Robert Swingler

Incidence of amyotrophic lateral sclerosis in Europe

Background Geographical differences in the incidence of amyotrophic lateral sclerosis (ALS) have been reported in the literature but comparisons across previous studies are limited by different methods in case ascertainment and by the relatively small size of the studied populations. To address these issues, the authors undertook a pooled analysis of European population based ALS registries. Methods All new incident ALS cases in subjects aged 18 years old and older were identified prospectively in six population based registries in three European countries (Ireland, UK and Italy) in the 2 year period 1998–1999, with a reference population of almost 24 million. Results Based on 1028 identified incident cases, the crude annual incidence rate of ALS in the general European population was 2.16 per 100 000 person years; 95% CI 2.0 to 2.3), with similar incidence rates across all registries. The incidence was higher among men (3.0 per 100 000 person years; 95% CI 2.8 to 3.3) than among women (2.4 per 100 000 person years; 95% CI 2.2 to 2.6). Spinal onset ALS was more common among men compared with women, particularly in the 70–80 year age group. Disease occurrence decreased rapidly after 80 years of age. Conclusions ALS incidence is homogeneous across Europe. Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among men, and the age related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of ageing.

Prognostic factors in ALS: A critical review

We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 ;months, but 10–20% of ALS patients have a survival longer than 10 ;years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.

Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues

Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100 000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.

Urinary, faecal and sexual dysfunction in patients with multiple sclerosis

Abstract The prevalence and nature of bladder and bowel dysfunction were examined in a population-based study of 221 patients with multiple sclerosis who returned postal questionnaires. This preliminary investigation was supplemented by personal review which also provided information on sexual dysfunction in 174 and laboratory and urodynamic tests in 152 participants. Thirty of 221 (14%) currently used an indwelling catheter, and 84 of the remainding190 (44%) reported symptoms of urinary dysfunction, of which the most common were urgency and frequency. Thirteen of 144 (9%) patients had biochemical evidence of renal dysfunction, and 40 of 132 (30%) had infected urine samples. Eleven of 54 patients in whom investigation of upper urinary tract was thought to be appropriate demonstrated abnormalities. Sixty-four of 221 (29%) patients had experienced faecal incontinence, and 120 of 221 (54%) were constipated. Fifty-six of 68 (82%) men and 55 of 106 (52%) women reported a deterioration in sexual activity, the commonest symptoms being erectile failure in men and fatigue in women.

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% Cl, 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 BP 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.

Increasing prevalence and incidence of multiple sclerosis in South East Wales

Background and aim: Epidemiological studies of multiple sclerosis suggest a trend of increasing disease prevalence in susceptible populations. The reasons for this are unclear and may be the results of methodological differences between studies, incomplete ascertainment or advances in technologies that allow the increased identification of early or mild disease. In addition, direct comparison of cross sectional prevalence estimates performed in different epochs in ethnically and geographically distinct populations may be inappropriate. Methods: Using detailed phenotypic information and standardised methodology, a geographically defined Welsh population was resurveyed after a significant interval, establishing contemporary prevalence rates and examining demographic and clinical data to determine causes of changing disease frequency. Results: Disease prevalence increased 45% from 101 to 146 per 100 000 population over 20 years. The greatest increase was observed in women between the ages of 45 and 54 years. No significant increase in disease frequency was observed in the male population overall, or within specific age groups. There was no demographic evidence for a pattern of earlier age at onset or diagnosis to explain increased disease frequency or decrease in mean age of the prevalent population. In addition, we failed to identify a pattern of recognition of patients with less severe disability. Although there was a modest 13% increase of 2.2 years in mean disease duration, and eight new previously prevalent patients were identified, the main cause of rising disease frequency was related to a 2.8-fold increase in disease incidence for women over 23 years from 2.65 to 7.30/100 000/year increasing the sex ratio of incident patients from 1.8 to 4.3 (women:men). Conclusion: Recent change in disease incidence and prevalence in this population is likely to be the result of environmental factors that have been operative in the past few decades in women alone and infers avoidable risk factors. Modelling of current overall incidence suggests a further increase in prevalence to 260 per 100 000 population within the next 20–40 years. Further studies are needed in order to identify recent changes in sex specific environment and lifestyle that confer susceptibility.

Survival and cause of death in multiple sclerosis: a prospective population-based study

Background: Detailed studies of mortality in multiple sclerosis (MS) are limited. Studying death certificates in a prospective cohort of patients known to have MS is of value in establishing mortality data and can also provide important information on the accuracy and use of death certificates for epidemiological studies. Methods: A population-based survey performed in South Wales in 1985 identified 441 patients. Cases were flagged with the Office of Population Censuses and Surveys and death certificates collected prospectively for more than 20 years. Results: Median observed survival time was 38.0 years from symptom onset. Mean age at death was 65.3 for women and 65.2 years for men. Mean age at death in patients dying from MS-related causes was 62.5 and 69.3 years (p<0.001) for unrelated deaths. Those dying of MS-related causes had a younger age at disease onset (32.5) compared with those dying of unrelated causes (36.8 years) (p = 0.01). Cause of death was related to MS in 57.9% and unrelated in 42.1% of individuals. In 27% of patients, “MS” was absent from the death certificate. The most common cause of death was respiratory disease (47.5%). The standardised mortality ratio was 2.79 (95% CI 2.44 to 3.18) so that MS patients were almost three times more likely to die prematurely relative to the general population. Conclusions: These results confirm a continuing trend of premature death in patients with MS. Relying on data derived from death certificates will underestimate disease prevalence. Differences were identified between those dying from MS-related causes and those dying from other causes.

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 epidemiology and treatment of ALS : focus on the heterogeneity of the disease and critical appraisal of therapeutic trials

Abstract Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.