Differences in disease burden between neuromyelitis optica spectrum disorder and multiple sclerosis in South China

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) differ substantially in pathophysiological mechanisms, clinical manifestations and therapeutic management.

Objectives

To investigate the disease burden of NMOSD and MS in South China and analyse the differences in disease burden between the two.

Methods

We extracted the demographic characteristics, diagnoses, duration of hospitalization and mortality from the direct reporting system of health information.

Results

From 2016 to 2022, the study identified 12,799 hospital admissions for 8204 patients with NMOSD and 6783 hospital admissions for 5125 patients with MS. The female-to-male ratio among patients with MS was 1.82. The peak age of NMOSD diagnosis was 45–55 years. The peak age of MS diagnosis was 25–35 years. The average duration of hospitalization for patients with NMOSD was 12 (7–17) days, whereas that for patients with MS was 10 (6–14) days. The percentage of NMOSD admissions to the intensive care unit was higher than that of MS admissions. The mortality rate for both NMOSD and MS was 0.2%.

Conclusions

In South China, the disease burden of NMOSD is heavier than that of MS. The NMOSD exhibited a higher number of cases, longer duration of hospitalization and more severe clinical conditions than MS.

Keywords

Neuromyelitis optica spectrum disorder multiple sclerosis epidemiology disease burden

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are classic demyelinating diseases of the central nervous system. However, the pathogenesis, epidemiology, clinical symptoms and treatment of both are distinct. The identification of highly specific autoantibodies against aquaporin-4 (AQP-4) in 2005 characterized NMOSD as a disease entity distinct from MS.^1,2 Antibodies against AQP4, a water channel found at high density on astrocytes, are thought to be pathogenic to NMOSD.³ The NMOSD is a disease characterized by severe optic neuritis and transverse myelitis in Western countries and often follows a relapsing course. The occurrence of NMOSD is global; however, a higher incidence among non-Caucasian populations, particularly in Asian countries, has been noted.⁴

The occurrence of brainstem, cerebellar and cerebral hemisphere lesions is more common in patients with MS. The optic nerve and spinal cord may also be affected, although the manifestations are typically less severe in these patients than in those with NMOSD. The global prevalence of MS is 35.9 per 100,000 individuals.⁵ The highest age-standardized MS prevalence was 164.6 per 100,000 in high-income North America.⁶ The prevalence estimates of MS in Asians are among the lowest worldwide, indicating a lower risk of MS in this population.⁷ The reported prevalence in Japan in 2017 was 14.2 per 100,000.⁸ The age-standardized prevalence was 3.23 per 100,000 persons in Korea.⁹ In 2020, epidemiological data from China reported an incidence of 0.278 per 100,000 people with NMOSD and 0.235 per 100,000 people with MS.^10,11

Presently, most Chinese studies on NMOSD and MS are based on a single-centre study design with a limited sample size. Large-scale comparative studies of the disease burden between NMOSD and MS in China are lacking. The province of Guangdong in South China, with a population of 127 million, is the most populous region in China and accounts for two-thirds of South China's population. The objective of our study was to analyse and compare the differences in disease burden between NMOSD and MS in South China on the basis of the direct reporting system (DRS) of health information. The DRS is an official data collection system covering all tertiary hospitals and is maintained by the National Health Commission in China.¹² The DRS includes data on demographic characteristics, diagnoses, duration of hospitalization and mortality of all inpatients.

Methods

Study data

The data for this retrospective study was exclusively obtained from the Guangdong Provincial DRS database. The system consistently collects a comprehensive dataset from all inpatient medical records across each hospital through a standardized protocol and includes demographic characteristics, diagnoses, in-hospital mortality and expenses, among other data. Each patient in the DRS has a unique identification number.

The data was collected from the DRS of hospitalized patients across Guangdong Province from 1 January 2016 to 31 December 2022. The DRS requires a ‘quality assurance physician’ and coder for each uploaded record to review the diagnostic accordance per the International Classification of Diseases, Tenth Revision (ICD-10) code. The ICD-10 code for NMO is G36.0. After 2021, the ICD-10 code for NMOSD remained G36.0. The ICD-10 code for MS is G35.0. This study included patients who were discharged with a primary diagnosis of NMOSD or MS. In accordance with the WHO guidelines, the study classified individuals aged ≥18 years as adults, while those aged <18 years were considered children.

Continuous variables were assessed for normality using the Shapiro–Wilk test. Normally distributed data is presented as mean ± standard deviation (SD), while non-normally distributed data is presented as median with interquartile range. The Cochran–Armitage test for trend was used to analyse the changing trends of the hospitalization composition ratios of NMOSD and MS over time. P < 0.05 was considered statistically significant.

Ethics statement and anonymization processing

This study is based on the DRS of health information. The study involving human participants was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (Ethics number: [2024]460). All patient records are anonymized. Patient consent for this analysis was waived because of the retrospective nature of the study.

Data availability

Anonymized data not published within this article will be made available upon request to any qualified investigator.

Results

Epidemiology

From 2016 to 2022, the study identified a total of 12,799 hospital admissions for 8204 patients diagnosed with NMOSD and 6783 admissions for 5125 patients diagnosed with MS. The ratio of NMOSD to MS was 1.60:1. The number of patients with NMOSD consistently increased annually from 2016 to 2022, whereas the number of patients with MS remained relatively stable without considerable fluctuations (Figure 1). The Cochran–Armitage trend test indicated that there was a significant trend in the proportion of hospitalizations for the two diseases from 2016 to 2022 (z = 10.23, p < 0.001) (Figure 2). The results indicated that the hospitalization proportion of NMOSD showed a significant upward trend, while that of MS showed a significant downward trend.

Figure 1.

The number of patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) from 2016 to 2022.

Figure 2.

The trend of hospitalization rates of patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) from 2016 to 2022.

The study revealed a significant predominance of females with NMOSD, with a female-to-male ratio of 5.04 (Figure 3). The female-to-male ratio among those with MS was 1.82 (Figure 3). Obviously, the sex disparity in the MS cohort was comparatively less pronounced than that in the NMOSD.

Figure 3.

The number of male and female patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) between 2016 and 2022.

The mean age at NMOSD diagnosis was 44.6 (SD: 15.8) years, with a peak age between 45 and 55 years. The mean age of adult individuals diagnosed with NMOSD was 45.9 (SD: 14.6) years. The mean age of paediatric patients diagnosed with NMOSD was 11.9 (SD: 3.9) years. The proportion of paediatric patients in the NMOSD cohort was 3.75% (308/8204). The female-to-male ratio in paediatric NMOSD patients was 2.24 (213/95).

The mean age at MS diagnosis was 41.3 (SD: 15.9) years, with a peak age between 25 and 35 years. The mean age of adult individuals diagnosed with MS was 42.3 (SD: 15.2) years. The mean age of paediatric patients diagnosed with MS was 13.1 (SD: 3.8) years. The proportion of paediatric patients in the MS cohort was 3.94% (202/5125). The female-to-male ratio among paediatric MS patients was 1.38 (117/85).

The distribution of individuals across different diagnosed age groups is shown in Figure 4. The epidemiological data from 2016 to 2022 is presented in Table 1.

Figure 4.

The age distribution of patients at the time of diagnosis.

Table 1.

Age and sex characteristics of patients with NMOSD and MS.

	2016		2017		2018		2019		2020		2021		2022
	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS
Number of hospitalizations, n	732	716	878	647	1079	738	1231	720	1255	678	1479	815	1550	808
Female, n (%)	632 (86.3)	473 (66.1)	723 (82.3)	430 (66.5)	890 (82.5)	465 (63.0)	1028 (83.5)	474 (65.8)	1036 (82.5)	438 (64.6)	1236 (83.6)	526 (64.5)	1301 (83.9)	503 (62.3)
Adults, n (%)	709 (96.9)	689 (96.2)	849 (96.7)	621 (96.0)	1041 (96.5)	703 (95.3)	1189 (96.6)	697 (96.8)	1208 (96.3)	660 (97.3)	1430 (96.7)	773 (94.8)	1474 (95.1)	780 (96.5)
Age, mean (SD), years	43.3 (14.9)	42.5 (15.3)	44.0 (15.4)	42.0 (15.7)	43.9 (15.2)	41.5 (15.9)	44.5 (15.5)	41.9 (16.4)	44.9 (15.8)	40.7 (16.2)	46.5 (15.7)	38.1 (15.1)	46.9 (15.7)	38.1 (15.5)

Duration of hospitalization

The average duration of hospitalization for patients with NMOSD was 12 (7–17) days, whereas that for patients with MS was 10 (6–14) days. Since 2021, the average duration of hospitalization has decreased (Table 2). The duration of hospitalization was shorter for paediatric patients than for adult patients; this was observed in both the NMOSD and MS cohorts (Table 2).

Table 2.

Mean duration of hospitalization for patients with NMOSD and MS.

	2016		2017		2018		2019		2020		2021		2022
	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS	NMOSD	MS
Length of hospital stay, median (IQR), days	12(8–18)	10(6–15)	12(8–12)	10(6–15)	12(8–18)	10(6–15)	12(7–17)	10(6–14)	12(7–17)	10(6–14)	12(8–17)	9(6–13)	11(7–16)	8(6–12)
length of stay for adult patients, median (IQR), days	12(8–18)	11(7–15)	12(8–18)	11(7–15)	12(8–18)	10(6–15)	12(7–17)	10(6–4)	12(7–17)	10(6–14)	12(8–17)	9(6–13)	11(7–16)	8(6–13)
Length of hospital stay for children, median (IQR), days	10(6–16)	7(3–11)	10(6–16)	7(4–12)	12(5–18)	11(5–17)	9(3–17)	7(4–16)	8(3–15)	7(4–12)	5(2–12)	7(3–11)	10(4–18)	7(3–10)

Admission departments

The admission departments with the highest frequency of NMOSD patients included neurology (69.3%), rehabilitation (8.7%), internal medicine (6.4%), ophthalmology (3.3%) and orthopaedics (1.4%). The top five admission departments for MS patients are neurology (71.7%), internal medicine (10.4%), rehabilitation (4.5%), neurosurgery (1.6%) and orthopaedics (0.6%).

Complications

In the NMOSD cohort, the most prevalent co-morbidities included hyperlipidaemia (15.0%); diabetes (6.4%) and connective tissue disease (5.5%, including systemic lupus erythematosus [SLE], Sjogren's syndrome and rheumatoid arthritis). Notably, 0.8% of patients with NMOSD experience concurrent femoral head necrosis. The most common co-morbidities in the MS cohort were hyperlipidaemia (13.4%), hypertension (5.5%) and diabetes (4.2%). Furthermore, 0.8% of the patients had concurrent connective tissue diseases, and 0.3% had femoral head necrosis.

Severe cases and mortality

There were 152 intensive care unit (ICU) hospitalizations for patients with NMOSD (1.2%, 152/12,799). The number of ICU hospitalization records for children was 21. The number of ICU hospitalizations for patients with MS was 20 (0.3%, 20/6783); of these, the number of ICU hospitalization records for children was 2. The number of ICU hospitalization records in both the NMOSD and MS cohorts from 2016 to 2022 is shown in Figure 5(a). The number of patients with NMOSD admitted to the ICU has been on the rise. However, the number of MS patients admitted to the ICU remained relatively stable.

Figure 5.

Intensive care unit (ICU) admission and mortality among patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) from 2016 to 2022. (a) The number of ICU hospitalization records among patients with NMOSD and MS from 2016 to 2022, (b) The number of deaths among patients with NMOSD and MS from 2016 to 2022.

Between 2016 and 2022, 18 (0.2%) patients with NMOSD died, including one child, and 12 (0.2%) adult patients with MS died. The number of deceased NMOSD and MS patients from 2016 to 2022 is presented in Figure 5(b). The most common cause of death in patients with NMOSD was infection (5/18, 27.8%), which included lung infection, sepsis and bedsores. The most common cause of death in patients with MS was lung infection (2/12, 16.7%).

Discussion

Both NMOSD and MS are common types of demyelinating diseases of the central nervous system. However, given their low incidence, both are considered rare diseases. Currently, evidence regarding the burden of rare diseases in China is lacking. The DRS is a unique and unparalleled resource for obtaining data on these rare diseases. The data for this study is derived from the DRS of Guangdong Province, which has the largest population in China. This study not only presents the disease burden of NMOSD and MS in South China but also conducts a comparative analysis of these two demyelinating diseases affecting the central nervous system.

A previous study reported that the geographical distribution of MS risk is generally divided into three zones, with North American and northern European countries considered high-prevalence zones and Asia as a region with low prevalence.¹³ However, multiple studies have confirmed that the incidence rate of NMOSD is higher in Asian populations.^9,14 In 2020, epidemiological data from China reported an incidence of 0.287 per 100,000 people with NMOSD and 0.235 per 100,000 people with MS.^10,11 This data is sourced from the national database of the Hospital Quality Monitoring System (HQMS) in China. Our research confirmed that the number of hospitalized patients with NMOSD is much greater than that with MS in Guangdong Province. The ratio of NMOSD to MS was 1.60:1. This proportion is higher than the overall proportion in China, which is 1.21:1.¹⁰ This difference may be related to the geographical location. At present, it is well established that the incidence of MS is related to the geographical location.¹⁵ For every 1 degree increase in latitude, the prevalence of MS increases by 1.03 times.⁶ One study in China reported that the prevalence of MS is greater in provinces at higher latitudes than in those closer to the equator.¹¹ Additionally, the descending altitude from west to east corresponds with decreased incidence of MS in China.¹¹ South China is a low-latitude and low-altitude region. The incidence of MS in South China is lower than that in northern China. From 2016 to 2022, there were 12,799 hospital admissions for 8204 patients diagnosed with NMOSD. On average, each patient was hospitalized 1.56 times. In contrast, there were only 6783 hospital admissions for 5125 patients with MS. Each patient was hospitalized 1.32 times on average. This data shows that some patients have experienced repeated hospitalizations, and this situation is more common among patients with NMOSD. As is well known, disease recurrence represents the predominant indication for hospitalization. Therefore, we speculate that the recurrence rate of NMOSD might be higher than that of MS in South China.

As shown in Figures 1 and 2, the number of patients with NMOSD has been increasing annually from 2016 to 2022, especially with noticeable growth since 2021. We analysed that there may be two reasons for the increasing number of NMOSD patients year by year. One is the wide application of AQP-4 antibody testing, especially for patients experiencing their first episode of the disease. The second reason is the revision of the diagnosis. Since 2021, the DRS started using NMOSD diagnostics, replacing the neuromyelitis optica (NMO) diagnostics system. Most studies indicate a very high female-to-male ratio in patients with NMOSD.^16,17 Our female-to-male ratio (5.04) is close to the median value reported in most other studies.^10,17–19 Our research revealed the female-to-male ratio of MS was 1.82. This finding was similar to other research results.²⁰

In our study, the mean age of MS diagnosis was younger than that of patients with NMOSD. The peak age of MS diagnosis is 25–35 years, which is also younger than the peak age of 45–55 years for patients with NMOSD. In East Asian studies, there was a tendency towards a younger onset of MS. In Japan, the mean age of onset of MS decreased from 33 ± 13 years in 1972 to 28.3 years in 2011.^20,21 In China, the mean age of MS patients ranged from 46.4 years in 1993 to 32.6 years in 2006.^22,23 Certain explanations for a decline in the mean age include more frequent utilization of MRI, improved neurological care, and, more importantly, updated diagnostic criteria for MS. Approximately 3–5% of NMOSD patients present in the paediatric age range.²⁴ Studies have shown that disease onset during the paediatric period occurs in 3–5% of individuals with MS.²⁵ Our data is similar to those of previous reports. Prepubertal MS is a rare diagnosis and comprises <1% of all cases.²⁶ Our data revealed that 32 patients who were diagnosed with MS before the age of 10 accounted for only 0.62% of the sample. Our study revealed that the sex differences in paediatric patients with NMOSD and MS are both smaller than those in adult patients. This conclusion is consistent with previous reports.^27,28 This data suggests that oestrogen may play a role in the pathogenesis of both NMOSD and MS.

In this study, hyperlipidaemia was the most common co-morbidity in both the NMOSD and MS cohorts. The proportion of patients with combined hyperlipidaemia in one study was 10.9%, which is similar to our findings.²⁹ The proportion of patients with NMOSD with concurrent connective tissue diseases is much greater than that of patients with MS. This finding is consistent with the phenomena observed in clinical practice. The connective tissue diseases associated with NMOSD include SLE, Sjögren's syndrome and sarcoidosis. One study investigating the relationship between NMOSD and SLE in 210 patients with clinically and serologically confirmed SLE reported two patients with confirmed NMOSD on the basis of MR-evident optic neuritis and transverse myelitis, as well as elevated AQP4 antibodies.³⁰ Another study reported that MG autoantibodies are significantly more common in patients with NMOSD than in those with MS or healthy individuals.³¹ Patients with NMOSD have a heightened frequency of other organ-specific and non-organ-specific autoimmune disorders.³² Multiple reports have described the co-occurrence and possible associations between NMOSD and other autoimmune diseases, raising questions of shared autoimmune pathophysiology and genetic susceptibility.³¹ In contrast, a recent population-based study revealed no excess of autoimmune disorders among 5031 patients with MS compared with their spousal controls.³³ These studies further demonstrated that the immunopathogenesis of NMOSD is distinct from that of MS.

Notably, 0.8% of patients with NMOSD have concurrent femoral head necrosis; it is very likely that this is an underestimate. Owing to the lack of obvious symptoms, some patients do not undergo an MRI of the hip joint. Glucocorticoid-induced osteonecrosis of the femoral head is the most common type of nontraumatic femoral head necrosis.³⁴ Patients with NMOSD receive long-term glucocorticoid therapy, which leads to femoral head necrosis. It is essential to screen these patients’ hip joints regularly using MRI. Furthermore, the use of new monoclonal antibodies may reduce the dependence on glucocorticoids, which in turn could decrease the occurrence of femoral head necrosis.

Figure 5(a) shows that the number of patients with NMOSD admitted to the ICU has been on the rise. This trend may be related to the increasing number of patients with NMOSD from 2016 to 2022.

We found more patients with NMOSD than with MS in China, and these patients also have longer hospital stays and probably face higher hospitalization costs. The proportion of NMOSD patients admitted to the ICU is higher than that of MS patients, and this trend is increasing year by year. These findings indicate that NMOSD imposes a greater disease burden in China than MS.

Both NMOSD and MS are treatable and have a low mortality rate; hence, timely and accurate treatment is very important. The most common cause of death for both NMOSD and MS patients is infection. This is consistent with the findings of other observational studies.^10,11,29

Limitations

Our study has some limitations. First, the data only includes the data of inpatients. Due to restrictions on information, we can’t enroll the outpatient data. Therefore, it is possible that the number of patients may be underestimated. Second, the database of DRS does not contain comprehensive information, such as symptoms, antibody status, treatments and outcomes. We will include more factors such as outpatient data, treatment strategy and efficacy in the prospective study in the future. Third, using these data, we cannot accurately calculate the incidence rates of NMOSD and MS in South China.

Conclusion

This study not only investigated the disease burden of NMOSD and MS in South China but also compared the two. The DRS database ensures the reliability and wide availability of data. The main finding of our study is that the NMOSD cohort had a greater number of cases, experienced longer hospitalization and had more severe conditions than the MS cohort. Therefore, NMOSD has a greater disease burden in South China. The results of this study call for clinicians to focus on early diagnosis, differential diagnosis and appropriate treatment of these two diseases. The prevention and treatment of femoral head necrosis caused by long-term use of hormones in patients with NMOSD are also important.

Footnotes

Acknowledgements

The authors thank Guangdong Provincial Health Commission for supporting this study and providing data. This article was supported by grants from National Natural Science Foundation of China (82201554). This work is attributed to the Department of Neurology of The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases and National Key Clinical Department and Key Discipline of Neurology.

Author contributions

Xin Huang contributed to conceptualization; writing – original draft; writing – review and editing; project administration; data curation; methodology and funding acquisition. Huiyu Feng contributed to validation; visualization; project administration and methodology. Jingjing Li contributed to validation; writing – review and editing; data curation and methodology. Yuhua Fan contributed to validation; visualization; writing – review and editing; supervision; project administration and data curation. Jinsheng Zeng contributed to validation; visualization; writing – review and editing; data curation; supervision; resources; project administration; conceptualization and formal analysis.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

This study is based on the DRS of health information. The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (Ethics number: [2024]460).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This article was supported by grants from National Natural Science Foundation of China (82201554), Guangdong Provincial Clinical Research Center for Neurological Diseases (2020B1111170002), Guangdong Province International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases (2020A0505020004), Guangdong Provincial Engineering Center for Major Neurological Disease Treatment, Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease, Guangzhou Clinical Research and Translational Center for Major Neurological Diseases.

ORCID iD

Xin Huang

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