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Epidemiology of multiple sclerosis in Arabs in Jordan: a comparative study between Jordanians and Palestinians
JOURNAL OF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 135(I 996) 162- 167
Epidemiology of multiple sclerosis in Arabs in Jordan: a comparative study between Jordanians and Palestinians Amir S. Najim Al-Din a,*, Ashraf Kurdi a, Ammar Mubaidin b, Mohammed El-Khateeb a, Raida W. Khalil a, Abdel-Latif Wriekat b a Faculty ofMedicine, Ammun, Jordm b King Hussein Me&d Centre, Amman, Jordm
Received 19 April 1995;revised 18 August 1995;accepted28 August 1995
Abstract
In a 2-year hospital-based study in Jordan 131 Arab multiple sclerosis patients were identified including 84 Palestinians and 36 Jordanians. Based on MS/ALS case ratio, multiple sclerosis was found to be twice as common among Palestinians than Jordanians. Other than the less marked female preponderance among Jordanian patients, the disease had the same clinical and paraclinical characteristics in both groups. It was more likely for Palestinian and Jordanian patients to originate from the northern parts of their countries, to be Rh negative and to be HLA-DR2 positive than their controls. Palestinians (patients and controls) did not show significant differences from Jordanians(patients and controls) in relation to their eye color, ABO and Rh blood groups distribution nor the HLA-DR or HLA-DQ (apart from HLA-DQ3) epitopes frequency, thus not offering any significant difference in the genetic-racial markers studies to explain the difference in the observed disease susceptibility. Previous studies demonstrated that 2 racially different populations sharing the same environment can have different risk of developing multiple sclerosis, but this study has shown that this can also be true for 2 racially similar populations sharing the same environment. Keywords: Multiple sclerosis; Epidemiology; Comparative study; Arabs; Jordan
1. Introduction
Extensive epidemiological studies of multiple sclerosis (MS) have consistently demonstrated that the disease is unequally distributed (Kurtzke, 1975, 1980). The basis for this geographical variation is not clear, but both environmental and genetic factors seem to influence the disease frequency. Reports from several Arab countries (Shaby, 1958; Kurdi and Rifai, 1973; Hamdi, 1974; Kurdi et al., 1977; Ben Hamida, 1982; Radhakrishnan et al., 1985; Al-Din, 1986; Al-Din et al., 1987; Al-Deeb et al., 1988; Yaqub and Daif, 1988; Al-Din et al., 1990, 1992a, b) have demonstrated that MS in Arabs is less common than is reported in Western Europe and North America, but is not uncommon. A significantly higher risk of developing MS in Palestinians resident in Kuwait was noted compared to
* Corresponding author. At: Pinderfields General Hospital, Aberford Road, Wakefield, WFI 4DG, UK. Tel. +441924-201688; Fax: +441924-8 14483. 0022.510X/96/$15.00 0 1996 Elsevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00276-6
native Kuwaitis, a difference which was postulated to be due to genetic rather than environmental factors (Al-Din et al., 1990, 1992b). Almost one half of the Jordanian population is of Palestinian ancestry: we thus report on the characteristics of MS among the 2 groups and examine the possible genetic and environmental factors that affect disease susceptibility. 1.l. Physical characteristics Jordan is a small country located in the eastern Mediterranean region between longitudes 29”E and 33”E of Greenwich and between latitudes 34”N and 39”N. Its surface area is 89000 km2 and has a climate typical of the eastern Mediterranean basin. The population of nearly 3.6 million (December 1993) is mainly concentrated in the largest cities Amman, Zarqa and Irbid, but small towns and villages are widely spread from the north to the south of the country mainly in the hilly region and low lands east of the river Jordan. The large desert in the east and south of the kingdom is only sparsely populated. The age strata are typical of a developing third world country, with 60% of
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the population below the age of 20 years. Although a few Palestinians have always lived in Jordan, two major waves of refugees in 1948 and 1967 have substantially increased their numbers to about half the population of Jordan. High quality medical services are provided both by public and private institutes. Health manpower indicators for 1987 showed that there was one physician for approximately 700 persons. The available official statistical data refer to the population of Jordan in 2 broad categories: Jordanians and those of other nationalities. Palestinians are grouped among the Jordanians, as they are Jordanian citizens. Thus, an age and gender comparison of the Jordanian and Palestinian populations in Jordan is not readily available, but there is no reason to believe of any differences. The health care utilization of the two groups seems to be similar. In both hospitals where the study was done, the medical and neurological services are readily available to both Jordanian citizens and other nationals. The study was limited to the population living in Jordan; any patients with MS or ALS residing outside Jordan and coming to Jordan for health care were excluded. 1.2. Study population and methods All MS patients who were regularly attending the neurology services of the Jordan University Hospital and the King Hussain Medical Center on December 3 1st 1993 were included provided that the Poser et al. (1983) criteria for clinically definite (CDMS), laboratory supported definite (LSDMS), clinically probable (CPMS) and laboratory supported probable (LSPMS) MS were met. The diagnosis of MS was made in all instances by a neurologist (ASN, AK, AM, AW). Comparison between the Jordanian and Palestinian groups was made using the normal Z-test when appropriate.
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2. Results On December 31st, 1993, there were 126 Arab MS patients resident in Jordan (83 women and 43 men). 81 were classified as CDMS, 6 as LSDMS, 37 as CPMS and 2 as LSPMS. Their mean age was 35.6 (SD k 8.2) years. The mean age at onset was 29.6 + 8.1 SD, being 28.9 ?c7.9 for women and 29.2 f 8.3 for men. The female:male ratio was 1.9: 1. Of the 126 Arab MS patients, there were 84 Palestinians, 36 Jordanians, 2 Syrians, 2 Iraqi, and 2 were the product of mixed marriages. The first of such patients has a Jordanian father and a Palestinian mother and the second a Palestinian father and an Algerian mother. Two of the Jordanians were non-Arabs (a Kurd and a Chechen). During the same period of study, a total of 19 Arab patients (10 Palestinians and 9 Jordanians) with amyatrophic lateral sclerosis (ALS) were seen in the same departments. Based on MS/ALS case ratios (presuming a fairly constant 5/ 100000, prevalence of ALS), an estimated prevalence for Palestinians was 42/ 100000 (95% CI 2.8-90.8) and 20/100000 (95% CI 9.5-47.2) for Jordanians. The female preponderance among the Jordanian patients (1.4: 1) was less marked than among the Palestinian patients (2.1: l), yet this difference was not statistically significant. A comparative study of the characteristics of MS among Palestinians and Jordanians was then done. Table 1 shows the age and sex distribution of patients from both groups. Minor differences were noted mainly reflecting the less apparent female preponderance among Jordanian patients. A study of the presenting symptoms in both groups revealed no significant differences. Common presenting symptoms included unilateral optic or retrobulbar neuritis in 19 (22.6%) of the Palestinian patients and 7 (19.4%) of the Jordanian patients. 18 (21.4%) and 27 (32%) of the Palestinian patients presented with motor and sensory
Table I Age and sex distribution of MS patients Age group
IO-19
Palestinians
Jordanians
Men (%)
Women (%)
Both sexes (%)
Men (%o)
Women (o/o)
Both sexes (%)
1 (3.7)
2
3
I (6.7)
0 0
1 (2.8)
(44.8)
C3.3)
2207.8,
IR,
746.7)
F3S.I) 6 (28.6)
(829.6)
($0,
;:3.8)
(822.2)
:2.7)
G3.3) 0 0 I5
(29.5, 0 0 21
(41.1) 0 0 36
20-29 30-39
ll6.1,
40-49 50-59 60+ Total
:2.7) 27
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symptoms, respectively, and 9 (25%) of the Jordanian patients presented with motor symptoms whereas 11 (30.5%) presented with sensory symptoms. In 91 (64 Palestinian and 27 Jordanian) patients the follow-up was regular enough to allow an analysis of the frequency of symptoms and signs during the course of the disease. After a mean duration of 7.7 years (range l-27 years) the frequency of symptoms and signs were widely distributed within the central nervous system. No significant differences were found in the two groups. 2.1. Place of birth of subjects and their parents Fig. 1 shows the map of the region divided into 8 arbitrary regions; 4 in relation to the main city for Jordanians (Amman) and the same for the Palestinians’ main city (Jerusalem). Table 2 shows the frequency of the place of birth of Jordanian patients (including the one with a Palestinian mother) and their parents (including the one married to a Palestinian) compared to their respective controls. It was more likely for Jordanian patients and their parents to be born in the north of the kingdom than their respective controls. This was particularly true for the parents as 49.3% of the parents of the patients were born in the north compared to 25.8% of the parents of the controls (P < 0.001). It was less likely for parents of Jordanian patients to originate from Amman or the towns around it, than the parents of the controls (P < 0.01). Table 3 shows the frequency of the place of birth of Palestinian patients (including the patient with an Algerian mother) and their parents (including the two who were not married to a Palestinian) compared to their controls. Only 24 (28.6%) of the Palestinian patients were born in Jordan compared to 61 (40.7%) of the controls but the difference was not statistically significant. More of the Palestinian patients were born in the towns of Nablis, Ram-Allah and Tulkeram (North) located on the West Bank, north of Jerusalem (31 (36.5%)) than their controls (25 (16.7%)) (P < 0.001). The same significant difference was found when the parents of the Palestinian patients were compared to their controls, as 82 (48.2%) of the patients’ parents were born in these towns compared to 97 (33.1%) of the
Fig. 1. The map of the region divided into 8 arbitrary areas in relation to the main city for each population.
parents of the controls (P < 0.002). The parents of the Palestinian patients were less likely to have been born in the coastal towns of Jaffa, Haifa and Gaza (Coastal) than their controls (P < 0.01). Even if the Jordanian and Palestinian patients originating from the north were excluded, there were more than twice as many Palestinian patients (44) as Jordanian patients (18), probably reflecting that the increased risk of developing MS was true in Palestinians regardless of the place of origin. 2.2. Genetic characteristics 2.2.1. Eye color The eye color of 150 Jordanian and 150 Palestinian controls was recorded and compared to each other and to the patients in the 2 groups. No significant differences in the frequency of having black, dark brown or hazel colored eyes was found when the Jordanian patients were compared to Palestinian patients, furthermore no significant differences were found when the patients were compared to their respective controls, nor when the Jordanian controls were compared to Palestinian controls. The only
Table 2 Place of birth of Jordanian patients and their parents, in relation to Amman, compared to controls and their parents Place of birth
Patients n = 37 (%o)
Controls n= 150(%)
Parents of patients n=73(%)
Parents of controls n = 298 (%)
North Middle
14 (37.81) * 16 (43.2) 6 (16.2) 1 (2.7) 0
29 (19.3) 91 (60.7) 17 (11.3) 1 (0.7) 12 (8)
36 (49.3) * * * 24 (32.8) * * 11 (15.1) 2 (2.7) 0
77 (25.8) 157 (52.7) 60 (20.1) 4 (1.3) 0
SOUth
East Outside
* P < 0.5 when patients were compared to controls; * ’ P < 0.01; * * * P < 0.001 when the parents of patients were compared to the parents of controls.
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Table 3 Place of birth of Palestinian patients and their parents, in relation to Jerusalem, compared to controls and their parents Place of birth
Patients n=85(%)
Controls n= ISO
Parents of patients n = 170 (o/o)
Parents of controls n = 293 (%o)
North Jerusalem south Coastal Jordan Gulf states
31 (36.5) * * * 9 (10.6) 8 (9.4) 6 (7) 24 (28.2) 7 (8.2)
25 (16.7) 16 (10.7) 12 (8) 14 (9.3) 61 (40.7) 22 (14.7)
82 (48.2) * * 29 (17.1) 26 (15.3) 33 (14.4) ’ 0 0
97 (33.1) 57 ( 14.4) 48 (16.4) 84 (30.4) 2 (0.71) 0
* P < 0.01 and * * P < 0.002 when the parents of patients were compared to the parents of controls; * * * P < 0.001 when patients were compared to controls.
observed difference was the observation that more Palestinian patients (17 (20.2%)) had green or blue eyes than their controls (16 (10.7%)) (P < 0.05). 2.2.2. Blood groups
The ABO and Rh blood groups were studied in the Palestinian and Jordanian patients and compared to 150 healthy controls in each group. No significant differences were found when either patients group was compared to their controls in the ABO blood groups. Yet the frequency of Rh negative blood group was significantly higher in patients of both groups when compared to their respective controls: 15.5% of Palestinian patients compared to 4.1% of their controls (P < 0.005) and in (8.3%) of the Jordanian patients compared to 2.7% of their controls (P < 0.005). No significant differences existed when Palestinian patients were compared to Jordanian patients, nor when the Palestinian controls were compared to Jordanian controls. 2.2.3. Histocompatibility
system
The HLA-DR and HLA-DQ epitopes were studied in 52 Palestinian and 30 Jordanian patients and compared to 90 Table 4 Distribution (%) HLA-DR
Patients (n= 52)
DQl DQ2
3. Discussion In previous studies, in Kuwait, it was found that multiple sclerosis was commoner among the Palestinians, resident in Kuwait, than the native Kuwaitis (Al-Din, 1986, et al., 1990). In these studies we tried to investigate several racial and genetic characteristics of patients as well as healthy controls of each group. It was found that the difference in the risk of developing MS could not be explained solely on environmental factors, as both groups
and -DQ characteristics of Palestinians and Jordanians Palestinians
DRl DR2 DR3 DR4 DR5 DR6 DR7 DR8 DR9 DRlO
and 45 Palestinian and Jordanian controls respectively (Table 4). An association between MS and HLA-DR2 epitope was significant in both patient groups (P < 0.01 for both). Apart from the finding that HLA-DQ3 was more frequently observed in normal Jordanians than normal Palestinians (P < 0.011, no significant differences in the frequency of HLA-DR or HLA-DQ epitopes were found when Palestinian patients were compared to Jordanian patients, nor when Palestinian controls were compared to Jordanian controls.
3.8 34.6 * 42.3 36.5 17.3 11.5 5.8 5.8 0 3.8 51.9 30.8 61.5 9.6
Jordanians Controls (n=90) 12.2 16.6 28.9 28.9 27.8 2.2 27.8 1.1 2.2 7.8 54.4 41.1 56.7 * * 4.4
Patients (n = 30)
Controls (n = 45)
0 50 ’ 46.7 3.3 16.6 3.3 13.3 10.0 6.7 6.7 63.3 36.7 66.6 0
* P < 0.01 (Patients compared to respective controls); * * P < 0.01 (Jordanian controls compared to Palestinian Controls).
4.4 20 28.9 35.6 35.6 0 22.2 0 2.2 2.2 44.4 31.1 77.8 * * 0
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shared the same environment for 30-40 years prior to 1990, but significant differences in their genetic racial markers were found (Al-Din et al., 1990). Furthermore, a study of the possible influence of age at migration to Kuwait, in Palestinians, revealed that Palestinians were more at risk of developing MS regardless of the age at migration to Kuwait. This observation was even true for Palestinians born in Kuwait (Al-Din et al., 1992a). These studies in Kuwait addressed two Arab populations who used to be separated by the massive desert between the Persian Gulf and the Mediterranean region, but who had lived in the same location for the last 30-40 years. We were thus interested in conducting a comparative study of Jordanians and Palestinians, considering that there are no major geographical barriers between the two localities. MS in Arabs resident in Jordan seems to have the same clinical, paraclinical, imaging and CSF characteristics as in Europeans. However, we observed that the disease was nearly twice as frequent in Palestinians resident in Jordan than in Jordanians. The observation was the result of a hospital based study rather than population-based, and thus was calculated on MS/ALS case ratios. We can postulate two major pitfalls in this method of calculation. First, the prevalence of ALS in Jordan is not known, but with 60% of the population younger than 20 years, it is probably less common than in Europe and North America. Thus the estimated prevalence rates for MS for both populations probably represents the minimum. The second pitfall for the MS/ALS case ratio is the possibility of drawing conclusions based on a number of patients representing only a small percentage of the actual number of patients. The difference in prevalence was observed despite the fact that the two groups lived in neighboring countries with nearly the same latitude, habitat and weather. Furthermore, since the 1948 and 1967 wars, massive waves of Palestinian refugees have settled in Jordan, representing nearly 50% of the Jordanian population. As citizens of Jordan, Palestinians and Jordanians have similar living standards, attend the same schools and utilize the same medical services. No differences in the clinical characteristics of the disease were found when Palestinians were compared to Jordanians except for a less prominent female preponderance among the Jordanian patients. We felt that the place of origin of patients (as judged by the place of birth of their parents), is reflective of several variables, some related to ancestral (possibly racial) origin and some environmental. This is particularly true, because the population of the region, other than Bedouins was a fairly stable population prior to the 1948 war. The place of birth of patients and their controls, being relatively young, probably reflects the pattern of migration resulting from population movement due to wars and urbanization. Thus, the place of birth of the parents (of the patients and controls) is more reflective of the ancestral origin of the patients and their controls.
Sciences 135 (1996)
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Differences between patients and their respective controls existed. It was more likely for Palestinian patients and their parents to originate from the towns north of Jerusalem (Nablis, Tulkarem and Ram-Allah) than their controls. Likewise it was more common for Jordanian patients and their parents to originate from the towns north of Amman (Irbid, Ajloun and Ramtha) than their controls. These three Jordanian towns are located near and were closely linked to the 3 Palestinian towns previously mentioned. These towns (in Jordan and the West Bank) are in mountainous areas, except for Tulkarem whose villages extend to the Mediterranean coast. The people of the region used to work in farming though the towns were market towns for the neighboring villages. Furthermore, the cities of Irbid and Ramtha in Jordan had always had strong links to the southern parts of Syria. It is also of interest that in the studies from Kuwait, the disease seemed to be commoner in Palestinians originating from the same 3 towns north of Jerusalem, than from elsewhere. Unlike the study in Kuwait no significant differences in the genetic characteristics of the normal populations were found. Thus no significant differences were found in the frequency of the different eye colors, ABO blood groups, nor of the HLA-DR and HLA-DQ characteristics, when normal Jordanians were compared to normal Palestinians. Yet the number of patients and controls was too small to investigate if that was true regardless of the place of origin Palestinians. When patients were compared to controls, it was found that Palestinian patients were more likely to have green or blue eyes than their controls (P < 0.05) patients from both groups were more likely to have Rh negative blood groups than their respective controls (P < 0.005). The green or blue eye colors and the Rh negative blood group are commoner among European Caucasians than Arabs and might thus possibly reflect genetic-racial influence in a particular population. More than 250 prevalence surveys for MS have SeNed as a basis for the delineation for risk areas for MS. Environmental (place-related) factors were proposed to explain the observed latitude gradient (Kurtzke, 1983). However, observations on 2 genetically different populations sharing the same environment have consistently shown differences in the risk of developing MS in Israel, South Africa, India, Canada and Kuwait (Alter et al., 1971; Francis and Louw, 1977; Bharucha et al., 1988; Hader et al., 1985; Al-Din et al., 1990). What is interesting in this study is the observation in 2 genetically similar populations sharing the same environment but still having significant difference in the risk of developing MS.
Acknowledgements This study was supported by Jordan University search Grant No. 243.
Re-
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References Al-Deeb, S.M., A.J. Phadke, A.J. Jabbar, A. Ghani and M. Al-Jaberi (1988) Multiple sclerosis in Saudi Arabia. J. Neurol., 235 (Suppl): 8 1. Al-Din, A.S.N. (1986) Multiple sclerosis in Kuwait: Clinical and epidemiological study. J. Neural. Neurosurg. Psychiatry, 49: 928-93 I. Al-Din, A.S.N., M. Alsaffar, R. Siboo and K. Behbahani (1987) Association between HLA-D region epitopes and multiple sclerosis in Arabs. Tissue Antigens, 27: 196-200. Al-Din, A.S.N., M. Khogali, C.M. Poser, K.E. Al-Nassar, R. Shakir, J. Hussain, K. Behbahani and G. Ghadha (19901 Epidemiology of multiple sclerosis in Arabs in Kuwait: A comparative study between Kuwaitis and Palestinians. J. Neural. Sci., 100: 137-141. Al-Din, A.S.N., C.M. Poser, R. Shakir and M. Khogali (I992 a) Risk of multiple sclerosis in Palestinians related to age at migration. J. Trop. Geog. Neural., 2: 166-171. Al-Din, A.S.N. R. Shakir, CM. Poser and M. Khogali (I992 b). Multiple sclerosis in Arabs. J. Trop. Geog. Neural., 2: 57-62. Alter, M., M. Okihiro, W. Rowley et al. (1971) Multiple sclerosis among Orientals and Caucasia ns in Hawaii. Neurology (Minneapolis), 21: 122- 130. Ben Hamida, M. (1982) Epidemiological study of multiple sclerosis in Tunisia. Afr. J. Neurol. Sci., I: 45-47. Bharucha, N.E., E.P. Bharucha, N.H. Wadia, B.S. Singhal, A.E. Bharucha, A.V. Bhise, J.F. Kurtzke and B.S. Schoenberg (1988) Prevalence of multiple sclerosis in the Parsis of Bombay. Neurology, 38: 727-729. Francis, R.A. and S. Louw (1977) Multiple sclerosis in coloured South Africans. J. Neurol. Neurosurg. Psychiatry, 40: 729-735.
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Hader, W.J., T.E. Feasby, J.H. Noseworthy, G.P.A. Rice and G.C. Ebers (1985) Multiple sclerosis in Canadian native people (Abstract). Neurology, 35 (SuppI. 1): 300. Hamdi, T.I. (1974) Multiple sclerosis in Iraq: A clinical and geomedical survey. J. Postgr. Med., 21: 1-9. Kurdi, A., A. Abdullat, I. Ayesh, W.I. McDonald, D.A.S Compston and J.R. Batchelor (1977) Different B lymphocyte alloantigens associated with multiple sclerosis in Arabs and North Europeans. Lancet, i: 1123-1125. Kurdi, A. and F. Rifai (1973) Clinical studies of multiple sclerosis in Jordan. Report of six cases. Jordan Med. J., 8: 47-53. Kurt&e, J.F. (1975) A reassessment of the distribution of multiple sclerosis. Acta Neurol. Stand., 51: 1 lo-139 and 137- 157. Kurtzke, J.F. (1980) The geographic distribution of multiple sclerosis: an update with special reference to the Mediterranean region. Acta Neural. Stand., 62: 65-80. Kurt&e, J.F. (1983) Epidemiology of multiple sclerosis. In: Hallpike J.F., C.W.M. Adams and W.W. Touretelotte (Eds.). Multiple Sclerosis. Williams and Wilkins, Baltimore, pp. 47-95. Poser, C.M., D.W. Paty, L. Schienberg, et al. (19831 New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann. Neurol., 13: 227-23 I. Radhakrishnan, K., P.P. Ashok, R. Sridharan and M.E. Mousa (1985) Prevalence and pattern of multiple sclerosis in Benghazi, Nortl-Eastem Libya. J. Neural. Sci. 70: 39-46. Shaby, J.A. (1958) Multiple sclerosis in Iraq. Wien. 2. Nervenheilk., 15: 276-283. Yaqub, B.A. and A.K. Daif (1988) Multiple sclerosis in Saudi Arabia. Neurology, 38: 621-623.
NEUROLOGICAL SCIENCES
ELSEVIER
Journal of the Neurological Sciences 135(I 996) 162- 167
Epidemiology of multiple sclerosis in Arabs in Jordan: a comparative study between Jordanians and Palestinians Amir S. Najim Al-Din a,*, Ashraf Kurdi a, Ammar Mubaidin b, Mohammed El-Khateeb a, Raida W. Khalil a, Abdel-Latif Wriekat b a Faculty ofMedicine, Ammun, Jordm b King Hussein Me&d Centre, Amman, Jordm
Received 19 April 1995;revised 18 August 1995;accepted28 August 1995
Abstract
In a 2-year hospital-based study in Jordan 131 Arab multiple sclerosis patients were identified including 84 Palestinians and 36 Jordanians. Based on MS/ALS case ratio, multiple sclerosis was found to be twice as common among Palestinians than Jordanians. Other than the less marked female preponderance among Jordanian patients, the disease had the same clinical and paraclinical characteristics in both groups. It was more likely for Palestinian and Jordanian patients to originate from the northern parts of their countries, to be Rh negative and to be HLA-DR2 positive than their controls. Palestinians (patients and controls) did not show significant differences from Jordanians(patients and controls) in relation to their eye color, ABO and Rh blood groups distribution nor the HLA-DR or HLA-DQ (apart from HLA-DQ3) epitopes frequency, thus not offering any significant difference in the genetic-racial markers studies to explain the difference in the observed disease susceptibility. Previous studies demonstrated that 2 racially different populations sharing the same environment can have different risk of developing multiple sclerosis, but this study has shown that this can also be true for 2 racially similar populations sharing the same environment. Keywords: Multiple sclerosis; Epidemiology; Comparative study; Arabs; Jordan
1. Introduction
Extensive epidemiological studies of multiple sclerosis (MS) have consistently demonstrated that the disease is unequally distributed (Kurtzke, 1975, 1980). The basis for this geographical variation is not clear, but both environmental and genetic factors seem to influence the disease frequency. Reports from several Arab countries (Shaby, 1958; Kurdi and Rifai, 1973; Hamdi, 1974; Kurdi et al., 1977; Ben Hamida, 1982; Radhakrishnan et al., 1985; Al-Din, 1986; Al-Din et al., 1987; Al-Deeb et al., 1988; Yaqub and Daif, 1988; Al-Din et al., 1990, 1992a, b) have demonstrated that MS in Arabs is less common than is reported in Western Europe and North America, but is not uncommon. A significantly higher risk of developing MS in Palestinians resident in Kuwait was noted compared to
* Corresponding author. At: Pinderfields General Hospital, Aberford Road, Wakefield, WFI 4DG, UK. Tel. +441924-201688; Fax: +441924-8 14483. 0022.510X/96/$15.00 0 1996 Elsevier Science B.V. All rights reserved SSDI 0022-5 10X(95)00276-6
native Kuwaitis, a difference which was postulated to be due to genetic rather than environmental factors (Al-Din et al., 1990, 1992b). Almost one half of the Jordanian population is of Palestinian ancestry: we thus report on the characteristics of MS among the 2 groups and examine the possible genetic and environmental factors that affect disease susceptibility. 1.l. Physical characteristics Jordan is a small country located in the eastern Mediterranean region between longitudes 29”E and 33”E of Greenwich and between latitudes 34”N and 39”N. Its surface area is 89000 km2 and has a climate typical of the eastern Mediterranean basin. The population of nearly 3.6 million (December 1993) is mainly concentrated in the largest cities Amman, Zarqa and Irbid, but small towns and villages are widely spread from the north to the south of the country mainly in the hilly region and low lands east of the river Jordan. The large desert in the east and south of the kingdom is only sparsely populated. The age strata are typical of a developing third world country, with 60% of
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the population below the age of 20 years. Although a few Palestinians have always lived in Jordan, two major waves of refugees in 1948 and 1967 have substantially increased their numbers to about half the population of Jordan. High quality medical services are provided both by public and private institutes. Health manpower indicators for 1987 showed that there was one physician for approximately 700 persons. The available official statistical data refer to the population of Jordan in 2 broad categories: Jordanians and those of other nationalities. Palestinians are grouped among the Jordanians, as they are Jordanian citizens. Thus, an age and gender comparison of the Jordanian and Palestinian populations in Jordan is not readily available, but there is no reason to believe of any differences. The health care utilization of the two groups seems to be similar. In both hospitals where the study was done, the medical and neurological services are readily available to both Jordanian citizens and other nationals. The study was limited to the population living in Jordan; any patients with MS or ALS residing outside Jordan and coming to Jordan for health care were excluded. 1.2. Study population and methods All MS patients who were regularly attending the neurology services of the Jordan University Hospital and the King Hussain Medical Center on December 3 1st 1993 were included provided that the Poser et al. (1983) criteria for clinically definite (CDMS), laboratory supported definite (LSDMS), clinically probable (CPMS) and laboratory supported probable (LSPMS) MS were met. The diagnosis of MS was made in all instances by a neurologist (ASN, AK, AM, AW). Comparison between the Jordanian and Palestinian groups was made using the normal Z-test when appropriate.
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2. Results On December 31st, 1993, there were 126 Arab MS patients resident in Jordan (83 women and 43 men). 81 were classified as CDMS, 6 as LSDMS, 37 as CPMS and 2 as LSPMS. Their mean age was 35.6 (SD k 8.2) years. The mean age at onset was 29.6 + 8.1 SD, being 28.9 ?c7.9 for women and 29.2 f 8.3 for men. The female:male ratio was 1.9: 1. Of the 126 Arab MS patients, there were 84 Palestinians, 36 Jordanians, 2 Syrians, 2 Iraqi, and 2 were the product of mixed marriages. The first of such patients has a Jordanian father and a Palestinian mother and the second a Palestinian father and an Algerian mother. Two of the Jordanians were non-Arabs (a Kurd and a Chechen). During the same period of study, a total of 19 Arab patients (10 Palestinians and 9 Jordanians) with amyatrophic lateral sclerosis (ALS) were seen in the same departments. Based on MS/ALS case ratios (presuming a fairly constant 5/ 100000, prevalence of ALS), an estimated prevalence for Palestinians was 42/ 100000 (95% CI 2.8-90.8) and 20/100000 (95% CI 9.5-47.2) for Jordanians. The female preponderance among the Jordanian patients (1.4: 1) was less marked than among the Palestinian patients (2.1: l), yet this difference was not statistically significant. A comparative study of the characteristics of MS among Palestinians and Jordanians was then done. Table 1 shows the age and sex distribution of patients from both groups. Minor differences were noted mainly reflecting the less apparent female preponderance among Jordanian patients. A study of the presenting symptoms in both groups revealed no significant differences. Common presenting symptoms included unilateral optic or retrobulbar neuritis in 19 (22.6%) of the Palestinian patients and 7 (19.4%) of the Jordanian patients. 18 (21.4%) and 27 (32%) of the Palestinian patients presented with motor and sensory
Table I Age and sex distribution of MS patients Age group
IO-19
Palestinians
Jordanians
Men (%)
Women (%)
Both sexes (%)
Men (%o)
Women (o/o)
Both sexes (%)
1 (3.7)
2
3
I (6.7)
0 0
1 (2.8)
(44.8)
C3.3)
2207.8,
IR,
746.7)
F3S.I) 6 (28.6)
(829.6)
($0,
;:3.8)
(822.2)
:2.7)
G3.3) 0 0 I5
(29.5, 0 0 21
(41.1) 0 0 36
20-29 30-39
ll6.1,
40-49 50-59 60+ Total
:2.7) 27
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symptoms, respectively, and 9 (25%) of the Jordanian patients presented with motor symptoms whereas 11 (30.5%) presented with sensory symptoms. In 91 (64 Palestinian and 27 Jordanian) patients the follow-up was regular enough to allow an analysis of the frequency of symptoms and signs during the course of the disease. After a mean duration of 7.7 years (range l-27 years) the frequency of symptoms and signs were widely distributed within the central nervous system. No significant differences were found in the two groups. 2.1. Place of birth of subjects and their parents Fig. 1 shows the map of the region divided into 8 arbitrary regions; 4 in relation to the main city for Jordanians (Amman) and the same for the Palestinians’ main city (Jerusalem). Table 2 shows the frequency of the place of birth of Jordanian patients (including the one with a Palestinian mother) and their parents (including the one married to a Palestinian) compared to their respective controls. It was more likely for Jordanian patients and their parents to be born in the north of the kingdom than their respective controls. This was particularly true for the parents as 49.3% of the parents of the patients were born in the north compared to 25.8% of the parents of the controls (P < 0.001). It was less likely for parents of Jordanian patients to originate from Amman or the towns around it, than the parents of the controls (P < 0.01). Table 3 shows the frequency of the place of birth of Palestinian patients (including the patient with an Algerian mother) and their parents (including the two who were not married to a Palestinian) compared to their controls. Only 24 (28.6%) of the Palestinian patients were born in Jordan compared to 61 (40.7%) of the controls but the difference was not statistically significant. More of the Palestinian patients were born in the towns of Nablis, Ram-Allah and Tulkeram (North) located on the West Bank, north of Jerusalem (31 (36.5%)) than their controls (25 (16.7%)) (P < 0.001). The same significant difference was found when the parents of the Palestinian patients were compared to their controls, as 82 (48.2%) of the patients’ parents were born in these towns compared to 97 (33.1%) of the
Fig. 1. The map of the region divided into 8 arbitrary areas in relation to the main city for each population.
parents of the controls (P < 0.002). The parents of the Palestinian patients were less likely to have been born in the coastal towns of Jaffa, Haifa and Gaza (Coastal) than their controls (P < 0.01). Even if the Jordanian and Palestinian patients originating from the north were excluded, there were more than twice as many Palestinian patients (44) as Jordanian patients (18), probably reflecting that the increased risk of developing MS was true in Palestinians regardless of the place of origin. 2.2. Genetic characteristics 2.2.1. Eye color The eye color of 150 Jordanian and 150 Palestinian controls was recorded and compared to each other and to the patients in the 2 groups. No significant differences in the frequency of having black, dark brown or hazel colored eyes was found when the Jordanian patients were compared to Palestinian patients, furthermore no significant differences were found when the patients were compared to their respective controls, nor when the Jordanian controls were compared to Palestinian controls. The only
Table 2 Place of birth of Jordanian patients and their parents, in relation to Amman, compared to controls and their parents Place of birth
Patients n = 37 (%o)
Controls n= 150(%)
Parents of patients n=73(%)
Parents of controls n = 298 (%)
North Middle
14 (37.81) * 16 (43.2) 6 (16.2) 1 (2.7) 0
29 (19.3) 91 (60.7) 17 (11.3) 1 (0.7) 12 (8)
36 (49.3) * * * 24 (32.8) * * 11 (15.1) 2 (2.7) 0
77 (25.8) 157 (52.7) 60 (20.1) 4 (1.3) 0
SOUth
East Outside
* P < 0.5 when patients were compared to controls; * ’ P < 0.01; * * * P < 0.001 when the parents of patients were compared to the parents of controls.
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Table 3 Place of birth of Palestinian patients and their parents, in relation to Jerusalem, compared to controls and their parents Place of birth
Patients n=85(%)
Controls n= ISO
Parents of patients n = 170 (o/o)
Parents of controls n = 293 (%o)
North Jerusalem south Coastal Jordan Gulf states
31 (36.5) * * * 9 (10.6) 8 (9.4) 6 (7) 24 (28.2) 7 (8.2)
25 (16.7) 16 (10.7) 12 (8) 14 (9.3) 61 (40.7) 22 (14.7)
82 (48.2) * * 29 (17.1) 26 (15.3) 33 (14.4) ’ 0 0
97 (33.1) 57 ( 14.4) 48 (16.4) 84 (30.4) 2 (0.71) 0
* P < 0.01 and * * P < 0.002 when the parents of patients were compared to the parents of controls; * * * P < 0.001 when patients were compared to controls.
observed difference was the observation that more Palestinian patients (17 (20.2%)) had green or blue eyes than their controls (16 (10.7%)) (P < 0.05). 2.2.2. Blood groups
The ABO and Rh blood groups were studied in the Palestinian and Jordanian patients and compared to 150 healthy controls in each group. No significant differences were found when either patients group was compared to their controls in the ABO blood groups. Yet the frequency of Rh negative blood group was significantly higher in patients of both groups when compared to their respective controls: 15.5% of Palestinian patients compared to 4.1% of their controls (P < 0.005) and in (8.3%) of the Jordanian patients compared to 2.7% of their controls (P < 0.005). No significant differences existed when Palestinian patients were compared to Jordanian patients, nor when the Palestinian controls were compared to Jordanian controls. 2.2.3. Histocompatibility
system
The HLA-DR and HLA-DQ epitopes were studied in 52 Palestinian and 30 Jordanian patients and compared to 90 Table 4 Distribution (%) HLA-DR
Patients (n= 52)
DQl DQ2
3. Discussion In previous studies, in Kuwait, it was found that multiple sclerosis was commoner among the Palestinians, resident in Kuwait, than the native Kuwaitis (Al-Din, 1986, et al., 1990). In these studies we tried to investigate several racial and genetic characteristics of patients as well as healthy controls of each group. It was found that the difference in the risk of developing MS could not be explained solely on environmental factors, as both groups
and -DQ characteristics of Palestinians and Jordanians Palestinians
DRl DR2 DR3 DR4 DR5 DR6 DR7 DR8 DR9 DRlO
and 45 Palestinian and Jordanian controls respectively (Table 4). An association between MS and HLA-DR2 epitope was significant in both patient groups (P < 0.01 for both). Apart from the finding that HLA-DQ3 was more frequently observed in normal Jordanians than normal Palestinians (P < 0.011, no significant differences in the frequency of HLA-DR or HLA-DQ epitopes were found when Palestinian patients were compared to Jordanian patients, nor when Palestinian controls were compared to Jordanian controls.
3.8 34.6 * 42.3 36.5 17.3 11.5 5.8 5.8 0 3.8 51.9 30.8 61.5 9.6
Jordanians Controls (n=90) 12.2 16.6 28.9 28.9 27.8 2.2 27.8 1.1 2.2 7.8 54.4 41.1 56.7 * * 4.4
Patients (n = 30)
Controls (n = 45)
0 50 ’ 46.7 3.3 16.6 3.3 13.3 10.0 6.7 6.7 63.3 36.7 66.6 0
* P < 0.01 (Patients compared to respective controls); * * P < 0.01 (Jordanian controls compared to Palestinian Controls).
4.4 20 28.9 35.6 35.6 0 22.2 0 2.2 2.2 44.4 31.1 77.8 * * 0
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shared the same environment for 30-40 years prior to 1990, but significant differences in their genetic racial markers were found (Al-Din et al., 1990). Furthermore, a study of the possible influence of age at migration to Kuwait, in Palestinians, revealed that Palestinians were more at risk of developing MS regardless of the age at migration to Kuwait. This observation was even true for Palestinians born in Kuwait (Al-Din et al., 1992a). These studies in Kuwait addressed two Arab populations who used to be separated by the massive desert between the Persian Gulf and the Mediterranean region, but who had lived in the same location for the last 30-40 years. We were thus interested in conducting a comparative study of Jordanians and Palestinians, considering that there are no major geographical barriers between the two localities. MS in Arabs resident in Jordan seems to have the same clinical, paraclinical, imaging and CSF characteristics as in Europeans. However, we observed that the disease was nearly twice as frequent in Palestinians resident in Jordan than in Jordanians. The observation was the result of a hospital based study rather than population-based, and thus was calculated on MS/ALS case ratios. We can postulate two major pitfalls in this method of calculation. First, the prevalence of ALS in Jordan is not known, but with 60% of the population younger than 20 years, it is probably less common than in Europe and North America. Thus the estimated prevalence rates for MS for both populations probably represents the minimum. The second pitfall for the MS/ALS case ratio is the possibility of drawing conclusions based on a number of patients representing only a small percentage of the actual number of patients. The difference in prevalence was observed despite the fact that the two groups lived in neighboring countries with nearly the same latitude, habitat and weather. Furthermore, since the 1948 and 1967 wars, massive waves of Palestinian refugees have settled in Jordan, representing nearly 50% of the Jordanian population. As citizens of Jordan, Palestinians and Jordanians have similar living standards, attend the same schools and utilize the same medical services. No differences in the clinical characteristics of the disease were found when Palestinians were compared to Jordanians except for a less prominent female preponderance among the Jordanian patients. We felt that the place of origin of patients (as judged by the place of birth of their parents), is reflective of several variables, some related to ancestral (possibly racial) origin and some environmental. This is particularly true, because the population of the region, other than Bedouins was a fairly stable population prior to the 1948 war. The place of birth of patients and their controls, being relatively young, probably reflects the pattern of migration resulting from population movement due to wars and urbanization. Thus, the place of birth of the parents (of the patients and controls) is more reflective of the ancestral origin of the patients and their controls.
Sciences 135 (1996)
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Differences between patients and their respective controls existed. It was more likely for Palestinian patients and their parents to originate from the towns north of Jerusalem (Nablis, Tulkarem and Ram-Allah) than their controls. Likewise it was more common for Jordanian patients and their parents to originate from the towns north of Amman (Irbid, Ajloun and Ramtha) than their controls. These three Jordanian towns are located near and were closely linked to the 3 Palestinian towns previously mentioned. These towns (in Jordan and the West Bank) are in mountainous areas, except for Tulkarem whose villages extend to the Mediterranean coast. The people of the region used to work in farming though the towns were market towns for the neighboring villages. Furthermore, the cities of Irbid and Ramtha in Jordan had always had strong links to the southern parts of Syria. It is also of interest that in the studies from Kuwait, the disease seemed to be commoner in Palestinians originating from the same 3 towns north of Jerusalem, than from elsewhere. Unlike the study in Kuwait no significant differences in the genetic characteristics of the normal populations were found. Thus no significant differences were found in the frequency of the different eye colors, ABO blood groups, nor of the HLA-DR and HLA-DQ characteristics, when normal Jordanians were compared to normal Palestinians. Yet the number of patients and controls was too small to investigate if that was true regardless of the place of origin Palestinians. When patients were compared to controls, it was found that Palestinian patients were more likely to have green or blue eyes than their controls (P < 0.05) patients from both groups were more likely to have Rh negative blood groups than their respective controls (P < 0.005). The green or blue eye colors and the Rh negative blood group are commoner among European Caucasians than Arabs and might thus possibly reflect genetic-racial influence in a particular population. More than 250 prevalence surveys for MS have SeNed as a basis for the delineation for risk areas for MS. Environmental (place-related) factors were proposed to explain the observed latitude gradient (Kurtzke, 1983). However, observations on 2 genetically different populations sharing the same environment have consistently shown differences in the risk of developing MS in Israel, South Africa, India, Canada and Kuwait (Alter et al., 1971; Francis and Louw, 1977; Bharucha et al., 1988; Hader et al., 1985; Al-Din et al., 1990). What is interesting in this study is the observation in 2 genetically similar populations sharing the same environment but still having significant difference in the risk of developing MS.
Acknowledgements This study was supported by Jordan University search Grant No. 243.
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