Shahrukh Mallik

Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial

BACKGROUND Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. METHODS We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593. FINDINGS We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 μm (SD 16.27) in the phenytoin group (a mean decrease of 16.69 μm [SD 13.73] from baseline) versus 74.29 μm (15.14) in the placebo group (a mean decrease of 23.79 μm [13.97] since baseline; adjusted 6-month difference of 7.15 μm [95% CI 1.08-13.22]; p=0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with five (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group. INTERPRETATION These findings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted. FUNDING US National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland, Novartis, UK National Institute for Health Research (NIHR), and NIHR UCLH/UCL Biomedical Research Centre.

Imaging outcomes for trials of remyelination in multiple sclerosis

Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures.

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

BACKGROUND The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. OBJECTIVES There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. DESIGN The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. SETTING Twenty-seven UK sites. PARTICIPANTS Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. INTERVENTIONS Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. ASSESSMENT VISITS Three and 6 months, and then 6-monthly up to 36 or 42 months. MAIN OUTCOME MEASURES Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). RESULTS Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. PRIMARY OUTCOMES no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. CONCLUSIONS The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. TRIAL REGISTRATION Current Controlled Trials ISRCTN62942668. FUNDING The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: A voxel-based analysis study

Background: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). Methods: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. Results: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. Conclusions: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently.

CANNABINOID USE IN PROGRESSIVE INFLAMMATORY BRAIN DISEASE (CUPID) MRI SUB–STUDY

Introduction In progressive Multiple Sclerosis (MS), there is no proven therapy for preventing accumulation of irreversible disability. The pathological substrate of irreversible disability in MS is neuroaxonal loss, and brain tissue volume loss on MRI can infer such pathology. There is experimental evidence to suggest that cannabinoids may have a neuroprotective and anti–inflammatory effect, although in a recent UK clinical trial (CUPID), oral cannabinoid did not slow the development of disability in progressive MS compared with placebo. Aims Using serial MRI brain scans obtained during the CUPID trial, we compared oral Delta 9–tetrahydrocannabinol (Δ9–THC) versus placebo for the following: (i) rates of new T2 hyperintense and new T1 hypointense lesions, and (ii) rate of brain atrophy. Methods A subset of progressive MS patients from the CUPID trial, who were randomised to either Δ9–THC or placebo, were followed up for 3 years with MRI scans at 4 time points: baseline, and years 1, 2 and 3. MRI sequences included axial dual echo, fast (turbo) spin echo proton density and T2 weighted scans, as well as a conventional T1 weighted spin echo scan. 46 contiguous 3 mm thick axial slices were performed for each acquisition. Scans from each time point were compared with the immediately preceding scan. New T2 lesions and new T1 lesions were marked by review of the electronic data using imaging software application JIM 6.0. If a scan had been missed, comparison was made with the last scan performed. Normalised brain volume (NBV) was estimated with SIENAX. Two–time–point percentage brain volume change (PBVC) was estimated with SIENA for three time–point pairs: baseline to year 1, year 1 to year 2, and year 2 to year 3. Results 273 patients were entered into the sub–study. 182 (67%) received active treatment, and 91 (33%) received placebo. 45 subjects missed one or more scan. Those that only had the baseline scan were excluded from all further analyses. Losses to follow up were 27 at 1 year, 18 at 2 years, and 18 at 3 years. 32 patients did not have a baseline NBV. There was no evidence of an association between treatment group and number of new T1 lesions or T2 lesions, at any of the three time–point pairs (new T1 lesions: baseline to year 1 p=0.99, year 1 to year 2 p=0.17, year 2 to year 3 p=0.90; new T2 lesions: baseline to year 1 p=0.55, year 1 to year 2 p=0.076, year 2 to year 3 p=0.90). Mean baseline NBV was 1420ml (SD 89.02) for all subjects, with no significant difference between the arms (p=0.7). At each of the three time–point pairs, there was no evidence of a difference in mean PBVC between active and placebo arms (baseline to year 1: active –0.60%, placebo –0.59%, p=0.93; year 1 to year 2: active –0.58%, placebo –0.65%, p=0.62; year 2 to year 3: active –0.88%, placebo –0.76%, p=0.39). Conclusion Δ9–THC was not better than placebo at reducing the rates of new T1 or T2 lesions or brain atrophy in patients with progressive MS.

REGIONAL PATTERNS OF GREY MATTER ATROPHY AND MAGNETISATION TRANSFER RATIO ABNORMALITIES IN MULTIPLE SCLEROSIS CLINICAL SUBGROUPS

Background In Multiple Sclerosis (MS), demyelination and neuronal loss occur in the brain grey matter (GM) and are associated with a progressive disease course. Using MRI measures of atrophy and GM magnetization transfer ratio (MTR), we investigated the regional localisation of consistent volume loss (reflecting neuronal loss) and intrinsic tissue abnormalities (particularly demyelination) in MS clinical subgroups. Objective To map regions of consistent GM atrophy and MTR reduction in relapsing–remitting (RR), secondary progressive (SP) and primary progressive (PP) MS. Methods 102 patients (51 RRMS, 30 SPMS, 21 PPMS) and 32 controls had T1–weighted volumetric and magnetisation transfer scans, both acquired at 1x1x1mm3. MTR maps were calculated using MT on and off sequences. MTR in grey matter was extracted by segmenting grey matter on T1–weighted images and binarising the resulting tissue maps with a conservative threshold of 90%. Using SPM8, T1 scans were non–linearly registered to create a DARTEL template, registered to MNI space using affine transformation, and smoothed with an 8 mm full–width half maximum Gaussian kernel. Voxel–based morphometry (VBM) was used to compare regional differences in GM atrophy and a VBM–type analysis was carried out on the grey matter MTR of MS patient subgroups versus controls, adjusting for age and gender, using family wise error (FWE) correction at p<0.05. Results Compared with controls, PPMS and SPMS groups exhibited more areas of MTR reduction than atrophy while RRMS subjects showed more areas of atrophy than reduced MTR. Co–localisation of atrophy and reduced MTR was most evident in the thalamus in all MS subtypes. There were more areas of cortical MTR reduction and atrophy than where both were co–localised. Compared to controls, there were more areas of cortical MTR reduction in SPMS and PPMS than in RRMS. Conclusions Assuming that reduced GM MTR implies demyelination and atrophy reflects neuronal loss, the results suggest that: (i) in progressive (SP and PP) MS there is overall more extensive GM demyelination than neuronal loss; (ii) in RRMS there is overall more extensive GM neuronal loss with less noticeable demyelination, (iii) cortical demyelination occurs in more regions in SPMS and PPMS than RRMS; (iv) demyelination and neuronal loss often occur in different locations in the cortex, and (v) co–existent demyelination and neuronal loss is most evident in the thalamus. The variation in regional abnormalities argue against a single common mechanism for demyelination and neuronal loss in MS GM.

Movement disorders and tremors

Movement disorders are common, and can be difficult to categorise correctly. In this article, we present the common movement disorders seen by GPs and provide an overview of their classification. Most movement disorders presenting in primary care will need referral to a neurologist for full diagnosis and management. However, essential tremor is usually managed in primary care, and being able to differentiate it from other forms of tremor, especially Parkinsons disease, as well as being familiar with its initial management, is important. For all patients, being aware of the potential impact on daily function is paramount, and adopting a multidisciplinary approach to management should always be considered.