FACTORS INFLUENCING THE INCIDENCE OF REFRACTORY EPILEPSY: A SCOPING REVIEW
DOI:
https://doi.org/10.20961/magnaneurologica.v4i2.2572Keywords:
DRE, drug-resistant epilepsy, refractory epilepsy, risk factorsAbstract
Background: Epilepsy affects around 50 million people worldwide, with an incidence of 100 cases per 100,000 people annually in developing countries where access to adequate treatment is limited. Refractory epilepsy occurs in 20-40% of cases of patients whose seizures remain uncontrolled despite 1-2 years of adequate anti-seizure medication (ASM) therapy with good adherence. This condition poses significant challenges for management.
Objective: This scoping review aimed to systematically identify the factors associated with refractory epilepsy.
Methods: A scoping review was conducted in accordance with the PRISMA-ScR guidelines and the PEO/PET framework. A systematic PubMed search identified studies published between 2020 and 2025 on factors influencing refractory epilepsy. Eligible studies underwent a three-phase screening process (title, abstract, and full-text review).
Results: Twenty studies met the inclusion criteria, comprising seven review articles and thirteen clinical studies, most of which were observational. Recurrent associations between refractory epilepsy and several factors were identified, such as one large cohort of 5,794 patients reporting seizure onset within the first year of life to be the strongest predictor of refractory epilepsy, while another study showed that structural etiology increased the odds more than threefold (OR 3.47; 95% CI: 1.15-10.43). Psychiatric comorbidities, developmental delay, abnormal EEG or neuroimaging findings, and systemic contributors such as inflammation and metabolic disorders were also found to be commonly associated with refractory epilepsy.
Conclusion: The most frequently reported factors for developing refractory epilepsy across studies were younger age at first seizure, structural etiology, and genetic factors.
References
1. Abokrysha NT, Taha N, Shamloul R, et al. Clinical, Radiological and Electrophysiological Predictors for Drug-Resistant Epilepsy. Egypt J Neurol Psychiatry Neurosurg; 2023. 59:44. DOI: 10.1186/s41983-023-00647-1
2. Berg AT, Altalib HH, Devinsky O. Psychiatric and Behavioral Comorbidities in Epilepsy: A Critical Reappraisal. Epilepsia; 2017. 58(7):1123-30. DOI: 10.1111/epi.13766
3. Bjorke AB, Nome CG, Falk RS, Gjerstad L, Taubøll E, Heuser K. Evaluation of Long-Term Antiepileptic Drug Use in Patients with Temporal Lobe Epilepsy: Assessment of Risk Factors for Drug Resistance and Polypharmacy. Seizure; 2018. 61:63-70. DOI: 10.1016/j.seizure.2018.07.011
4. Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, et al. Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery. N Engl J Med; 2017. 377(17):1648-56. DOI: 10.1056/NEJMoa1703784
5. Brigo F, Turcato G, Lattanzi S, et al. Retrospective External Validation of the Status Epilepticus Severity Score (STESS) to Predict In-hospital Mortality in Adults with Nonhypoxic Status Epilepticus: A Machine Learning Analysis. Neurocrit Care; 2023. 38(2):254-262. DOI: 10.1007/s12028-022-01610-3
6. Campos-Bedolla P, Feria-Romero I, Orozco-Suárez S. Factors Not Considered in the Study of Drug-Resistant Epilepsy: Assessment of Neuroinflammation. Epilepsia Open; 2022. 7(S1):S68-S80. DOI: 10.1002/epi4.12590
7. Cao C, Mu J, Hu G, Wang Y, Gong Y. A Correlation between Inflammatory Factors and Epileptic Seizures: A Meta-analysis. Actas Esp Psiquiatr; 2025. 53(4):902-13. DOI: 10.62641/aep.v53i4.1790
8. Carazo Barrios L, Martín GG, Godoy JR, Acebal MR, Muñoz MIC. Forced Normalization: Case Series from a Spanish Epilepsy Unit. Seizure; 2020. 81:132-37. DOI: 10.1016/j.seizure.2020.07.020
9. Chipaux M, Szurhaj W, Vercueil L, Milh M, Villeneuve N, Cances C, et al. Epilepsy Diagnostic and Treatment Needs Identified with a Collaborative Database Involving Tertiary Centers in France. Epilepsia; 2016. 57(5):757-69. DOI: 10.1111/epi.13368
10. Erturk Cetin O, Işler C, Uzan M, Ozkara C. Epilepsy-Related Brain Tumors. Seizure; 2017. 44:93-97. DOI: 10.1016/j.seizure.2016.12.012
11. Fattorusso A, Matricardi S, Mencaroni E, Dell’Isola GB, di Cara G, Striano P, et al. The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies. Front Neurol; 2021. p. 12. DOI: 10.3389/fneur.2021.674483
12. Gasparini S, Ferlazzo E, Gigli G, Pauletto G, Nilo A, Lettieri C, et al. Predictive Factors of Status Epilepticus and Its Recurrence in Patients with Adult-Onset Seizures: A Multicenter, Long Follow-Up Cohort Study. Seizure; 2021. 91:397-401. DOI: 10.1016/j.seizure.2021.07.009
13. Giovannini G, Monti G, Tondelli M, Marudi A, Valzania F, Leitinger M, et al. Mortality, Morbidity and Refractoriness Prediction in Status Epilepticus: Comparison of STESS and EMSE Scores. Seizure; 2017. 46:31-37. DOI: 10.1016/j.seizure.2017.01.004
14. Gorjipour H, Darougar S, Mansouri M, Karimzadeh P, Amouzadeh MH, Sohrabi MR. Hypoallergenic Diet May Control Refractory Epilepsy in Allergic Children: A Quasi Experimental Study. Sci Rep; 2019. 9(1). DOI: 10.1038/s41598-019-43252-0
15. Gowrinathan TG, Kumar SA. Risk Factors for Childhood Refractory Epilepsy in a Tertiary Care Centre, Chennai, India. Int J Contemp Pediatr; 2019. 6(4):1432. DOI: 10.18203/2349-3291.ijcp20192624
16. Herrero JR, Villarroya EC, Peñas JJG, Alcolea BG, Fernández BG, Macfarland LAP, et al. Safety and Effectiveness of the Prolonged Treatment of Children with a Ketogenic Diet. Nutrients; 2020. 12(2). DOI: 10.3390/nu12020306
17. Hu Y, Zhang H, Adilijiang A, et al. Seizure outcomes and prognostic factors in patients with gangliogliomas associated with epilepsy. Front Surg; 2022. 9:946201. DOI: 10.3389/fsurg.2022.946201
18. Jiruska P, Freestone D, Gnatkovsky V, Wang Y. An Update on the Seizures Beget Seizures Theory. Epilepsia; 2023. 64(S1):S13-S24. DOI: 10.1111/epi.17721
19. Kumar S, Goel RK. Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine-pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug-resistant epilepsy. Animal Model Exp Med; 2020. 3(3):245-255. DOI: 10.1002/ame2.12131
20. Magdy R, Kishk NA, Fouad AM, Alsayyad E. Risk Estimation of SUDEP during COVID-19 Pandemic Era in a Tertiary Referral Center. Epilepsy Res; 2021. p. 173. DOI: 10.1016/j.eplepsyres.2021.106625
21. Marouf H, Mohamed LA, el Ftatary A, Gaber DE. Prevalence and Risk Factors Associated with Drug-Resistant Epilepsy in Adult Epileptic Patients. Egypt J Neurol Psychiatry Neurosurg; 2023. 59(1). DOI: 10.1186/s41983-023-00750-3
22. Miszewska D, Sugalska M, Jóźwiak S. Risk Factors Associated with Refractory Epilepsy in Patients with Tuberous Sclerosis Complex: A Systematic Review. J Clin Med; 2021. 10(23). DOI: 10.3390/jcm10235495
23. Meguins LC, Adry RA, Silva Júnior SC, et al. Gross-total resection of temporal low grade gliomas is a critically important factor in achieving seizure-freedom. Arq Neuropsiquiatr; 2015. 73(11):924-928. DOI: 10.1590/0004-282X20150141
24. Nazish S. Obesity and Metabolic Syndrome in Patients with Epilepsy, Their Relation with Epilepsy Control. Ann Afr Med; 2023. 22(2):136-44. DOI: 10.4103/aam.aam_139_22
25. Oshino S, Tani N, Khoo HM, Kagitani-Shimono K, Nabatame S, Tominaga K, et al. Clinical Factors Related to Outcomes in Pediatric Epilepsy Surgery: Insight into Predictors of Poor Surgical Outcome. Neurol Med Chir (Tokyo); 2023. 63(5):173-78. DOI: 10.2176/jns-nmc.2022-0300
26. Rodrigo Marinowic D, Bottega Pazzin D, Prates da Cunha de Azevedo S, Pinzetta G, Victor Machado de Souza J, Tonon Schneider F, et al. Epileptogenesis and Drug-Resistant in Focal Cortical Dysplasias: Update on Clinical, Cellular, and Molecular Markers. Epilepsy Behav; 2024. p. 150. DOI: 10.1016/j.yebeh.2023.109565
27. Russo A, Pruccoli J, Cesaroni CA, Belotti LMB, Zenesini C, Bonanni P, et al. Brivaracetam Add-on Treatment in Pediatric Patients with Severe Drug-Resistant Epilepsy: Italian Real-World Evidence. Seizure; 2022. 102:120-24. DOI: 10.1016/j.seizure.2022.10.001
28. Specchio N, Nabbout R, Aronica E, Auvin S, Benvenuto A, de Palma L, et al. Updated Clinical Recommendations for the Management of Tuberous Sclerosis Complex Associated Epilepsy. Eur J Paediatr Neurol; 2023. 47:25-34. DOI: 10.1016/j.ejpn.2023.08.005
29. Tan Y, Hashimoto K. Therapeutic Potential of Ketamine in Management of Epilepsy: Clinical Implications and Mechanistic Insights. Asian J Psychiatr; 2024. p. 101. DOI: 10.1016/j.ajp.2024.104246
30. Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med; 2018. 169(7):467-73. DOI: 10.7326/M18-0850
31. Ulamek-Koziol M, Czuczwar SJ, Pluta R, Januszewski S. Ketogenic Diet and Epilepsy. Nutrients; 2019. 11(10). DOI: 10.3390/nu11102510
32. van Hezik-Wester V, de Groot S, Kanters T, Versteegh M, Wagner L, Ardesch J, et al. Burden of Illness in People with Medically Refractory Epilepsy Who Suffer from Daily to Weekly Seizures: 12-Month Follow-Up of Participants in the EPISODE Study. Front Neurol; 2022. 13:1012486. DOI: 10.3389/fneur.2022.1012486
33. Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, et al. Epilepsy-Associated Genes. Seizure; 2017. 44:11-20. DOI: 10.1016/j.seizure.2016.11.030
34. World Health Organization. Epilepsy. 2024 Feb 7. Retrieved on May 28, 2025 Available from: https://www.who.int/news-room/fact sheets/detail/epilepsy
35. Yuan F, Jia R, Gao Q, Yang F, Yang X, Jiang Y, et al. Early Predictors of Drug-Resistant Epilepsy Development after Convulsive Status Epilepticus. Eur Neurol; 2018. 79(5-6):325-32. DOI: 10.1159/000490900
36. Zhang MN, Zou LP, Wang YY, Pang LY, Ma SF, Huang LL, et al. Calcification in Cerebral Parenchyma Affects Pharmacoresistant Epilepsy in Tuberous Sclerosis. Seizure; 2018. 60:86-90. DOI: 10.1016/j.seizure.2018.06.011
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Naufal, Desin Pambudi Sejahtera, Ishana Nafeeza Mukhtar, Atitya Fithri Khairani, Nur Chayati
This work is licensed under a Creative Commons Attribution 4.0 International License.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
