Research trends on herpes simplex encephalitis in children: a bibliometric analysis from 1975 to 2024

Introduction

Herpes simplex encephalitis (HSE) is a life-threatening viral infection of the central nervous system caused by herpes simplex virus type 1 (HSV-1) (1). It remains one of the most common causes of sporadic viral encephalitis in children, leading to significant morbidity and mortality worldwide (2). Even with prompt antiviral treatment, the disease can lead to severe neurological sequelae, including cognitive impairments, motor dysfunction, and seizures (3,4). The global incidence of HSE is estimated to range from 1 in 250,000 to 500,000 individuals annually, with children being disproportionately affected (5). Recent epidemiological studies underscore the substantial disease burden. Nationwide data from France [2015–2022] reported an annual incidence of 2.3 per million population, with a 6-month mortality of 16.5% and more than half of patients requiring intensive care (6). In the United States, neonatal HSV infection was estimated at 15.7 per 100,000 births in 2019, with a mortality rate of 4.6% and marked disparities by race and socioeconomic status (7). Long-term pediatric follow-up further shows that approximately one-third of survivors develop epilepsy, highlighting the persistent morbidity despite antiviral treatment (8). The high disease burden, combined with the potential for long-term neurological damage, imposes considerable challenges on healthcare systems and profound psychological and financial strain on affected families (9). In children, HSE typically presents with non-specific symptoms such as fever, headache, and vomiting, which may rapidly progress to more severe manifestations like seizures, focal neurological deficits, and altered consciousness (10). These overlapping symptoms with other common pediatric conditions complicate early diagnosis. While prompt initiation of antiviral therapy—most often acyclovir—is essential for improving patient outcomes, many children continue to experience residual deficits despite treatment (11). As research on pediatric HSE has advanced, it has become increasingly critical to examine the trends in diagnostic approaches, clinical management, and therapeutic developments in order to enhance care and alleviate the disease burden (12).

Bibliometrics, a quantitative and qualitative method of analyzing scientific publications, has emerged as a valuable tool for evaluating research trends, identifying hotspots, and mapping collaborations within a given field (13). By applying bibliometric analysis, researchers can pinpoint influential studies, prominent institutions, and emerging areas of interest, providing a comprehensive understanding of the field’s development (14,15). Despite the considerable volume of clinical and basic science research on HSE, no bibliometric analysis has systematically evaluated the research landscape on pediatric HSE. This study aims to address this gap by conducting a comprehensive bibliometric analysis of the published literature on pediatric HSE. The goal is to identify key research trends, evaluate the most impactful studies, and highlight under-explored areas. By addressing these gaps, this analysis seeks to inform future research directions and contribute the development of more effective diagnostic and therapeutic strategies for managing pediatric HSE. We present this article in accordance with the BIBLIO reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-408/rc).

Methods

Search strategies and data collection

A comprehensive literature search was conducted in the Web of Science Core Collection (WoSCC) on HSE in children (from 1975 to 2024), which has extensive coverage of more than 12,000 scholarly journals and provides the most comprehensive and reliable bibliometric analysis compared to databases such as Scopus, Medline, and PubMed (16). The search strategy involved using a combination of keywords to retrieve studies related to this field, including terms such as: (TS=(“herpes simplex encephalitis”)) AND TS=(pediatric* OR child*). The publication language in this study was set to English. Of various document types, only articles were considered. To avoid deviations from database renewal, we performed the literature retrieval on a single day (August 23, 2024). All information was collected in the format of text.

Statistical analysis

The tools employed for bibliometric analysis included Microsoft Excel (Version 2402, Microsoft Corporation, Redmond, WA, USA), VOSviewer (version 1.6.20, developed by the Centre for Science and Technology Studies, Leiden University), CiteSpace (version 6.3.R1, developed by Chaomei Chen, Drexel University), and R (version 4.3.3, https://www.r-project.org/).

VOSviewer is a versatile software tool that plays a critical role in mapping institutional collaboration, author collaboration, co-authorship, citation, and co-citation. Using VOSviewer, co-occurrence analysis exhibited the association among different keywords. The size of nodes represents the number of publications, the thickness of lines between two nodes symbols the strength of the link, and nodes of the same color belong to a cluster or grouping of similar items. Link strength is defined as the number of links of an item with other items (e.g., for co-authorship, link strength refers to the amount of association of a given author with other authors) (17).

CiteSpace was utilized to identify emerging trends and research hotspots through burst keyword analysis. The parameters were set as follows: time slicing from January 1994 to August 2024, with a 1-year interval. This analysis produced a keyword timeline graph that visually depicts the progression of research themes in pediatric HSE over time.

R-bibliometrix is an important R-tool for comprehensive bibliometric analysis designed in R language (18). Bibliometrix has powerful functions for creating bibliographic coupling networks, co-citation networks, co-authorship networks, and co-occurrence networks. With a complete process of data import, data transformation, data analysis, and scientific visualization, Bibliometrix basically meets the requirements of bibliometric analysis.

Microsoft Excel was used to compute key bibliometric indicators, including the annual number of publications, citation frequency, average citation frequency, journal names, journal impact factors (IF), countries/regions of publication, publishing institutions, and authors. Journals were classified into quartiles (Q1, Q2, Q3, Q4) based on their IFs within their respective academic fields, as reported by the 2023 Journal Citation Reports (JCR). Further bibliometric metrics such as the H-index, G-index, and M-index were calculated to quantify the academic impact of authors and journals. The H-index is the most widely used bibliometric metric and is defined as the number of papers h cited at least h times (19). The G-index is introduced as an improvement of the H-index to measure the global citation performance of a set of articles (20), whereas the M-index is the average number of citations received by the papers that make up the H-index (21). In this study, the H-index of each author was obtained from WoSCC.

Results

An overview of publications in research of HSE in children

This study initially included 413 records, with 127 non-article types removed, resulting in 286 eligible publications from 151 sources, as shown in the flowchart in Figure 1. Our investigation showed that 1,738 authors from 1,256 institutions across 200 countries contributed to producing 286 manuscripts in this study. These publications appeared in 151 different journals and collectively cited 7,071 references. As illustrated in Figure 2A, international collaborations were noted in 19.23% of the studies. On average, each document received 45.1 citations, with the average age of the documents being 15.6 years. The ‘average age of the documents’ refers to the mean time elapsed between the publication year of each article and the year of our analysis [2024]. This metric was calculated by subtracting the publication year of each article from 2024 and averaging the results across all 286 publications.

Figure 1 Flowchart of the literature screening process.

Figure 2 Analysis of general information. (A) Summary information of the included studies. (B) Growth trend of the publications worldwide.

The figure illustrates the growth in the number of publications related to HSE in children from 1991 to 2024. After a relatively fluctuating trend with notable peaks and drops in the 1990s, major fluctuations occurred throughout the years, with significant peaks in 2007 (n=13), 2012 (n=15), and 2015 (n=16). The number of publications reached a peak of 16 in 2015, reflecting a strong and growing research interest in the field. In addition, in order to further evaluate the change trend on HSE in children, the predictive equation for cumulative publication count (Y) as a function of publication year (x) is Y = 9.52x − 18933.30, The R-squared value for predicting the number of annual publications was 97.5% (R²=0.975) (Figure 2B).

Country insights and trends of HSE in children

A total of 200 countries contributed publications in this field. The top 20 most productive countries generated 243 articles, accounting for 85.0% of the papers of the total publications worldwide, spanning continents such as Asia, North America, Europe, and Oceania. The United States emerged as the leading contributor, with 57 articles, followed by the United Kingdom (n=28) and China (n=23). In terms of citations, the United States amassed the highest number, with 2,991 citations. The United Kingdom followed with 2,125 citations, France with 2,198 citations, and Japan with 1,115 citations (Table 1). Denmark had the highest multiple-country publications (MCP) ratio at 60%, followed by France (47.1%) and Spain (42.9%) (Figure 3A), indicating strong international collaboration in these countries. Further analysis of co-authorship patterns using VOSviewer included 24 countries with a minimum of three co-authored documents (Figure 3B). The United States led in international collaborations, with 93 co-authorship links, followed by France (n=77) and the United Kingdom (n=41).

Figure 3 Analysis of countries/regions. (A) Distribution of corresponding author’s publications by country. (B) Visualization map depicting the collaboration among different countries/regions. MCP, multiple country publications; SCP, single country publications.

Journals insights and trends

The general characteristics of the 20 most productive journals that publishing research on HSE in children over the past years are presented in Table 2. These journals published 120 studies, accounting for 42% of all retrieved publications. The most influential contributions appeared in high-impact journals, such as Pediatric Neurology and Clinical Infectious Diseases. Pediatric Neurology (IF =3.2; H-index =7; TP =13) had the highest total publications. It was followed by Journal of Child Neurology (IF =2.0; H-index =6; TP =12). Clinical Infectious Diseases (IF =8.2; H-index =7; TP =7) had the highest total citations (n=342). Other notable contributors include Pediatrics (IF =6.2; H-index =8; TP =9) and Pediatric Infectious Disease Journal (IF =2.9; H-index =6; TP =10), both of which made significant contributions to the literature. In terms of total citations, Clinical Infectious Diseases (n=342) ranked first, followed by Neurology (n=324) and Pediatrics (n=213). The majority of top-ranking journals, including Pediatric Neurology and Clinical Infectious Diseases, are classified in Q1 according to the 2023 JCR rankings.

The network visualization of journal co-citation analysis showed that 24 journals with at least three occurrences formed co-occurrence networks (Figure 4A). The journals with the highest total link strength were Clinical Infectious Diseases (n=40), and Pediatrics (n=37), Neurology (n=32). Additionally, journal coupling networks revealed 24 journals with at least three coupling connections (Figure 4B). The journals with the highest total link strength in co-occurrence networks were the Journal of Child Neurology (n=564), Journal of Experimental Medicine (n=443), and Journal of Infection (n=436).

Figure 4 Analysis of journals. (A) Visualization map depicting the co-occurrence network. (B) Visualization map depicting the coupling network.

Authors insights and trends

A total of 1,738 authors contributed to the publications in this field. The top 20 most influential authors are listed in Table 3. Casanova JL is the most influential author, holding the highest H-index of 14, with 2,550 total citations and leading in total publications (TP =19). Zhang SY follows closely with an H-index of 13, 2,397 citations, and ranks second in total publications (TP =17). Rozenberg F and Abel L both have H-index values of 12 and 11, respectively, with Abel L showing a strong M-index of 0.611. Other notable contributors include Lorenzo L (H-index =10; TP =12) and Solomon T (H-index =9; TP =11), both of whom have made significant impacts in the field with over 1,000 citations each. The network of co-authors of research findings on HSE in children showed division into 5 groups (Figure 5). Among the 133 authors involved in international collaborations with a minimum of 2 articles, Casanova JL has the highest number of collaborations with other authors (n=67), followed by Zhang SY (n=64) and Abel L (n=55).

Figure 5 Visualization map depicting the collaboration among different authors.

Institutions insights and trends

The top 10 institutions contributing to the literature on HSE in children are displayed in Figure 6A. Université Paris Cité leads the list with 84 articles, followed by Assistance Publique Hôpitaux Paris (APHP) with 61 articles, and Institut National de la Santé et de la Recherche Médicale (INSERM) with 37 articles. Other key institutions include Hôpital Universitaire Necker-Enfants Malades-APHP (24 articles) and the University of London (23 articles). Collaborative relationships among 66 institutions, each with a total link strength of at least 3, were visualized (Figure 6B). The top three cooperation groups exhibited strong collaborations with other institutions. Rockefeller University had the highest number of collaborations (n=77), followed by the Howard Hughes Medical Institute (n=45) and Hôpital des Enfants Malades (Hospital of the Sick Children) (n=43).

Figure 6 Analysis of institutions. (A) Top ten institutions by article count and rank. (B) Visualization networks of institution collaborations.

Keywords analysis

A comprehensive keyword analysis was performed using VOSviewer, identifying 88 keywords with a minimum of three occurrences (Figure 7A). Between 2006 and 2010, terms like “herpes-simplex encephalitis”, “children”, and “cerebrospinal fluid” were prevalent, reflecting early research focus areas. From 2010 to 2012, keywords such as “virus infections”, “infections”, and “acyclovir” gained prominence, indicating increased attention to treatment approaches and viral mechanisms. Between 2012 and 2014, keywords like “toll-like receptor-3”, “immunity”, and “deficiency” became significant. After 2014, terms such as “autoimmunity”, “interferons”, and “susceptibility” became prominent, highlighting recent research emphasis on immune modulation and genetic susceptibility in encephalitis.

Figure 7 Analysis of keywords. (A) Visual analysis of keyword co-occurrence network analysis. (B) Top 20 keywords with the strongest citation bursts. NMDAR, N-methyl-D-aspartate receptor.

In addition, keyword burst detection was employed to identify research hotspots. The top 20 strongest keywords bursts during the period of 1994–2024 are shown in Figure 7B. The most significant citation burst belongs to “cerebrospinal fluid”. Notably, since 2017, the keywords “acute disseminated encephalomyelitis”, “antibody”, “anti-NMDAR encephalitis”, and “expression” has been more prominently concentrated, indicating promising developments. The keyword “cerebrospinal fluid” has the highest citation burst strength, with a value of 5.89. Keywords such as “polymerase chain reaction” began gaining influence between 1996 and exhibited bursts from 2012 to 2013. Similarly, “infection” showed a burst starting in 2014 and continuing until 2016. More recent bursts include terms like “antibody” and “anti-NMDAR encephalitis” which exhibited bursts from 2017 to 2021 and 2017 to 2020, respectively. The keyword “expression” has been showing influence since 2017, with its burst projected to last until 2024, indicating continued interest in gene expression and its role in the pathology of encephalitis.

Discussion

This bibliometric analysis of research on HSE in children highlights the global scientific activity in the field from 1975 to 2024. Over this period, countries, institutions, authors, and journals have emerged as prominent contributors, driving the research forward and demonstrating several commonalities that may explain their leadership in this area.

General information

In the field of pediatric HSE research, the number of publications on pediatric HSE decreased from 11 per year to 5 per year from 2019 to 2020. This decline can be attributed to several factors. First, the coronavirus disease 2019 (COVID-19) pandemic diverted significant academic resources toward urgent public health priorities, affecting research across various fields, including HSE. This shift is reflected in changes to publication volumes, as resources were reallocated to more immediate needs (22). Additionally, with major genetic and immunological breakthroughs now established, such as the identification of mutations in TLR3 and UNC-93B genes, the focus of research may have shifted toward more specialized areas, contributing to a decrease in overall publication growth (23). In terms of countries, the United States leads in both the number of publications and citations, driven in part by significant funding from the National Institutes of Health (NIH). Institutions such as Rockefeller University and the Howard Hughes Medical Institute have made notable contributions, particularly in genetic studies investigating susceptibility factors such as TLR3 and UNC-93B mutations (24). In Europe, France and the United Kingdom have excelled in immunological research, with institutions like Université Paris Cité and INSERM focusing on the genetic basis of immune responses to HSE in children (3). Countries like Denmark have strong international collaborations, indicated by high MCP ratios, facilitating research on genetic mutations across borders (25). Influential researchers like Zhang SY and Casanova JL have contributed to understanding genetic immunodeficiencies, advancing treatment approaches for children predisposed to severe HSE. Although author and institutional collaboration networks provide valuable insights into global research trends, we acknowledge the potential risks of conflicts of interest when detailing these relationships. We have therefore ensured that the focus remains on understanding the global landscape of HSE research. Journals such as Pediatric Neurology and Clinical Infectious Diseases play key roles in disseminating high-impact research on neurological and infectious aspects of HSE in children (26). While some of the journals cited in the manuscript may have IF below 3, they are highly regarded within the field of pediatric infectious diseases and neurology. The selection of these journals was based on their relevance to the topic of pediatric HSE, rather than solely their IF. Many influential studies have been published in specialized journals that focus on specific aspects of the disease, and their contribution to advancing research in HSE is significant.

Co-occurrence analysis of keywords

The co-occurrence analysis of keywords reveals a distinct shift in research focus over time. During the early years [2006–2010], research centered around diagnosis and treatment, with polymerase chain reaction (PCR) and acyclovir being key themes. Studies demonstrated that PCR, by detecting HSV-1 DNA in cerebrospinal fluid (CSF), significantly improved early diagnosis and facilitated more effective antiviral treatment (27,28). The introduction of acyclovir revolutionized HSE treatment, reducing mortality rates. From 2010 to 2014, the focus shifted towards immune mechanisms, such as toll-like receptors (TLRs) and interferons, with research identifying genetic mutations in the TLR3 pathway that compromised innate immune responses to HSV-1, increasing susceptibility in children (25). From 2015 onward, research has increasingly focused on autoimmune responses, particularly involving N-methyl-D-aspartate receptor (NMDAR) antibodies. Sutcu et al. reported that NMDAR antibodies were frequently detected in children with relapsing autoimmune encephalitis following HSE, indicating a crucial area for further study (29). These findings underscore the dynamic evolution in understanding the immune processes involved in pediatric HSE.

Burst analysis of keywords

The burst analysis identified significant research trends from 1975 to 2024, with particular emphasis on pediatric HSE and its complications. Autoimmunity, NMDAR encephalitis, and gene expression have gained prominence, reflecting increased attention to immune complications following HSE, particularly in children. A prospective study revealed that 27% of children with HSE developed autoimmune encephalitis, often mediated by NMDAR antibodies. This condition is linked to severe neurological relapses, including movement disorders and psychosis, making it a critical concern (30). These findings highlight the need for early detection and timely immunotherapy to mitigate long-term neurological impacts. Additionally, research by Piret and Boivin emphasized that deficiencies in the TLR3-IFN pathway in pediatric patients can impair immune responses to HSV-1, increasing the risk of severe encephalitis (31). Moving forward, continued research into autoimmune responses and gene expression will likely drive personalized therapies aimed at reducing the long-term neurological sequelae of HSE in children.

Implications for future research

As research progresses, several key areas warrant further investigation. First, there is increasing recognition of the role of genetic mutations and immune dysregulation in the pathogenesis of HSE (32). Identifying specific genetic markers, such as mutations in the TLR3 and interferon pathways, could lead to personalized treatment strategies that target both viral replication and immune responses (33,34). Genetic screening may help identify children at higher risk for severe HSE, enabling earlier intervention and improved clinical outcomes (3,24). In addition, future research is likely to explore novel therapeutic approaches that combine antiviral drugs with immunomodulatory agents. Some studies propose that combining antivirals, such as acyclovir, with targeted immunosuppressive therapies could prevent both viral reactivation and immune-mediated damage in children with HSE (26,35). Clinical trials investigating such combination therapies may offer new opportunities for improving survival rates and minimizing long-term neurological impairments in pediatric HSE patients.

Strengths and limitations

There are several strengths in this study. First, it is the first bibliometric analysis to assess nearly five decades of research on pediatric HSE worldwide. Second, the analysis provides comprehensive insights into the contributions of leading countries, authors, institutions, and journals in this field. However, there are also limitations in this study. The reliance on citation counts may not fully capture the clinical impact of certain articles, and the exclusion of non-English publications could restrict the scope of the analysis.

Conclusions

This bibliometric analysis offers a comprehensive evaluation of research on HSE in children, providing valuable insights into global publication trends and collaborative networks across countries, institutions, and authors. The analysis identified key research hotspots in diagnostics and therapeutic strategies, particularly antiviral therapies and immune mechanisms. This study highlights emerging trends in pediatric HSE research and offers a roadmap for future investigations. For researchers and clinicians in this field, the study underscores the importance of exploring areas such as genetic screening and immunomodulatory therapies, which hold promise for advancing clinical practice and improving patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-408/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-408/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-408/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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