1 SUBMITTED 8 NOV 22 1 REVISION REQ. 22 JAN 23; REVISION RECD. 2 MAR 23 2 ACCEPTED 4 APR 23 3 ONLINE-FIRST: MAY 2023 4 DOI: https://doi.org/10.18295/squmj.5.2023.029 5 6 Incidence of Optic Neuritis Among Omani Patients with Multiple Sclerosis 7 at the Sultan Qaboos University Hospital, Muscat, Oman 8 Fatma Alkharusi,1 Buthaina Sabt,2 *Abdullah S. Al-Mujaini3 9 10 3Department of Ophthalmology, 1College of Medicine and Health Sciences, Sultan Qaboos 11 University, Muscat, Oman; 2Department of Ophthalmology, Sultan Qaboos University 12 Hospital, Sultan Qaboos University, Muscat, Oman 13 *Corresponding Author’s e-mail: abdullah.almujaini@gmail.com 14 15 Abstract 16 Objectives: Multiple sclerosis (MS) is a chronic, multifaceted, heterogeneous autoimmune 17 disease, with optic neuritis (ON) being a common early manifestation. This study aimed to 18 estimate the incidence of ON among Omani patients with MS. Methods: This retrospective 19 cross-sectional study included all Omani patients diagnosed with MS at the Sultan Qaboos 20 University Hospital, Muscat, Oman, between January 1991 and December 2019. Data were 21 collected from the neurology registry and electronic medical records. The data was analysed 22 descriptively using univariant and multivariant statistical techniques. Results: Of the 185 23 patients diagnosed with MS during the study period, 170 were included in the analysis. The 24 male-to-female ratio was 1:3 and the mean age was 28 years. The incidence of ON in the 25 population was 28.8%, with 83.7% of ON patients presenting with relapse-remitting MS 26 (RRMS). Overall, 28.6% presented with ON as an initial manifestation of MS, while 42.8% 27 developed ON at a later stage. Most patients (49.4%) were from higher-latitude regions of 28 Oman, like Muscat and Al Batinah. Conclusion: The incidence of both MS and ON 29 increased over the study period. While the overall incidence was low in comparison with 30 Western data, it was similar to rates reported elsewhere in the Arabian Peninsula. Overall, 31 ON was the most common manifestation of MS in the cohort, with younger female patients 32 mailto:abdullah.almujaini@gmail.com 2 more frequently presenting with both MS and ON. There was a significant association 33 between the RRMS subtype and ON presentation. 34 Keywords: Demyelinating Diseases; Optic Neuritis; Multiple Sclerosis; Multiple Sclerosis, 35 Relapsing-Remitting; Incidence; Epidemiology; Oman. 36 37 Advances in Knowledge 38 - The overall incidence of optic neuritis (ON) among patients diagnosed with multiple 39 sclerosis (MS) at a tertiary hospital in Oman over a 29-year period was 28.8%. While 40 this is lower than rates reported elsewhere around the globe, it remains in line with 41 findings reported by other Arabian Gulf countries. 42 - Moreover, the incidence of both MS and ON was found to increase over time, 43 particularly over the past decade, likely as a result of the application of more stringent 44 diagnostic criteria. In particular, younger female patients were more likely to present 45 with both MS and ON and there was a significant association between the relapse-46 remitting MS subtype and ON presentation. 47 - The number of cases originating from the Muscat and Al Batinah regions of Oman 48 supports the hypothesis that latitude affects MS incidence. 49 50 Application to Patient Care 51 - As the findings show that ON is a common early manifestation of MS in Omani 52 patients, ophthalmologists and family physicians should ensure that they refer patients 53 presenting with symptoms of vision loss for neurological assessment, especially 54 young female patients who are at greater risk of developing both ON and MS. 55 - Moreover, in light of the fact that the incidence of both MS and ON increased 56 considerably over the study period, there is a need for enhanced suspicion of MS in 57 the differential diagnosis process. Moreover, a national MS-specific registry should 58 be established to more accurately monitor the number of cases recorded every year. 59 60 Introduction 61 Multiple sclerosis (MS) is a chronic, multifaceted, complicated, and heterogeneous 62 autoimmune disease which results in central nervous system inflammation, demyelination, 63 gliosis, and axonal degeneration.1 Neurological deficits are common due to interrupted 64 communication between neurons in the brain and spinal cord as a result of the demyelination 65 process. Clinically, MS takes a variety of forms which can be distinguished through disease 66 3 activity and patterns of relapse and remission.1 According to current international 67 classifications, four MS subtypes are recognised: relapsing-remitting MS (RRMS), primary 68 progressive MS, secondary progressive MS (SPMS), and progressive-relapsing MS.2 The 69 primary cause of MS is still unknown, although both environmental and genetic factors are 70 believed to play a role. The epidemiology of MS varies according to demographic 71 characteristics and latitude, a well-established risk factor; in addition, ethnicity/race has also 72 been found to influence the global distribution of MS.3 73 74 Optic neuritis (ON) is an acute, inflammatory, demyelinating disease of the optic nerve 75 resulting from an autoimmune process, characterised by unilateral, painful, and rapid loss of 76 vision.4,5 Typically, ON is recognised as an early clinical manifestation of MS in 20% of 77 patients, but this condition can occur over the course of the disease in up to 50% of all MS 78 patients.6 In particular, female patients between 18–45 years of age have an increased 79 tendency to develop ON in comparison to other MS patients.7 This study aimed to estimate 80 the incidence of ON among Omani patients diagnosed with MS at a tertiary hospital over a 81 29-year period and compare the findings to internationally published data. 82 83 Methods 84 This retrospective cross-sectional study was conducted at the Sultan Qaboos University 85 Hospital (SQUH), a tertiary hospital in Muscat, Oman, from January 1991 until December 86 2019. This study included all Omani patients seen at SQUH with confirmed MS diagnoses 87 according to the 2017 McDonald diagnostic criteria.8 Patients without confirmed MS 88 diagnoses were excluded from the study. Data were collected from the SQUH neuro-89 ophthalmology clinic registry, the patients’ electronic medical records, and the hospital 90 information system database. 91 92 Electronic medical records were established at SQUH in 2006; as such, the data of patients 93 diagnosed with MS prior to 2006 were retrieved from the hospital’s neurology clinic registry, 94 while data from 2006 onwards were collected from the patients’ electronic medical records 95 (TrakCare®, InterSystems Corp., Cambridge, Massachusetts, USA). Various information 96 was recorded, including sociodemographic characteristics (i.e., age, gender, and location of 97 residence), year of diagnosis, subtype of MS, and the presence of ON. In addition, additional 98 data were collected and reported for patients with ON, including age at presentation, number 99 of attacks during follow-up period, and progression of the disease. Patients were contacted 100 4 directly to confirm their location of residence in order to estimate the geographic distribution 101 of the disease. 102 103 Collected data were analysed using the Statistical Package for the Social Sciences (SPSS), 104 Version 23 (IBM Corp., Armonk, New York, USA). Ethical approval for this study was 105 obtained from the Medical Research & Ethics Committee of the College of Medicine & 106 Health Sciences at Sultan Qaboos University. Further authorisation was obtained from the 107 relevant hospital authorities to access the patients’ electronic medical records and the hospital 108 information system database. 109 110 Results 111 A total of 185 patients were diagnosed with MS at SQUH between January 1991 and 112 December 2019; of these, 15 patients (8.1%) were excluded due to diagnostic uncertainty, 113 resulting in a 170 patients (85.4%) being included in the analysis. Overall, 59 (34.7%) were 114 male and 111 (65.3%) were female, with a male-to-female ratio of 1:3 and a mean age of 28 115 years. The youngest patient began showing signs of MS at the age of 9 years, whereas the 116 eldest was 60 years old. In terms of subtype, most patients had RRMS (n = 135; 79.4%), 117 followed by clinically isolated syndrome (CIS; n = 21; 12.4%), and SPMS (n = 14; 8.2%). 118 Other MS subtypes were not detected or diagnosed during the study period. 119 120 Of the 135 patients with RRMS, 50 were male (37%) and 85 were female (63%), while there 121 were six male (28.6%) and 15 female (71.4%) patients with CIS, and three male (21.4%) and 122 11 female (78.6%) patients with SPMS [Figure 1A]. The association between gender and MS 123 subtype was not significant (P >0.050). The first documented case of MS in the neurology 124 registry was recorded in 1991. Subsequently, the number of MS diagnoses per year began to 125 increase, particularly from 2010 onwards. The greatest number of cases per year was 126 recorded in 2016 (n = 23), comprising six male (26.1%) and 17 female (73.9%) patients 127 [Figure 1B]. 128 129 In terms of geographic distribution, the majority of MS patients originated from Muscat (n = 130 48; 28.2%) [Figure 1C], with 16 male (33.3%) and 32 female (66,7%) patients, followed by 131 Al Batinah (n = 36; 21.2%), with seven male (19.4%) and 29 female (80.6%) patients. The 132 region with the fewest cases was Ad Dhakhiliyah (n = 16; 9.4%), of which six patients 133 (37.5%) were male and 10 (62.5%) were female. No cases were reported from three 134 5 governorates of Oman (Musandam, Al Buraimi, and Al Wusta) [Table 1]. The association 135 between disease incidence and areas of high latitude was not significant (P >0.050). 136 137 Over the 29-year study period, 49 MS patients developed ON, resulting in an incidence of 138 28.8%; of these, 11 patients (22.5%) were male and 38 (77.5%) were female [Figure 2A]. 139 The first case of ON at SQUH appeared in the registry in 2004, with the number of diagnoses 140 per year increasing considerably from 2012 onwards. The highest number of cases was 141 reported in 2016 for male patients (n = 2) and 2017 for female patients (n = 7) [Figure 2B]. 142 Overall, 28.6% of patients with both MS and ON presented with ON as an initial presentation 143 of MS, while 42.8% developed ON over the course of the disease [Table 2]. The association 144 between gender and the development of ON was not significant (P = 0.050); however, there 145 was a significant association with MS subtype (P <0.050), with the majority of ON cases 146 occurring in patients with the RRMS subtype (83.7%) [Table 3]. 147 148 Discussion 149 The incidence of ON among MS patients at SQUH over the 29-year study period was 28.8%, 150 lower than rates reported elsewhere around the world. According to a prospective study 151 conducted in India, the incidence of ON among MS patients was 70% (n = 20/30).9 Another 152 study reported an incidence of 50% at a tertiary care unit in Turkey, with ON often reported 153 as an initial presenting feature of MS.10 The low incidence rate of ON noted in the current 154 study could be due to several reasons, including methodological differences in sample size 155 and study design, as well as genetic variations between different populations. 156 157 However, it is also possible that this finding is due to the generally low incidence of MS in 158 Oman, given the previously reported prevalence rate of 4 in 100,000 individuals.11 Other 159 Arabian Gulf countries have reported similarly low rates of MS, although there are 160 methodological concerns to such studies which may hinder definitive conclusions as to 161 regional prevalence.12 A more recent study indicated that the rate of MS in Oman may be 162 much higher than previously believed, with a crude estimated prevalence of 15.9 per 100,000 163 individuals, designating the country as a medium-risk zone.13 164 165 In the present study, the incidence of both MS and ON at SQUH was found to increase 166 considerably over time, beginning from 2010–2012 onwards. This increase over the past 167 decade may be due to the application of the McDonald criteria to support the diagnosis of 168 6 suspected cases of MS at SQUH, resulting in fewer cases going undiagnosed.8In the present 169 study, ON represented the first clinical manifestation of MS in 28.6% of patients who 170 developed ON. This finding is in parallel with other research conducted elsewhere around the 171 globe. In Bosnia and Herzegovina, 10 out of 89 MS patients (11.2%) demonstrated clinical 172 signs of ON as the first sign of disease, a finding which was statistically significant compared 173 to other disease manifestations (P = 0.01).7 In addition, a previous review of the literature 174 suggested that ON is the initial presentation in approximately 20% of MS patients.14 175 176 Overall, 79.4% of MS patients in the present study had the RRMS subtype, while the 177 remaining 12.4% and 8.2% of patients had CIS and SPMS, respectively. A retrospective 178 study conducted in the United Arab Emirates (UAE) reported a comparable distribution of 179 these subtypes among Emirati MS patients (77.8%, 12.3%, and 8.2%, respectively).15 180 Moreover, there was a significant association between the RRMS subtype and ON 181 presentation in the current Omani cohort, with 83.7% of patients with both ON and MS 182 having the RRMS subtype; this result was found to be slightly higher in comparison to other 183 research reporting that 70% of MS patients with ON demonstrated relapsing-remitting 184 disease activity.16 In addition, female patients were found to be more frequently diagnosed 185 with MS compared to male patients in the present study, at a ratio of 1.9. The gender ratio of 186 MS cases varies depending on country and region, with higher ratios of 2.6 and 3.0 reported 187 in the USA and East Asia, respectively.17 In turn, the female preponderance of MS is lower in 188 Arabian Gulf countries, with ratios of 1.8 and 1.3 reported in Kuwait and Saudi Arabia, 189 respectively.17,18 In the present study, 34.2% of female patients with MS developed ON 190 compared to 18.6% of male patients, with a female-to-male ratio of 3.5. The female 191 predominance of ON is well-established in the existing literature at a ratio of 3 or higher.19 192 193 In the present study, the mean age of the enrolled population was 28 years, with similar mean 194 ages observed for both males and females at 29 and 28 years, respectively. Corresponding 195 findings have been reported from Iran (mean age: 25 years), while MS patients in the UAE 196 are reportedly somewhat older (mean age: 34 years).15,20 In turn, the mean age of ON patients 197 in the current research was found to be 26 years, with a mean age of 24 and 27 years for male 198 and female patients, respectively. Overall, the majority of ON patients (59.2%) were between 199 21–30 years of age. This finding was lower in comparison with data originating from Hong 200 Kong showing the mean age of ON patients to be 40 years; however, 90% of MS patients 201 presenting with ON in Bosnia and Herzegovina were between 18–30 years of age.7,21 Such 202 7 results suggest that the demographic epidemiology for MS-associated ON may be similar to 203 that of MS in general. 204 205 Latitude is a well-established factor affecting the incidence of both MS and ON; for instance, 206 previous research has indicated that the incidence of MS in Argentina is six times higher than 207 that recorded in Ecuador.22 It is therefore unsurprising that Oman, a country located in the 208 East Mediterranean region, should demonstrate a lower incidence of MS compared with 209 Western countries of higher latitude.23 Moreover, according to the geographical distribution 210 of patients in the present study, certain regions of Oman at higher latitudes (i.e., Muscat and 211 Al Batinah) accounted for the greatest number of patients, with fewer cases originating from 212 lower-latitude regions like Dhofar, Ash Sharqiyah, Ad Dhakhiliyah, Ad Dhahirah, and Al 213 Wusta. 214 215 Nonetheless, the association between latitude and disease incidence was not statistically 216 significant in the present study, which may be due to several reasons. First, no cases were 217 reported from the highest-latitude areas in Oman (Musandam and Al Buraimi). Second, such 218 associations are difficult to ascertain in a single country that does not span a considerable 219 latitude or longitude. Finally, as the capital city of Oman, Muscat is home to a large 220 proportion of the national population, followed by the surrounding region of Al Batinah, 221 which may account for the large number of cases from these areas. However, it was found 222 that male patients more frequently originated from areas of lower latitude like Dhofar 223 compared with other governorates. The idea that the gender ratio in MS may vary with 224 changes in latitude might be another possible explanation for these findings.24 225 226 Interpretation of the findings of this study is contingent upon certain limitations. 227 Generalisation of the results is difficult as the study was conducted using a retrospective 228 cross-sectional design and was limited to a single institution. While SQUH is a tertiary care 229 institution which accepts referrals from all over the country, the catchment area remains 230 limited; moreover, the presence of other tertiary institutions in Muscat which might also 231 receive MS and ON patients prohibits generalisation of the incidence of these conditions to 232 the whole of Oman. In addition, as a partially heritable disease, genetic factors play a 233 considerable role in the epidemiology and incidence of MS. Unfortunately, data concerning 234 such genetic factors were missing for the majority of patients in the present study. Further 235 8 prospective research is therefore recommended to counteract these limitations using a larger 236 sample size. 237 238 Conclusion 239 Over the 29-year study period, the incidence of ON among MS patients at SQUH was low 240 (28.8%), a rate in keeping with other Arabian Gulf countries. Nonetheless, ON remained the 241 most common early manifestation of MS among the enrolled patients, with almost one-third 242 of MS patients presenting initially with ON as their first symptom. Moreover, the incidence 243 of both MS and ON appeared to increase over time, particularly over the last decade, 244 supporting the need for further research on this topic. Finally, more MS cases were reported 245 from higher-latitude areas of Oman, a result in line with previous research supporting latitude 246 as a well-established risk factor for MS. 247 Further research is needed that can focus on more in-depth analysis such as comparing the 248 difference between the initial presentation (ON versus other MS) and gender, governorate 249 and year and whether sub-types (RRMS vs other sub-types) are significantly different by 250 gender, governorate and year. 251 252 Authors’ Contribution 253 AM designed the study. FK and BS collected the data. FK performed the statistical analysis. 254 FK and BS drafted the manuscript. AM critically reviewed and revised the manuscript. All 255 authors approved the final version of the manuscript. 256 257 Conflict of Interest 258 The authors declare no conflicts of interest. 259 260 Funding 261 No funding was received for this study. 262 263 References 264 1. Sutherland JM, Tyrer JH, Eadie MJ. 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PLoS One 327 2012; 7:e48078. https://doi.org/10.1371/journal.pone.0048078. 328 11 329 330 331 332 333 Figure 1: Distribution of multiple sclerosis (MS) cases according to gender by (A) subtype, 334 (B) over time at the Sultan Qaboos University Hospital, Muscat, Oman, from 1991–2019 (N = 335 170) and (C) among governorates. 336 0% 20% 40% 60% 80% 100% RRMS CIS SPMS Males Females Figure 1A Figure 1B Figure 1C Dhofar Al Wusta Musandam Al Buraimi Al Batinah Ash Sharqiyah Adh Dhahirah Ad Dakhiliyah 12 SPMS = secondary progressive multiple sclerosis; CIS = clinically isolated syndrome; RRMS 337 = relapse-remitting multiple sclerosis. 338 339 340 341 342 343 344 Figure 2: Distribution of combined optic neuritis and multiple sclerosis cases by (A) gender 345 and (B) over time at the Sultan Qaboos University Hospital, Muscat, Oman, from 2004–2019 346 (N = 49). 347 ON = optic neuritis. 348 349 350 351 71.2% 77.5% 22.5% 28.8% Figure 2A Figure 2B 13 Table 1: Regional distribution of multiple sclerosis cases according to gender at the Sultan 352 Qaboos University Hospital, Muscat, Oman, from 1991–2019 (N = 170) 353 Governorate Gender, n (%) Male Female Total Muscat 16 (33.3) 32 (66.7) 48 (28.2) Al Batinah (North and South) 7 (19.4) 29 (80.6) 36 (21.2) Dhofar 12 (48) 13 (52) 25 (14.7) Ash Sharqiyah (North and South) 8 (33.3) 16 (66.7) 24 (14.1) Ad Dhahirah 10 (47.6) 11 (52.4) 21 (12.4) Ad Dhakhiliyah 6 (37.5) 10 (62.5) 16 (9.4) Musandam 0 (0) 0 (0) 0 (0) Al Buraimi 0 (0) 0 (0) 0 (0) Al Wusta 0 (0) 0 (0) 0 (0) Total 59 (34.7) 111 (65.3) 170 (100) 354 Table 2: Initial presentation of combined optic neuritis and multiple sclerosis cases by gender 355 at the Sultan Qaboos University Hospital, Muscat, Oman, from 1991–2019 (N = 49) 356 Gender Initial presentation, n (%) ON Other MS manifestations Both Total Male 2 (18.2) 3 (27.4) 6 (54.5) 11 (22.4) Female 12 (31.6) 18 (47.4) 8 (21.1) 38 (77.6) Total 14 (28.6) 21 (42.8) 14 (28.6) 49 (100) ON = optic neuritis; MS = multiple sclerosis. 357 358 Table 3: Incidence of combined optic neuritis and multiple sclerosis (MS) cases according to 359 gender and MS subtype at the Sultan Qaboos University Hospital, Muscat, Oman, from 2004–360 2019 (N = 49) 361 MS = multiple sclerosis; RRMS = relapse-remitting multiple sclerosis; CIS = clinically 362 isolated syndrome; SPMS = secondary progressive multiple sclerosis. 363 364 Gender MS subtype, n (%) RRMS CIS SPMS Total Male 10 (90.9) 1 (9.1) 0 (0) 11 (22.4) Female 31 (81.6) 4 (10.5) 3 (7.9) 38 (77.6) Total 41 (83.7) 5 (10.2) 3 (6.1) 49 (100)