J. Neurol. 212, 205--213 (1976) © by Springer-Verlag 1976
Original Investigations AmyotropMc Lateral Sclerosis* A Population
Study
E s t h e r K a h a n a 1, M i l t o n A l t e r ~, a n d S h a u l F e l d m a n 3 z Barzilai Hospital, Ashkelon, Israel The Neuroepidemiology and Genetics Unit, University of Minnesota, Minneapolis, Minnesota 8 The Uri Leibowitz l~euroepidemiology Unit, Hadassah University Hospital, Jerusalem Received December 30, 1975
Summary. A country-wide study of the frequency of amyotrophie lateral sclerosis (ALS) was undertaken in Israel for the period 1960--1970. Israel was chosen for this study because of its excellent medical facilities and detailed demographic information. Moreover, the population includes representative groups from all parts of the world for comparison of frequency. A wide variety of motor system disease was screened in all hospitals, clinics, and chronic care facilities in the country, death certificates were reviewed and physicians with a neurological practice were contacted to derive a tentative list of cases. Only those who fit strict clinical diagnostic criteria or had autopsy confirmation were included in estimates of prevalence and incidence. On January 1, 1965, the mid-point of the study, 62 patients with ALS were living in Israel. The age-adjusted prevalence of ALS on that date was 3 per 100000 population. The average annual age-adjusted incidence for the period 1960---1970 was 0.78 per 100000 population (0.86 in males, 0.46 in females; ratio 1.9:1). There was no appreciable change in trend of incidence over the study interval. Age-specific incidence rates were similar in native-born inhabitants of Israel, immigrants from Europe and immigrants from Afro-Asian countries. The range in age-adjusted incidence among subgroups of immigrants to Israel from various countries was 0.25 to 1.20 per 100000 population but small numbers precluded testing the statistical significance of these rather narrow differences. Mean age at onset was 55.4 years for males and 52.4 years for females. The mean age at death was 60.2 for males and 58.0 for females. The average annual mortality from ALS was 0.58 per 100000 population. There were no familial aggregates of ALS in Israel and autopsy data showed no neurofibrillary changes, granulovaeuolar or inclusion bodies. There are only a few other population studies of ALS in different regions of the world. The average annual incidence in these other studies ranged from 0.4 to 1.4 per 100000 population. Thus, the incidence in Israel falls within this narrow range. The present study lends further support to the impression that ALS has a remarkably uniform geographic distribution with Guam and the Kii peninsula of Japan being the only known areas with significantly high rates. I f an environmental factor contributes to the pathogenesis of ALS, the factor must also have a uniform geographic distribution.
Key words: Amyotrophic lateral sclerosis - - Epidemiology of ALS. Zusammen/azsunp. W/~hrend der Zeit zwischen 1960 und 1970 wurde eine landesweite Untersuchung fiber die H~ufigkeit der amyotrophischen Lateralsklerose (ALS) in Israel durchgeffihrt. Das Land Israel wnrde ffir diese Studie ausgesucht wegen der ausgezeichneten medizinischen Versorgung und der detaillierten demographischen Informationen. Aul3erdem umfaBt die Bev61kerung repr/~sentative Gruppen aus allen Teilen der Welt, so dab vergleichende * Supported in part by the Minneapolis Veterans Administration Hospital.
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E. Kahana et al.
H£ufigkeitsun~ersuchungen m6glich waren. Es wurden in allen Spit~lern, Kliniken und Chronisch-Krankenheimen des Landes zahlreiche Erkrankungen des motorischen Systemes analysiert. Im weiteren wurden die Zeugnisse fiber die Todesursachen analysiert sowie die neurologiseh t~tigen _Arztekonsultiert. Iqur jene F/ille wurden sehlieBlich zur Errechnung der H/iufigkeit der Erkrankung verwertet, bei welchen die typischen klinischen Symptome oder ein Autopsiebefund die Diagnose rechtfertigten. Am 1. Januar 1965, der Tag, welcher in der Mitte der beriieksichtigten Periode lag, lebten 62 Patienten mit ALS in Israel. Die alterskorrigierte H~ufigkeit der ALS an jenem Tage betrug 3 auf 100000 Einwohner. Die j~hrlichen Neuerkrankungen, alterskorrigiert, ffir die Periode zwischen 1960 und 1970 betrug 0,78 auf 100000 Einwohner (0,86 f/Jr M~nner und 0,46 ffir Frauen, Verh/iltnis 1,9:1). Es lag keine nennenswerte Anderungstendenz mit Bezug auf die Neuerkrankung wEhrend der Dauer der Studie vor. Altersspezifische H~ufigkeiten waren iihnlich bei Israel-Geborenen wie bei aus Europa oder afroasiatisehen L~ndern emigrierten Einwohnern. Die Schwankungen der alterskorrigierten HEufigkeiten zwischen den Untergruppen der Emigranten aus den verschiedenen L/£ndern betrug zwischen 0,25---1,20 ffir 100000 Einwohner. Aber die Kleinheit einzelner Gruppen verunm6gliehte es, die statistisehe Signifikanz dieser eher kleinen Untersehiede zu errechnen. Das Durehschnittsalter beim Beginn betrug 55,4 Jahre ffir die M~nner und 52,4 Jahre ffir die Frauen. Das mittlere Sterbealter der Manner war 60,2, dasjenige der Frauen 58,0 Jahre. Die mittlere j~hrliehe Mortalit£t infolge ALS war 0,58 auf 100000 Einwohnern. In Israel fanden sich keine famili~re H~ufungen yon ALS, und bei den SektionsfEllen wurden keine neurofibrill~ren Veriinderungen oder granulovaeuolKre bzw. EinschluBk6rperchen gefunden. Es liegen nur einige wenige Populationsstudien mit Bezug auf die ALS in den verschiedenen Regionen der Welt vor. Die mittlere j~hrliche Neuerkrankung in jenen anderen Studien schwankt zwisehen 0,4 und 1,4 pro 100000 Einwohner. Somit f/illt die H~ufigkeit in Israel eher in den unteren Bereieh dieser Schwankungsbreite. Die vorliegende Studie sprieht daffir, dab die ALS eine bemerkenswert einheitliehe geographische Verteilung hat. Als einzige Ausnahme haben Guam und die Kii-Halbinsel Japans eine signifikant hShere HEufigkeit. Falls ein umgebungsgebundener Faktor bei der Pathogenese der ALS mit eine Rolle spielt, muB dieser Faktor eine einheitliche geographische Verbreitung haben.
A m y o t r o p h i c l a t e r a l sclerosis (ALS) a p p e a r s t o h a v e a r e m a r k a b l y u n i f o r m g e o g r a p h i c d i s t r i b u t i o n . T h e r e p o r t e d p r e v a l e n c e is a b o u t five cases p e r 100000 p o p u l a t i o n in m a n y p a r t s of t h e world ( K u r l a n d et al., 1969; K u r t z k e , 1969; B o b o w i c k a n d B r o d y , 1973). Chamorros living on G u a m ( K u r l a n d a n d Mulder, 1955) a n d in California (Torres et al., 1957), as well as J a p a n e s e on t h e K i i Peninsula (Yase, 1970) are exceptions in t h a t these groups h a v e m u c h higher prevalence r a t e s of A L S . On t h e o t h e r h a n d , Mexicans in Mexico C i t y as well as in t h e U n i t e d S t a t e s h a v e been r e p o r t e d t o h a v e c o n s i d e r a b l y lower r a t e s t h a n t h e a v e r a g e (Olivares et al., 1972). W h e n t h e d a t a on t h e f r e q u e n c y of A L S in different p a r t s of t h e world are e x a m i n e d critically, m o s t are f o u n d to be b a s e d on d e a t h certificates alone a n d t h u s m a y be incomplete. A m o r e a c c u r a t e reflection o f t h e t r u e f r e q u e n c y of t h e disease is o b t a i n e d b y including a d d i t i o n a l sources of medical i n f o r m a t i o n b u t o n l y a few c o m p l e t e p o p u l a t i o n studies h a v e been carried out. Therefore, a d d i t i o n a l i n f o r m a t i o n on t h e f r e q u e n c y of A L S based on complete p o p u l a t i o n studies is desirable. Such d a t a m a y reveal groups who, like t h e Chamorros, t h e J a p a n e s e on t h e K i i p e n i n s u l a a n d t h e Mexicans, h a v e rates of A L S different from t h e average. Studies o f " d e v i a n t " p o p u l a t i o n s m a y c o n t r i b u t e clues t o factors influencing pathogenesis. A c o m p l e t e p o p u l a t i o n s t u d y of A L S was u n d e r t a k e n in Israel. I n h a b i t a n t s o f t h a t c o u n t r y include a large n u m b e r of different p o p u l a t i o n groups, m a n y of
Amyotrophic Lateral Sclerosis
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whom are r e c e n t i m m i g r a n t s . I n addition, Israel has excellent medical facilities which are r e a d i l y accessible to t h e p o p u l a t i o n . U p - t o - d a t e a n d detailed demographic d a t a are also available t h r o u g h official g o v e r n m e n t a l publications. Therefore, i n Israel, t h e f r e q u e n c y of ALS could readily be compared a m o n g p o p u l a t i o n groups from m a n y different p a r t s of t h e world.
Method An effort was made to identify all patients with ALS diagnosed in Israel between 1960 and 1970. A large group of motor system diseases was screened so as to include patients with ALS who may have been listed under a different diagnostic label. Besides amyotrophic lateral sclerosis, the list included progressive muscular atrophy, progressive spinal atrophy, progressive bulbar palsy, primary lateral sclerosis and motor neuron disease. ~edical records of hospitals and neurological outpatient clinics were searched for patients with any of these diagnoses. Physicians with neurological practices were personally contacted and asked to provide data on patients with any of these diagnoses who were under their care. Mortality data were also collected. The clinical records on all patients identified in the above sources were reviewed. Attention was given not only to the clinical details but also to X-ray and electromyographic information when available, and to post mortem details. Efforts were made to contact all patients whose clinical records were compatible with ALS and, if the patient was deceased, additional information from hospitals, physicians and the family was solicited to obtain as complete a picture as possible of the patient's disorder. Demographic data were derived from official publications of the Central Bureau of Statistics (1959--1970). The data on frequency were analyzed to provide age-specific incidence rates of ALS among various groups in the population. Age-adjusted rates were computed based on the total population of the U.S.A. in 1970. Prevalence and mortality rates were also derived. Diagnostic criteria were formulated and rigidly applied to each case in the tentative list. All patients with autopsy confirmation of ALS were accepted. The clinical criteria were as follows: a patient was accepted as having ALS if the clinical data showed evidence of lower motor neuron involvement in the form of muscle atrophy and muscle fascicnlation at more than one level of the spinal cord. Patients with sensory loss were excluded. Upper motor neuron and bulbar involvement was an added hut not an absolute requirement for inclusion in the study. Among patients who had an electromyogram, only those whose results were compatible with lower motor neuron deficit were included and a normal electromyogram constituted absolute grounds for exclusion. Patients with only pyramidal tract signs (i.e. primary lateral sclerosis) and patients with infantile (Werning-Hoffman Disease) or childhood forms (i.e. Kugelberg-Welander disease) of motor system disease were also excluded. Patients certified as having died of ALS in whom no other clinical data were available were noted as a special group but were not included in estimates of prevalence or incidence.
Results I n t h e c o u n t r y - w i d e search for ALS i n Israel, 213 p a t i e n t s were identified. Of these, 16 h a d onset after 1969, the date a r b i t r a r i l y chosen as t h e e n d of t h e s t u d y period, a n d were excluded. Twelve p a t i e n t s h a d a c o n c o m i t a n t disease which could a c c o u n t for features of ALS (8 h a d cervical spondylosis a n d 4 h a d a carcinoma) a n d those were also excluded. Of the r e m a i n i n g 185, 12 h a d onset of ALS prior to coming to Israel a n d 10 h a d onset before 1960, the b e g i n n i n g of the s t u d y period. I n 21 patients, t h e diagnosis was based o n a d e a t h certificate alone. A u t o p s y c o n f i r m a t i o n was available i n 11 patients.
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Table 1. Age adjusted prevalence rates of amyotrophic lateral sclerosis in Israel, 1.1. 1965 Region of birth
Number of patients
Age adjusteda prevalence per 100000 population
Europe Afro-Asia Israel
41 16 5
3.2 2.4 4.9
Total
62
3.0
a To total population U.S.A. 1970. Table 2. ALS patients in Israel by year of onset of illness Year of onset 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 Unknown Total
No. patien~ with onset in Israel
Population
Crude incidence rate per 100000 population
7 6 11 12 11 14 15 11 13 15 22 5
1810148 1858841 1911189 1981702 2 068 882 2155552 2239127 2 299078 2344877 2434832 2496438 --
0.39 0.32 0.58 0.61 0.53 0.65 0.67 0.48 0.55 0.62 0.88 --
142
2 360066 a
0.60
a Mean population.
On J a n u a r y 1, 1965, t h e m i d - p o i n t o f t h e s t u d y i n t e r v a l , 62 p a t i e n t s w i t h A L S were living in Israel. A t o t a l o f 124 p a t i e n t s w i t h A L S d i e d d u r i n g t h e s t u d y i n t e r v a l , 1960 t h r o u g h 1970. T h e a g e - a d j u s t e d prevalence of A L S in I s r a e l on J a n u a r y 1, 1965 excluding t h o s e cases b a s e d on d e a t h certificates alone was 3.0 p e r 100000 p o p u l a t i o n . P r e v a l e n c e was n o t s t a t i s t i c a l l y different a m o n g t h e t w o m a j o r J e w i s h i m m i g r a n t groups in I s r a e l n o r in t h e I s r a e l i - b o r n J e w i s h p o p u l a t i o n (Table 1). T h e a v e r a g e a n n u a l a g e - a d j u s t e d incidence o f A L S d u r i n g t h e p e r i o d 1960 to 1970 was 0.78 p e r 100000 p o p u l a t i o n . I n males, t h e a v e r a g e a n n u a l incidence was 0.86 a n d in females, it was 0.46 (ratio: 1.87:1) p e r 100000 p o p u l a t i o n . I f t h o s e b a s e d on d e a t h certificates alone were excluded, t h e incidence was 0.68 p e r 100000 p o p u l a t i o n . N o secular t r e n d in incidence was a p p a r e n t over t h e s t u d y i n t e r v a l (Table 2). T h e age-specific incidence r a t e s of A L S were similar for n a t i v e b o r n i n h a b i t a n t s of Israel, i m m i g r a n t s from E u r o p e a n d i m m i g r a n t s from AfroA s i a n countries (Fig. 1).
Amyotrophie Lateral Sclerosis
209
5.5 Born in: Europe
~. 5.0
A
....... Afr0-Asia - - Israel
/
_ ~,\
/I/~\
o
o
2.0
,-/
_
1.5
\,.
i
0
,
~
20-Z9
~
50-59
~
40-49 50-59
~ 60-69
I 704"
Age (years)
Fig. 1. Average annual age-specific incidence of amyotrophic lateral sclerosis in Israel by ethnic group (1960---1970)
Table 3. Average yearly incidence rates of amyotrophic lateral sclerosis in Israel by country of birth 1960--1970 Country of birth
No. of patients
Europe Bulgaria, Greece East Europe West and Central Europe
96 3 80 13
Afro-Asia Egypt Turkey Iran Iraq Libya Morocco, Algeria, Tunisia Yemen Other
Israel Specific country unknown Total
38 1 5 4 6 4 9 4 5 7 1 142
Population at risk 1.1.1965
Age adjusteda incidence rate per I00000 population
757 755 46893 513149 154526
0.32 0.78 0.57
600943 35098 43187 45043 120575 30625 265 544 60871 42177
0.25 0.79 1.20 0.47 1.01 0.42 0.46 0.89
881490
0.72
0.60
0.65 0.68
a Adjusted to total population of U.S.A., 1970.
I n T a b l e 3, t h e average a n n u a l incidence of ALS a m o n g n a t i v e - b o r n Israelis a n d i m m i g r a n t groups from different countries of origin is shown. The age-adjusted incidence i n various groups r a n g e d from 0.25 to 1.20 per 100000 p o p u l a t i o n .
210
E. Kahana et al. 3.0
2.5
t.5
0.5 0 :30-39 40-49 50-59 60-69
70-79
Age ot deoth
(yeors)
Fig. 2. Age-specificmortality rates from amyotrophic lateral sclerosis in Israel (1960-1970)
Because the numbers were small for most groups, analysis of statistical significance of difference among these subpopulations was not carried out. The age at onset of symptoms among patients with onset in Israel was well documented in 122 cases; it ranged from 26 to 81 years. The mean age at onset was 55.4 years in males and 52.4 years in females. The mean age at death was 60.2 for males and 58.0 for females. The average annual mortality was 0.58 per 100000 population. Age-specific mortality is shown in Figure 2. The duration of illness ranged from 7 to 120 months. The mean was 36.8 months for males and 31.5 months for females. Patients with onset before age 45 years had a somewhat longer mean duration of 46.8 months. The autopsy data in 11 patients showed a typical histology with anterior horn cell loss and demyelination of the pyramidal tracts. One patient had degeneration of Betz cells. None showed neurofibrillary changes, granulovacuolar bodies or inclusion bodies. There were no familial aggregates of ALS in this series.
Discussion
There are only a few population studies of ALS in which the methods of casefinding and diagnostic criteria were similar to those used in Israel. One of the most thorough of these studies was reported by Kurland et al. (1969) from Rochester, Minnesota. Using the Mayo Clinic which provides virtually all of the medical care for the surrounding population, these investigators found 17 cases of ALS during a 40 year period (1925--1964) and estimated the average annual age- and sexadjusted incidence rate to be 1.3 per 100000 population. Another community-wide study which included ALS among the disorders investigated was carried out by Brewis et al. (1966} in Carlisle, England. Five patients with ALS were found during the period 1955 to 1961. The average annual incidence rate was 1 per 100000 population.
Amyotrophie Lateral Sclerosis
211
I n both of the above studies the population base and hence, the total number of patients identified, was small. Several larger populations have been studied. Between 1952 and 1969, a total of 118 patients with ALS was identified in Hawaii, which has about three-quarters of a million inhabitants. The average annual incidence rate of ALS in Hawaii was 1.04 per 100000 population. Hawaii, like Israel, includes a variety of ethnic groups. Analysis of incidence b y ethnic group gave age- and sex-adjusted rates of 0.82 for Caucasians, 0.86 for Japanese and 1.56 for Filipinos per 100000 population. I t should be noted, however, t h a t not all the diagnoses could be confirmed in the Hawaiian study and in autopsies on 10 patients, 4 were inadequate or atypical of ALS (Matsumoto et al., 1972). A nation-wide study of neurological disease, including ALS, was reported from Iceland b y Gudmundsson (1968). During the period of 1954 to 1963, he found 24 patients and estimated the average annual incidence rate of 0.76 per 100000 population. An average annual incidence of 1.4 per 100000 population was reported b y Lorez (1969) from northwestern Switzerland. T h e estimate was based on 89 patients ascertained during the period 1951 to 1967. Cendrowski et al. (1970) collected data from the Poznafi Province of Poland, an area with 2.5 million inhabitants. During the period 1955 to 1965, he found 56 patients with ALS and estimated an annual incidence rate of 0.78 per 100000 population. I n Mexico City, where about one-half million individuals were available for study, Olivares et al. (1972) reported an average annual incidence rate of 0.40 per 100000 population. Besides these population studies, estimates of the frequency of ALS based on other types of analysis are available from different parts of the world (Kurtzke, 1969). I f it is accepted t h a t the disease is invariably fatal within 3 or 4 years, at least in its classical form, incidence rates can be derived from prevalence data Prevalence using the relationship: Incidence ~ Duration of Illness " However, it is not really easier to obtain data on prevalence t h a n incidence because the same sources of data are usually used. Therefore, m a n y investigators have resorted to use of mortality reports in estimating the frequency of ALS. The number of individuals certified in death records as having died of ALS can be obtained from the official vital statistics published b y most countries of the world, and political subdivisions of some countries. Kurland and associates (1969) have summarized mortality reports on ALS from 23 countries as well as from a large number of different nationalities who were residents in the United States. Although the range in reported mortality among the different countries and among different national groups was wide (0.06 to 1.54 and 0.2 to 6.2 per 100000 population respectively), the authors could detect no geographic pattern of distribution. They believed t h a t sampling variation due to small numbers, differences in medical facilities and diagnostic differences probably accounted for the observed differences in mortality reports on ALS from different countries and states and concluded t h a t the mortality of ALS was probably uniform, near 0.5 to 1 per 100000 population. A similar conclusion was drawn b y Edgar et al. (1973) based on mortality reports of ALS in California and WashingtonState. Among native-bornindividuals, the age-sex-adjusted death rates per 100000 population from ALS were 0.62 and 0.57 in California and Washington State respectively. The rates among non-native born individuals in California varied in the narrow range of 0.43 to 1.2 per 100000
212
E. Kahana et al.
population in nine geographic subdivisions of the United States (total 0.64). Similarly, the range was between 0 to 1.0 per 100000 population (total 0.76) in W a s h i n g t o n State. The general uniformity in frequency of ALS is in marked contrast to the distribution of multiple sclerosis which appears to increase in frequency with geographic latitude (Leibowitz and Alter, 1973). The incidence of ALS in Israel of 0.78 per 100000 population falls within the range reported in other population studies. Moreover, the similarity in incidence a m o n g subpopniations from different parts of the world living in Israel b u t having different national origins, suggests t h a t factors associated with geographic latitude play little or no role in determining the distribution of ALS. The Israeli d a t a are therefore consistent with conclusions based on the population groups compared in Hawaii which were also of widely disparate ethnic origins (Matsumoto et al., 1972). The Israeli results agree with the analysis of mortality d a t a in California and W a s h i n g t o n State (Edgar et al., 1973) which showed no significant difference in mortality rate between those who had come to each state from n o r t h e r n areas compared to southern areas. I f an environmental factor is i m p o r t a n t in causing ALS, it m u s t be quite uniformly distributed across the world. The similarity in frequency of ALS among different nationality groups and different ethnic groups suggests t h a t genetic factors are n o t of m a j o r importance. The low frequency of familial cases is likewise against the existence of a genetic factor in the etiology of most cases of ALS. McComas et al. (1973) suggested t h a t ALS m a y represent an unusually accelerated manifestation of a " n o r m a l " attrition of m o t o r neurons with age. This concept is compatible with a uniform geographic distribution of ALS.
References Bobowick, A. R., Brody, J. A. : Epidemiology of motor-neuron diseases. New Engl. J. Med. 288, 1047--1055 (1973) Brewis, M., Poskanzer, D. C., Rolland, C., Miller, H.: Neurological disease in an English city. Acta neurol, stand. 42 (Suppl. 24), 1--89 (1966) Cendrowski, W., Wender, M., Owsianowski, M. : Analyse epidemiologique de la sclerose laterale amyotrophique sur le territoire de la Grande-Pologne. Acta neurol, stand. 46, 609--617 (1970) Central Bureau of Statistics: Statistical abstracts of Israel. Jerusalem: Central Bureau of Statistics 1959--1970 Edgar, A. H., Brody, J. A., Detels, R. : Amyotrophic lateral sclerosis mortality among nativeborn and migrant residents of California and Washington. Neurology (Minneap.) 23, 48--51 (1973) Gudmundsson, K. R. : The prevalence of some neurological diseases in Iceland. Acta neurol. scand. 44, 57--69 (1968) Kurland, L. T., Choi, N. W., Sayre, G. P. : Implications of incidence and geographic patterns on the classification of amyotrophie lateral sclerosis. In: Motor neuron diseases (eds. F. H. Norris, Jr., L. T. Kurland), pp. 28--50. New York: Grune and Stratton 1969 Kurland, L. T., Mulder, D. W. : Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. Neurology (Minneap.) 5, 182--196, 249--268 (1955) Kurtzke, J. F.: Comments on the epidemiology of amyotrophic lateral sclerosis (ALS). In: Motor neuron diseases (eds. F.H. Norris, Jr., L.T. Kurland), pp. 85---94. New York: Grune and Stratton 1969
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Leibowitz, U., Alter, M.: Multiple sclerosis: clues to its cause. Amsterdam: North-Holland Publishing Company 1973 Lorez, A.: Ein Beitrag zu Klinik und Vorkommen der amyotrophischen Lateralsklerose (isolierte und famili~re F~lle). Schweiz. reed. Wschr. 99, 51--57 (1969) Matsumoto, N., Worth, R.M., Kurland, L.T., Okazaki, H. : Epidemiologic study of amyotrophic lateral sclerosis in Hawaii. Identification of high incidence among Filipino men. Neurology (Minneap.) 22, 934---940 (1972) McComas, A. J., Upton, A. R.M., Sica, R. E. P.: Motoneurone disease and ageing. Lancet 1973 II, 1477--1480 Olivares, L., San E st6ban, E., Alter, M.: Mexican "resistance" to amyotrophic lateral sclerosis. Arch. Neurol. (Chic.) 27, 397--402 (1972) Torres, J., Iriarte, L. L., Kurland, L. T. : Amyotrophic lateral sclerosis among Guamanians in California. Calif. Med. 86, 385---388 (1957) Yase, Y. : :Neurologic disease in the Western Pacific Islands, with a report on the focus of amyotrophic lateral sclerosis found in the Kii peninsula, Japan. Amer. J. trop. Med. Hyg. 19, 155--166 (1970) Milton Alter, M.D. Chief, Neurology Service Veterans Hospital 54th St. and 48th Ave. So. Minneapolis, M_N55417, U.S.A.
Original Investigations AmyotropMc Lateral Sclerosis* A Population
Study
E s t h e r K a h a n a 1, M i l t o n A l t e r ~, a n d S h a u l F e l d m a n 3 z Barzilai Hospital, Ashkelon, Israel The Neuroepidemiology and Genetics Unit, University of Minnesota, Minneapolis, Minnesota 8 The Uri Leibowitz l~euroepidemiology Unit, Hadassah University Hospital, Jerusalem Received December 30, 1975
Summary. A country-wide study of the frequency of amyotrophie lateral sclerosis (ALS) was undertaken in Israel for the period 1960--1970. Israel was chosen for this study because of its excellent medical facilities and detailed demographic information. Moreover, the population includes representative groups from all parts of the world for comparison of frequency. A wide variety of motor system disease was screened in all hospitals, clinics, and chronic care facilities in the country, death certificates were reviewed and physicians with a neurological practice were contacted to derive a tentative list of cases. Only those who fit strict clinical diagnostic criteria or had autopsy confirmation were included in estimates of prevalence and incidence. On January 1, 1965, the mid-point of the study, 62 patients with ALS were living in Israel. The age-adjusted prevalence of ALS on that date was 3 per 100000 population. The average annual age-adjusted incidence for the period 1960---1970 was 0.78 per 100000 population (0.86 in males, 0.46 in females; ratio 1.9:1). There was no appreciable change in trend of incidence over the study interval. Age-specific incidence rates were similar in native-born inhabitants of Israel, immigrants from Europe and immigrants from Afro-Asian countries. The range in age-adjusted incidence among subgroups of immigrants to Israel from various countries was 0.25 to 1.20 per 100000 population but small numbers precluded testing the statistical significance of these rather narrow differences. Mean age at onset was 55.4 years for males and 52.4 years for females. The mean age at death was 60.2 for males and 58.0 for females. The average annual mortality from ALS was 0.58 per 100000 population. There were no familial aggregates of ALS in Israel and autopsy data showed no neurofibrillary changes, granulovaeuolar or inclusion bodies. There are only a few other population studies of ALS in different regions of the world. The average annual incidence in these other studies ranged from 0.4 to 1.4 per 100000 population. Thus, the incidence in Israel falls within this narrow range. The present study lends further support to the impression that ALS has a remarkably uniform geographic distribution with Guam and the Kii peninsula of Japan being the only known areas with significantly high rates. I f an environmental factor contributes to the pathogenesis of ALS, the factor must also have a uniform geographic distribution.
Key words: Amyotrophic lateral sclerosis - - Epidemiology of ALS. Zusammen/azsunp. W/~hrend der Zeit zwischen 1960 und 1970 wurde eine landesweite Untersuchung fiber die H~ufigkeit der amyotrophischen Lateralsklerose (ALS) in Israel durchgeffihrt. Das Land Israel wnrde ffir diese Studie ausgesucht wegen der ausgezeichneten medizinischen Versorgung und der detaillierten demographischen Informationen. Aul3erdem umfaBt die Bev61kerung repr/~sentative Gruppen aus allen Teilen der Welt, so dab vergleichende * Supported in part by the Minneapolis Veterans Administration Hospital.
206
E. Kahana et al.
H£ufigkeitsun~ersuchungen m6glich waren. Es wurden in allen Spit~lern, Kliniken und Chronisch-Krankenheimen des Landes zahlreiche Erkrankungen des motorischen Systemes analysiert. Im weiteren wurden die Zeugnisse fiber die Todesursachen analysiert sowie die neurologiseh t~tigen _Arztekonsultiert. Iqur jene F/ille wurden sehlieBlich zur Errechnung der H/iufigkeit der Erkrankung verwertet, bei welchen die typischen klinischen Symptome oder ein Autopsiebefund die Diagnose rechtfertigten. Am 1. Januar 1965, der Tag, welcher in der Mitte der beriieksichtigten Periode lag, lebten 62 Patienten mit ALS in Israel. Die alterskorrigierte H~ufigkeit der ALS an jenem Tage betrug 3 auf 100000 Einwohner. Die j~hrlichen Neuerkrankungen, alterskorrigiert, ffir die Periode zwischen 1960 und 1970 betrug 0,78 auf 100000 Einwohner (0,86 f/Jr M~nner und 0,46 ffir Frauen, Verh/iltnis 1,9:1). Es lag keine nennenswerte Anderungstendenz mit Bezug auf die Neuerkrankung wEhrend der Dauer der Studie vor. Altersspezifische H~ufigkeiten waren iihnlich bei Israel-Geborenen wie bei aus Europa oder afroasiatisehen L~ndern emigrierten Einwohnern. Die Schwankungen der alterskorrigierten HEufigkeiten zwischen den Untergruppen der Emigranten aus den verschiedenen L/£ndern betrug zwischen 0,25---1,20 ffir 100000 Einwohner. Aber die Kleinheit einzelner Gruppen verunm6gliehte es, die statistisehe Signifikanz dieser eher kleinen Untersehiede zu errechnen. Das Durehschnittsalter beim Beginn betrug 55,4 Jahre ffir die M~nner und 52,4 Jahre ffir die Frauen. Das mittlere Sterbealter der Manner war 60,2, dasjenige der Frauen 58,0 Jahre. Die mittlere j~hrliehe Mortalit£t infolge ALS war 0,58 auf 100000 Einwohnern. In Israel fanden sich keine famili~re H~ufungen yon ALS, und bei den SektionsfEllen wurden keine neurofibrill~ren Veriinderungen oder granulovaeuolKre bzw. EinschluBk6rperchen gefunden. Es liegen nur einige wenige Populationsstudien mit Bezug auf die ALS in den verschiedenen Regionen der Welt vor. Die mittlere j~hrliche Neuerkrankung in jenen anderen Studien schwankt zwisehen 0,4 und 1,4 pro 100000 Einwohner. Somit f/illt die H~ufigkeit in Israel eher in den unteren Bereieh dieser Schwankungsbreite. Die vorliegende Studie sprieht daffir, dab die ALS eine bemerkenswert einheitliehe geographische Verteilung hat. Als einzige Ausnahme haben Guam und die Kii-Halbinsel Japans eine signifikant hShere HEufigkeit. Falls ein umgebungsgebundener Faktor bei der Pathogenese der ALS mit eine Rolle spielt, muB dieser Faktor eine einheitliche geographische Verbreitung haben.
A m y o t r o p h i c l a t e r a l sclerosis (ALS) a p p e a r s t o h a v e a r e m a r k a b l y u n i f o r m g e o g r a p h i c d i s t r i b u t i o n . T h e r e p o r t e d p r e v a l e n c e is a b o u t five cases p e r 100000 p o p u l a t i o n in m a n y p a r t s of t h e world ( K u r l a n d et al., 1969; K u r t z k e , 1969; B o b o w i c k a n d B r o d y , 1973). Chamorros living on G u a m ( K u r l a n d a n d Mulder, 1955) a n d in California (Torres et al., 1957), as well as J a p a n e s e on t h e K i i Peninsula (Yase, 1970) are exceptions in t h a t these groups h a v e m u c h higher prevalence r a t e s of A L S . On t h e o t h e r h a n d , Mexicans in Mexico C i t y as well as in t h e U n i t e d S t a t e s h a v e been r e p o r t e d t o h a v e c o n s i d e r a b l y lower r a t e s t h a n t h e a v e r a g e (Olivares et al., 1972). W h e n t h e d a t a on t h e f r e q u e n c y of A L S in different p a r t s of t h e world are e x a m i n e d critically, m o s t are f o u n d to be b a s e d on d e a t h certificates alone a n d t h u s m a y be incomplete. A m o r e a c c u r a t e reflection o f t h e t r u e f r e q u e n c y of t h e disease is o b t a i n e d b y including a d d i t i o n a l sources of medical i n f o r m a t i o n b u t o n l y a few c o m p l e t e p o p u l a t i o n studies h a v e been carried out. Therefore, a d d i t i o n a l i n f o r m a t i o n on t h e f r e q u e n c y of A L S based on complete p o p u l a t i o n studies is desirable. Such d a t a m a y reveal groups who, like t h e Chamorros, t h e J a p a n e s e on t h e K i i p e n i n s u l a a n d t h e Mexicans, h a v e rates of A L S different from t h e average. Studies o f " d e v i a n t " p o p u l a t i o n s m a y c o n t r i b u t e clues t o factors influencing pathogenesis. A c o m p l e t e p o p u l a t i o n s t u d y of A L S was u n d e r t a k e n in Israel. I n h a b i t a n t s o f t h a t c o u n t r y include a large n u m b e r of different p o p u l a t i o n groups, m a n y of
Amyotrophic Lateral Sclerosis
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whom are r e c e n t i m m i g r a n t s . I n addition, Israel has excellent medical facilities which are r e a d i l y accessible to t h e p o p u l a t i o n . U p - t o - d a t e a n d detailed demographic d a t a are also available t h r o u g h official g o v e r n m e n t a l publications. Therefore, i n Israel, t h e f r e q u e n c y of ALS could readily be compared a m o n g p o p u l a t i o n groups from m a n y different p a r t s of t h e world.
Method An effort was made to identify all patients with ALS diagnosed in Israel between 1960 and 1970. A large group of motor system diseases was screened so as to include patients with ALS who may have been listed under a different diagnostic label. Besides amyotrophic lateral sclerosis, the list included progressive muscular atrophy, progressive spinal atrophy, progressive bulbar palsy, primary lateral sclerosis and motor neuron disease. ~edical records of hospitals and neurological outpatient clinics were searched for patients with any of these diagnoses. Physicians with neurological practices were personally contacted and asked to provide data on patients with any of these diagnoses who were under their care. Mortality data were also collected. The clinical records on all patients identified in the above sources were reviewed. Attention was given not only to the clinical details but also to X-ray and electromyographic information when available, and to post mortem details. Efforts were made to contact all patients whose clinical records were compatible with ALS and, if the patient was deceased, additional information from hospitals, physicians and the family was solicited to obtain as complete a picture as possible of the patient's disorder. Demographic data were derived from official publications of the Central Bureau of Statistics (1959--1970). The data on frequency were analyzed to provide age-specific incidence rates of ALS among various groups in the population. Age-adjusted rates were computed based on the total population of the U.S.A. in 1970. Prevalence and mortality rates were also derived. Diagnostic criteria were formulated and rigidly applied to each case in the tentative list. All patients with autopsy confirmation of ALS were accepted. The clinical criteria were as follows: a patient was accepted as having ALS if the clinical data showed evidence of lower motor neuron involvement in the form of muscle atrophy and muscle fascicnlation at more than one level of the spinal cord. Patients with sensory loss were excluded. Upper motor neuron and bulbar involvement was an added hut not an absolute requirement for inclusion in the study. Among patients who had an electromyogram, only those whose results were compatible with lower motor neuron deficit were included and a normal electromyogram constituted absolute grounds for exclusion. Patients with only pyramidal tract signs (i.e. primary lateral sclerosis) and patients with infantile (Werning-Hoffman Disease) or childhood forms (i.e. Kugelberg-Welander disease) of motor system disease were also excluded. Patients certified as having died of ALS in whom no other clinical data were available were noted as a special group but were not included in estimates of prevalence or incidence.
Results I n t h e c o u n t r y - w i d e search for ALS i n Israel, 213 p a t i e n t s were identified. Of these, 16 h a d onset after 1969, the date a r b i t r a r i l y chosen as t h e e n d of t h e s t u d y period, a n d were excluded. Twelve p a t i e n t s h a d a c o n c o m i t a n t disease which could a c c o u n t for features of ALS (8 h a d cervical spondylosis a n d 4 h a d a carcinoma) a n d those were also excluded. Of the r e m a i n i n g 185, 12 h a d onset of ALS prior to coming to Israel a n d 10 h a d onset before 1960, the b e g i n n i n g of the s t u d y period. I n 21 patients, t h e diagnosis was based o n a d e a t h certificate alone. A u t o p s y c o n f i r m a t i o n was available i n 11 patients.
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Table 1. Age adjusted prevalence rates of amyotrophic lateral sclerosis in Israel, 1.1. 1965 Region of birth
Number of patients
Age adjusteda prevalence per 100000 population
Europe Afro-Asia Israel
41 16 5
3.2 2.4 4.9
Total
62
3.0
a To total population U.S.A. 1970. Table 2. ALS patients in Israel by year of onset of illness Year of onset 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 Unknown Total
No. patien~ with onset in Israel
Population
Crude incidence rate per 100000 population
7 6 11 12 11 14 15 11 13 15 22 5
1810148 1858841 1911189 1981702 2 068 882 2155552 2239127 2 299078 2344877 2434832 2496438 --
0.39 0.32 0.58 0.61 0.53 0.65 0.67 0.48 0.55 0.62 0.88 --
142
2 360066 a
0.60
a Mean population.
On J a n u a r y 1, 1965, t h e m i d - p o i n t o f t h e s t u d y i n t e r v a l , 62 p a t i e n t s w i t h A L S were living in Israel. A t o t a l o f 124 p a t i e n t s w i t h A L S d i e d d u r i n g t h e s t u d y i n t e r v a l , 1960 t h r o u g h 1970. T h e a g e - a d j u s t e d prevalence of A L S in I s r a e l on J a n u a r y 1, 1965 excluding t h o s e cases b a s e d on d e a t h certificates alone was 3.0 p e r 100000 p o p u l a t i o n . P r e v a l e n c e was n o t s t a t i s t i c a l l y different a m o n g t h e t w o m a j o r J e w i s h i m m i g r a n t groups in I s r a e l n o r in t h e I s r a e l i - b o r n J e w i s h p o p u l a t i o n (Table 1). T h e a v e r a g e a n n u a l a g e - a d j u s t e d incidence o f A L S d u r i n g t h e p e r i o d 1960 to 1970 was 0.78 p e r 100000 p o p u l a t i o n . I n males, t h e a v e r a g e a n n u a l incidence was 0.86 a n d in females, it was 0.46 (ratio: 1.87:1) p e r 100000 p o p u l a t i o n . I f t h o s e b a s e d on d e a t h certificates alone were excluded, t h e incidence was 0.68 p e r 100000 p o p u l a t i o n . N o secular t r e n d in incidence was a p p a r e n t over t h e s t u d y i n t e r v a l (Table 2). T h e age-specific incidence r a t e s of A L S were similar for n a t i v e b o r n i n h a b i t a n t s of Israel, i m m i g r a n t s from E u r o p e a n d i m m i g r a n t s from AfroA s i a n countries (Fig. 1).
Amyotrophie Lateral Sclerosis
209
5.5 Born in: Europe
~. 5.0
A
....... Afr0-Asia - - Israel
/
_ ~,\
/I/~\
o
o
2.0
,-/
_
1.5
\,.
i
0
,
~
20-Z9
~
50-59
~
40-49 50-59
~ 60-69
I 704"
Age (years)
Fig. 1. Average annual age-specific incidence of amyotrophic lateral sclerosis in Israel by ethnic group (1960---1970)
Table 3. Average yearly incidence rates of amyotrophic lateral sclerosis in Israel by country of birth 1960--1970 Country of birth
No. of patients
Europe Bulgaria, Greece East Europe West and Central Europe
96 3 80 13
Afro-Asia Egypt Turkey Iran Iraq Libya Morocco, Algeria, Tunisia Yemen Other
Israel Specific country unknown Total
38 1 5 4 6 4 9 4 5 7 1 142
Population at risk 1.1.1965
Age adjusteda incidence rate per I00000 population
757 755 46893 513149 154526
0.32 0.78 0.57
600943 35098 43187 45043 120575 30625 265 544 60871 42177
0.25 0.79 1.20 0.47 1.01 0.42 0.46 0.89
881490
0.72
0.60
0.65 0.68
a Adjusted to total population of U.S.A., 1970.
I n T a b l e 3, t h e average a n n u a l incidence of ALS a m o n g n a t i v e - b o r n Israelis a n d i m m i g r a n t groups from different countries of origin is shown. The age-adjusted incidence i n various groups r a n g e d from 0.25 to 1.20 per 100000 p o p u l a t i o n .
210
E. Kahana et al. 3.0
2.5
t.5
0.5 0 :30-39 40-49 50-59 60-69
70-79
Age ot deoth
(yeors)
Fig. 2. Age-specificmortality rates from amyotrophic lateral sclerosis in Israel (1960-1970)
Because the numbers were small for most groups, analysis of statistical significance of difference among these subpopulations was not carried out. The age at onset of symptoms among patients with onset in Israel was well documented in 122 cases; it ranged from 26 to 81 years. The mean age at onset was 55.4 years in males and 52.4 years in females. The mean age at death was 60.2 for males and 58.0 for females. The average annual mortality was 0.58 per 100000 population. Age-specific mortality is shown in Figure 2. The duration of illness ranged from 7 to 120 months. The mean was 36.8 months for males and 31.5 months for females. Patients with onset before age 45 years had a somewhat longer mean duration of 46.8 months. The autopsy data in 11 patients showed a typical histology with anterior horn cell loss and demyelination of the pyramidal tracts. One patient had degeneration of Betz cells. None showed neurofibrillary changes, granulovacuolar bodies or inclusion bodies. There were no familial aggregates of ALS in this series.
Discussion
There are only a few population studies of ALS in which the methods of casefinding and diagnostic criteria were similar to those used in Israel. One of the most thorough of these studies was reported by Kurland et al. (1969) from Rochester, Minnesota. Using the Mayo Clinic which provides virtually all of the medical care for the surrounding population, these investigators found 17 cases of ALS during a 40 year period (1925--1964) and estimated the average annual age- and sexadjusted incidence rate to be 1.3 per 100000 population. Another community-wide study which included ALS among the disorders investigated was carried out by Brewis et al. (1966} in Carlisle, England. Five patients with ALS were found during the period 1955 to 1961. The average annual incidence rate was 1 per 100000 population.
Amyotrophie Lateral Sclerosis
211
I n both of the above studies the population base and hence, the total number of patients identified, was small. Several larger populations have been studied. Between 1952 and 1969, a total of 118 patients with ALS was identified in Hawaii, which has about three-quarters of a million inhabitants. The average annual incidence rate of ALS in Hawaii was 1.04 per 100000 population. Hawaii, like Israel, includes a variety of ethnic groups. Analysis of incidence b y ethnic group gave age- and sex-adjusted rates of 0.82 for Caucasians, 0.86 for Japanese and 1.56 for Filipinos per 100000 population. I t should be noted, however, t h a t not all the diagnoses could be confirmed in the Hawaiian study and in autopsies on 10 patients, 4 were inadequate or atypical of ALS (Matsumoto et al., 1972). A nation-wide study of neurological disease, including ALS, was reported from Iceland b y Gudmundsson (1968). During the period of 1954 to 1963, he found 24 patients and estimated the average annual incidence rate of 0.76 per 100000 population. An average annual incidence of 1.4 per 100000 population was reported b y Lorez (1969) from northwestern Switzerland. T h e estimate was based on 89 patients ascertained during the period 1951 to 1967. Cendrowski et al. (1970) collected data from the Poznafi Province of Poland, an area with 2.5 million inhabitants. During the period 1955 to 1965, he found 56 patients with ALS and estimated an annual incidence rate of 0.78 per 100000 population. I n Mexico City, where about one-half million individuals were available for study, Olivares et al. (1972) reported an average annual incidence rate of 0.40 per 100000 population. Besides these population studies, estimates of the frequency of ALS based on other types of analysis are available from different parts of the world (Kurtzke, 1969). I f it is accepted t h a t the disease is invariably fatal within 3 or 4 years, at least in its classical form, incidence rates can be derived from prevalence data Prevalence using the relationship: Incidence ~ Duration of Illness " However, it is not really easier to obtain data on prevalence t h a n incidence because the same sources of data are usually used. Therefore, m a n y investigators have resorted to use of mortality reports in estimating the frequency of ALS. The number of individuals certified in death records as having died of ALS can be obtained from the official vital statistics published b y most countries of the world, and political subdivisions of some countries. Kurland and associates (1969) have summarized mortality reports on ALS from 23 countries as well as from a large number of different nationalities who were residents in the United States. Although the range in reported mortality among the different countries and among different national groups was wide (0.06 to 1.54 and 0.2 to 6.2 per 100000 population respectively), the authors could detect no geographic pattern of distribution. They believed t h a t sampling variation due to small numbers, differences in medical facilities and diagnostic differences probably accounted for the observed differences in mortality reports on ALS from different countries and states and concluded t h a t the mortality of ALS was probably uniform, near 0.5 to 1 per 100000 population. A similar conclusion was drawn b y Edgar et al. (1973) based on mortality reports of ALS in California and WashingtonState. Among native-bornindividuals, the age-sex-adjusted death rates per 100000 population from ALS were 0.62 and 0.57 in California and Washington State respectively. The rates among non-native born individuals in California varied in the narrow range of 0.43 to 1.2 per 100000
212
E. Kahana et al.
population in nine geographic subdivisions of the United States (total 0.64). Similarly, the range was between 0 to 1.0 per 100000 population (total 0.76) in W a s h i n g t o n State. The general uniformity in frequency of ALS is in marked contrast to the distribution of multiple sclerosis which appears to increase in frequency with geographic latitude (Leibowitz and Alter, 1973). The incidence of ALS in Israel of 0.78 per 100000 population falls within the range reported in other population studies. Moreover, the similarity in incidence a m o n g subpopniations from different parts of the world living in Israel b u t having different national origins, suggests t h a t factors associated with geographic latitude play little or no role in determining the distribution of ALS. The Israeli d a t a are therefore consistent with conclusions based on the population groups compared in Hawaii which were also of widely disparate ethnic origins (Matsumoto et al., 1972). The Israeli results agree with the analysis of mortality d a t a in California and W a s h i n g t o n State (Edgar et al., 1973) which showed no significant difference in mortality rate between those who had come to each state from n o r t h e r n areas compared to southern areas. I f an environmental factor is i m p o r t a n t in causing ALS, it m u s t be quite uniformly distributed across the world. The similarity in frequency of ALS among different nationality groups and different ethnic groups suggests t h a t genetic factors are n o t of m a j o r importance. The low frequency of familial cases is likewise against the existence of a genetic factor in the etiology of most cases of ALS. McComas et al. (1973) suggested t h a t ALS m a y represent an unusually accelerated manifestation of a " n o r m a l " attrition of m o t o r neurons with age. This concept is compatible with a uniform geographic distribution of ALS.
References Bobowick, A. R., Brody, J. A. : Epidemiology of motor-neuron diseases. New Engl. J. Med. 288, 1047--1055 (1973) Brewis, M., Poskanzer, D. C., Rolland, C., Miller, H.: Neurological disease in an English city. Acta neurol, stand. 42 (Suppl. 24), 1--89 (1966) Cendrowski, W., Wender, M., Owsianowski, M. : Analyse epidemiologique de la sclerose laterale amyotrophique sur le territoire de la Grande-Pologne. Acta neurol, stand. 46, 609--617 (1970) Central Bureau of Statistics: Statistical abstracts of Israel. Jerusalem: Central Bureau of Statistics 1959--1970 Edgar, A. H., Brody, J. A., Detels, R. : Amyotrophic lateral sclerosis mortality among nativeborn and migrant residents of California and Washington. Neurology (Minneap.) 23, 48--51 (1973) Gudmundsson, K. R. : The prevalence of some neurological diseases in Iceland. Acta neurol. scand. 44, 57--69 (1968) Kurland, L. T., Choi, N. W., Sayre, G. P. : Implications of incidence and geographic patterns on the classification of amyotrophie lateral sclerosis. In: Motor neuron diseases (eds. F. H. Norris, Jr., L. T. Kurland), pp. 28--50. New York: Grune and Stratton 1969 Kurland, L. T., Mulder, D. W. : Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. Neurology (Minneap.) 5, 182--196, 249--268 (1955) Kurtzke, J. F.: Comments on the epidemiology of amyotrophic lateral sclerosis (ALS). In: Motor neuron diseases (eds. F.H. Norris, Jr., L.T. Kurland), pp. 85---94. New York: Grune and Stratton 1969
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Leibowitz, U., Alter, M.: Multiple sclerosis: clues to its cause. Amsterdam: North-Holland Publishing Company 1973 Lorez, A.: Ein Beitrag zu Klinik und Vorkommen der amyotrophischen Lateralsklerose (isolierte und famili~re F~lle). Schweiz. reed. Wschr. 99, 51--57 (1969) Matsumoto, N., Worth, R.M., Kurland, L.T., Okazaki, H. : Epidemiologic study of amyotrophic lateral sclerosis in Hawaii. Identification of high incidence among Filipino men. Neurology (Minneap.) 22, 934---940 (1972) McComas, A. J., Upton, A. R.M., Sica, R. E. P.: Motoneurone disease and ageing. Lancet 1973 II, 1477--1480 Olivares, L., San E st6ban, E., Alter, M.: Mexican "resistance" to amyotrophic lateral sclerosis. Arch. Neurol. (Chic.) 27, 397--402 (1972) Torres, J., Iriarte, L. L., Kurland, L. T. : Amyotrophic lateral sclerosis among Guamanians in California. Calif. Med. 86, 385---388 (1957) Yase, Y. : :Neurologic disease in the Western Pacific Islands, with a report on the focus of amyotrophic lateral sclerosis found in the Kii peninsula, Japan. Amer. J. trop. Med. Hyg. 19, 155--166 (1970) Milton Alter, M.D. Chief, Neurology Service Veterans Hospital 54th St. and 48th Ave. So. Minneapolis, M_N55417, U.S.A.
