Scottish Motor Neuron Disease Register Research Articles

Non-motor symptoms in motor neuron disease: prevalence, assessment and impact.

People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration and that may significantly reduce quality of life, despite being under-recognized and evaluated in clinical practice. Non-motor symptoms explored in this population-based study include pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical Audit Research and Evaluation of motor neuron disease platform, the Scottish Motor Neuron Disease Register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. A total of 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311); 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants, respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as 'severe' by 54% of participants who experienced them), followed by pain and problematic saliva (51%, respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease and being a long survivor [diagnosed over 8 years ago; Black et al. (Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017;51:178.e11-178.e20.)], were significantly associated with reporting more symptoms; 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care; 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.

Genotype–phenotype characterisation of long survivors with motor neuron disease in Scotland

BackgroundWe investigated the phenotypes and genotypes of a cohort of ‘long-surviving’ individuals with motor neuron disease (MND) to identify potential targets for prognostication.MethodsPatients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls.Results58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions.ConclusionsLong survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.

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.

Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland

Objectives: Launched in 1989, the Scottish Motor Neuron Disease Register (SMNDR) has provided a resource for prospective clinical data collection. However, in 2015 we aimed to evolve a system to allow: i) A patient-centered approach to care based on recognized standards, ii) Harmonized data sharing between Scottish health professionals in “real-time”, iii) Regular audit of care to facilitate timely improvements in service delivery, and iv) Patient participation in a diverse range of observational and interventional research studies including clinical trials. Methods: We developed a standardized national electronic data platform—Clinical Audit Research and Evaluation of MND (CARE-MND) which integrates clinical audit and research data fields. Data completion pre- and post-CARE-MND were compared, guided by recently published National Institute for Clinical Excellence (NICE) recommendations. Statistical difference in data capture between time periods was assessed using Z-test of proportions. Results: Data field completion for the historical 2011–2014 period ranged from 4 to 95%; median 50%. CARE-MND capture ranged from 32 to 98%; median 87%. 15/17 fields were significantly more complete post-CARE-MND (p < 0.001). All MND nurse/allied health specialists in Scotland use the CARE-MND platform. Management of MND in Scotland is now coordinated through a standardized template. Conclusions: Through CARE-MND, national audits of MND care and interventions have been possible, leading to protocols for harmonized service provision. Stratification of the MND population is facilitating participation in observational and interventional studies. CARE-MND can act as a template for other neurological disorders.

Changing epidemiology of motor neurone disease in Scotland.

Scotland benefits from an integrated national healthcare team for motor neurone disease (MND) and a tradition of rich clinical data capture using the Scottish MND Register (launched in 1989; one of the first national registers). The Scottish register was re-launched in 2015 as Clinical Audit Research and Evaluation of MND (CARE-MND), an electronic platform for prospective, population-based research. We aimed to determine if incidence of MND is changing over time. Capture-recapture methods determined the incidence of MND in 2015-2016. Incidence rates for 2015-2016 and 1989-1998 were direct age and sex standardised to allow time-period comparison. Phenotypic characteristics and socioeconomic status of the cohort are described. Coverage of the CARE-MND platform was 99%. Crude incidence in the 2015-2017 period was 3.83/100,000 person-years (95% CI 3.53-4.14). Direct age-standardised incidence in 2015 was 3.42/100,000 (95% CI 2.99-3.91); in 2016, it was 2.89/100,000 (95% CI 2.50-3.34). The 1989-1998 direct standardised annual incidence estimate was 2.32/100,000 (95% CI 2.26-2.37). 2015-2016 standardised incidence was 66.9% higher than Northern European estimates. Socioeconomic status was not associated with MND. Our data show a changing landscape of MND in Scotland, with a rise in incidence by 36.0% over a 25-year period. This is likely attributable to ascertainment in the context of improved neurological services in Scotland. Our data suggest that CARE-MND is a reliable national resource and findings can be extrapolated to the other Northern European populations.

11 Premorbid neuropsychiatric disease in patients with motor neurone disease in scotland

<h3>Objective</h3> Motor neurone disease (MND) is a rapidly progressive neurodegenerative disease, typically affecting limb, bulbar and respiratory muscles. Cognitive and behavioural change are also key features of the disease in up to 50% of patients (1). Neuropsychiatric symptoms may precede motor symptoms. A recent study highlighted that depression may be an independent risk factor for MND (2). We aimed to review the frequency of i) premorbid neuropsychiatric disease ii) premorbid psychotropic medication use iii) neuropsychiatric presentation of MND and iv) neuropsychiatric evolution of MND in an incident Scottish cohort. <h3>Method</h3> Patients were recruited via the Scottish MND Register (SMNDR). Patient characteristics (past medical and drug history, symptom onset and progression) were collected via the Scottish Clinical Audit Research and Evaluation for MND (CARE-MND) national care proforma. <h3>Results</h3> Incident cases of MND diagnosed in 2015/16 from a population-based national cohort will be presented. At interim analysis, 267 patients were eligible for review. 38 (14%) of patients had a documented past history of neuropsychiatric disease; 29 (11%) of mood disorder. 66 (25%) of patients had a history of psychotropic medication use. Frequency of premorbid neuropsychiatric disease will be compared with recent UK survey results (3). In 11 (4%) of patients, emotional lability, memory change or behavioural change was the presenting symptom. 32 (12%) of patients developed these features later in disease course. <h3>Conclusion</h3> From our preliminary analysis, rates of premorbid neuropsychiatric disease in patients with MND are comparable with population estimates. However, symptoms of low mood have been shown to have a negative impact on quality of life and are associated with faster disease progression (4). Clinical teams need to be mindful of these symptoms in all aspects of patient care, and ensure that appropriate therapies are offered and monitored.

Multidimensional apathy in ALS: validation of the Dimensional Apathy Scale

AimApathy is a prominent symptom of amyotrophic lateral sclerosis (ALS), but measurement is confounded by physical disability. Furthermore, it has been traditionally measured as a unidimensional symptom despite research demonstrating...

Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neurone Disease Register

Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neurone Disease Register

Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neurone Disease Register

Background: The Scottish Motor Neurone Disease Register is a population based register of amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) in Scotland, with high case ascertainment levels. Objective: To investigate the...

Charles Warlow: a career of “successive flukes”

Charles Warlow: a career of “successive flukes”

Frequency, timing and outcome of gastrostomy tubes for amyotrophic lateral sclerosis/motor neurone disease--a record linkage study from the Scottish Motor Neurone Disease Register.

To describe the frequency, timing and outcome from gastrostomy in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). The Scottish MND Register, a population based disease register (1989-1998), with record linkage to the Scottish Morbidity 1 dataset of hospital discharges coded for gastrostomy procedure was used. Descriptive statistics of patients undergoing gastrostomy were extracted. Survival analysis used Kaplan Meier and Cox proportional hazards methods. For patients diagnosed between 1989-98, 142 percutaneous endoscopic gastrostomy (PEG) insertion episodes were identified in 1226 patients, 130 of which occurred before the censoring date of 31 December 1999.Annually, on average, 5% of all revalent patients underwent gastrostomy, and this rate appeared to double between 1989-98. The cumulative incidence of gastrostomy was 11%. Mean age at PEG tube insertion was 66.8 years, with a mean disease duration of 24 months. Median survival from PEG tube insertion was 146 days. The 1 month mortality after gastrostomy was 25%. Gastrostomy did not confer a survival advantage compared with no gastrostomy. We found that gastrostomy feeding tubes are being inserted more frequently in people with ALS/MND. An unexpectedly high early mortality was detected which probably reflects a lack of selection bias compared with previously published data. It is possible that changes in the practice of gastrostomy placement since 1998 result in better outcomes for patients with ALS/MND. Prospective studies are required to assess the risks and benefits of enteral nutrition in ALS/MND.

Are the El Escorial and Revised El Escorial criteria for ALS reproducible? A study of inter-observer agreement.

For accurate diagnosis, inter-observer agreement of criteria is important. Using case records, the reproducibility of the original and revised El Escorial diagnostic criteria for amyotrophic lateral sclerosis were tested in a consecutive series of people referred to the Scottish Motor Neuron Disease Register. Agreement between independent observers was similar (weighted kappa: 0.783, 95% CI 0.656 to 0.911 (original criteria), 0.681, 95% CI 0.485 to 0.878 (revised)). Serious errors are unlikely, but the revised criteria may be less reproducible as they include more diagnostic categories. Revisions of diagnostic criteria should be tested for reproducibility and validity prior to widespread adoption.

Avoiding false positive diagnoses of motor neuron disease: lessons from the Scottish Motor Neuron Disease Register.

To describe the frequency and characteristics of those patients initially registered with the Scottish Motor Neuron Disease Register (SMNDR) but who subsequently had a diagnosis other than MND made (false positives), to analyse the features which led to a revised diagnosis, and to draw conclusions which might improve routine neurological practice. The Scottish Motor Neuron Disease Register is a community based, prospective disease register to identify and follow up all incident cases of motor neuron disease in Scotland. Fifty three patients out of a total of 552 registered are presented, who, after initial registration, were later excluded because they failed to satisfy the register's diagnostic criteria. Seven of these patients were labelled as "MND plus" syndromes and may represent a distinct subset of MND. The remaining 46 patients had an alternative diagnosis made (false positive group), accounting for 8% of the total. In half of these cases, potentially beneficial therapies are available. The predominant reasons which lead to a diagnostic revision were: failure of symptom progression, development of atypical clinical features for MND, and investigation results. Patients with MND should undergo thorough and relevant investigations at presentation with the emphasis on neuroradiological imaging and neurophysiology; all patients should be followed up by an experienced neurologist, particularly those in whom symptoms and signs are restricted to either the bulbar or spinal muscles; failure of symptom progression or development of atypical features should lead to an early reassessment; finally, patients should be informed of the diagnosis only when it is secure.

Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register.

In order to identify risk factors for the subsequent development of motor neuron disease (MND) we have carried out a case-control study of incident patients in Scotland, identified using the Scottish Motor Neuron Disease Register. A standard questionnaire was given to 103 patients and the same number of community controls matched on a one to one basis using the general practitioner's (GP) age and sex register. Recall bias was minimised by using GP records to verify the subject's report. There was an overall lifetime excess of fractures in patients, odds ratio (OR) = 1.3 (95% confidence interval (CI), 0.7-2.5) and this was highest in the 5 years before symptom onset (OR = 15, 95% CI, 3.3-654). There was no association with non-fracture trauma but the OR for a manual occupation in patients was 2.6 (95% CI, 1.1-6.3). Both occupational exposure to lead (OR = 5.7, 95% CI, 1.6-30) and solvents/chemicals (OR = 3.3, 95% CI 1.3-10) were significantly more common in patients. No consistent association was found between MND and factors reflecting socioeconomic deprivation in childhood; childhood infections or social class. Our results identify a number of different factors which may contribute to the aetiology of MND.

Utility of Scottish morbidity and mortality data for epidemiological studies of motor neuron disease.

To determine the accuracy of (1) hospital discharge data and (2) death certificates, coded as motor neuron disease (MND). Comparison of data from The Scottish Motor Neuron Disease Register (SMNDR) with routinely collected Scottish Hospital In-Patient Statistics (SHIPS) and death certificate coding. Scotland UK. 1) 379 adults (> 15 years) discharged for the first time from a Scottish hospital in 1989-90 and (2) 281 deaths in the same period assigned to the International Classification of Diseases (ICD)-9, category 335 (MND). The sensitivity and positive predictive value of a diagnosis of MND as retrieved by (1) the Information and Statistics Division of the Common Services Agency for the Scottish Health Service for morbidity data and (2) the Registrar General's office for mortality data, using the SMNDR as the 'gold standard'. (1) Thirty per cent of adult patients identified as having MND by SHIPS did not have this disease and 23% of patients with MND did not appear on SHIPS. The sensitivity of a diagnosis of MND, as retrieved by SHIPS, was 84% and the positive predictive value was 70% overall. Miscoding of patients with pseudobulbar palsy caused by cerebrovascular disease was the major source of false positive error. The incidence of adult onset sporadic MND was over estimated by SHIPS by a factor of 1.6. (2) Mortality data were more accurate, with a false negative rate of 6% and a positive predictive value of 90%. Coded hospital discharge data are an inaccurate record of a diagnosis of MND and cannot, in their present form, be used as a reliable measure of disease incidence in Scotland. Greater care is required in the preparation of discharge summaries and coding if these data are to be useful for health care planning and epidemiological research. SHIPS is, however, an important source of information to achieve a complete sample of patients with MND. There is also a problematic false positive rate for mortality data but this source more closely approximates true incidence.

The prognosis of adult-onset motor neuron disease: a prospective study based on the Scottish Motor Neuron Disease Register.

The Scottish Motor Neuron Disease Register (SMNDR) is a prospective, collaborative, population-based project which has been collecting data on incident patients since 1989. In this report we present the clinical features of 229 patients with motor neuron disease (218 sporadic and 11 familial) diagnosed in 1989 and 1990 and compare their prognosis with previous studies of survival. The overall 50% survival from symptom onset was 2.5 years (95% CI, 2.2-3.0) and 5-year survival 28% (95% CI, 20-36%). The presence of progressive bulbar palsy (PBP), either at presentation or developing during the course of the illness, significantly reduced survival and was the most important prognostic indicator. Patients who survived longer than 5 years from symptom onset did not have PBP as part of their presenting illness. The prognosis was worse for women, and this was in part related to the higher frequency of PBP in older women, but age was also an independent adverse risk factor. Differences in survival between this and previous series can probably be explained on the basis of variation in case definition and ascertainment methods.

The Scottish Motor Neuron Disease Register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989.

The Scottish Motor Neuron Disease Register (SMNDR) is a prospective, collaborative, population based study of motor neuron disease (MND) in Scotland. The register started in January 1989 with the aim of studying the clinical and epidemiological features of MND by prospectively identifying incident patients. It is based on a system of registration by recruitment from multiple sources, followed by the collection of complete clinical data and follow up, mainly through general practitioners. In this report the register's methodology and the demography and incidence data for the first year of study are presented. One hundred and fourteen newly diagnosed patients were identified in 1989 giving a crude incidence for Scotland of 2.24/100,000/year. Standardised incidence ratios showed a non-significant trend towards lower rates in north eastern regions and island areas.