Mortality From Amyotrophic Lateral Sclerosis in Finland 1987–2022

ABSTRACT

Background

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We assessed changes in the mortality from ALS in Finland from 1987 to 2022.

Methods

Numbers of deaths caused by ALS (ICD‐10 code G12.2) and population sizes by sex, age group, and year were obtained from Statistics Finland. Crude and age‐standardized mortality rates were calculated. The annual percentage change was estimated using Poisson regression, and joinpoint regression was used to identify changes in trend during the study period.

Results

Mortality from ALS increased in Finland from 1987 to 2022. The age‐standardized ALS mortality in the entire population was 2.24/100,000 in 1987 and 4.21/100,000 in 2022. The male: female ratio in mortality was 1.18. The age‐standardized mortality increased on average by 1.7% (95% CI 1.5%–2.0%) annually. In men, the age‐standardized mortality increased on average by 1.2% (95% CI 0.9%–1.6%) annually and in women by 2.0% (95% CI 1.6%–2.3%). The largest increase occurred in the oldest age group (70+ years), with an average annual increase of 2.4% (95% CI 2.0%–2.8%). In joinpoint regression, no changes in trend were identified overall or in men, but in women, the annual percentage change (APC) was 5.5% (95% CI 3.0%–8.0%) in 1987–1997 and 1.0% (95% CI 0.5%–1.4%) during 1997–2022.

Conclusion

Similar to some other countries, mortality from ALS has increased in Finland, nearly doubling in 35 years. Further research on possible reasons is needed.

Age‐standardized mortality from ALS has increased in Finland from 2.2/100,000 in 1987 to 4.2/100,000 in 2022. The increase was on average 1.7% (95% confidence interval 1.5%–2.0%) per year. There were no significant changes in the trend, except that in women, the mortality increased rapidly from 1987 until 1997, and at a substantially slower pace thereafter.

1. Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease affecting both the upper and lower motor neurons. Various clinical diagnostic criteria have been proposed with Awaji and El Escorial definitions widely used [1]. The etiology of ALS is poorly understood, and no curative treatment is available. ALS leads to progressive paralysis, and the average survival after the diagnosis is 2–5 years [2].

Even though its etiology is poorly understood, age, male sex, and family history of ALS (familial ALS) have been identified as risk factors of ALS. Of all cases, 10%–15% are familial, and the rest represent sporadic ALS. The incidence peak is around 50 years in familial and 60 years in sporadic ALS. The incidence of ALS is higher in men than in women with a sex ratio of approximately 1.5:1 [2, 3]. At least 15 genetic variants are associated with ALS [4]. The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS, especially in the European population [5]. It is related especially to familial ALS but also reported in sporadic cases. Enrichment of this variant has been reported in the Finnish population [6]. In addition, BMI, smoking, exposure to heavy metals (such as lead), and pesticides have been reported as possible risk factors of ALS [7]. An inverse association has been suggested for physical activity and the risk of ALS, but an increasing risk with the amount of physical activity has also been reported [8, 9]. In addition, systemic inflammation increases ALS mortality, but the potential mechanisms require further studies [10].

A previous study reported an increase in ALS mortality in Finland from 1.54/100,000 in 1986 to 2.27/100,000 in 1995 [11]. Higher ALS incidence rates than this have also been observed in different provinces of Finland. The age‐standardized incidence of ALS in 2010–2018 was 4.0/100,000 in Southwestern Finland and 4.8/100,000 in North Karelia [12].

The incidence of ALS varies worldwide, but comparable rates have been reported across Europe and in North America. For example, in East Asia incidence is lower than in Europe and North America [13]. Generally, incidence is higher in countries with a higher human development index (HDI) than in those with lower HDI [14]. The difference may, however, also be attributable to research activity or accuracy of diagnostics and cause of death statistics.

ALS mortality has been found to increase in other countries, including Sweden, Norway, Denmark, and Chile. In Denmark, the age‐standardized mortality from ALS increased on average by 3% annually between 1970 and 2009 [15, 16, 17, 18]. ALS mortality has not, however, increased everywhere or across all age groups. For instance, no change was observed in ALS mortality in the United States between 1999 and 2009 [19]. In addition, mortality from ALS decreased in the population younger than 70 years of age in Japan during 1995–2004 [20].

Our study aimed to examine the mortality rate from ALS in Finland and changes in it over 35 years, from 1987 to 2022.

2. Methods

The data for this study were obtained from the Finnish Death Certificate Register maintained by Statistics Finland. It includes the number of deaths from ALS between 1987 and 2022 by calendar year, sex, and 5‐year age group. Population data with similar stratification were also obtained from Statistics Finland [21].

Using the cause of death and population data, crude and age‐standardized annual mortality rates from ALS were calculated. The European standard population (2013 edition) was used for age‐standardization [22]. In reporting the results, four age groups were used: younger than 50 years, 50–59 years, 60–69 years, and 70 years or older. When calculating mortality, only deaths where ALS was the underlying cause of death were considered. ALS deaths were defined with ICD‐9 code 335.2 between 1987 and 1995 and ICD‐10 code G12.2 between 1996 and 2022. Data on deaths with ALS as a contributing factor were also obtained from Statistics Finland for the years 1996–2022. Only the overall number of such cases by year was obtained, and it was not broken down by age or sex due to the strict privacy regulation for health data, with any cell frequencies below five regarded as individual data.

Poisson regression with the number of deaths as the outcome and population size as an offset variable was used to estimate mortality rate ratios by age, sex, and calendar year. The results are presented as average annual percentage changes (APC). Differences in temporal trend by sex and age group were evaluated by adding an interaction term (age or sex with year) into a model with their main effects, and improvement in model fit was assessed using a likelihood ratio test. Joinpoint regression was used to detect any changes in trend. Joinpoint regression was performed on age‐standardized rates (and their standard errors) for the entire population, as well as separately for men and women, and for the four age groups. The minimum distance between join points was defined as 2 years. Stata (version 17.0, Stata Corp) and Joinpoint (U.S. National Cancer Institute) software were used in the statistical analysis.

Only aggregate data was obtained and used for the analysis, with no individuals identifiable. Therefore, no ethical committee review was required according to the Finnish regulation.

AI tools were used to refine the language and improve sentence structures in individual sentences. The AI tool used was ChatGPT (Version: GPT‐5).

3. Results

A total of 6122 deaths from ALS were recorded in the cause of death database during 1987–2022. Of these, 2909 (47.5%) were among men and 3213 (52.5%) among women, while 4.3% of the deaths were among people less than 50 years old and 47.0% among those aged 70 years and older. (Table 1). ALS was a contributing factor in 357 deaths with other underlying (primary) causes during the study period.

TABLE 1.

Number of deaths from amyotrophic lateral sclerosis (ALS) and crude mortality rates in Finland in 1987–2022 by age, sex, and calendar period.

Characteristic	Number of ALS deaths	Crude mortality rate/100,000	95% CI
Sex
Men	2909	3.13	3.02–3.25
Women	3213	3.32	3.20–3.43
Age (years)
0–19	—	—	—
20–39	27	0.05	0.04–0.08
40–49	238	0.89	0.78–1.01
50–59	992	3.98	3.74–4.24
60–69	1986	9.43	9.02–9.85
70–79	2012	13.80	13.21–14.42
80—	867	10.98	10.26–11.74
Calendar period
1987–1993	656	1.87	1.73–2.02
1994–2000	953	2.65	2.48–2.82
2001–2007	1158	3.15	2.98–3.34
2008–2014	1330	3.52	3.33–3.71
2015–2022	2025	4.58	4.38–4.79
Total	6122	3.23	3.15–3.31

Mortality from ALS increased in Finland from 1987 to 2022. The overall age‐standardized mortality among men and women combined was 2.24/100,000 (95% CI 1.76–2.71) in 1987 and 4.21/100,000 (95% CI 3.70–4.72) in 2022. The increase was reasonably similar in men and women. The age‐standardized ALS mortality increased in men during the study period from 2.61/100,000 (95% CI 1.84–3.38) to 4.65/100,000 (95% CI 3.86–5.44) and in women from 1.76/100,000 (95% CI 1.22–2.31) to 3.83/100,000 (95% CI 3.16–4.50) (Figure 1). Crude mortality rates were higher in men than in women across all age groups; the male to female ratio ranged between 1.1 and 1.2. The age‐adjusted mortality ratio was 1.18 (95% CI 1.13–1.25) for men relative to women during the entire study period, with a decrease in the sex ratio over time (Figure 2).

FIGURE 1.

Age‐standardized mortality rates (per 100,000) by calendar year in men and women in Finland in 1987–2022.

FIGURE 2.

Male to female sex ratio in age‐standardized mortality rates by calendar year in Finland in 1987–2022.

In Poisson regression analysis, the age‐standardized average annual percentage change (APC) in ALS mortality was 1.7% (95% CI 1.5%–2.0%) for the entire population during the study period. For men, it was 1.2% (95% CI 0.9%–1.6%), and for women, 2.0% (95% CI 1.6%–2.3%) (Table 2). The difference between the sexes was statistically significant (likelihood ratio test p = 0.008). We assessed the stability of the trend by leaving out every year one at a time from the analysis. The APC estimates ranged from 1.66 to 1.78, with all values well within the 95% confidence interval.

TABLE 2.

Temporal trend expressed as annual percentage change in mortality from amyotrophic lateral sclerosis overall and by age group and sex in Finland in 1987–2022.

	Annual percentage change: Crude rate	95% CI	Annual percentage change: Age‐standardized	95% CI
All	2.90%	2.65%–3.16%	1.72%	1.46%–1.99%
Sex
Men	3.04%	2.67%–3.42%	1.24%	0.85%–1.63%
Women	2.90%	2.43%–3.14%	1.96%	1.59%–2.33%
Age (years)
< 50	−0.16%	−1.30%, +1.01%	−0.23%	−1.43%, +0.98%
50–59	0.98%	0.34%–1.62%	1.02%	0.35%–1.68%
60–69	1.21%	0.77%–1.66%	1.12%	0.66%–1.58%
≥ 70	2.27%	1.89%–2.64%	2.40%	1.99%–2.80%

A statistically significant difference in mortality trend by age group was found (likelihood ratio p < 0.0001). The largest increase was in the oldest age group, 70 years old and older, with a slight increase in the youngest age group below 50 years. In the oldest age group, the mortality rate increased 2.3% (95% CI 1.9%–2.6%) annually. Mortality also increased in the age groups 50–59 years and 60–69 years. In the youngest age group, no increase in the ALS mortality was observed (APC –0.2%, 95% CI –1.3% to +1.0%).

In joinpoint regression, no changes in the overall trend during the study period were identified. In women, however, the annual percent change (APC) was 5.5% (95% CI 3.0%–8.0%) in 1987–1997 and 1.0% (95% CI 0.5%–1.4%) during 1997–2022. No change points were detected among men. No departure from a constant trend was found in any age group (Figure 3A–C).

FIGURE 3.

(A–C) Joinpoint analysis of ALS mortality overall, by sex and age group, Finland, 1987–2022 (A: Overall; B: Women; C: Men) (ASR = age‐standardized rate, APC = annual percentage change).

When also deaths with ALS as a contributing cause were included, the crude mortality was 3.10/100,000 in 1996 and 5.32/100,000 in 2022 compared with 2.74 in 1996 and 4.74 in 2022 when including only deaths with ALS as the underlying cause. The APC was 2.3% (95% CI 2.0%–2.7%) when cases with ALS as either the contributing or underlying cause of death were included.

4. Discussion

The age‐standardized mortality from ALS increased in both men and women in Finland, nearly doubling during 1987–2022. No significant changes in the trend were observed during the study period for the entire population or in men. In women, however, the mortality increased rapidly between 1987 and 1997 with a substantially slower increase thereafter. The largest increase was in the age group 70 years and older. The mortality rate also increased in the age groups 50–59 and 60–69 years with no increase in the ages under 50. The trend was constant in all age groups.

Our results are consistent with previous analyses in Finland. An earlier study reported an increase in ALS mortality: the crude rate was 0.63/100,000 in 1963 and 1.54/100,000 in 1986 [11]. We found that ALS mortality had continued to increase, with a crude mortality rate of 4.74/100,000 in 2022. Our age‐standardized mortality rates are in line with those observed in Southwestern and Eastern Finland during 2010–2018. In Southwestern Finland, the age‐standardized incidence of ALS was 4.0/100,000, and in North Karelia, 4.8/100,000 [12]. In our study, the ALS mortality in the entire Finnish population was 3.64/100,000 in 2010 and 4.28/100,000 in 2018.

The highest age‐standardized mortality rates of motor neuron diseases have been reported in regions with a high socio‐demographic index, including Australasia, North America, and Western Europe [23]. In these populations, the age‐standardized incidence rates ranging from 2.00–3.28/100,000 have been reported [23, 24, 25, 26].

An increasing trend in ALS mortality has been previously reported in the Nordic countries. The increase in ALS mortality in Finland between 1987 and 2022 was smaller than that reported in Denmark between 1970 and 2009. In Denmark, the mortality increased on average 3.0% annually, and after 1980 the rate increased on average 2.1% annually, while in Finland the APC was 1.7% [16]. In Denmark, ALS incidence was 2.8 times higher when comparing the period 2018–2021 to the period 1980–1983. At the same time, the mortality rate increased as well in Denmark [27]. In Norway, the mortality increased as well, but the increase was smaller (APC 1.1%) than in Finland and Denmark [18]. A larger increase in mortality than in Finland was observed in New Zealand, where the incidence increased by 3.3% between 1985 and 2006 [28]. In contrast, no increase was reported in the United States between 1999 and 2009 nor in 2011–2014 [19, 29]. The incidence rate also remained unchanged in Ireland between 1995 and 2004 [30]. In Italy, differences in the ALS incidence between various regions have been reported. For example, in Liguria the incidence remained stable between 2009 and 2014, but the incidence increased in Piemonte and Valle D'Aosta from 1995 to 2014 [31, 32].

Male sex has been recognized as a risk factor for ALS, with a male to female sex ratio of approximately 1.3 in populations of European origin [33]. Men also have shorter survival than women after the diagnosis of ALS [34]. Also in our study, ALS mortality was higher in men than in women, with the age‐adjusted male‐to‐female ratio 1.18 overall. The sex ratio decreased over time and ranged between 1.1 and 1.2 across the age groups. No clear decrease in the sex ratio was observed toward older ages.

Several possible explanations could contribute to the low sex ratio. First, the male/female ratio is lower in familial ALS [35]. We were unable to distinguish between sporadic and familial cases in our study, but a large proportion of familial ALS cases have been reported in Finland, largely attributable to C9orf72 and SOD1 mutations [6, 12]. It is also possible that the major risk factors are distributed more equally in Finland than in most other populations. For instance, occupational exposure levels to heavy metals and pesticides in predominantly male occupations in agriculture, farming, forestry, and industry are low in Finland, possibly decreasing especially male exposure and reducing the sex ratio. Yet, the most likely explanation of the low sex ratio is the enrichment of familial and founder mutations in the Finnish population.

The increasing mortality trend was more marked in women. A more pronounced increase in ALS incidence in women than men was also reported in Piemonte and Valle d'Aosta, Italy, 1995–2014 [31]. In Norway, men had a higher incidence than women, but there was no difference in trend between sexes in 1951–2014 [18].

In our study, the ALS mortality increased especially in the age groups above 50 years. In Norway, the mortality increased only in people older than 65 years, in Denmark over 51 years, and in Japan at ages above 70 years [16, 18, 20].

As mentioned above, the C9orf72 hexanucleotide repeat expansion is the most common genetic cause of ALS. It is more common in European than Asian populations and very frequent in Finland. Up to a third of Finnish ALS patients may have this gene mutation. In addition, enrichment of the SOD1 variant has also been reported in the Finnish population. These enrichments are likely key factors explaining the high incidence and mortality of ALS in Finland [6]. It is unlikely, however, to explain the increasing trend in mortality.

Our findings indicate that the increased ALS mortality is not solely due to the aging of the population, as the study used age‐standardization, which accounts for the changes in population size and age structure. Yet, the increasing proportion of the older age groups in the population explained a third of the increase in the crude mortality rates. New disease‐modifying treatments have been developed during the study period [36]. The oldest and most widely used medication is riluzole with the average survival benefit estimated as three months [37]. Other improvements, such as noninvasive ventilation and multidisciplinary home care, have slowed disease progression but without a material extension of life span [38]. Nevertheless, survival improvements of a few months are unlikely to substantially affect the mortality rates, and if anything, they would result in a decreasing mortality trend, contrary to our observations [39]. Invasive respiratory support with tracheostomy and mechanical ventilation is known to prolong life in late stages of ALS by up to several years. Use of invasive mechanical ventilation is uncommon in Finland [12, 40]. A recent nationwide analysis reported home invasive mechanical ventilation for a number of ALS patients that corresponded to < 2% of all ALS deaths during 2015–2022, with no clear sex difference [40].

Rather, we believe the increased mortality reflects increased incidence. Possible factors behind the increased mortality can include improved diagnostics or increased exposure to risk factors. For example, among the other risk factors, the prevalence of obesity (BMI > 30 kg/m²) has increased in Finland between 1972 and 2012 in both men and women. On the other hand, smoking has decreased, especially in men from 1992 to 2017 [41]. The total physical activity has decreased in Finland from 1972 to 2012. Simultaneously, occupational physical activity and commuting physical activity have decreased, but leisure time physical activity has increased [42]. Pesticide use decreased 22% in Finland in 1990–2021. In general, Finland uses relatively small amounts of pesticides compared to most other countries [43]. Exposure to lead has decreased due to the renewed fuel legislation in Finland, and exposure occurs mainly through food and drink [44, 45]. Hence, several risk factors have decreased, and no obvious explanation can be found for the increasing trend. Further etiologic research is needed to elucidate the causes underlying the increasing trends in ALS.

The differences between populations may be due to real variation in risk, driven by risk factors, or the recording of ALS deaths. Standardized WHO cause of death classification is employed across countries, but differences in accuracy of determinations, coding, and certification are likely, and they may substantially affect the international variation. Yet, tracking their impact is difficult. A recent study showed a relatively high proportion of 90% confirmed diagnoses out of cases listed in a nationwide healthcare registry [46].

One of the strengths of this study was the extensive and up‐to‐date mortality data. Statistics Finland compiles all causes of death for the Finnish population and maintains statistics on population size and structure. All information is recorded in accordance with the WHO coding rules, and death certificates are obtained comprehensively, covering all deaths among the Finns including also deaths abroad. The quality and reliability of Finland's vital statistics are among the best worldwide [47, 48]. ALS diagnoses in Finland are made exclusively by neurologists following international criteria and few, if any, diagnoses are likely to be made only at death. We were also able to perform an additional analysis, including deaths where ALS was only a contributory factor, and no material difference was observed compared to the analysis that considered only cases with ALS as the underlying cause of death. In addition, modern regression methods were employed in the data analyses. Also, the trend was not materially affected by an analysis excluding each year at a time (leave‐one‐out analysis). We not only calculated mortality rates but also analyzed the trend of ALS mortality, accounting for changes in population size and structure, and evaluated any deviations from the underlying trend.

A limitation of this study was that we could not verify the validity of the diagnoses using established clinical and neurophysiological criteria. Misclassification may have decreased over time, especially with the introduction of new diagnostic criteria (El Escorial, Awaji, Gold Coast), which would be expected to reduce the mortality rates. Secondly, we were unable to distinguish ALS from other motor neuron diseases due to the limited accuracy of coding of causes of death. The ICD‐10 code G12.2 used in our study includes all motor neuron diseases. Yet, it was used because the Finnish Death Certificate database registers causes of death with only four‐character accuracy. In previous studies, the proportion of ALS cases out of all motor neuron diseases has been reported to range 75%–95% [24, 25, 26, 29]. Therefore, our results are likely to overestimate ALS mortality by 5%–25%. The accuracy could have been improved if we had access to hospital records. The transition from ICD‐9 to ICD‐10 may affect the rates and trends. Our material covered the entire Finnish population, but the precision of the estimates was limited, especially for younger age groups. In addition, we were unable to distinguish familial versus sporadic ALS. Because the data includes only the number of deaths from ALS by calendar year, sex, and five‐year age group, we could not assess socioeconomics or regional differences.

5. Conclusion

Mortality from ALS has continued to increase in Finland, nearly doubling from 1987 to 2022. This is not attributable to aging of the population, and possible etiologic factors remain unclear.

Author Contributions

Anssi Auvinen: conceptualization, methodology, writing – review and editing, formal analysis. Milla Laine: writing – original draft, formal analysis, visualization.

Funding

The funder had no role in the design, data collection, data analysis, and reporting of this study. No external funding was obtained for the study.

Ethics Statement

We did not have any individual‐level data, and thus no consent or review by research ethics committee was required.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data are available from the authors upon reasonable request.