127th ENMC International Workshop: Implementation of a European Registry of ALS Naarden, The Netherlands, 8–10 October 2004
2006; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês
10.1016/j.nmd.2005.10.004
ISSN1873-2364
Autores Tópico(s)Neurogenetic and Muscular Disorders Research
ResumoThe aim of the meeting was to establish a database for the prospective collection of epidemiological information on patients diagnosed with ALS in Europe. In other words, the establishment of a pan European ALS register. The data collection will be performed pursuing two major objectives: 1. To recruit a large population-based sample of patients with ALS. This will be achieved by merging the information collected by the existing national and regional registries from Italy, Ireland, England, and Scotland; 2. To collect baseline information on newly diagnosed patients from Spain, Serbia, and other countries where population-based registries are not yet available. This data will be utilized in recruiting for parallel studies and therapeutic trials. Amyotrophic lateral sclerosis (ALS) is a rare neurological condition (overall annual incidence rate in Europe 0.4–2.5 per 100,000) [1Traynor B.J. Codd M.B. Corr B. Forde C. Frost E. Hardiman O. Incidence and prevalence of ALS in Ireland, 1995–1997: a population-based study.Neurology. 1999; 52: 504-509Crossref PubMed Google Scholar, 2The scottish motor neuron disease register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989. J Neurol Neurosurg Psychiatry 1992; 55: p. 536–541.Google Scholar, 3Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (PARALS) Incidence of ALS in Italy: evidence for a uniform frequency in Western countries.Neurology. 2001; 56: 239-244PubMed Google Scholar, 4Chazot F. Vallat J.M. Hugon J. Lubeau M. Dumas M. Amyotrophic lateral sclerosis in limousin (Limoges area, France).Neuroepidemiology. 1986; 5: 39-46Crossref PubMed Scopus (23) Google Scholar, 5Tysnes O.B. Vollset S.E. Aarli J.A. Epidemiology of amyotrophic lateral sclerosis in Hordaland county, western Norway.Acta Neurol Scand. 1991; 83: 280-285Crossref PubMed Scopus (63) Google Scholar, 6Forsgren L. Almay B.G. Holmgren G. Wall S. Epidemiology of motor neuron disease in northern Sweden.Acta Neurol Scand. 1983; 68: 20-29Crossref PubMed Scopus (117) Google Scholar, 7Alcaz S. Jarebinski M. Pekmezovic T. Stevic-Marinkovic Z. Pavlovic S. Apostolski S. Epidemiological and clinical characteristics of ALS in Belgrade, Yugoslavia.Acta Neurol Scand. 1996; 94: 264-268Crossref PubMed Scopus (32) Google Scholar] with severe prognosis and death within 3–5 years from diagnosis [8Lee J.R. Annegers J.F. Appel S.H. Prognosis of amyotrophic lateral sclerosis and the effect of referral selection.J Neurol Sci. 1995; 132: 207-215Abstract Full Text PDF PubMed Scopus (112) Google Scholar, 9Preux P.M. Couratier P. Boutros-Toni F. et al.Survival prediction in amyotrophic lateral sclerosis.Neuroepidemiology. 1996; 15: 153-160Crossref PubMed Scopus (65) Google Scholar, 10Traynor B.J. Codd M.B. Corr B. Forde C. Frost E. Hardiman O.M. Clinical features of amyotrophic lateral sclerosis according to the El escorial and airlie house diagnostic criteria.Arch Neurol. 2000; 57: 1171-1176Crossref PubMed Scopus (314) Google Scholar]. Several community studies have been performed to study the incidence and characteristics of ALS in Europe. These include surveys from well-defined populations [4Chazot F. Vallat J.M. Hugon J. Lubeau M. Dumas M. Amyotrophic lateral sclerosis in limousin (Limoges area, France).Neuroepidemiology. 1986; 5: 39-46Crossref PubMed Scopus (23) Google Scholar, 5Tysnes O.B. Vollset S.E. Aarli J.A. Epidemiology of amyotrophic lateral sclerosis in Hordaland county, western Norway.Acta Neurol Scand. 1991; 83: 280-285Crossref PubMed Scopus (63) Google Scholar, 6Forsgren L. Almay B.G. Holmgren G. Wall S. Epidemiology of motor neuron disease in northern Sweden.Acta Neurol Scand. 1983; 68: 20-29Crossref PubMed Scopus (117) Google Scholar, 7Alcaz S. Jarebinski M. Pekmezovic T. Stevic-Marinkovic Z. Pavlovic S. Apostolski S. Epidemiological and clinical characteristics of ALS in Belgrade, Yugoslavia.Acta Neurol Scand. 1996; 94: 264-268Crossref PubMed Scopus (32) Google Scholar] and studies from population-based regional [[3]Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (PARALS) Incidence of ALS in Italy: evidence for a uniform frequency in Western countries.Neurology. 2001; 56: 239-244PubMed Google Scholar] and national registries [1Traynor B.J. Codd M.B. Corr B. Forde C. Frost E. Hardiman O. Incidence and prevalence of ALS in Ireland, 1995–1997: a population-based study.Neurology. 1999; 52: 504-509Crossref PubMed Google Scholar, 2The scottish motor neuron disease register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989. J Neurol Neurosurg Psychiatry 1992; 55: p. 536–541.Google Scholar]. Although these registries provide fairly high and homogeneous incidence rates, they have insufficient power to study risk factors with low exposure levels, because of the small sample size. In addition, large numbers of patients with newly diagnosed ALS from different countries are needed to study the quality of care of the disease in different health care settings and to make sufficient patient numbers available for therapeutic trials recruitment. For these reasons, studies from larger populations obtained by merging data from multiple sources represent a major and logical step in the evolution of ALS epidemiology. The diagnosis of ALS is based on the presence of upper and lower motor neuron impairment, the detection of symptom progression over a limited period of time, and the exclusion of other conditions that may mimic ALS. Several diagnostic criteria have been devised for ALS [2The scottish motor neuron disease register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989. J Neurol Neurosurg Psychiatry 1992; 55: p. 536–541.Google Scholar, 11Ross M.A. Miller R.G. Berchest L. et al.Toward earlier diagnosis of amyotrophic lateral sclerosis. Revised criteria.Neurology. 1998; 50: 768-772Crossref PubMed Scopus (91) Google Scholar, 12del Aguila M.A. Longstreth W.T. McGuire V. et al.Prognosis in amyotrophic lateral sclerosis. A population-based study.Neurology. 2003; 60: 813-819Crossref PubMed Scopus (338) Google Scholar]; however, most of them have been used in single studies and none has undergone a formal validation process, which prevents meaningful comparisons across studies. The El Escorial criteria (ECC) are the only diagnostic criteria having widespread use and has being assessed for validity and reliability [[13]Brooks B.R. El escorial world federation of neurology criteria for the diagnosis of amyotrophic lateral sclerosis.J Neurol Sci. 1994; 124: 96-107Abstract Full Text PDF PubMed Scopus (1951) Google Scholar]. According to these criteria, an ALS patient can be classified as definite, probable, possible, or suspected ALS based on the impairment of upper and/or lower motor neuron and on the number of involved regions (bulbar, cervical, thoracic, lumbo-sacral) (Table 1).Table 1El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis (ALS) (13)The diagnosis of ALS requires the presence of each of the following:(1) Lower motor neuron (LMN) signs by clinical, electrophysiological, or neuropathological examination in one or more of four regions (bulbar, cervical, thoracic, lumbo-sacral)(2) Upper motor neuron (UMN) signs by clinical examination in one or more of the four regions(3) Progression of signs within a region or to other regionsDefinite ALS=UMN+LMN signs in three regions. Probable ALS=UMN+LMN signs in two regions with UMN signs rostral to LMN signs. Possible ALS=LMN signs in one region or UMN signs in two or three regions, such as monomelic ALS, progressive bulbar palsy, and primary lateral sclerosis. Suspected ALS=LMN signs in two or three regions, such as progressive muscular atrophy, and other motor syndromes. Open table in a new tab Definite ALS=UMN+LMN signs in three regions. Probable ALS=UMN+LMN signs in two regions with UMN signs rostral to LMN signs. Possible ALS=LMN signs in one region or UMN signs in two or three regions, such as monomelic ALS, progressive bulbar palsy, and primary lateral sclerosis. Suspected ALS=LMN signs in two or three regions, such as progressive muscular atrophy, and other motor syndromes. The advantages of the ECC include a high specificity when they are used in the selection of patients for clinical trials. By contrast, the ECC are difficult to apply in clinical practice, they are excessively rigid, and they assume ALS is a single disease entity. The overall burden of disease is not assessed and the four CNS regions are given equal weighting, thus preventing the EEC from having prognostic significance. Furthermore, some patients may be excluded if they are in the early stage of the disease or they have atypical features. The reliability of the ECC has been recently tested through evaluation of medical records and was found to be modestly reliable in the hands of neurologists with different background and experience [[14]Beghi E. Balzarini C. Bogliun G. et al.Reliability of the El escorial diagnostic criteria for amyotrophic lateral sclerosis.Neuroepidemiology. 2002; 21: 265-270Crossref PubMed Scopus (54) Google Scholar]. Specific training significantly improved the reliability of the diagnostic criteria, concordance remaining poor only at the lowest levels of the diagnostic certainty (‘suspected ALS’). The ECC were revised (the Airlie-House criteria) by dropping the category ‘suspected ALS’ and introducing a novel category (‘probable laboratory-supported ALS’) based on the results of the electrophysiological examination [[15]Miller R.G. Munsat T.L. Swash M. Brooks B.R. Consensus guidelines for the design and implementation of clinical trials in ALS. World federation of neurology committee on research.J Neurol Sci. 1999; 169: 2-12Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar] (Table 1). Although the reliability of the revised criteria has been found to be similar to the ECC [[16]Forbes R.B. Colville S. Swingler P.J. Are the El escorial and revised El escorial criteria for ALS reproducible. A study of inter-observer agreement.Amyotroph Lateral Scler Other Motor Neuron Disord. 2001; 2: 135-138Crossref PubMed Scopus (27) Google Scholar], they are also less reproducible because they include more diagnostic categories. In addition, patients with early symptoms (i.e.‘suspected’ ALS) are excluded, preventing assessment of the full spectrum of the disease for prognostic studies. This approach excluded less severe disease varieties (which may be more responsive to investigational treatments). In conclusion, even with these limitations, the ECC are the logical choice as ALS diagnostic and classification criteria for a population-based registry. However, proper training of the assessors is required, and detailed follow-up of patients falling into the lower levels of the diagnostic certainty, to confirm the appropriateness of the diagnosis and exclude ALS mimic syndromes or other clinical conditions. Several environmental risk factors have been implicated as putative causes of ALS [[17]Mitchell J.D. Beaumont A.M. Motor neuron disorders with other diseases and exposures.in: Eisen A. Clinical neurophysiology of motor neuron diseases. Handbook of clinical neurophysiology. vol. 4. Elsevier, Amsterdam2004: 451-466Google Scholar] including mechanical trauma, activity-related exposures (welding, agriculture, leather, rubber, solvent, chemicals, lead, mercury, aluminum, selenium, manganese and iron), electrical trauma, ionizing radiations, smoking, alcohol consumption, chemicals, and magnetic fields; pathogenic mechanisms have been postulated for some of these exposures. Long-term exposure to electromagnetic fields may result in the production of autoantibodies against calcium channels disrupting calcium homeostasis [[18]Walleczek J. Electromagnetic field effects on cells of the immune system: the role of calcium signaling.FASEB J. 1992; 6: 3177-3185PubMed Google Scholar]. Lead exposure has long been associated with motor neuron disease and since the early historical reports, several studies have suggested a possible link between the two conditions [[17]Mitchell J.D. Beaumont A.M. Motor neuron disorders with other diseases and exposures.in: Eisen A. Clinical neurophysiology of motor neuron diseases. Handbook of clinical neurophysiology. vol. 4. Elsevier, Amsterdam2004: 451-466Google Scholar]. Lead can cause peripheral neuropathy and encephalopathy in humans, with a dose-effect relationship existing between blood levels and clinical findings [[19]Cory-Schlecta D.A. Schaumburg H.H. Lead, inorganic.in: Spencer P.S. Schaumburg H.H. Ludolph A.C. Experimental and clinical neurotoxicology. 2nd ed. Oxford University Press, New York2000: 708-720Google Scholar]. Lead concentrations are elevated in the anterior horn cells of ALS patients previously exposed to high levels of lead [[20]Kurlander H.M. Patten B.M. Metals in spinal cord tissue of patients dying of motor neuron disease.Ann Neurol. 1979; 6: 21-24Crossref PubMed Scopus (81) Google Scholar] and may cause upper motor neuron degeneration in predisposed individuals. Lead mimics calcium and exerts its toxic action through several mechanisms, ranging from alteration of energy metabolism, to complex changes in neurotransmitters [[19]Cory-Schlecta D.A. Schaumburg H.H. Lead, inorganic.in: Spencer P.S. Schaumburg H.H. Ludolph A.C. Experimental and clinical neurotoxicology. 2nd ed. Oxford University Press, New York2000: 708-720Google Scholar]. The possibility of genetic susceptibility implying higher lead body burden [[21]Kamel F. Umbach D.M. Munsat T.L. Shefner J.M. Hu H. Sandler D.P. Lead exposure and amyotrophic lateral sclerosis.Epidemiology. 2002; 13: 311-319Crossref PubMed Scopus (148) Google Scholar] and thus linking ALS with lead exposure has been recently investigated [[22]Kamel F. Umbach D.M. Lehman T.A. et al.Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes.Environ Health Perspect. 2003; 111: 1335-1339Crossref PubMed Scopus (66) Google Scholar] but further studies are needed. Prolonged inorganic mercury intoxication may lead to an ALS-like syndrome, which may be reversible when the toxic agent is withdrawn [[23]Barber MD. Inorganic mercury intoxication reminiscent of amyotrophic lateral sclerosis. J Occupat Med 1978;20:667–9.Google Scholar]. Similar effects on anterior horn cells can be found in patients exposed to selenium, which may act through activation of free radicals and antioxidant enzymes (like superoxide-dysmutase) or even provoke genomic DNA alteration [[24]Vinceti M, Guidetti D, Pinotti M, et al. Amyotrophic lateral sclerosis after long-term exposure to drinking water with high selenium content. Epidemiology 1996;7:529–32.Google Scholar]. For aluminum and manganese, geochemical and pathological data from Western Pacific endemic areas suggested a role in ALS/Parkinson-Dementia-Complex. Aluminum organic and inorganic compounds administered by different routes provide an experimental model of progressive motor neuron degeneration with intraneuronal aggregation of neurofilaments in several animal species [[25]Strong M.J. Exogenous neuromtoxins.in: Brown Jr, R.H. Meininger V. Swash M. Amyotrophic lateral sclerosis. Martin Dunitz, London2000: 279-287Google Scholar]. Metal-triggered protein aggregation and misfolding could be a common mechanism in various neurodegenerative diseases, including ALS [26Uversky V.N. Li J. Fink A.L. Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular link between Parkinson's disease and heavy metal exposure.J Biol Chem. 2001; 276: 44284-44296Crossref PubMed Scopus (888) Google Scholar, 27Rakhit R. Cunningham P. Furtos-Matei A. et al.Oxidation-induced misfolding and aggregation of superoxide dysmutase and its implications for amyotrophic lateral sclerosis.J Biol Chem. 2002; 277: 47551-47556Crossref PubMed Scopus (265) Google Scholar]. Chronic exposure to solvents may produce progressive muscular atrophy, particularly in individuals with a family history of neurodegenerative disorders and thyroid dysfunction [[28]Gunnarsson L.G. Bodin L. Soderfeldt B. Axelson O. A case-control study of motor neuron disease: its correlation to heritability, and occupational exposures, particularly to solvents.J Ind Med. 1992; 49: 791-798Google Scholar]. Heavy physical activity and trauma may provoke or accelerate motor neuron degeneration in predisposed individuals [[29]Strickland D. Smith S.A. Dolliff G. et al.Physical activity, trauma, and ALS: a case-control study.Acta Neurol Scand. 1996; 94: 45-50Crossref PubMed Scopus (85) Google Scholar]. Despite a considerable literature, none of the putative risk factors has been found to fulfil the correct requirements for a cause-effect relationship. Finding a correlation between a risk factor or brain abnormality and ALS does not necessarily establish a causal association. In order for a given variable to be considered a risk factor for a disease, the association should require the satisfaction of the following conditions [[30]Schlesselman J.J. Case-control studies. Design, conduct, analysis. Oxford University, Oxford1982Google Scholar]: 1. Temporal sequence: the exposure must precede the disease in time; 2. Strength: a greater risk of disease is present among those exposed compared to those non-exposed; and the larger the difference of the exposure the greater the strength of the association; 3. Consistency: the association should be reproducible in different populations and under different conditions; 4. Biological gradient: the evidence of a dose-response effect; 5. Biological plausibility: the association between the disease and exposure should be consistent with a recognized biologic mechanism. The lack of evidence in support of a cause-effect relationship between ALS and the reported exposures may be explained by the poor design of the published studies, most of which do not qualify for class I or class II studies based on suggested standard EBM criteria [[31]Armon C. An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis.Neuroepidemiology. 2003; 22: 217-228Crossref PubMed Scopus (173) Google Scholar]. Regardless of the type of exposure, individual susceptibility may be implicated through concurrent clinical conditions (eg, osteoporosis or hyperparathyroidism) or simply through an altered genetic background; thus, ALS may be the consequence of a complex interaction between genetic and environmental factors. It has long been recognized that ALS sometimes aggregates within kindreds, which often suggests autosomal dominant inheritance. There are also reports of apparent geographical aggregations of sporadic ALS in Italy and the United Kingdom [32Malaspina A. Alimonti D. Poloni T.E. Ceroni M. Disease clustering: the example of ALS, PD, dementia and hereditary ataxias in Italy.Funct Neurol. 2002; 17: 177-182PubMed Google Scholar, 33Mitchell J.D. Gatrell A.C. Al-Hamad A. et al.Geographical epidemiology of residence of patients with motor neuron disease in Lancashire and South Cumbria.J Neurol Neurosurg Psychiatry. 1998; 65: 842-847Crossref PubMed Scopus (32) Google Scholar]. This yields a genetic explanation for an observation at first thought to a have an environmental basis. While such occurrences suggest a truly familial and genetically determined illness, this view has not always universally accepted. There were those who argued that this reflects common environmental exposure rather than genetically determined disease. Epidemiological research has thus yielded a wide range of confusing potential leads. However, rather than introducing unwanted confusion, they may hold important lessons: 1. There might be no unitary pathogenic mechanism for ALS; 2. The clinical syndrome of ALS might be a final common pathway with multiple and diverse triggers; 3. As no more than 20% of familial ALS is linked to a SOD1 mutation [[34]Majoor-Krakauer D. Willems P.J. Hoffman A. Genetic epidemiology of amyotrophic lateral sclerosis.Clin Genet. 2003; 63: 83-101Crossref PubMed Scopus (130) Google Scholar], a multiplicity of factors, some environmental, may be implicated; 4. ALS might occur in genetically susceptible individuals. To date, the interaction of gene and environment has not been carefully studied in the pathogenesis of ALS. It is possible that exposure to a particular environmental agent leads to motor neuron degeneration in individuals with specific genotypes that convey susceptibility. Individuals with different genotypes will not develop the phenotype, even after prolonged exposure to the same environmental toxin. The ability to detect gene-environment effect is limited by the small sample size of published studied and the use of different methods of ascertainment of the risk factors (which prevents pooling and comparability of data from different studies). Only studies with adequate design performed in large population-based samples may throw some light on genetic and exogenous risk factors and their complex interactions. Multicenter studies are a valuable tool for assessing the distribution and causative risk factors of a rare disease. Compared to studies done in a single institution, multicenter studies have an increased power, assess more properly the heterogeneity of the disease (demographics, spectrum, exposures) in the general population. However, multicenter studies imply multiple investigators with different background and training, multiple instruments, and challenges in communication. In addition, random noise (i.e. interacting and confounding variables) may be randomly distributed across centers, leading to loss of power and decreased precision. A more important issue is that the implementation of the study protocol may vary across centers. This can lead to an incorrect assessment of the distribution of the disease and of its relation with a given exposure. The existing ALS national and regional registries have different referral sources for ascertaining ALS cases (Table 2). The type of referral sources are largely dictated by the organization of the health care systems within each country. In addition, the populations may differ in their age and socio-cultural structure and the use of different languages complicates collection of the required demographic and analytical epidemiological information.Table 2Study areas, populations and modalities of case ascertainmentGeographic areaPopulation (in million)Source of PatientsHospital recordsAdministrative data (DRGs)GPsNeurologistsNeurophysiology UnitsTreatment filesOtherEngland (London)0.8++++++England (Preston) (*)1.8+France (Limousin)0.8++Ireland (*)5.0++++Israel6.5+++Italy (Lombardia) (*)5.0+++++Italy (Piemonte) (*)4.3+++Italy (Puglia) (*)4.0++Russian Federation28.6+++++Scotland (*)5.1+Serbia (Belgrade)1.6+±±Spain (Madrid)1±±±(*) Population-based registry. Regions or local areas in parentheses. Open table in a new tab (*) Population-based registry. Regions or local areas in parentheses. Standardization of the measurement methods is a prerequisite to performing a pan European multi-center epidemiological study. This entails the following: (a) Inter-observer agreement should be measured before the onset of the study; all sources of disagreement should be detected and discussed; (b) All observers should be trained and certified; (c) Questionnaires used to collect information on risk factor exposures should be refined; (d) Inter-observer agreement should be tested through a pilot study by using the adopted measurement methods before and after training. Ideally, a single person (a neurologist specializing in ALS) should be nominated for each site, who should verify that each patient entered in the database conforms to the diagnosis of ALS as defined by the ECC. A clinical panel should be also elected to discuss disputable cases (ALS vs. other clinical conditions) and for the attribution of the cases to the ECC diagnostic categories. A successful data management in a multicenter registry of ALS is based on the collection of a minimum number of variables. The choice should be based on a limited number of goal-directed, strictly defined and comprehensive variables to be collected in a simple, user-friendly, web-based registry. The principal goals of multicenter community-based registries are: (a) To share information and merge epidemiological and clinical data using population-based series of patients; and (b) To test hypotheses on the etiology and pathogenesis of ALS. For these reasons, a series of demographic and clinical variables are required for a correct definition of the spectrum of the disease and a number of exploratory variables should be identified to investigate the putative etiology and pathogenesis of the disease. Demographic and clinical (disease) variables to be collected by the pan European ALS registry include main clinical features of the disease such as age at symptom onset, gender and site of onset. Place of residency (urban vs. rural) and place of birth will also be collected. A detailed occupational history (including occupational exposures) should be collected and coded according to standard classification systems. The exploratory variables are selected to investigate pre-defined hypotheses. Therefore, information should be collected on diet, recreational substances, drugs, hormonal and reproductive variables, life habits, trauma, and family history of ALS and other neurodegenerative disorders. Diet should be referred to the year preceding the clinical onset of the disease and should be investigated by using a food frequency questionnaire, computing the energy intake in calories, and calculating the premorbid body mass index (BMI). Recreational substances should include cigarette smoking, alcohol intake, and use of illicit drugs, with period, dose and time relationship to ALS onset. Leisure activities should be also coded when investigating physical exercise. These should include sport participation, with indication whether professional or amateur, and specification of type, duration, and period. Physical activity should be then quantified using common standards. History of trauma should be investigated in detail, with type (mechanical/electrical/other), severity, time relation to ALS onset, and anatomical site. The recent observation that the incidence of ALS is increased among veterans of the Gulf war suggest that military service should be accurately described, with details on deployment and missions in foreign countries. Other recreational activities as well as environmental (home) exposures (e.g. high power lines, use of wells) should be also investigated, with type, period and duration. Women should give details about their reproductive history. Family history of ALS and other neurodegenerative disorders should be collected, with information from first and second-degree relatives. A correct interpretation of the cause-effect relationship between a given exposure and a disease is based on several assumptions, which include: (1) A correct diagnosis of the disease under scrutiny (see above); (2) The representativeness of the cases and the controls; (3) A sizable target population, from which cases and controls can be identified in sufficient numbers, estimated through adequate power calculations. Several methods of case ascertainment have been identified, leading to different levels of case selection. Patients with ALS may be identified when symptoms bring them to medical attention, there is an easy access to medical care, a correct diagnosis is made by an experienced physician, and they are willing to participate in the study. Patients identified through national or regional registries are the source of representative ALS cases because they provide a clear definition of the population-time experience (well-defined geographic boundaries and calendar periods) and a full roster of cases. To exclude subjects who might have moved to the study area for the management of their disease, care should be taken to enroll patients with ALS in whom the diagnosis has been made for at least one year or resident of the area of the study for at least one year. Controls must be then selected among people who approximate the exposure prevalence of the population generating the cases. Failure to select controls not reflecting the exposure prevalence of the general population may bias the study results toward an over- or an under-representation of the given exposure. Controls may be identified through different sources, including neighbors, people traced by random digit dialing, spouses/best friends, hospitalized patients, or people included in the rosters of the physician who referred the case. For the pan European register, the best strategy could be to select controls from the rosters of the general practitioners having in charge the ALS case. Controls should be resident of the same area of residency of the cases and should be matched for age and sex. The assessment of the exposures in the cases and controls should be performed as indicated in the section on data collection. Every patient to be registered in the pan European ALS register should fulfill the ECC l for suspected, possible, probable or definite ALS. This requires the presence of upper and/or lower motor-neuron impairment in at least one region of the CNS and documented retrospective evidence of progression over a 6 month period. The phenotype of
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