The International League Against Epilepsy (ILAE) classification of epilepsies was updated on 2017, and it now classifies epilepsy according to seizure type, epilepsy type, and etiology.¹ Generalized epilepsy refers to the seizures originating at some point within or rapidly engaging distributed networks bilaterally, the subcortical or cortical structures, or frequently both of these.¹ A genetic etiology is defined when epilepsy directly results from a known or presumed genetic defect and the seizures are the core symptom of the disorder.¹ The term genetic generalized epilepsy (GGE) is used when a patient has generalized seizures of genetic origin and a well-recognized and established epilepsy syndrome, and includes childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with tonic-clonic seizures alone.^1,2 GGE has previously been termed “idiopathic generalized epilepsy,” but the ILAE recommend changing this to “genetic generalized epilepsy” due to “idiopathic” being considered too imprecise.¹ Individuals with GGE account for 20% of all epilepsy cases.³ GGE occurs mostly in young people, and with a proper diagnosis and management can be controlled with medications in 80% of cases.³

The number of times that a previously published work is cited is an indicator of its recognition and impact in an area of investigation.^4-6 Citation analysis is a systematic approach for identifying scientific studies that have had a high impact in a particular field. Reviewing articles that are cited frequently can provide information about the dominant areas of a discipline, as well as identify growth areas in particular fields. Furthermore, the top-cited articles are often written by recognized experts who can offer novel insight into the future directions of the discipline.^4-6

Several recent studies have applied citation analysis or bibliometric analysis to various neurological fields, including stroke,⁷ headache disorders,⁸ central nervous system inflammatory demyelinating disease,⁹ Guillain-Barré syndrome,¹⁰ epilepsy and status epilepticus,¹¹ and general neurology.¹² However, to the best of our knowledge, no previous study has comprehensively investigated the top-cited articles in the field of GGE. The purpose of this study was to identify the top-100 cited articles (designated as “citation classics”) published in journals on GGE that have made key contributions to the field of epilepsy.

A citation analysis is a bibliometric method that examines the frequency and patterns of citations in articles. We performed a citation analysis in the field of GGE by searching the Web of Science website (https://www.webofknowledge.com) produced by Clarivate Analytics.

In January 2020 we searched for articles published since 1950 with titles that included any of the following expressions: “genetic generalized epilepsy,” “idiopathic generalized epilepsy,” “childhood absence epilepsy,” “juvenile absence epilepsy,” “juvenile myoclonic epilepsy,” “epilepsy with generalized tonic-clonic seizures alone,” or “epilepsy with generalized tonic-clonic seizures on awakening.” The top-100 cited articles were then selected according to the number of citations, and we manually reviewed their contents. We examined various aspects of the articles, such as the number of citations, ranking, authorship, title, year of publication, publishing journal, publication type, and topic categories. The publication types were categorized into original articles, case series, and systematic reviews, and the topics were subtyped as clinical features, epidemiology, pharmacotherapy, laboratory investigations, electrophysiology, neuroimaging, genetics, neuropsychiatry, and general reviews. When the authors of an article had more than one affiliation, the department, institution, and country of origin were defined by either the first or the corresponding affiliation of the first author. Data were presented using descriptive statistics, and no tests of statistical significance were performed. This study did not need to be reviewed by an ethics committee because it performed a bibliometric analysis of existing published studies.

We ranked the top-100 cited articles according to the number of citations (Table 1). The most-cited and least-cited articles had been cited 580 and 76 times, respectively. Approximately two-thirds of the articles (64 articles) had been cited more than 100 times.

The top-100 cited articles were published in 27 journals (Table 2), with the largest proportion appearing in Epilepsia (19 articles), followed by Neurology (15 articles) and Brain (10 articles). The top-100 cited articles originated from institutions in 17 countries, with 31 articles from the USA, followed by the UK (14 articles), Germany (11 articles), and Australia (11 articles) (Table 3). The 100 articles comprised 40 originating from North America (the USA and Canada), 38 from Europe (the UK, Germany, France, Italy, Netherlands, Switzerland, and Sweden), 12 from Oceania (Australia and New Zealand), 8 from Asia (Saudi Arabia, China, South Korea, Israel, and Japan), and 2 from South America (Brazil).

Tables 4 and 5 list the top-ranked institutions and authors for articles published in the field of GGE, respectively. The institution associated with the largest number of articles was the University of Melbourne, Australia (nine articles), followed by the University of California in Los Angeles, USA (seven articles), and University College London, UK (six articles). Panayiotopoulos C. P. was the first author of three articles, and was listed most frequently in the GGE citation classics.

The publication years were mostly concentrated in the 2000s, when 56 articles were published. Twenty-three articles were published in the 1990s, followed by 13 articles in the 2010s, and 8 in the 1980s. The earliest recorded article was published in 1983 and the most-recent article was published in 2015.

Regarding the types of articles, 95 were original articles while 5 were systematic review articles. The subjects of the articles comprised 22 on childhood absence epilepsy, 38 on juvenile myoclonic epilepsy, and 40 on GGE as a whole. The topic subtypes of the articles comprised 35 on genetics, 17 on neuroimaging, 13 on pharmacotherapy, 13 on electrophysiology, 8 on neuropsychiatry, 5 on epidemiology, 5 on general reviews, and 4 on clinical features (Fig. 1).

This study identified and characterized the top-100 cited articles in the field of GGE. These citation classics may enable the identification of seminal advances in GGE and provide a historical perspective on the scientific progress of the field of epilepsy.

The top-ranked article had a title of “Mutant gamma-aminobutyric acid receptor subtype A (GABA)(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizure,” its first author was Wallace, it was published in Nature Genetics, and it has been cited 580 times.¹³ The authors found a mutation in a gene encoding a GABA(A) receptor subunit in a large family with epilepsy, and the two main phenotypes were childhood absence epilepsy and febrile seizures.¹³ The second-ranked article was also published in Nature Genetics, and reported that an Ala322Asp mutation in the GABRA1 gene that encodes the alpha1 subunit of GABA(A) was found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy.¹⁴ Both of these articles reported on genetic studies. The third-ranked article was a review article on childhood absence epilepsy by Crunelli V that appeared in Nature Reviews Neuroscience.

Citation analysis can identify emerging topics and the relevant trends in a particular field.^5,6 The present study found that genetics was the most-common topic in the top-100 cited articles on GGE, followed by neuroimaging. Genetics and neuroimaging were the most-common topics for each decade from the 1990s to the 2010s. Since genetic epilepsy directly results from a known or presumed genetic mutation whose core symptom is seizures,¹ it is not surprising that genetics was the most-common topic in the field of GGE. In addition, due to the introduction and advent of next-generation sequencing and genome-wide association studies, the development and application of high-throughput genetic testing has resulted in the discovery of hundreds of epilepsy-associated genes.¹⁵ Thus, we can assume that the number of articles on genetics will increase in the future.

The application of neuroimaging in epilepsy has also increased rapidly and evolved thanks to the substantial advancements in image-analysis techniques in recent decades.¹⁶ Early studies involving brain magnetic resonance imaging (MRI) did not reveal abnormalities in patients with GGE. However, more-recent voxel-based morphometry and structural/functional connectivity studies based on diffusion-tensor imaging and functional MRI have revealed abnormal morphologies and networks of the brain in GGE.^17-20 These developments are associated with increasing numbers of related articles being published in scientific journals that could have a great impact on GGE.

The topics addressed in the citation classics varied among the decades, and we discovered some interesting trends in the topics over time. We noted that the most-cited articles on GGE were published during the 2000s. This contrasts with most bibliometric analyses on other topics demonstrating that the most-cited articles are published during the 1990s.^7-11,21 Thus, we can infer that there have been considerable developments in research on GGE in recent years, which might be attributable to recent developments in research techniques such as genetics and neuroimaging in this field.

We also found that the most-cited articles were published in Epilepsia, which is the official publication of the ILAE. This is perhaps related to the epilepsy-specific journals with high impact factors being focused on GGE. Moreover, we found that about one-third of the 100 top-cited articles originated from institutions in the USA, reflecting the huge influence of the USA in health science research in general, which is probably due to both the large size of the American scientific community and its high research budget.^22-25 However, a citation analysis in the field of neurology found that from half to two-thirds of the articles originated from the USA. In addition, we found that 20 articles reported on studies performed in Asia and Oceania (12 and 8 articles, respectively), which was a prominently higher ratio than in other citation analyses. We can assume that this finding is associated with the most-cited articles on GGE being published during the 2000s. Recently there have been increasing numbers of articles originating from Asia and Oceania in the field of neurology research, especially from China.²⁶

This study is the first to perform a citation analysis of GGE. The findings could be used to identify recent advances in the field of GGE, provide a historical perspective of its scientific progress, and be used for education purposes. However, there were several inherent limitations in the research methodology. There is ongoing debate about the value of citation rates. A naïve argument is that an article of greater value will be cited more often.²⁷ However, the number of citations could be influenced by factors other than the quality and originality of the reported research, such as the characteristics of the involved researchers, institutions, and funding agencies.²¹ Furthermore, analyzing the total number of citations favors older articles.²⁸ The citation frequency of a scientific article is typically associated with a time delay of 1-2 years after its publication.²⁹ This interval will bias evaluations of the rank and significance of recent publications. However, the use of citation rates is still widely accepted as the best method for judging the impact of the articles, with the impact factor considered indicative of the quality and rank of a given journal in its specific field of interest.³⁰

This study has identified the top-100 cited articles on GGE. The identified citation classics represent landmark articles on GGE, and they provide useful insights into international research leaders and the research trends in the field.