Incidence of ALS in Italy

Methods.

Study area.

The study was performed in Piemonte and Valle d’Aosta, two regions of Northwestern Italy, with a total area of 28,662 Km² (figure 1). The population of the study area was 4,418,503 inhabitants at the time of the last general population census, in 1991.16 The area is highly industrialized and has high-level health services. Twenty-six neurologic departments are operating in the two regions, which are subdivided in nine provinces. According to the data of the Italian National Health System (NHS), few patients seek medical care outside the region; moreover, because the provision of benefits from the NHS and the National Social Security is based on prescription by a specialist practicing in the area where the patient is resident, patients with ALS are likely to be visited by a hospital neurologist at least once during the course of disease. In the area there are two tertiary referral ALS centers, one located in Veruno, at the Salvatore Maugeri Center for Neurologic Rehabilitation, and the other in Torino, at the Department of Neuroscience, University of Torino.

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Figure 1. Map of Piemonte and Valle d’Aosta.

Results.

During the 2-year surveillance period (January 1, 1995, to December 31, 1996) a total of 221 patients (120 men and 101 women) were diagnosed with probable or definite ALS. Among these, 193 were directly reported by the collaborating centers and 28 were found through secondary sources. Twenty-three patients were found through the Lombardia Central Archive, but all of them had already been detected by PARALS. All 16 possible ALS cases at the time of diagnosis evolved to probable or definite ALS during follow-up. Of the 15 patients with suspected ALS, 6 evolved to probable or definite ALS within a mean of 14 months after diagnosis. Of the other 9 cases, 2 were classified as PSMA, 2 as PLS, and 2 as monomelic motor neuron disease, and therefore were not considered in the epidemiologic study. The three remaining cases were reclassified as affected by cervical myelopathy2 and motor neuropathy1 (false positive diagnoses).

Ten patients (5%) had a positive familial history of ALS. None of these cases had a Cu-Zn superoxide dismutase (SOD1) gene mutation.

Mean age at diagnosis of ALS was 63.7 years (SD 11.2), without gender differences (women, 64.3 [SD 11.2]; men, 63.4 [SD 11.2]; p = NS). The site of onset of symptoms was lower limbs in 87 cases (39.4%), upper limbs in 64 (29.0%), bulbar region in 69 (31.2%), and respiratory muscles in 1 (0.4%).

The mean annual crude incidence rate was 2.50 per 100,000 population (95% CI 2.21 to 2.88); 2.89 (95% CI 2.41 to 3.47) for men and 2.28 (95% CI 1.88 to 2.78) for women, corresponding to a male to female rate ratio of 1.26:1. The mean annual incidence rate, age, and sex adjusted to the 1991 Italian population was 2.25 (95% CI 1.87 to 2.49). The incidence rate, age-adjusted to the 1990 US population, for the 45 to 74 age group was 5.3 (95% CI 4.6 to 6.3) for the overall population, 5.9 (95% CI 4.9 to 7.1) for men, and 4.7 (95% CI 3.8 to 5.7) for women. Age-specific incidence rates according to gender of patients are reported in figure 2. An increase of incidence was evident with increasing age in both genders, with a peak in the 75 to 79 age group among men and in the 70 to 74 age group among women. The crude and adjusted incidence rates and the SIR for the nine provinces of the area are reported in table 1. When comparing the SIR of the nine provinces, no significant difference was found.

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Figure 2. Age- and gender-specific incidence rates of ALS in Piemonte and Valle d’Aosta, Italy, 1995–1996. Full line = men; dotted line = women.

Discussion.

The epidemiologic characteristics of ALS remain uncertain, despite the large number of studies performed in the last two decades. Three main issues are still debated: Are there geographic differences in the incidence of ALS among and/or within countries? Is ALS incidence increasing over time? Does the age-specific incidence of ALS increase with age up to the oldest age groups, indicating a strong age–risk effect? The data reported in the literature give little help in answering these questions. A meta-analysis of various studies is made difficult by the different methodologies used in case finding (clinical series and referral centers versus multiple concurrent sources) and by the differences in demographic structure of the populations studied.12 Moreover, the issue of choosing appropriate diagnostic criteria has been largely neglected in ALS epidemiologic literature until recently. In several studies, explicit criteria were not given14,20⇓; when criteria were indicated, wide variations were seen. Moreover, some epidemiologic studies failed to separate ALS from other forms of motor neuron disease, such as CSMA.5,6,14,20-22⇓⇓⇓⇓⇓ Due to the these intrinsic differences, a direct comparison of crude rates of the results of various studies can be misleading.

We performed a population-based, collaborative survey with a prospective design, with the involvement of all neurologists practicing in the study area. To improve case finding further, we also utilized some secondary sources of cases, such as the regional discharge archive and nonneurologic departments. The use of a prospective design allowed us to perform an intensive collection of cases, to utilize the same diagnostic criteria and identical questionnaires for diagnosis and follow-up, and to revise uncertain diagnoses during the follow-up. Moreover, this is the second epidemiologic survey to use WFN diagnostic criteria.

We have compared our data to a selected group of studies performed in the United States and in Europe. We considered 15 surveys ( table 2), including 86,20,21,23-27⇓⇓⇓⇓⇓⇓⇓ judged to have the most complete case ascertainment in a previous review3; 6 recent studies performed during the 1990s—3 with a prospective5,13,14⇓⇓ and 3 with a retrospective design22,29,30⇓⇓; and a previous retrospective study performed in Piemonte, Italy, during the period 1966 to 1985,28 because it refers to the same area, although it was performed with a retrospective design. In order to carry out a more correct comparison, crude incidence rates were age- and sex-adjusted to the 1990 US population. The 45 to 74 age band was selected because this age interval is likely to be the least affected by differences in completeness of ascertainment methodologies.3,5⇓ Table 2 shows adjusted incidence rates for the 44 to 54, 55 to 64, and 65 to 74 age groups, and for the overall 45 to 74 age band.

According to 95% confidence intervals, the incidence rate observed in Piemonte in 1995 to 1996 is within the range of most previous studies. Some surveys performed during the 1970s and the 1980s have significantly lower values,6,21,23,28,29⇓⇓⇓⇓ but these low incidences are likely to reflect underdiagnosis as well as different study designs rather than a real lower risk. Conversely, the emphasis on diagnosis and the involvement of neurologists practicing in the study area in our survey could have increased the incidence rate, shortening the average time from first symptoms to ALS diagnosis and increasing awareness of the disease.

When comparing the four studies that used a similar prospective design,5,13,14⇓⇓ the figures are remarkably similar, with little variation both in age-specific and overall incidence. Therefore, it can be suggested that when similar design and diagnostic criteria are used, ALS incidence seems to be steady geographically, despite the large differences in terms of genetics, environment, and socioeconomic background of the areas analyzed in these studies. Moreover, this finding does not support the recent suggestion of a north-to-south decreasing gradient in ALS incidence rates both in the United States and in Europe.4,5⇓

The overall male to female rate ratio (1.3:1) observed in our study is lower than that found in most retrospective clinical31,32⇓ and population-based studies (see table 2). Male preponderance could be the result of hormone influence or a confounder for putative risk factors such as trauma, occupational exposure, and physical activity,33 or it could be simply due to an underascertainment of cases among older women.12 However, several papers have suggested an increase of ALS incidence and mortality rates among women during the last decades6-9⇓⇓⇓; this could be due to modifications of lifestyle and behavior among women during the last decades.

The mean age at diagnosis in our series was 62.8 years; i.e., in the range of most recent prospective studies,5,13,14⇓⇓ but higher than that reported in older epidemiologic studies.6,23,24⇓⇓ As suggested by some authors,5,12⇓ a higher mean age at onset could be an index of a more complete case ascertainment among the elderly.

We observed an increase in age-specific incidence rate up to the 75 to 79 age group in men and the 70 to 74 age group in women, with a decline thereafter, similar to the trend reported in most epidemiologic studies.5,6,13,14,21,22,25,26,29⇓⇓⇓⇓⇓⇓⇓⇓ On the contrary, in the Rochester study, a continuous rise in incidence with age was found,27 although this observation was based on a small population with large confidence intervals and was observed only among men. The question of the age-dependent increase of ALS incidence is quite important, as it could be related to ALS pathogenesis. In fact, a progressive increase of ALS incidence with age, as in the Rochester study, could reflect an interaction between the pathologic process and the neuronal loss due to age.34 Conversely, the identification of a peak of incidence in a specific age group, as in the current and in other studies, could be related to a time period of maximal susceptibility to the disease, or it could be the consequence of the length of latency period, exposure intensity, or cumulative exposure related to specific toxin(s).35

In our series, lower limbs were found to be a more frequent site of onset than the upper limbs, contrary to other studies.6,32⇓ This difference could be related to an underdiagnosis of patients with onset in lower limbs in older studies, as false-negative diagnoses are more common in patients with lower limb onset.36 The more common onset in lower limbs supports the hypothesis that motor axons with greater length may be more susceptible to the degenerative process,37 as observed, for example, in most peripheral motor neuropathies.

Geographic clusters other than Western Pacific foci have been extensively researched in ALS. Until now, only two small geographic clusters have been detected, the first supposedly related to high consumption of freshly caught fish from Lake Michigan,38 the other to environmental exposure to lead.39 However, due to the small number of cases and the retrospective analysis of putative risk factors in these two studies, their results need to be replicated. Moreover, other surveys did not find any significant difference in geographic distribution of ALS.5,13,30⇓⇓ We detected only slight, nonsignificant differences in the incidence rates and SIR of ALS among the provinces of Piemonte and Valle d’Aosta.

The findings of this and other recent prospective surveys could help in clarifying ALS epidemiology. ALS distribution in Western countries seems to be remarkably similar and the perceived differences are likely to be mostly due to methodologic and demographic factors. If confirmed, these observations could have a significant impact on the research of ALS pathogenesis, as they point to diffuse environmental or genetic factors rather than to exogenous toxins specifically acting in defined areas. The PARALS will continue to operate in order to confirm these findings in coming years and to verify possible temporal modifications of the epidemiology of ALS.

Appendix

Coordinating center: Department of Neuroscience, University of Torino, Italy. Project coordinator: A. Chiò, MD. Study monitors: A. Terreni, MD; A. Cucatto, MD; and A. Calvo, MD. Scientific Committee: A. Bertolotto, MD; E. Bottacchi, MD; A. Chiò, MD; A. Cognazzo, MD; D. Cocito, MD; M. Teresa Giordana, MD; M. Leone, MD; L. Mazzini, MD; and G. Mora, MD. Collaborating centers: Department of Neuroscience, Section of Neurology, University of Torino, and Azienda Ospedaliera San Giovanni, Torino (A. Chiò, MD; D. Schiffer, MD; R. Mutani, MD; D. Cocito, MD; B. Bergamasco, MD; I. Rainero, MD); Department of Neuroscience, Section of Neurology, University of Torino, and Azienda Ospedaliera San Luigi Gonzaga, Orbassano (A. Bertolotto, MD; A. Tribolo, MD; R. Sciolla, MD; F. Mondino, MD; and M.T. Giordana, MD); Department of Neurology, University of Piemonte Orientale ‘”Amedeo Avogadro,” Azienda Ospedaliera Maggiore, Novara (M. Leone, MD; P. Gaviani, MD; and F. Monaco, MD); Department of Neurology, Azienda Ospedaliera San Giovanni, Torino (M. De Mattei, MD; and E. Morgando, MD); Department of Neurology, Ospedale Mauriziano, Torino (L. Sosso, MD; and M. Gionco, MD); Department of Neurology, Ospedale Martini, Torino (U. Morino, MD; and M. Nobili, MD); Department of Neurology, Ospedale Maria Vittoria, Torino (L. Appendino, MD); Department of Neurology, Ospedale Giovanni Bosco, Torino (D. Piazza, MD); Department of Neurology, Ospedale Gradenigo, Torino (E. Oddenino, MD; and W. Liboni, MD); Department of Neurology, Ospedale di Ivrea (G. Vaula, MD; and G. Ferrari, MD); Department of Neurology, Ospedale di Pinerolo (M. Favero, MD; and C. Doriguzzi Bozzo); Department of Neurology, Ospedale di Vercelli (P. Santamaria, MD); Department of Neurology, Ospedale di Biella (U. Massazza, MD; and E. Bollani, MD); Department of Neurology, Ospedale di Domodossola (A. Villani, MD; and R. Conti, MD); Department of Neurological Rehabilitation, Fondazione S. Maugeri, Clinica del Lavoro e della Riabilitazione, IRCCS, Scientific Institute of Veruno (G. Mora, MD; L. Mazzini, MD; and C. Balzarini, MD); Department of Neurology, Alessandria (M. Palermo, MD); Department of Neurology, Ospedale di Casale Monferrato (F. Vergnano, MD); Department of Neurology, Ospedale di Novi Ligure (S. Cordera, MD; and C. Buffa, MD); Department of Neurology, Ospedale di Tortona (M.T. Penza, MD); Department of Neurology, Ospedale di Asti (F. Fassio, MD); Department of Neurology, Azienda Ospedaliera Santa Croce e Carle, Cuneo (P. Meineri, MD); Department of Neurology, Ospedale di Savigliano (A. Cognazzo, MD; C. Mocellini, MD; and A. Dutto, MD); Department of Neurology, Ospedale di Alba (C. Cavestro, MD; and W. Troni, MD); Department of Neurology, Ospedale Regionale di Aosta (G. Corso, MD; and E. Bottacchi, MD).