In the current study, we conducted a bibliometric analysis to provide an overview of developmental trends and hotspots in research on DRE from the SCI-expanded database, using a variety of bibliometric tools. Due to many leading affiliations, funding agencies, and researchers, the USA made the most important contribution to this particular research field. As the predominant research teams in Asian countries, China, India, and Japan must make more efforts to conduct innovative research to increase the impact. Regarding journals, Epilepsia is the most influential journal in this field owing to the number and importance of publications.

As seen in the analysis of the top 100 most cited publications, the most influential studies were clinical studies. These studies analyzed the diagnosis of DRE, disease characteristics and screening, and multiple treatments such as medication, surgery, neuromodulation, and dietary therapies.

For a long time, the definition of DRE was not unified and potentially conflicting, varying among studies. The study with the highest number of co-citations and the strongest citation bursts was published in 2010 by the ILAE, which delivered a formal consensus on the definition of DRE (3). Only one of the 100 most cited articles evaluated the reliability and validity of the ILAE definitions compared to three other definitions (Berg, Kwan, and Brodie, Camfield, and Camfield) in a clinical setting (13). The ILAE definition received similar acclaim from several subsequent studies (14, 15).

Although DRE patients do not receive two medication regimens, trying other ASMs remains the primary treatment option. From 2011 to 2021, a series of clinical trials on newer third-generation ASMs have been published. Perampanel was approved for treating partial-onset seizures in 2012 and primary generalized tonic clinic seizures in 2016. A pooled analysis demonstrated a significant reduction in seizure frequency (16). Brivaracetam is a modulator of the presynaptic release machinery SV2A closely related to levetiracetam, which was approved in 2016 for treating partial-onset seizures in patients aged 16 years and older. In three phase III trials, adjunctive brivaracetam (50–200 mg/day) showed statistically significant reductions in seizure frequency and was well-tolerated (17–20). Eslicarbazepine acetate was confirmed to be effective and well-tolerated; regardless it was administered as adjunctive therapy or monotherapy (21). Tremendous progress has been made in identifying the genetic causes of epilepsy and investigating the underlying molecular mechanisms, which helps identify potential therapeutic targets and achieve precision medicine (22). Everolimus is a mammalian target of rapamycin inhibitor, which was investigated as an adjunctive therapy to treat focal seizures associated with tuberous sclerosis complex (23). Cannabinoids, mainly cannabidiol, are a potential treatment for patients with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, and febrile infection-related epilepsy syndrome (24–28). In 2018, a purified form of cannabidiol (Epidiolex) was approved for treating patients aged 2 years and older with rare epilepsy syndromes (e.g., Lennox-Gastaut syndrome or Dravet syndrome). Fenfluramine, a serotonin-releasing agent, showed efficacy and safety in treating Dravet syndrome (27) and was approved in 2020 to prevent seizures in pediatric patients with Dravet syndrome.

The current choice of ASMs can be described as empirical and based primarily on the patient's demographic profile, seizure type, comorbidity, concomitant medication, and adverse drug reaction. Exploration of pharmacogenomics in epilepsy may help to predict drug responses and improve effectiveness and tolerability. Genetic variations of drug transporters may be associated with a higher risk of DRE (29). ATP-binding cassette subfamily B member 1 (ABCB1) polymorphisms affect ASM brain penetration and efficiency. A meta-analysis showed a relationship between ABCB1 C3435T polymorphism and poor treatment response (30). Given multiple factors are involved in DRE, pharmacokinetic factors may not be enough to explain the differences in drug response. Whole-genome sequencing technology, genome-wide association studies, and polygenic risk score (PRS) open a broader window to understand the mechanisms of drug resistance and specific ASM responses. Several candidate rare genetic variants were found in the exome-based research of patients with non-familial non-acquired focal epilepsy and DEPDC5 was regarded as a potential risk factor for drug resistance (31). For the specific drug response, common genetic variants were not significantly associated with common ASMs in a study containing 3,649 individuals with focal epilepsy or generalized genetic epilepsy (32). However, an exome-based study targeting rare genetic variants revealed an increased burden of damaging variants in gene groups associated with pharmacokinetics or targeting in patients resistant to valproic acid or levetiracetam (33). These findings may hold promise for patients with epilepsy, allowing early prediction of drug efficacy and optimization of treatment strategies.

To treat DRE, non-AED treatment options may be considered, including epilepsy surgery, neurostimulation, and dietary therapy. Among these, epilepsy surgery carries the potential for long-term seizure control; however, only some patients with drug-resistant focal epilepsy are good surgical candidates. An MRI lesion that can be completely resected is a significant prognostic factor for long-term postoperative seizure control (1). A meta-analysis suggested that the median proportion of long-term seizure-free patients with temporal lobe surgery was 66% (34), which was similar to short-term outcomes (35). Short disease duration was correlated with better postoperative seizure control for intractable frontal lobe epilepsy, whereas left-sided resections and acute seizures after surgery were poor prognostic indicators (35). In children, epilepsy surgery significantly increased the rate of freedom from seizures and improved quality of life (36). However, conventional surgical procedures are associated with high inherent risks, such as visual field deficits, decreased memory, stroke, hemorrhage, and infection (37). In recent times, new techniques with minimal injury have been developed to avoid making a craniotomy. These techniques include radiofrequency ablation (RF-TC) and laser interstitial thermal therapy (LITT). Due to the emergence of stereo electroencephalography (SEEG) recording of ictal activity to guide RF thermocoagulation, RF-TC is considered a palliative treatment for patients who are not eligible for open surgery. A meta-analysis of six retrospective studies revealed that seizure-free and responder rates 1 year after SEEG-guided RF-TC were 23 and 58%, respectively. Subgroup analyses showed that the greatest efficacy was found in patients with periventricular nodular heterotopia (38% seizure-free and 81% responders) and the lowest in patients with normal MRI (11% seizure-free and 41% responders) (38). A study of 162 patients with SEEG-guided RF-TC found that 67% of responders at 2 months, 48% at 1 year, and 58% of responders maintained their status during a 10-year follow-up (39). Current data have affirmed the superiority of SEEG-guided RF-TC in terms of safety. However, differences exist in underlying lesions and management strategies across centers, which affect the clinical efficacy (40). LITT utilizes laser thermal ablation via a fiber probe inserted through a twist drill hole with the advantage of ablating difficult-to-reach epileptogenic regions. A multicenter cohort study including 234 patients who underwent LITT for mesial temporal lobe epilepsy demonstrated that Engel I outcome was achieved in 58% of patients at both 1 and 2 years after LITT. A single-center study including pediatric patients with drug-resistant lesional epilepsy showed that Engel class I outcome was achieved in 41% patients (41). In a quantitative analysis of novel “minimally invasive” approaches, the pooled seizure-free rate per person-year was 0.59 with LITT and 0.38 with RF-TC, which were not as efficacious as open surgery (42). Nevertheless, LITT and RF-TC remain surgical options, even as a first-line treatment for certain epilepsy indications, while more high-quality evidence is needed.

Neuromodulation is an alternative therapy for patients who fail to respond to ASMs and are not suitable for open surgery; this has become a research hotspot. Neuromodulation includes invasive therapies such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), responsive neurostimulation (RNS), and non-invasive methods including transcutaneous VNS and transcranial stimulation. Neuromodulation is considered a palliative treatment, that only some patients might benefit from for longer than 12 months (43). VNS was the first neurostimulation device approved for epilepsy. A retrospective study of 436 consecutive adults and children who underwent VNS demonstrated that 63.75% of the patients achieved ≥ 50% seizure reduction during the treatment period ranging from 10 days to 11 years (44). Two large systematic reviews found that the prevalence of 50% responder rate and seizure freedom at the last follow-up (mean 2.54 years) were 56.4 and 11.6%, respectively, in children and 63 and 8.2%, respectively, in adults (45, 46). VNS has also proven to improve the quality of life in patients with DRE (47).

The closed-loop responsive neurostimulation system was designed to abort possible impending seizures by monitoring the electrocorticogram at the seizure focus and delivering short bursts of high-frequency electrical stimulation. The acute and sustained efficacy and safety of the RNS system were confirmed in a long-term study (mean 5.4 years). The median percent seizure reduction rate ranged from 44 to 66% over 1–6 years post-implant (48). A 9-year follow-up study of patients continuing RNS revealed RNS system progressively increased the median reduction in seizure frequency and 50% responder rate, which reached 75 and 73%, respectively (49). The challenge of neuromodulation lies in selecting the most suitable neuromodulation techniques and targets according to the type of epilepsy. In addition, a flowchart of neuromodulation and other treatments for drug-resistant focal epilepsy has been developed, which provides a route for treatment from the beginning of drug resistance (43).

Ketogenic dietary therapy has been used since the 1920's, mainly in pediatric patients with severe and refractory epilepsy. In the past decade, owing to the availability of broader dietary options and the expansion of the target population, the ketogenic diet has received renewed attention. The efficacy of the ketogenic diet has been well-established in children with various seizure types and epileptic syndromes. Children given ketogenic diets may be up to six times more likely to achieve a 50% or greater reduction in seizure frequency and up to three times more likely to become seizure-free than children given the usual care (50). Furthermore, a longitudinal study with a long follow-up period (mean follow-up of 9 years) found that 20.5% of children given a ketogenic diet achieved seizure freedom, and 36% of children had a 75–99% decrease in seizures. (51). However, the ketogenic diet is less effective in adult patients with DRE. Two randomized controlled trials compared the effects of ketogenic diets with those undergoing usual care. Both studies reported 0% seizure freedom in the modified Atkins diet group, with >50% seizure reduction in 8 and 35% of patients in the modified Atkins diet group, respectively (52, 53).

Based on the bibliometric analysis of the literature in DRE, we provide a comprehensive and objective insight into the global status and hotspots in this field. However, this study has some limitations. First, only articles written in English from the SCI-expanded database were included. Second, some emerging significant papers and trends may not have been captured due to a low number of citations. Despite these limitations, this study provides insight into research from the last decade in this special field, demonstrating that there is sustained and intense interest in identifying the mechanisms of DRE and developing various antiseizure therapies to improve the outcome of patients with DRE.