Acta Neurol Scand 1996: 94: 264-268 Printed in UK - all rights reserved

Copyright 0 Munksgaard 1996 ACTA NEUROLOGICA

SCANDINAVICA ISSN OOO1-6314

Epidemiological and clinical characteristics of ALS in Belgrade, Yugoslavia

AlEaz S, Jarebinski M, Pekmezovic T, Stevic-Marinkovic Z, PavloviC S, Apostolski S. Epidemiological and clinical characteristics of ALS in Belgrade, Yugoslavia. Acta Neurol Scand 1996: 94: 264-268. 0 Munksgaard 1996.

We present the results of the first epidemiological study of ALS in Belgrade. The distribution of 58 newly discovered cases in a 7-year survey period (1985-1991) showed that the average annual age-adjusted incidence rate was 0.42 per 100,000 population (95 YO confidence interval, 0.18483). The rate for males was 1.5 times higher than the rate for females. The greatest age- specific average incidence rate was observed in patients between 60 and 64 (3.66 per 100,000 population; 95% confidence interval, 2.17-5.78). The actual age-adjusted prevalence rate on December 31, 1991 was 1.07 per 100,000 (95% confidence interval, 0.71-1.71). The mean age at onset of the disease was 56.21t9.8 and it ranged from 24 to 74. We studied the natural course of the disease through the mean duration and cumulative probability of survival. The mean duration of the disease was 27.7f18.2 months. The cumulative probability of survival was 27% for the whole population in a 5-year interval. Elderly patients and those with bulbar signs at onset had a poorer prognosis. Patients under 49 at onset and those with the spinal form of the disease survived longer.

The frequency of ALS is relatively uniform throughout the world with the exception of endemic regions. Recent epidemiological studies have shown that the average annual incidence rates range from 0.59 (1) to 2.4 (2) per 100,000 inhabi- tants. Lower average rates were reported mainly for less developed countries, probably due to inac- curate diagnosis (3). All morbidity and mortality studies showed male preponderance, indicating that the sex is a risk factor for ALS. An increasing age-specific risk with increasing age and well defined peak of incidence between 55 and 75 years has been demonstrated. Age-specific incidence rates in Rochester appeared to rise continuously with age, but without the earlier described peak (4). Mortality studies in Sweden (5 ) and Italy (6) confirmed the results of American survey, but some differences were observed. Age-specific rates were maximal in the 70-79 age group in Sweden and in the 65-69 age group in Italy. Nevertheless, cohort analysis in both studies proved that the age-specific rates tend to increase progressively without decline in the elderly. These results support the hypothesis that ALS is pathogenetically related to ageing.

S. AICaz', M. Jarebinski', T. PekmezoviC', 2. SteviC-MarinkoviC3, S. PavloviC3, S. Apostolski3 Institutes of 'Addictions - Neurocenter, Belgrade, 2Epidemiology, 3Neurology. School of Medicine, University of Belgrade, Yugoslavia

Key words: amyotrophic lateral sclerosis; epidemiology; clinical characteristics

S. Apostolski. Institute of Neurology, School of Medicine, University of Belgrade, 11000 Belgrade, Dr SubotiCa 6. Yugoslavia

Accepted for publication May 29. 1996

Material and methods

The district of Belgrade is divided into 16 units and extends over an area of 3,222 km2. According to the 1991 census, the area has a population of 1,602,226 inhabitants. ALS cases were collected by analysing hospital registers in the Institute of Neurology which is the referential neurological center, and in all other departments of neurology which belong to additional two Clinical centers and one Military Hospital in Belgrade. Due to the severity of the disease and diagnostic procedures required, hospitalisation was necessary for a correct diagnosis of ALS in our conditions. Only clearly diagnosed and fully documented cases were included. The presented rates are the minimum rates, since some cases may not have been hospi- talized and therefore not registered. The diagnostic criteria included progressive upper and lower motor neuron signs in bulbar and two spinal regions, or upper and lower motor neuron signs in three spinal regions, absence of sensitive and bladder function disturbances and typical EMG findings. Radiological examinations (X-rays,

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myelography, CAT scans and MRI) were carried out when other conditions had to be ruled out. The outcome in 54 cases was determined by directly contacting patients and their families. Four patients (2 men and 2 women) could not be reached for follow-up and dropped out of the study after diagnostic hospitalisation.

Clinical methods included a physical and neuro- logical examination (48 patients examined by S.A. and Z.S-M.) or a careful review of hospital records with special attention to the complaints of the patients and their neurological status (10 patients). A11 rates were adjusted to a standard in order to make them comparable with rates in other popu- lations. We used the world population according to Segi (7) and the method of direct standardization. The calculation of the confidence interval (CI) was based on a Poisson’s frequency distribution for rare events (8). Cumulative risks were derived from age-specific rates using the density method (9).

The differences between two arithmetic means were tested by Student’s t-test. Pearson’s X2 test was used to assess differences between frequencies. The probability of survival was obtained by the life table method (10). Differences in survival between subpopulations were evaluated by long-rank test

The source of population data were official pub- lished and unpublished documents of the Republic Institute for Statistics of Serbia.

(11).

Results

In the 1985-1991 period, 58 patients with ALS were discovered in the Belgrade district. In five patients the diagnosis was confirmed during a later hospi- talisation, not once was it denied. Thirty-two patients died before December 31, 1991. Four patients dropped out of the study after the diagno- sis was established, since no contact with them was possible. Our series comprised 35 men and 23 women. The youngest patient (woman) was 24 at onset and the two oldest patients (women) were 74. The mean age at onset of symptoms was 56.2-t-9.8 (55.9f7.6 in the male and 56.6k12.5 in the female group). Even though women were some- what older than men at onset of the disease, this difference was not statistically significant (t=0.805; p>0.05).

?he clinical presentation at the onset of the disease was bulbar in nine (15.5%) and spinal in 49 (84.5Y0) patients. The latter group comprised of 42 patients with classic ALS and 7 patients with the pseudo-polyneuritic (peroneal) form of ALS. The mean age at onset was 56.of9.5 in the group with spinal ALS. The patients with bulbar ALS were older at onset (57.3f9.Q but this difference was

not statistically significant (t=0.49; p>0.05). Only one case of familial ALS was registered. This patient noticed the first symptoms at the age of 62 and died 23 months later. He was affected with the classic form of the disease. The patient’s father and uncle died from the same disease at the age 51 and 76, respectively.

Clinical characteristics

Special attention was paid to the initial symptoms during data collection. The time of onset was not obtained for one patient since part of her medical documentation was lost. Due to the slowly progres- sive course of the disease, the patients were often unsure as to the time and localisation of their initial symptoms. Some patients with clear signs of bulbar palsy, including hypotrophy of the tongue muscles, claimed that their speech and swallowing distur- bances were of abrupt onset, often after stress situations. Others complained of disturbances which can in no way be related to motor neuron disease. In all cases where, in our opinion, the symptom in question could not be caused by pathological processes in ALS, the first following symptom was taken as the initial symptom (Table 1). The most prominent initial symptom was weak- nesS No sensitive symptoms were verified objec- tively at neurological examination. Cramps and pain were the cause of diagnostic difficulties in some patients; rheumatic disease, gonarthrosis and lumbago had to be ruled out in these cases. In 30% cases the weakness at onset was focal, i.e. it was limited to a single limb.

incidence and prevalence

Using the distribution of new cases of the disease beginning in a given year, we calculated the so called crude rates. The average annual incidence rate during the period 1985 through 1991 was 0.68 per 100,OOO population (95 % CI, 0.22-1.58) for men, 0.41 per 100,000 population (95% CI, 0.09-1.20) for

Table 1. Initial symptoms in ALS population in Belgrade

Symptoms No.

Weakness Amyotrophy Fasciculations Stiffness Cramps and pain Dysaesthesiae Dysarthria and dysphagia Loss of weight No data Total

28 (49.1) 1 il .El 5 (8.8) 3 15.21 6 (10.5)

9 (15.8) 1 (1.8) 1 (1.8) 58 (1 00)

4 (7.0)

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AlEaz et al.

Table 2. Age-adjusted incidence rates of ALS in Belgrade in comparison with the results in other studies

Study Rate’ 95% CI’ Cumulative Incidence* Risk’

Male Minnesota. 1925-84’2 Mexico. 1962-69’3 Ferrara. Italy. 1964-82’4 Florence, Italy, 1967-7615 Middle Finland, 197641’ Messina. Italy. 1976-8516 Harris county, Texas 1985-88’’ Belgrade, Yugoslavia. 1985-91

Female Minnesota, 1925-84’’ Mexico. 1962-69’3 Ferrara, Italy, 1964-132’~ Florence, Italy, 1967-7615 Middle Finland, 1976-812 Messina, Italy. 1976-8516 Harris county, Texas 1985-88’’ Belgrade, Yugoslavia. 1985-91

2.91 0.31 0.62 0.68 2.04 0.90 1.27 0.56

1 .89 0.46 0.34 0.47 2.29 0.22 1.03 0.36

1.83440 0.10-0.72

0.50-0.91 0.41-2.90

1.1 4-3.37 0.61-1 27 0.951 69 0.1&1.30

1.18-2.85 0.30-0.82 0.20-0.55 0.33-0.64 1.42-3.51 0.10-0.43 0.75-1 3 8 0.190.87

0.0038 0.0001 0.0008 0.0008 0.0023 0.0010 0.0015 0.00075

0.0025 0.0002 0.0004 0.0005 0.0027 0.0002 0.0013 0.00045

1 263 1 8461 1 1250 1 1250 1 435 1 1000 1 667 1 1508’

1 400 1 5709 1 2500 1 2000 1 370 1 5000 1 769 1 2252’

~~~ ~

Rates per 100,000 population. 1970 US total population as standard t 95% Confidence interval t Computed using incidence density method (to age 80 years) § Computed using incidence density method (to age 74 years)

females, and 0.54 per 100,000 population (95% CI, 0.23-1.06) for both sexes. These rates were then adjusted according to the Segi’s world population and the method of direct standardization. The average age-adjusted annual incidence rate was 0.52 (95% CI, 0.17-1.21) for men and 0.34 (95% CI, 0.07-0.99) for women; for both sexes it was 0.42 (95% CI, 0.18-0.83) per 100,000 population. The male/female ratio of age-adjusted rates was 1.5 : 1. Age standardized to the US population of 1970, the incidence rate was 0.56/100,000 for men, 0.36/ 100,000 for women and 0.44/100,000 for the total population. In comparison with other populations, our incidence rates are close to Italian (Table 2). The incidence rates in USA and Finland are three to five times greater. Cumulative incidence served to assess the individual risk of acquiring ALS in Belgrade. In the total Belgrade population under 74 the risk for ALS was 1 : 1 869 (1 : 1 508 for men and 1 : 2 252 for women). It is obvious that the maximal risk of being affected with ALS for all three categories lies within the 60-64 age range with a tendency to decline further on (Fig. 1). The age-specific incidence rate in the 60-64 age group was 4.85/100,000 (95% CI, 2.42-8.68) for males, and 3.02/100,000 (95% CI, 1.30-5.95) for women, while it was 3.66/100,000 (95% CI, 2.17-5.78) for both sexes.

On December 31, 1991, 22 patients were alive (11 men and 11 women). Age-adjusted point prev- alence rates for 1991 were: 1.00 (95% CI, 0.50-1.79) per 100,000 population for males, 1.14 per 100,000 population (95% CI, 0.57-2.04) for females, and 1.07 per 100,000 (95% CI, 0.71-1.70) for the total

Fig. 1. Average annual age- and sex-specific incidence rates of ALS per 100,OOO population.

population. In correlation with the annual inci- dence rates for 1991 which were 1.6 times greater for males, this fact indicates a longer duration of the disease in women.

In order to gain better insight into the natural course of ALS in our population, we focused special attention on 32 patients who died during the survey period. The onset of the disease was determined by the moment of appearance of the first symptoms and not by the time the diagnosis was established; this was done for greater precision. The mean duration of ALS was 27.7f18.2 months (approximately 2 years and 4 months). Women

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Epidemiology of ALS

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lived almost 16 months longer. The mean duration of the disease was 38.6e5.6 months in the female group and 22.8H1.0 in the male group. This differ- ence was statistically significant (t=3.8; ~ ~ 0 . 0 1 ) . In relation to the form of the disease, the mean survival for patients with spinal ALS was approxi- mately 2 months longer (28.W17.7) than for those with bulbar ALS (26.0f19.8). This difference was not statistically significant (t=0.27; ~>0.05). Patients under 49 lived almost 10 months longer than those over 49 (36.3k12.0 and 26.8f16.9, respectively); the difference in survival between these two subgroups was also statistically insignif- ican t (t=0.92; p>0.05).

The statistical probability of survival of our patients was derived from life table analyses of ALS. This method includes patients who were lost during the study as well as those who were living at the end of the survey period. The cumulative probabilities of survival of a two-, five- and seven- year period were 62%, 27%, and 27%, respectively. These findings refer to the total population.

We also analysed survival in relation to sex, age and clinical form of ALS. There was a difference of survival according to sex. A five-year survival was 22% for men and 36% for women; the same was noted after a seven-year survey period. The long-rank test detected no statistically significant difference (X2=2.65; p>0.05).

Survival was compared between subgroups of patients with different forms of the disease (spinal and bulbar ALS). At the end of a four-year period not one of the patients with bulbar ALS was living, while 38.4% patients with spinal ALS were still alive (Fig. 2). This difference was statistically highly significant (long-rank test; X2=3.44; k=l; p<O.Ol).

There was a significant difference in survival between patients under and over 49 (Fig. 3). A two- year survival for patients under 49 was 88% and 57% for those over 49. At the end of a five-year period these figures were 53% and 23%, respec- tively. More than 50% of the patients under 49 and only 19% of those over 49 were alive at the end of the survey period (X2=21.87; k=l; ~ ~ 0 . 0 1 ) .

<,

Discussion

During the period from 1985 to 1991, 58 patients were diagnosed as the newly cases of ALS in Belgrade. The most frequent initial symptom in the population of our patients was weakness (49%). Lopez-Vega et al. (18) and Gubbay et al. (19) noted weakness as the initial complaint in 63% and 86% cases, respectively. Other symptoms included dys- phagia and dysarthria; the frequency of these symp- toms correlates with the frequency of bulbar ALS. Cramps and pain often present at onset (10%).

Fig. 2. Survival of ALS patients according to clinical forms.

Stiffness as a spasticity equivalent is rarely encoun- tered and it was noted in only 5% of our patients, what is very similar to the results (1%) obtained in Israel (19).

The adjusted incidence rate of ALS in Belgrade was 0.42 per 100,000 population in a 7-year period (1985-1991). Low rates were registered in Mexico (0.4/100,000) (13) and Poland (0.22/100,000) (20). The latter is the lowest rate reported so far. With the exception of Italy where the incidence rates were similar to ours (0.44-0.78 per 100,000 popu- lation) (14-16, 21-23), we are not aware of any descriptive epidemiological study conducted in neighbouring countries. Studies in some Northern European countries, as well as in Canada and USA show incidence rates up to 5 times greater (2,22-24).

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The percentage of patients under 49 is relatively high in our population (19%). Not one incident case was found in the group of patients over 75. Conversely, incidence rates in patients over 75 are high in other populations. The maximal rate for this group was found in Rochester (4). This fact may indicate some missed diagnoses of ALS in our oldest population. At older age, symptoms of ALS are often interpreted by others as part of the ageing process. Furthermore, physicians who first see the patient are more motivated to refer younger patient to a specialist. The elderly are also less agile and rarely visit neurological centres.

Advanced age and bulbar signs at onset indi- cated poorer prognosis in our population. The patients under 49 had significantly higher survival rates than the older patients. The more benign course of ALS in younger patients was also con- firmed by the other authors (18,22-25). The bulbar form of ALS had a significantly lower survival rate in comparison with the spinal form. These findings are also consistent with findings in other popula- tions (19, 26).

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