Clinical and Demographic Characteristics of Immigrant and Local Multiple Sclerosis Patients in Turkey

Abstract

Introduction:

Increasing migration, due to wars, is one of the environmental factors in the etiology of multiple sclerosis. This study aims to compare demographic and clinical features of immigrant and local MS patients, as well as relapses during pregnancy and postpartum in female patients.

Method:

Immigrant (Group 1) and local (Group 2) MS patients were evaluated between January 2019 – September 2020 retrospectively. Below-mentioned data of two groups were recorded and compared: i) demographic data, ii) cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) findings, iii) MS subtypes, iv) expanded disability status scores (EDSS), v) the time between first two relapses, vi) comorbidities, vii) treatment, viii) age of migration and country of origin, ix) pregnancy, x) relapse during pregnancy, xi) birth number, xii) breastfeeding, xiii) postpartum relapses.

Results:

Both of the groups were composed of 34 MS patients (in total n=68). Gender distribution, mean age, MS subtypes, the time between first two relapses, disease duration, EDSS, CSF findings and comorbidities were similar between groups. Symptom of onset was predominantly sensory in both groups. Local patients had more cervical lesions and higher lesion load (p=0.003, p=0.006). 20.6% of migrant MS patients were untreated, all local patients were on treatment. Rates of injection and infusion therapies were similar, the rate of receiving oral therapy was higher in the second group. Clinical features and fertility status of female patients were similar.

Conclusion:

According to the study no differences were preseentpresent between immigrant and local MS patients except for MRI lesion load and treatment parameters. The language barrier and irregular follow-ups were the major problems in treatment management.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the most frequent cause of neurological disability in young adults (1). Initial presentation is usually clinically isolated syndrome (CIS) and 85% of this group develops relapsing and remitting MS (RRMS), 25%–40% of these patients progress into secondary progressive MS (SPMS), but 10%–15% of all patients show disability accumulation from the beginning and are diagnosed with primary progressive MS (PPMS) (2,3). Multiple sclerosis is more frequently seen in women than men, between the ages of 20 to 40 (3).

Genetic predisposition and environmental factors play a role in MS etiology. Latitude, viral infections, exposure to sunlight and vitamin D levels are shown to correlate with disease prevalence (3,4). Turkey is located between Northern Europe, which has a high MS prevalence, and Asia where it’s relatively rare (5). Immigration studies highlight the importance of the time of migration regarding MS risk. Migration after the age of 15 does not affect the MS risk, on the other hand, people who migrate before 15 carry the risk of their country of destination (6). Differences in comorbid diseases that affect MS prognosis have also been reported (7).

After the Syrian Civil War, broke in 2011, approximately 4 million (3,710,497) people, mostly women and children, migrated to Turkey, causing Syrian refugees to be the largest immigrant population (85%) (8). In parallel to high immigration numbers, we observed a steep increase in immigrant patients in our hospital. In our country, immigrants are granted the same access to healthcare as nationals, even though treatments for chronic diseases like MS are expensive and cause a burden on the healthcare system. In this study, we aim to compare demographic and clinical features, laboratory findings, comorbid diseases and treatments of immigrant and local MS patients. Additionally, we evaluated the differences between these two groups regarding labour and postpartum relapses.

Highlights

• Both immigrant and local MS patients showed similar clinical and demographic characteristics.

• In both groups, the burden of comorbidity was higher in women than in men.

• Language barrier and irregular follow-up of the immigrant group constitute the biggest problem in treatment management.

Method

Our hospital, a tertiary referral center, is located in a highly populated part of Istanbul where the immigrant population is large. Our cohort is chosen retrospectively in the ratio of 1:1 from immigrant and MS patients, who attended our outpatient clinic between January 2019 and September 2021, with or without healthcare insurance. Both inpatient and outpatient information is collected via the Probel database management system.

Three-hundred-twenty-eight immigrant and 1087 local MS patients between the ages of 18 and 65, who fulfill the 2017 McDonald Criteria were included. From the immigrant group 294 patients, who did not have G35 ICD code, were excluded. The remaining 34 immigrant MS patients (Group 1; 28 Syrian nationals, 6 other nationalities (1 Uzbekistan, 1 Moldova, 2 Iran, 1 Belarus, 1 Armenia)) and 34 national patients randomly chosen from local MS patients (Group 2) were included. Their medical history was investigated and their demographical data, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) findings, MS subtypes, extended disability status scores (EDSS), the time between first two relapses, comorbid diseases, treatment, obstetric, peri- and postpartum history were recorded. For Group 1, age of migration and country of origin was documented. This study is approved by Haseki Training and Research Hospital Ethics Committee (Date 03/12/2020, Protocol no: 404).

Comparison of demographic, clinic, laboratory and MRI features, as well as treatments were made between the immigrant and local MS patients. pregnancy, birth count, pregnancy, abortus, breastfeeding and postpartum relapses for women were evaluated.

For statistical analysis, SPSS for Windows, Version 20.0 is used. For Groups 1 and 2, key features are summarized with descriptive statistics. Categorical variables are provided as numbers, and percentages, numerical variables as mean, standard deviation, minimum and maximum. Comparison between independent groups are made through Mann Whitney U Test due to abnormal distribution. Ratios are compared with the chi-square test. Statistical significance of alpha is accepted as p<0.05.

RESULTS

Group 1 consisted of 23 women, 11 men; Group 2 consisted of 19 women and 15 men, in total 68 MS patients’ data were analyzed. Number of women was higher than men (F/M: 23/11 and 19/15, respectively). Mean ages were similar (Group 1 33.2±9.6, Group 2 35.4±9.8) and no statistical difference was observed in gender distribution (Table 1). All patients in Group 1 migrated after the age of 15. The average age of immigration is 24 (17–48). Group 1 composed of 88.2% RRMS, 8.8% SPMS, 2.9% PPMS and no CIS, group 2 composed of 2.9% CIS, 76.4% RRMS, 14.7% SPMS and 5.8% PPMS. Group 2 had longer time between the first two relapses and disease duration and although EDSS was higher, no statistical difference was observed (Table 1).

Table 1.

Clinical and demographic features of immigrant and local MS groups

		Group 1		Group 2		p
		n	%	n	%
Gender	Male	11	32.4	15	44.1	0.318
	Female	23	67.6	19	55.9
Age (year) Mean ± SD (Min-Max)		33.2±9.6 (19–58)		35.4±9.8 (17–52)		0.261
Disease duration (year) Mean ± SD (Min-Max)		7.85±6.12 (0–32)		9.53±5.41 (2–27)		0.117
EDSS Mean ± SD (Min-Max)		1.92±1.67 (0–6.5)		2.07±1.42 (1–6.5)		0.457
Time between first 2 relapses (year) Mean ± SD (Min-Max)		2.08±1.95 (0–9)		2.26±2.56 (0–14)		0.896
Comorbid diseases		18	52	19	55	0.787
	Male	3	16.6	5	26.3
	Female	15	83.3	14	73.6
MS subtype	RRMS	30	88.2	26	76.4	0.484
	SPMS	3	8.8	5	14.7
	PPMS	1	2.9	2	5.8
Initial symptoms	ON	7	20.6	6	17.6	0.741
	Sensory	11	32.4	12	35.3
	Motor	10	29.4	7	20.6
	Brainstem	6	17.6	9	26.5

EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; ON: optic neuritis; PPMS: primary progressive multiple sclerosis; RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.

Both groups had similar percentages for patients with comorbidities (52% (n=18) and 55% (n=19), respectively) and there were prominently more women with comorbidities than men (F/M for group 1 15/3, for group 2 14/5). Depression and anxiety disorder were most common comorbidities in Group 1 (n=7, and n=4), others include hepatitis-C, Reynaud disorder, migraine, hypertension, scoliosis, vitiligo, thyroid disease, bipolar disorder. Depression and anxiety disorder were also the most common disorders in Group 2, followed by thyroid disease and hypertension (n=5, n=4, n=4, n=4, respectively). Other comorbidities include migraine, diabetes, thalassemia, rheumatoid arthritis and syringomyelia. No statistical difference in disease duration and EDSS scores were observed between patients with comorbidities from two groups (Table 1).

In both groups, the initial symptom was more commonly sensory deficit. Second in frequency was motor deficit in Group 1 and brainstem findings in Group 2. Optic neuritis (ON) was least frequent in both groups (Figure 1). For CSF findings, oligoclonal band (OCB) positivity was 90.9% for Group 1 and 100% in Group 2. High immunoglobulin G (IgG) index was seen in 72.7% of Group 1 and 66.6% of Group 2. Cerebrospinal fluid protein levels and cell counts were also not statistically different (p>0.005).

Figure 1.

Magnetic resonance imaging symptoms at onset.

All patients had brain lesions in MRI, 70.6% of immigrants and 97.1% of locals had cervical lesions and thoracic lesions were seen in 20.6% of both groups. 73.5% of Group 1 had both brain and spinal cord lesions, this percentage was 97.1% for Group 2. Significantly more patients from group 2 had spinal lesions, as well as higher lesion load (Table 2).

Table 2.

Magnetic resonance imaging lesion distribution

		Group 1		Group 2		p
		n	%	n	%
All cohort	Cranial	34	100	34	100	-
	Cervical	24	70.6	33	97.1	0.003
	Thoracic	7	20.6	7	20.6	1
	Cranial + spinal	25	73.5	33	97.1	0.006
Female MS patients	Cranial	23	100	19	100	-
	Cervical	15	65.2	19	100	0.005
	Thoracic	4	17.4	5	26.3	0.707
	Cranial + spinal	16	69.6	19	100	0.011

MS: multiple sclerosis.

All local patients were under treatment whereas, 20.6% of immigrant MS patients didn’t receive treatment (p=0,010). Patients who received first line treatment was 61.8% in Group 1 and 64.7% in Group 2. Second line treatment percentages were 17.6% and 35.3%. We didn’t observe statistical difference in treatments (p=0.151). For local MS patients rate of oral and second line treatment usage was statistically higher (p=0.031 and p=0.009 respectively). Infusion treatment rate was same (11.8%) in both groups. (Figure 2).

Figure 2.

Treatment status.

Female patients were younger in the immigrant group (p=0.029), no statistical difference was observed in pregnancy, birth number, abortus, children with malformation, postpartum relapses, lactation status, disease duration, EDSS, time between first 2 relapses between groups (p>0.005). It is observed that all patients with partners have children. One patient from immigrant MS group had postpartum relapse, but none were recorded in local group. Some differences were observed in MS subtype, initial symptoms, treatments, comorbidities, but none reached statistical significance. Oligoclonal band positivity rate was higher in women in Group 2, but high IgG index rate was similar between groups. Magnetic resonance imaging findings showed all female patients had brain lesions, whereas local patients had statistically higher rates of spinal cord lesions (Table 3).

Table 3.

Clinical and demographic features of immigrant and local female MS patients

		Group 1		Group 2		p
		Mean ± SD (Min-Max)		Mean ± SD (Min-Max)
Age (year)		32.9±9.4 (19–58)		38.9±8.4 (26–52)		0.029
Number of pregnancy		2.22±2.97 (0–14)		2.26±2.18 (0–10)		0.624
Number of live birth		2.00±2.13 (0–9)		2.16±2.24 (0–10)		0.787
Abortus		0.22±1.04 (0–5)		0.11±0.32 (0–1)		0.479
Children with malformation/anomaly		0.00±0.00 (0–0)		0.00±0.00 (0–0)		1
Relapse rate 3 months postpartum		0.0±90.29 (0–1)		0.16±0.37 (0–1)		0.485
Relapse rate 1 year postpartum		0.13±0.34 (0–1)		0.32±0.58 (0–2)		0.258
Length of stay (day)		4.61±5.22 (0–18)
Disease duration (year)		7.70±4.70 (2–17)		10.89±6.06 (2–27)		0.080
EDSS		2.14±1.77 (0–6.5)		2.03±1.21 (1–4.5)		0.678
Time between first two relapses (year)		1.90±1.63 (0–6)		2.87±3.09 (0–14)		0.241
		n	%	n	%	p
MS subtype	SPMS	3	13.0	4	21.1	0.425
	RRMS	20	87.0	14	73.7
	CIS	0	0.0	1	5.3
Initial symptoms	ON	7	30.4	5	26.3	0.623
	Sensory	6	26.1	7	36.8
	Motor	7	30.4	3	15.8
	Brainstem	3	13.0	4	21.1
Treatment	No treatment	3	13.0	0	0.0	0.288
	First line	14	60.9	12	63.2
	Second line	6	26.1	7	36.8
Type of treatment	No treatment	3	13.0	0	0.0	0.419
	Injection	11	47.8	11	57.9
	Oral	5	21.7	6	31.6
	Infusion	4	17.4	2	10.5
Postpartum relapse		1	4.3	0	0.0	1
Breastfeeding		16	69.6	16	84.2	0.305

CIS: clinically isolated syndrome; EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; ON: optic neuritis; PPMS: primary progressive multiple sclerosis; RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis;

DISCUSSION

Multiple sclerosis is an autoimmune demyelinating disease of the central nervous system that is related to genetic and environmental factors, although its etiology is at large unknown. Migration is one of those environmental factors, especially if it occurs before puberty (6). Almost 4 million Syrian has migrated to Turkey after civil war started on 2011 (8), therefore Syrian refugees are the majority (83%) of our immigrant MS cohort. Female population is remarkably larger in our group and RRMS is the most common subtype of our cohort (Group 1 88.2%; group 2 76.4%), this finding is compatible with previous studies (1). Between two groups, the time between 2 relapses, disease duration and EDSS scores did not differ. All of the patients in the first group migrated after the age of 15, nevertheless their clinic and demographic features were similar to the second group. This finding can be related to geographical proximity and is not unpredictable.

In previous literature, a variety of comorbidities have been reported alongside MS (9). Rotstein et al. reported higher rates of comorbidities in immigrant MS patients (7). Gender and age independent factors for comorbidities (10). Our study showed similar average age and comorbidities, although women showed higher comorbidity rates. A study from Canada reported higher rates of comorbidity, including hypertension, diabetes, epilepsy, depression and anxiety in male patients (11). We observed no statistical difference between disease duration and EDSS scores in patients with comorbid diseases, but disease duration correlated with higher risk of comorbid diseases. Depression and anxiety were the most common comorbid disorders. Despite anxiety being similar in both groups (Group 1 14.7%, Group 2 11.7%), depression was significantly higher in immigrants and women (Group 1 20.5% F/M: 6/1; Group 2 11.7% F/M: 5/0). Previous studies reported various rates for depression and anxiety in MS patients, ranging from 14% to 54% (12,13). Lo et al. stated that psychiatric disorders are frequent in MS, depression being the most prominent (14). It’s known that depression is more common in women than men in MS patients (15,16). Our findings are in support of the literature; we also did not find statistical difference between two groups. Difficulties in communication due to language barrier, traumatic life experiences during and after migration, economic instability and social adjustment issues might be the reason we observed more depression in our immigrant cohort. The reason for higher depression rate in women could be related to financial struggles, poorer social integration by means of at-home duties, as well as experiencing more stress due to traumatic life experiences and larger linguistic barriers (17).

Local MS patients had higher rates of CSF OCB positivity, though it didn’t reach statistical significance. Higher IgG index rates in immigrant population can be explained by the fact that immigrant patients tend to apply to emergency clinics during acute relapses, therefore their tests are done and diagnosis are given during relapses. Local patients have more MRI lesions, this finding can be explained with longer disease duration and higher EDSS scores (18).

In many countries, due to healthcare policies, immigrant and refugee populations experience difficulties in access to treatment (19), however Turkey’s healthcare system provides all treatment options for all documented migrants. Therefore 20% of our immigrant cohort, who don’t receive any treatment, is not the result of inability to access treatment, rather a result of irregular follow-ups. A study from Turkey supports this idea, as they report 96.1% of Syrian immigrants have neurological disorders that need frequent follow-up, but fail to come to outpatient clinics (20). Rate of first line treatment is similar in both groups and this can also be observed in second line treatments, still we observed lower rates of second line and oral treatment rates in immigrants. This can be associated with irregular follow-up and bigger concern for safety as a result of linguistic barriers. Infusion therapies are used at the same rate, this might be because these therapies are applied in hospitals and require less effort for test and follow-up from patients. We believe the reason behind failure to attend to follow-up is inadequate Turkish knowledge, difficulty to adjust to healthcare system and socioeconomic problems. Immigrant patients show tendency to apply to emergency clinics rather than inpatient clinics (5), this can also be related to adjustment issues with the healthcare system. Furthermore, easy and fast access to emergency clinics play a mediating role.

Female immigrant patients were statistically younger than local patients (p=0.029). Cerebrospinal fluid findings were similar to overall cohort, as well as MRI findings (Table 2). No difference between two groups was observed in regards to pregnancy, live birth, abortus, children with malformation, postpartum relapses, lactation, disease duration, EDSS, time between first two relapses (Table 3). In regards to fertility, we observed every patient with a partner had children. Previous studies show decreased fertility in MS patients (21,22). In spite of these findings, we observed both of these MS groups to have a tendency to conceive more children, which is supported by a newer study from Nguyen et al. (23) (Figure 3). We are of the belief that this is the consequence of increased awareness and knowledge of MS, better risk management in pregnancy and earlier intervention with effective treatments in postpartum. One patient from immigrant MS group had postpartum relapse, but none were recorded in local group. We argue that this is associated with better follow-up and drug compliance in local group. Breastfeeding rate was similar between two groups, as well as MS subtype, symptoms at onset, treatment and comorbid diseases (Table 3).

Figure 3.

Number of live births.

Strengths of our study: We evaluated a wide spectrum of clinical, demographic, laboratory findings, as well as comorbidities, pregnancy, obstetric history, postpartum relapse information. This is the first study, as we know, that surveys immigrant female MS patients.

Limitations of our study: First of all, small cohort of immigrant patients has limited our ability to provide stronger statistical outcome. Additionally, there may have been difficulties in communication despite attending translators, due to differences in local dialect. This might have caused miscommunication between parties.

CONCLUSION

Our studies showed that there are no statistical differences between local and immigrant MS patients, except for brain and spinal involvement and treatment parameters. We believe this is caused by geographical proximity to Syria, where majority of our immigrant cohort is from. The most important problem in regards to treatment of immigrant patient is shown to be language barrier and irregular follow-up. Larger studies are needed to increase the awareness around migration and better definition of immigrant MS patient profiles.

Part of this study was presented as a poster at the 55^th National Neurology Congress (November 2019, Antalya, Turkey).