Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014; 15: 269–274

ORIGINAL ARTICLE

Incidence of amyotrophic lateral sclerosis in Rhineland-Palatinate, Germany

JOACHIM WOLF1, JOHANNES C. WÖHRLE2, FREDERICK PALM1, WILFRED A. NIX3, MATTHIAS MASCHKE4, ANTON SAFER5, HEIKO BECHER5 & ARMIN J. GRAU1 1Department

of Neurology, Klinikum der Stadt Ludwigshafen, 2Department of Neurology, Katholisches Klinikum, Brüderhaus, Koblenz, 3Department of Neurology, Universitätsmedizin, Mainz, 4Department of Neurology, Krankenhaus der Barmherzigen Brüder, Trier, and 5Institute of Public Health, Medical Faculty, Ruprecht-Karls-University, Heidelberg, Germany

Abstract There is a lack of prospective and population based epidemiological data on amyotrophic lateral sclerosis in Germany to date. The ALS registry Rhineland-Palatinate was established to investigate the incidence, course and phenotypic variety of ALS in this south-west German state of about 4 million inhabitants. During the period 2010–2011, consecutive incident patients with amyotrophic lateral sclerosis according to the revised El Escorial criteria were included and followed up using multiple overlapping sources of case ascertainment. One hundred and forty-six patients were enrolled. The annual crude incidence for amyotrophic lateral sclerosis in Rhineland-Palatinate was 1.8/100,000 person-years (95% CI 1.6–2.2). Male to female ratio was 1.1:1. Incidence increased with age reaching a peak in the 70–74 years age group and declined thereafter. Late-onset ALS ( 75 years) was found in 14.4% of patients. About 32% of patients presented with bulbar onset. In conclusion, incidence rate of amyotrophic lateral sclerosis in Rhineland-Palatinate is within the range of other prospective population based registers in Europe and North America. Gender ratio is nearly balanced. Key words: Amyotrophic lateral sclerosis, epidemiology, incidence, population register

Introduction

Methods

Over the last two decades, valid epidemiological and phenotypic data on amyotrophic lateral sclerosis (ALS) have been established by a series of well designed prospective population based registries, mainly in European countries (Ireland, Scotland, England, Italy, The Netherlands), New Zealand and the USA (1–9). The reported incidence rates vary between 1.6 and 2.9/100,000 person-years with male gender slightly predominating (1.3:1). There is a lack of prospective and population based data on ALS patients in Germany to date. The ALS registry Rhineland-Palatinate was established to investigate the incidence, course and phenotypic variety of ALS in this south-west German state of about 4 million inhabitants. Here we studied incident cases during the two study years, 2010 and 2011.

Study area and study population The ALS registry Rhineland-Palatinate is a prospective population based register that was started on 1 October 2009. Rhineland-Palatinate is a predominantly rural state in the south-west of Germany covering an area of 19,854 km2. Based on official statistical data the population included 4,003,745 inhabitants at the mid-point of this study period (31 December 2010: 1,967,106 males and 2,036,639 females) (10).

Case ascertainment Neurologists of 18 neurological departments and 173 registered neurologists with their own practices in the state, as well as 15 neurological departments and 93 registered ambulatory neurologists in states

Correspondence: J. Wolf, Department of Neurology, Klinikum der Stadt Ludwigshafen, Bremserstra ße 79, 67063 Ludwigshafen, Germany. Fax: 49 621/503 4465. E-mail: [email protected] (Received 29 November 2013 ; accepted 21 January 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.887733

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adjacent to the study area were informed and invited to participate. They all received detailed study information as well as training on diagnostic criteria and disability scores where necessary. All neurologists were contacted at regular intervals by the study team in Ludwigshafen. In hospitals, regular queries on ALS diagnosis at discharge were performed using the International Classification of Diseases 10, code G12.2. We spread the information targeted to general practitioners and other specialized physicians by multiple articles in the official medical journal of Rhineland-Palatinate (www.aerzteblattrheinlandpfalz.de) as a precaution for missed patients. Furthermore, we asked local self-help groups as well as the national society for neuro muscular patients to remind all ALS patients of the existence of the registry. All patients considered for enrolment underwent full neurological examination and neurophysiological testing by cooperating neurologists. Data collection for the registry was restricted to the measurement results from examinations necessary for diagnostic evaluation. Neurological investigators used a standardized data sheet form to transfer information on patient’s demography, clinical history, date of symptom onset on a monthly level according to patients’ statement, date of diagnosis, site of onset (bulbar versus spinal), phenotype of the disease, results of diagnostic work-up and methods of treatment. A patient questionnaire was used to collect socioeconomic and lifestyle data. The principal investigator of the registry (JW) reviewed all questionnaires for completeness and diagnostic coherence. Each patient had a clinical follow-up at regular intervals of 3–6 months. Data on follow-up (body mass index, forced vital capacity, new symptoms, complications, ALS Functional Rating Scale, diagnostic criteria, therapy, and home care) were collected using a follow-up data form. If local follow-up examinations at a neurologist site were not feasible, the central administration of the registry kept track of the disease progression by written investigations or by telephone interviews. In order to achieve case ascertainment as completely as possible and to track deceased ALS patients, pseudonymized death certificates from the local health authorities were collected. Inclusion criteria Patients were included into the registry if they had a new diagnosis of ALS, a minimum age of 18 years and lived in Rhineland-Palatinate for at least six months before date of diagnosis. Diagnosis was based upon the revised El Escorial criteria (11), which provide a classification into four categories (possible, probable laboratory-supported, probable, and definite). Patients with a pure lower (progressive muscular atrophy) or a pure upper (primary lateral sclerosis) motor neuron disease were not considered

for the registry. ALS-mimic syndromes such as spinobulbar muscular atrophy, cervical myelopathy, multifocal motor neuropathy or inclusion body myositis were excluded from the register. To assess an additional dementia, standardized neuropsychological tests (Mini Mental State Examination, Montreal Cognitive Assessment, and Frontal Assessment Battery) were recommended; the participating centres selected the appropriate test according to the preference of the respective institution. Familial ALS was diagnosed in cases with a positive history of ALS in a first or second degree relative of the patient, independent of genetic testing. Functional impairment of patients was measured using the ALS Functional Rating Scale (ALSFRS) in the initial published version (score from 0 to 40) (12). Ethics aspects and data protection The registry was approved by the data protection commissioner of Rhineland-Palatinate and by the local ethics committee. According to legal requirements, patients could be registered at the data holding centre (Department of Neurology, Klinikum Ludwigshafen), including personal data, if written informed consent signed by the patient or the legal representative was available. In the absence of written informed consent, a basic data set (demographic and phenotypic data) was generated with the use of a pseudonymization code, a procedure to avoid double registration. In pseudonymized cases self-reported socioeconomic data and data on follow-up could not be obtained. Data from all patients were collected in a computerized database. In order to comply with the guidelines of the data protection commissioner, the database is kept strictly separated from any personal data that would break anonymity. Statistical analysis We calculated crude, age-specific, and agestandardized incidence rates in the study area. Population counts categorized into five-year age groups at the mid-point of the study period (31 December 2010) were multiplied by two and used as approximate estimates of observed personyears. To facilitate comparisons we used the direct method of standardization to the United States 1990 population (age group 45–74 years), as this was the standard used in previous population based registries. Exact 95% confidence intervals (CI) for the incidence rates based on an assumed Poisson distribution were calculated. To discern differences in ALS frequency between rural and urban areas, rates were calculated for the different inhabitant population numbers in the communities of residence categorized into five classes separated by the cut-points 2000, 5000, 20,000 and 100,000. By definition rural places of residence in Germany have less than 2000 inhabitants. The

Incidence of ALS in Germany Cochran-Armitage trend test was used to assess a possible trend. To avoid excessive calculation we used a Monte Carlo version of the exact calculation with 10,000 samples, resulting in a p-value with 95% confidence limits. To check the quality of death ascertainment, we applied a two-source capturerecapture method (13). Statistical analyses were carried out using independent t-test, Mann-Whitney U-test, χ2 test or Fisher’s exact test, as appropriate. p-values  0.05 were considered significant. Calculations were performed with SAS v9.3 software. Results During the period of observation (1 January 2010 to 31 December 2011), 146 patients (males, 76; females, 70) with a new diagnosis of ALS were registered according to the revised El Escorial criteria: 22.6% were classified as possible, 26.7% as probable laboratory-supported, 34.2% as probable and 16.5% as definite ALS cases. Mean age at diagnosis was 66.2 (SD  10.6) years (median 69 years; range 23–85 years; males, 64.9 (SD  10.7) years: females, 67.5 (SD  10.5) years, p  0.14). Mean delay between onset of symptoms and diagnosis was 12.6 (SD  12.1) months (median nine months). Bulbar onset was found in 47 patients (32.2%, age 67.4 years, SD  11.3), with a trend to reduced incidence in males (n  19, 25%; age 64.9 years, SD  13.8) than females (n  28; 40%, age 69.2 years, SD  9.2, p  0.06). A total of 99 patients suffered spinal onset (67.8%, age 65.5 years, SD  10.3), among them six patients with an initial respiratory or trunk involvement (4.1%), 50 patients with symptom onset in lower extremities (34.2%), and 33 patients with early symptoms in upper extremities (22.6%). Clear signs of an additional frontotemporal dementia (FTD) at diagnosis or in the first year of follow-up were seen in 11 patients (7.5%).

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Written informed consent was obtained in 110 patients (75.3%). In these patients, socioeconomic data as well as follow up-data were available. In the remaining 36 patients, a basic data set at diagnosis was captured. In seven of 110 patients, a familial history of motor neuron disease was evident (6.4%). Overall, 39 patients (17 males, 22 females) died within the first year after diagnosis. Notifications of deceased patients by clinics, neurologists, general practitioners or family members identified 35 deceased patients (six unique to this source), whereas death certificates of public health departments identified 33 patients (three unique to that source). In a twosource capture-recapture model, we estimated that one deceased patient was unobserved. The crude annual incidence rate for ALS in Rhineland-Palatinate for the years 2010 and 2011 was 1.8/100,000 person-years (95% CI 1.6–2.2). The incidence rate in males (1.9, 95% CI 1.5–2.4) and females (1.7, 95% CI 1.4–2.2) did not differ significantly. The male:female rate ratio was 1.1:1. Age- and genderspecific incidence rates are presented in Table I. For both males and females, incidence rates increased with age with a peak in the age group 70–74 years, while rates markedly decreased in the older age groups. Late-onset ALS ( 75 years) was found in 13.2% of males and 15.7% of females. Figure 1 demonstrates age-specific incidence rates for males and females with regard to site of onset. We analysed the incidence rate of ALS depending on the size of place of residence. In 134 ALS patients, the exact place of residence was known.The CochranArmitage trend test showed a significant trend (z  1.919, p  0.029) towards higher incidence rates in urban places of residence (Figure 2). Discussion This study is the first population based register in a well defined geographic area in south-west Germany

Table I. Age- and gender-specific crude incidence rates of ALS in Rhineland-Palatinate, 2010 to 2011. Total Age (years)

cases

population

 18 18 –29 30 –34 35 –39 40 – 44 45 – 49 50 – 54 55 – 59 60 – 64 65 – 69 70 –74 75 –79 80 – 84  85 Total

0 1 1 0 5 5 8 14 15 27 49 9 11 1 146

670,452 565,082 218,075 232,542 319,858 348,872 316,075 278,691 230,799 198,281 238,239 161,813 122,075 102,891 4,003,745

Male

Female

IR

95% CI

cases

population

IR

95% CI

cases

population

IR

95% CI

0 0.1 0.2 0 0.8 0.7 1.3 2.5 3.3 6.8 10.3 2.8 4.5 0.5 1.8

0 – 0.2 0 – 0.5 0 –1.3 0 – 0.1 0.3 –1.8 0.2 –1.7 0.6 –2.5 1.4 – 4.2 1.8 – 5.4 4.5 – 9.9 7.6 –13.6 1.3 – 5.3 2.3 – 8.0 0 –2.7 1.6 –2.2

0 1 0 0 3 4 3 10 8 16 21 5 5 0 76

344,821 2,871,26 108,637 115,942 162,609 177,685 159,556 139,785 115,320 96,096 111,421 712,09 47,182 29,717 1,967,106

0 0.2 0 0 0.9 1.1 0.9 3.6 3.5 8.3 9.4 3.5 5.3 0 1.9

0 – 0.4 0 –1.0 0 –1.4 0 –1.3 0.2 –2.7 0.3 –2.9 0.2 –2.7 1.7– 6.6 1.5 – 6.8 4.8 –13.5 5.8 –14.4 1.1– 8.2 1.7–12.3 0 – 5.1 1.5 –2.4

0 0 1 0 2 1 5 4 7 11 28 4 6 1 70

325,631 277,956 109,438 116,600 157,249 171,187 156,519 138,906 115,479 102,185 126,818 90,604 74,893 73,174 2,036,639

0 0 0.5 0 0.6 0.3 1.6 1.4 3.0 5.4 11.0 2.2 4.0 0.7 1.7

0 – 0.5 0 – 0.5 0 –2.6 0 –1.3 0.1–2.3 0 –1.6 0.5 –3.7 0.4 –3.7 1.2 – 6.2 2.7– 9.6 7.3 –16.0 0.6 – 5.7 1.5 – 8.7 0 –3.8 1.4 –2.2

IR: incidence rate (per 100,000 person-years); CI: confidence interval.

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Figure 1. Incidence rates of ALS in Rhineland-Palatinate by age groups, gender and site of onset.

Figure 2. Incidence rates (IR) of ALS by the categorized inhabitant number of place of residence in Rhineland-Palatinate. IR per 100,000 inhabitants with exact 95% confidence interval.

(Rhineland-Palatinate). We made strong efforts to ensure completeness of case ascertainment and used multiple overlapping sources of information to determine the incidence of ALS. The total crude incidence rate (1.8/100,000 person-years) and incidence rate of the 45–74 years age group, standardized to the 1990 US population, lie within the lower range

compared to those calculated in previous population based registers (Table II). The lower incidence rate might be a consequence of the rigid application of the revised El Escorial criteria, as we did not include patients fulfilling the ‘suspected’ category of the former El Escorial criteria, unlike registers in Scotland (2), south-east England (3),

Table II. Comparison of selected prospective ALS registries with regard to crude incidence rates and age-standardized incidence rates (45 –74 years age group) referring to the 1990 US population. Register Ireland [1] Scotland [2] Piemonte [4] Lombardy [5] Puglia [6] Washington [9] Rhineland-Palatinate

Years

Population

Cases

Crude IR

95% CI

M:F rate

IR (US 45 –74 y)

95% CI

1995 –1997 1989 –1998 1995 –1996 1998 –2002 1998 –1999 1990 –1995 2010 –2011

3,626,087 5,035,315 4,418,503 4,947,554 4,086,613 2,589,164 4,003,745

231 1226 221 517 130 235 146

2.1 2.40 2.5 2.09 1.6 1.8 1.8

1.8 –2.4 2.22 –2.58 2.2 –2.9 1.17–3.18 1.3 –1.9 1.3 –2.4 1.6 –2.2

1.3:1 1.4:1 1.3:1 1.3:1 1.6:1 1.1:1 1.1:1

6.0 5.5 5.4 4.2 4.1 5.5 3.8

5.1– 6.9 5.0 – 6.0 4.6 – 6.3 3.4 – 5.1 2.6 – 5.7 4.7– 6.4 3.4 – 4.6

IR: incidence rate (per 100,000 person-years); CI: confidence interval.

Incidence of ALS in Germany Lombardy (5), or Puglia (6), where ‘suspected’ cases account for 9.9–14.6% of all included cases. In agreement with previous prospective registers, age-specific incidence rates increase after the age of 40 years and show a maximum in the age group 70–74 years (Figure 1). We also found a rapid decline of incidence in older age groups, both in males and females. Other competing reasons for death may at least partly explain the decline of rate. Another problem arises from higher comorbidity rates, which increase the difficulty to diagnose ALS. However, older age groups may also show a decline of susceptibility to motor neuron damage (14). In Western countries proportions of late-onset ALS ( 75 years) seem to exceed 10%, which indicates that our registry (14.4%) has achieved a sufficient case ascertainment in elderly patients (Table III). The percentage of late-onset ALS might be a marker of high quality case ascertainment contributing to a higher mean age at diagnosis (4). However, these estimates have to be handled cautiously due to very small numbers of patients in the youngest and oldest age groups and due to possibly different age structures of the reference populations. Comparable to the Washington register, an almost balanced gender ratio was conspicuous in our study (Table II). In contrast to former retrospective registers with a male to female ratio of almost 2:1, recent studies report a growing similarity of gender distribution (14,15). This might either reflect a better case ascertainment of female ALS patients, or an increasing prevalence of risk factors for the development of ALS in females during the last decades, for example smoking (16–18). About one-third of our patients (32.2%) presented with bulbar onset and another third (34.2%) with symptoms in lower limbs. Symptom onset in upper limbs was less frequent (22.6%), similar to studies in Ireland (1) and Piemonte (4). Compared to the Piemonte registry (0.4%), we found a considerably higher percentage of patients with an initial trunk or respiratory involvement (4.1%). In our study mean diagnostic delay (12.6 months) was strikingly high. The current ALS registry should contribute to an increasing awareness of symptoms of motor neuron disease in medical care, such as has

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been detected in context with the Piemontese registry a few years after the implementation of the register (19). As in other registries, the definition of familial ALS did not depend on a positive genetic test. It was solely based on a positive history of ALS in first- or second-degree relatives. The frequency of familial ALS in our study (6.4%) was similar to that reported in registers of Piemonte (5.8%) (19) and south-east England (6.6%) (3). The overall frequency in the Irish register within a six-year period (1995–1997 plus 2002–2004) was 6.2%; in the 2002–2004 cohort it was 8.5% (20). Overt symptoms of FTD were detected at diagnosis or within the first year thereafter in 7.5% of patients, which is in the same order as the Irish register (6.9%) (20). Again in the Irish 2002–2004 cohort, the frequency of associated FTD was clearly higher (11.9%), which might be explained by the growing awareness and thorough assessment of cognitive dysfunction in ALS patients (21). In contrast to some previous studies (22,23), we could not identify elevated incidence rates of ALS in rural areas, which is in accordance with the Irish register (1). We observed even a trend towards higher incidence rates in urban areas; the same has been reported for the South-East England registry (24). However, the information content of our data is limited by the relatively small number of patients, which is the consequence of the small population size of the region of interest. Larger populations could provide adequately powered data. For this reason the EURALS consortium was established covering 25 million Europeans (14), and a German countrywide registry has recently been initiated (German MND-Net). Indicators show that we have achieved a close-to-complete case ascertainment. Nevertheless, we cannot completely rule out that we possibly missed ALS patients. Capture-recapture analysis for an estimation of possibly missed ALS patients was not applicable as different sources of ascertainment were not completely independent (e.g. ascertainment of in-patients versus out-patients) and a statewide discharge diagnosis data bank as a reliable independent source was not available.

Table III. Percentage of early-onset ALS ( 45 years) and late onset ALS ( 75 years) in different ALS registries. Early-onset ALS (%)

Late-onset ALS (%)

Register

Cases

Total

males

females

Total

males

females

South-East England [3] Scotland [2] Lombardy [5] Puglia [6] Washington [9] Rhineland-Palatinate

138 1226 517 130 235 146

8.0 4.6 8.7 7.7 14.5 4.8

9.2 6.0 10.9 4.9 22.8 5.3

6.5 2.9 5.8 12.2 4.6 4.3

13.0 23.8 17.4 10.0 14.5 14.4

19.4 20.7 14.7 11.1 11.0 13.2

7.9 27.4 21.0 8.2 18.5 15.7

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In spite of some limitations, this registry also has several strengths; such as its multiple overlapping sources of ascertainment with additional mortality coding from health authorities, its special patient questionnaire, which extends the spectrum of socioeconomic and lifestyle data, and its active follow-up of patients in 3–6 months intervals. Furthermore, the register has initiated a growing cooperation of all medical subspecialties in the Rhineland-Palatinate taking care of ALS patients to date. Acknowledgements The authors are grateful to all patients who participated in the register. We particularly thank Mrs. Streib (Study nurse) and all collaborating neurologists and general practitioners. Declaration of interest: The authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O. Incidence and prevalence of ALS in Ireland, 1995–1997. Neurology. 1999;52:504–9. 2. Forbes RB, Colville S, Parratt J, Swingler RJ. The incidence of motor neuron disease in Scotland. J Neurol. 2007;254:866–9. 3. Abhinav K, Stanton B, Johnston C, Hardstaff J, Orrell RW, Howard R, et al. Amyotrophic lateral sclerosis in south-east England: a population based study. Neuroepidemiology. 2007;29:44–8. 4. 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. 5. Beghi E, Millul A, Micheli A, Vitelli E, Logroscino G. Incidence of ALS in Lombardy, Italy. Neurology. 2007;68:141–5. 6. Logroscino G, Beghi E, Zoccolella S, Palagano R, Fraddosio A, Simone IL, et al. Incidence of amyotrophic lateral sclerosis in southern Italy: a population based study. J Neurol Neurosurg Psychiatry. 2005;76:1094–8. 7. Huisman MH, de Jong SW, van Doormaal PT, Weinreich SS, Schelhaas HJ, van der Kooi AJ, et al. Population based epidemiology of amyotrophic lateral sclerosis using capturerecapture methodology. J Neurol Neurosurg Psychiatry. 2011;82:1165–70.

8. Murphy M, Quinn S, Young J, Parkin P, Taylor B. Increasing incidence of ALS in Canterbury, New Zealand: a 22-year study. Neurology. 2008;71:1889–95. 9. McGuire V, Longstreth WT, Koepsell TD, van Belle G. Incidence of amyotrophic lateral sclerosis in three counties in western Washington State. Neurology. 1996;47:571–3. 10. Statistisches Landesamt Rheinland-Pfalz. Statistics Yearbook of Rhineland-Palatinate 2011 (Statistisches Jahrbuch Rheinland-Pfalz 2011). Bad Ems 2012. 11. Ross MA, Miller RG, Berchert L, Parry G, Barohn RJ, Armon C, et al. Toward earlier diagnosis of amyotrophic lateral sclerosis: revised criteria. Neurology. 1998;50:768–72. 12. The ALS CNTF treatment study (ACTS) phase I-II Study Group. The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. Arch Neurol. 1996;53:141–7. 13. Hook E, Regal R. Capture-recapture methods in epidemiology: methods and limitations. Epidemiol Rev. 1995;17:243–64. 14. Logroscino G, Traynor BJ, Hardiman O, Chio A, Couratier P, Mitchell JD, et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry. 2008;79:6–11. 15. Sorenson EJ, Stalker AP, Kurland LT, Windebank AJ. Amyotrophic lateral sclerosis in Olmsted County, Minnesota, 1925–1998. Neurology. 2002;59:280–2. 16. Armon C. Smoking may be considered an established risk factor for sporadic ALS. Neurology. 2009;73:1693–8. 17. Gallo V, Bueno-De-Mesquita HB, Vermeulen R, Andersen PM, Kyrozis A, Linseisen J, et al. Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort. Ann Neurol. 2009;65:378–85. 18. Wang H, O’Reilly EJ, Weisskopf MG, Logroscino G, McCullough ML, Thun MJ, et al. Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of five prospective cohorts. Arch Neurol. 2009;68:207–13. 19. Chio A, Mora G, Calvo A, Mazzini L, Bottacchi E, Mutani R. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. 2009;72:725–31. 20. O’Toole O, Traynor BJ, Brennan P, Sheehan C, Frost E, Corr B, Hardiman O. Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004. J Neurol Neurosurg Psychiatry. 2008;79:30–2. 21. Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65:586–90. 22. Furby A, Beauvais K, Kolev I, Rivain JG, Sebille V. Rural environment and risk factors of amyotrophic lateral sclerosis: a case-control study. J Neurol. 2010;257:792–8. 23. Das K, Naq C, Ghosh M. Familial, environmental, and occupational risk factors in development of amyotrophic lateral sclerosis. N Am J Med Sci. 2012;4:350–5. 24. Scott KM, Abhinav K, Wijesekera L, Ganesalingam J, Goldstein LH, Janssen A, et al. The association between ALS and population density: a population based study. Amyotroph Lateral Scler. 2010;11:435–8.

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Incidence of amyotrophic lateral sclerosis in Rhineland-Palatinate, Germany.

There is a lack of prospective and population based epidemiological data on amyotrophic lateral sclerosis in Germany to date. The ALS registry Rhinela...
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