Sage Journals: Discover world-class research

Abstract

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system, causing inflammation, demyelination, and neurodegeneration. Infection can play a role in its etiology. Herein, a review is presented of studies that have reported an association between infection and MS risk in countries of the Arabian Gulf region. Searches of the PubMed, Google Scholar, and Science Direct databases were carried out using various search terms, and relevant studies published through January 2019 on the epidemiology of MS in Gulf Cooperation Council countries identified. MS has been found to be associated with measles in Saudi Arabia and Epstein–Barr virus in Kuwait whereas no association has been identified between risk of MS and varicella-zoster virus, mumps, or human herpesvirus-6. However, few epidemiological studies on this topic have been conducted in countries of the Gulf region. Longitudinal and serological studies to establish robust evidence between infection and risk of MS are highly recommended, and a regional MS registry is needed.

Keywords

Multiple sclerosis infection Gulf Cooperation Council countries measles Epstein–Barr virus epidemiological study

Introduction

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system. In this pathological condition, the myelin sheath of the nerve fibers is attacked by the immune system.¹ MS is similar to other autoimmune diseases in that it disproportionately affects women, at nearly twice the frequency as men, probably owing to immunologic variations such as the stronger Th1-mediated immune responses in female mammals.² Moreover, the X chromosome is likely to be a contributing factor in the elevated MS susceptibility among women.^3,4 MS susceptibility is broadly acknowledged to be mediated by a complex interaction between unidentified ecological and/or behavioral aspects that exist in certain regions of the world and within genetically suspect hosts.^5,6 Although the complete etiology of MS remains unknown, autoimmunity has been implicated in this process.⁷ MS arises from complex interactions between individual genetic susceptibility and environmental factors. Nearly 50% of the MS risk is attributed to alleles and genes mapped in the HLA-II locus.⁸ Variations in HLA-II genes and allele frequencies and types have been observed among different nations and ethnic groups worldwide.⁹ The genetic profile of MS is heterogeneous in the Gulf region, comprising Gulf Cooperation Council countries, where the MS profile is not unique but is unlike that observed in other regions. In Saudi Arabia, HLA-DRB1*15:01 is the most frequently observed risk allele for MS among Saudi patients.¹⁰ This is in line with MS risk alleles observed in patients from Iran.^11–14 Likewise, it is the same allele reported among patients with MS from Sweden, Australia, the Netherlands, Spain, and Italy.^15–19 By contrast, in Bahrain, another Gulf region country, the HLA-DRB1*15:01 allele is not a risk allele for MS; instead, HLA-DR3, HLA-DR4 and HLA-DR16 have been reported as MS risk alleles in Bahraini patients.²⁰ In Kuwait, some patients with MS express HLA-DR4, similar to some Bahraini patients. In addition, Kuwaiti patients also express HLA-DQ6, HLA-DQ7, and HLA-DQ8.²¹ From another viewpoint, HLA-DR6 and HLA-DQ1 are protective alleles among Kuwaiti patients²¹ whereas HLA-A10 is protective among Bahraini individuals.²⁰ In a Saudi study, HLA-DQB1*02:02, HLA-DQB1*05:03, and HLA-DQB1*06:14 were found to be protective alleles against MS.¹⁰ This is in contrast to protective alleles against MS like HLA-DRB1*11, which have been documented by the World Health Organization and in reports from Spain and India.^22–24 Another protective allele is HLA-DRB1*1001, which has been reported in Iran.¹³ Various studies have shown that infectious and noninfectious environmental factors in children and young adults are correlated with a strong risk of MS.²⁵ Several theories on the cause of MS have emerged, supported by varying degrees of evidence; these include infectious diseases,^26,27 an autoimmune state,^28,29 and vascular diseases.^30,31 Presently, the most widely accepted hypothesis is that MS is an immune-mediated illness with variable stages of immune activity within individuals and sometimes among individuals within a population. Many common mechanisms of autoimmunity are suspected as playing a role in this process, such as major and minor failures of normal self-tolerance, induced by various causes such as bacterial or viral infectivity or target tissue abnormality.³² High antibody titers against viruses have been reported in MS patients. Notably, most studies on the infectious causes of MS, which are generally based on clinical, experimental, and pathological observations in animals, have been conducted in Western countries.^33,34 The six countries of the Gulf Cooperation Council (GCC) include the Arabian Gulf nations, specifically, Saudi Arabia, United Arab Emirates, Bahrain, Oman, Kuwait, and Qatar. Together, the GCC countries have a population of 50 million (Figure 1).³⁵ These GCC nations have many commonalities and share aspects such as borders, experiences of climate change, cultural values, lifestyles, and socioeconomic development. Over the past 20 years, oil and gas revenues have led to drastic social and cultural changes as well as an epidemiologic transformation,³⁶ which may be leading to increases in environmental factors that result in conditions such as vitamin D deficiency,^37,38 infections,^39,40 obesity,^41,42 and smoking.^43,44 In addition, increasing younger populations and the availability of free medical services for citizens may facilitate early diagnosis and partially explain an increase in the MS incidence. The aim of the current study was to review published studies that have reported an association between infection and the risk of MS in GCC countries.

Figure 1.

Gulf Cooperation Council (GCC) countries.

Methods

To identify relevant studies on the epidemiology of MS in the GCC countries, a number of search terms were used to search the PubMed, Google Scholar, and Science Direct databases. All studies included in this review were published during or before January 2019. The three databases were searched using keywords or phrases that included MS (multiple sclerosis) and the name of each GCC nation, as follows: [“multiple sclerosis”] AND [“Saudi Arabia” OR “Kuwait” OR “United Arab Emirates” OR “Oman” OR “Qatar” OR “Bahrain”]. Thereafter, the identified articles on MS were reviewed using their abstracts, titles, tables, and references (Figure 2). The original search was broad, to help achieve the main objective of the current study. Ethical approval and informed consent were not required owing to the nature of the study.

Figure 2.

Flow chart of strategy used for article selection.

Results

Five studies were conducted on MS in GCC countries and fulfilled the criteria for inclusion in this review. Among these five articles reporting an association between MS and infection, only two GCC countries were represented, Saudi Arabia and Kuwait.^45–49 The relevant details of these studies are listed in Table 1.

Table 1.

Studies in Gulf Cooperation Council countries of multiple sclerosis and reporting infection.

Reported infection	Author and country	Age range or (mean)	Methods	MS patients (n)	Controls (n)	OR (95% CI)	p
Measles	Halawani AT et al., 2018⁴⁵Saudi Arabia	18–57 years	Face-to-face interview	80	160	3.76(1.46–9.70)	<0.05
	Al Wutayd et al., 2018⁴⁶Saudi Arabia	18–69 years	SAQ	307	307	3.77 (2.05–6.96)	<0.001
	Al Afasy HH et al., 2013⁴⁷Kuwait	(33.8 years)	Face-to-face interview	101	202	NI^†	NS
VZV	Halawani AT et al., 2018⁴⁵Saudi Arabia	18–57 years	Face-to-face interview	80	160	1.25 (0.73–2.15)	NS
	Al Wutayd et al., 2018⁴⁶Saudi Arabia	18–69 years	SAQ	307	307	0.90 (0.65–1.24)	NS
	Al Afasy HH et al., 2013⁴⁷Kuwait	(33.8 years)	Face-to-face interview	101	202	NI	NS
Mumps	Al Afasy HH et al., 2013⁴⁷Kuwait	(33.8 years)	Face-to-face interview	101	202	NI	NS
EBV	Al Afasy HH et al., 2013⁴⁷Kuwait	(33.8 years)	Face-to-face interview	101	202	NI	NS
EBV	Al-Temaimi et al., 2015⁴⁸Kuwait	14–60 years	ELISA assay	141	40	22.59(5.07–40.45)	0.008
HHV-6	Al-Shammari et al., 2003⁴⁹Kuwait	NI	Serum PCR	24	33	NI	NS

Abbreviations: SAQ: self-administered questionnaire, NI: no information, EBV: Epstein–Barr Virus, HHV-6: human herpesvirus-6, VZV: varicella-zoster virus, MS: multiple sclerosis, PCR: polymerase chain reaction, ELISA: enzyme-linked immunosorbent assay, NS: not significant, OR: odds ratio, CI: confidence interval.

Measles

Measles is a highly contagious virus belonging to the paramyxovirus family. The virus is transmitted through airborne droplets or VIA direct contact and infects the respiratory tract, with subsequent spread to the rest of the body.⁵⁰ Three case-control studies were conducted in GCC countries to assess the association between measles and MS. Two of these studies were conducted in Saudi Arabia, and both reported that measles infection increased the MS risk by approximately 4-fold. The first study reported an odds ratio (OR) of 3.76 and confidence interval (CI) of 1.46 to 9.70;⁴⁵ the second study reported an OR of 3.77 and 95% CI of 2.05 to 6.96.⁴⁶ In contrast, a study on measles and MS conducted in Kuwait found that measles posed a statistically insignificant risk for MS.⁴⁷

Varicella-zoster virus (VZV)

Chickenpox is a contagious infection, usually occurring in children, which is caused by primary infection with VZV.⁵¹ Three case-control studies on VZV and MS that were conducted in GCC countries were identified, two in Saudi Arabia^45,46 and one in Kuwait.⁴⁷ All three studies reported that VZV was associated with a statistically insignificant risk for MS.

Mumps

Mumps is a common and highly contagious childhood disease caused by the mumps virus.⁵² Only one study was found on mumps and MS, conducted in Kuwait.⁴⁷ The study findings showed no association between mumps and MS risk.

Epstein–Barr virus (EBV)

EBV is considered one of the most prevalent human viruses worldwide. EBV belongs to the herpesvirus family. The virus is spread primarily through saliva and causes infectious mononucleosis.⁵³ Only two studies on EBV and MS were conducted in a GCC country (both in Kuwait), and these reported conflicting results. An epidemiological study showed no association between EBV and MS,⁴⁷ whereas a serological study showed a strong association between EBV and MS.⁴⁸

Human herpesvirus-6 (HHV-6)

Primary infection with HHV-6 is commonly acquired in childhood and is spread via saliva between children, caregivers, and siblings. HHV-6 viral particles enter through the nasopharynx and olfactory system.⁵⁴ Only one study on HHV-6 and MS conducted in a GCC country (Kuwait) was identified.⁴⁹ That study reported no association between HHV-6 and MS risk.

Discussion

Two studies conducted in Saudi Arabia found an association between MS and measles,^45,46 which is consistent with a case-control study conducted in 2017 in Iran that identified an association between a history of measles and MS.^55,56 This is also consistent with a report that a history of measles during childhood increases the MS risk.⁵⁷ The association between MS and measles infection has been studied for many years, and this association has been postulated as a host response to viral infection, which may cause the demyelinating and inflammatory lesions in MS.⁵⁸ A serological study in Kuwait found that EBV increased the MS risk and the authors identified a strong association between EBV and MS.⁴⁸ The findings of that study are consistent with a meta-analysis reporting that a history of infectious mononucleosis more than doubles the risk of MS.⁵⁹ It is currently unclear whether EBV is independently associated with MS or whether some other factors predispose an individual to both EBV infection and MS. EBV affects people of all ages, and, after causing an asymptomatic primary infection early in childhood, the virus exists in a latent form in B cells, from which it can later progress to infectious mononucleosis.⁶⁰ A strong association between EBV and MS has been demonstrated in various epidemiological⁶¹ and serological studies conducted in Western countries.^62,63 The autoimmune reactions in MS may be induced by viral infection, which leads to inflammatory disease in the central nervous system via mimicry or bystander activation. These two mechanisms are not mutually exclusive because, for successful molecular mimicry, viral antigens may have structures that are sequential or similar to self-antigens, and bystander activation is not specific to autoreactive cells because of the inflammatory events that result from infection.⁶⁴ Inconsistently, a study in Kuwait found no association between the risk of MS and measles, EBV, or mumps.⁴⁷ Moreover, two studies conducted in Saudi Arabia and one study conducted in Kuwait found no association between VZV and MS.^45–47 VZV has long been considered a potential etiologic agent of MS, but previous comprehensive reviews analyzing 40 studies did not identify any causal associations.⁶⁵ Similarly, a population-based case-control study in Iran (547 cases and 1057 controls) found no association between VZV and MS.⁶⁶ A study in Kuwait reported no association between the risk of MS and mumps, consistent with a large-scale case-control study (14,362 cases and 7671 controls).⁶⁷ Another study in Kuwait found no association between HHV-6 and MS, which was inconsistent with a recent meta-analysis of 34 molecular studies and seven serological studies showing increased MS risk.⁶⁸ Viral infections have long been considered potential risk factors for MS. However, some studies have reported that viral infections such as CMV, HIV, and HCV are negatively associated with MS risk.^69–71 There is a disproportionately high migrant worker population in GCC countries, and although this large anomaly could skew all epidemiological research emerging from the region, the relevant studies were conducted almost exclusively among GCC citizens.

We identified and evaluated five published articles on MS and infection conducted in Saudi Arabia and Kuwait. There were no relevant published reports of research conducted in the remaining four GCC countries. The first relevant paper from a GCC country was from Kuwait, published in 2003.⁴⁹ Two additional articles were from Kuwait, published in 2013 and 2015;^47,48 the two most recent articles included in this review were published in Saudi Arabia in 2018.^45,46 The number of published studies of infection and MS risk is relatively low in this region, as compared with that in Western and Middle Eastern countries. Moreover, there is a gap in the literature between 2003 and 2013. This may be because MS was previously considered to be an uncommon disease in GCC countries, although the most recently published papers show that MS is more common than previously realized.^72,73 The prevalence of MS in Kuwait is 85 cases per 100,000 individuals, the highest of any GCC country.⁷⁴ MS prevalence in the United Arab Emirates is 64.44 cases per 100,000,⁷⁵ and that in Qatar is 64.56 cases per 100,000.⁷⁶ Global MS prevalence has increased from 30 cases per 100,000 in 2008 to 33 cases per 100,000 in 2013, with significant variation between countries.⁷⁷ The highest MS prevalence in the world is in high-income areas: North America with 164.6 cases per 100,000 and in Western Europe with 127 cases per 100,000 individuals. The lowest MS prevalence is found in eastern Sub-Saharan Africa with 2.8 cases per 100,000 and Oceania with 2 cases per 100,000.⁷⁸ Countries neighboring the Gulf region, such as Iran and Turkey, have an MS prevalence of 74.28 and 101.4 cases per 100,000 individuals, respectively.⁷⁹ Retrospective epidemiological studies were the most commonly published article type, followed by serological studies; thus, there is a need for additional prospective and serological studies on this topic. The present findings also emphasize the need for a regional MS registry in Gulf countries.⁸⁰ Importantly, future work on this topic should also investigate the age of infection, as contracting an infection in early life may be a protective factor for MS whereas contracting the same disease at a later age may be a risk factor of MS,²⁶ given that the development of a normal immune system requires challenges via exposure to infections early in life, which is the basic concept behind the hygiene hypothesis.^81–83

Study limitations

The lack of an adequate number of relevant studies from the Arabian Gulf region prevented us from conducting a meta-analysis or even a systematic review. Most published papers included in this review were hospital-based and had limitations such as a small sample size and recall bias. Thus, additional studies regarding the association between infection and MS, using serological tests rather than questionnaires or interviews, are needed to provide more robust evidence.

Conclusion

An association between MS and measles has been reported in Saudi Arabia, and an association of MS with EBV was reported in Kuwait. However, only a few studies on the associations of MS with infectious diseases have been conducted in GCC countries, most of which were epidemiological studies with a small sample size. MS research in the GCC countries is currently far surpassed by that in Western countries. Further longitudinal and serological studies to investigate the relationship between infection and MS are highly recommended, as is creation of an MS regional registry in the GCC countries.

Footnotes

Acknowledgements

The author would like to thank the authors of the studies included in this review as well as Katie Oakley, PhD, from Edanz Group for editing a draft of this manuscript.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iD

O Al Wutayd

References

Raine

CS.

Multiple sclerosis: the resolving lesion revealed.

J Neuroimmunol 2017; 304: 2–6.

Schwendimann

Alekseeva

Gender issues in multiple sclerosis.

Int Rev Neurobiol 2007; 79: 377–392.

Harbo

Gold

Tintoré

Sex and gender issues in multiple sclerosis.

Ther Adv Neurol Disord 2013; 6: 237–248.

Airas

Hormonal and gender‐related immune changes in multiple sclerosis.

Acta Neurol Scand 2015; 132: 62–70.

Ebers

Daumer

Natural history of MS.

Eur J Neurol 2008; 15: 881–882.

Handel

Handunnetthi

Giovannoni

, et al. Genetic and environmental factors and the distribution of multiple sclerosis in Europe. Eur J Neurol 2010; 17: 1210–1214.

Thompson

Baranzini

Geurts

, et al. Multiple sclerosis. Lancet 2018; 391: 1622–1636.

Dyment

Ebers

Sadovnick

AD.

Genetics of multiple sclerosis.

Lancet Neurol 2004; 3: 104–110.

Hollenbach

Oksenberg

JR.

The immunogenetics of multiple sclerosis: a comprehensive review.

J Autoimmun 2015; 64: 13–25.

10.

Al Jumah

Kojan

Al Shehri

, et al. HLA class II polymorphism in Saudi patients with multiple sclerosis. HLA 2018; 91: 17–22.

11.

Abolfazli

Samadzadeh

Sabokbar

, et al. Relationship between HLA-DRB1* 11/15 genotype and susceptibility to multiple sclerosis in Iran. J Neurol Sci 2014; 345: 92–96.

12.

Amirzargar

Tabasi

Khosravi

, et al. Optic neuritis, multiple sclerosis and human leukocyte antigen: results of a 4‐year follow‐up study. Eur J Neurol 2005; 12: 25–30.

13.

Kollaee

Ghaffarpor

Ghlichnia

, et al. The influence of the HLA‐DRB1 and HLA‐DQB1 allele heterogeneity on disease risk and severity in Iranian patients with multiple sclerosis. Int J Immunogenet 2012; 39: 414–422.

14.

Mazdeh

Taheri

Sayad

, et al. HLA genes as modifiers of response to IFN-β-1a therapy in relapsing-remitting multiple sclerosis. Pharmacogenomics 2016; 17: 489–498.

15.

Stewart

Teutsch

Castle

, et al. HLA‐DR,‐DQA1 and‐DQB1 associations in Australian multiple sclerosis patients. Eur J Immunogenet 1997; 24: 81–92.

16.

de Jong

Huizinga

Zanelli

, et al. Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region. Neurology 2002; 59: 549–555.

17.

Fernández

Alonso

, et al. DQB1* 0602 allele shows a strong association with multiple sclerosis in patients in Malaga, Spain. J Neurol 2004; 251: 440–444.

18.

Montanaro

Sanna

Matarese

, et al. The fine specificity of human T cell lines towards myelin basic protein peptides in southern Italian multiple sclerosis patients. Clin Exp Immunol 2001; 123: 288–293.

19.

Masterman

Ligers

Olsson

, et al. HLA‐DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol 2000; 48: 211–219.

20.

Al-Nashmi

Taha

Salem

, et al. Distinct HLA class I and II genotypes and haplotypes are associated with multiple sclerosis in Bahrain. Biomed Rep 2018; 9: 531–539.

21.

Al-Shammri

Nelson

Al-Muzairi

, et al. HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population. Mult Scler 2004; 10: 381–386.

22.

World Health Organization. Multiple Sclerosis International Federation. Atlas Multiple Sclerosis Resources in the World 2008. Geneva; 2008 [cited 23 Sep 2019]. Available from: https://apps.who.int/iris/bitstream/handle/10665/43968/9789241563758_eng.pdf?sequence=1&isAllowed=y.

23.

Romero-Pinel

Pujal

Martínez-Yélamos

, et al. HLA‐DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population. Eur J Neurol 2011; 18: 337–342.

24.

Kankonkar

Jeyanti

Singhal

, et al. Evidence for novel DRB1* 15 allele association among clinically definite multiple sclerosis patients from Mumbai, India. Hum Immunol 2003; 64: 478–482.

25.

Correale

Gaitan

MI.

Multiple sclerosis and environmental factors: the role of vitamin D, parasites and Epstein-Barr virus infection.

Acta Neurol Scand 2015; 132: 46–55.

26.

Ascherio

Munger

KL.

Environmental risk factors for multiple sclerosis. Part I: the role of infection.

Ann Neurol 2007; 61: 288–299.

27.

Marrodan

Alessandro

Farez

, et al. The role of infections in multiple sclerosis. Mult Scler 2019; 25: 891–901.

28.

Hafler

Weiner

HL.

MS: a CNS and systemic autoimmune disease.

Immunol Today 1989; 10: 104–107.

29.

Hemmer

Kerschensteiner

Korn

Role of the innate and adaptive immune responses in the course of multiple sclerosis.

Lancet Neurol 2015; 14: 406–419.

30.

Zamboni

The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis.

J R Soc Med 2006; 99: 589–593.

31.

Spencer

Bell

DeLuca

GC.

Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier.

J Neurol Neurosurg Psychiatry 2018; 89: 42–52.

32.

Anaya

JM.

The autoimmune tautology.

Arthritis Res Ther 2010; 12: 147.

33.

Gilden

DH.

Infectious causes of multiple sclerosis.

Lancet Neurol 2005; 4: 195–202.

34.

Owens

Gilden

Burgoon

, et al. Viruses and multiple sclerosis. Neuroscientist 2011; 17: 659–676.

35.

Gulf Research Center. Total population and percentage of nationals and nonnationals in GCC countries (latest national statistics, 2010-2015) [cited 2019]. Available from: http://gulfmigration.eu/total-population-and-percentage-of-nationals-and-non-nationals-in-gcc-countries-latest-national-statistics-2010-2015/.

36.

Sturm

Strasky

Adolf

, et al. The Gulf Cooperation Council Countries: Economic Structures, Recent Developments and Role in the Global Economy. In: Vol 92. European Central Bank, Frankfurt, Germany; 2008. European Central Bank Occasional Paper.

37.

Muhairi

Mehairi

Khouri

, et al. Vitamin D deficiency among healthy adolescents in Al Ain, United Arab Emirates. BMC Public Health 2013; 13: 33.

38.

Alfawaz

Tamim

Alharbi

, et al. Vitamin D status among patients visiting a tertiary care center in Riyadh, Saudi Arabia: a retrospective review of 3475 cases. BMC Public Health 2014; 14: 159.

39.

Al-Temaimi

Alroughani

Jacob

, et al. Gender influence in EBV antibody response in multiple sclerosis patients from Kuwait. J Neuroimmunol 2015; 285: 57–61.

40.

Al-Salam

Dhaheri

Awwad

, et al. Prevalence of Epstein–Barr virus in tonsils and adenoids of United Arab Emirates nationals. Int J Pediatr Otorhinolaryngol 2011; 75: 1160–1166.

41.

Fleming

Robinson

, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766–781.

42.

Musaiger

Al-Mannai

Al-Lalla

, et al. Obesity among adolescents in five Arab countries; relative to gender and age. Nutr Hosp 2013; 28: 1922–1925.

43.

Almutairi

KM.

Smoking among Saudi students: a review of risk factors and early intentions of smoking.

J Community Health 2014; 39: 901–907.

44.

Aden

Karrar

Shafey

, et al. Cigarette, water-pipe, and medwakh smoking prevalence among applicants to Abu Dhabi's Pre-Marital Screening Program, 2011. Int J Prev Med 2013; 4: 1290.

45.

Halawani

Zeidan

Kareem

, et al. Sociodemographic, environmental and lifestyle risk factors for multiple sclerosis development in the Western region of Saudi Arabia. A matched case control study. Saudi Med J 2018; 39: 808–814.

46.

Al Wutayd

Mohamed

Saeedi

, et al. Environmental exposures and the risk of multiple sclerosis in Saudi Arabia. BMC Neurol 2018; 18: 86.

47.

Al-Afasy

Al-Obaidan

Al-Ansari

, et al. Risk factors for multiple sclerosis in Kuwait: a population-based case-control study. Neuroepidemiology 2013; 40: 30–35.

48.

Al-Temaimi

Alroughani

Jacob

, et al. Gender influence in EBV antibody response in multiple sclerosis patients from Kuwait. J Neuroimmunol 2015; 285: 57–61.

49.

Al-Shammari

Nelson

Voevodin

HHV-6 DNAaemia in patients with multiple sclerosis in Kuwait.

Acta Neurol Scand 2003; 107: 122–124.

50.

World Health Organization, Fact sheets – Measles. May 2019 [cited September 16, 2019]. Available from: https://www.who.int/news-room/fact-sheets/detail/measles.

51.

Folusakin

Gossman

WG.

Varicella Zoster (Chickenpox). StatPearls. StatPearls Publishing, 2018 [cited November 23, 2018]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448191/.

52.

Colligan

LH.

Mumps. Salt Lake (UT): Benchmark Books, 2010.

53.

Centers for Disease Control and Prevention, Epstein–Barr virus and infectious mononucleosis. May 2018 [cited September 16, 2019]. Available from: https://www.cdc.gov/epstein-barr/about-ebv.html

54.

Harberts

Yao

Wohler

, et al. Human herpesvirus-6 entry into the central nervous system through the olfactory pathway. PNAS 2011; 108: 13734–13739.

55.

Abbasi

Nabavi

Fereshtehnejad

, et al. Multiple sclerosis and environmental risk factors: a case-control study in Iran. Neurol Sci 2017; 38: 1941–1951.

56.

Shaygannejad

Rezaie

Paknahad

, et al. The environmental risk factors in multiple sclerosis susceptibility: a case-control study. Adv Biomed Res 2016; 5: 98.

57.

Eftekharian

Ghannad

Taheri

, et al. Frequency of viral infections and environmental factors in multiple sclerosis. Hum Antibodies 2016; 24: 17–23.

58.

Mentis

Dardiotis

Grigoriadis

, et al. Viruses and endogenous retroviruses in multiple sclerosis: from correlation to causation. Acta Neurol Scand 2017; 136: 606–616.

59.

Handel

Williamson

Disanto

, et al. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 2010; 5: e12496.

60.

Crawford

Macsween

Higgins

, et al. A cohort study among university students: identification of risk factors for Epstein–Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis 2006; 43; 276–282.

61.

Thacker

Mirzaei

Ascherio

Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis.

Ann Neurol 2006; 59: 499–503.

62.

Ascherio

Munger

Lennette

, et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001; 286: 3083–3088.

63.

Lunemann

Munz

Epstein-Barr virus and multiple sclerosis.

Curr Neurol Neurosci Rep 2007; 7: 253–258.

64.

Fujinami

von Herrath

Christen

, et al. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 2006; 19: 80–94.

65.

Marrie

Wolfson

Multiple sclerosis and varicella zoster virus infection: a review.

Epidemiol Infect 2001; 127: 315–325.

66.

Abdollahpour

Nedjat

Mansournia

, et al. Infectious exposure, antibiotic use, and multiple sclerosis: a population‐based incident case‐control study. Acta Neurol Scand 2018; 138: 308–314.

67.

Ramagopalan

Valdar

Dyment

, et al. Association of infectious mononucleosis with multiple sclerosis. Neuroepidemiology 2009; 32: 257–262.

68.

Pormohammad

Azimi

Falah

, et al. Relationship of human herpes virus 6 and multiple sclerosis: a systematic review and meta‐analysis. J Cell Physiol 2018; 233: 2850–2862.

69.

Sundqvist

Bergström

Daialhosein

, et al. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult Scler 2014; 20: 165–173.

70.

Gold

Goldacre

Maruszak

, et al. HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study. J Neurol Neurosurg Psychiatry 2015; 86: 9–12.

71.

Söderholm

Yilmaz

Svenningsson

, et al. Lower risk of multiple sclerosis in patients with chronic hepatitis C: a nationwide population-based registry study. J Neurol 2019; 266: 2208–2215.

72.

Inshasi

Thakre

Prevalence of multiple sclerosis in Dubai, United Arab Emirates.

Int J Neurosci 2011; 121: 393–398.

73.

Bohlega

Inshasi

Al Tahan

, et al. Multiple sclerosis in the Arabian Gulf countries: a consensus statement. J Neurol 2013; 260: 2959–2963.

74.

Alroughani

Ahmed

Behbahani

, et al. Increasing prevalence and incidence rates of multiple sclerosis in Kuwait. Mult Scler 2014; 20: 543–547

75.

Schiess

Huether

Fatafta

, et al. How global MS prevalence is changing: a retrospective chart review in the United Arab Emirates. Mult Scler Relat Disord 2016; 9: 73–79.

76.

Deleu

Mir

Al Tabouki

, et al. Prevalence, demographics and clinical characteristics of multiple sclerosis in Qatar. Mult Scler 2013; 19: 816–819.

77.

Belbasis

Bellou

Evangelou

, et al. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 2015; 14: 263–273.

78.

Wallin

Culpepper

Nichols

, et al. Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18: 269–285.

79.

Heydarpour

Khoshkish

Abtahi

, et al. Multiple sclerosis epidemiology in Middle East and North Africa: a systematic review and meta-analysis. Neuroepidemiology 2015; 44: 232–244.

80.

Alroughani

Al-Jumah

MA.

The need for a multiple sclerosis registry in the Gulf Region.

Neurosciences (Riyadh) 2014; 19: 85–86.

81.

Bach

JF.

The effect of infections on susceptibility to autoimmune and allergic diseases.

N Engl J Med 2002; 347: 911–920.

82.

Fleming

Cook

TD.

Multiple sclerosis and the hygiene hypothesis.

Neurology 2006; 67: 2085–2086.

83.

Wendel‐Haga

Celius

EG.

Is the hygiene hypothesis relevant for the risk of multiple sclerosis?.

Acta Neurol Scand 2017; 136: 26–30.

Association of infections with multiple sclerosis in Gulf Cooperation Council countries: a review

Abstract

Keywords

Introduction

Methods

Results

Measles

Varicella-zoster virus (VZV)

Mumps

Epstein–Barr virus (EBV)

Human herpesvirus-6 (HHV-6)

Discussion

Study limitations

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interest

Funding

ORCID iD

References