Team G and the Association of British Neurology Meeting Glasgow

Team G and the ABN in Glasgow. #MSBlog #MSResearch

“The following are the abstracts that were presented by our team at the last Association of British Neurology meeting in Glasgow. This is an important meeting for neurology trainees in the UK and medical students to present at. The work is varied and looks at causation (endophenotyping), MS service development, the impact of neutralizing antibodies (NABs), databasing and an upper limb outcome measure.”

Dobson R, Topping J, Ramagopalan S, Giovannoni G. Towards an endophenotype in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2.

OBJECTIVE: An endophenotype is a concept that allows us to describe complex diseases with genetic and environmental contributions. This enables the identification of an “at risk” population. We aim to describe an endophenotypic gradient between healthy controls (HC), siblings of people with MS (PwMS) and PwMS.

BACKGROUND: Siblings of PwMS have an increased risk of developing MS. This increased risk is thought to be a result of genetic and environmental contributions. Epidemiological studies have identified factors contributing to MS including smoking, vitamin-D, infection with and IgG titres against Epstein-Barr virus and HLA-DRB1*1501. A genome wide association study (GWAS) in 2011 gave information regarding the contribution of HLA-type and non-HLA SNPs to MS risk. We set out to integrate these into an endophenotypic risk score for MS.

METHODS: PwMS (n=78), their unaffected siblings (n=121) and healthy controls (HC; n=103) were recruited. Serum anti-EBNA-1 IgG, vitamin D and nicotinine were measured. Subjects were genotyped for HLA-DRB1*1501 and all HLA and non-HLA SNPs associated with MS using the Illumina immunochip. Previous infectious mononucleosis, smoking and month of birth were recorded. The relative risks associated with these factors were established from meta-analyses and integrated into an overall risk score for each individual. Full genetic data was available for 73 people with MS, 107 siblings and 99 HC. Risk scores with genetic contribution from HLA-DRB1*1501 only, and from all MS-associated genetic variants were calculated.

RESULTS: When the genetic contribution from HLA-DRB1*1501 alone was used, the mean risk score was significantly higher for PwMS (2.82; SD 1.18) than for siblings (1.98; SD 1.38) or HC (1.53; SD 1.34) (p<0.0005 between MS and siblings and MS and HC; p=0.042 between siblings and HC). A ROC curve comparing PwMS to HC generated an AUC of 0.772 (95% CI 0.702-0.842). PwMS had an OR of 6.29 (95% CI 2.64-14.98, p<0.0001) compared to HC of having a score >1.25 SD higher than the mean HC score. When full genetic data was included, the mean risk score was highest for people with MS (9.71; SD 1.38) intermediate for siblings (8.83; SD 1.47) and lowest for HC (8.00; SD 1.49) (p<0.0005 for all comparisons). A ROC curve comparing PwMS to HC generated an AUC of 0.801 (0.735-0.866). PwMS had an OR of 7.05 (3.31-15.06, p<0.00001) compared to HC of being in the highest risk score group. PwMS had an OR of 1296.00 (95% CI 78.02-21,527.34; p<0.00001) and siblings 33.06 (95% CI 7.37-148.41; p<0.00001) of being in the highest risk score vs the lowest risk score group. As people with MS had significantly higher vitamin D than HC, presumably secondary to behavioural modification post-diagnosis, a model excluding vitamin D was created. This generated an AUC of 0.818 (95% CI 0.754-0.881).

CONCLUSIONS: This study demonstrates the validity of the risk score generated, which integrates genetic and environmental risk factors. Siblings have a risk score intermediate to PwMS and HC, confirming their “at risk” position in the endophenotype construct. Much of the MS risk in siblings can be attributed to genetics, with environmental factors potentially providing the trigger for clinically apparent disease.

CoI: This work from Team G

Hadavi S, Giovannoni G, Dobson R. A Service development audit of fampridine use in MS. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2.

BACKGROUND: Impairment of walking and the resultant reduction in physical function together with pathological fatigue are major concerns for patients with Multiple Sclerosis (MS). Patients are in need of interventions to improve walking. Slow-release 4-aminopyridine (Fampridine; Fampyra) improves walking speed in approximately 35% of MS patients. The Timed 25-Foot Walk (T25FW) is used to measure response to treatment. There are concerns that the T25FW is a poor estimate of walking speed, and only able to provide a snapshot of walking impairment under controlled circumstances. Funding bodies have raised uncertainties regarding the possibility of increased falls with Fampridine.

OBJECTIVES: T25FW is not the most pragmatic measure of either walking impairment and or Fampridine efficacy. Alternative objective outcome measures including accelerometry or longer walking distance tests may be more informative of patients’ walking ability in real-life situations. We therefore set out to evaluate objective and subjective outcome measures of walking impairment, falls risk and fatigability for use in MS patients.

METHODS: Thirty-two MS patients underwent a battery of objective and subjective assessments, including 48-hour accelerometry. Appropriate statistical tests were selected for data analysis. Pearson correlation coefficient and Spearman’s rho were used for parametric and non-parametric data, respectively. Group mean comparisons were made using the un-paired t-test and one-way analysis of variance (ANOVA) on parametric data, and Mann-Whitney U test and Kruskal-Wallis test on non-parametric data.

RESULTS: The study group consisted of 13 women and 19 male (5 primary progressive, 19 secondary progressive, and 8 relapsing-remitting; EDSS range 2.5-7). Median age was 48.5, (range 30-68). All patients had fallen in the past 6 months, and 19 used an assistive device at all times. The mean duration since MS diagnosis was 8.3 years (SD=6.6). T25FW, 2-minute walk (2MWT) and average daily activity measured by accelerometry showed significant correlations with all other objective measures of walking impairment. The MS walking scale-12 (MSWS-12) correlated significantly with T25FW and 2MWT. The Activities-specific Balance Confidence (ABC) scale scores increased significantly with higher falls frequency (p=0.03). Assistive device use was significantly associated with worse scores on all subjective and objective tools, and with falls frequency. Accelerometry was a discriminator of physical fatigability in MS patients, when comparing the average activity in the morning with the average activity in the afternoon. Patients in this study suffering from fatigue were less active in the afternoon compared to the early morning (p=0.01).

CONCLUSIONS: The 2MWT and accelerometry are good objective measures of walking disability in addition to the T25FW. Accelerometry provides additional real-life data regarding activity during the day, and offers information regarding the impact of fatigue on a patient. The MSWS-12 subjectively measures impact of walking disability and the ABC score predicts falls. The use of an assistive device identifies walking disability and predicts risk of falls. Given the uncertainty regarding falls risk in patients using fampridine, physicians should consider using these tools to monitor patients under consideration for the drug.

Gafson A, Worthington V, Lakdawala N, Giovannoni G, Farrell R.NEUTRALISING ANTIBODIES TO INTERFERON-BETA PREDICT CONVERSION TO SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS IN PATIENTS WITH MULTIPLE SCLEROSIS. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2. doi: 10.1136/jnnp-2013-306573.176.

BACKGROUND: Multiple Sclerosis (MS) is the most common non-traumatic cause of acquired neurological disability in young people. Interferon-Beta (IFNβ) is a safe and well-tolerated first-line treatment for patients with MS (PwMS) in the relapsing-remitting phase of the disease (RRMS) and has been shown to reduce relapse rates by an average of 30% (Compston and Coles 2002). Neutralising antibodies (NAbs) are known to occur in approximately 25% of patients and in high titres reduce or eliminate the bioactivity of the drug [Pachner (Insight study) 2009, Farrell 2011]. Nabs are more likely to occur with high dose high frequency compounds-IFNβ 1a and IFNβ 1b (MS Study group 1996). Increased relapse rates and MRI activity have been described in patients with NAbs however effect on disability progression has been ambivalent [MS Study group 1996, Francis 2005, Kappos 2005, Farrell 2008]. Despite the existence of clinical guidelines recommending routine NAb testing with a view to switching therapy in those with persistent positive NAbs, uptake in the UK has been low [Polman 2010].

OBJECTIVE: To assess the effect on disability in a UK cohort of patient attending the National Hospital for Neurology and Neurosurgery, London.

METHODS: A historical sample library of sera from PwMS treated with IFNβ was utilised. Subjects were eligible if they had a diagnosis of RRMS (Poser/McDonald) and had been treated for a minimum of 3-6 years. Serial samples were tested using the luciferase NAb assay (Farrell 2011) for the presence of NAbs and medical records reviewed to determine the clinical disease state at each time point (RRMS vs SPMS).

RESULTS: 112 subjects were identified, 53 remained RRMS up to at least the date of their last available sample and 59 patients had converted to secondary-progressive MS (SPMS) whilst on IFNβ or at a time point after the date of their last sample. Within the RRMS cohort (n=53), 4 were persistently positive at 2 years (7.5 %). Within the RRMS-SPMS cohort (n=59), 20 were persistently NAb positive at 2 years (34%). A positive NAb status at 24 months conferred a 4.25 fold increase in relative odds of progression to SPMS (95% CI: 1.53 to 11.84, p=0.006) using a logistic regression analysis. A sub-group analysis separating patients into high NAb titres (>400 neutralising units (NU)), low NAb titres (<100 NU) and negative titres (<20 NU) did not reveal a titre-dependent associated increase in risk of progression to SPMS (p>0.05).

CONCLUSION: This study demonstrates a significantly increased risk of progression from RRMS to SPMS in patients who become NAb positive. As no current disease modifying treatments are effective in this phase of the disease patients at risk should be detected early and routine NAb testing can help to inform this decision.

CoI: This work from Team G 

Albor C, Richards O, Ramagopalan S, Boomla K, Schmierer K. Using routinepoint of care data for research: The East Londn multiple sclerosis cohort J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2.

BACKGROUND: Few geographically-linked datasets of people with Multiple Sclerosis (MS) exist in the UK. The development of these datasets enriched with clinical information would aid in testing etiological hypotheses, comparing disease progression between treatment regimes, and recruiting clinical trial participants. The population in East London (defined here as The City, Hackney, Tower Hamlets, and Newham) is of particular interest because of its ethnic mix, which is reflected by its population with MS. 

METHODS: Identifying cases: Based on existing outpatient clinic lists at The Royal London Hospital, a list of MS patients was created on ‘Cerner Millennium Software’ (CRS). MS patients that were matched to the PCTs of Tower Hamlets, Newham, and City & Hackney formed our East London MS Cohort. Phase 1 of coding clinical data (ongoing): Scanned clinical letters are manually searched to code key variables on each patient’s CRS hospital record: MS course, year of onset, first symptoms, and whether on disease-modifying treatment. Phase 2 of coding clinical data (ongoing): When patients attend outpatient clinics, they are given questionnaires asking for further MS-related information. Completed questionnaires combined with updates from consulting clinicians are used to code further variables on patients’ CRS hospital records. Preparing data for analysis: Coded clinical data of MS patients are extracted from CRS hospital records using the CRS ‘Explorer Menu’. This data is then anonymised in the secure network, before analysis with Stata statistical software.

RESULTS: 1,144 MS patients attending the Royal London outpatients department have been identified. 451 of these patients make up our East London MS Cohort. They account for 60% of the count of MS patients identified by GP records. The mean age of the cohort is 48 and there is a 2.4:1 female:male ratio. 62% are White, 16% Black, 9% Asian, 6% Other, and 7% Unknown. This shows an over-representation of White MS patients relative to the area’s population, hence based on GP counts crude prevalence figures per 100,00 are 145 for White, 78 for Black, 28 for South Asian, and 18 for Other (92 overall). Currently, data coding of all MS patients using the outpatient service is in progress, and the majority of our variables of interest have been coded for about 10% of patients.

CONCLUSION: The demographic characteristics of the White MS patients in our cohort are very similar to those recently described in another UK-based geographically-linked MS cohort of 620 patients in Wales which was 97% White (J Neurol, Neurosurg & Psychiatry 80 (4):386-391). They described a mean age of 51, a female:male ratio of 2.4:1, and a prevalence of 146 per 100,000. However, what is unique to our cohort is its ethnic diversity, allowing us to show prevalences for ethnic minorities. What is more, when data coding is complete, we will be able to conduct further epidemiological studies, including migration studies, treatment effectiveness studies, and case-control studies of risk factors.

CoI: This work from Team G 

Hadavi S, Shribman S, Nagy A, Acharya S, Fearnley J, Dobson R, Lees A, Giovannoni G, Noyce A.The bradykinesia-akinesia incoordination test: a simple objective test in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Nov;84(11):e2.

BACKGROUND: The Bradykinesia Akinesia Incoordination (BRAIN) test is an online computer keyboard-tapping task based on the alternate finger tap test. It has previously been used to measure upper limb motor function in Parkinson’s disease (PD). Multiple Sclerosis (MS) is an autoimmune demyelinating disorder with a wide clinical spectrum, within which pyramidal motor impairment is encountered frequently. There is a need for simple objective measures of upper limb function in clinical studies of symptomatic and disease-modifying treatment in MS. We therefore set out to evaluate whether the BRAIN test would be a suitable objective test of upper limb motor impairment in MS patients. 

METHODS: The BRAIN test records the following parameters: kinesia score (KS30), number of key taps in 30 seconds; akinesia time (AT30), mean dwell time on each key in milliseconds; dysmetria score (DS30), a weighted index using the number of incorrectly hit keys scored in a target fashion; and incoordination score (IS30), the variance of the time interval between keystrokes. The study was undertaken in 32 MS patients (5 primary progressive, 19 secondary progressive, and 8 relapsing-remitting). These data were compared to that from 53 PD patients and 86 non-neurological controls. Participants were recruited from outpatient departments at the Royal London Hospital and the National Hospital for Neurology and Neurosurgery. All participants submitted informed consent. Mean KS30 and median AT30, DS30 and IS30 were compared between groups using the unpaired t-test for parametric data and the Mann Whitney U test for non-parametric data. Furthermore, in MS patients, KS30 and AT30 were correlated against Expanded Disability Status Scale (EDSS), a validated method of quantifying disability, and 9-Hole Peg Test (9-HPT), a test of upper limb function in MS. Correlations were undertaken using Pearson’s test and Spearman’s rank test as necessary.

RESULTS: Mean KS30 scores in PD and MS were similar (46.1 versus 45.7 taps respectively, p=0.88) and were significantly different when compared to controls (63.3 taps, p<0.0001). There was a significant difference between median AT30 in PD and MS (139.5 ms versus 108 ms, p=0.0014) but no difference between MS and controls (108 ms versus 97.5 ms, p=0.16). Median IS30 scores in PD and MS were different (21763 versus 9524 respectively, p=0.004), as were DS30 scores (1.05 versus 1.0 respectively, p=0.003). In MS patients, KS30 correlated strongly with EDSS (KS30 r=-0.59, p=0.0004) and 9-HPT (KS30 r=-0.57, p=0.0006). Other parameters did not show a significant correlation with EDSS and 9-HPT.

CONCLUSION: The BRAIN test is a widely-available, objective test of upper limb motor function in neurological disease and can be use in the outpatient clinic, home and in clinical trials. Tapping speed is reduced in MS patients when compared to healthy controls and by a similar extent to that seen in PD. MS patients do not have prolonged dwell time when pressing keys, which is a feature of the PD patient group and perhaps extra-pyramidal slowing. This potential for the BRAIN test in differentiating pyramidal from extra-pyramidal motor dysfunction requires further study.

CoI: This work from Team G 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

1 comment

  • Dear Prof G,

    In respect of the impact of NAbs, can you explain that even with low NAb titres, would the risk of progression to SPMS be the same?

    Concerned due to the fact that development of NAbs had happened to myself some years ago. Subsequently changed therapies due to having very active RRMS (Mitoxantrone then Copaxone, which has worked very well with no current evidence of disease activity). Due to issues with lipoatrophy, Beta-Interferon 1a (Avonex) has been suggested as an option. Would it be wise to ask for an antibody test before even considering this, if at all?

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