How common is truly benign MS in a UK population?

Objectives The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations. Methods We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions. Results Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1). Conclusions Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term ‘benign’ in clinical settings

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Temporal evolution of remission following multiple sclerosis relapse and predictors of outcome

Background: Relapse is a characteristic clinical feature of multiple sclerosis (MS) and is commonly employed as a measure of efficacy following therapeutic intervention. However, less is known about the temporal evolution of subsequent disability or factors predicting recovery. Objectives: The objective of this study was to assess the pattern of recovery following relapse and identify factors which predict recovery and residual disability following relapse. Methods: A total of 226 relapses were studied prospectively in a cohort of 144 patients with standardised clinical assessments of physical disability including Expanded Disability Status Scale (EDSS), 10-m timed walk, 9-hole peg test and Multiple Sclerosis Impact Scale (MSIS-29) at 0, 2, 6 and 12 months. A total of 82 patients completed 12 months of follow up without further relapse. Results: Thirty per cent of relapses were severe (change in EDSS >2.0) of which 11% failed to recover. All measures showed significant improvement at 2 months but additional improvement was also observed in 9-hole peg test and MSIS-29 up to 12 months following initial assessment. Mean time to second relapse was 382 days. The only predictor of relapse severity in the model tested was younger age; however, increasing age and initial relapse severity were also predictors of poor outcome. Conclusions: This study shows that the majority of improvement in physical disability following relapse occurs by 2 months but that more subtle recovery can take place over 12 months in a small sub-group of patients. These data will aid in patient counselling and will also inform the timing of therapeutic intervention and physical support

Modelling the natural history of primary progressive multiple sclerosis

BACKGROUND: A minority of patients with multiple sclerosis (MS) have primary progressive disease (PPMS). Treatment options are currently limited, but as prospects for interventional studies become more realistic, understanding contemporary outcome data will be key to successful trial design. METHODS: 234 PPMS patients were identified from a population-based cohort of 2131 (11.0%) and mean follow-up of 13.1 years. Time to established disability endpoints was compared with patients with relapsing-onset MS (ROMS) using survival analysis, and Cox regression employed to explore factors contributing to disability accumulation. Results were used to create predictive power models for clinical trials in PPMS. RESULTS: Time to fixed disability milestones was shorter than in ROMS (Expanded Disability Status Scale (EDSS) 4.0:8.1 vs. 17.1 years, p<0.001; EDSS 6.0: 9.6 vs. 22.1 years, p<0.001; EDSS 8.0: 20.7 vs. 39.7 years, p<0.001), but there were no differences in age-related disability. Age and cerebellar symptoms at onset affected rate of progression. Modelling of these data indicated that trials employing EDSS change of 1.0 as the primary outcome measure would be powered to detect a 20% difference in progression using 600 patients with initial EDSS of 4.0 per trial arm, or 400 patients with initial EDSS of 5.0 per arm. However, trials including patients with fixed EDSS of ≥6.0 will be underpowered even with large numbers or prolonged duration. CONCLUSIONS: Disability progression in PPMS is variable and influenced by age at onset. Although progression is more rapid, age-related disability milestones are identical to relapsing-onset disease. These data offer a contemporary paradigm for clinical trial design in progressive MS

Contemporary study of multiple sclerosis disability in South East Wales

Background A contemporary understanding of disability evolution in multiple sclerosis (MS) is an essential tool for individual disease management and planning of interventional studies. We have used prospectively collected longitudinal data to analyse disability progression and variation in a British MS cohort. Methods Cox proportional hazards regression was used to estimate hazard of Expanded Disability Status Scale (EDSS) 4.0 and 6.0. A continuous Markov model was used to estimate transitional probabilities for individual EDSS scores. Models were adjusted for age at MS onset, sex and disease-modifying treatments (DMTs) exposure. Results 2135 patients were included (1487 (70%) female, 1922 (89%) relapsing onset). 865 (41%) had used DMTs. Median time to EDSS 4.0 and 6.0 was 18.2 years (95% CI 16.3 to 20.2) and 22.1 years (95% CI 20.5 to 24.5). In the Markov model, the median time spent at EDSS scores of <6 (0.40–0.98 year) was shorter than the time spent at EDSS scores of ≥6 (0.87–4.11 year). Hazard of change in EDSS was greatest at EDSS scores <6 (HR for increasing EDSS: 1.02–1.33; decreasing EDSS: 0.34–1.27) compared with EDSS scores ≥6 (HR for increasing EDSS: 0.08–0.61; decreasing EDSS: 0.18–0.54). Conclusions These data provide a detailed contemporary model of disability outcomes in a representative population-based MS cohort. They support a trend of increasing time to disability milestones compared with historical reference populations, and document disability variation with the use of transitional matrices. In addition, they provide essential information for patient counselling, clinical trial design, service planning and offer a comparative baseline for assessment of therapeutic interventions

Long-term outcome of paediatric-onset multiple sclerosis: a population-based study

Background Age of onset of multiple sclerosis (MS) peaks in the 3rd and 4th decades and is rarely less than 18. Robust longitudinal studies in paediatric-onset MS (POMS) are limited, and a clearer understanding of outcome could optimise management strategies. Methods Patients with disease onset <18 years were identified from a prospective population-based register. Clinical features including presenting symptoms, time to Expanded Disability Status Scale (EDSS) 4.0, 6.0 and 8.0 and onset of secondary progression were compared with patients with adult-onset MS (AOMS). Results 111 POMS patients were identified from a cohort of 2068. No significant differences in sex ratio, familial recurrence, relapse rate, ethnicity or clinical symptoms at presentation were identified between POMS and AOMS. However, interval to second relapse was longer (5 vs 2.6 years, p=0.04) and primary progressive disease was less common (0.9% vs 8.5%, p=0.003) in POMS than in AOMS. POMS patients also took longer to develop secondary progressive disease (32 vs 18 years, p=0.0001) and to reach disability milestones (EDSS 4.0, 23.8 vs 15.5 years, p<0.0001; EDSS 6.0, 30.8 vs 20.4 years, p<0.0001; EDSS 8.0, 44.7 vs 39 years, p=0.02), but did so between 7.0 and 12 years younger than in AOMS. Conclusions 5.4% of patients with MS have POMS (2.7% <16 years; 0.3% <10 years) and have distinct phenotypic characteristics in early disease. Furthermore, while patients with POMS take longer to reach disability milestones, they do so at a younger age than their adult counterparts and could be considered to have a poorer prognosis. Management strategies for these patients should take account of these data

Cluster of atypical adult Guillain-Barré syndrome temporally associated with neurological illness due to EV-D68 in children, South Wales, United Kingdom, October 2015 to January 2016

We report a cluster of atypical Guillain-Barré syndrome in 10 adults temporally related to a cluster of four children with acute flaccid paralysis, over a 3-month period in South Wales, United Kingdom. All adult cases were male, aged between 24 and 77 years. Seven had prominent facial diplegia at onset. Available electrophysiological studies showed axonal involvement in five adults. Seven reported various forms of respiratory disease before onset of neurological symptoms. The ages of children ranged from one to 13 years, three of the four were two years old or younger. Enterovirus testing is available for three children; two had evidence of enterovirus D68 infection in stool or respiratory samples. We describe the clinical features, epidemiology and state of current investigations for these unusual clusters of illness

Demographic and clinical factors associated with changes in employment in multiple sclerosis

Objective: The objective of this paper is to investigate demographic and disease factors associated with changes in employment role and status in multiple sclerosis (MS). Methods: Questionnaires on current symptoms, employment status and factors associated with changes in employment were sent to a community sample of 566 MS patients. Results: A total of 221 completed questionnaires were analysed. Of 169 employed at diagnosis, 43.3% had left employment at a mean of 11.9 years after disease onset. Of those still employed, 55% had changed their role or working hours to accommodate symptoms relating to their disease. These patients reported greater fatigue (p = 0.001), pain (p = 0.033) and memory problems (p = 0.038) than those whose employment had remained unaffected. Multinomial logistic regression revealed the factors most strongly predictive of employment status were disability level, years of education, disease duration and fatigue (p = 0.032). Conclusions: Despite changes to public perceptions and legislative protection over the last 20 years, high rates of MS patients still leave the workforce prematurely, reduce working hours or change employment roles. These data have significant implications when considering social and economic impacts of MS, support the value of employment metrics as long-term outcome measures, and demonstrate the need to improve employment requirements and flexibility of working practices in individuals with MS