Peculiarities of the Course of Epilepsy in Neurofibromatosis Type 1

Neurofibromatosis type 1 is an inherited neurocutaneous disorder occurring with an incidence of 1 in 2,000–4,000 newborns. Epilepsy is one of its neurological manifestations; however, data on its frequency, pathogenesis, and treatment approaches have not been fully elucidated. Aim: to summarize current data on the pathogenesis, clinical features, diagnosis and treatment of epilepsy in type I neurofibromatosis based on literature analysis and the results of our own prospective patient observation.

This article presents an analysis of current literature on epilepsy in neurofibromatosis type 1, including data on molecular mechanisms (the «second hit», hyperactivation of the Ras/Raf/MAPK and PI3K-mTOR pathways). In addition, we present the results of a prospective observational study of 724 patients with neurofibromatosis type 1 (aged 1 to 19 years) from 2021 to 2026. According to the literature, the prevalence of epilepsy in neurofibromatosis type 1 ranges from 4% to 14%. Focal seizures predominate (up to 83%). In our own cohort (n=724), epileptiform activity was recorded in 34 patients (4.7%), and epilepsy was diagnosed in 28 of these (82.4% of those with epileptiform activity). Among patients with epilepsy (n=28), focal seizures prevailed (82.1%), while structural changes on magnetic resonance imaging (MRI) were identified in only 14.3% of cases, which is consistent with international data. Remission was achieved in 67.9% of patients. The article also presents a clinical case of a 14-year-old patient with neurofibromatosis type 1, plexiform neurofibromas, and photosensitive focal epilepsy. Epilepsy in neurofibromatosis type 1 is relatively uncommon, but establishing the diagnosis and determining treatment strategies requires mandatory additional investigations, including MRI and video-EEG monitoring. The pathogenesis involves a combination of structural changes (gliomas, cortical dysplasias, hippocampal sclerosis) and molecular neuronal dysfunction resulting from hyperactivation of the Ras-MAPK and PI3K-mTOR pathways. The prognosis is generally favourable, and clinical remission can be achieved in most cases. Surgical treatment options should be considered in drug resistant forms of epilepsy. Patients with negative MRI findings are potential candidates for pathogenetic therapy with MEK inhibitors.

1. Multidisciplinary Diagnosis and Treatment Collaboration Group for Neurofibromatosis Type of China Alliance for Rare Diseases. Guidelines for the multidisciplinary diagnosis and treatment of neurofibromatosis type 1 (2023 version). J Rare Dis. 2023;2(2):210-230. doi: 10.12376/j.issn.2097-0501.2023.02.009

2. Almuqbil M, Alshaikh FY, Altwayri W, et al. Epidemiology and outcomes of Neurofibromatosis type 1 (NF-1): multicenter tertiary experience. J Multidiscip Healthc. 2024;17:1303-1314. doi: 10.2147/JMDH.S454921

3. Ren Y, Hu W, Su S, et al. Recent advances of epilepsy associated with neurofibromatosis type 1. Front Neurol. 2025;16:1640309. doi: 10.3389/fneur.2025.1640309

4. Nix JS, Blakeley J, Rodriguez FJ. An update on the central nervous system manifestations of neurofibromatosis type 1. Acta Neuropathol. 2020;139(4):625-641. doi: 10.1007/s00401-019-02002-2

5. Faidi R, Reid AY. Early-life immune activation is a vulnerability factor for adult epileptogenesis in neurofibromatosis type 1 in male mice. Front Neurol. 2024;15:1284574. doi: 10.3389/fneur.2024.1284574

6. Bernardo P, Cinalli G, Santoro C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst. 2020;36(10):2333–2350. doi: 10.1007/s00381-020-04710-7

7. Sabetghadam A, Wu C, Liu J, et al. Increased epileptogenicity in a mouse model of neurofibromatosis type 1. Exp Neurol. 2020;331:113373. doi: 10.1016/j.expneurol.2020.113373

8. Ostendorf AP, Gutmann DH, Weisenberg JL. Epilepsy in individuals with neurofibromatosis type 1. Epilepsia. 2013;54(10):1810–1814. doi: 10.1111/epi.12348

9. Pecoraro A, Arehart E, Gallentine W, et al. Epilepsy in neurofibromatosis type 1. Epilepsy Behav. 2017;73:137–141. doi: 10.1016/j.yebeh.2017.05.011

10. Santoro C, Bernardo P, Coppola A, et al. Seizures in children with neurofibromatosis type 1: is neurofibromatosis type 1 enough? Ital J Pediatr. 2018;44(1):41. doi: 10.1186/s13052-018-0477-x

11. Barba C, Jacques T, Kahane P, et al. Epilepsy surgery in Neurofibromatosis type 1. Epilepsy Res. 2013;105(3):384–395. doi: 10.1016/j.eplepsyres.2013.02.021

12. Khoshkhoo S, Wang Y, Chahine Y, et al. Contribution of somatic Ras/Raf/mitogen-activated protein kinase variants in the hippocampus in drug-resistant mesial temporal lobe epilepsy. JAMA Neurol. 2023;80(6):578–587. doi: 10.1001/jamaneurol.2023.0473

13. Pekmezci M, Villanueva-Meyer JE, Goode B, et al. The genetic landscape of ganglioglioma. Acta Neuropathol Commun. 2018;6(1):47. doi: 10.1186/s40478-018-0551-z

14. Rizwan G, Sabetghadam A, Wu C, et al. Increased seizure susceptibility in a mouse model of neurofibromatosis type 1. Epilepsy Res. 2019;156:106190. doi: 10.1016/j.eplepsyres.2019.106190

15. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506–1513. doi: 10.1038/s41436-021-01170-5

16. Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1349–1397. doi: 10.1111/epi.17239

17. Cui Y, Costa RM, Murphy GG, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell. 2008;135(3):549–560. doi: 10.1016/j.cell.2008.09.060

18. Oliveira AF, Yasuda R. Neurofibromin is the major ras inactivator in dendritic spines. J Neurosci. 2014;34(3):776–783. doi: 10.1523/JNEUROSCI.3096-13.2014

19. Moutal A, Dustrude ET, Khanna R. Sensitization of ion channels contributes to central and peripheral dysfunction in Neurofibromatosis type 1. Mol Neurobiol. 2017;54(5):3342–3349. doi: 10.1007/s12035-016-9907-1

20. Wang Y, Brittain JM, Wilson SM, et al. Altered calcium currents and axonal growth in nf1 haploinsufficient mice. Transl Neurosci. 2010;1(2):106–114. doi: 10.2478/v10134-010-0025-8

21. DeClue JE, Papageorge AG, Fletcher JA, et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell. 1992;69(2):265–273. doi: 10.1016/0092-8674(92)90407-4

22. Hébert J, De Santis RJ, Daniyal L, et al. Epilepsy in neurofibromatosis type 1: prevalence, phenotype, and genotype in adults. Epilepsy Res. 2024;202:107336. doi: 10.1016/j.eplepsyres.2024.107336

23. SorrenНФtino U, Bellonzi S, Mozzato C, et al. Epilepsy in NF1: epidemiologic, genetic, and clinical features. A monocentric retrospective study in a cohort of 784 patients. Cancers (Basel). 2021;13(24):6336. doi: 10.3390/cancers13246336

24. Serdaroglu E, Konuskan B, Oguz KK, et al. Epilepsy in neurofibromatosis type 1: diffuse cerebral dysfunction? Epilepsy Behav. 2019;98(Pt A):6–9. doi: 10.1016/j.yebeh.2019.06.022

25. Pemov A, Li H, Patidar R, et al. The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas. Oncogene. 2017;36(22):3168–3177. doi: 10.1038/onc.2016.464

26. McDaniel SS, Rensing NR, Thio LL, et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011;52(3):e7–e11. doi: 10.1111/j.1528-1167.2011.02981.x

27. Genzer Y, Dadon M, Burg C, et al. Ketogenic diet delays the phase of circadian rhythms and does not affect AMP-activated protein kinase (AMPK) in mouse liver. Mol Cell Endocrinol. 2015;417:124–130. doi: 10.1016/j.mce.2015.09.012

28. Wilson BN, John AM, Handler MZ, Schwartz RA. Neurofibromatosis type 1: new developments in genetics and treatment. J Am Acad Dermatol. 2021;84(6):1667–1676. doi: 10.1016/j.jaad.2020.07.105

29. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med. 2020;382(15):1430–1442. doi: 10.1056/NEJMoa1912735

30. Cantor E, Meyer A, Morris SM, et al. Dose-dependent seizure control with MEK inhibitor therapy for progressive glioma in a child with neurofibromatosis type 1. Childs Nerv Syst. 2022;38(11):2245–2249. doi: 10.1007/s00381-022-05571-y

31. Barrière S, Faure-Conter C, Leblond P, et al. Antiseizure effect of MEKinhibitor in a child with neurofibromatosis type 1-developmental and epileptic encephalopathy and optic pathway glioma. Epileptic Disord. 2024;26(1):133–138. doi: 10.1002/epd2.20180

32. Wu F, Ji XN, Shen MX, et al. Clinical characteristics of epileptic seizure in neurofibromatosis type 1 in 15 cases. (In Chinese). Zhonghua Er Ke Za Zhi. 2023;61(12):1124–1128. doi: 10.3760/cma.j.cn112140-20230829-00146