Although the development of population based registers has accurately measured the epidemiology of amyotrophic lateral sclerosis (ALS) in European and North American populations,1 it is not known whether the incidence of this disease has changed over time (see page 6). It is also unclear if the clinical course of ALS has changed over the past decade as a result of improvements in supportive care, such as non-invasive ventilation and early gastrostomy nutrition, and the introduction of riluzole. Changes in the prognosis of ALS would significantly impact on clinical trial design and healthcare delivery.

The purpose of this study was to examine the temporal pattern of ALS epidemiology within Ireland over the 10 year period from 1 January 1995 to 31 December 2004.

METHODS

Details of the Irish ALS Register have been published previously.2 Briefly, the Irish ALS Register was used to identify Irish residents diagnosed with suspected, possible, probable or definite ALS according to the El Escorial criteria3 during the 3 year period from 1 January 1995 to 31 December 1997 and during the 3 year period from 1 January 2002 to 31 December 2004. Overall incidence rates were calculated as observed number of new cases during the 6 years of study (1995–1997 and 2002–2004) divided by the total Irish population during the same time period.4 5 There has been significant immigration to Ireland over the past decade (226 100 in the past 9 years, Irish population in 2002 was 3 917 2035). To analyse the temporal trend of ALS in the face of shifting demographics, incidence rates for the 2002–2004 cohort were age and gender adjusted to the 1996 Irish population using the direct method.

The denominator for the calculation of prevalence rates was the Irish population on 31 December 1996 and 31 December 2003.4 5 Survival was estimated by the Kaplan–Meier method using time from date of diagnosis to death, tracheostomy (1995–97, n = 2; 2002–2004, n = 2) or last follow-up.

RESULTS

During the 6 years of study (1995–1997 and 2002–2004), 465 Irish residents were diagnosed with suspected, possible, probable or definite ALS. Of these, 29 (6.2%) had familial ALS based on a detailed family history, and 32 cases (6.9%) had clearly documented frontotemporal dementia (according to the Manchester–Lund criteria).

Demographics and clinical features of Irish patients with ALS did not change significantly between the 1995–1997 and 2002–2004 cohorts (table 1).

Based on 465 newly diagnosed cases, the average annual incidence rate of ALS in Ireland was 2.0 cases per 100 000 person-years (95% CI 1.9, 2.2; see supplementary table 1 and supplementary fig 1). The average annual incidence rate for the population older than 15 years was 2.6 per 100 000 person-years (95% CI 2.4, 2.9). ALS incidence remained almost stable over the 10 year period of the study: The incidence rate was 2.1 per 100 000 (95% CI 1.8, 2.4) between 1995 and 1997,2 and 1.9 (95% CI 1.5, 2.4) for the 2002–2004 cohort after age and gender adjustment to the 1996 Irish population.

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Figure 1 Kaplan–Meier cumulative (Cum.) survival curves comparing survival of the 1995–1997 and 2002–2004 incidence cohort with the prevalence cohort on 31 December 2003.

The incidence of bulbar onset ALS was identical among men and women (0.9 per 100 000 person-years, 95% CI 0.7, 1.0; see supplementary fig 2). In contrast, the incidence of limb onset ALS was almost twice as high among men compared with women (1.5 per 100 000 person years (95% CI 1.3, 1.7) vs 0.8 (95% CI 0.7, 1.0)). Women had similar incidence rates for limb onset and bulbar onset disease at nearly all ages whereas the male incidence rate of limb onset disease was consistently higher than bulbar onset disease for all age groups in men.

The crude prevalence rate of ALS on 31 December 1996 was 6.2 per 100 000 population over the age of 15 years (n = 172, 95% CI 5.3, 7.1).2 The prevalence rate on 31 December 2003 was almost identical (6.4 per 100 000, n = 200, 95% CI 5.5, 7.2; see supplementary table 2). The clinical features of the prevalent and incident cohorts were markedly different (table 2). For example, bulbar onset disease accounted for less than one-third of the overall prevalence rate (2.0 vs 6.6, 31.3%) but formed a larger percentage of incidence rate (1.1 vs 2.6, 42.3%).

Median survival among Irish ALS patients was 16.4 months from the time of diagnosis. Prognosis did not change significantly over the 10 years of the study (see supplementary fig 3, log rank = 0.376, p = 0.54), regardless of the site of symptom onset (see supplementary fig 4, log rank = 0.281, p = 0.60).

DISCUSSION

The incidence and prevalence rates of ALS were remarkably stable in the Irish population over the 10 year study period, 1995–2004. A previous incidence study of the population of Rochester, Minnesota, USA, also reported the incidence of ALS to be constant at 1.7 per 100 000 person-years between 1925 and 1998.6 However, the small size of Olmsted County (28 014 in 1920; 124 277 in 2000) limited recruitment to approximately one case per year and precluded reliable conclusions about the temporal pattern of ALS incidence. In contrast, the current study examined the epidemiology of ALS for an entire country with a population of nearly 4 million, albeit over a shorter time frame. Increasing ALS incidence over time has been reported by mortality studies,7^–9 but this is almost certainly due to improvements in case ascertainment and diagnostic methods rather than a genuine increase in incidence.

Survival of Irish patients with ALS was similar to that reported in other population based studies6 and did not change over the 10 year study period, 1995–2004. This is an unexpected finding as there have been at least minor advances in treatment during the past decade. Several factors may explain this observation. Riluzole was available to a small number of Irish patients on compassionate grounds from 1994 and, thus, the therapeutic effect of this medication, albeit mild, may have influenced prognosis in both cohorts. Enteral nutrition became widely utilised in Ireland from the late 1990s onwards, and was expected to improve survival of the 2002–2004 cohort. However, although early evidence suggested that percutaneous endoscopic gastrostomy insertion and enteral nutrition improved life expectancy,10 more recent studies failed to demonstrate a significant survival advantage and a study in the Scottish ALS population suggested that patients undergoing percutaneous endoscopic gastrostomy have reduced survival.11 The most significant beneficial intervention in the management of ALS over the past 10 years has been the use of non-invasive ventilation.12 Non-invasive ventilation was not widely used in Ireland until after 2004, meaning that the positive survival benefits of this intervention would not have been apparent in the 2002–2004 cohort.

There were significant differences in the demographics, clinical features and survival times of the prevalent and incident cohorts of Irish ALS cases (table 2). The prevalent cohort had fewer bulbar onset patients (31.3% vs 42.3%) and fewer patients over the age of 65 years (37.0% vs 52.5%) compared with the incidence cohort. These differences are most likely a result of the shorter prognosis associated with bulbar onset disease (414 days vs 605 days among limb onset) and with disease onset over 65 years of age (373 days vs 649 days among patients younger than 65 years). Indeed, the survival pattern of the 2003 prevalent cases differs markedly from that of the Irish incident cohort (fig 1; log rank = 127.4, p<0.0001). This has important implications for the current North American and UK efforts to collect large numbers of ALS DNA samples.13 14 The North American initiative focuses on collecting prevalent cases and it is likely that cases with a poor prognosis, such as bulbar onset and elderly patients, will be under represented in the final cohort. In contrast, the UK DNA Bank collects only newly incident cases. Although this approach results in a slower collection rate, the final cohort may more accurately represent the general ALS population.

The observed increase in the rate of familial cases and cases with frontotemporal dementia between the two time periods is almost certainly a result of improved collection of familial aggregation data and a growing awareness among neurologists of cognitive dysfunction associated with ALS.

The multiple sources of information and prospective patient follow-up employed by the Irish ALS Register mean that an Irish resident diagnosed with ALS is likely to have been ascertained and included in the current study.2 However, there is currently no diagnostic test for ALS, and relying on clinical details to achieve a diagnosis may impede case ascertainment. The use of probable and definite ALS El Escorial categories3 as eligibility criteria for clinical trials and ALS research has been generally criticised as it means that a patient must be quite advanced in their clinical course prior to enrolment. To overcome this, the Irish ALS Register includes patients with suspected or possible ALS, and the prospective patient follow-up inherent to the Register’s design allows the diagnosis of ALS to be ultimately confirmed or refuted.

Analysis of the pattern of bulbar and limb onset ALS yields a number of important observations. First, age and gender adjusted incidence among Irish ALS patients is remarkably similar to a recent report of an Italian population of comparable size.15 The incidence of bulbar and limb onset disease among women is similar for all ages whereas limb onset ALS was consistently more common than bulbar onset disease among men. This observation confirms the clinical perception that bulbar onset disease is proportionally more common among women than among men. Second, our data indicate that the higher incidence of ALS among men that has been consistently reported in ALS epidemiological studies is largely a result of the higher rate of limb onset disease among middle aged men. Finally, the age distribution of bulbar onset and limb onset disease is the same among both genders, increasing rapidly after the age of 45 years, reaching a peak in approximately the eight decade of life and declining rapidly thereafter. This pattern is distinct from that observed with Alzheimer’s disease and Parkinson’s disease, where incidence continues to rise with increasing age, and is consistent with the existence of a genetically susceptible cohort within the general population. Alternatively, this pattern of disease incidence may reflect poor case ascertainment among the 80+ age group or a naturally shrinking pool of very elderly in the general population (1% of the Irish population is over the age of 85 years). It will not be possible to determine which of these possibilities is correct until the pathogenesis of ALS is more fully understood.