Abstract
Objective: To assess the incidence and trends of ALS in a large population at risk.
Methods: This study was performed in nine provinces of Lombardy in Northern Italy (population 4,947,554). Patients with newly diagnosed ALS were enrolled during the period 1998 to 2002 through a prospective regional register. For each patient, the main demographic and clinical information was collected by the caring physicians and reviewed by a panel of experts according to the original and revised El Escorial diagnostic criteria. Overall, age- and sex-specific and standardized annual incidence rates were calculated for the entire population and for each year and province separately.
Results: We studied 517 patients (M:F ratio 1.3) aged 18 to 92 years (mean 63.6). Onset of symptoms was bulbar in 29% of cases. ALS was definite in 45%, probable in 27%, probable laboratory supported in 3.5%, possible in 15%, and suspected in 10%. Mean disease duration at diagnosis was 10.6 months. The standardized incidence rate was 2.09 per 100,000/year (95% CI: 1.17 to 3.18). The rate, which was 2.43 in men and 1.76 in women, tended to increase up to ages 65 to 74 and to decrease thereafter. The rate was unchanged over time and presented moderate variations across provinces. The incidence rate of definite ALS was 0.93 (spinal-onset ALS 1.35; bulbar-onset ALS 0.74) and was consistently higher in men with spinal-onset ALS vs men with bulbar-onset ALS and women.
Conclusions: The incidence of ALS varied according to age, sex, and site of onset. No temporal and geographic clusters were detected over a 5-year period.
Until the mid-1990s, the worldwide incidence of ALS was reported to range from 0.4 to 2.6 cases per 100,000 population per year.1 The wide variability of the published rates can be mostly interpreted based on the small study populations, thus leading to fluctuating rates and fairly wide CIs. In addition, different diagnostic criteria and methods of case ascertainment have been used, which may have led to over- or underascertainment of patients with ALS.2 Large populations must be thus investigated using standard classification criteria to provide more stable incidence rates and make comparative findings available. Recently, fairly large ALS samples have been reported from European national or regional registries.3–6 using the El Escorial diagnostic criteria,7 which are unanimously recognized as a valuable instrument for the diagnosis and the categorization of the level of diagnostic accuracy. In these studies, the incidence of ALS was found to be fairly stable, ranging from 1.7 to 2.5 per 100,000 per year. However, few data were available from these studies regarding the incidence rates across key demographic and clinical variables, including the level of diagnostic accuracy. In this study, we sought to investigate a large population sample to calculate the incidence of ALS as a whole and by selected demographic and clinical features and to assess the variability of the rates based on the level of diagnostic accuracy.
Methods.
Population.
The study population included all the residents of nine administrative districts (provinces) of the Lombardy region, a 23,851-km2 area located in northern Italy (figure 1). This is a largely industrialized area with a fairly stable population. The entire population at risk included 4,947,554 individuals (2001 census). Two provinces (Milan and Mantova; total population 4,085,000) were excluded because the patients could not be traced easily (Milan) or the local neurologists were unwilling to participate (Mantova).
Figure 1. Study area, population, and map of Lombardy.
The regional registry.
The registry was implemented in 1997. Details on the organization of the registry have been presented elsewhere.8 In summary, neurologists working in all the local hospitals were invited to ascertain patients with ALS admitted to their hospitals or seen in ambulatory consultations. Patients seen at the local neurophysiology units for the diagnosis of motor neuron diseases were also traced. To obtain an almost complete case ascertainment, other sources of cases were examined. These included the Regional Archive of Discharges (ICD-9-CM code 335.2), which includes all the patients discharged from the local hospitals during the study period, the archives of the Italian ALS lay association (AISLA), the records of all the ALS regional outpatient services and those of a hospital equipped to assist patients with ALS (the Veruno Medical Center) located in a nearby region. In addition, ALS experts working in regions adjacent to the study area were contacted looking for local residents seen in consultation. In summary, we used a multisource ascertainment for the inception.
Each putative case underwent full neurologic examination and neurophysiologic testing. Other diagnostic investigations (e.g., spinal tap, MRI) were performed only where clinically indicated. Each case was then classified according to the El Escorial categories and then reclassified according to the revised criteria.9 According to this classification, a patient was diagnosed with ALS at the presence of upper motor neuron (UMN) and lower motor neuron (LMN) findings in four regions (bulbar, cervical, thoracic, and lumbosacral). Depending on the extent of involvement of the UMN and LMN and the number of affected regions, ALS was diagnosed as definite, probable, possible, and suspected in the original El Escorial classification (table 1). The revised version requires exclusion of suspected ALS and identification of probable laboratory-supported ALS (UMN and LMN signs in one region or UMN signs in one region with LMN signs defined by EMG criteria in at least two limbs). To increase the homogeneity of reporting and diagnostic classification, the study participants were trained by participating in teaching sessions, during which the modalities of the study conduct and the use of the El Escorial categories were illustrated.
Table 1 El Escorial criteria for the diagnosis of ALS7
Ad hoc semistructured forms were used by the local investigators to register all the eligible patients. Records were taken of the main demographic and clinical findings, the latter including date of onset of symptoms, date of diagnosis, type of onset (bulbar vs spinal), and presence of upper and lower motor neuron signs in the four regions, as indicated by the El Escorial classification. For the purposes of this study, bulbar-onset ALS includes patients with generalized (bulbar and spinal) onset.
The forms were revised by investigators from the study coordinating center and checked for accuracy and completeness. Discrepancies were solved by discussing each case with the local investigators to reach a consensus.
Registration of patients with ALS was started on January 1, 1998. For the purposes of the present study, only patients registered until December 31, 2002, have been considered.
Statistical analysis.
Incidence rates are provided for the entire study population and for specific age groups and by sex, year of diagnosis, province, type of onset, and El Escorial category. Rates were computed with 95% CI according to the Poisson distribution. Crude and standardized rates were indicated separately, the latter being adjusted to the 2001 Italian population and the 1990 U.S. population, using the direct method. Descriptive statistics were also performed using the Student t test, Pearson and Cochrane-Mantel-Haenszel χ2 tests, and the Wilcoxon and Mann-Whitney tests as appropriate. Multivariate analysis using logistic regression models adjusting for age, sex, and El Escorial category was performed in selected instances, when statistical correlations were detected by univariate analysis.
Results.
During the study period, a total of 517 patients were registered (1998: 98; 1999: 96; 2000: 96; 2001: 118; and 2002: 109). The sample included 293 men and 224 women aged 18 to 92 years (mean 63.6 years). The age at registration was younger than 45 years in 8.7% of cases and older than 74 years in 17.6%. The percentage of women tended to increase with age, being 28.9% among patients aged younger than 45 years and 52.2% among those aged 75 years and older (p < 0.0001). Sixty-five percent of patients had spinal-onset ALS and 28.8% had bulbar-onset ALS, and 6.4% had generalized-onset ALS. Bulbar-onset ALS was present in 28.7% of men and 43.8% of women (p < 0.0001). Disease duration at diagnosis was less than 6 months in 34% of cases and longer than 12 months in 27.7%. The mean (SD) disease duration at diagnosis was 10.6 (9.4) months. There was an increasing proportion of bulbar-onset ALS with age, but only in women (p < 0.002) (data not shown). Disease duration at diagnosis did not vary with age, but it varied when the two sexes were compared, being less than 6 months in 54.9% of men and 36.6% of women (p < 0.005). Definite ALS was diagnosed in 44.7% of cases, probable ALS in 26.7%, possible ALS in 18.8%, and suspected ALS in 9.9%. After recoding each case using the revised El Escorial classification, possible ALS was changed to probable laboratory-supported ALS in 18 cases (3.5%). There was a significant correlation between El Escorial category and type of onset of symptoms. Bulbar-onset ALS represented 40.7% of cases with definite ALS and 13.7% of cases with suspected ALS (p < 0.0001). No correlation was found between diagnostic categories and age, sex, and disease duration at diagnosis.
The average annual incidence of ALS in the entire study population was 2.09 per 100,000 (95% CI: 1.17 to 3.18). The rate was 2.43 in men and 1.76 in women, tended to increase with age up to 65 to 74 years and to decrease thereafter (table 2). The incidence rates were constantly higher in men than in women for each age group. The rate was virtually unchanged in each year of the study period and presented moderate variations when comparing the different provinces within the study area (table 3). The incidence of definite ALS was 0.93 per 100,000. The comparative rates for the other El Escorial categories are illustrated in table 3. The incidence of spinal-onset ALS was 1.35 and that of bulbar-onset ALS was 0.74.
Table 2 Age-specific incidence rates of ALS by sex
Table 3 Crude incidence rates of ALS by main demographic and clinical variables
The age-specific incidence of ALS by sex and site of onset is illustrated in figure 2. The rate was consistently higher in men with spinal-onset ALS, peaking at ages 75 to 79 years, compared to men with bulbar-onset ALS and women. In the latter, the rate tended to overlap when comparing spinal-onset to bulbar-onset ALS. The disease peaked at ages 70 to 74 years in women and fluctuated at ages 65 to 69 years through ages 80 to 84 years in men with bulbar-onset ALS.
Figure 2. Crude incidence rate by sex, site of onset, and age.
Discussion.
Our study provided incidence rates for ALS, which are fairly comparable to those of other population-based studies using the same strategy for case ascertainment and the same diagnostic criteria.4–6 The accuracy of our study is confirmed by the large number of investigated sources, the consistency of the rates during the entire study period, and the modest differences found comparing the different provinces within the study area. To date, with one exception,10 our study is the largest population-based survey. Our incidence rates are slightly lower than those of the Irish4 and Piemontese5 registries and slightly higher than those of the Puglia registry (SLAP), a regional registry started in 1998 in southern Italy with the same methodology and conduct6 (table 4). Different methods of case ascertainment may explain in part the differences (see also below).
Table 4 Comparison of age-specific and age-adjusted incidence rates to the 1990 U.S. population from selected prospective register studies
The large reference population and the length of follow-up gave us the adequate sample to look at distribution of clinical features in the incident cases. The proportion of our patients with bulbar-onset ALS (29%) was lower than that of other reports.4,10 The difference may be explained by the lower proportion of elderly individuals affected by ALS in our cohort (table 2). In our study, 15% were patients aged 75 years and older compared to 24% of Scottish patients.10 As bulbar-onset ALS may be most common in the elderly, this disease variety may be underdiagnosed in our population and in the SLAP registry.
The disease peaked at age 65 to 74 years, in keeping with several reports, which confirms that ALS is probably an age-related clinical condition. However, the small numbers in the oldest age categories still prevent definite conclusions on this issue.
Interestingly, when gender and site of onset were assessed separately, the incidence rate seemed consistently higher in men with spinal-onset ALS compared to the other categories. An as yet unknown sex-related environmental risk factor may explain our findings. Strenuous exercise and repeated traumatic events (most common in men as a consequence of selected occupational or sport activities) may be implicated, as reported by others.11–13
Disease duration at registration was significantly longer in women than in men. This might be explained by the greater tendency to misdiagnosis of onset symptoms in women. However, the lack of correlation between disease duration and age seems to contrast with the assumption of a decreased tendency of the elderly to promptly seek medical advice.
Bulbar-onset ALS, but not age, sex, and disease duration affected the level of diagnostic accuracy. Patients with bulbar-onset ALS were also most commonly women and predominated in the oldest age groups. This is in keeping with other reports.14 However, the correlation between age and this type of onset is significant only in women. Given the similarity in the age-specific incidence rates in men and women with bulbar-onset ALS (figure 2), this discrepancy may be only explained by the increasing proportion of women surviving to the oldest age groups.
In this study, we confirmed that the incidence of ALS varies with the level of diagnostic accuracy, ranging from 0.93 per 100,000 per year, when only definite ALS is considered, to 2.09 per 100,000 per year after including suspected ALS. Based on this finding, the different rates provided by the old reports may be also related to a different level of diagnostic accuracy and the use of differing diagnostic criteria.
The inclusion of suspected ALS in epidemiologic studies is still a matter of debate. Although this diagnostic category may be largely represented by progressive muscular atrophy (PMA) and there are reports defining pure sporadic lower motor neuron disease as a separate nosographic entity,15 still PMA can be considered as part of the spectrum of ALS because neurophysiologic and pathologic studies detect pyramidal tract involvement in patients with LMN signs,16,17 and ubiquinated inclusions (typical ALS findings) have been found in most PMA cases.17 In addition, patients with familial ALS carrying different superoxide dismutase-1 mutations present at the onset with a LMN phenotype18,19 and are included in the revised El Escorial categories as clinically definite familial, laboratory-supported ALS. In our population, the 1998 cohort was followed for a fairly long period of time (1,480 person-months), providing data on the transition of the suspected ALS cases into more definite El Escorial categories.20 In that cohort, 22% of cases had suspected ALS at registration. All but two of them moved to a different diagnostic category during follow-up, thus suggesting that almost all patients with LMN signs at first diagnosis may eventually have ALS.
Our study has several limitations. First, after excluding suspected ALS, our rates compare unfavorably with other epidemiologic reports, which only dealt with definite and probable ALS.5 Comparing age-specific incidence rates, we found that the largest differences were present in patients diagnosed in the more advanced age groups (table 4). This may be explained by misdiagnosis of ALS in the very old by the local investigators or by other doctors dealing with elderly patients. This may be the case in Italy, where these patients commonly live in nursing homes and may not be traced. The difficulty of case ascertainment in aged patients with ALS is well-known21 and may explain an ascertainment bias similar to that of the SLAP registry in Southern Italy.6 Second, the diagnostic categories were re-revised during follow-up only in a limited number of cases. This may have resulted in an unknown number of diagnostic errors, which might have biased our incidence rates. However, extrapolating our data from the results of the prolonged follow-up of our 1998 cohort (with only five patients having a confirmatory diagnosis of possible or suspected ALS),20 we assume that the degree of misdiagnosis is fairly low.
Appendix
The SLALOM Group: D. Alimonti, Ospedale Policlinico (Monza); D. Baldini, Ospedale Civile (Sondrio); C. Balzarini, (Sesto Calende); C. Bendotti, Istituto Mario Negri (Milan); M.D. Benedetti, Clinica Neurologica Università di Verona (Verona); G. Bianchi, Ospedale di Lecco (Lecco); G. Bogliun, Ospedale S. Gerardo (Monza); V. Bonito, Ospedali Riuniti (Bergamo); A. Brambilla, Ospedale Bolognini (Seriate); L. Brunati, Ospedale S. Carlo (Milan); R. Causarano, Ospedale Niguarda Ca'Granda (Milan); M. Ceroni, Clinica Neurologica C. Mondino, Ospedale S. Gerardo, (Pavia, Monza); A. Cheldi, Ospedale di Desio (Desio); L. Chiveri, Ospedale Valduce (Como); A. Citterio, IRCCS C. Mondino (Pavia); M. Clerici, Ospedale Policlinico (Milan); M. Corbo, Istituto Auxologico (Milan); M.L. Delodovici, Ospedale di Circolo (Varese); C. Ferrarese, Ospedale S. Gerardo (Monza); G. Filippini, Istituto Neurologico C. Besta (Milan); A. Galli, Ospedale S. Gerardo (Monza); G. Guarneri, Ospedale Generale Provinciale (Cremona); M. Guidotti, Ospedale Valduce (Como); I. La Spina, Ospedale Generale Provinciale (Busto Arsizio); M. Leone, Ospedale Maggiore della Carità (Novara); L. Lo Russo, Azienda Ospedaliera (Chiari-Rovato); E. Magrotti, Ospedale di Voghera (Voghera); G. Mariani, Azienda Ospedaliera di Legnano (Legnano); L. Mazzini, Ospedale Maggiore della Carità (Novara); T. Mennini, Istituto Mario Negri (Milan); G. Meola, Ospedale Clinicizzato (San Donato); G. Mora, Fondazione S. Maugeri (Pavia); S. Moroni, Ospedali Riuniti (Bergamo); E. Munerati, IRCCS San Raffaele/Università (Milan); M. Perini, Ospedale S. Antonio Abate (Gallarate); P. Perrone, Azienda Ospedaliera di Legnano (Legnano); M. Poloni, Ospedali Riuniti (Bergamo); A. Prelle, Università di Milan (Milan); M. Rezzonico, Ospedale S. Anna (Como); T. Riccardi, Ospedale di Crema (Crema); R. Riva, Ospedali Riuniti (Bergamo); A. Romorini, Ospedale Magenta (Magenta); F. Sasanelli, Ospedale di Circolo Vizzolo Predabissi (Melegnano); V. Silani, Istituto Auxologico (Milan); F. Tavernelli, Ospedale S. Antonio Abate (Gallarate); D. Testa, Istituto Neurologico C. Besta (Milan); M.C. Tonini, Ospedale G. Salvini (Garbagnate).
Footnotes
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↵*See the appendix for a list of SLALOM Group members.
The SLALOM Register has been supported by the Fondazione Monzino and by the Istituto Superiore di Sanità (contract no. 526/A31).
Disclosure: The authors report no conflicts of interest.
Received May 1, 2006. Accepted in final form September 27, 2006.
References
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