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 They support a trend of increasing time to disability milestones compared with historical reference populations, and document disability variation with the use of transitional matrices.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

Serum neurofilament-light concentration and real-world outcome in MS.

BACKGROUND: Prognostication in multiple sclerosis (MS) remains challenging. Biomarkers capable of providing this information at diagnosis would be valuable in shaping therapeutic decisions. Measurement of neurofilament light (NfL) has shown promise in predicting clinical outcomes in established MS, but its ability to predict outcomes in real-world cohorts at diagnosis requires further validation. METHODS: We used linear regression to evaluate the relationship between serum NfL (sNfL), measured at the time of diagnosis with short-term (1-year) and medium-term (5-year) clinical outcomes in 164 people with MS from a real-world, population-based cohort. Cox proportional hazards regression was used to analyse the association between sNfL and subsequent hazard of relapse or sustained accumulation of disability (SAD). Analyses were adjusted for age and disease-modifying treatment (DMT). RESULTS: sNfL concentration at diagnosis was modestly associated with baseline EDSS score (ß = 0.272, 95% CI 0.051 to 0.494, p = 0.016). However, no significant associations were found between baseline sNfL and odds of relapse at 12-months, 5-year EDSS change, or the hazard of relapse or SAD over 5 years follow-up. Dichotomising baseline sNfL according to the median sNfL did not change these findings. CONCLUSIONS: sNfL appears to be of limited clinical utility in predicting future irreversible neurological disability in a largely untreated real-world population, and remains insufficiently validated to shape treatment decisions at the time of diagnosis. Further studies may be needed for sNfL to be considered as a prognostic marker in the MS clinic. However the masking effect of DMTs on the natural disease trajectory will continue to pose challenges.

Eligibility and implementation of disease-modifying therapy for primary progressive multiple sclerosis in a UK cohort.

BACKGROUND: As disease-modifying therapies become approved for primary progressive multiple sclerosis (PPMS), services must be aligned in readiness. METHODS: In this paper we use population and clinic-based data to estimate eligibility rates for ocrelizumab, and the extent of additional service requirements necessary to ensure its widespread introduction in PPMS. RESULTS: Overall population estimates for the incidence and prevalence of people with PPMS who are eligible for ocrelizumab are 1.6 and 4.2 per 100,000 respectively. The majority (87%) of incident cases of PPMS satisfied clinical eligibility criteria for ocrelizumab but lacked radiological evidence of disease activity due to a historical tendency not to routinely monitor using MRI in this group. The majority of prevalent patients did not satisfy clinical eligibility criteria for ocrelizumab, mainly because of advanced disease duration or disability. CONCLUSIONS: These findings illustrate the fact that there has been a tendency for people with PPMS not to receive routine clinical and radiological monitoring. Additional planning or resources will be required to facilitate contemporary disease re-evaluation and surveillance at a population level.

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.

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.

Sarcoidosis following alemtuzumab treatment for multiple sclerosis.

Despite proven efficacy of alemtuzumab in multiple sclerosis (MS), approximately 50% of individuals will develop a new autoimmune disease following treatment. To date, these have largely been antibody mediated and organ specific (primarily affecting the thyroid gland). In a retrospective case series of 187 patients from two UK specialist centres (Cardiff and Cambridge) followed up for a median of 10 years, we report three (1.6%) cases of sarcoidosis following alemtuzumab treatment of MS. This report increases the spectrum of auto-inflammatory disease following alemtuzumab and should be considered by clinicians when using this therapeutic agent for MS.

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.

Neurolupus.

Systemic lupus erythematosus (SLE) is not an uncommon condition. Most neurologists are well aware that it can cause a wide range of neurological complications, and SLE almost invariably appears on 'differential diagnosis' lists in cases of clinical uncertainty. However, the precise nature of the manifestations of SLE in the central and peripheral nervous systems is perhaps less widely understood, and misperceptions about phenomenology and treatment are common. Here we survey some of the main primary neurological complications of SLE--'neurolupus'--while acknowledging that secondary problems, either iatrogenic or relating to other consequences of SLE (eg, hypertensive CNS disease, for example, secondary to renal lupus) are neither less serious nor less treatable.

CNS lupus: a study of 41 patients.

BACKGROUND: CNS lupus is a serious but potentially treatable illness, which, though long recognized, may still present very difficult diagnostic challenges. We believed that further detailed study of patients with neuropsychiatric lupus would yield clinical information of practical value in improving both recognition and management of this difficult illness. METHODS: A retrospective case analysis of 41 patients with CNS systemic lupus erythematosus (CNS-SLE) was performed largely in the southwest of England and South Wales, covering the period 1990 to 2002. RESULTS: We found that primary neurologic presentation of SLE was not rare (10/41 patients), and there was an unexpected emergence of movement disorders (particularly parkinsonism and myoclonus) early in the disease course (4/10 patients). These showed a good response to immunosuppressants, but not to standard dopaminergic therapy. Typically, the erythrocyte sedimentation rate (ESR) or plasma viscosity was elevated during neurologic episodes while C-reactive protein levels were normal, and lupus-related serum antibody tests usually supportive. But, significantly, neither a normal ESR nor negative serology excluded CNS lupus. MR brain imaging is more commonly abnormal in patients with focal neurologic deficits and normal or shows wholly nonspecific change with more diffuse manifestations (cognitive decline, epilepsy). Abnormal CSF correlated significantly with poorer outcome. At the end of the period of study, 54% had no more than minor functional disability, the remainder having a severe or fatal outcome. CONCLUSIONS: Our observations, particularly the emergence of non-choreic movement disorders, the blood, serum, and imaging findings, and the prognostic importance of CSF abnormalities, should help improve both the recognition of CNS systemic lupus erythematosus, perhaps particularly in elderly individuals, and its management.

Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy.

Idiopathic or primary angiitis of the CNS (PACNS) and cerebral amyloid angiopathy (CAA) are unusual vasculopathies generally regarded as unrelated disorders. A few case reports have, however, described granulomatous angiitis in patients with sporadic, amyloid beta peptide (Abeta)-related CAA. Here we describe the clinical, neuroradiological and neuropathological features of nine patients with Abeta-related angiitis (ABRA). Combining these with the individual case reports drawn from the literature has allowed us to define ABRA as a clinical entity and to compare its features with those of PACNS. The mean age of presentation of ABRA (67 years) is higher than that of PACNS but lower than that of sporadic non-inflammatory Abeta-related CAA. Alterations in mental status (59%), headaches (35%), seizures and focal neurological deficits (24%) are common. Hallucinations are a presenting manifestation in 12% of cases. Most patients have white matter hyperintensities on MRI but these are of similar appearance to those in PACNS. Cerebrospinal fluid usually shows modest elevation of protein and pleocytosis. Neuropathology reveals angiodestructive inflammation, often granulomatous, and meningeal lymphocytosis. Abeta is consistently present in abundance in affected blood vessels but usually scanty within the parenchyma of the cerebral cortex. However, the cortex includes numerous activated microglia, occasionally in a plaque-like distribution and containing cytoplasmic Abeta. The cerebral white matter shows patchy gliosis and rarefaction, in some cases marked. Our findings (i) help to dissect one separate clinicopathological entity from what is likely to be a spectrum of primary angiitides of the CNS; (ii) have important therapeutic implications for one category of patients with amyloid-related vasculopathy; and (iii) may provide valuable insights into the development of amyloid-associated inflammation, of relevance not only to ABRA but also to Abeta-immunization-related encephalitis and to Alzheimer's disease.