Global research on cysticercosis and neurocysticercosis: A bibliometric analysis

Abstract

Introduction

Neglected tropical diseases (NTDs) are a heterogeneous group, defined by their prevalent nature in tropical or subtropical areas and their disproportional impact on impoverished communities, for which they impose a significant human, social and economic burden (1–3).

NTDs mainly comprise parasitic infections, such as Chagas disease, dracunculiasis, echinococcosis, trypanosomiasis, leishmaniasis, lymphatic filariasis, onchocerciasis, or taeniasis/cysticercosis. These diseases pose a major challenge due to their endemic nature in countries with relatively underdeveloped health systems and limited scientific capacity. Thus, research must prioritize the burdens and healthcare needs associated with the disease, which frequently encompass its proper diagnosis and assured treatment for the affected populations (4, 5).

Cysticercosis is caused by the larval stage of cestode T. solium. It is acquired by the ingestion of T. solium eggs, shed in the stool of a human tapeworm carrier. Following ingestion, embryos (oncospheres) hatch in the small intestine, invade the bowel wall, and disseminate hematogenously to brain (neurocysticercosis, causing different neurological symptoms like “epilepsy”) “striated muscles,” “liver,” and/or other tissues.

Neurocysticercosis is endemic to much of Asia, sub-Saharan Africa, and Latin America, where it constitutes a prominent public health problem associated with poverty and poor sanitary and hygienic conditions (6). Its prevalence is probably underestimated due both to the difficulty in diagnosing it (since it often produces mild and non-specific symptoms) and the lack of observational studies in different populations and countries (7). The estimated burden of human cysticercosis, according to systematic reviews or similar studies published from 2010 to 2015, is 2.78 million disability-adjusted life years (DALYs) (95% uncertainty intervals 2.14-3.61 million) (8). Neurocysticercosis is responsible for 30% to 70% of epilepsies in some endemic countries and regions (9, 10).

The literature contains extensive bibliometric analyses of NTDs such as leishmaniasis, Chagas, schistosomiasis, trypanosomiasis, and echinococcosis, among others, including some papers that focus on specific regions or countries such as Nigeria and India (11–15). However, no publications are available that analyze the scientific production on cysticercosis/neurocysticercosis.

The objective of this study is to describe the research on cysticercosis and neurocysticercosis, analyzing the evolution of scientific production, the distribution of contributions from different countries based on the endemicity of the disease and income level of the country, the relevance of international collaboration, and the defining features that characterize research on this NTD at the thematic and methodological level.

Materials and methods

The MEDLINE database was used to carry out the analysis since it has the Medical Subject Headings (MeSH) thesaurus that allows very precise searches and because it is the most widely used source of information in the field of health sciences (mainly, English).

Results

In the MeSH search, the term “cysticercosis” and/or “neurocysticercosis” was assigned to 6,448 documents between 1928 (oldest reference identified) and 2021, while the free text search yielded another 1,499 records, a total 7,947 documents. The terms coenurosis and/or neurocoenurosis/cerebral coenurosis are present in the title of 104 documents and the abstract of 96 documents (in total 148 different documents, only 1.88% of the total number of documents analyzed). Eighty-seven records were excluded: 49 editorials and 38 other document types. The final analysis included only 7,860 articles, reviews, and letters—the document types commonly used in bibliometric studies because of their relevance for research and their reporting of original knowledge.

The main document type was journal article (n = 6,474; 82.4%), followed by review (n = 873, 11.1%) and letter (n = 513; 6.5%) (Table 1). Figure 1 shows the annual number of publications, which follows a linear growth trend (R² = 0.92). Fewer than 20 documents were published annually from 1928 to 1948, 20 to 49 documents from 1950 to 1969, 50 to 99 from 1970 to 1987, 100 to 200 from 1988 to 1999, and more than 200 documents from 2010 to 2021.

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Figure 1

Evolution of the annual number of documents published on cysticercosis and neurocysticercosis and included in the MEDLINE database.

There were 2,931 documents (37.3% of the total) with specific information available on the study design or type of evidence provided. Case reports were the most common type of study (n = 2,155, 27.4%), whereas papers presenting the highest levels of scientific evidence, such as clinical studies (1.9%, n = 149) or systematic reviews (0.8%, n = 63), were quite sparse, and the presence of clinical practice guidelines was anecdotal (0.1%, n = 6).

The 7,860 papers about cysticercosis were published in 1,554 journals. There were 23 journals (1.5%) that published more than 49 papers; together, these journals were responsible for 25.6% of the total records. Another 767 journals (49.4%) published a single document on the topic. The leading journals were Arquivos de Neuro-Psiquiatria (the official journal of the Brazilian Academy of Neurology) and the American Journal of Tropical Medicine and Hygiene (the official journal of the American Society of Tropical Medicine and Hygiene); each published 188 documents (2.4%). Veterinary Parasitology (the official organ of the American Association of Veterinary Parasitologists, the European Veterinary Parasitology College, and the World Association for the Advancement of Veterinary Parasitology) also stood out with 148 documents (1.9%) (Table 2).

The most productive journals included 7 high-impact journals (Q1 according to the journal impact factor ranking in the 2021 edition of Journal Citation Reports, JCR), along with various others with less visibility (4 journals in Q2, 4 journals in Q3, 5 journals in Q4 and one journal as a candidate in the Emerging Source Citation Index). Only two of the most productive journals (Chinese Journal of Parasitology and Parasitic Diseases and The Journal of the Association of Physicians of India) are not included in the JCR.

Of the countries represented in the authors' institutional affiliations, 46.4% were non-endemic and 40.7%, endemic. The proportion of contributions by researchers from endemic countries increased from 39% in 1980–2000 to 69.4% in 2001–2021. In terms of economic development as measured using the GNI, authors in high-income countries participated in 47.7% of the documents, well ahead of participation by authors in upper middle-income (29.6%), lower middle-income (19.6%), and low-income countries (2.6%), even though endemic countries are concentrated in these latter categories (Table 3). Figure 2 shows research activity in endemic countries and Supplementary Annex I contains the complete list of scientific activity in endemic countries and countries where transmission is suspected.

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Figure 2

Research on cysticercosis and neurocysticercosis from countries where T. solium is endemic included in the MEDLINE database (> 10 papers).

In the analysis of scientific production by country, the most significant finding is that the highest production levels (>100 documents) were shared by countries endemic for T. solium along with some countries with the highest scientific development. Thus, after the USA (n = 2,292 documents), research output was highest in India (n = 1,749), Mexico (n = 1,414, non-endemic country, but classified as having “few pigs with risk factors”), Brazil (n = 941) and Peru (n = 898). Next, research was carried out in different countries in Europe and Asia (China, Japan, and South Korea), along with Australia, Canada, and other endemic countries such as Ecuador, Tanzania, Thailand, and Kenya (Table 4).

The manuscripts where there are authors from two or more institutions from different countries was considered an international collaboration (information available in 4,642 documents). Globally, 28.6% (n = 1,330) of the documents analyzed were produced in international collaboration. Collaboration increased throughout the study period, from 5.2% of the documents (n = 7) published before 1980, to 17.7% (n = 190) in 1980–2000, to 32.9% in 2001–2021.

In the case of documents with international collaboration, we also analyzed the country of the first author and corresponding author (information available in 4,642 documents), roles that can be associated with research leadership, that is, a more relevant contribution to the conception, promotion, and responsibility for the studies carried out The level of international collaboration varied widely by country, with some countries presenting very low values, such as India (9.9% of documents in international collaboration) or Brazil (18.7%); and others displaying high levels of collaboration, such as Peru (91.3%), Tanzania (88.2%), or Kenya (93.1%). However, this high international collaboration contrasts with their low levels of research leadership, with limited participation as first or corresponding authors (Table 4).

In relation to the thematic areas, research in animals shares the spotlight with research in humans, with both spheres coinciding more and more (Table 5). Overall, 46.9% of the documents (n = 3,690) are focused exclusively on research in humans compared to 16.8% in animals, although the documents assigned with both descriptors rose from 24.1% (n = 570) in 1980–2000 to 32.8% (n = 1,400) in 2001–2021.

“Diagnosis” (n = 2,299) is the main qualifier assigned to the descriptors cysticercosis and neurocysticercosis, followed by “epidemiology” (n = 1,133), “complications” (n = 1,125) and “drug therapy” (n = 1,043). “Parasitology” (n = 1,019) and “veterinary” (n = 930) also have a notable presence (Table 6).

The most prominent descriptors related to diagnostic procedures and techniques were the diagnostic imaging procedures “tomography, x-ray computed” (n = 961), “magnetic resonance imaging” (n = 823) and, less frequently, “radiography” (n = 186) and “ultrasonography” (n = 86). Different methods and procedures for diagnosing diseases of the nervous system are also present, such as “electroencephalography” (n = 113) and “cerebral ventriculography” (n = 57).

Although “adult” (n = 2,315) is the main descriptor in relation to age groups, research linked to “adolescent” (n = 1,214) and “child” (n = 1,128) also has a notable presence (Table 7).

Figure 3 presents the network of thematic clusters generated from the co-occurrence of the MeSH terms. Research interest is concentrated in three spheres:

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Figure 3

Thematic clusters generated from the MeSH descriptors assigned to the documents published on cysticercosis and neurocysticercosis and indexed in MEDLINE.

- Basic research. This cluster addresses the development of animal models, DNA sequencing, immunization, and vaccine development, among other aspects.

- Parasitism, animal health and zoonoses. Parasitic diseases linked to different animal species stand out in this cluster (echinococcosis, toxoplasmosis, trichinellosis, schistosomiasis, etc.). The possibility that the pathogens causing them are transmitted to humans (zoonosis) through food or inadequate hygienic conditions is reflected through different terms (e.g., health education, food health, rural health).

- Diagnosis and therapeutic approach. Within this area, brain diseases and eye diseases show specific development. There is a well-defined research cluster focusing on diseases that affect the brain, including epilepsy, hydrocephalus, brain neoplasms, gliomas, and meningitis. This cluster also encompasses associated symptoms and clinical manifestations, such as headache, intracranial pressure, and granulomas; and general descriptions of diagnostic methods, treatments (anti-inflammatory, antiparasitic, antiprotozoal or anthelmintic agents), and compounds (albenzadole, praziquantel, prednisone, prednisolone). Several eye diseases also stand out for the research interest they attract, including parasitic, conjunctive, retinal and orbital eye diseases.

Supplementary Annex II contains the list of the main MeSH terms (assigned to > 99 documents).

Discussion

The evolution of scientific output on cysticercosis and neurocysticercosis shows a moderate but sustained increase in productivity in comparison to the study by Delgado et al. (16), who analyzed the publications indexed in MEDLINE from 1965 to 1995. Our results show that Latin American countries, together with the USA and Asian countries like India, China, Japan, and South Korea, lead research on the topic, while African countries are less present in the literature. These findings reflect a shift in scientific production since Delgado et al. (16) published their analysis, in which Asian and African researchers and institutions of reference were absent.

The scientific production on cysticercosis and neurocysticercosis in the present study (147–197 documents/year between 2001 and 2010 and over 200 documents per year since 2010) is significantly lower than that observed for other NTDs in MEDLINE, for example Chagas disease, with values above 500 documents per year since 2000 (17), or leishmaniasis, whose scientific output has been above 800 documents per year since the same date (18). There also seems to be more research activity on chikungunya, as the scientific output of the most recent year (2014) reported in the study by Vera-Polania et al. (19) was over 300 papers. This lower scientific production in global terms, together with other factors observed in this study, such as the lack of participation in research activities in many endemic countries or the fact that the damage associated with cysticercosis assessed using DALYs is higher than many other NTDs in recent published reports, including Chagas disease and leishmaniasis used as comparative references, highlights the relevance of promoting research in the field analyzed (20).

Research production on cysticercosis and neurocysticercosis is much greater in the USA than in Europe. The reasons for this difference reside in various factors, particularly the flow of immigrants from endemic countries to the USA (21, 22), which has led to the spread of neurocysticercosis to this country and its local transmission, making it a prominent public health problem. Researchers have highlighted the relevance of screening high-risk patients, prompt care for those infected, and transmission control, while the greater access to health and diagnostic systems in the USA compared to endemic countries also contributes to the research interest here.

The endemicity of the infection in the Indian subcontinent and in a large part of Latin America, areas where there is close contact with domestic animal hosts and less hygienic conditions (23–26), helps to explain the outstanding scientific production in countries such as India, Mexico, Brazil, and Peru, where there are prominent reference centers for research on the disease and its associated conditions, such as epilepsy (27, 28). In this regard, some studies have pointed out that infection is responsible for 30% of all epilepsies in developing countries (27, 28). On the other hand, other endemic countries in Latin America show little to no scientific production: no documents were authored by researchers in Paraguay, while the presence of other countries such as Haiti, the Dominican Republic, Nicaragua, and El Salvador is negligible. This is also the case for endemic countries in Africa: institutional affiliations in Togo, Rwanda, Gambia, the Republic of the Congo, Ghana, and Namibia are very limited, and no publications were identified with authors in Angola, Chad, South Sudan, Guinea-Bissau, or Cape Verde. The null participation in research on cysticercosis and neurocysticercosis also extends to “suspected endemic” countries (Bangladesh, Guinea, Sierra Leone, Lesotho, Equatorial Guinea, Eswatini, and Timor-Leste) or countries with “possible transmission” according to the WHO (Eritrea, Somalia and Turkmenistan). Furthermore, many other endemic countries have only made limited scientific contributions to the international literature (just 9 of the 55 endemic countries have published more than 100 papers). It is therefore essential to promote economic investments, structures, and collaborative initiatives to foster research in the geographical areas and low- to middle-income countries where the disease has the largest impact. Such initiatives are relevant both in the case of cysticercosis and neurocysticercosis, analyzed in the present study, and more broadly for the rest of the NTDs (29, 30).

The case of Peru is paradigmatic in terms of the development of biomedical research on cysticercosis and neurocysticercosis. There, policies aimed at promoting training programs and international alliances have nurtured the country's research culture and attracted international funding, which has resulted in a significant increase in scientific productivity, particularly on topics such as the most prevalent infectious diseases or endemic NTDs that affect the country (31).

Scientific collaboration has emerged as a crucial mechanism for promoting research and particularly for generating synergies between countries with more and less economic development. This has also been the experience in relation to other endemic as HIV infection or emerging NTDs as Chagas disease, that are difficult to control in countries with less socioeconomic development (12, 32, 33). In countries with lower income levels, smaller populations, and scientific systems with less capacity, including Peru but also Ecuador, Tanzania, Kenya and Thailand, the high level of international collaboration (65% to 93% of the documents on cysticercosis and neurocysticercosis) contrasts with the lower levels observed in larger countries like Mexico, Brazil, and India (< 31%). While international collaboration is positive, the fact that few researchers from low- to middle-income countries (e.g., Peru or Tanzania) take on leadership roles as first or corresponding authors shows the need to promote balance in research development, which involves strengthening the national scientific systems and scientific excellence in these settings (31, 34).

Research on cysticercosis and neurocysticercosis in humans is dominated by case studies (27.4% of publications vs. only 3.1% of clinical studies or 0.8% of systematic reviews). This can be explained by the fact that the disease has unusual manifestations, presents an atypical course, and requires differential treatments that need to be clearly communicated to the scientific community for clinical practice (35). Moreover, diagnosing neurocysticercosis is complex, especially in many endemic areas that lack the necessary diagnostic imaging equipment (36). For all these reasons, despite the fact that case studies are located at the bottom of the hierarchy of scientific evidence (37), this study design has outstanding relevance for diagnosis and clinical practice, as also determined in relation to other rare diseases and NTDs (38).

The fact that cysticercosis is a zoonotic disease, transmissible between animals and humans, reinforces the relevance of the One Health approach. This research paradigm integrates animal, human, and environmental health, and it favors mechanisms that allow the translation of evidence to health policies and practices (39). The impact of this approach on cysticercosis research is evident: the proportion of documents assigned with descriptors for both “human” and “animal” has increased from just 13% of those published before 1979 to 36% from the year 2000 onward. Furthermore, there is a notable presence of journals focused on tropical medicine in relation to human health (American Journal of Tropical Medicine and Hygiene); parasitology journals that cover human and animal health (particularly in the tropics and sub-tropics), the control of parasitic diseases, and the relationship between the host and the parasite (Acta Tropica or Parasitology Research); and veterinary journals, more focused on animal health, but whose research is crucial for global health (Veterinary Parasitology).

The thematic analysis enabled the identification and characterization of the main lines of inquiry that have shaped the development of research on cysticercosis and neurocysticercosis:

- Basic research and animal models allow a better understanding of the pathophysiology of the disease, determining the processes that take place during the development of the infection in the different species of animals and their immune response. As described in the literature, basic research in animals can contribute to determining risk factors and identifying specific biomarkers that signal the development of the disease or inform the development of vaccines (40, 41).

- The transmission models of the T. solium parasite and the animal health control measures represent tools for controlling the disease in humans, as reflected through different works that address food control, education, and health in rural areas, particularly in countries with low resources where this parasitism has a significant economic impact (42).

- Research on the disease in humans, its prognosis and therapeutic approach, constitute the third main research focus on cysticercosis and neurocysticercosis. Within this area, in relation to diagnosis, which remains the primary reference for research (16), research on brain diseases and parasitic eye diseases show specific development.

The fact that neurocysticercosis is one of the most common causes of epilepsy and other neurological manifestations, especially in endemic areas, is reflected in clinical research on brain diseases (9, 10, 43). The analysis also shows the relevance of the manifestations of cysticercosis outside the central nervous system, through ophthalmological involvement of the eyelids, the conjunctiva, and the anterior chamber (44), or the co-occurrence of intracranial and intraocular cysticercosis as a common phenomenon in clinical practice. Indeed, numerous cases of unusual presentations of cysticercosis in the eyes have also been published. Other organs that can be affected are the subcutaneous tissue, skeletal muscles, lungs, heart, thyroid, and pancreas (45).

Regarding the therapeutic approach to cysticercosis and neurocysticercosis, Singhi and Saini (46) highlighted the lack of a gold standard test to diagnose neurocysticercosis and the incipient nature of the management recommendations. Anthelmintics (drugs to treat worm infections) such as albendazole and praziquantel have been used to treat central nervous system lesions in neurocysticercosis, as have cysticides, although there is no clearly established clinical evidence (47). Thus, it is crucial to perform clinical trials that generate knowledge on adequate treatments (48, 49). Other aspects of treatment in humans relate to antiepileptic drugs to treat seizures (41) and the use of steroids, their indication, and duration (50, 51).

Limitations

The main limitations of this study include the use of the MEDLINE database as a source of bibliographic data, which may have led to the omission of relevant publications in the analysis, particularly those published in endemic countries in languages other than English and literature related to psychosocial aspects. As an example, the same search carried out in the databases of the Virtual Health Library (VHL, https://bvsalud.org/en/), excluding MEDLINE, identifies 1,438 (18.09%) additional documents, with Spanish (n = 555, 6.98%), Portuguese (n = 298, 3.75%), Korean (n = 128, 1.61%) and Chinese (n = 77, 0.97%) standing out. Another relevant aspect to keep in mind is that the MeSH thesaurus includes the term coenurosis as a synonym for cysticercosis. This larval form, although present in members of the genus Taenia, is unrelated to T. solium or cysticercosis. This circumstance has had a limited incidence in the present analysis, may be relevant for future studies if these entities are not differentiated in the MeSH thesaurus. In addition, there are limitations inherent to the use of bibliometrics as a research methodology, which offers a quantitative vision of the development of research, as reflected in the form of publications and particularly scientific journals. Future lines of research can analyze the participation of research groups in publications on cysticercosis/neurocysticercosis and their impact.

Conclusions

The generation of knowledge about cysticercosis as a neglected tropical disease presents different features from other areas of research. Case studies are the most prominent study design used, and some endemic countries are among the most prolific producers of research, in many cases overtaking the countries with far more established scientific systems. Nevertheless, authors from many other countries—especially those with less economic development—show negligible levels of participation. The relevance of comprehensive approaches to research (animal and human health) is also noteworthy. Studies that provide higher levels of scientific evidence should be promoted, and the participation and leadership of researchers from all endemic countries should be encouraged.

Data availability statement

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

Author contributions

J-MR-R and GG-A planned and designed the project, performed the analysis of data, and write original draft. NS, LS, and IB-R performed the interpretation of data. All authors reviewed the manuscript.

Funding Statement

This study was financed in part through a grant from the Spanish Ministry of Universities, in Modality A, Research stays by senior professors and researchers in foreign centers, 2021 (No: PRX21/00396).

References