Shuna Colville

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.

Abstract.Aims:To describe the frequency, timing and outcome from gastrostomy in amyotrophic lateral sclerosis/motor neurone disease (ALS/MND).Methods: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.Results: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.Conclusions: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.

Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis

Article abstract We analyzed genomic DNA from ALS patients for mutations in the apurinic/apyrimidinic endonuclease (APEX nuclease) gene. We identified three rare polymorphisms in the untranslated region of the gene and one common two-allele polymorphism (D148E). The allelic frequency D148E was significantly different in sporadic ALS patients compared with controls. A conserved amino acid change and a 4-base pair deletion were also identified in sporadic ALS patients. These data suggest that APEX nuclease may contribute to the etiology of ALS.

The incidence of motor nueron disease in Scotland

AbstractBetween 1989 and 1998, 1226 cases of ALS/MND were identified in Scotland, with mean age of onset 65.2 (SD 11.9) years for men and 67.2 (SD 11.0) for women. Annual standardized incidence was 2.40 per 100,000 (95% CI 2.22-2.58). Using capture recapture methods we confirm a high level of case ascertainment for each year of study. Incidence and ascertainment of ALS has remained stable in a large population over a prolonged period of time. Large population-based databases can be used to test aetiological hypotheses.

Unexpected decline in survival from amyotrophic lateral sclerosis/motor neurone disease

Objectives: To describe survival of 1226 Scottish adults with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND). Methods: Ten year, prospective, population based disease register. Cox time dependent proportional hazards modelling for multivariate survival analyses. Results: Median survival from onset was 25 months (interquartile range 16–34 months). In multivariate models we found an increased hazard with more recently diagnosed cases—that is, there was an unexpected decline in survival over the 10 year period (hazard ratio (HR) 1.06 (95% CI 1.04 to 1.09). Positive effects on survival were demonstrated for longer time from onset to diagnosis (HR 0.38 (95% CI 0.33 to 0.42), assessment by a neurological specialist (HR 0.56 (95% CI 0.40 to 0.77), and treatment with riluzole (HR 0.24 (95% CI 0.14 to 0.42). Poor prognosis was associated with bulbar onset (HR 1.25 (95% CI 1.09 to 1.46) and a mixed lower and upper motor neurone syndrome (HR 1.23 (95% CI 1.01–1.49) and increasing age. Conclusions: We found an unexpected decline in survival over the 10 year period, despite controlling for potential confounding variables. We would be cautious about overinterpreting these observations and suggest that further research is required to confirm or refute these findings.

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 cause of death by autopsy and assess grading criteria in a cohort of cases of ALS from the Scottish MND Register. Methods: The records of 44 patients undergoing autopsy were reviewed to determine the cause of death, clinical assessment (El Escorial and modified World Federation of Neurology criteria) during life and neuropathological autopsy findings. Results: In a cohort of 44 cases undergoing autopsy between 1989 and 1998, the cause of death could be directly or indirectly (bronchopneumonia, aspiration/pneumonia and respiratory failure) attributed to MND in 32/44 (73%) cases. The clinical diagnosis of MND was confirmed at autopsy in 44/44 (100%) cases, 3/44 (7%) cases showed coexistent neurodegenerative disease and 5/44 (11%) were familial MND cases. Conclusions: Within our cohort, MND contributes to death in the majority of cases and there is excellent clinicopathological correlation, irrespective of the clinical grading criteria used. However, the autopsy rate is low (4%) and further larger studies are required to identify heterogeneity within the disease.

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

INTRODUCTION: For accurate diagnosis, inter-observer agreement of criteria is important. METHODS: 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. RESULTS: 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)). CONCLUSIONS: 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.

Corrigendum to “Genetic epidemiology of motor neuron disease-associated variants in the Scottish population.” [Neurobiol. Aging 51 (2017) 178.e11–178.e20]

“The authors thank the patients for consenting to research. In addition, they acknowledge Alona Sosinsky and the Imperial College BRC Genomics facility for bioinformatics support. They acknowledge Generation Scotland for providing control samples and thank Shona Kerr and Archie Campbell for assistance in provision of Generation Scotland samples. The authors acknowledge Cat Graham for providing statistical guidance and also thank David Parry and Sophie Marion de Proce for providing helpful comments on the manuscript.

A population based study of respiratory function in motor neuron disease patients living in Tayside and North East Fife, Scotland

Respiratory failure is a major cause of morbidity and the principal cause of death in motor neuron disease; non-invasive ventilation is increasingly used worldwide to palliate the respiratory symptoms. This observational study was designed to evaluate the prevalence of respiratory insufficiency within the motor neuron disease population of Tayside and North East Fife, Scotland. Twenty-six patients were identified, their diagnosis confirmed according to agreed criteria and subjected to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, the Epworth Sleepiness questionnaire; spirometry, sniff nasal inspiratory pressure and nocturnal pulse oximetry measurements.Twenty-two (84.6%) patients reported one or more symptoms of respiratory insufficiency, 19 patients (73%) had forced vital capacity <80% of predicted in the sitting position and 10 (38.5%) had oxygen saturation <90% for >5% of night. On this basis a potential 10 patients required consideration for ventilation. As well as probable improvement in quality of life and survival for those patients this potential increase in workload has major educational, management and resource implications for health care providers.

ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS

Objective To elucidate the relationship between disease stage in amyotrophic lateral sclerosis (ALS), as measured with the Kings Clinical Staging System, and cognitive and behavioral change, measured with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Methods A large multicenter observational cohort of 161 cross-sectional patients with ALS and 80 healthy matched controls were recruited across 3 research sites (Dublin, Edinburgh, and London). Participants were administered the ECAS and categorized into independent groups based on their Kings clinical disease stage at time of testing. Results Significant differences were observed between patients and controls on all subtests of the ECAS except for visuospatial functioning. A significant cross-sectional effect was observed across disease stages for ALS-specific functions (executive, language, letter fluency) and ECAS total score but not for ALS-nonspecific functions (memory, visuospatial). Rates of ALS-specific impairment and behavioral change were also related to disease stage. The relationship between cognitive function and disease stage may be due to letter fluency impairment, whereas higher rates of all behavioral domains were seen in later Kings stage. The presence of bulbar signs, but not site of onset, was significantly related to ALS-specific, ECAS total, and behavioral scores. Conclusion ALS-specific cognitive deficits and behavioral impairment are more frequent with more severe disease stage. By end-stage disease, only a small percentage of patients are free of neuropsychological impairment. The presence of bulbar symptoms exaggerates the differences observed between disease stages. These findings suggest that cognitive and behavioral change should be incorporated into ALS diagnostic criteria and should be included in future staging systems.

PREDICTING CLINICAL DIAGNOSIS FROM PATTERNS OF IMPAIRED PERFORMANCE ON COMPUTERISED COGNITIVE TESTING IN A MIXED NEUROLOGICAL SAMPLE

computerized tests and traditional neuropsychological tests to predict amyloid status will be presented along with cognitive results for additional participants. Conclusions:Our findings demonstrate the validity of the ReVeRe cognitive test battery, including the first successful automation and validation in clinic and at home of a test of verbal memory using speech recognition software. Such tests will enable widespread testing in home, primary care, and clinical trial settings and improve identification of patients in the earliest stages of AD.