Abstract
Objective: To investigate a possible increase in incidence of ALS in Norway.
Methods: Death certificate data from all deaths in Norway in the period 1961 to 1994 for ALS, PD, and MG were obtained from Statistics Norway and related to population statistics. Data on ALS was obtained on sex, age, and place of death and compared with mortality data in PD and MG for the same period. Data were standardized using the 1990 population as standard population. Poisson regression was used to test for trends in mortality. The data from the death certificates were related to a clinical study performed on ALS in one of the counties during the same period.
Results: The annual mortality of ALS almost doubled during the period studied, rising from 1.38 to 2.54 per 100,000 inhabitants at the end of the study. The increased mortality appeared solely in the population older than 60 years of age, with a peak in mortality in the age group 80 to 84 years. The increase was larger in women than in men, and the ratio between the sexes was 1.32 (men–women, age-adjusted at the end of the study). The mortality in patients with PD showed a similar increase to that seen in ALS, whereas no increase in mortality was observed in patients with a diagnosis of MG. There were considerable differences in ALS mortality in different counties, but no clear regional trends were observed.
Conclusion: The authors report increasing ALS mortality. Although the increase in mortality is restricted to the population aged 65 years or older, it cannot be explained by increasing age of the general population alone.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neuromuscular disease. The annual incidence of ALS shows small differences between countries, mostly varying between 1 and 2 cases per 100,000 inhabitants.1-4⇓⇓⇓
Over the last years, an increased mortality of the disease has been reported.1-3,5-7⇓⇓⇓⇓⇓ The mortality from ALS increased in the United States from 1962 to 1984, and environmental factors were proposed to be involved in the pathogenesis of the disease.7 However, increasing ascertainment in making the diagnosis of ALS also should be considered a factor. The total mortality from ALS was shown to increase in Norway during the same period,6 but an incidence study in a Norwegian county from 1970 to 1990 failed to show increased ALS incidence.8 The general increase reported in neurodegenerative disorders has been attributed to the increase in life expectancy in the general population.2,3,5,9⇓⇓⇓
Norway is a country characterized by a stable population both at regional and at national levels. There are, nevertheless, considerable differences of population density as well as clear rural and urban areas.
In the current work, we study sex, age, and place of death of all registered patients with ALS from 1961 through 1994. Moreover, ALS mortality is compared with the mortality in patients diagnosed with another neurodegenerative disease, PD, and a nondegenerative disease, MG.
Material and methods.
Data on sex, age, and residence at death from all death certificates in the period 1961 through 1994 with mention of ALS, PD, and MG, and with general population data for the period, were obtained from Statistics Norway. This national bureau of statistics regularly collects information from all deaths, and this information is related to place of birth, eventual migrations, place of death, and various occupational and educational parameters in censuses performed every decade.
From 1961 through 1994, there were 15,856 such deaths: 2,598 persons with ALS, 13,045 patients with PD, and 213 with a diagnosis of MG recorded in the death certificate. Five patients had diagnoses of both ALS and PD, and two had diagnoses of both ALS and MG. The validity of the data ascertained in Hordaland County was tested by comparing it with data from the Department of Neurology, Haukeland Hospital, of patients discharged with the diagnosis ALS in the period 1970 to 1989. The Department of Neurology, Haukeland Hospital, is the only neurologic hospital service in Hordaland County, and 148 patients were discharged with a diagnosis of definite ALS between 1970 and 1989.
The data were coded as ICD-7 (International Classification of Diseases) from 1961 to 1968, ICD-8 from 1969 to 1985 and ICD-9 from 1986 through 1994. The codes used for ALS were 356 and 356.1 (ICD-7), 348, 348.1, 348.2 and 348.9 (ICD-8), 335.0, 335.1, 335.2, and 335.9 (ICD-9). The codes used for PD were 350 (ICD-7), 342 (ICD-8), and 332.0 (ICD-9). The codes used for MG were 744.0 (ICD-7), 733 (ICD-8), and 358.0 (ICD-9). These codes were recoded to one code each for ALS, PD, and MG. Most patients defined here as having ALS were diagnosed using the codes 356 or 356.1 (ICD-7), 348 or 348.1 (ICD-8), and 335.2 (ICD-9).
Age–sex standardization was carried out by using the population in 1990 to 1994 as the standard population. Poisson regression was used to compute age-adjusted sex ratios in the different periods and to test for a time trend in the sex ratios and rates. The time trend in sex ratios was tested by including a sex-period product term in the model with sex, age (12 5-year age groups represented by indicator terms), and period (linear representation: coded 0, 1, 2, or 3 for the periods 1961 to 1969, 1970 to 1979, 1980 to 1989, and 1990 to 1994, respectively).
Results.
In Norway during the period 1961 through 1994, 2,598 people had a recorded diagnosis of ALS. The annual mortality rate is given in figure 1. The average annual mortality rates per 100,000 population were 1.38 in 1961 to 1969, 1.77 in 1970 to 1979, 2.18 in 1980 to 1989, and 2.54 in 1990 to 1994, changing to 1.52, 1.87, 2.20, and 2.54 when standardized for age and sex. The mortality increased during this whole period, although there may be a levelling off toward the end of the period. A comparison between the annual mortality data for ALS, PD, and MG is given in figure 2. The annual mortality is divided by the mean of the annual mortality during the period 1961 to 1965 for each disease. Absolute mean mortality numbers in the period 1961 to 1965 were 2 per 100,000 for ALS, 5.66 per 100,000 for PD, and 0.27 per 100,000 for individuals with MG. The increase in mortality appeared to be similar in ALS and in patients with PD, whereas no increase in mortality was observed in patients with a diagnosis of MG.
Figure 1. ALS mortality per 100,000 per year in Norway in the period 1961 to 1994.
Figure 2. Annual mortality of ALS (▴), PD (▪) and MG (•) in Norway compared with a baseline for each disease. The baseline is the mean of the disease mortality for ALS, PD, and MG for the years 1961 to 1965.
The increase in mortality from ALS during the study period was entirely confined to patients aged 65 years or older (figure 3). The age-specific mortality rate in ALS was found to have a peak at 75 to 79 years of age (7.02 per 100,000) in the period 1961 to 69. In contrast, the peak was in the age group 80 to 84 years for the periods 1980 to 1989 (11.8 per 100,000) and 1990 to 1994 (15.1 per 100,000). During the entire period, ALS mortality declined in the oldest age group compared with the immediate, younger groups (see figure 3). During the study period, the mean age at death increased from 63.5 years in the 1961 to 1969 period, to 70.0 years in the 1990 to 1994 period. The mean increase in age for the general population has been 2.7 years during the same period. During the last period of the study, 50% of the ALS patients died between the ages of 64 and 77 years. The mortality for the group aged younger than 60 years ranged from 0.43 to 0.53 per 100,000 during the entire period of the study.
Figure 3. Age-related annual ALS mortality during the periods 1961 to 1969 (▪), 1971 to 1979 (♦), 1980 to 1989 (▴), and 1990 to 1994 (X).
Figure 4 shows the relative change in mortality according to age group. The ALS mortality increased by a factor of 2.31 for the population older than 70 years of age from the first to the last decade of the study, 1.29 for the population between 60 and 69 years of age, whereas the group aged younger than 60 years had an almost stable mortality.
Figure 4. Relative standardized ALS mortality during the period of the study for the age groups younger than 59 years (♦), 60 to 69 years (•), and older than 70 years (▴). The first period (1961 to 1969) represents the reference group.
The sex-specific ALS mortality rate increased in men from 1.61 per 100,000 in 1961 to 1969, to 2.58 per 100,000 in 1990 to 1994, and from 1.17 to 2.50 per 100,000 in women during the same period (table 1). The increase in ALS mortality was highly significant in both men and women. The relative increase was 1.6 in men and 2.14 in women. When standardization was performed, the increase was less obvious, being 1.53 for men and 1.87 for women. The sex ratio (men–women) showed a decreasing trend (see table). The estimated linear trend in sex ratio of 0.93 means that the sex ratio is changed by a factor of 0.93 per period (i.e., a decrease of 7% from one period to the next). The sex ratio did not differ between different age groups.
Annual ALS mortality in men and women and trend in sex ratio in the periods 1961 to 1969, 1970 to 1979, 1980 to 1989, and 1990 to 1994 estimated by Poisson regression
The data show an increase in ALS mortality in all Norwegian counties from the first to the last period (figure 5, table 2), ranging from a factor of 1.2 to 3.1, with an average relative increase for the whole country of 1.8. We did not observe any trend concerning urban versus rural districts.
Figure 5. Map showing the Norwegian counties listed in table 2.
Annual ALS mortality in the 19 Norwegian counties in four periods
Discussion.
The current study shows an increase in annual ALS mortality from 1.38 to 2.54 per 100,000 (age–gender standardized 1.52 to 2.54 per 100,000) from 1961 to 1994 in Norway. This increase agrees well with the data from Sweden,1,2⇓ the United States,7 France,10 and England and Wales.5 The increase in ALS mortality is related mainly to an increased occurrence in the elderly (older than 65 years). Moreover, the increase in ALS mortality was higher in women than men. A similar increase in total mortality was found in cases with a diagnosis of PD but not in the immunologic disease, MG. We found that the gender difference in ALS mortality reported in earlier studies,1-4,7,8,11-13⇓⇓⇓⇓⇓⇓⇓⇓ and also found in the earlier periods of our study, gradually became less apparent.
A similar increase in total mortality for two neurodegenerative diseases could indicate that some factors contributing to the occurrence of the diseases have become more common. Several theories concerning such factors have been proposed, the most commonly accepted being age.1-4,6-8,10,11,13,14⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ We find that the increase in ALS mortality is age related. During the study period, the mortality remained unchanged in the group aged younger than 65 years, whereas there was a marked increase in ALS mortality in the population aged 65 years or older. This increase in ALS mortality in the population older than 65 years of age explains the considerable increase in mean age at death in patients with ALS. Increasing ALS mortality has been proposed related to a growing population at risk of the disease.2,3,5,9⇓⇓⇓ More people are living to older ages and, therefore, are more susceptible to getting ALS. This theory of a susceptible group also is strengthened by the fact that the mortality declines sharply in the oldest age groups,1-3,7⇓⇓⇓ which can be attributed to the earlier death of the susceptible individuals. According to the current data, the relative increase in ALS deaths in patients older than 70 years was 275%. During the same period, the increase of the general population aged older than 70 years was 69%, which clearly is below the relative increase in ALS deaths for the same age group, suggesting that the increase in ALS mortality cannot be related solely to an increase in age in the general population.
The diagnosis of ALS is recognized more often than was the case earlier because of better health services in general and better neurologic service in particular. In addition, more resources are available for making the diagnosis in the elderly population. The reporting on the death certificates also may be better, although ALS reporting in death certificates has been shown to be good during the entire study period.1,3,15,16⇓⇓⇓ When the current figures are compared with an earlier incidence study in Hordaland County,8 the number of diagnosed patients for the period 1970 to 1990 almost equals the number of patients in this study material from Statistics Norway for the same period: 148 for the incidence data versus 155 for the mortality data.
In our study, we report a relative increase in ALS mortality in women of 2.14 compared with 1.6 in men. During this period, the mean life expectancy in women increased by 1.07 years more than in men, and when corrected for sex and age, the relative increase in women was 1.87 compared with 1.53 in men. A relative stronger increase in women than men has been observed previously and was proposed to be artifactual, related to the relatively larger increase in life expectancy in women than in men, making more women live in the “high-risk ages.”3 Based on the current data, we suggest that the increase in life expectancy in women compared with men is insufficient to fully explain the larger increase in mortality observed in women, and other factors may contribute. Underreporting of ALS in women in previous years and environmental factors should be considered.14 In Norway, women currently are exposed to a more similar array of environmental toxins as men.
Norway has large, regional differences concerning topography and main income. If environmental factors are of importance, some differences between the regions could be expected. We found more than a twofold difference in mortality between different counties in Norway, and the increase in mortality also varied more than twofold. However, we were unable to find clear regional trends concerning the mortality of the disease. The observed higher mortality in an agricultural county in Sweden,1 therefore, could not be reproduced in Norway.
- Received December 29, 1999.
- Accepted July 14, 2000.
References
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