Multiple sclerosis: long-term outcomes in ethnic minorities. Analysis of a UK population-based registry.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is most frequent in Caucasian populations. However, studies of MS in other ethnic groups may offer unique insights into genetic and environmental influences on the disease, and data on long-term outcomes in these patients is limited. In this work clinical features and time to disability milestones were investigated in ethnic minority (EM) patients with MS in a UK population and comparisons were made to a Caucasian cohort from the same region. METHODS: In all, 1949 MS patients (1866 Caucasian, 83 EM) were identified from a regional disease registry. Cox proportional hazards regression was used to analyse the time to Expanded Disability Status Scale (EDSS) 3.0, 4.0 and 6.0. RESULTS: Ethnic minority patients were younger at disease onset (28.6 years vs. 32.8 years, P = 0.001), and primary progressive MS was less common (EM 4.8%, Caucasian 11.6%, P = 0.03). After correction for clinical variables, ethnicity was associated with time to EDSS 3.0 [EM: hazard ratio (HR) 1.75, P < 0.0001] and 4.0 (HR 1.46, P = 0.03), but not 6.0 (HR 1.5, P = 0.05). CONCLUSIONS: Ethnic minority patients reach early levels of fixed disability more rapidly than Caucasian patients, but this effect diminishes at later stages of the disease. This has implications for clinical management of these patients.

Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort.

BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve. OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab. METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review. RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity. CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.

Site-specific clinical disease onset in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated. METHODS: Employing prospective clinical database data from 1482 patients who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse. RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms. CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.

Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis.

BACKGROUND: Age at onset modifies prognosis in multiple sclerosis (MS) and may also exert an effect on the characteristics of disease ignition. Understanding how age influences presentation informs disease management and may allow differentiation of distinct clinical sub-groups. OBJECTIVES: To determine the nature of age-specific presentations of relapsing-remitting MS (RRMS) with respect to onset symptoms, gender ratios and index event outcomes. METHODS: In a prospective, population-based sample of 1424 patients in South-East Wales we examined associations between age at onset, clinical features and outcome of the onset event, making specific comparisons between paediatric, adolescent and late-onset MS. RESULTS: Age at onset varied significantly between sexes (Male 31.2, Female 29.3, p = 0.002), 0.7% had paediatric onset, 2.7% adolescent onset and 2.8% late-onset MS (>50 years). Optic neuritis was common in younger patients and declined after age 30. Lower limb motor, facial sensory, sexual and sphincteric symptoms rose with age independent of sex and disease course. F:M ratios were highest <16 years of age and declined with increasing age, with a male excess in those over 50. Probability of complete recovery from index event declined with age from 87.4% in the youngest group to 68% in the eldest (p = 0.009). CONCLUSIONS: Age at disease onset in RRMS exerts a significant effect on gender ratios and presenting phenotype, and allows identification of specific clinical sub-groups. In addition, ability to recover from initial relapse declines with age, suggesting accumulation of disability in MS is an age-dependent response to relapse.

Systemic complement profiling in multiple sclerosis as a biomarker of disease state.

BACKGROUND: There is increasing evidence of significant and dynamic systemic activation and upregulation of complement in multiple sclerosis (MS), which may contribute to disease pathogenesis. OBJECTIVE: We aimed to investigate the pathological role of complement in MS and the potential role for complement profiling as a biomarker of MS disease state. METHODS: Key components of the classical, alternative and terminal pathways of complement were measured in plasma and cerebrospinal fluid (CSF) of patients with MS in different clinical phases of disease and in matched controls. RESULTS: Increased plasma levels of C3 (p<0.003), C4 (p<0.001), C4a (p<0.001), C1 inhibitor (p<0.001), and factor H (p<0.001), and reduced levels of C9 (p<0.001) were observed in MS patients compared with controls. Combined profiling of these analytes produced a statistical model with a predictive value of 97% for MS and 73% for clinical relapse when combined with selected demographic data. CSF-plasma correlations suggested that source of synthesis of these components was both systemic and central. CONCLUSION: These data provide further evidence of alterations in both local and systemic expression and activation of complement in MS and suggest that complement profiling may be informative as a biomarker of MS disease, although further work is needed to determine its use in distinguishing MS from its differential.

Multiple sclerosis and COVID-19: Assessing risk perception, patient behaviors and access to disease-modifying therapies.

BACKGROUND: Following the outbreak of COVID-19, global healthcare systems have had to rapidly adapt. People with multiple sclerosis (pwMS) were required to make decisions about their individual risk and consequent work and social behaviors. This study aimed to evaluate risk perception and patterns of shielding behavior amongst pwMS at the onset of the COVID-19 pandemic and the subsequent impact on patients' employment and access to disease modifying therapies (DMTs). METHODS: Postal surveys were sent to 1690 people within a UK population-based MS cohort during the first wave of the COVID-19 pandemic. Patients were surveyed on: (i) perceived vulnerability to COVID-19; (ii) isolation behavior; (iii) interruption to DMT; (iv) employment status; (v) level of satisfaction with their current working arrangement. RESULTS: Responses were received from 1000 pwMS. Two thirds of patients reported isolating at home during the first wave of the pandemic. This behavior was associated with increased age (p<0.0001), higher disability (p<0.0001) and use of high-efficacy DMTs (p = 0.02). The majority of patients reported feeling vulnerable (82%) with perceived vulnerability associated with higher EDSS (p<0.0001) and receiving a high-efficacy DMT (p = 0.04). Clinician-defined risk was associated with shielding behavior, with those at high-risk more likely to self-isolate/shield (p<0.0001). Patients on high-efficacy DMTs were more likely to have an interruption to their treatment (50%) during the first wave of the pandemic. Most pwMS experienced a change to their working environment, and most were satisfied with the adjustments. CONCLUSION: This study highlights the risk perception, social behavioral practices and changes to treatment experienced by pwMS during the first wave of the COVID-19 pandemic in a large, well-described UK cohort. The results may help inform management of pwMS during future pandemic waves.

Validity of patient-derived disability and clinical data in multiple sclerosis.

Patient-derived historical data are widely employed to make fundamental management decisions in multiple sclerosis, although the validity of the information provided is unclear. The objectives of this study were to determine validity of patient-derived historical data and to describe the utility of a locally relevant, patient-administered questionnaire designed to ascertain current disability and other important disease milestones. A well-described cohort of 99 patients was identified for whom comparable, detailed, prospective longitudinal clinician-derived data were available. Patient-derived data were collected by completion of a standardized questionnaire or telephone interview for comparison. Reliability analysis for current Expanded Disability Status Scale (EDSS) demonstrated an intraclass correlation coefficient of 0.79 between questionnaire and clinician-derived data in 79 patients, with complete agreement in 75.9%. Intraclass correlation coefficient for year of disease onset, diagnosis and onset of secondary progression was 0.86, 0.91 and 0.78, respectively. Time to EDSS >4.0, 6.0 and 8.0 all had an intraclass correlation coefficient of >0.9. Less robust agreement was observed for current disease course (Kappa coefficient 0.71), initial relapse rate (intraclass correlation coefficient 0.37) and clinical features at disease onset (Kappa 0.25). We conclude that self-reported questionnaires can provide reliable current and retrospective data on time-to-disability milestones with high levels of correlation observed for some additional elements, supporting the use of selected components of patient-derived data in clinical practice and for epidemiological studies.

CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients.

OBJECTIVE: Oligoclonal band (OCB) negative multiple sclerosis (MS) is well recognised but uncommon, studied in only a few usually small case series. These reached differing conclusions on whether its clinical features or course differ from OCB positive disease. The study hypothesis was that a definitive study would not only be of clinical and prognostic value but also potentially offer information about the possible role of CSF oligoclonal immunoglobulins in MS disease processes. METHODS: A collaborative cohort of well documented patients in southwest England and south Wales was used to identify and analyse a large group of patients with OCB negative MS and make comparisons with age and sex matched OCB positive controls. RESULTS: An approximate minimum 3% of patients with MS were OCB negative. They were significantly more likely to exhibit neurological or systemic clinical features atypical of MS (headaches, neuropsychiatric features and skin changes). Non-specific MRI, blood and (other) CSF abnormalities were also more common, emphasising the need for continued diagnostic vigilance, although the incautious application of McDonald diagnostic criteria in OCB negative cases renders categorisation as "definite" MS more likely. Studying the uniformly assessed Cardiff group (69 patients), we found the prognosis for neurological disability was significantly better for OCB negative cases. The age adjusted hazard ratio for OCB negative and OCB positive subjects to reach Disability Scale Status (DSS) 4 and DSS 6 was, respectively, 0.60 (95% CI 0.39 to 0.93; p = 0.02) and 0.51 (95% CI 0.27 to 0.94; p = 0.03). CONCLUSION: There are clear clinical differences between OCB negative and OCB positive MS, in particular a better prognosis for disability. This is consistent with a secondary but nonetheless contributory role in disease process for intrathecally synthesised immunoglobulins.

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis.

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.

Clinical skills evaluation of trainees in a neurology department.

Three to 12 evaluations of clinical performance using the mini-clinical evaluation exercise (Mini-CEX) (n = 124) or direct observation of procedural skills (DOPS) (n = 21) were performed on 27 trainees working in an NHS neurology department. The communications/ counselling skills subdomain was scored in 64 evaluations. For Mini-CEX the focus was on gathering data (22%), diagnosis (31%), management (34%) and counselling (7%) (focus not recorded in 6%). For DOPS, lumbar puncture was the most common evaluated procedure (57%). Mini-CEX evaluations lasted 23.8 minutes (10.6) (mean, sd) and DOPS 25.9 minutes (12.6). Mini-CEX scores for overall competence and communication skills were mean 5.99 (sd 0.95, range 4-8) and 5.98 (sd 1.21, range 3-9) and for DOPS 5.71 (sd 0.90, range 4-8) both on scales of 1 to 9. Overall trainee competence and communication scores increased with year of training (p < 0.001, p < 0.004 univariate analysis). Assessors undertook up to three or four assessments in a session. Assessors and trainees considered that the observation and feedback had been 'very' or 'quite' useful in providing a relevant element of assessment. These assessments were feasible and useful in a neurology department and provided some evidence for increasing performance with trainee seniority. More assessor time (approximately one hour) than trainee time (24-26 min) was needed for each assessment undertaken.

Abnormal patterns of breathing during swallowing in neurological disorders.

Swallowing momentarily inhibits breathing, and normally the great majority of apnoeas which accompany a swallow are followed by expiration (xE swallows). This swallowing-breathing interaction is regarded as one of several mechanisms by which the airway is protected from aspiration during swallowing. The purpose of this study was to investigate the interaction of breathing and swallowing in two groups of neurological patients. Twenty-two patients with defined neurological disorders involving various structures or pathways (brain, spinal cord and peripheral nerves) were studied to determine whether particular lesions resulted in breakdown of the normal breathing pattern (22 normal subjects were also assessed and their breathing-swallowing pattern was compared with that of neurological patients). Subsequently, 32 patients with motor neurone disease (MND) were studied to identify factors associated with an abnormal pattern (i.e. swallow apnoeas followed by inspiration) and to clarify whether an abnormal pattern is related to chest infections, episodes of coughing and choking during meals, and prognosis. The swallow apnoea in patients with brain, spinal cord and peripheral neurological diseases was followed by inspiration more frequently than expected [20/22 (91%) patients compared with 2/22 (9%) of normal subjects, P: < 0.001], but this was not associated with a specific site of lesion(s). However, patients with corticobulbar involvement tended to have post-apnoea inspiration more often than those without. MND patients commonly displayed an abnormal pattern during swallowing [14/32 (44%) patients] characterized by inspiration after swallow, prolonged swallow apnoea and multiple swallows per bolus. Over the period of follow-up (12-18 months) this pattern did not predict chest infections, coughing and choking episodes during meals or survival. It seems likely that post-swallowing apnoea inspiration is a non-specific concomitant of disordered swallowing and/or breathing rather than being an important mechanism of aspiration per se or of symptom production.

Controlled randomised crossover trial of the effects of physiotherapy on mobility in chronic multiple sclerosis.

OBJECTIVES: To determine whether physiotherapy can improve mobility in chronic multiple sclerosis and whether there is a difference between treatment at home and as a hospital outpatient? METHODS: A randomised controlled crossover trial was undertaken in patients with chronic multiple sclerosis who had difficulty walking and were referred from neurology clinics: allocation was to one of six permutations of three 8 week treatment periods separated by 8 week intervals: treatments consisted of physiotherapy at home, as an outpatient, or "no therapy". The main outcome measures were based on independent assessments at home and included mobility related disability (primary outcome: the Rivermead mobility index), gait impairments, arm function, mood, and subjective patient and carer ratings. Therapy was assessed by recording delivery, achievement of set targets, patient and carer preference, and cost. RESULTS: On the Rivermead mobility index (scale 0-15) (primary outcome) there was a highly significant (p<0.001) treatment effect of 1.4-1.5 units favouring hospital or home based therapy over no therapy: this was supported by other measures of mobility, gait, balance, and the assessor's global "mobility change" score: there was no major difference between home and hospital. Carers preferred home treatment but neither they nor patients discerned greater benefit there. Estimated costs of home physiotherapy were 25 pounds/session and those at hospital were 18 pounds (including 7 pounds patient travel costs). CONCLUSION: A course of physiotherapy is associated with improved mobility, subjective wellbeing, and improved mood in chronic multiple sclerosis compared with no treatment but benefit may only last a few weeks: there is little to choose between home and hospital based therapy but the first is more costly, mainly due to skilled staff travelling time.