Journal of family & community medicine · 2025
Триггеры рецидива множественных склерозов в Саудовской Аравии: исследование поперечного сечения.
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Alshamrani Foziah J, Zafar Azra, AlSheikh Mona H, Alamri Abdullah S, Alshammari Alaa K, Alajmi Modhi S, Zeeshan Mohammad A, Alghnimi Ibrahim A, Fardan Ghadeer M, Almuaigel Mohammed F
Аннотация
Множественный склероз (MS) — аутоиммунная демиелинирующая болезнь, воздействующая на центральную нервную систему. Возвращение MS связано с появлением новых неврологических симптомов, связанных с MS, или ухудшением существующих симптомов по меньшей мере в течение 24 часов, по меньшей мере через 30 дней после начала последнего рецидива. Стресс, отсутствие сна, высокая/низкая температура, инфекционные заболевания, пропускаемые дозы препаратов для борьбы со СПИДом, высокие высоты, использование антибиотических средств, использование оральных противозачаточных средств и курение являются возможными стимулами для рецидива распространения MS. Насколько нам известно, в Саудовской Аравии не было выявлено ни одного случая рецидива НР.МАТЕРИАЛЫ И МЕТОДЫ: Это перекрестное исследование проводилось среди саудовских пациентов в возрасте 16 лет и старше, которые отвечали критериям повторного образования эмиссий MS (RRMS) или вторичных MS (SPMS). Пациенты были завербованы через общество Arfa MS. Собранные данные включали демографическую информацию, тип MS, возраст диагноза, историю семьи MS и возможные пусковые факторы. Медицинская информация была извлечена из электронных файлов, в то время как информация о пусковых факторах была получена пациентами в ходе опроса пациентов. Категории переменных были представлены в виде частоты и процентной доли, в то время как среднее и стандартное отклонение рассчитывалось для постоянных переменных. Для сопоставления данных по категорическим переменным использовался тест " Чиквар " . Результаты: В этом исследовании приняли участие в общей сложности 305 пациентов с НР. Большинство участников составляли женщины (61,6 процента) и были в возрасте более 30 лет (63,9 процента); 89,5 процента имели ОРМС и 11,1 процента пациентов имели семейную историю НРМ. Наиболее часто участники сообщали о том, что они испытывают беспокойство и стресс (77,4%). Беспокойство и стресс, лишение сна и беременность или грудное вскармливание в значительной степени характерны для респондентов в возрасте <30 лет (P < 0,05). ЗАКЛЮЧЕНИЕ: Это исследование является первым шагом на пути к выявлению пусковых факторов для рецидива использования MS в Саудовской Аравии. Она будет оказывать поддержку расширению исследований в целях разработки стратегий, направленных на то, чтобы избежать этих факторов.
Оригинал публикации
Triggers for multiple sclerosis relapse in Saudi Arabia: An exploratory cross-sectional study.
BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease that affects the central nervous system. Relapse of MS involves the development of new MS-related neurological symptoms or the worsening of existing symptoms for at least 24 h, at least 30 days after the start of the last relapse. Stress, lack of sleep, high/low temperatures, infections, missed doses of MS medications, high-altitudes, antibiotic use, the use of oral contraceptives, and smoking are possible triggers for an MS relapse. To our knowledge, no studies have identified triggers for MS relapse in Saudi Arabia.
MATERIALS AND METHODS: This cross-sectional study was conducted among Saudi MS patients aged 16 years or older who met the criteria of relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS). Patients were recruited through Arfa MS society. Data collected included demographic information, type of MS, age at diagnosis, family history of MS, and possible trigger factors. Medical information was abstracted from electronic files whereas information about trigger factors was patients obtained through interviewing the patients. Categorical variables were presented as frequency and percentage, whereas mean and standard deviation were calculated for continuous variables. Chi-square test was used to compare the data across categorical variables.
RESULTS: A total of 305 MS patients were included in the study. Majority of the participants were females (61.6%) and were aged >30 years (63.9%); 89.5% had RRMS and 11.1% patients had a family history of MS. Anxiety and stress were the most frequently reported triggers by the participants (77.4%). Anxiety and stress, sleep deprivation, and pregnancy or breastfeeding were significantly common in respondents aged <30 years (P < 0.05).
CONCLUSION: This study is the first step toward identifying the triggers for MS relapse in Saudi Arabia. It will support the expansion of research for the establishment of strategies to avoid these triggers.
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Introduction
Multiple sclerosis (MS), an autoimmune demyelinating inflammatory disease that affects the central nervous system (CNS),[ 1 ] is considered one of the leading causes of disability in young people.[ 2 ] The etiology of the disease is unknown; however, genetic, environmental, and infectious factors are thought to contribute to MS.[ 3 ] The disease is associated with a vast spectrum of clinical manifestations, posing a diagnostic challenge for neurologists.[ 4 ] The primary disabling symptoms include mood disorder, cognitive impairment, and sexual dysfunction.[ 5 6 ]
Relapses are episodes of new MS neurological symptoms or the worsening of existing symptoms that last for at least 24 h and occur at least 30 days after the start of the last relapse. Symptoms such as heat, stress, or infection so often overlap in MS and pseudoexacerbation[ 1 2 3 4 5 6 7 ] that it is hard to differentiate between the two. Relapses are clinical correlates of neurophysiologically impaired axonal conductivity triggered by flare-ups of localized autoimmune processes within the CNS.[ 8 ]
The literature on triggering factors for acute MS relapse has increased substantially in recent years.[ 9 ] Stress, lack of sleep, high/low environmental temperatures, poor compliance to MS medication, climbing to high altitudes, antibiotic use, the use of oral contraceptives, and smoking are all possible triggers of MS relapse.[ 10 11 12 13 14 15 ]
Upon reviewing the literature, no study that analyzed the possible triggering factors for acute exacerbation/relapse of MS in Saudi Arabia was found. Therefore, this study aimed to identify the triggers for MS relapse in Saudi Arabia.
Materials and Methods
This was a cross-sectional study conducted in all regions of Saudi Arabia between April and June 2023. Patients were recruited through Arfa MS society (a community institution that gathers MS patients across all regions of Saudi Arabia). Ethical approval was obtained from the Institutional Review Board vide Letter NO.2023-01-117 dated 12/3/2023, and written informed consent was taken from all patients in the study.
The study included Saudi MS patients of both sexes residing in Saudi Arabia, who met the following inclusion criteria: relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS) following the 2010 revised McDonald criteria for MS diagnosis[ 16 ] and aged ≥16 years. Excluded were patients diagnosed with a type of MS other than RRMS or SPMS, those who had had pseudorelapse, or an illness before the relapse in order to differentiate between relapse and pseudorelapse, and those presenting with other comorbidities that might resemble a relapse (e.g., psychiatric disorder, degenerative disease, cerebrovascular disease, and vitamin deficiency), and identified by the E-files and by the patients themselves. Conditions like depression, cardiovascular disease, autoimmune disorders, and sleep disturbances can amplify relapse risks.
Based on Qualtrics, a sample-size calculator, a minimum of 259 RRMS and SPMS patients with a 95% confidence interval and margin error was placed at 5% decided by the authors were required from the general MS population in Saudi Arabia. In 2016, the reported number of MS patients in Saudi Arabia was 8235.[ 17 ]
The patients contact information in Saudi Arabia was obtained from the Arfa Society, and the patients were contacted for consent and given the date of the interview. During the interview, the questionnaire addressed the following variables: independent variables included possible trigger factors, dependent variables included MS relapse, and covariants included age, sex, family history, marital status, education level, employment status, and medical comorbidities. The medical records number was obtained from the patient, so that the electronic files could be reviewed. The reliability coefficient was found to be >0.6, using a Cronbach’s alpha analysis that was conducted to determine the internal consistency and reliability of our data related to “Triggers for MS relapse.”
For anxiety and the stressor, we asked the patient if he/she had any stressful event or something that caused him or her anxiety before the relapse, for example, divorce, marriage, death of a relative, bad news, and examinations. As regards high altitude, we asked if they had travelled by airplane, or they had been to places or cities at high attitudes before the relapse. As regards special diet, we asked the patient if he/she was on a specific diet, such as a low carbohydrate diet and keto diet before the start of the relapse. With regard to dehydration, we asked the patients if they were not drinking enough water in the period before the relapse (proper amount of fluid was based on the men 2.5 L/day and women 2 L/day).[ 18 ]
The collected data were analyzed using IBM SPSS, version 21 (IBM Corp., Armonk, New York, United States of America). Categorical variables were presented as frequency and percentages. Continuous variables (age and age at onset) were presented as mean (standard deviation [SD]). Pearson’s Chi-square tests were used to compare the data. Differences with a P < 0.05 were considered statistically significant.
The participants’ data were coded, and the data files were password-secured. For reasons of confidentiality, the study data were available only to the authors of this research. The data were available on reasonable request to the journal.
Results
The final analysis was on 305 MS patients whose demographic characteristics are presented in Table 1 . The majority were women ( n = 188, 61.6%), with a male-to-female ratio of 1:1.6. Most participants ( n = 195, 63.9%) were aged >30 years. The participants’ mean age was 34.4 (SD 8.0) years, and the mean age at onset of MS was 26.7 (SD 6.9) years. Most respondents were married ( n = 181, 59.3%), 156 (51.1%) had a bachelor’s degree, and 137 (44.9%) were unemployed.
Table 1 Characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305) Characteristics3 N (%) Sex Male 117 (38.4) Female 188 (61.6) Age (years), mean (SD) 34.4 (8.0) ≤4 110 (36.1) 31–41 166 (54.4) >45 29 (9.5) Highest academic level Elementary school diploma 40 (13.1) High school or intermediate 93 (30.5) Bachelor’s 156 (51.1) Postgraduate 16 (5.2) Employment status Student 21 (6.9) Employed 131 (43.0) Unemployed 137 (44.9) Retired 16 (5.2) Marital status Single 98 (32.1) Married 181 (59.3) Divorced or widowed 26 (8.5) Region Eastern 137 (44.9) Central 89 (29.2) Western 49 (16.1) Southern 22 (7.2) Northern 7 (2.3) SD=Standard deviation
Characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305)
SD=Standard deviation
Clinical characteristics are presented in Table 2 . RRMS was diagnosed in 273 (89.5%) patients, and 32 (10.9%) were diagnosed with SPMS. A family history of MS was found in 34 (11.1%) participants; 13 (4.3%) patients had a history of drug abuse, 62 (20.3%) patients were smokers, while only 4 (1.3%) reported the use of alcohol.
Table 2 Clinical characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305) Characteristics Type of multiple sclerosis N (%) Relapsing-remitting 273 (89.5) Secondary-progressive 32 (10.5) Family history of MS 34 (11.1) Drug abuse history 13 (4.3) Smoking 62 (20.3) Alcohol use 4 (1.3) MS=Multiple sclerosis
Clinical characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305)
MS=Multiple sclerosis
Trigger factors for MS relapse are shown in Table 3 and represented in Figure 1 . Anxiety and stress were the most frequently reported triggers by the participants ( n = 236, 77.4%), followed by an increase in the surrounding temperature ( n = 201, 65.9%), sleep deprivation ( n = 157, 51.5%), and missing doses of MS medication ( n = 93, 30.5%).
Table 3 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients, Saudi Arabia, 2023 ( n =305) Trigger factors N (%) Anxiety and stress 236 (77.4) Increase ambient temperature 201 (65.9) Sleep deprivation 157 (51.5) Physical exertion 157 (51.5) Recent illness (flu symptoms, etc.) 96 (31.5) Missed dose of MS medication 93 (30.5) Changes in medical type 77 (25.2) Dehydration 62 (20.3) Following a special diet 48 (15.7) High-altitude climbing 27 (8.9) Pregnancy or breastfeeding 26 (8.5) Recent vaccine exposure 11 (3.6) OCP use 6 (2.0) MS=Multiple sclerosis, OCP=Oral contraceptive pill
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients, Saudi Arabia, 2023 ( n =305)
MS=Multiple sclerosis, OCP=Oral contraceptive pill
Relapse trigger factors of multiple sclerosis ( n = 305). MS=Multiple sclerosis, OCP = Oral contraceptive pill
A comparison of MS relapse trigger factors between men and women is presented in Table 4 . Trigger factors of men and women were similar. A comparison of trigger factors between the age groups (≤30 vs. >30 years) is presented in Table 5 . Anxiety and stress, sleep deprivation, and pregnancy or breastfeeding were significantly common in respondents aged ≤30 years ( P < 0.05).” All other triggers were similar between the age groups. A comparison of MS relapse triggers with MS Types is presented in Table 6 . Several relapse triggers were found to be significantly more common in SPMS patients than those with RRMS. These include an increase in the ambient temperature, recent illness (e.g., flu symptoms), changes in medication type, and dehydration ( P < 0.05). These findings suggested that SPMS patients may have a heightened sensitivity to certain triggers, which underlines the need for targeted management strategies.
Table 4 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by gender, Saudi Arabia, 2023 ( n =305) Trigger factors Male N (%) Female N (%)
P-value
OR (CI 95%) Anxiety and stress 86 (73.5) 150 (79.8) 0.19 0.7 (0.4–1.2) Sleep deprivation 62 (53.0) 95 (50.5) 0.7 1.1 (0.7–1.7) Increase in ambient temperature 80 (68.4) 121 (64.4) 0.4 1.2 (0.7–1.9) High altitude climbing 6 (5.1) 21 (11.2) 0.07 0.14 (0.2–1.1) Missed dose of MS medication 35 (29.9) 58 (30.9) 0.7 0.9 (0.6–1.5) Changes in medication type 24 (20.5) 53 (28.2) 0.2 0.7 (0.4–1.2) OCP use NA 6 (3.2) NA NA Pregnancy or breastfeeding NA 26 (13.8) NA NA Recent vaccination exposure 7 (6.0) 4 (2.1) 0.14 2.3 (0.7–7.5) Dehydration 22 (18.8) 40 (21.3) 0.6 0.8 (0.5–1.5) Physical exertion 65 (55.6) 92 (48.9) 0.3 1.3 (0.8–2.0) Following a special diet 20 (17.1) 28 (14.9) 0.6 1.2 (0.6–2.2) CI=Confidence interval, MS=Multiple sclerosis, NA=Not applicable, OCP=Oral contraceptive pill, OR=Odds ratio
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by gender, Saudi Arabia, 2023 ( n =305)
CI=Confidence interval, MS=Multiple sclerosis, NA=Not applicable, OCP=Oral contraceptive pill, OR=Odds ratio
Table 5 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by age, Saudi Arabia, 2023 ( n =305) Trigger factors Age (years)
P-value
OR (CI 95%)*
≤30 N (%) >30 N (%) Anxiety and stress 76 (69.1) 160 (82.1) 0.011 0.5 (03–0.9) Sleep deprivation 43 (39.1) 114 (58.5) 0.002 0.5 (0.3–0.8) Increase in ambient temperature 75 (68.2) 126 (64.6) 0.6 1.1 (0.7–1.8) High-altitude climbing 6 (5.5) 21 (10.8) 0.1 0.5 (0.2–1.2) Missed dose of MS medication 32 (29.1) 61 (31.3) 0.8 1 (1.6–0.6) Change in medication type 28 (25.5) 49 (25.1) 0.9 1 (0.6–1.5) OCP use 2 (1.8) 4 (2.1) 0.9 0.9 (0.2–4.9) Pregnancy or breastfeeding 4 (3.6) 22 (11.3) 0.021 0.3 (0.1–0.9) Recent vaccination exposure 3 (2.7) 8 (4.1) 0.8 0.9 (0.3–2.9) Dehydration 25 (22.7) 37 (19.0) 0.4 1.3 (0.7–2.3) Physical exertion 50 (45.5) 107 (54.7) 0.13 0.7 (0.4–1.1) Following a special diet 17 (15.5) 31 (15.9) 0.9 1 (0.5–1.8) *Age ≤30 is a reference group for OR. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by age, Saudi Arabia, 2023 ( n =305)
*Age ≤30 is a reference group for OR. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio
Table 6 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by MS type, Saudi Arabia, 2023 ( n =305) Trigger factors MS types
P-value
OR (CI 95)*
Relapsing-remitting MS N (%) Secondary-progressive MS N (%) Anxiety and stress 208 (76.2) 28 (87.5) 0.0148 2.2 (0.7–6.5) Sleep deprivation 138 (50.6) 19 (59.4) 0.35 1.4 (0.68–3) Increase in ambient temperature 173 (63.4) 28 (87.5) 0.006 4.05 (1.4–11.9) High-altitude climbing 22 (8.1) 5 (15.6) 0.15 2.1 (0.74–6) Recent illness (flu symptoms, etc.) 78 (28.6) 18 (56.3) 0.001 3.2 (1.5–6.8) Missed dose of MS medication 79 (28.9) 14 (43.8) 0.085 1.9 (0.91–4.8) Changes in medication type 64 (23.4) 13 (40.6) 0.034 2.2 (1.05–4.8) OCP use 6 (2.2) 0 0.397 NA Pregnancy or breastfeeding 24 (8.8) 2 (6.3) 0.63 0.7 (0.16–3.1) Recent vaccination exposure 10 (3.7) 1 (3.1) 0.88 0.85 (0.11–6.9) Dehydration 51 (18.7) 11 (34.4) 0.037 2.3 (1.03–6.03) Physical exertion 139 (50.9) 18 (56.3) 0.57 1.24 (0.6–2.6) Following a special diet 40 (14.7) 8 (25.0) 0.128 1.94 (0.82–4.6) *Relapsing-remitting MS is a reference group. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio, NA=Not applicable
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by MS type, Saudi Arabia, 2023 ( n =305)
*Relapsing-remitting MS is a reference group. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio, NA=Not applicable
Discussion
Previously, the Saudi Arabian region was thought to have a low prevalence of MS, but in the last few years, studies have shown a significant increase in the number of MS patients in Saudi Arabia.[ 17 ] Since this was a community-based study, it is likely to reflect the true situation in Saudi Arabia. Our study’s aim was to evaluate the most common MS relapse triggers in Saudi Arabia. A sample of 305 MS patients, with the average age of 34 years, was included and an average age of 26 years at the onset of MS was revealed. The majority of the study participants were aged >30 years. Of this sample, 61.6% of patients were female, similar to the proportion reported in a previous study.[ 19 ] RRMS was the diagnosis for 89.5% of the respondents, also consistent with what was reported in a previous study.[ 1 ]
Earlier studies had focused on MS relapse triggers, but none had analyzed these in Saudi Arabia. It is envisaged that the present research would fill this gap in the scientific literature. In the present study, anxiety and stress were the most common triggering factors, as reported by 77.4% of the respondents. This rate is consistent with the results of a systematic review conducted by McKay et al .,[ 15 ] whose aim was to identify factors associated with MS exacerbation. They reported that anxiety and stress were associated with an increased relapse rate. On comparing triggering factors for MS relapse between age groups, we found that anxiety and stress were significantly common in respondents aged ≤30 years ( P < 0.05). The second most prevalent trigger reported in our study was a rise in ambient temperature, (reported in 65.9% of the participants). The association between the ambient temperature and the acute worsening of physical functioning in RRMS ( P = 0.028) and SPMS ( P = 0.026) patients has been documented in previous studies.[ 20 ]
Sleep deprivation was reported as a trigger by 51.5% of the respondents and was significantly more common in respondents aged >30 years ( P < 0.05). The relationship between poor sleep quality and exacerbation of MS is well documented, and a significant increase in the rate of MS relapse following sleep deprivation has been reported, particularly in RRMS patients ( P < 0.001).[ 21 ]
The likelihood of relapse was found to be significantly lower in patients who adhere to disease modifying therapy (DMT) than in those who did not. Burks et al .,[ 22 ] reported that patients who adhered to DMT were less likely to have a relapse ( P < 0.001). In comparison, our analysis found that 30.5% of the respondents had not adhered to their MS medication before the MS relapse. However, we found no association between adherence and new relapse.
The influence of high altitude on preexisting neurological conditions was studied by Hsieh et al .,[ 13 ] who reported a case of a United States Air Force serviceman who had an MS relapse in day 1 of climbing Mount Fuji (3776 m), suggesting a possible association between these factors. This finding is supported by our study finding that 27 (8.9%) of respondents reported relapses after being in locations of high altitude.
Oral contraceptive pill (OCP) users have been reported to have a lower relapse rate than those who have never used OCPs ( P = 0.031).[ 23 ] This is inconsistent with our findings, although only 2% of the respondents in our survey reported OCP use.
Exposure to vaccines, such as those for hepatitis B, tetanus, and influenza, in the preceding 2 months is not associated with increased MS relapse rates,[ 15 ] and several studies have suggested that MS relapse rate decreases with vaccination.[ 24 ] In our study, 11 (3.6%) respondents reported having a relapse after being vaccinated.
Pregnancy and breastfeeding have been reported to have a protective effect against MS exacerbation/relapse.[ 15 ] However, 26 of the 188 women in the present study reported that their MS relapses were triggered by pregnancy and/or breastfeeding.
Hydration status was reported to be correlated with fatigue in patients with MS ( P = 0.022),[ 25 ] and it was thus concluded that better hydration might be beneficial for MS patients experiencing fatigue. This is consistent with our study finding: 62 (20.3%) respondents reported dehydration as a trigger for MS relapse.
A systematic review of randomized controlled trials reported that exercise has a protective effect in MS patients.[ 26 ] In contrast, Tallner et al .,[ 27 ] found no association between MS relapse rate and the level of physical activity ( P = 0.0279). Fifty-one percent of the respondents in our study noticed exacerbation of their MS disease during physical exertion. We found that exercise as a triggering factor was similar between age groups and between men and women.
A total of 48 (15.7%) respondents reported that diet acted as a triggering factor for MS relapse, supporting several previous studies. A large study on 2469 MS patients found that healthy dietary habits were associated with a lower rate of MS exacerbation and disability ( P < 0.001).[ 28 ] Saturated fat intake was associated with an increased MS relapse rate, while increasing vegetable intake by one cup per day was associated with a 50% reduction in MS relapse rate.[ 29 ] Conversely, a low-fat diet was found to be associated with a lower MS relapse rate and less fatigue.[ 30 ] Moreover, the same study showed a significant improvement in the expanded disability status scale with the intake of a low-fat diet.
In this study, 77 (25.2%) respondents reported that a change in DMT type was the trigger for their relapses. This is consistent with the findings of a study that showed the impact of switching treatment from natalizumab to fingolimod on MS, with reactivation and relapse during the washout period and shortly after initiating the fingolimod treatment. The study concluded that a washout period shorter than 3 months was associated with a lower risk of relapse ( P = 0.001).[ 31 ]
The current study has helped establish an understanding of possible modifiable triggers for MS relapse. Avoiding these triggers would be the best approach for disease control. Further studies are required to identify other triggering factors, and radiological studies are needed to assess neurological changes during/after relapse.
Conclusion
This study is the first step taken to identify the triggers for MS relapse in Saudi Arabia. It will support further research to establish strategies to avoid these triggers.
Conflicts of interest
There are no conflicts of interest.
Multiple sclerosis (MS), an autoimmune demyelinating inflammatory disease that affects the central nervous system (CNS),[ 1 ] is considered one of the leading causes of disability in young people.[ 2 ] The etiology of the disease is unknown; however, genetic, environmental, and infectious factors are thought to contribute to MS.[ 3 ] The disease is associated with a vast spectrum of clinical manifestations, posing a diagnostic challenge for neurologists.[ 4 ] The primary disabling symptoms include mood disorder, cognitive impairment, and sexual dysfunction.[ 5 6 ]
Relapses are episodes of new MS neurological symptoms or the worsening of existing symptoms that last for at least 24 h and occur at least 30 days after the start of the last relapse. Symptoms such as heat, stress, or infection so often overlap in MS and pseudoexacerbation[ 1 2 3 4 5 6 7 ] that it is hard to differentiate between the two. Relapses are clinical correlates of neurophysiologically impaired axonal conductivity triggered by flare-ups of localized autoimmune processes within the CNS.[ 8 ]
The literature on triggering factors for acute MS relapse has increased substantially in recent years.[ 9 ] Stress, lack of sleep, high/low environmental temperatures, poor compliance to MS medication, climbing to high altitudes, antibiotic use, the use of oral contraceptives, and smoking are all possible triggers of MS relapse.[ 10 11 12 13 14 15 ]
Upon reviewing the literature, no study that analyzed the possible triggering factors for acute exacerbation/relapse of MS in Saudi Arabia was found. Therefore, this study aimed to identify the triggers for MS relapse in Saudi Arabia.
Materials and Methods
This was a cross-sectional study conducted in all regions of Saudi Arabia between April and June 2023. Patients were recruited through Arfa MS society (a community institution that gathers MS patients across all regions of Saudi Arabia). Ethical approval was obtained from the Institutional Review Board vide Letter NO.2023-01-117 dated 12/3/2023, and written informed consent was taken from all patients in the study.
The study included Saudi MS patients of both sexes residing in Saudi Arabia, who met the following inclusion criteria: relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS) following the 2010 revised McDonald criteria for MS diagnosis[ 16 ] and aged ≥16 years. Excluded were patients diagnosed with a type of MS other than RRMS or SPMS, those who had had pseudorelapse, or an illness before the relapse in order to differentiate between relapse and pseudorelapse, and those presenting with other comorbidities that might resemble a relapse (e.g., psychiatric disorder, degenerative disease, cerebrovascular disease, and vitamin deficiency), and identified by the E-files and by the patients themselves. Conditions like depression, cardiovascular disease, autoimmune disorders, and sleep disturbances can amplify relapse risks.
Based on Qualtrics, a sample-size calculator, a minimum of 259 RRMS and SPMS patients with a 95% confidence interval and margin error was placed at 5% decided by the authors were required from the general MS population in Saudi Arabia. In 2016, the reported number of MS patients in Saudi Arabia was 8235.[ 17 ]
The patients contact information in Saudi Arabia was obtained from the Arfa Society, and the patients were contacted for consent and given the date of the interview. During the interview, the questionnaire addressed the following variables: independent variables included possible trigger factors, dependent variables included MS relapse, and covariants included age, sex, family history, marital status, education level, employment status, and medical comorbidities. The medical records number was obtained from the patient, so that the electronic files could be reviewed. The reliability coefficient was found to be >0.6, using a Cronbach’s alpha analysis that was conducted to determine the internal consistency and reliability of our data related to “Triggers for MS relapse.”
For anxiety and the stressor, we asked the patient if he/she had any stressful event or something that caused him or her anxiety before the relapse, for example, divorce, marriage, death of a relative, bad news, and examinations. As regards high altitude, we asked if they had travelled by airplane, or they had been to places or cities at high attitudes before the relapse. As regards special diet, we asked the patient if he/she was on a specific diet, such as a low carbohydrate diet and keto diet before the start of the relapse. With regard to dehydration, we asked the patients if they were not drinking enough water in the period before the relapse (proper amount of fluid was based on the men 2.5 L/day and women 2 L/day).[ 18 ]
The collected data were analyzed using IBM SPSS, version 21 (IBM Corp., Armonk, New York, United States of America). Categorical variables were presented as frequency and percentages. Continuous variables (age and age at onset) were presented as mean (standard deviation [SD]). Pearson’s Chi-square tests were used to compare the data. Differences with a P < 0.05 were considered statistically significant.
The participants’ data were coded, and the data files were password-secured. For reasons of confidentiality, the study data were available only to the authors of this research. The data were available on reasonable request to the journal.
Results
The final analysis was on 305 MS patients whose demographic characteristics are presented in Table 1 . The majority were women ( n = 188, 61.6%), with a male-to-female ratio of 1:1.6. Most participants ( n = 195, 63.9%) were aged >30 years. The participants’ mean age was 34.4 (SD 8.0) years, and the mean age at onset of MS was 26.7 (SD 6.9) years. Most respondents were married ( n = 181, 59.3%), 156 (51.1%) had a bachelor’s degree, and 137 (44.9%) were unemployed.
Table 1 Characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305) Characteristics3 N (%) Sex Male 117 (38.4) Female 188 (61.6) Age (years), mean (SD) 34.4 (8.0) ≤4 110 (36.1) 31–41 166 (54.4) >45 29 (9.5) Highest academic level Elementary school diploma 40 (13.1) High school or intermediate 93 (30.5) Bachelor’s 156 (51.1) Postgraduate 16 (5.2) Employment status Student 21 (6.9) Employed 131 (43.0) Unemployed 137 (44.9) Retired 16 (5.2) Marital status Single 98 (32.1) Married 181 (59.3) Divorced or widowed 26 (8.5) Region Eastern 137 (44.9) Central 89 (29.2) Western 49 (16.1) Southern 22 (7.2) Northern 7 (2.3) SD=Standard deviation
Characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305)
SD=Standard deviation
Clinical characteristics are presented in Table 2 . RRMS was diagnosed in 273 (89.5%) patients, and 32 (10.9%) were diagnosed with SPMS. A family history of MS was found in 34 (11.1%) participants; 13 (4.3%) patients had a history of drug abuse, 62 (20.3%) patients were smokers, while only 4 (1.3%) reported the use of alcohol.
Table 2 Clinical characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305) Characteristics Type of multiple sclerosis N (%) Relapsing-remitting 273 (89.5) Secondary-progressive 32 (10.5) Family history of MS 34 (11.1) Drug abuse history 13 (4.3) Smoking 62 (20.3) Alcohol use 4 (1.3) MS=Multiple sclerosis
Clinical characteristics of multiple sclerosis patients in Saudi Arabia, 2023 ( n =305)
MS=Multiple sclerosis
Trigger factors for MS relapse are shown in Table 3 and represented in Figure 1 . Anxiety and stress were the most frequently reported triggers by the participants ( n = 236, 77.4%), followed by an increase in the surrounding temperature ( n = 201, 65.9%), sleep deprivation ( n = 157, 51.5%), and missing doses of MS medication ( n = 93, 30.5%).
Table 3 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients, Saudi Arabia, 2023 ( n =305) Trigger factors N (%) Anxiety and stress 236 (77.4) Increase ambient temperature 201 (65.9) Sleep deprivation 157 (51.5) Physical exertion 157 (51.5) Recent illness (flu symptoms, etc.) 96 (31.5) Missed dose of MS medication 93 (30.5) Changes in medical type 77 (25.2) Dehydration 62 (20.3) Following a special diet 48 (15.7) High-altitude climbing 27 (8.9) Pregnancy or breastfeeding 26 (8.5) Recent vaccine exposure 11 (3.6) OCP use 6 (2.0) MS=Multiple sclerosis, OCP=Oral contraceptive pill
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients, Saudi Arabia, 2023 ( n =305)
MS=Multiple sclerosis, OCP=Oral contraceptive pill
Relapse trigger factors of multiple sclerosis ( n = 305). MS=Multiple sclerosis, OCP = Oral contraceptive pill
A comparison of MS relapse trigger factors between men and women is presented in Table 4 . Trigger factors of men and women were similar. A comparison of trigger factors between the age groups (≤30 vs. >30 years) is presented in Table 5 . Anxiety and stress, sleep deprivation, and pregnancy or breastfeeding were significantly common in respondents aged ≤30 years ( P < 0.05).” All other triggers were similar between the age groups. A comparison of MS relapse triggers with MS Types is presented in Table 6 . Several relapse triggers were found to be significantly more common in SPMS patients than those with RRMS. These include an increase in the ambient temperature, recent illness (e.g., flu symptoms), changes in medication type, and dehydration ( P < 0.05). These findings suggested that SPMS patients may have a heightened sensitivity to certain triggers, which underlines the need for targeted management strategies.
Table 4 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by gender, Saudi Arabia, 2023 ( n =305) Trigger factors Male N (%) Female N (%)
P-value
OR (CI 95%) Anxiety and stress 86 (73.5) 150 (79.8) 0.19 0.7 (0.4–1.2) Sleep deprivation 62 (53.0) 95 (50.5) 0.7 1.1 (0.7–1.7) Increase in ambient temperature 80 (68.4) 121 (64.4) 0.4 1.2 (0.7–1.9) High altitude climbing 6 (5.1) 21 (11.2) 0.07 0.14 (0.2–1.1) Missed dose of MS medication 35 (29.9) 58 (30.9) 0.7 0.9 (0.6–1.5) Changes in medication type 24 (20.5) 53 (28.2) 0.2 0.7 (0.4–1.2) OCP use NA 6 (3.2) NA NA Pregnancy or breastfeeding NA 26 (13.8) NA NA Recent vaccination exposure 7 (6.0) 4 (2.1) 0.14 2.3 (0.7–7.5) Dehydration 22 (18.8) 40 (21.3) 0.6 0.8 (0.5–1.5) Physical exertion 65 (55.6) 92 (48.9) 0.3 1.3 (0.8–2.0) Following a special diet 20 (17.1) 28 (14.9) 0.6 1.2 (0.6–2.2) CI=Confidence interval, MS=Multiple sclerosis, NA=Not applicable, OCP=Oral contraceptive pill, OR=Odds ratio
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by gender, Saudi Arabia, 2023 ( n =305)
CI=Confidence interval, MS=Multiple sclerosis, NA=Not applicable, OCP=Oral contraceptive pill, OR=Odds ratio
Table 5 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by age, Saudi Arabia, 2023 ( n =305) Trigger factors Age (years)
P-value
OR (CI 95%)*
≤30 N (%) >30 N (%) Anxiety and stress 76 (69.1) 160 (82.1) 0.011 0.5 (03–0.9) Sleep deprivation 43 (39.1) 114 (58.5) 0.002 0.5 (0.3–0.8) Increase in ambient temperature 75 (68.2) 126 (64.6) 0.6 1.1 (0.7–1.8) High-altitude climbing 6 (5.5) 21 (10.8) 0.1 0.5 (0.2–1.2) Missed dose of MS medication 32 (29.1) 61 (31.3) 0.8 1 (1.6–0.6) Change in medication type 28 (25.5) 49 (25.1) 0.9 1 (0.6–1.5) OCP use 2 (1.8) 4 (2.1) 0.9 0.9 (0.2–4.9) Pregnancy or breastfeeding 4 (3.6) 22 (11.3) 0.021 0.3 (0.1–0.9) Recent vaccination exposure 3 (2.7) 8 (4.1) 0.8 0.9 (0.3–2.9) Dehydration 25 (22.7) 37 (19.0) 0.4 1.3 (0.7–2.3) Physical exertion 50 (45.5) 107 (54.7) 0.13 0.7 (0.4–1.1) Following a special diet 17 (15.5) 31 (15.9) 0.9 1 (0.5–1.8) *Age ≤30 is a reference group for OR. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by age, Saudi Arabia, 2023 ( n =305)
*Age ≤30 is a reference group for OR. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio
Table 6 Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by MS type, Saudi Arabia, 2023 ( n =305) Trigger factors MS types
P-value
OR (CI 95)*
Relapsing-remitting MS N (%) Secondary-progressive MS N (%) Anxiety and stress 208 (76.2) 28 (87.5) 0.0148 2.2 (0.7–6.5) Sleep deprivation 138 (50.6) 19 (59.4) 0.35 1.4 (0.68–3) Increase in ambient temperature 173 (63.4) 28 (87.5) 0.006 4.05 (1.4–11.9) High-altitude climbing 22 (8.1) 5 (15.6) 0.15 2.1 (0.74–6) Recent illness (flu symptoms, etc.) 78 (28.6) 18 (56.3) 0.001 3.2 (1.5–6.8) Missed dose of MS medication 79 (28.9) 14 (43.8) 0.085 1.9 (0.91–4.8) Changes in medication type 64 (23.4) 13 (40.6) 0.034 2.2 (1.05–4.8) OCP use 6 (2.2) 0 0.397 NA Pregnancy or breastfeeding 24 (8.8) 2 (6.3) 0.63 0.7 (0.16–3.1) Recent vaccination exposure 10 (3.7) 1 (3.1) 0.88 0.85 (0.11–6.9) Dehydration 51 (18.7) 11 (34.4) 0.037 2.3 (1.03–6.03) Physical exertion 139 (50.9) 18 (56.3) 0.57 1.24 (0.6–2.6) Following a special diet 40 (14.7) 8 (25.0) 0.128 1.94 (0.82–4.6) *Relapsing-remitting MS is a reference group. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio, NA=Not applicable
Report of relapse in multiple sclerosis after one or more of the trigger factors among Saudi MS patients by MS type, Saudi Arabia, 2023 ( n =305)
*Relapsing-remitting MS is a reference group. CI=Confidence interval, MS=Multiple sclerosis, OCP=Oral contraceptive pill, OR=Odds ratio, NA=Not applicable
Discussion
Previously, the Saudi Arabian region was thought to have a low prevalence of MS, but in the last few years, studies have shown a significant increase in the number of MS patients in Saudi Arabia.[ 17 ] Since this was a community-based study, it is likely to reflect the true situation in Saudi Arabia. Our study’s aim was to evaluate the most common MS relapse triggers in Saudi Arabia. A sample of 305 MS patients, with the average age of 34 years, was included and an average age of 26 years at the onset of MS was revealed. The majority of the study participants were aged >30 years. Of this sample, 61.6% of patients were female, similar to the proportion reported in a previous study.[ 19 ] RRMS was the diagnosis for 89.5% of the respondents, also consistent with what was reported in a previous study.[ 1 ]
Earlier studies had focused on MS relapse triggers, but none had analyzed these in Saudi Arabia. It is envisaged that the present research would fill this gap in the scientific literature. In the present study, anxiety and stress were the most common triggering factors, as reported by 77.4% of the respondents. This rate is consistent with the results of a systematic review conducted by McKay et al .,[ 15 ] whose aim was to identify factors associated with MS exacerbation. They reported that anxiety and stress were associated with an increased relapse rate. On comparing triggering factors for MS relapse between age groups, we found that anxiety and stress were significantly common in respondents aged ≤30 years ( P < 0.05). The second most prevalent trigger reported in our study was a rise in ambient temperature, (reported in 65.9% of the participants). The association between the ambient temperature and the acute worsening of physical functioning in RRMS ( P = 0.028) and SPMS ( P = 0.026) patients has been documented in previous studies.[ 20 ]
Sleep deprivation was reported as a trigger by 51.5% of the respondents and was significantly more common in respondents aged >30 years ( P < 0.05). The relationship between poor sleep quality and exacerbation of MS is well documented, and a significant increase in the rate of MS relapse following sleep deprivation has been reported, particularly in RRMS patients ( P < 0.001).[ 21 ]
The likelihood of relapse was found to be significantly lower in patients who adhere to disease modifying therapy (DMT) than in those who did not. Burks et al .,[ 22 ] reported that patients who adhered to DMT were less likely to have a relapse ( P < 0.001). In comparison, our analysis found that 30.5% of the respondents had not adhered to their MS medication before the MS relapse. However, we found no association between adherence and new relapse.
The influence of high altitude on preexisting neurological conditions was studied by Hsieh et al .,[ 13 ] who reported a case of a United States Air Force serviceman who had an MS relapse in day 1 of climbing Mount Fuji (3776 m), suggesting a possible association between these factors. This finding is supported by our study finding that 27 (8.9%) of respondents reported relapses after being in locations of high altitude.
Oral contraceptive pill (OCP) users have been reported to have a lower relapse rate than those who have never used OCPs ( P = 0.031).[ 23 ] This is inconsistent with our findings, although only 2% of the respondents in our survey reported OCP use.
Exposure to vaccines, such as those for hepatitis B, tetanus, and influenza, in the preceding 2 months is not associated with increased MS relapse rates,[ 15 ] and several studies have suggested that MS relapse rate decreases with vaccination.[ 24 ] In our study, 11 (3.6%) respondents reported having a relapse after being vaccinated.
Pregnancy and breastfeeding have been reported to have a protective effect against MS exacerbation/relapse.[ 15 ] However, 26 of the 188 women in the present study reported that their MS relapses were triggered by pregnancy and/or breastfeeding.
Hydration status was reported to be correlated with fatigue in patients with MS ( P = 0.022),[ 25 ] and it was thus concluded that better hydration might be beneficial for MS patients experiencing fatigue. This is consistent with our study finding: 62 (20.3%) respondents reported dehydration as a trigger for MS relapse.
A systematic review of randomized controlled trials reported that exercise has a protective effect in MS patients.[ 26 ] In contrast, Tallner et al .,[ 27 ] found no association between MS relapse rate and the level of physical activity ( P = 0.0279). Fifty-one percent of the respondents in our study noticed exacerbation of their MS disease during physical exertion. We found that exercise as a triggering factor was similar between age groups and between men and women.
A total of 48 (15.7%) respondents reported that diet acted as a triggering factor for MS relapse, supporting several previous studies. A large study on 2469 MS patients found that healthy dietary habits were associated with a lower rate of MS exacerbation and disability ( P < 0.001).[ 28 ] Saturated fat intake was associated with an increased MS relapse rate, while increasing vegetable intake by one cup per day was associated with a 50% reduction in MS relapse rate.[ 29 ] Conversely, a low-fat diet was found to be associated with a lower MS relapse rate and less fatigue.[ 30 ] Moreover, the same study showed a significant improvement in the expanded disability status scale with the intake of a low-fat diet.
In this study, 77 (25.2%) respondents reported that a change in DMT type was the trigger for their relapses. This is consistent with the findings of a study that showed the impact of switching treatment from natalizumab to fingolimod on MS, with reactivation and relapse during the washout period and shortly after initiating the fingolimod treatment. The study concluded that a washout period shorter than 3 months was associated with a lower risk of relapse ( P = 0.001).[ 31 ]
The current study has helped establish an understanding of possible modifiable triggers for MS relapse. Avoiding these triggers would be the best approach for disease control. Further studies are required to identify other triggering factors, and radiological studies are needed to assess neurological changes during/after relapse.
Conclusion
This study is the first step taken to identify the triggers for MS relapse in Saudi Arabia. It will support further research to establish strategies to avoid these triggers.
Conflicts of interest
There are no conflicts of interest.