Abstract
Epilepsy is one of the possible neurological manifestations of the neurofibromatosis type 1 (NF1) that represents the most common neurocutaneous disorder. We performed a systematic review of the literature on epilepsy associated with NF1 since 1995 in order to better define prevalence and describe type and causes of seizures. Data on type, nature of studies, number of patients, gender, and inheritance of NF1 were recorded as well as data on causes, type, EEGs, brain imaging, intellectual disability (ID), surgical treatment, and outcome of epilepsy. We identified a total of 141 references through the literature search of Pubmed and Embase. After screening, 42 records were identified, including 11617 individuals with NF1 (53% of males). Overall prevalence was estimated at 5.4% lifelong with values that seemed to be slightly lower in children, 3.7% (p 0.0016). Neither gender differences nor correlation with NF1 inheritance was found. Focal with or without bilateral tonic-clonic seizures were the most common seizure type encountered (60.9%). Structural causes were identified in half of cases (114/226). Low-grade gliomas were the most frequent associated lesions followed by mesial temporal sclerosis, malformation of cortical development, dysembryoplastic neuroepithelial tumor, and cerebrovascular lesions. In these cases, the surgical approach improved the epileptic outcome. Prevalence of epilepsy is higher in subjects with NF1 respect of the general population, with values apparently significantly lower in pediatric age. Brain tumors and cytoarchitectural abnormalities are the most frequent causes of epilepsy in this population, although many other brain complications should be taken in account.
Similar content being viewed by others
References
Algın Dİ, Tezer FI, Oguz KK, Bilginer B, Soylemezoglu F, Saygi S (2019) Pharmacoresistant seizures in neurofibromatosis type 1 related to hippocampal sclerosis: three case presentation and review. J Clin Neurosci 64:14–17
Banerjee PN, Filippi D, Allen Hauser W (2009) The descriptive epidemiology of epilepsy-a review. Epilepsy Res 85:31–45
Barba C, Jacques T, Kahane P, Polster T, Isnard J, Leijten FS, Ozkara C, Tassi L, Giordano F, Castagna M, John A, Oz B, Salon C, Streichenberger N, Cross JH, Guerrini R (2013) Epilepsy surgery in neurofibromatosis type 1. Epilepsy Res 105:384–395
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde BW, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51:676–685
Bergqvist C, Servy A, Valeyrie-Allanore L, Ferkal S, Combemale P, Wolkenstein P, NF France Network (2020) Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis 15:37
Bhat S, Ming X, Dekermenjian R, Chokroverty S (2014) Continuous spike and wave in slow-wave sleep in a patient with Rett syndrome and in a patient with Lhermitte-Duclos syndrome and neurofibromatosis 1. J Child Neurol 29:NP176–NP180
Budişteanu M, Burloiu CM, Papuc SM, Focşa IO, Riga D, Riga S, Arghir A (2019) Neurofibromatosis type 1 associated with moyamoya syndrome. Case report and review of the literature. Romanian J Morphol Embryol 60:713–716
Caraballo RH, Portuondo E, Fortini PS (2016) Neurofibromatosis and epilepsy. J Pediatr Epilepsy 5:59–63
Cheong JH, Kim CH, Kim JM, Oh YH (2010) Three novel NF1 gene mutations in a cohort of Bulgarian neurofibromatoses patients transformation of intracranial anaplastic astrocytoma associated with neurofibromatosis type I into gliosarcoma: case report. Clin Neurol Neurosurg 112:701–706
Créange A, Zeller J, Rostaing-Rigattieri S, Brugières P, Degos JD, Revuz J, Wolkenstein P (1999) Neurological complications involving the central nervous system in neurofibromatosis type 1. Brain 122:473–481
Darrigo Júnior LG, Valera ET, Machado Ade A, Santos AC, Scrideli CA, Tone LG (2011) Moyamoya syndrome associated with neurofibromatosis type I in a pediatric patient. Sao Paulo Med J 129:110–112
Farmer JP, Khan S, Khan A, Ortenberg J, Freeman C, O'Gorman AM, Montes J (2002) Neurofibromatosis type 1 and the pediatric neurosurgeon: a 20-year institutional review. Pediatr Neurosurg 37:122–136
Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A (2007) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44:81–88
Fisher RS, Acevedo C, Arzimanoglou A et al (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55:475–482
Forte D, Nabais A, Pontinha C, Mafra M, Mateus L (2018) Simultaneous supratentorial and infratentorial pilocytic astrocytomas in an adult patient with concurrent neurofibromatosis type 1 and HIV infection. World Neurosurg 117:172–177
Giulioni M, Marucci G, Matteo Martinoni M, Marliani AF, Toni F, BartiromoF VL, Riguzzi P, Bisulli F, Naldi I, Michelucci R, Baruzzi A, Tinuper P, Rubboli G (2014) Epilepsy associated tumors: review article. World J Clin Cases 2:623–641
Glushkova M, Yordanova I, Todorov T, Bojinova V, Koleva M, Dimova P, Tournev I, Angelova L, Todorova A, Mitev V (2018) Three novel NF1 gene mutations in a cohort of Bulgarian neurofibromatoses patients. Russ J Genet 54:110–116
Gowda VK, Srinivasan VM, Srinivas SM, Chadaga H (2018) A rare association of Sturge Weber syndrome with neurofibromatosis type-1. Indian J Pediatr 85:703–704
Gupta A, de Bruyn G, Tousseyn S, Krishnan B, Lagae L, Agarwal N, TSC Natural History Database Consortium (2019) Epilepsy and neurodevelopmental comorbidities in tuberous sclerosis complex: a natural history study. J Pediatr Neurol 106:10–16
Hariharan S, Donahue JE, Garre C, Origone P, Grewal RP (2006) Clinico pathologic and genetic analysis of siblings with NF1 and adult-onset gliomas. J Neurol Sci 247:105–108
Hirabaru K, Matsuo M (2018) Neurological comorbidity in children with neurofibromatosis type 1. Pediatr Int 60:70–77
Hsieh HY, Wu T, Wang CJ, Chin SC, Chen YR (2007) Neurological complications involving the central nervous system in neurofibromatosis type 1. Acta Neurol Taiwanica 16:68–73
Hsieh HY, Fung HC, Wang CJ, Chin SC, Wu T (2011) Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure 20:606–611
Jang HM, Park HR, Mun JK, Hwang KJ, Kim J, Hong SC, Seo DW (2013) Surgical treatment of mesial temporal lobe epilepsy in a patient with neurofibromatosis type 1. J Epilepsy Res 3:35–38
Kenborg L, Duun-Henriksen AK, Dalton SO, Bidstrup PE, Doser K, Rugbjerg K, Pedersen C, Krøyer A, Johansen C, Andersen KK, Østergaard JR, Hove H, Sørensen SA, Riccardi VM, Mulvihill JJ, Winther JF (2020) Multisystem burden of neurofibromatosis 1 in Denmark: registry- and population-based rates of hospitalizations over the life span. Genet Med. https://doi.org/10.1038/s41436-020-0769-6
Kim MJ, Cheon CK (2014) Neurofibromatosis type 1: a single center’s experience in Korea. Korean J Pediatr 57:410–415
Kokkinou E, Roka K, Alexopoulos A, Tsina E, Nikas I, Krallis P, Thanopoulou I, Nasi L, Makrygianni E, Tsoutsou E, Kosma K, Tsipi M, Tzetis M, Frysira H, Kattamis A, Pons R (2019) Development of a multidisciplinary clinic of neurofibromatosis type 1 and other neurocutaneous disorders in Greece. A 3-year experience. Postgrad Med 131:445–452
Kulkantrakorn K, Geller TJ (1998) Seizures in neurofibromatosis 1. Pediatr Neurol 19:347–350
Kuroda N, Fujimoto A, OKanishi T, Sato K, Nishimura M, EnOKi H (2019) Epilepsy surgery for a patient with neurofibromatosis type 1 concomitant with moyamoya syndrome. J Clin Neurosci 61:307–310
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G et al (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:1069–1077
Lellouch-Tubiana A, Bourgeois M, Vekemans M, Robain O (1995) Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1. Acta Neuropathol 90:319–322
Lisewski D, Ryan S, Lim EM, Frost F, Nguyen H Concomitant compostite adrenal phoechromocytoma, multipte gastric stromal tumours and pseudohermaphrodism in a patient with von Recklinghausen’s disease. Int Semin Surg Oncol 3:11
Mastrangelo M, Mariani R, Spalice A, Ruggieri M, Iannetti P (2009) Complex epileptic (Foix-Chavany-Marie like) syndrome in a child with neurofibromatosis type 1 (NF1) and bilateral (opercular and paracentral) polymicrogyria. Acta Paediatr 98:758–762
McGaughran JM, Harris DI, Donnai D, Teare D, MacLeod R, Westerbeek R, Kingston H, Super M, Harris R, Evans DG (1999) Seizure, spinal schwannoma, peripheral neuropathy and pulmonary stenosis-a rare combination in a patient of neurofibromatosis 1A clinical study of type 1 neurofibromatosis in north west England. J Med Genet 36:197–203
Mirzaa GM, Yuskaitis CJ, Poduri A (2018) 74 - Focal structural epilepsy. Swaiman’s Pediatric Neurology Book, 6th Edition; 583-589
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta analyses: the PRISMA statement. BMJ 339:b2535
Ostendorf AP, Gutmann DH, Weisenberg JL (2013) Epilepsy in individuals with neurofibromatosis type 1. Epilepsia 54:1810–1814
Pecoraro A, Arehart E, Gallentine W, Radtke R, Smith E, Pizoli C, Kansagra S, Abdelnour E, McLendon R, Mikati MA (2017) Epilepsy in neurofibromatosis type 1. Epilepsy Behav 73:137–141
Ray AC, Karjyi N, Roy AN, Dutta AK, Biswas A (2012) Seizure, spinal schwannoma, peripheral neuropathy and pulmonary stenosis - a rare combination in a patient of neurofibromatosis 1. Ann Indian Acad Neurol 15:51–53
Ruggieri M, Iannetti P, Clementi M, Polizzi A, Incorpora G, Spalice A, Pavone P, Praticò AD, Elia M, Gabriele AL, Tenconi R, Pavone L (2009) Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 25:211–216
Ruggieri M, Mastrangelo M, Spalice A, Mariani R, Torrente I, Polizzi A, Bottillo I, Di Biase C, Iannetti P (2011) Bilateral (opercular and paracentrallobular) polymicrogyria and neurofibromatosistype 1. Am J Med Genet A:582–585
Runke M, Salanova V (2013) Epilepsy due to a cortical malformation in a neurofibromatosis type 1 patient. Seizure 22:476–479
Santoro C, Di Rocco F, Kossorotoff M, Zerah M, Boddaert N, Calmon R, Vidaud D, Cirillo M, Cinalli G, Mirone G, Giugliano T, Piluso G, D'Amico A, Capra V, Pavanello M, Cama A, Nobili B, Lyonnet S, Perrotta S (2017) Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience. Am J Med Genet A 173:1521–1530
Santoro C, Bernardo P, Coppola A, Pugliese U, Cirillo M, Giugliano T, Piluso G, Cinalli G, Striano S, Bravaccio C, Perrotta S (2018) Seizures in children with neurofibromatosis type 1: is neurofibromatosis type 1 enough? Ital J Pediatr 44:41
Scheffer IE, Berkovic S, Capovilla G et al (2017) ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–521
Serdaroglu E, Konuskan B, Karli Oguz K, Gurler G, Yalnizoglu D, Anlar B (2019) Epilepsy in neurofibromatosis type 1: diffuse cerebral dysfunction? Epilepsy Behav 98:6–9
Srivastava K, Kalyan P, Oswal JS, Lalwani S (2013) A rare association of neurofibromatosis type 1 with Sturge-Weber syndrome. J Pediatr Neurol 11:111–113
Stafstrom CE, Staedtke V, Comi AM (2017) Epilepsy mechanisms in neurocutaneous disorders: tuberous sclerosis complex, neurofibromatosis type 1, and Sturge-Weber syndrome. Front Neurol 8:87
Stone TJ, Keeley A, Virasami A, Harkness W, Tisdall M, Izquierdo Delgado E, Gutteridge A, Brooks T, Kristiansen M, Chalker J, Wilkhu L, Mifsud W, Apps J, Thom M, Hubank H, Forshew TJ, Cross JH, Hargrave D, Ham J, Jacques TS (2018) Comprehensive molecular characterization of epilepsy-associated glioneuronal tumours. Acta Neuropathol 135:115–129
Szudek J, Birch P, Riccardi VM, Evans DG, Friedman JM (2000) Associations of clinical features in neurofibromatosis 1 (NF1). Genet Epidemiol 19:429–439
Tanyıldız HG, Yeşil Ş, Bozkurt C, Çandır MO, Akpınar-Tekgündüz S, Toprak Ş, Yüksel D, Şahin G (2016) Are the methylenetetrahydrofolate reductase 1298 and 677 gene polymorphisms related to optic glioma and hamartoma risk in neurofibromatosis type 1 patients? Turk J Pediatr 58:152–158
Thara K, Sharma R, Thiagarajan G, Ramdas A, Varghese RG (2017) Anaplastic pleomorphic xanthoastrocytoma in a case of neurofibromatosis type 1: a case report. J Clin Diagn Res 11:ED23–ED24
van Eeghen AM, Pulsifer MB, Merker VL, Neumeyer AM, van Eeghen EE, Thibert RL, Cole AJ, Leigh FA, Plotkin SR, Thiele EA (2013) Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach. Dev Med Child Neurol 55:146–153
Vivarelli R, Grosso S, Calabrese F, Farnetani M, Di Bartolo R, Morgese G, Balestri P (2003) Epilepsy in neurofibromatosis 1. J Child Neurol 18:338–342
Wintermark P, Meagher-Villemure K, Villemure JG, Maeder-Ingvar M, Maeder P, Ghariani S, Roulet-Perez E (2007) Progressive unilateral hemispheric atrophy in an infant with neurofibromatosis. Neuroped 38:100–104
Wu BL, Schneider GH, Korf BR (1997) Deletion of the entire NF1 gene causing distinct manifestations in a family. Am J Med Genet 69:98–101
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
For this type of study formal consent is not required
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 24 kb)
Rights and permissions
About this article
Cite this article
Bernardo, P., Cinalli, G. & Santoro, C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst 36, 2333–2350 (2020). https://doi.org/10.1007/s00381-020-04710-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00381-020-04710-7