148th ENMC international workshop on the scientific contributions of the EURALS consortium on amyotrophic lateral sclerosis

Article Outline

• 1. Introduction
• 2. Validity and reliability of the ALS diagnostic criteria
• 3. Representativeness of ALS cohorts from referral centers
• 4. Etiologic studies for the investigation of environmental and genetic studies of ALS
• 5. Comparability of ALS patients enrolled in population-based registries
• 6. Methodological pitfalls and results of therapeutic ALS trials
• 7. Meeting participants (∗)
• Acknowledgements
• Reference
• Copyright

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1. Introduction 

Sixteen experts in the field of motor neuron disorders from France, Ireland, Italy, Serbia, Spain, The Netherlands, United States, and United Kingdom convened in Naarden, The Netherlands, from February 2 to 4 2007, to participate in a workshop focusing on the most controversial issues in the epidemiology and treatment of amyotrophic lateral sclerosis (ALS). The meeting attendants were members of the European ALS Consortium (EURALS).

EURALS was established in 2004 to coordinate the scientific activities of ALS population-based registries and tertiary centers and to conduct epidemiological, genetic studies, and randomized clinical trials of new pharmaceutical compounds and other therapeutic devices. The background and rationale of the consortium have been outlined in a previous workshop [1]. In the present workshop the following topics were addressed: (1) The validity and reliability of the past and current ALS diagnostic criteria; (2) The representativeness of the patients cohorts seen in referral centers; (3) The implementation of etiologic studies for the investigation of environmental and genetic risk factors; (4) The comparability of ALS patients enrolled in different population-based registries; (5) The results of therapeutic trials in light of the major methodological pitfalls.

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2. Validity and reliability of the ALS diagnostic criteria 

Robert Swingler reported on the validity of the ALS diagnostic criteria used in the Scottish population-based registry by reviewing the autopsy reports during the period 1989–1998. ALS diagnoses were performed using the modified WFN criteria (1989–1993) and the El Escorial criteria (1994–1998). 1226 patients were registered, 1101 of whom (90%) died. Autopsies were found in 70 cases (6%). Autopsy confirmed the diagnosis of ALS in 66 cases (94%); 11 autopsied patients were unregistered. Of these, six were diagnosed in life. Based on the autopsy reports, the diagnosis of ALS made upon registration is reasonably sensitive and specific.

Andrea Millul reported the results of a study on the validation of the El Escorial diagnostic criteria (EEC). Participants were ten members of the EURALS Consortium, each examining the medical records (or summary sheets) of 40 patients with ALS and 39 individuals with clinical conditions considered in the differential diagnosis. The records varied in terms of accuracy and completeness. Patients and controls underwent diagnostic assessment with the original and the revised (Eirlie-House) criteria. The validity of the EEC was tested by confronting each investigator with the treating neurologists (the “gold standard”). The inter-rater agreement was tested with the kappa statistic.

Kappa indicated a moderate inter-observer agreement (overall kappa 0.65 for the original EEC and 0.59 for the revised EEC). The agreement was unchanged when subgroup analyses were performed based on different types of records. Kappa values indicated a moderate to good agreement between the raters and the gold standard for the original EEC, but they were slightly lower for the revised EEC.

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3. Representativeness of ALS cohorts from referral centers 

Bryan Traynor presented data from three European ALS registries (Ireland, Piemonte and Puglia) to measure the extent of referral bias by comparing clinical features, demographics and survival of population-based cohorts with clinic-based cohorts from the same populations. Within each region, there was a specialist clinic catering exclusively to ALS patients. The population cohorts were 584 residents of Piemonte, 309 Irish residents and 130 residents of Puglia. Of these, 241 (41.3%), 84 (64.6%) and 88 (28.5%) attended a specialist clinic.

Patients attending an ALS clinic were younger than the corresponding population cohort (Ireland 4.5 years; Piemonte 2.4 years; Puglia 1.6 years). The male to female gender ratio was almost identical except for Puglia, where more male patients attended the ALS clinic (1.7:1). The rate of familial ALS was higher in Ireland than in Italy (5.2% versus 1.9%). Except for Puglia, patients with familial disease were more likely to attend the ALS specialist clinic. Bulbar-onset ALS patients were underrepresented in the Irish ALS specialist clinic and in Piemonte, while in Puglia they were slightly more likely to attend a specialist clinic. Delay in diagnosis was considerably longer for Irish ALS patients compared to Italian patients. Survival of patients attending the specialist clinic was significantly longer than the general ALS population in Piemonte and Ireland, but not in Puglia. Based on these findings, the ALS cohorts seen in referral centers do not represent the spectrum of the disease of the entire ALS population.

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4. Etiologic studies for the investigation of environmental and genetic studies of ALS 

A population-based case-control study has been promoted by Ettore Beghi and activated in Italy, Ireland and UK. Cases were patients with newly diagnosed definite, probable or possible ALS (EEC). For each case, two age- and sex-matched controls were selected, mostly from a referent general practitioner’s list. Cases and controls were asked about history of occupation(s), physical exercise, and sport(s). For each activity, duration and intensity was indicated. Traumatic events and drug exposure were also recorded. Included were 44 cases and 82 controls. The mean number of years spent doing any sport was 7.9 in cases and 3.3 in controls (p<0.01). ALS patients practiced strenuous physical exercise during work more than controls (OR 7.6; 95% CI 1.5–38.2). Three patients (no controls) reported a history of professional sport (soccer 2; athletics 1; p<0.05). Traumatic events and drug exposure were no different.

Leonard van den Berg and Jan Veldink reported on recent findings on selected genetic and environmental factors from the Dutch database and biobank, started in Utrecht in 1999. A case-control study was conducted in the period 1999–2005 with enrolment of 350 referral patients. In these patients, one copy of SMN1 was associated with an increased risk of ALS (OR 4.1; 95% CI 1.2–14.2) and ALS patients carried fewer SMN2 copy numbers (p<0.001). Lower levels of estimated SMN protein (HR 1.3; 95% CI 1.1–1.6) were associated with an increased mortality rate. Homozygosity for H63D in the HFE gene was associated with an increased risk of ALS (OR 2.2; 95% CI 1.1–4.1). Smoking and alcohol use were independently associated with ALS (current smoking OR 1.8; 95% CI 1.0–3.0, ever/current alcohol use OR 0.6; 95% CI 0.3–0.9). Higher leisure time activities were associated with an earlier age at onset. A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: OR 0.4; 95% CI 0.2–0.7; vitamin E: OR 0.4; 95% CI 0.2–0.7). In a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37, and that for PUFA from 0.60 to 0.26, with a significant interaction term (p=0.03).

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5. Comparability of ALS patients enrolled in population-based registries 

Giancarlo Logroscino made a meta-analysis of the 1998–99 data on the incidence and geographic trends of ALS from three countries (Italy, UK and Ireland) and six population-based registries. The diagnosis of ALS at inception was based on the first version of the EEC. Population denominators were obtained from local government censuses from the year 2000. The ALS cases recruited were 1028. The crude ALS incidence in Europe was 2.2/100,000. The incidence in men was 2.4/100,000 and in women 1.95/100,000 and was homogenous across Europe. Incidence steeply increased with age and the peak was at age 75–79 years in women and at age 70–74 in men. Age, gender distribution and onset-diagnosis intervals were fairly similar across all registries. Bulbar-onset ALS was more common in Ireland than in the other European countries.

Using the capture–recapture method, the incidence of ALS was calculated by Philippe Couratier and Pierre Marie Preux in Limousin, a rural region located in West-central France (total population about 711,000). The major town is Limoges, hosting one university regional hospital (15 neurologists) and one ALS center. Every year, there are approximately 20 patients with newly diagnosed ALS, giving a standardized annual incidence rate of 2.5 per 100,000 population. In a prospective study of 158 patients, the overall 5-year survival rate was 14.7% with an inverse correlation with age. Bulbar-onset and upper-limb onset had the worst prognosis. In a prospective 7-month study of 55 ALS patients, occurrence of malnutrition was 16.4%. Survival was worse for malnourished patients, with a 7.7-fold increased risk of death. Only reduced vital capacity and malnutrition were found to have an independent prognostic value.

Zorica Stevic reported on the Belgrade ALS registry. The study population includes the residents of the Belgrade area (total 1,576,124). During the period 1993–2005, 218 patients with ALS were traced through hospital and outpatient records and followed for up to 5 years. 175 died before December 31 2005. The sex ratio was 1.4. Forty patients (18.3%) were aged less than 49 years. Familial ALS was present in 3.7% of cases. Mean age at onset of symptoms was 58 years. Spinal-onset ALS was present in 70% of cases.

Mortality rate was 0.85 per 100,000 per year (men 1.05; women 0.68). Mortality increased with time (1.36 per 100,000 per year in 2000–04) and peaked in 2001–03. Mean survival was 3.4 years (5-year survival 22%). Mortality peaked at 65–69 years in men and at 70–74 years in women. Site of onset and age were independent predictors of survival.

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6. Methodological pitfalls and results of therapeutic ALS trials 

A critical appraisal of the published reports was undertaken by Elisabetta Pupillo to investigate the methodological pitfalls and provide the basis for better studies in the future. Each trial was assessed in terms of diagnostic criteria, population, design, duration, primary end-points, and drop-outs. 165 articles were found, 55 fulfilling all requirements for review. El-Escorial diagnostic criteria were used only in 22 studies. Patients included were >50 in 34 studies and >100 in 24. Disease duration at entry varied across studies and was not specified in 10. Forced vital capacity was not measured in 22 studies. Patients were stratified according to symptom onset in only 37 studies. Trial duration was between 6 and 12 months in 38 studies. Baseline characteristics were similar in the experimental and control group in 35 studies. Primary end-points varied across studies and were clinically relevant in 22. Setting and outcome were reliable in 22 studies. Thirteen studies had more than 20% drop-outs. The drop-out rate was not specified in 21 studies. The rationale was inadequate for 14 drugs and animal studies were negative for 24. Randomization was described in 21 studies and blinding in 10. Study power was calculated in 32 studies. These drawbacks may explain the predominantly negative results of randomized clinical trials in ALS.

Based on the results of the workshop, the meeting attendants convened on the following points: (1) To acknowledge the inclusion of the Limousin and Belgrade registries in the EURALS database; (2) To encourage the implementation of a Dutch population-based registry; (3) To initiate a large case-control study on ALS, physical activity, sports, and traumatic events; (4) To perform a meta-analysis on the mortality of the 1998–99 ALS cohort included in the incidence study.

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7. Meeting participants (^∗) 

Ettore Beghi, Milano, Italy

Adriano Chiò, Torino, Italy

Philippe Couratier, Limoges, France

Jesùs Esteban, Madrid, Spain

Orla Hardiman, Dublin, Ireland

Giancarlo Logroscino, Bari, Italy

Andrea Millul, Milano, Italy

Douglas Mitchell, Preston, UK

Pierre-Marie Preux, Limoges, France

Elisabetta Pupillo, Milano, Italy

Zorica Stevic, Belgrade, Serbia

Robert Swingler, Dundee, UK

Bryan J. Traynor, Bethesda, MD, USA

Leonard H. van den Berg, Utrecht, The Netherlands

Jan H. Veldink, Utrecht, The Netherlands

Stefano Zoccolella, Bari, Italy

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Acknowledgements 

This workshop was made possible by the financial support of the European Neuromuscular Centre (associated) members: Austria, Österreichische Muskelforschung; Denmark, Muskelsvindfonden; France, Association Française contre les Myopathies; Germany, Deutsche Gesellschaft für Muskelkranke; Italy, Fondazione Telethon; Netherlands, Prinses Beatrix Fonds; Netherlands, Vereniging Spierziekten Nederland; Slovenia, Muscular Dystrophy Association of Slovenia; Switzerland, Schweizerische Stiftung für die Erforschung der Muskelkrankheiten; United Kingdom, Muscular Dystrophy Campaign; and the support of the MDA (USA) for the attendance of participants from the USA.

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Reference 

1. Beghi E. 127th ENMC International Workshop: Implementation of a European Registry of ALS. 8–10 October 2004, Naarden, The Netherlands. Neuromusc Disord 2006;16:46–53.
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