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Epidemiological and clinical features of pediatric-onset multiple sclerosis: A population-based study in Isfahan, Iran, between 1997-2020

Background: Pediatric-onset multiple sclerosis (POMS) is an autoimmune demyelinating disorder of the central nervous system (CNS), affecting individuals younger than 18 years of age. We sought to characterize the epidemiological and clinical features of patients with POMS in Isfahan, Iran, from April 1997 to March 2020. Methods: The medical records of patients with POMS in the databases of Isfahan Department of Public Health and Isfahan Multiple Sclerosis Society (IMSS) were retrospectively reviewed. The 2006 and 2016 Isfahan Province population censuses were used as reference values for assessing the temporal trend of POMS. Results: From April 1997 to March 2020, 509 individuals under18 years of age were diagnosed with POMS in Isfahan. 404 of these patients (79.4%) were girls, and 105 patients (20.6%) were boys (a female to male ratio of 3.85:1). Most of the patients (83%) were monosymptomatic at onset, with optic neuritis and brainstem-cerebellar disorders being the most frequent initial presentations. Mean ± standard deviation (SD) of age at disease diagnosis was 15.8 ± 2.5 years (ranging from 3 to 18, mode = 18). From April 2019 to March 2020, the crude prevalence and the crude incidence rate of the POMS were 5.42 per 100000 and 1.86 per 100000, respectively. Poisson regression analysis revealed a 3.4% increase in the incidence rate of POMS from April 1997 to March 2020 [relative rate:1.034, 95% confidence interval (CI): 1.021-1.048]. Conclusion: The female to male ratio in our cohort was significantly higher than any other studies conducted previously. The high female to male ratio and increasing incidence of the disease suggest increasing regionalization of care.


Introduction
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. 1 Pediatric-onset MS (POMS) is a subset of MS occurring in children and young adolescents aged under 18 years presenting with distinct features from MS in adults. It accounts for almost 2%-10% of all MS cases. 2 According to numerous worldwide studies in recent years, POMS is considered a rare complication with an incidence of 0.45 to 2.85 per 100000 person-years, 3 whereas it is the most common entity among neurological disorders affecting young adults. 4 POMS is frequently associated with sensory defects, motor defects, and brainstem dysfunction. 5 Given the variable clinical presentation, medical and psychosocial complications, and irreversible disability occurring so early in life, early diagnosis and adequate POMS management are crucial. As such, a detailed investigation of demographic and clinical characteristics of patients with POMS will improve the efficiency and utility of healthcare services for this patient cohort. We present demographic and clinical features of POMS to evaluate the epidemiological trajectory of this disease.

Materials and Methods
This population-based study was carried out in Isfahan Province, situated in the central part of Iran, within the latitudes and the longitudes of 30-34º North and 49-55º East, respectively. The population of Isfahan was 5120850 (including 2599477 men and 2521373 women) in 2016. In 2013, Isfahan Province had the highest MS prevalence in Iran (89/100000). 6 We retrospectively identified and reviewed the medical records of patients with POMS in the database of Isfahan Department of Public Health, which had registered all patients with MS in the province since 2007, and Isfahan MS Society (IMSS) database, the primary referral center in the province before 2007.
The IMSS is located in Isfahan City (center of Isfahan Province), the third most populous metropolitan area in Iran. Including this database allowed incorporating patients registered since April 1997. All study participants were residents of Isfahan Province. Demographic and clinical data, including patient's age (at onset), gender, disease course, risk of seizure, symptoms at onset, comorbidities, treatment, and family history were obtained from their files. Expert neurologists made definitive MS diagnoses based on patients' radiological findings and clinical features following the Poser criteria 7 for patients admitted before 2001 and the latest McDonald criteria 8 for all other patients. Following the International Pediatric MS Study Group (IPMSSG) consensus definition, only patients with an MS diagnosis before their 18 th birthday were included. 9 Patients with other demyelinating disorders such as neuromyelitis optica spectrum disorder (NMOSD) and acute disseminated encephalomyelitis (ADEM) were excluded from the study. Since 2015, cell-based assays were applied for MS-susceptible patients in Isfahan Province to detect antibodies against aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) in order to rule out MOG-associated disease and NMOSD, the more common differential diagnoses of POMS. The Ethical Committee of Isfahan University of Medical Sciences approved the study protocol, and the need for informed consent was waived. Although a vast majority of patients with POMS were registered in the two databases, some cases could be missed. The primary objective of this study was to elucidate the epidemiological and clinical features of POMS in Isfahan.
Mean and standard deviation (SD) of all numerical characteristics (e.g., age) were calculated and stratified by sex. A Mann-Whitney U test was conducted to assess the significance of the difference in mean age in female and male patients with POMS. A linear graph was applied to illustrate the trend between April 1997 and March 2020, for male and female patients of Isfahan Province. The pediatric population of Isfahan Province in 2006 and 2016 was used as the reference values (comprehensive national censuses were conducted all across the country in 2006 and 2016). Trends over time were compared between female and male patients using Poisson regression http://cjn.tums.ac.ir 07 October analysis with a 95% confidence interval (CI). The data were analyzed at a significance criterion of 5%, using SPSS software (version 26, IBM Corporation, Armonk, NY, USA).

Results
Demographic features: From April 1997 to March 2020, 509 individuals under 18 years of age were diagnosed with POMS in Isfahan Province. 404 of these patients (79.4%) were girls, and 105 patients (20.6%) were boys (female to male ratio as 3.85:1). The mean ± SD of age at the onset of the disease was 15.8 ± 2.5 years (ranging from 3 to 18, mode = 18). The difference in the mean age at onset between boys (16.43 ± 2.20) and girls (15.68 ± 2.73) was significant (P = 0.003). Only 24 patients (0.05%) were under the age of 10 years old. Of them, 20 individuals (83%) were girls, and 4 (17%) were boys. The majority of patients were older than ten years old (95.05%), of which 384 (79.2%) were girls, and 101 (20.8%) were boys. The total population of patients with POMS by age and sex is represented in table 1. From April 2019 to March 2020, the crude prevalence and the crude incidence rate of the disease were 5.42 per 100000 and 1.86 per 100000, respectively. Poisson regression analysis revealed that the POMS incidence rate increased by 3.4% from April 1997 to March 2020 (relative rate:1.034, 95% CI: 1.021-1.048), and the incidence of the POMS in girls was more likely to be increased than boys (relative rate: 1.40, 95% CI: 1.18-1.61) ( Table 2).
The total and gender-specific trends of POMS incidence are depicted in figure 1. It is worth mentioning that the annual incidence of the disease before 2001 should be taken into account with caution, considering the limited sensitivity of the Poser criteria in diagnosing POMS. No mortality occurred in our population.
Clinical features: The numbers and statistics presented below pertain to 473 patients, as the data regarding the clinical features of 36 patients, primarily diagnosed a long time ago, were not available.
Risk of seizure: Seizure episodes were recorded in 20 patients (4.2%), more frequently in those with a polysymptomatic onset (7 patients, 8.4%) as compared to those with a monosymptomatic onset of POMS (13 patients, 3.3%). Two patients had seizure episodes both before and after the MS diagnosis was made.
Family history: We divided relatives into three groups as follows: 1) first-degree relatives, including mother, father, sister/brother, and offspring, 2) second-degree relatives, including grandmother, grandfather, maternal aunt/uncle, and paternal aunt/uncle, and 3) third-degree relatives, including maternal cousins, paternal cousins, and others. 45 patients (9.5%) had a positive family history of MS, of them 35 were girls and 10 were boys. Among those forty-five, 16 (3.3%) had first-degree affected relatives, 6 (1%) had second-degree affected relatives, and 23 (4.8%) had third-degree affected relatives. 19 patients had maternal affected relatives, and 18 had paternal affected relatives. Two patients had a history of MS in both maternal and paternal relatives.
Comorbidity: Comorbidity was defined as the coexistence of 2 or more disorders that are not obvious complications of each other. 10 We divided our patients' comorbidities into five categories: psychiatric disorders, autoimmune disorders, vascular and blood disorders, cancers, and hypersensitivity reactions. 44 patients (9.3%) were suffering from another disorder besides MS.  The distribution of these disorders is shown in table 3.

Discussion
Although POMS comprises only a small portion of MS cases, between 1997 and 2020, 509 pediatric individuals were physically and psychologically afflicted. The annual incidence of POMS exhibited a 2.8-fold increase from 0.66 per 100000 in 1997 to 1.86 per 100000 in 2020. This unfortunate upward trend was also observed in similar studies in Germany, 11,12 Kuwait, 13 and Canada. 14 However, the incidence rate was relatively stable in a study conducted in Denmark. 15 Increased prevalence of obesity, a risk factor for MS, due to a sedentary lifestyle in children, 16 an increase in overall MS prevalence, higher accuracy and precision of http://cjn.tums.ac.ir 07 October diagnostic criteria, enhanced POMS awareness, and increased healthcare access can explain the rising incidence of POMS. However, these factors cannot explain the significant decrease in the incidence rate in April 2014-March 2015.
The worldwide prevalence of POMS ranges from 0.69 to 26.92 per 100000 population. 17 According to four previous studies conducted in the Middle East, POMS prevalence was reportedly between 5.25 and 16.25. 18,19 The pooled global prevalence of the disease was estimated to be 8.11 (95% CI: 2.28-13.93), and the pooled prevalence in the Middle East was calculated to be 8.55 (95% CI: 0.27-16.82). 3 Although the prevalence of adult-onset MS in Isfahan was higher than in Tehran (capital of Iran), POMS was less prevalent in Isfahan than in Tehran. 6 In the Middle East, only Israel has a lower POMS prevalence than Isfahan (5.25 vs. 5.42 per 100000).
The mean age at disease onset was 15.8 ± 2.5 years in our patients, which was higher than what had been observed in other studies, including Kuwait (15.40 ± 2.10), 13 23 and Italy (15.40 ± 2.20). 24 Only one study conducted in the United Arab Emirates (UAE) reported a higher mean age than that in our study (15.90 ± 2.80). 25 The difference in the mean age of girls and boys was statistically significant in our study, suggesting that sex hormones may be partially involved in the induction of demyelination. 26 The female-to-male ratio in our cohort was significantly higher than other studies conducted previously (3.85:1). Notably, there was a meaningful difference in this ratio between studies in Iran (3.5:1 in Tehran 19 27 and Brazil (2.4:1). 28 We hypothesize that the female preponderance in Iran could be partly due to the Iranian dress code, leading to vitamin D deficiency from reduced sunlight exposure. In a previous study, female high school students (aged from 10 to 18) were four times more likely to have vitamin D deficiency. 29 Additionally, there are possible correlations between serum vitamin D levels and the risk of MS development and severity. 30,31 For example, Blaschek et al. observed significantly lower 25-hydroxy vitamin D levels in patients with POMS than healthy controls. 32 Moreover, vitamin D may have an immunomodulatory effect by conferring an antiinflammatory profile to CD8+ T cells in patients with POMS. 33 Thus, vitamin D supplementation in young Iranian girls may help to reduce the sex ratio of the POMS. It may even help prevent the development of adult-onset MS by ameliorating vitamin D deficiency in this population. Further studies are needed to clarify the potential factors contributing to the high female-to-male ratio of POMS in the Iranian population.
Psychiatric disorders were the most common comorbidities among this patient population, which occurred either as a side effect of the treatments applied or due to the disabling nature of the disease. Moreover, psychiatric disorders and MS could share a common pathomechanism, correlated with brain demyelination. 34 38 The occurrence of epileptic seizures in MS is well-documented (previously, seizures were included in the spectrum of MS manifestations 39 ), tending to affect pediatric patients more frequently than adult patients. 40,41 Concerning the contribution of genetic inheritance to the pathogenesis of MS, a multifactorial disorder, we investigated the family history of each patient. The frequency of familial POMS in our study (9.5%) was less than that in France (13.5%), 9 Germany (13.9%) 12 and Canada (16.0%). 21 Familial POMS prevalence in other Iranian studies was 14.9% in Tehran 19 and 10% in Fars. 20 The lower prevalence of positive family history in patients with POMS in Isfahan, compared to other studies, may imply the crucial role of environmental interactions in the pathogenesis of MS in this region.
Studies suggest that monosymptomatic onset is a prevailing characteristic of POMS, as detected in 83% of patients of this study. It is worth noting that the frequency of polysymptomatic presentations in POMS is higher than that in adult-onset MS. 42,43 Such manifestations are quite helpful in distinguishing the disease from ADEM, which is a challenging differential diagnosis for POMS. In the