David Rog

Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis

Background: Central pain in multiple sclerosis (MS) is common and often refractory to treatment. Methods: We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours. Results: Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale. CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change −2.7, 95% CI: −3.4 to −2.0, placebo –1.4 95% CI: −2.0 to −0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change –2.5, 95% CI: −3.4 to −1.7, placebo –0.8, 95% CI: −1.5 to −0.1, comparison between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage. Conclusions: Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial

Summary Background Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. Methods The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. Findings Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ2 on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40–1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. Interpretation We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. Funding The Motor Neurone Disease Association of Great Britain and Northern Ireland.

Validation and reliability of the Neuropathic Pain Scale (NPS) in multiple sclerosis.

ObjectiveCentral neuropathic pain occurs in around 28% of patients with multiple sclerosis (MS). The Neuropathic Pain Scale (NPS) has received preliminary validation in peripheral neuropathic pain conditions. The aim of this study was to validate its use in MS central pain syndromes. MethodsWe administered the NPS to 141 patients with MS, together with the Short Form McGill Pain Questionnaire (SFMPQ), the Hospital Anxiety and Depression Scale (HADS), and Short Form 36 Health Survey (SF-36). ResultsCronbachs α was 0.78 (95% CI 0.69; 0.83), implying a high degree of internal consistency. Three factors, “Familiar,” “Superficial,” and “Alien Perception,” were extracted, accounting for 64% of the variance. The NPS 10-item total correlates with: the SFMPQ 15-item total score, ρ=0.63 (95% CI 0.49; 0.74), its Visual Analog Scale, ρ=0.49 (95% CI 0.33; 0.64), the transformed Pain domain of the SF-36 ρ=−0.49 (95% CI −0.63; −0.32), but not with its remaining seven health domains, or with either the HADS anxiety or the depression scores. Limits of agreement for short-term test or re-test reliability of the 100 point NPS total (median 2 days, range 1 to 7) were −12 to 14 and when administered to 78 patients who rated their neuropathic pain the “Same” [median interval 33 days (range 19 to 126), the long-term test or re-test correlation coefficient was 0.71 (95% CI 0.6; 0.79)]. DiscussionThe NPS appears a useful tool in the assessment of neuropathic pain in MS patients and possibly in measuring outcomes of therapeutic interventions.

Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis

We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy.

Can Autonomous Sensor Systems Improve the Well-being of People Living at Home with Neurodegenerative Disorders?

In this paper, we describe the development of an autonomous tracking system to be used in the home of the elderly population living with neurodegenerative disorders including dementia. The technology advancement has potential to produce low-cost solutions for elder-care in a residential setting. Our approach is based on the concept that body tracking interventional systems can be developed by utilizing low-cost technological solutions affordable to the aged population and can be deployed in the residential settings. We are exploring the usefulness of such systems in providing information that can assist with assessment of performance of activities of daily living in the periods between hospital clinic visits. Management of neurodegenerative disorders such as dementia and multiple sclerosis involve periodic review of patients at a specialist clinic. At these reviews the clinician solicits information about activities of daily living over the preceding period. This period can be a long interval of 6 to 12 months. When self-reports of activity are compared with independent objective measures, discrepancies are found in many areas of healthcare. This can cause difficulties in management of treatment. The autonomous sensor tracking systems developed here could improve care by giving clinicians objective assessments of relapses in the intervals between clinic visits. This could reduce the time spent on in- clinic examination as clinicians can use objective measures instead of semistructured interviews aimed at eliciting an accurate history. This will allow more time to spend on well-being and treatment options.

PO141 Audit of the first line oral disease modifying treatments in greater manchester

In 2014, teriflunomide and dimethyl fumarate were approved by NHS regulators as first-line oral treatments for multiple sclerosis in England. We audited the safety, tolerability and treatment retention rates of the first line oral DMTs in Greater Manchester. Case notes of MS patients treated with first line oral DMTs were analysed for drug discontinuation reason, blood monitoring compliance and drug related side effects within the first 12 months of treatment. Of 39 patients, treated with teriflunomide, 89% were still on treatment at 12 months and reported very few side effects. 5% withdrew from treatment due to non-adherence with blood test monitoring, 3% due to lack of efficacy and 3% due to side effects. 273 patients treated with dimethyl fumarate, had a retention rate of 75% after 12 months. 12% discontinued treatment due to gastrointestinal side effects and 3% due to fatigue, headache and depression. Occasionally patients reported appetite/weight changes and altered hair appearances. 6% of patients were non-adherent with blood test monitoring. Lymphocyte drop below 0.5 for more than 3 months occurred in 2%, hence treatment was discontinued. Patient retention rate was better with teriflunomide than with dimethyl fumarate. Teriflunomide blood monitoring carries a significant administrative burden but it seems to be well tolerated in our cohort.

ANALYSIS OF THE TOPIC STUDY USING 2010 MCDONALD CRITERIA

Introduction TOPIC (NCT00622700) was designed to evaluate teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis (MS). Teriflunomide 14 mg reduced risk of relapse determining conversion to clinically definite MS by 42.6%, and of new relapse or magnetic resonance imaging lesion by 34.9% vs placebo. After study initiation, the 2005 McDonald criteria were revised, potentially allowing earlier MS diagnosis. Methods The 2010 McDonald criteria were applied retrospectively. Patients who received teriflunomide 14 mg or placebo for ≤108 weeks were grouped according to fulfilment of 2010 criteria at baseline. Time to MS was analysed for those not fulfilling the 2010 criteria at baseline. Additional post hoc analyses will evaluate differences in outcomes based on baseline radiological characteristics of reclassified patients. Results Patients receiving teriflunomide 14mg (n=214) or placebo (n=197) were analysed. For those not meeting the 2010 criteria (n=163), probability of conversion to MS was 54.1% (14 mg) and 74.4% (placebo). Teriflunomide 14mg reduced the probability of conversion to MS by 39.1% vs placebo. Data regarding time to MS based upon baseline radiological characteristics will be presented. Conclusions Teriflunomide demonstrates a consistent treatment effect in patients with MS diagnosed according to differing diagnostic criteria. (Study supported by Genzyme, a Sanofi company).