected groups, and the spectrum of their clinical effects.

Clinical outcome measures in multiple sclerosis

Quantifying the clinical impact of multiple sclerosis (MS) is a critical issue for judging experimental therapies tested in clinical trials, and, in everyday practice, for optimizing individual patient care. Proposed clinical outcome measures for MS belong to four main categories. In the first, information is based on the objective neurological examination. Examples in this category include the Expanded Disability Status Scale and related instruments, the Scripps Neurological Rating Scale and the MS Impairment Scale. The second category is represented by quantitative tests of neurological function: the most important example is represented by the Multiple Sclerosis Functional Composite. In the third category, information is provided by the patient or a family member. Measures of disability and handicap (as the Incapacity Status Scale, and the Environmental Status Scale), and generic or disease-specific quality of life instruments are included in this class. Finally, the last category consists of measures which present hybrid characteristics, such as the Ambulation Index and the Cambridge Multiple Sclerosis Basic Score. To date, no single measure has emerged as the ideal outcome measure: the main advantages and disadvantages of currently available measurement tools are discussed.

A double-blind, randomized, controlled study of oral pirfenidone for treatment of secondary progressive multiple sclerosis

Currently, there are no approved treatments for secondary progressive multiple sclerosis (MS) that stabilize or reverse the neurological disabilities associated with this disease. Oral pirfenidone was found to stabilize and overcome the disabilities in two published independent open-label studies in secondary progressive MS. This led us to study pirfenidone in a phase II double-blind, randomized and controlled, clinical trial in patients with advanced secondary progressive MS for 12 months. Forty-three patients met the eligibility criteria approved by the IRB and accepted by the FDA. Of these patients, 18 were randomly assigned to placebo and 25 patients to oral pirfenidone groups. All eligible patients were included in the statistical analysis of the data according to intention-to-treat principles. Some patients on oral pirfenidone manifested mild drug-related adverse effects, but it was well tolerated overall. By one month, pirfenidone significantly (P < 0.05) improved the Scripps Neurological Rating Scale (SNRS) scores, and scores remained significantly improved for 3, 6 and 12 months when compared to the baseline SNRS scores. In contrast, the SNRS scores of patients on oral placebo were not significantly improved at 1, 3, 6 or 12 months of the study, when compared with baseline scores. Oral pirfenidone significantly (P <0.04) reduced the incidence of relapses (27.8% on placebo versus 8.0% on pirfenidone). Furthermore, oral pirfenidone treatment was associated with a marked improvement in bladder dysfunction (40.0% on pirfenidone versus 16.7% on placebo). Expanded Disability Status Scale scores and MRI lesion count were not significantly different in the placebo and pirfenidone groups. These findings indicate a significant effect of pirfenidone on clinical disability and bladder function for secondary progressive MS patients. A major multicentre, double-blind, randomized, controlled trial is justified.

Epidemiologic, Clinical and Socioeconomic Study of Cuban Women with Multiple Sclerosis

Multiple sclerosis is one of the main causes of disability among young Cuban women. The objective of these studies was to evaluate the clinical and social economic status of Cuban women with MS. First, an epidemiological case-control study was conducted among 50 women with clinically definite MS (by Poser criteria). The controls were women ranging from 15 to 65 years who were matched for age. Data collection forms were modified from Boiko's guidelines. Risk factors for MS included having two or more children (OR = 2.84; 95% CI = 1.22–6.59), acute stress (OR = 3.76; 95% CI = 1.64–8.62), and insomnia (OR = 2.95; 95% CI = 1.14–7.14). A disability and socioeconomic analysis was conducted based on data from the Cuban Computed Register of MS (CUBARMS) of 271 women with clinically definite MS as defined by Poser or McDonald criteria. Most were between 31 and 50 years of age (61.2%) and Caucasian (73.06%). There were antecedents of familial psychiatric diseases (34.69%), neurological disorders (26.57%), general autoimmune diseases (21.7%), and MS (7.85%). Triggered factors at onset of MS were present in 56%, the most frequent being acute stress (52%). 169 patients (62.36%) drank coffee. Main initial symptoms of MS were weakness in limbs (51.66%); numbness of limbs (28.04%); poor balance (20.3%); blurred vision (18.81%); and paresthesias (18.81%). The most frequent symptoms of MS in women at the time of their medical consultation included weakness of limbs (71.59%); numbness (29.15%); paresthesias (28.41%); fatigue (24.73%); poor balance (23.62%); loss of vision (22.51%); rigidity (22.14%); blurred vision (17.71%); incontinence (16.97%); lack of coordination (16.24%); memory disorders (14.39%); and depression (12.92%). Expanded Disability Status Scale (EDSS) scores ranged between 1 and 6.5 in 78.6% of patients, while Scripps Neurological Rating Scale (SNRS) scores ranged between 61 and 80 in 69.9%. In terms of social status, 58.3% were married; 33.9% were single or divorced; 32% had a high school education; 29.1% had university-level education, and 21% had secondary education. Over half (53.1%) were unemployed; 18% of female MS patients lived alone, and 48.6% received a monthly income between 100 and 401 pesos. The data gathered in these studies highlight the importance of improving knowledge of MS in Cuba, mainly in the primary care setting, in order to increase early diagnosis. With these data, we expect to achieve a better quality of life for female MS patients, thus improving their socioeconomic and work status. A program is in progress to improve the primary medical attention, disability, handicap, quality of life, and socioeconomic status of Cuban women with MS.

Effect of relapses on development of residual deficit in multiple sclerosis

Objective: To determine the percentage of patients with residual deficits following multiple sclerosis (MS) exacerbations and the magnitude of those deficits using a database of pooled placebo patients from clinical trials. Methods: A database of patients assigned to the placebo group in several randomized clinical trials was queried to determine those patients with Expanded Disability Status Scale (EDSS) and Scripps Neurologic Rating Scale assessments prior to, at the time of, and after an acute exacerbation of MS. The extent of deficit present at these time points was compared to determine the acute effect of exacerbations and the degree of persistent disability. Results: Forty-two percent of patients had residual deficit of at least 0.5 and 28% had residual of ≥1.0 EDSS units, at an average of 64 days after an exacerbation. The results were reproduced across subsequent exacerbations and were sustained over time. The subgroup of patients with measurable change in EDSS during the exacerbation had more extensive residual impairment on the follow-up visits. Similar results were seen when the Scripps score was examined. Conclusion: MS exacerbations produce a measurable and sustained effect on disability.

Randomised, double blind, placebo controlled study of interferon β-1a in relapsing-remitting multiple sclerosis analysed by area under disability/time curves

OBJECTIVESThe commonly employed outcome measures on disability and relapse rates in treatment trials of relapsing-remitting multiple sclerosis have well demonstrated sensitivity to treatment effects, but their clinical interpretation is problematic....

Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis

OBJECTIVEThe association between brain atrophy and permanent functional deficits in multiple sclerosis and the temporal relation between atrophy and the clinical disease course have seldom been investigated. This study aims...

The psychometric properties of clinical rating scales used in multiple sclerosis.

OullII;l y Many clinical rating scales have been proposed to assess the impact of multiple sclerosis on patients, but only few have been evaluated formally for reliability, validity and responsiveness. We assessed the psychometric properties of five commonly used scales in multiple sclerosis, the Expanded Disability Status Scale (EDSS), the Scripps Neurological Rating Scale (SNRS), the Functional Independence Measure (FIM), the Ambulation Index (AI) and the Cambridge Multiple Sclerosis Basic Score (CAMBS). The score frequency distributions of all five scales were either bimodal (EDSS and AI) or severely skewed (SNRS, FIM and CAMBS). The reliability of each scale depended on the definition of 'agreement'. Inter-and intra-rater reliabilities were high when 'agreement' was considered to exist despite a difference of up to 1.0 EDSS point (two 0.5 steps), 13 SNRS points, 9 FIM points, 1 AI point and 1 point on the various CAMBS domains. The FIM, AI, and the relapse and progression domains of the CAMBS were sensitive to clinical change, but the EDSS and the SNRS were unresponsive. The validity of these scales as impairment (SNRS and EDSS) and disability (EDSS, FIM, AI and the disability domain of the CAMBS) measures was established. All scales correlated closely with other measures of handicap and quality of life. None of these scales satisfied the psychometric requirements of outcome measures completely, but each had some desirable properties. The SNRS and the EDSS were reliable and valid measures of impairment and disability, but they were unresponsive. The FIM was a reliable, valid and responsive measure of disability, but it is cumbersome to administer and has a limited content validity. The AI was a reliable and valid ambulation-related disability scale, but it was weakly responsive. The CAMBS was a reliable (all four domains) and responsive (relapse and progression domains) outcome measure, but had a limited validity (handicap domain). These psychometric properties should be considered when designing further clinical trials in multiple sclerosis.

Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS

There is only limited evidence from adequately controlled clinical trials to support high-dose methylprednisolone therapy for attacks of multiple sclerosis (MS) and none supporting oral administration. We assessed the effect of oral high-dose methylprednisolone therapy in attacks of MS. Twenty-five patients with an attack of MS lasting less than 4 weeks were randomized to placebo treatment. Twenty-six patients received oral methylprednisolone (500 mg once a day for 5 days with a 10-day tapering period). The patients received scores on the Scripps Neurological Rating Scale (NRS) and Kurtzke Expanded Disability Status Scale. The symptoms were scored on a visual analog scale (VAS) before treatment and after 1, 3, and 8 weeks of treatment. Primary efficacy measures were NRS and VAS scores in the first 3 weeks and changes in NRS score and answers to an efficacy questionnaire administered after 8 weeks of treatment. Changes in NRS scores among methylprednisolone- and placebo-treated patients differed significantly in the first 3 weeks and after 8 weeks (p = 0.005 and p = 0.0007). VAS scores the first 3 weeks and treatment efficacy after 8 weeks also favored a beneficial effect of methylprednisolone treatment (p = 0.02 and p = 0.05). After 1, 3, and 8 weeks, 4%, 24%, and 32% in the placebo group and 31%, 54%, and 65% in the methylprednisolone group had improved one point on the Expanded Disability Status Scale score (all p < 0.05). No serious adverse events were seen. Oral high-dose methylprednisolone is recommended for managing attacks of MS.

Assessing information in T2-weighted MRI scans from secondary progressive MS patients.

Magnetic resonance imaging is used routinely for diagnosing MS and for objective assessment of the extent of disease as a marker of treatment efficacy in MS clinical trials. Nevertheless, in many clinical studies only weak correlations have been reported between MRI findings and clinical outcome measures. The purpose of this study is to compare clinical outcome measures (neurologic scales) with MRI findings (evaluation of T2-weighted MRI scans using a semiautomated quantitative technique and with an independent assessment by a neurologist) in the context of a randomized clinical trial evaluating the efficacy of cladribine for treatment in secondary progressive MS. Baseline, 6-month, and 12-month scans from 41 secondary progressive MS patients were examined and ranked in terms of lesion burden from the quantitative assessment and independently in terms of severity by neurologic evaluation. Comparison is made to monthly Expanded Disability Status Scale (EDSS) and Scripps Neurologic Rating Scale (SNRS) determinations in these patients with a nonparametric statistical procedure. Average rank correlations between any of the MRI assessment procedures and either clinical outcome measure were less than 0.15 in absolute magnitude. The average rank correlation between the two MRI assessment procedures was 0.10. There is only a weak degree of association between the MRI assessment procedures and the clinical parameters, although the study has statistical power in excess of 0.90 to find even a moderate level of association between them. Disease-related activity in T2-weighted scans of secondary progressive MS patients is a multidimensional construct, and is not summarized adequately solely by quantification of overall lesion burden or by assessment of severity. Neither method of summarizing information from T2-weighted scans is strongly related to measures of the clinical course of disease as assessed by the EDSS or SNRS.