European Journal of Epidemiology

, Volume 22, Issue 11, pp 781–790 | Cite as

Geographic distribution of amyotrophic lateral sclerosis through motor neuron disease mortality data

  • Raffaella Uccelli
  • Alessandra Binazzi
  • Pierluigi Altavista
  • Stefano Belli
  • Pietro Comba
  • Marina Mastrantonio
  • Nicola Vanacore


Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurological disorder of the adult age with a prognosis of about 2–3 years from the onset of the disease. No clear cause has been identified but it seems to be a multifactorial disease with genetic and environmental components involved. Increments of mortality rates were observed since 1980 both in Italy and in many other countries. The objective of the present study is to describe the distribution of ALS mortality in Italy in the period 1980–2001 detecting single municipalities or clusters with high mortality levels for motor neuron disease (MND). ALS represents the main part (85%) of the MND group which is globally identified by the IX ICD (International Classification of Diseases and Causes of Death) 335.2 code. Death numbers and standardized mortality ratios (SMR) for MND were calculated for all Italian municipalities through the ENEA mortality database system (data source: National Institute of Statistics—ISTAT), using national mortality rates as reference. Subsequently, in order to detect municipal clusters, spatial analysis was performed. Out of the 8,099 Italian municipalities, 132 where characterized by SMR values higher than expected. Moreover 16 clusters with significant high relative risk values (RR) were identified, 12 out of them including only a single municipality. Only 22 of the municipalities with high SMR were included in the clusters. In conclusion, the two different epidemiological methodologies demonstrated to be widely complementary in detecting the geographical distribution of the disease in terms of risk for populations. A first selection of the priority areas where analytical studies should be carried on, in order to identify risk factors associated to ALS, is tentatively suggested.


Amyothrophic lateral sclerosis Cluster analysis Enviromental epidemiology Geographic distribution Mortality Motor neuron disease 



Amyotrophic lateral sclerosis


Confidence Intervals


International Classification of Diseases


Italian National Institute of Statistics


The National Agency for New Technologies, Energy and the Environment


Log likelihood ratio


Motor neuron disease


Observational unit


Standardized mortality ratio


Relative risk


Statistically significant


  1. 1.
    Pritchard C, Sunak S. The epidemiology and etiology of ALS: an interactive and interdisciplinary perspective. ALS Therapy Development Foundation, ALSTDF, 2005.Google Scholar
  2. 2.
    Siddique T, Figlewicz DA, Pericak-Vance M, Haines JL, Rouleau G, Jeffers AJ, Sapp P, Hung WY, Bebout J, McKenna-Yasek D, Deng G, Horvitz HR, Gusella JF, Brown RH Jr, Roses AD. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med 1991;324:1381–4. Erratum in: N Engl J Med 1991;325:524. N Engl J Med 1991;325:71.PubMedCrossRefGoogle Scholar
  3. 3.
    Hand CK, Mayeux-Portas V, Khoris J, Briolotti V, Clavelou P, Camu W, Rouleau GA. Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family. Ann Neurol 2001;49:267–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowsk T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001;29:166–73.PubMedCrossRefGoogle Scholar
  5. 5.
    Jonsson PA, Backstrand A, Andersen PM, Jacobsson J, Parton M, Shaw C, Swingler R, Shaw PJ, Robberecht W, Ludolph AC, Siddique T, Skvortsova VI, Marklund SL. CuZn-superoxide dismutase in D90A heterozygotes from recessive and dominant ALS pedigrees. Neurobiol Dis 2002;10:327–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Charcot JM. Des amyotrophies spinales chroniques. Progrés Médicale 1874;2:573–4.Google Scholar
  7. 7.
    Roman GC. Neuroepidemiology of amyotrophic lateral sclerosis: clues to aetiology and pathogenesis. J Neurol Neurosurg Psychiatry 1996;61:131–7.PubMedGoogle Scholar
  8. 8.
    Del Aguila MA, Longstreth WT Jr, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003;60:813–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Sejvar JJ, Holman RC, Bresee JS, Kochanek KD, Schonberger LB. Amyotrophic lateral sclerosis mortality in the United States, 1979–2001. Neuroepidemiology 2005;25:144–52.PubMedCrossRefGoogle Scholar
  10. 10.
    Altavista P, Belli S, Binazzi A, Comba P, Mastrantonio M, Uccelli R, Vanacore N. Incremento della mortalità per malattia del motoneurone in Italia negli anni 1980–1999. Epidemiol Prev 2006;30:108–113.PubMedGoogle Scholar
  11. 11.
    Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 1995;118:707–19.PubMedCrossRefGoogle Scholar
  12. 12.
    Walton J. Brain’s diseases of the nervous system. Oxford: Oxford University Press, 1993.Google Scholar
  13. 13.
    Victor M, Ropper AH. Adam and Victor’s Principles of Neurology. New York: Mc Graw-Hill, 2005.Google Scholar
  14. 14.
    Conradi S, Ronnevi LO, Nise G, Vesterberg O. Abnormal distribution of lead in amyotrophic lateral sclerosis–reestimation of lead in the cerebrospinal fluid. J Neurol Sci 1980;48:413–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Gait R, Maginnis C, Lewis S, Pickering N, Antoniak M, Hubbard R, Lawson I, Britton J. Occupational exposure to metals and solvents and the risk of motor neuron disease. A case–control study. Neuroepidemiology 2003;22:353–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Kamel F, Umbach DM, Munsat TL, Shefner JM, Hu H, Sandler DP. Lead exposure and amyotrophic lateral sclerosis. Epidemiology 2002;13:311–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Bar-Sela S, Reingold S, Richter ED. Amyotrophic lateral sclerosis in a battery-factory worker exposed to cadmium. Int J Occup Environ Health 2001;7:109–12.PubMedGoogle Scholar
  18. 18.
    Gunnarsson LG, Bodin L, Soderfeldt B, Axelson O. A case-control study of motor neurone disease: its relation to heritability, and occupational exposures, particularly to solvents. Br J Ind Med 1992;49:791–8.PubMedGoogle Scholar
  19. 19.
    Strickland D, Smith SA, Dolliff G, Goldman L, Roelofs RI. Division of Epidemiology, School of Public Health, University of Minnesota, USA. Amyotrophic lateral sclerosis and occupational history. A pilot case-control study. Arch Neurol 1996;53:730–3.PubMedGoogle Scholar
  20. 20.
    Rosati G, Pinna L, Granieri E, Aiello I, Tola R, Agnetti V, Pirisi A, de Bastiani P. Studies on epidemiological, clinical and etiological aspects of ALS disease in Sardinia, Southern Italy. Acta Neurol Scand 1977;55:231–44.PubMedGoogle Scholar
  21. 21.
    Holloway SM, Emery AE. The epidemiology of motor neuron disease in Scotland. Muscle Nerve 1982;5:131–133.PubMedCrossRefGoogle Scholar
  22. 22.
    Pall HS, Williams AC, Waring R, Elias E. Motoneurone disease as manifestation of pesticide toxicity. Lancet 1987;2:685.PubMedCrossRefGoogle Scholar
  23. 23.
    Steventon GB, Waring RH, Williams AC. Pesticide toxicity and motor neuron disease. J Neurol Neurosurg Psychiatry 1990;53:621–2.PubMedGoogle Scholar
  24. 24.
    McGuire V, Longstreth WT Jr, Nelson LM, Koepsell TD, Checkoway H, Morgan MS, van Belle G. Occupational exposures and amyotrophic lateral sclerosis. A population-based Case–Control study. Am J Epidemiol 1997;145:1076–88.PubMedGoogle Scholar
  25. 25.
    Burns CJ, Beard KK, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945–94: an update. Occup Environ Med 2001;58:24–30.PubMedCrossRefGoogle Scholar
  26. 26.
    Chung-Yi Li, Fung-Chang Sung. Association between occupational exposure to power frequency electromagnetic fields and amyotrophic lateral sclerosis: a review. Am J Ind Med 2003;43:212–20.CrossRefGoogle Scholar
  27. 27.
    Hakansson N, Gustavsson P, Johansen C, Floderus B. Neurodegenerative diseases in welders and other workers exposed to high levels of magnetic fields. Epidemiology 2003;14:420–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Weisskopf MG, McCullough ML, Morozova N, Calle EE, Thun MJ, Ascherio A. Prospective study of occupation and amyotrophic lateral sclerosis mortality. Am J Epidemiol 2005;162:1146–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Slowik A, Tomik B, Partyka D, Turaj W, Pera J, Dziedzic T, Szermer P, Figlewicz DA, Szczudlik A (2006) Paraoxonase-1 QI92R polymorphism and risk of sporadic amyotrophic lateral sclerosis. Clin Genet 69:358–359PubMedCrossRefGoogle Scholar
  30. 30.
    Nelson LM, McGuire V, Longstreth WT Jr, Matkin C. Population-based case–control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. Am J Epidemiol 2000;151:156–63.PubMedGoogle Scholar
  31. 31.
    Chen KM. Disappearance of ALS from Guam: implications for exogenous causes. Rinsho Shinkeigaku 1995;35:1549–53.PubMedGoogle Scholar
  32. 32.
    Vinceti M, Guidetti D, Pinotti M, Rovesti S, Merlin M, Vescovi L, Bergomi M, Vivoli G. Amyotrophic lateral sclerosis after long-term exposure to drinking water with high selenium content. Epidemiology 1996;7:529–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Gellein K, Garruto RM, Syversen T, Sjobakk TE, Flaten TP. Concentrations of Cd, Co, Cu, Fe, Mn, Rb, V, and Zn in formalin-fixed brain tissue in amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam determined by High-resolutionICP-MS. Biol Trace Elem Res 2003;96:39–60.PubMedCrossRefGoogle Scholar
  34. 34.
    Bastone A, Micheli A, Beghi E, Salmona M. The imbalance of brain large-chain aminoacid availability in amyotrophic lateral sclerosis patients treated with high doses of branched-chain aminoacids. Neurochem Int 1995;27:467–72.PubMedCrossRefGoogle Scholar
  35. 35.
    Cruz DC, Nelson LM, McGuire V, Longstreth WT Jr. Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-based case–control study. Neuroepidemiology 1999;18:101–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Gallagher JP, Sanders M. Trauma and amyotrophic lateral sclerosis: a report of 78 patients. Acta Neurol Scand 1987;75:145–50.PubMedGoogle Scholar
  37. 37.
    Scarmeas N, Shih T, Stern Y, Ottman R, Rowland LP. Premorbid weight, body mass, and varsity athletics in ALS. Neurology 2002;59:773–5.PubMedGoogle Scholar
  38. 38.
    Vanacore N. Premorbid weight, body mass, and varsity athletics in ALS. Neurology 2003;61:1024–5.PubMedGoogle Scholar
  39. 39.
    Belli S, Vanacore N. Proportionate mortality of Italian soccer players: Is amyothrophic lateral sclerosis an occupational disease? Eur J Epidemiol 2005;20:237–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Chiò A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 2005;128:472–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Murakami T, Warita H, Hayashi T, Stato K, Manabe Y, Mitzuno S, Yamane K, Abe K. A novel SOD1 gene mutation in familial ALS with low penetrance in females. J Neurol Sci 2001;189:45–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Sato T, Yamamoto Y, Nakanishi T, Fukada K, Sugai F, Zhou Z, Okuno T, Nagano S, Hirata S, Shimizu A, Sakoda S. Identification of two novel mutations in the Cu/Zn superoxide dismutase gene with familial amyotrophic lateral sclerosis: mass spectrometric and genomic analysis. J Neurol Sci 2004;218:79–83.PubMedCrossRefGoogle Scholar
  43. 43.
    Tanaka H, Furuya T, Kameda N, Kobayashi T, Mizusawa H. Triad proteins and intracellular Ca2+ during development of human skeletal muscle cells in aneural and innervated cultures. J Muscle Res Cell Motil 2000;21:507–26.PubMedCrossRefGoogle Scholar
  44. 44.
    O’Malley F, Dean G, Elian M. Multiple sclerosis and motor neurone disease: survival and how certified after death. J Epidemiol Commun Health 1987;41:14–7.Google Scholar
  45. 45.
    Ragonese P, Salemi G, Aridon P, Conte S, Cuccia G, Lupo I, Savettieri G. Accuracy of Death Certificates for Motor Neuron Disease and Multiple Sclerosis in the Province of Palermo in Southern Italy. Neuroepidemiology 2002;21:148–52.PubMedCrossRefGoogle Scholar
  46. 46.
    Chio A, Magnani C, Oddenino E, Tolardo G, Schiffer D. Accuracy of death certificate diagnosis of amyotrophic lateral sclerosis. J Epidemiol Commun Health 1992;46:517–8.Google Scholar
  47. 47.
    Ragonese P, Filippini G, Salemi G, Beghi E, Citterio A, D’Alessandro R, Marini C, Monsurro MR, Aiello I, Morgante L, Tempestini A, Fratti C, Ragno M, Pugliatti M, Epifanio A, Testa D, Savettieri G. Accuracy of death certificates for amitrophic lateral sclerosis varies significantly from north to south of Italy: implications for mortality studies. Neuroepidemiology 2004;23:73–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Ferro S, Giovannini A, Fiorani L, Carmentano P, D’Alessandro R. Mortality from motor neuron disease in the province of Bologna, Italy, 1986 through 1988. Arch Neurol 1992;49:661–3.PubMedGoogle Scholar
  49. 49.
    Buckley J, Warlow C, Smith P, Hilton-Jones D, Irvine S, Tew JR. Motor neuron disease in England and Wales, 1959–1979. J Neurol Neurosurg Psychiatry 1983;46:197–205.PubMedGoogle Scholar
  50. 50.
    Lilienfeld DE, Chan E, Ehland J, Godbold J, Landrigan PJ, Marsh G, Perl DP. Rising mortality from motoneuron disease in the USA, 1962–84. Lancet 1989;1:710–3.PubMedCrossRefGoogle Scholar
  51. 51.
    Durrleman S, Alperovitch A. Increasing trend of ALS in France and elsewhere: are the changes real? Neurology 1989;39:768–73.PubMedGoogle Scholar
  52. 52.
    Bharucha NE, Schoenberg BS, Raven RH, Pickle LW, Byar DP, Mason TJ. Geographic distribution of motor neuron disease and correlation with possible etiologic factors. Neurology 1983;33:911–5.PubMedGoogle Scholar
  53. 53.
    Ferrarini M, Testa D, Cazzaniga G, Tasco C, Cislaghi C, Filippini G. Trends in amyotrophic lateral sclerosis mortality in Italy, 1970–1989. Neurology 1996;46:A290–1.Google Scholar
  54. 54.
    Vanacore N, Belli S, Binazzi A, Comba P, Di Rezze P, Mastrantonio M, Meco G, Uccelli R. Mortalità per malattia del motoneurone in Piemonte, Lombardia e Puglia (1980–1997). XXVI Riunione annuale della Associazione Italiana di Epidemiologia, 2002. Napoli: Associazione Italiana di Epidemiologia: 244.Google Scholar
  55. 55.
    Kulldorff M. A spatial scan statistic. Communications in Statistics: Theory Methods 1997;26:1481–96.CrossRefGoogle Scholar
  56. 56.
    Kulldorff M, Nagarwalla N. Spatial disease clusters: detection and inference. Stat Med 1995;14:799–810.PubMedCrossRefGoogle Scholar
  57. 57.
    Gunnarsson LG, Lindberg G, Soderfelt B, Axelson O. The mortality of motor neuron disease in Sweden. Arch Neurol 1990;47:42–46.PubMedGoogle Scholar
  58. 58.
    Hudson AJ, Davenport A, Hader WJ. The incidence of amyotrophic lateral sclerosis in southwestern Ontario, Canada. Neurology 1986;36:1524–8.PubMedGoogle Scholar
  59. 59.
    Holloway SM, Mitchell JD. Motor neurone disease in the Lothian Region of Scotland 1961–81. J Epidemiol Community Health 1986;40:344–50.PubMedCrossRefGoogle Scholar
  60. 60.
    Chio A, Magnani C, Schiffer D. Amyotrophic lateral sclerosis mortality in Italy, 1958 to 1987: a cross sectional and cohort study. Neurology 1993;43:927–30.PubMedGoogle Scholar
  61. 61.
    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;56:239–44.Google Scholar
  62. 62.
    Chio A, Cucatto A, Calvo A, Terreni AA, Magnani C, Schiffer D. Amyotrophic lateral sclerosis among the migrant population to Piemonte, northwestern Italy. J Neurol 1999;246:175–180.PubMedCrossRefGoogle Scholar
  63. 63.
    Iwami O, Niki Y, Watanabe T, Ikeda M. Motor neuron disease on the Kii Peninsula of Japan: cycad exposure. Neuroepidemiology 1993;12:307–12.PubMedCrossRefGoogle Scholar
  64. 64.
    Figlewicz DA, Garruto RM, Krizus A, Yanagihara R, Rouleau GA. The Cu/Zn superoxide dismutase gene in ALS and parkinsonism-dementia of Guam. Neuroreport 1994;5:557–60.PubMedCrossRefGoogle Scholar
  65. 65.
    Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W. A clustering of conjugal amyotrophic lateral sclerosis in southeastern France. Arch Neurol 2003;60:553–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Peltonen L, Jalanko A, Varilo T. Molecular genetics of the Finnish disease heritage. Hum Mol Genet 1999;8:1913–23.PubMedCrossRefGoogle Scholar
  67. 67.
    Sabel CE, Boyle PJ, Loytonen M, Gatrell AC, Jokelainen M, Flowerdew R, Maasilta P. Spatial clustering of Amyotrophic Lateral Sclerosis in Finland at place of birth and place of death. Am J Epidemiol 2003;157:898–905.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Raffaella Uccelli
    • 1
  • Alessandra Binazzi
    • 2
  • Pierluigi Altavista
    • 1
  • Stefano Belli
    • 3
  • Pietro Comba
    • 3
  • Marina Mastrantonio
    • 1
  • Nicola Vanacore
    • 4
  1. 1.Section of Toxicology and Biomedical SciencesNational Agency for New Technologies, Energy and the Environment (ENEA)RomeItaly
  2. 2.Epidemiology Unit, Occupational Medicine DepartmentNational Institute for Occupational Safety and Prevention (ISPESL)RomeItaly
  3. 3.Department of Environment and Primary Prevention (DACPP)Istituto Superiore di Sanità (ISS)RomeItaly
  4. 4.National Centre for Epidemiology, Surveillance and Health Promotion (CNESPS)Istituto Superiore di Sanità (ISS)RomeItaly

Personalised recommendations