Advertisement

Journal of Neurology

, Volume 265, Issue 4, pp 817–827 | Cite as

Riluzole and other prognostic factors in ALS: a population-based registry study in Italy

  • Jessica Mandrioli
  • Sara Angela Malerba
  • Ettore Beghi
  • Nicola Fini
  • Antonio Fasano
  • Elisabetta Zucchi
  • Silvia De Pasqua
  • Carlo Guidi
  • Emilio Terlizzi
  • Elisabetta Sette
  • Alessandro Ravasio
  • Mario Casmiro
  • Fabrizio Salvi
  • Rocco Liguori
  • Lucia Zinno
  • Yasmin Handouk
  • Romana Rizzi
  • Annamaria Borghi
  • Rita Rinaldi
  • Doriana Medici
  • Mario Santangelo
  • Enrico Granieri
  • Vittoria Mussuto
  • Marina Aiello
  • Salvatore Ferro
  • Marco Vinceti
  • ERRALS Group
Original Communication
  • 374 Downloads

Abstract

Objective

In this prospective population-based registry study on ALS survival, we investigated the role of riluzole treatment, together with other clinical factors, on the prognosis in incident ALS cases in Emilia Romagna Region (ERR), Italy.

Methods

A registry for ALS has been collecting all incident cases in ERR since 2009. Detailed clinical data from all patients diagnosed with ALS between 1.1.2009 and 31.12.2014 have been analyzed for this study, with last follow up date set at 31.12.2015.

Results

During the 6 years of the study, there were 681 incident cases with a median tracheostomy-free survival of 40 months (95% CI 36–44) from onset and of 26 months (95% CI 24–30) from diagnosis; 573 patients (84.14%) were treated with riluzole, 207 (30.39%) patients underwent gastrostomy, 246 (36.12%) non invasive ventilation, and 103 (15.15%) invasive ventilation. Patients who took treatment for ≥ 75% of disease duration from diagnosis had a median survival of 29 months compared to 18 months in patients with < 75% treatment duration. In multivariable analysis, factors independently influencing survival were age at onset (HR 1.04, 95% CI 1.02–1.05, p < 0.001), dementia (HR 1.56, 95% CI 1.05–2.32, p = 0.027), degree of diagnostic certainty (HR 0.88, 95% CI 0.78–0.98, p = 0.021), gastrostomy (HR 1.46, 95% CI 1.14–1.88, p = 0.003), NIV (HR 1.43, 95% CI 1.12–1.82, p = 0.004), and weight loss at diagnosis (HR 1.05, 95% CI 1.03–1.07, p < 0.001), diagnostic delay (HR 0.98, 95% CI 0.97–0.99, p = 0.004), and % treatment duration (HR 0.98, 95% CI 0.98–0.99, p < 0.001).

Conclusions

Independently from other prognostic factors, patients who received riluzole for a longer period of time survived longer, but further population based studies are needed to verify if long-tem use of riluzole prolongs survival.

Keywords

Amyotrophic lateral sclerosis Survival Prognostic factors Therapeutic intervention Riluzole 

Notes

Acknowledgements

The authors acknowledge ERRALS group: Project coordinator: J. Mandrioli. Collaborating centers: Department of Neuroscience, St. Agostino Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Italy (J. Mandrioli, N. Fini, A. Fasano, E. Zucchi, A. Gessani, L. Ferri, S. Malerba, P. Nichelli). Department of Neurology, Bufalini Hospital, Cesena, Italy (Y. Handouk, S. Biguzzi, W. Neri). Department of Neurology, Forlì Hospital, Forlì, Italy (C. Guidi, W. Neri). Department of Neurosciences and Rehabilitation, St Anna Hospital, Ferrara (E. Sette, V. Tugnoli and M. R. Tola). Department of Neurology, G. Da Saliceto Hospital, Piacenza, Italy (E. Terlizzi, D. Guidetti). Department of Neurology, Infermi Hospital, Rimini, Italy (M. Currò Dossi, M. Pasquinelli, J. Andruccioli, A. Ravasio). Department of Neurology, Faenza and Ravenna Hospital, Ravenna, Italy (M. Casmiro,F. Rasi). Department of Neurology and IRCCS Istituto delle Scienze Neurologiche di Bologna, Bellaria Hospital, Bologna, Italy (F. Salvi, I. Bartolomei, R. Michelucci). Department of Biomedical and Neuromotor Science and IRCCS Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Bologna, Italy (P. Avoni, S. De Pasqua, R. Liguori). Department of Neurology, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy (R. Rizzi, E. Canali, L. Codeluppi, F. Valzania). Department of Neuroscience, University of Parma, Parma, Italy (A. Taga, V. Pietrini, M. C. Trapasso, and L. Zinno). Department of Clinical and Experimental Medicine, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy (M. Aiello). Department of Neurology, Fidenza Hospital, Parma, Italy (D. Medici, E. Chierici, E. Montanari). Department of Neurology, Carpi Hospital, Modena, Italy (M. Santangelo, S. Amidei). Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy (I. Casetta, M. Pugliatti, E. Della Coletta, V. Govoni, E. Granieri). Department of Neurology, Imola Hospital, Bologna, Italy (P. De Massis, V. Mussuto). Department of Neurology and IRCCS Istituto delle Scienze Neurologiche di Bologna, Maggiore Hospital, Bologna, Italy (A. Borghi, A. Gabellini, R. Michelucci). Neurology Unit, St. Orsola-Malpighi University Hospital, AOU di Bologna, Italy (R. Rinaldi, F. Cirignotta). Department of Hospital Services, Emilia Romagna Regional Health Authority, Bologna, Italy (S. Ferro). Neuroepidemiology Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy (R. D’Alessandro). CREAGEN Research Center for Environmental, Genetic and Nutritional Epidemiology, University of Modena and Reggio Emilia, Modena, Italy.

Funding

Emilia Romagna Registry for ALS is supported by a Grant from the Emilia Romagna Regional Health Authority.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflicts of interest.

Ethical standards

The study has been approved by the ethics committees of ERR and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

References

  1. 1.
    Chiò A, Calvo A, Moglia C, Mazzini L, Mora G, PARALS study group (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 82:740–746CrossRefPubMedGoogle Scholar
  2. 2.
    Al-Chalabi A, Hardiman O, Kiernan MC et al (2016) Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 15:1182–1194.  https://doi.org/10.1016/S1474-4422(16)30199-5 CrossRefPubMedGoogle Scholar
  3. 3.
    Calvo A, Moglia C, Lunetta C et al (2017) Factors predicting survival in ALS: a multicenter Italian study. J Neurol 264:54–63.  https://doi.org/10.1007/s00415-016-8313-y CrossRefPubMedGoogle Scholar
  4. 4.
    Rooney J, Byrne S, Heverin M, Tobin K, Dick A, Donaghy C, Hardiman O (2015) A multidisciplinary clinic approach improves survival in ALS: a comparative study of ALS in Ireland and Northern Ireland. J Neurol Neurosurg Psychiatry 86:406–501CrossRefGoogle Scholar
  5. 5.
    Georgoulopoulou E, Fini N, Vinceti M et al (2013) The impact of clinical factors, riluzole and therapeutic interventions on ALS survival: a population based study in Modena, Italy. Amyotroph Lateral Scler Frontotemporal Degener 8421:1–8.  https://doi.org/10.3109/21678421.2013.763281 Google Scholar
  6. 6.
    Mitsumoto H, Brooks BR, Silani V (2014) Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 13:1127–1138.  https://doi.org/10.1016/S1474-4422(14)70129-2 CrossRefPubMedGoogle Scholar
  7. 7.
    Hardiman O, van den Berg LH, Kiernan MC (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol 7:639–649CrossRefPubMedGoogle Scholar
  8. 8.
    Vucic S, Lin CS, Cheah BC, Murray J, Menon P, Krishnan AVKM (2013) Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain 136:1361–1370CrossRefPubMedGoogle Scholar
  9. 9.
    Gutierrez J, Federici T, Peterson B, Bartus R, Betourne A, Boulis NM (2016) Development of intrathecal riluzole: a new route of administration for the treatment of amyotrophic lateral sclerosis patients. Neurosurgery 63:193CrossRefPubMedGoogle Scholar
  10. 10.
    Dyer AM (2017) Riluzole 5 mg/mL oral suspension : for optimized drug delivery in amyotrophic lateral sclerosis. Drug Design Dev Ther.  https://doi.org/10.2147/dddt.s123776 Google Scholar
  11. 11.
    Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)(Review). Forbes 3:1–34.  https://doi.org/10.1002/14651858.CD001447 Google Scholar
  12. 12.
    Zoccolella S, Beghi E, Palagano G et al (2007) Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy. Eur J Neurol 14:262–268.  https://doi.org/10.1111/j.1468-1331.2006.01575.x CrossRefPubMedGoogle Scholar
  13. 13.
    Mitchell JD, O’Brien MR, Joshi M (2006) Audit of outcomes in motor neuron disease (MND) patients treated with riluzole. Amyotroph Lateral Scler Other Mot Neuron Disord 7:67–71CrossRefGoogle Scholar
  14. 14.
    Turner MR, Bakker M, Sham P, Shaw CE, Leigh PN, Al-Chalabi A (2001) The Kings’ Database 1999–2000: an analysis of the effect on survival of interventions in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Mot Neuron Disord 2:43CrossRefGoogle Scholar
  15. 15.
    Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O (2003) An outcome study of riluzole in amyotrophic lateral sclerosis—a population-based study in Ireland, 1996–2000. J Neurol 250:473–479CrossRefPubMedGoogle Scholar
  16. 16.
    Cetin H, Rath J, Füzi J et al (2015) Epidemiology of amyotrophic lateral sclerosis and effect of riluzole on disease course. Neuroepidemiology 44:6–15.  https://doi.org/10.1159/000369813 CrossRefPubMedGoogle Scholar
  17. 17.
    Chen L, Liu X, Tang L et al (2016) Long-term use of riluzole could improve the prognosis of sporadic amyotrophic lateral sclerosis patients: a real-world cohort study in China. Front Aging Neurosci 8:1–8.  https://doi.org/10.3389/fnagi.2016.00246 Google Scholar
  18. 18.
    Mandrioli J, Biguzzi S, Guidi C et al (2014) Epidemiology of amyotrophic lateral sclerosis in Emilia Romagna Region (Italy): a population based study. Amyotrop Later Scler Frontotemp Degener 8421:262–268.  https://doi.org/10.3109/21678421.2013.865752 CrossRefGoogle Scholar
  19. 19.
    Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299.  https://doi.org/10.1080/146608200300079536 CrossRefPubMedGoogle Scholar
  20. 20.
    Franchignoni F, Mora G, Giordano A et al (2013) Evidence of multidimensionality in the ALSFRS-R Scale: a critical appraisal on its measurement properties using Rasch analysis. J Neurol Neurosurg Psychiatry 84:1340–1345.  https://doi.org/10.1136/jnnp-2012-304701 CrossRefPubMedGoogle Scholar
  21. 21.
    Franchignoni F, Mandrioli J, Giordano A, Ferro S (2015) A further Rasch study confirms that ALSFRS-R does not conform to fundamental measurement requirements. Amyotroph Lateral Scler Front Degener 8421:1–7.  https://doi.org/10.3109/21678421.2015.1026829 Google Scholar
  22. 22.
    Fasano A, Fini N, Ferraro D et al (2017) Percutaneous endoscopic gastrostomy, body weight loss and survival in amyotrophic lateral sclerosis: a population-based registry study. Amyotroph Lateral Scler Front Degener.  https://doi.org/10.1080/21678421.2016.1270325 Google Scholar
  23. 23.
    Andersen PM, Abrahams S, Borasio GD et al (2012) EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS)—revised report of an EFNS task force. Eur J Neurol 19:360–375.  https://doi.org/10.1111/j.1468-1331.2011.03501.x CrossRefPubMedGoogle Scholar
  24. 24.
    Fini N, Georgoulopoulou E, Vinceti M et al (2014) Noninvasive and invasive ventilation and enteral nutrition for ALS in Italy. Muscle Nerve 50:508–516CrossRefPubMedGoogle Scholar
  25. 25.
    Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167:492–499CrossRefPubMedGoogle Scholar
  26. 26.
    Labra J, Menon P, Byth K et al (2015) Rate of disease progression: a prognostic biomarker in ALS. J Neurol Neurosurg Psychiatry.  https://doi.org/10.1136/jnnp-2015-310998 PubMedGoogle Scholar
  27. 27.
    Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sørensen HT (2011) The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol 11:83.  https://doi.org/10.1186/1471-2288-11-83 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bensimon G, Lacomblez L, Meiningier V (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group 330:585–591Google Scholar
  29. 29.
    Miller RG, Jackson CE, Kasarskis EJ et al (2009) Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American. Neurology 73:1227–1233CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cetin H, Klickovic U, Rath J et al (2015) Associations between co-medications and survival in ALS—a cohort study from Austria. J Neurol.  https://doi.org/10.1007/s00415-015-7767-7 PubMedGoogle Scholar
  31. 31.
    Gordon PH (2013) Amyotrophic Lateral Sclerosis: an update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging Dis 4:295–310.  https://doi.org/10.14336/AD.2013.0400295 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sívori M, Rodríguez GE, Pascansky D, Sáenz C, Sica RE (2007) Outcome of sporadic amyotrophic lateral sclerosis treated with non-invasive ventilation and riluzole. Med (B Aires) 67:326–330Google Scholar
  33. 33.
    Tavakoli M (2002) Disease progression in amyotrophic lateral sclerosis. Identifying the cost-utility of riluzole by disease stage. Eur J Heal Econ 3:156–165CrossRefGoogle Scholar
  34. 34.
    Chio A, Logroscino G, Hardiman O et al (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10:310–323.  https://doi.org/10.3109/17482960802566824 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chio A, Mora G, Leone M et al (2002) Early symptom progression rate is related to ALS outcome: a prospective population-based study. Neurology 59:99–103.  https://doi.org/10.1212/WNL.59.12.2012-a CrossRefPubMedGoogle Scholar
  36. 36.
    Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955.  https://doi.org/10.1016/S0140-6736(10)61156-7 CrossRefPubMedGoogle Scholar
  37. 37.
    Lee CT-C, Chiu Y-W, Wang K-C et al (2013) Riluzole and prognostic factors in amyotrophic lateral sclerosis long-term and short-term survival: a population-based study of 1149 cases in Taiwan. J Epidemiol 23:35–40.  https://doi.org/10.2188/jea.JE20120119 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Knibb JA, Keren N, Kulka A et al (2016) A clinical tool for predicting survival in ALS. J Neurol Neurosurg Psychiatry 87:1361–1367.  https://doi.org/10.1136/jnnp-2015-312908 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chiò A, Canosa A, Gallo S et al (2011) ALS clinical trials: do enrolled patients accurately represent the ALS population? Neurology 77:1432–1437.  https://doi.org/10.1212/WNL.0b013e318232ab9b CrossRefPubMedGoogle Scholar
  40. 40.
    Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V (1996) Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347:1425–1431CrossRefPubMedGoogle Scholar
  41. 41.
    Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Truffinet P, Meininger V (2002) A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol 249:609–615CrossRefPubMedGoogle Scholar
  42. 42.
    Rooney J, Fogh I, Westeneng HJ et al (2017) C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 88:281PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jessica Mandrioli
    • 1
  • Sara Angela Malerba
    • 1
  • Ettore Beghi
    • 2
  • Nicola Fini
    • 1
  • Antonio Fasano
    • 1
  • Elisabetta Zucchi
    • 1
  • Silvia De Pasqua
    • 3
  • Carlo Guidi
    • 4
  • Emilio Terlizzi
    • 5
  • Elisabetta Sette
    • 6
  • Alessandro Ravasio
    • 7
  • Mario Casmiro
    • 8
  • Fabrizio Salvi
    • 9
  • Rocco Liguori
    • 3
  • Lucia Zinno
    • 10
  • Yasmin Handouk
    • 11
  • Romana Rizzi
    • 12
  • Annamaria Borghi
    • 13
  • Rita Rinaldi
    • 14
  • Doriana Medici
    • 15
  • Mario Santangelo
    • 16
  • Enrico Granieri
    • 17
  • Vittoria Mussuto
    • 18
  • Marina Aiello
    • 19
  • Salvatore Ferro
    • 20
  • Marco Vinceti
    • 21
  • ERRALS Group
  1. 1.Department of Neuroscience, St. Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di ModenaUniversity of Modena and Reggio EmiliaModenaItaly
  2. 2.Department of NeuroscienceIRCCS-Istituto di Ricerche Farmacologiche Mario NegriMilanItaly
  3. 3.Department of Biomedical and Neuromotor SciencesUniversity of Bologna and IRCCS Istituto delle Scienze Neurologiche di BolognaBolognaItaly
  4. 4.Department of NeurologyForlì HospitalForlìItaly
  5. 5.Department of NeurologyG. Da Saliceto HospitalPiacenzaItaly
  6. 6.Department of NeurologySt. Anna HospitalFerraraItaly
  7. 7.Department of NeurologyInfermi HospitalRiminiItaly
  8. 8.Department of NeurologyFaenza and Ravenna HospitalRavennaItaly
  9. 9.Neurology UnitBellaria Hospital, IRCCS Istituto delle Scienze Neurologiche di BolognaBolognaItaly
  10. 10.Department of Neuroscience, Neurology UnitUniversity of ParmaParmaItaly
  11. 11.Department of NeurologyBufalini HospitalCesenaItaly
  12. 12.Department of NeurologyIRCCS Arcispedale Santa Maria NuovaReggio EmiliaItaly
  13. 13.Neurology Unit, Maggiore HospitalIRCCS Istituto delle Scienze Neurologiche di BolognaBolognaItaly
  14. 14.Department of NeuroscienceSt. Orsola-Malpighi University HospitalBolognaItaly
  15. 15.Department of NeurologyFidenza HospitalParmaItaly
  16. 16.Department of NeurologyCarpi HospitalModenaItaly
  17. 17.Department of NeuroscienceUniversity of FerraraFerraraItaly
  18. 18.Department of NeurologyImola HospitalBolognaItaly
  19. 19.Department of Clinical and Experimental Medicine, Respiratory Disease and Lung Function UnitUniversity of ParmaParmaItaly
  20. 20.Department of Hospital Services, Emilia Romagna Regional Health AuthorityBolognaItaly
  21. 21.Environmental, Genetic and Nutritional Epidemiology Research Center (CREAGEN)University of Modena and Reggio Emilia Medical SchoolModenaItaly

Personalised recommendations