Balance Right in Multiple Sclerosis (BRiMS): a feasibility randomised controlled trial of a falls prevention programme.

BACKGROUND: Balance, mobility impairments and falls are problematic for people with multiple sclerosis (MS). The "Balance Right in MS (BRiMS)" intervention, a 13-week home and group-based exercise and education programme, aims to improve balance and minimise falls. This study aimed to evaluate the feasibility of undertaking a multi-centre randomised controlled trial and to collect the necessary data to design a definitive trial. METHODS: This randomised controlled feasibility study recruited from four United Kingdom NHS clinical neurology services. Patients ≥ 18 years with secondary progressive MS (Expanded Disability Status Scale 4 to 7) reporting more than two falls in the preceding 6 months were recruited. Participants were block-randomised to either a manualised 13-week education and exercise programme (BRiMS) plus usual care, or usual care alone. Feasibility assessment evaluated recruitment and retention rates, adherence to group assignment and data completeness. Proposed outcomes for the definitive trial (including impact of MS, mobility, quality of life and falls) and economic data were collected at baseline, 13 and 27 weeks, and participants completed daily paper falls diaries. RESULTS: Fifty-six participants (mean age 59.7 years, 66% female, median EDSS 6.0) were recruited in 5 months; 30 randomised to the intervention group. Ten (18%) participants withdrew, 7 from the intervention group. Two additional participants were lost to follow up at the final assessment point. Completion rates were > 98% for all outcomes apart from the falls diary (return rate 62%). After adjusting for baseline score, mean intervention-usual care between-group differences for the potential primary outcomes at week 27 were MS Walking Scale-12v2: - 7.7 (95% confidence interval [CI] - 17.2 to 1.8) and MS Impact Scale-29v2: physical 0.6 (CI - 7.8 to 9), psychological - 0.4 (CI - 9.9 to 9). In total, 715 falls were reported, rate ratio (intervention:usual care) for falls 0.81 (0.41 to 2.26) and injurious falls 0.44 (0.41 to 2.23). CONCLUSIONS: Procedures were practical, and retention, programme engagement and outcome completion rates satisfied a priori progression criteria. Challenges were experienced in completion and return of daily falls diaries. Refinement of methods for reporting falls is therefore required, but we consider a full trial to be feasible. TRIAL REGISTRATION: ISRCTN13587999 Date of registration: 29 September 2016.

Balance Right in Multiple Sclerosis (BRiMS): a guided self-management programme to reduce falls and improve quality of life, balance and mobility in people with secondary progressive multiple sclerosis: a protocol for a feasibility randomised controlled trial.

BACKGROUND: Impaired mobility is a cardinal feature of multiple sclerosis (MS) and is rated by people with MS as their highest priority. By the secondary progressive phase, balance, mobility and physical activity levels are significantly compromised; an estimated 70% of people with secondary progressive MS fall regularly. Our ongoing research has systematically developed 'Balance Right in MS' (BRiMS), an innovative, manualised 13-week guided self-management programme tailored to the needs of people with MS, designed to improve safe mobility and minimise falls. Our eventual aim is to assess the clinical and cost effectiveness of BRiMS in people with secondary progressive MS by undertaking an appropriately statistically powered, multi-centre, assessor-blinded definitive, randomised controlled trial. This feasibility study will assess the acceptability of the intervention and test the achievability of running such a definitive trial. METHODS/DESIGN: This is a pragmatic multi-centre feasibility randomised controlled trial with blinded outcome assessment. Sixty ambulant people with secondary progressive MS who self-report two or more falls in the previous 6 months will be randomly allocated (1:1) to either the BRiMS programme plus usual care or to usual care alone. All participants will be assessed at baseline and followed up at 15 weeks and 27 weeks post-randomisation. The outcomes of this feasibility trial include:Feasibility outcomes, including trial recruitment, retention and completionAssessment of the proposed outcome measures for the anticipated definitive trial (including measures of walking, quality of life, falls, balance and activity level)Measures of adherence to the BRiMS programmeData to inform the economic evaluation in a future trialProcess evaluation (assessment of treatment fidelity and qualitative evaluation of participant and treating therapist experience). DISCUSSION: The BRiMS intervention aims to address a key concern for MS service users and providers. However, there are several uncertainties which need to be addressed prior to progressing to a full-scale trial, including acceptability of the BRiMS intervention and practicality of the trial procedures. This feasibility trial will provide important insights to resolve these uncertainties and will enable a protocol to be finalised for use in the definitive trial. TRIAL REGISTRATION: ISRCTN13587999.

Standing up in multiple sclerosis (SUMS): protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. METHODS/DESIGN: SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. DISCUSSION: This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. TRIAL REGISTRATION: ISRCTN69614598 DATE OF REGISTRATION: 3.2.16 (retrospectively registered).

Can the ABILHAND handle manual ability in MS?

BACKGROUND: Hand dysfunction is common in multiple sclerosis (MS). Recent interest has focused on incorporating patient-reported outcome (PRO) instruments into clinical trials. Nevertheless, examinations are rare in MS of existing manual ability measures. OBJECTIVES: The objective of this paper is to evaluate the 23-item ABILHAND, developed for use after stroke, in people with MS, comparing the findings from two psychometric approaches. METHODS: We analysed ABILHAND data from 300 people with MS using: 1) traditional psychometric methods (data completeness, scaling assumptions, reliability, internal and external construct validity); and 2) Rasch measurement methods (including targeting, item response category ordering, data fit to the Rasch model, spread of item locations, item scoring bias, item stability, reliability, person response validity). RESULTS: Traditional psychometric methods implied ABILHAND was reliable and valid in this sample. Rasch measurement methods supported this finding. The three-category scoring function worked as intended and item fit to Rasch model expectations was acceptable. The 23 items (location range -3.16 to +2.73 logits) mapped a continuum of manual ability. Reliability was high (Person Separation Index (PSI) = 0.95). CONCLUSION: Both psychometric evaluations supported ABILHAND as a robust manual ability PRO measure for MS. Rasch measurement methods were more informative and, consistent with its role of detecting anomalies, identified ways of advancing further ABILHAND's measurement performance to reduce any potential for type II errors in clinical trials.

Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease.

AIMS: Δ9-tetrahydrocannabinol (Δ9-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ9-THC. METHODS: Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. RESULTS: We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ9-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ9-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ9-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ9-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation. CONCLUSIONS: We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ9-THC that may be mediated through PPARγ activation.

The use of multiple sclerosis condition-specific measures to inform health policy decision-making: mapping from the MSWS-12 to the EQ-5D.

BACKGROUND: Walking impairment has a major influence on the quality of life of people with multiple sclerosis (MS). The Multiple Sclerosis Walking Scale (MSWS-12) assesses the impact of MS on walking ability from the patient's perspective, but in its current form, is not amenable for use in many policy decision-making settings. OBJECTIVES: Statistical 'mapping' methods were used to convert MSWS-12 scores to EQ-5D health state values. METHODS: The relationship between the measures was estimated using cohort data from people with MS in South West England. Regression analyses were conducted, estimation errors assessed, and predictive performance of the best models tested using longitudinal data. RESULTS: Model performance was in line with that of other mapping studies, with the best-performing models being an ordinary least squares (OLS) model using MSWS-12 item scores, and an OLS model using the total MSWS-12 score and its squared term. CONCLUSIONS: A process has been described whereby data from a patient-reported outcome measure (MSWS-12) can be converted to (EQ-5D) health state values. These values may be used to consider the health-related quality of life of people with MS, to estimate quality adjusted life-years for use in effectiveness and cost-effectiveness analyses, and to inform health policy decisions.

Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review.

BACKGROUND: The social and economic burden of Alzheimer's disease (AD) and its increasing prevalence has led to much work on new treatment strategies and clinical trials. The search for surrogate markers of disease progression continues but traditional parallel group trial designs that use well-established, but often insensitive, clinical outcome measures predominate. METHODS: We performed a systematic search across the Cochrane Library and PubMed abstracts published between January 2004 and August 2009. Information regarding the clinical trial methodology, outcome measures, intervention type and primary statistical analysis techniques was extracted and categorized, according to a standard protocol. RESULTS: We identified 149 papers describing results from clinical trials in AD containing sufficient detail for our purposes. The largest proportion (38%) presented results of trials based on tests of cognition as the primary outcome measure. The primary analysis in most papers (85%) was a univariate significance test of a single primary outcome measure. CONCLUSIONS: The majority of trials reported a comparison of baseline and end-point assessment over relatively short patient follow-up periods, using univariate statistical methods to compare differences between intervention and control groups in the primary analysis. There is considerable scope to introduce newer statistical methods and trial designs in treatment evaluations in AD.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort.

OBJECTIVE: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). METHODS: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3). RESULTS: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression. CONCLUSIONS: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

Changes in iron-regulatory gene expression occur in human cell culture models of Parkinson's disease.

BACKGROUND: Neuronal iron accumulation is thought to be relevant to the pathogenesis of Parkinson's disease (PD), although the mechanism remains elusive. We hypothesized that neuronal iron uptake may be stimulated by functional mitochondrial iron deficiency. OBJECTIVE: To determine firstly whether the mitochondrial toxin, 1-methyl-4-phenylpyridinium iodide (MPP(+)), results in upregulation of iron-import proteins and transporters of iron into the mitochondria, and secondly whether similar changes in expression are induced by toxins with different mechanisms of action. METHODS: We used quantitative PCR and Western blotting to investigate expression of the iron importers, divalent metal transporter, transferrin receptor 1 and 2 (TfR1 and TfR2) and mitoferrin-2 and the iron exporter ferroportin in differentiated SH-SY5Y cells exposed to three different toxins relevant to PD, MPP(+), paraquat (a free radical generator) and lactacystin (an inhibitor of the ubiquitin-proteasome system (UPS)). RESULTS: MPP(+) resulted in increased mRNA and protein levels of genes involved in cellular iron import and transport into the mitochondria. Similar changes occurred following exposure to paraquat, another inducer of oxidative stress. Lactacystin also resulted in increased TfR1 mRNA levels, although the other changes were not found. CONCLUSION: Our results support the hypothesis of a functional mitochondrial iron deficit driving neuronal iron uptake but also suggest that differences exist in neuronal iron handling induced by different toxins.

Designing clinical trials in older people.

Adequate medical care of the increasingly ageing population requires robust clinical trial data both to inform treatment decisions, and to understand the natural history of diseases which primarily affect the elderly. However, this information is widely lacking, which is likely to have significant clinical consequences. Under-representation of older people in clinical trials is well documented, the reasons including physicians' perception, protocol eligibility criteria, and functional status requirements. Many clinical trial designs remain conservative and there is no established standardised methodology for recruiting more elderly patients with co-morbidities and disability into clinical trials. Designing clinical trials in older people poses a unique set of challenges, particularly regarding recruitment, retention and data analysis. In this review we outline the difficulties encountered in conducting clinical trials in older patients and describe some of the initiatives that can be put in place to counteract them. It is only by addressing these challenges with careful and adequately resourced protocol design that clinical trials may successfully address the therapeutic questions raised by our ageing population.

Beyond the reach of traditional analyses: using Rasch to evaluate the DASH in people with multiple sclerosis.

BACKGROUND: Few upper limb functioning patient rating scales have been used in multiple sclerosis (MS) research and none developed specifically for people with MS. OBJECTIVES: In this study, we examined the Disabilities of the Arm, Shoulder and Hand (DASH) to determine its utility as a useful, scientifically robust and clinically meaningful tool in MS. METHODS: DASH data from 300 people with MS underwent two independent phases of psychometric analyses: (1) a traditional psychometric analysis (including data quality, scaling assumptions, reliability and validity); and (2) a Rasch analysis (including response option thresholds ordering, tests of fit, spread of item locations, residual correlations, and person separation index). RESULTS: Overall, the traditional psychometric analysis supported the DASH as a reliable and valid measure of upper limb function in people with MS. However, several issues were raised by the Rasch analysis that questioned the validity of the DASH, including misfit in 13/30 items, disordered item response option thresholds for 9/30 items, and six pairs of items with high residual correlations (> 0.60). CONCLUSION: Rasch analysis highlights areas for potential improvement for the use of the DASH. Our findings further support our previous arguments that traditional psychometric methods provide weak scale evaluations and can mislead clinicians as to the reliability and validity of outcome measures.

Holding personal information in a disease-specific register: the perspectives of people with multiple sclerosis and professionals on consent and access.

OBJECTIVE: To determine the views of people with multiple sclerosis (MS) and professionals in relation to confidentiality, consent and access to data within a proposed MS register in the UK. DESIGN: Qualitative study using focus groups (10) and interviews (13). SETTING: England and Northern Ireland. PARTICIPANTS: 68 people with MS, neurologists, MS nurses, health services management professionals, researchers, representatives from pharmaceutical companies and social care professionals. RESULTS: People with MS expressed open and altruistic views towards the use of their personal information to facilitate service provision and research, placing trust in responsible guardianship and legitimate use of their information. Participant's proposed that people with MS should be able to select their individual level of involvement in a register using levels of consent. It was agreed that access to the register should be governed by a guardianship committee composed of a range of stakeholders. People with MS did not wish their details to be used by marketing agencies and did not consider this a legitimate use of their data. Whilst participants were positive of the role a register could play in promoting research, participants felt that access to data by pharmaceutical industries should be administered by the guardianship committee. People with MS are concerned should their employers be able to access their personal information. Professionals were more cautious than people with MS in their approach to the use of patient personal data within a register. CONCLUSIONS: Whilst all stakeholders were positive of the benefits of an MS register, development of such a resource must incorporate robust data security and guardianship measures in order to ensure that, whilst opportunities are maximised, risks to the privacy of individuals and legal challenges to professionals are avoided.

High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells.

Cannabinoids bind to two G-protein-coupled receptors, CB1 and CB2, expressed by neurons and cells of the immune system, respectively. Glioma cells (astrocyte-derived brain tumor cells) express cannabinoid receptors, and numerous in vitro and in vivo studies performed in rodents have concluded that apoptosis could be induced by cannabinoids in these cells. Whether this also applies to human cells is controversial; we, therefore, assessed the effect of cannabinoids on human glioma cell viability with the human astrocytoma cell line U373MG. We report here that U373MG human glioma cells are sensitive only to high concentrations of cannabinoids (>5 microg/ml for Delta(9)-THC). Similar concentrations of the compounds promoted a rapid activation of extracellular-regulated kinase and c-Jun NH2-terminal kinase, suggesting that cannabinoid receptors are functional in U373MG cells. Nevertheless, these kinases are not involved in cannabinoid-induced cell death in U373MG cells, insofar as blocking their activation with specific inhibitors does not reduce cell death. CB1 is expressed in U373MG cells and is involved in cannabinoid-induced cell death, in that blocking its activation with a specific antagonist (AM251) almost totally prevented cell death following incubation of the cells with Delta(9)-THC. In addition, as already reported, some cannabinoids may have modest proproliferative properties in U373MG cells. Human U373MG glioma cells are sensitive only to very high, pharmacologically irrelevant concentrations of cannabinoids, so it seems unlikely that cannabinoids would constitute promising molecules for treating malignant astrocytoma; they do not induce glioma cell death at doses that could be applied safely to humans.

Therapeutic potential of cannabis in pain medicine.

Advances in cannabis research have paralleled developments in opioid pharmacology whereby a psychoactive plant extract has elucidated novel endogenous signalling systems with therapeutic significance. Cannabinoids (CBs) are chemical compounds derived from cannabis. The major psychotropic CB delta-9-tetrahydrocannabinol (Delta(9)-THC) was isolated in 1964 and the first CB receptor (CB(1)R) was cloned in 1990. CB signalling occurs via G-protein-coupled receptors distributed throughout the body. Endocannabinoids are derivatives of arachidonic acid that function in diverse physiological systems. Neuronal CB(1)Rs modulate synaptic transmission and mediate psychoactivity. Immune-cell CB(2) receptors (CB(2)R) may down-regulate neuroinflammation and influence cyclooxygenase-dependent pathways. Animal models demonstrate that CBRs play a fundamental role in peripheral, spinal, and supraspinal nociception and that CBs are effective analgesics. Clinical trials of CBs in multiple sclerosis have suggested a benefit in neuropathic pain. However, human studies of CB-mediated analgesia have been limited by study size, heterogeneous patient populations, and subjective outcome measures. Furthermore, CBs have variable pharmacokinetics and can manifest psychotropism. They are currently licensed as antiemetics in chemotherapy and can be prescribed on a named-patient basis for neuropathic pain. Future selective peripheral CB(1)R and CB(2)R agonists will minimize central psychoactivity and may synergize opioid anti-nociception. This review discusses the basic science and clinical aspects of CB pharmacology with a focus on pain medicine.

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis.

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.

The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS).

OBJECTIVE: To test whether cannabinoids reduce urge incontinence episodes without affecting voiding in patients with multiple sclerosis. This was part of the multicentre trial of the Cannabinoids in Multiple Sclerosis (CAMS) study. SUBJECTS AND METHODS: The CAMS study randomised 630 patients to receive oral administration of cannabis extract, Delta(9)-tetrahydrocannabinol (THC) or matched placebo. For this substudy subjects completed incontinence diaries. RESULTS: All three groups showed a significant reduction, p<0.01, in adjusted episode rate (i.e. correcting for baseline imbalance) from baseline to the end of treatment: cannabis extract, 38%; THC, 33%; and placebo, 18%. Both active treatments showed significant effects over placebo (cannabis extract, p=0.005; THC, p=0.039). CONCLUSION: The findings are suggestive of a clinical effect of cannabis on incontinence episodes in patients with MS. This is in contrast to the negative finding of the CAMS study, where no difference was seen in the primary outcome of spasticity.

Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88).

Spasticity is most commonly defined as an inappropriate, velocity dependent, increase in muscle tonic stretch reflexes, due to the amplified reactivity of motor segments to sensory input. It forms one component of the upper motor neuron syndrome and often leads to muscle stiffness and disability. Spasticity can, therefore, be measured through electrophysiological, biomechanical and clinical evaluation, the last most commonly using the Ashworth scale. None of these techniques incorporate the patient experience of spasticity, nor how it affects people's daily lives. Consequently, we set out to construct a rating scale to quantify the perspectives of the impact of spasticity on people with multiple sclerosis. Qualitative methods (in-depth patient interviews and focus groups, expert opinion and literature review) were used to develop a conceptual framework of spasticity impact, and to generate a pool of items with the potential to convert this framework into a rating scale with multiple dimensions. This item pool was administered, in the form of a questionnaire, to a sample of people with multiple sclerosis and spasticity. Guided by Rasch analysis, we constructed and validated a rating scale for each component of the conceptual framework. Decisions regarding item selection were based on the integration and assimilation of seven specific analyses including clinical meaning, ordering of thresholds, fit statistics and differential item functioning. The qualitative phase (17 patient interviews, 3 focus groups) generated 144 potential scale items and a conceptual model with eight components addressing symptoms (muscle stiffness, pain and discomfort and muscle spasms,), physical impact (activities of daily living, walking and body movements) and psychosocial impact (emotional health, social functioning). The first postal survey was sent to 272 people with multiple sclerosis and had a response rate of 88%. Findings supported the development of scales for each component but demonstrated that five item response options were too many. The 144-item questionnaire, reformatted with four-item response options, was administered with four validating instruments to an independent sample of 259 people with multiple sclerosis (response rate 78%). From the responses, an 88-item instrument with eight subscales was developed that satisfied criteria for reliable and valid measurement. Correlations with other measures were consistent with predictions. The 88-item Multiple Sclerosis Spasticity Scale (MSSS-88) is a reliable and valid, patient-based, interval-level measure of the impact of spasticity in multiple sclerosis. It has the potential to advance outcomes measurement in clinical trials and clinical practice, and provides a new perspective in the clinical evaluation of spasticity.

Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.

OBJECTIVE: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. METHODS: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here. RESULTS: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. CONCLUSIONS: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Diagnosis and disease modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) refers to scattered areas of hardening found on sectioning central nervous system tissue of affected people, usually after many years of illness. It rarely causes early death but is the commonest cause of neurological disability among young people. Overall results from controlled trials over the past 50 years have been rather disappointing but the comparatively recent licensing of drugs such as interferon beta and glatiramer acetate has led to a reappraisal of many aspects of MS. There are now new diagnostic criteria, which encompass developments in magnetic resonance imaging. Older clinical methods of measuring disease impact are now being re-evaluated to facilitate clinical trials of the approximate 150 new products currently being developed as potential disease modifying agents. The success and failure of agents that should be effective on theoretical grounds, together with advances in neuropathology, have led to fundamental questions regarding our basic understanding of disease pathogenesis being re-addressed.