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 They support a trend of increasing time to disability milestones compared with historical reference populations, and document disability variation with the use of transitional matrices.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.

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.

Alemtuzumab-induced remission of multiple sclerosis-associated uveitis.

PURPOSE: The purpose of the study was to report a case of multiple sclerosis (MS)-associated uveitis refractory to conventional immunosuppressants, with subsequent remission following treatment with alemtuzumab. METHODS: Case report Patient was treated with intravenous alemtuzumab, a lymphocyte depleting anti-CD52 monoclonal antibody that has recently been approved for use in relapsing MS. RESULTS: A 17-year-old female presented with bilateral optic neuritis and subsequently bilateral intermediate uveitis and secondary macular oedema. She was diagnosed with active relapsing MS for which she received treatment with alemtuzumab. The intraocular inflammation previously refractory to conventional immunosuppressants responded to alemtuzumab, inducing remission. CONCLUSIONS: To our knowledge, this is the first such report of alemtuzumab treatment in MS-associated ocular inflammatory disease and may demonstrate a potential utility for this drug in related conditions.

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.

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.

The aetiology of acute neurological decline in multiple sclerosis: experience from an open-access clinic.

BACKGROUND: Multiple sclerosis (MS) relapses contribute to disability and influence treatment decisions. Many centres now provide open access to specialist services for patients with new symptoms. However, there is scarce literature on the spectrum of presentations encountered in this setting. OBJECTIVE: The objective of this paper is to characterise presentations to an open, rapid-access MS relapse clinic and the impact on disease management. METHODS: A retrospective review of outpatient episodes over a three-year period was conducted. Demographic and service data, symptoms, disability, diagnosis and management were recorded according to a standardised proforma. RESULTS: A total of 371 attendances were analysed. A new MS relapse was diagnosed in 216 (58%) episodes, of which 56 (26%) patients had an additional diagnosis which had also contributed to their presentation. Of 266 reports of non-relapse-related symptoms, 73 were unrelated to MS. Treatment interventions were made in almost all relapsing patients and in 70% of patients presenting with acute, non-relapse-related symptoms of MS. Changes to disease-modifying therapies were considered in 28% of consultations. CONCLUSION: Diagnosing MS relapses is crucial for disease management and yet remains challenging. Clinicians should be aware of differential diagnoses and confounding factors. The high incidence of therapeutic interventions observed suggests that rapid-access clinics represent an effective platform for responsive disease management.

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.

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.

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.

Complement regulator factor H as a serum biomarker of multiple sclerosis disease state.

Multiple sclerosis has a variable phenotypic presentation and subsequent disease course that, although unpredictable at disease onset, is of crucial importance in guiding interventions. Effective and accessible biomarkers are required in order to stratify patients and inform treatment. We examined whether the complement regulator factor H and its Tyr402His polymorphism, recently implicated as biomarkers in other chronic inflammatory central nervous system conditions, might identify or predict specific pathological processes and outcomes in multiple sclerosis. Employing novel assays, we measured factor H and its His402 variant in serum from 350 patients with multiple sclerosis classified according to disease course and relapse status. Serum factor H levels were significantly higher in progressive disease (P < 0.001) compared to controls and relapsing patients, after controlling for variables including disease duration, age, gender, disability and treatment. Serum factor H levels were capable of distinguishing secondary progressive from relapsing remitting disease (excluding patients in clinical relapse) with a sensitivity of 89.41%, specificity of 69.47% and a positive predictive value of 72.38%. Acute relapse was also associated with transiently increased factor H levels (P = 0.009) compared to stable relapsing disease. In clinically stable patients, factor H levels remained constant over 1 year (coefficient of variation percentage = 6.8), however, in patients in transition from relapsing to progressive disease, factor H levels significantly increased over a period of 2 years (P = 0.007). Concentration of the His402 variant in heterozytgotes was significantly higher in secondary progressive (P < 0.01) and primary progressive (P < 0.05) disease, suggesting altered expression or consumption of variants when factor H is upregulated. Serum factor H may be an effective indicator of progression and a practical and accessible biomarker and stratifying tool in determining disease course, providing objective evidence to help guide therapeutic decisions.

Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis.

Importance: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline. Objective: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy. Design, Setting and Participants: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45). Exposures: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]). Main Outcomes and Measures: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group. Results: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (ß = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation. Conclusions and Relevance: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.

Contribution of relapses to disability in multiple sclerosis.

The impact of relapses on long-term disability in multiple sclerosis remains unclear; however some evidence suggests that relapses play an important role in determining subsequent prognosis. We report on outcome, prognostic factors for recovery and the contribution of relapses to the accumulation of fixed disability in a large series of patients with documented relapses. Two hundred and seventy-nine relapses in 182 patients were assessed before, during and after relapse by expanded disability status scale and data analysed to assess degree of recovery. Factors affecting outcome were considered including sex, age and site of relapse. Mean EDSS prior to relapse was 3.73, during relapse 5.18 and post relapse 4.23. Mean interval to post relapse assessment was 127 days post relapse. Mean residual change in EDSS score (pre to post relapse) was 0.50 points. Overall 49.4 % of patients had a residual increase in disability post relapse of at least 0.5 EDSS points and 32.7 % had an increase of at least 1 point. No significant difference was observed in mean residual EDSS for sex, site of relapse or age at relapse or in the proportion of patients with a residual increase in disability of > or = 1 EDSS point post relapse. 14.4 % of patients had no increase in EDSS score during relapse compared to pre relapse. These results suggest that acute relapses are commonly associated with an objective worsening of disability in the majority of patients with MS and that recovery is incomplete in approximately half and not influenced by gender, age or site of lesion. Therapies which reduce relapse frequency and/or severity might therefore be expected to slow or prevent worsening of disability if initiated prior to the onset of more permanent damage.

A contemporary study of mortality in the multiple sclerosis population of south east Wales.

BACKGROUND: Mortality studies in multiple sclerosis (MS) are valuable to identify changing disease patterns and inform clinical management. This study examines mortality in a British MS cohort. METHODS: Patients were selected from the southeast Wales MS registry. Hazard of death was analysed using Cox proportional hazards regression, adjusted for onset age, annualised relapse rate, initial disease course, time to EDSS 4.0, sex, socioeconomic status, and onset year. Age- and sex-stratified standardised mortality ratios (SMRs) were calculated by EDSS scores. RESULTS: Median time from MS diagnosis to death was 35.5 years and median age 73.9. Older onset age (hazard ratio [HR] 1.05, 95% confidence interval 1.03-1.06) was associated with increased hazard of death. Primary progressive course was associated with increased hazard of death in women (HR 2.04, 1.15-3.63) but not men (HR 1.23, 0.61-2.47). Slow time to EDSS 4.0 (HR 0.41, 0.28-0.60) and high socioeconomic status (HR 0.54, 0.37-0.79) were associated with reduced hazard of death. SMR increased from EDSS 6.0 (3.86, 2.63-5.47) but more substantially at EDSS 8.0 (22.17, 18.20-26.75). CONCLUSIONS: Risk of death in MS varies substantially with degree of disability. This has important implications for clinical management and health economic modelling.

Seasonal variation in multiple sclerosis relapse.

Relapses are a characteristic clinical feature of multiple sclerosis (MS), but an appreciation of factors that cause them remains elusive. In this study, we have examined seasonal variation of relapse in a large population-based MS cohort and correlated observed patterns with age, sex, disease course, and climatic factors. Relapse data were recorded prospectively in 2076 patients between 2005 and 2014. 3902 events were recorded in 1158 patients (range 0-24). There was significant seasonal variation in relapse rates (p < 0.0001) and this was associated with monthly hours of sunshine (odds ratio OR 1.08, p = 0.02). Relapse rates were highest in patients under the age of 30 (OR 1.42, p = 0.0005) and decreased with age. There was no evidence of different relapse rates for males compared to females (OR 0.90, p = 0.19). Identification of potentially modifiable environmental factors associated with temporal variation in relapse rates may allow alteration of risk on a population basis and alteration of outcome of established disease once established. Future epidemiological studies should examine dynamic environmental factors with serial prospective measurements and biological sampling. Significant seasonal differences in relapse rates highlight the importance of environmental factors in disease expression and should be taken into account when planning clinical trials in which relapse frequency is an outcome. In addition, identification of potentially modifiable factors associated with this variation may offer unique opportunities for alteration of risk of relapse and long-term outcome on a population level, and suggest putative biological mechanisms for relapse initiation.

Nitrous oxide misuse and vitamin B12 deficiency.

A 36-year-old man presented to hospital with a 5-week history of ascending limb paraesthesiae and balance difficulties. He had no medical or travel history of note, but admitted habitual nitrous oxide (N2O) inhalation. Neurological examination revealed a sensory ataxia with pseudoathetosis in the upper limbs and reduced vibration sensation to the hips bilaterally. Significant investigation results included a low serum vitamin B12 concentration, mild macrocytosis and raised serum homocysteine concentration. T2 MRI of the spinal cord demonstrated increased signal extending from C1 to T11 in keeping with a longitudinal myelitis. The patient was diagnosed with a myeloneuropathy secondary to vitamin B12 deficiency, resulting from heavy N2O inhalation. He was treated with intramuscular vitamin B12 injections and received regular physiotherapy. At discharge, he was able to mobilise short distances with the aid of a zimmer frame, and was independently mobile 8 weeks later.

Transient femoral neuropathy after harvest of bone from the iliac crest.

A 31-year-old woman had bone harvested from the left anterior iliac crest as a graft for an augmentation genioplasty. For postoperative analgesia, she was given a bupivacaine infusion into the iliac wound. She developed a temporary left femoral mononeuropathy from which she recovered completely.

Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis.

OBJECTIVE: Alemtuzumab is potentially a highly effective treatment for relapsing multiple sclerosis (MS) acting via complement-mediated lysis of circulating lymphocytes. Variability in posttreatment lymphocyte recovery time is observed, with some patients showing striking durability in the efficacy of treatment. This study aims to establish whether this observed variation affects clinical and imaging parameters of disease activity. METHODS: A total of 56 patients were followed for a median of 39.5 months post alemtuzumab treatment with interval clinical assessments, lymphocyte immunophenotyping, and MRI. Timing and degree of CD4+, CD8+, and CD19+ recovery were correlated with the re-emergence of disease activity defined as clinical relapse, increasing disability, and new T2/enhancing lesions on MRI. RESULTS: New disease activity was recorded in 14% of patients. Mean time to CD19+, CD8+, and CD4+ reconstitution was 6, 10, and 36 months. No differences were observed in CD8+ and CD19+ reconstitution between patients with active disease and those in remission. Patients with active disease showed an accelerated recovery of CD4+ cells (p = 0.001) with a difference in absolute CD4+ counts at 24 months (p = 0.009). CD4+ counts <388.5 × 10(6) cells/mL predicted MRI stability. CONCLUSIONS: Differential lymphocyte recovery in MS following alemtuzumab may be a biomarker for relapse and also inform monitoring and treatment protocols. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that differential lymphocyte reconstitution after alemtuzumab treatment may be a biomarker for relapse.

Genotype-phenotype correlation for non-HLA disease associated risk alleles in multiple sclerosis.

BACKGROUND: Recent advances in MS genetics have led to the successful identification of a number of novel disease associated non-HLA genes. It is now becoming possible to begin to analyse the possible effects of these genes on aspects of disease phenotype where longitudinal clinical data is available. OBJECTIVE: We examined phenotypic impact of 10 non-HLA disease associated single nucleotide polymorphisms (SNPs) in 1003 patients with MS followed for an average of 14.1 years. METHODS: Association of SNPs with time to established disability milestones (Expanded Disability Status Scale (EDSS) 4.0, 6.0, 8.0), onset of secondary progression and cross-sectional aspects of early phenotype were tested using survival analysis. RESULTS: No SNP was associated with systematic deflection in time to disability milestones, age at onset or time to secondary progression. CONCLUSIONS: Genotypic information from non-HLA associated SNPs is unlikely to inform individual patient prognosis in the clinical setting although minor phenotypic effects operative at specific phases of disease cannot be excluded. This preliminary study provides a framework for future genotype-phenotype analysis in MS and will need to be replicated in independent patient cohorts.