Pain and cognitive performance in adults with multiple sclerosis: A systematic review.

INTRODUCTION: Pain and cognitive dysfunction are separately known to be important manifestations of multiple sclerosis (MS). Although pain is a complex subjective phenomenon with affective and cognitive aspects, it is not known if people with MS reporting pain are at greater risk of reduced performance in objective tests of cognition. The presence or direction of any association remains to be clarified, as do the roles of confounders such as fatigue, medication and mood. METHODS: We conducted a systematic review of studies examining the relationship between pain and objectively measured cognition in adults with confirmed MS, according to a pre-registered protocol (PROSPERO 42,020,171,469). We carried out searches in MEDLINE, Embase and PsychInfo. Studies of adults with any subtype of MS, with chronic pain and in which cognitive evaluation was conducted by validated instruments were included. We evaluated the role of potential confounders (medication, depression, anxiety, fatigue and sleep) and described findings by eight pre-specified cognitive domains. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: 11 studies (n = 3714 participants, range 16 to 1890 per study) were included in the review. Four studies included longitudinal data. Nine studies identified a relationship between pain and objectively measured cognitive performance. In seven of these studies, higher pain scores were associated with poorer cognitive performance. However, no evidence was available for some cognitive domains. Heterogeneous study methodology precluded meta-analysis. Studies infrequently controlled for the specified confounders. Most studies were judged to be at risk of bias. DISCUSSION: Several studies, but not all, identified a negative relationship between pain severity and objectively measured cognitive performance. Our ability to further characterise this relationship is limited by study design and lack of evidence in many cognitive domains. Future studies should better establish this relationship and delineate the neurological substrate underpinning it.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Demographics of Cauda Equina Syndrome: A Population-Based Incidence Study.

INTRODUCTION: Cauda equina syndrome (CES) has significant medical, social, and legal consequences. Understanding the number of people presenting with CES and their demographic features is essential for planning healthcare services to ensure timely and appropriate management. We aimed to establish the incidence of CES in a single country and stratify incidence by age, gender, and socioeconomic status. As no consensus clinical definition of CES exists, we compared incidence using different diagnostic criteria. METHODS: All patients presenting with radiological compression of the cauda equina due to degenerative disc disease and clinical CES requiring emergency surgical decompression during a 1-year period were identified at all centres performing emergency spinal surgery across Scotland. Initial patient identification occurred during the emergency hospital admission, and case ascertainment was checked using ICD-10 diagnostic coding. Clinical information was reviewed, and incidence rates for all demographic and clinical groups were calculated. RESULTS: We identified 149 patients with CES in 1 year from a total population of 5.4 million, giving a crude incidence of 2.7 (95% CI: 2.3-3.2) per 100,000 per year. CES occurred more commonly in females and in the 30-49 years age range, with an incidence per year of 7.2 (95% CI: 4.7-10.6) per 100,000 females age 30-39. There was no association between CES and socioeconomic status. CES requiring catheterization had an incidence of 1.1 (95% CI: 0.8-1.5) per 100,000 adults per year. The use of ICD-10 codes alone to identify cases gave much higher incidence rates, but was inaccurate, with 55% (117/211) of patients with a new ICD-10 code for CES found not to have CES on clinical notes review. CONCLUSION: CES occurred more commonly in females and in those between 30 and 49 years and had no association with socioeconomic status. The incidence of CES in Scotland is at least four times higher than previous European estimates of 0.3-0.6 per 100,000 population per year. Incidence varies with clinical diagnostic criteria. To enable comparison of rates of CES across populations, we recommend using standardized clinical and radiological criteria and standardization for population structure.

The influence of disease-modifying therapy on hidden disability burden in people with newly diagnosed relapsing-remitting multiple sclerosis.

BACKGROUND: In addition to motor disability, "hidden disability" such as depression, anxiety, fatigue, sleep disturbance, cognitive impairment and pain is a major complaint of people with multiple sclerosis. We explored changes in hidden disability burden in the early post-diagnostic period and examined the hypothesis that disease modifying therapies have a beneficial effect on hidden disability burden. METHODS: Adults with recently diagnosed (< 6 months) relapsing-remitting multiple sclerosis (n = 440, mean age 37.4 ± 10.4, 76% female), from a national multicentre cohort study (FutureMS) underwent testing with clinical and neuropsychological instruments as well as brain MRI at baseline and after 12-months. Disease modifying therapies were only started after baseline assessment and were classified into injectables (n = 70, interferons, glatiramer acetate), other DMTs (n = 215) and no DMT (n = 117, reference). Sensitivity analyses were undertaken using alternative classifications (disease modifying therapy vs none, and a 3-category system). We performed latent transition analysis with hidden disability burden as the latent variable including propensity score weights. RESULTS: We identified three classes with low (58%), moderate (25%) and high (17%) hidden disability burden. 70% did not transition ("unchanged", reference), 26% transitioned into a lower burden class ("improvement") and 4% transitioned into a higher burden class ("worsening"). Median treatment duration was 11 months (IQR 9-12). Injectables [OR 1.3 (95%CIs 0.7, 2.3); P = 0.4] and other DMTs [OR 1.4 (95%CIs 0.9, 2.1); P = 0.2] were not associated with significant change in hidden disability burden in either direction ("improvement" or "worsening"). In the alternative 3-category classification, category 2 treatment (fingolimod, cladribine, n = 22) was associated with improvement [OR 4.3 (2.6, 7.0); P < 0.001]. CONCLUSION: Hidden disability was present in most newly diagnosed people with multiple sclerosis. The majority remained unchanged and approximately a quarter improved over the immediate post-diagnostic period. Disease modifying therapy had no significant influence on hidden disability burden in the study period of one year following diagnosis. The trend towards favourable outcomes with fingolimod and cladribine should be interpreted with caution due to the small sample size. Our exploratory data are observational, with scope for attendant biases, but highlight the need for further study including longer-term evaluation as well as randomised trials for non-motor disability.

Prevalence of multimorbidity and its impact on survival in people with motor neuron disease.

BACKGROUND AND PURPOSE: This study was undertaken to determine the prevalence of multimorbidity in people with motor neuron disease (MND) and to identify whether specific patterns of multimorbidity impact survival beyond age alone. METHODS: We performed a retrospective analysis of the Scottish national MND register from 1 January 2015 to 29 October 2019. People with amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy were included. We fitted latent class regression models incorporating comorbidities (class indicators), age, sex, and bulbar onset (covariates), and survival (distal outcome) with multimorbidity as a hypothesised latent variable. We also investigated the association between the Charlson Comorbidity Index and survival in Cox regression and compared its discrimination and calibration to age alone. RESULTS: A total of 937 people with MND were identified (median age = 67 years, 60.2% male); 64.8% (n = 515) had two or more comorbidities. We identified a subpopulation with high prevalence of cardiovascular disease, but when accounting for the relationship between age and individual comorbidities, there was no difference in survival. Both Charlson Comorbidity Index (hazard ratio [HR] per unit increase = 1.11, 95% confidence interval [CI] = 1.07-1.15, p < 0.0001) and age (HR per year increase = 1.04, 95% CI = 1.03-1.05, p < 0.0001) were significantly associated with survival, but discrimination was higher for age compared to Charlson Comorbidity Index (C-index = 0.63 vs. 0.59). CONCLUSIONS: Multimorbidity is common in MND, necessitating holistic interdisciplinary management, but age is the dominant predictor of prognosis in people with MND. Excluding people with MND and multimorbidity from trial participation may do little to homogenise the cohort in terms of survival potential and could harm generalisability.

Prospective observational cohort study of factors influencing trial participation in people with motor neuron disease (FIT-participation-MND): a protocol.

INTRODUCTION: Motor neuron disease (MND) is a rapidly progressive and fatal neurodegenerative disorder with limited treatment options. The Motor Neuron Disease Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) is a multisite UK trial seeking to address the paucity in effective disease-modifying drugs for people with MND (pwMND). Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. Failure to recruit and/or retain participants can cause insufficiently representative samples, terminated trials or invalid conclusions. This study investigates patient-specific factors affecting recruitment and retention of pwMND to MND-SMART. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention. METHODS AND ANALYSIS: PwMND on the Scottish MND Register, Clinical Audit Research and Evaluation of MND (CARE-MND), will be invited to participate in a prospective observational cohort study that investigates factors affecting trial participation and attrition. We hypothesise that patient-specific factors will significantly affect trial recruitment and retention. Participants will complete the Hospital Anxiety and Depression Scale, 9-Item Patient Health Questionnaire and State-Trait Anxiety Inventory-Form Y to evaluate neuropsychiatric symptoms, the ALS-Specific Quality of Life Questionnaire-Brief Form and Centre for Disease Control and Prevention-Health-Related Quality of Life for quality of life and a novel study-specific questionnaire on Attitudes towards Clinical Trial Participation (ACT-Q). Clinical data on phenotype, cognition (Edinburgh Cognitive and Behavioural ALS Screen) and physical functioning (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) will also be collated. Caregivers will complete the Brief Dimensional Apathy Scale. After 12 months, a data request to MND-SMART will evaluate recruitment and retention. Descriptive statistics will summarise and compare assessments and participants reaching impairment thresholds. Variable groupings: attitudes, quality of life, cognition, behaviour, physical functioning, neuropsychiatric and phenotype. Univariate and multivariable logistic regression will explore association with participation/withdrawal in MND-SMART; presented as ORs and 95% CIs. ETHICS AND DISSEMINATION: Ethical approval was provided by the West of Scotland Research Ethics Committee 3 (20/WS/0067) on 12 May 2020. The results of this study will be published in a peer-reviewed journal, presented at academic conferences and disseminated to participants and the public.

Systematic review of prediction models in relapsing remitting multiple sclerosis.

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice.

The Prevalence and Management of Saliva Problems in Motor Neuron Disease: A 4-Year Analysis of the Scottish Motor Neuron Disease Register.

INTRODUCTION: Saliva problems are common and distressing for people with motor neuron disease (pwMND). Despite clinical guidelines for assessment and treatment, management of saliva problems has received little research attention. OBJECTIVE: We aimed to investigate the prevalence of saliva problems in pwMND, their association with clinical factors, and their management practice using a highly curated population-based register for motor neuron disease (MND) with 99% case ascertainment. METHODS: We conducted an analysis of pwMND diagnosed between January 2015 and October 2019 using the Scottish MND Register (CARE-MND [Clinical, Audit, Research, and Evaluation of MND]). The association between clinical factors and saliva problems was investigated using univariate and multivariable logistic regression; results are reported as odds ratio (OR) and 95% confidence intervals. A survey of health-care professionals involved in the care of pwMND was performed to contextualize the findings. RESULTS: 939 pwMND were included. Prevalence of saliva problems was 31.3% (294). Bulbar onset (OR 9.46 [4.7, 19.2]; p < 0.001) but not age, sex, time to diagnosis, or MND subtype were independently associated with the presence of saliva problems in multivariable regression, and 52.7% (155) of those with saliva problems received pharmacological management. The most commonly used medications were hyoscine, amitriptyline, carbocisteine, glycopyrrolate, and atropine. Evidence base (8, 72.7%) and local guidelines (10, 90.9%) were cited as the most important factors influencing treatment decision by survey respondents (n = 11). CONCLUSION: Saliva problems are common and associated with bulbar onset MND. A substantial proportion of pwMND with saliva problems did not receive recommended treatments. Future research is required to determine the relative efficacy of individual pharmacological treatments.

Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis.

Importance: The c9orf72 repeat expansion (c9 or c9orf72RE) confers a survival disadvantage in amyotrophic lateral sclerosis (ALS); its effect on prognosis in frontotemporal dementia (FTD) remains uncertain. Data on prognostic factors in c9orf72RE disorders could inform patient care, genetic counseling, and trial design. Objective: To examine prognostic factors in c9ALS, c9FTD, c9ALS-FTD, and atypical phenotypes. Data Sources: The MEDLINE, Embase, Amed, ProQuest, PsychINFO, CINAHL, and LILACS databases were searched between January 2011 and January 2019. Keywords used were c9orf72 and chromosome 9 open reading frame 72. Reference lists, citations of eligible studies, and review articles were also searched by hand. Study Selection: Studies reporting disease duration for patients with a confirmed c9orf72RE and a neurological and/or psychiatric disorder were included. A second author independently reviewed studies classified as irrelevant by the first author. Analysis began in January 2019. Data Extraction and Synthesis: Data were extracted by 1 author; a further author independently extracted 10% of data. Data were synthesized in univariate and multivariable Cox regression and are displayed as hazard ratios (HR) and 95% confidence intervals. Main Outcomes and Measures: Survival after symptom onset. Results: Overall, 206 studies reporting on 1060 patients were included from 2878 publications identified (c9ALS: n = 455; c9FTD: n = 296; c9ALS-FTD: n = 198; atypical phenotypes: n = 111); 197 duplicate cases were excluded. The median (95% CI) survival (in years) differed significantly between patients with c9ALS (2.8 [2.67-3.00]), c9FTD (9.0 [8.09-9.91]), and c9ALS-FTD (3.0 [2.73-3.27]); survival in atypical phenotypes varied substantially. Older age at onset was associated with shorter survival in c9ALS (HR, 1.03; 95% CI, 1.02-1.04; P < .001), c9FTD (HR, 1.04; 95% CI, 1.02-1.06; P < .001), and c9ALS-FTD (HR, 1.02; 95% CI, 1.004-1.04; P = .016). Bulbar onset was associated with shorter survival in c9ALS (HR, 1.64; 95% CI, 1.27-2.08; P < .001). Age at onset and bulbar onset ALS remained significant in multivariable regression including variables indicating potential diagnostic ascertainment bias, selection bias, and reporting bias. Family history, sex, study continent, FTD subtype, or the presence of additional pathogenic sequence variants were not significantly associated with survival. Clinical phenotypes in patients with neuropathologically confirmed frontotemporal lobar degeneration-TDP-43, motor neuron disease-TDP-43 and frontotemporal lobar degeneration-motor neuron disease-TDP-43 were heterogenous and impacted on survival. Conclusions and Relevance: Several factors associated with survival in c9orf72RE disorders were identified. The inherent limitations of our methodological approach must be considered; nonetheless, the reported prognostic factors were not significantly associated with the bias indicators examined.