Emerging trends and research foci of neuromyelitis optica spectrum disorder: a 20-year bibliometric analysis

Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system (CNS) autoimmune inflammatory demyelinating disease characterized by recurrent episodes of acute optic neuritis and transverse myelitis (1). The global annual incidence of NMOSD was estimated at 0.037-0.37 per 100,000 person-year, and the global prevalence was 0.7-10.0 per 100,000 persons (2). For almost a century, neuromyelitis optica (NMO) was considered a variant of multiple sclerosis (MS) that spared the brain (3). It is considered a monophasic disease with bilateral optic neuritis and transverse myelitis, but relapsing cases have been reported in the 20th century (4). A breakthrough was the discovery that the majority of patients with NMO had detectable serum antibodies to aquaporin 4 (AQP4) that were not detected in MS. It is highly specific for clinical diagnosis and has proven NMO to be a distinct disease with a chronic, relapsing course (5, 6). More than 80% of patients with NMOSD have AQP4-IgG autoantibodies (7, 8). NMOSD manifests clinically with six core symptoms, which were classified by their location: optic neuritis, transverse myelitis, area postrema syndrome, brain-stem syndrome, cerebral syndrome, and symptomatic narcolepsy or acute diencephalic clinical syndrome. In 2015, the international NMO diagnostic panel revised a new international diagnostic standard for NMOSD (9). The onset of NMOSD typically reaches its worst within a few days, often leaving a moderate to severe and permanent disability (10). Current treatment options for NMOSD include acute relapse treatment with intravenous glucocorticoids and preventive immunotherapy with a variety of non-specific immunosuppressants and targeted biological agents (11). With the rapid advancement of the NMOSD research field, the randomized controlled trials (RCT) of targeted biological agents in NMOSD have obtained positive results (12–14), which have been approved for AQP4-NMOSD, including eculizumab, inebilizumab, and satralizumab.

Bibliometric analysis has been recently used as a quantitative analysis method for scientific research evolution (15). In addition, it can be used to identify hotspots and emerging trends in a specific field (16). With the evolution and broadening of the concept of NMOSD and the accumulated new data, there have been a growing number of publications about NMOSD. However, as far as we know, there is no bibliometric analysis on this topic. Our research aims to provide an overview of NMOSD over the past two decades with the purpose of assisting researchers, especially beginners, in understanding the field more quickly and effectively.

In the past two decades, the number of annual publications and citations in the NMOSD field has increased steadily and reached a peak in 2021. With the discovery of the AQP4 antibody, researchers have put in great efforts and there have been great strides made in the diagnosis and treatment of NMOSD. Therefore, we conducted a bibliometric analysis that provided a comprehensive overview of the development of NMOSD research and predicts future research hotspots. This is the first bibliometric analysis of NMOSD. As of 13 October 2022, 3,057 publications had been published in 198 journals by 200 authors from 200 institutions in 93 countries/regions.

It has long been controversial whether NMOSD is an independent disease or a subgroup of MS. The discovery of the anti-NMO antibody in 2004 and its target AQP4 in 2005 revolutionized the diagnosis and treatment of the disease and provided insight into its pathophysiology (5, 6). The discovery of the AQP4 antibody facilitated early diagnosis and the use of immunotherapy to prevent attacks and improve outcomes. A better understanding of the pathogenesis of NMOSD has led to the rational development of mechanism-based therapies. Since then, the NMOSD field has rapidly developed and shown continued growth. The number of NMOSD publications and citations reached a new level in 2020 and continues to grow until this day. The possible reason for this phenomenon is that RCTs on many targeted immunotherapies for NMOSD have been published in high-quality journals (13, 14, 22), and, based on clinical trial results published over the past three years, some of these biological agents have been approved for the treatment of NMOSD. The success of these studies has greatly promoted the progress of NMOSD treatment.

In terms of country analysis, the USA contributed the most NP, NC, AC, and H-index, suggesting that the USA is a highly productive and leading country in the NMOSD field. The USA has the most outstanding researchers and institutions globally, suggesting the USA holds the leading position in the NMOSD field. Although the NP of China ranked second, the numbers of NC, AC, and H-index were relatively low.

Based on these data, it appears that China has an imbalance between quantity and quality. This issue may be addressed in the following aspects: (1) enhancing collaboration with other countries, especially the USA, Japan, and Germany; and (2) keeping a close eye on scientific innovation and conducting more in-depth studies to improve publication quality. Among the top 10 most productive institutions, 60% were from the USA and Germany. This might explain why the USA was the most productive country in the NMOSD field. These findings indicated that global academic resources are unbalanced and that the establishment of world-class academic institutions is an important basis for improving national academic status.

Of the top 10 prolific authors, Fujihara, K was the most productive author with 117 articles and 8,573 citations in the NMOSD field, while the NC and AC of Weinshenker, BG were ranked first. Furthermore, among the top co-cited authors, it is evident that Wingerchuk, DM had the highest centrality. Fujihara, K, from Fukushima Medical University School of Medicine, participated in many clinical trials of NMOSD (12, 13, 23) and was involved in the development of guidelines for demyelinating diseases of the central nervous system, including NMOSD, MS, and myelin oligodendrocyte glycoprotein antibody-associated disease (9, 24, 25). Weinshenker, BG is a neurologist from the Mayo Clinic. He is famous for his contributions to exploring the diagnosis and treatment of NMOSD. He, as the corresponding author, published the article about the serum autoantibody marker of neuromyelitis optica (5); since then, NMOSD has been recognized as an independent disease different from MS. Wingerchuk, DM is also from Mayo Clinic, and had many collaborations with Weinshenker, BG in the NMOSD field (26–28); he, as first author, published the international consensus diagnostic criteria for NMOSD (9), and also published many high-quality reviews in the Lancet and The New England Journal of Medicine (1, 27). The VOSviewer software automatically divided all authors into different clusters. The authors from the same clusters contributed excellent scientific works to their region. We also observed Bennett JL as a bridge connecting Shi Fudong and other authors from different institutions (Figure 4A). They jointly published an open-label, multicenter, randomized, phase 2 trial of NMOSD (22). Collaboration has always been an important requirement for the advancement of scientific discovery.

In the top 10 most productive journals, Multiple Sclerosis and Related Disorders and Multiple Sclerosis Journal were the most productive journals, which were the specialist journals in the MS and NMOSD fields. In the future, it is expected that more important research results will be published in this journal, and the impact factor and scientific value will improve. The other remaining journals specialized in Neurology and Immunology. It is important for scientists to follow these journals to see how NMOSD is progressing and what might happen in the future. Furthermore, the journal analysis could help researchers avoid delays in the research process by quickly identifying the best journals for submission.

Co-citation analysis is an effective method to assess the level of correlation between articles. It is generally considered that the more frequently an article is cited, the greater its importance in the professional field (29). Most of the top 10 cited references were published in top-ranked journals, and three articles were written by Wingerchuk, DM (9, 27, 30); this result also confirmed the results of the author analysis. In the top 10 cited references, three of them were the diagnostic criteria for NMOSD. The formulation of guidelines plays an important role in the treatment of diseases. As a clinical decision-making tool to narrow the gap between current evidence-based medicine and clinical practice, clinical guidelines could improve diagnosis and treatment levels, standardize medical behavior, and improve service quality. Three of the top 10 cited references described the serological mechanism of NMOSD and the relationship between anti-AQP4 and NMOSD. The second cited article, entitled “A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis”, identified an NMO-IgG (5), which is a specific marker autoantibody that binds at or near the blood-brain barrier. It distinguishes NMO from MS. This important finding broadened the pathological concept of NMOSD. Additionally, the 10 most cited articles (20) were published in the Journal of Neuroinflammation”, which provided an overview of the clinical features of NMOSD and demonstrated a few distinct characteristics in seropositive and seronegative patients. Since the discovery of anti-AQP4, most of the hot topics have focused on seropositive patients, while some seronegative patients with typical NMOSD performance have also gradually attracted the attention of researchers in recent years. Therefore, on the basis of understanding the clinical characteristics of seropositive patients, we should further explore the field of seronegative patients, which is conducive to the diagnosis of seronegative patients, precision treatment, and guidance of clinical research. From the reference burst, the first burst reference emerged in 2003 owing to one study published in 2002 (7). This article used the pathological method to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. The strongest burst reference was the international consensus diagnostic criteria for NMOSD (9), which was the authoritative publication to guide clinicians in the NMOSD field. There were four articles still burst (12, 13, 21, 24), and three of them were RCTs on targeted immunotherapy of NMOSD. The successful publication of these articles provided evidence-based medical evidence for targeted immunotherapy for NMOSD. Among them, eculizumab, inbelizumab, and satralizumab have been approved for AQP4-NMOSD patients. These targeted biological agents are expected to improve the symptoms rapidly, accurately, and effectively, reduce the risk of relapse of NMOSD, reduce the side effects of steroids and traditional immunosuppressants, and reduce the disease burden on patients. There will need to be further exploration of more targeted biological agents for different targets in the future.

Keywords are a summary of the core ideas of an article and are generally considered to be important indicators reflecting research direction and hotspots in a specific field. The evolution and change of keywords over time reflect, to some extent, the development of hotspots and can guide future research directions. Through the overlay visualization, we can observe that the keywords gradually shifted from serological mechanisms and clinical characteristics to diagnosis and treatment for NMOSD, which also indicates that the research hotspots gradually changed from the basic study to clinical translation. The yellow nodes indicate emerging hotspots. We found that the research topics “COVID-19”, “neuroinflammation”, and “myelin oligodendrocyte glycoprotein” have received attention in recent years due to the COVID-19 pandemic, which has been a challenge for patients with autoimmune diseases. For patients with NMOSD, long-term use of steroids or traditional immunosuppressants may cause an immunosuppressive state. Therefore, they were at high risk of COVID-19 infection, and infection with COVID-19 may lead to NMOSD relapse or aggravation. Furthermore, the COVID-19 vaccination was an additional concern. On the one hand, it was necessary to consider whether the COVID-19 vaccination would lead to a relapse of NMOSD (31, 32). On the other hand, some patients would have new-onset NMOSD after the COVID-19 vaccination (33–36). This is why COVID-19 became a hot topic in NMOSD research. Since the discovery of anti-AQP4 in 2005 (6), the focus of research has always been on patients with anti-AQP4 seropositive NMOSD. In anti-AQP4 seronegative patients, anti-myelin oligodendrocyte glycoprotein (MOG) has been detected in patients with optic neuritis and longitudinally extensive transverse myelitis. MOG antibody-associated disease (MOGAD) has the same clinical characteristics as demyelinating diseases of the central nervous system, such as NMOSD and MS, but the difference is that its main manifestation is a monophasic or relapsing disease course, which has no marked sex or racial predominance in populations with MOGAD. The histopathological characteristics, imaging characteristics, treatment response, and outcomes of MOGAD are different from those of MS and NMOSD, so it is necessary to establish its diagnostic criteria as a distinct entity. The researchers still need to explore this area in the future.

The word “marker” was the strongest burst keyword, because in the development of NMOSD, the discovery of anti-AQP4 is very important. After the discovery of anti-AQP4 as a serum marker, NMOSD was separated from MS as an independent disease (6). Since then, the number of publications on NMOSD has increased over the past year, and many articles (37–40) have been published on its epidemiology, diagnosis, clinical characteristics, treatment regimens, treatment response, and outcomes. “Pathogenesis” was the keyword that burst for the longest time. This was because after exploring and establishing the pathogenesis of NMOSD, we could better understand its diagnosis and treatment and develop targeted biological agents acting on different targets of its pathogenesis. It can be seen from the keyword burst analysis that “safety”, “efficacy”, “tolerability”, and “multicenter” were the keywords around RCT, which indicates that the research of NMOSD entered the era of evidence-based medicine. The “interleukin 6 receptor blockade” was still burst, which due to the RCT on satralizumab showed positive results. Tocilizumab, another targeting IL-6R drug, also carried out a multi-center, randomized, phase II trial in NMOSD (22), which compared the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD. The results showed that tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD. It can be seen from the above mentioned keyword analysis that future research will focus on the targeted immunotherapy of NMOSD, on the development of targeted biological agents for different targets of its pathogenesis, and on conducting RCTs on the existing targeted biological agents to obtain higher-quality evidence-based medical evidence. Targeted immunotherapy will quickly and effectively reduce the relapse of NMOSD and further reduce the disease burden for patients.

This study has some limitations. First, this study utilized the WoSCC database as its data source and the data from other databases, such as PubMed, Cochrane, Scopus, and Embase library databases, has not been included. We used the same search strategy to search PubMed, and a total of 3,341 studies related to NMOSD were retrieved. After merging and duplicating the studies from WOS and PubMed, except for a few of them, almost all of the studies in PubMed were included in the WOS database, especially the significant influence and epoch-making significant studies in the field of NMOSD. Additionally, with the availability of many bibliometric indicators and containing 12,000 influential high-quality journals from countries worldwide, the WOS database is regarded as one of the most authoritative and optimal databases for the bibliometric analysis of scientific publications. Therefore, this limitation would not have impacted the analysis results. Second, only article/review publications in English were searched, and non-English or non-article/review publications were not included in this search, so some publications may have been missed. Third, the number of citations was not a complete indicator of the quality of publications because it takes time to cite manuscripts. Older publications may be cited more frequently, so influential manuscripts may take several years to be cited. Finally, bibliometric software such as CiteSpace and VOSviewer cannot provide statistical functions, so it is impossible to understand the actual situation of publications in different countries/regions.

To our knowledge, this study is the first bibliometric analysis of publications in the field of NMOSD using visualization software to obtain the direction, hotspots, and developments of this field, which may provide helpful information for researchers. Future research hotspots should obtain higher-quality evidence-based medical evidence on targeted immunotherapy in the NMOSD field.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

TC and ZL contributed to the conception and design of the study. YS, ZR, and SL performed the statistical analysis. YS, ZR, and SL were involved in writing the manuscript and drafting the article. YS, ZR, and SL contributed to data acquisition. All authors contributed to the article and approved the submitted version.