OBJECTIVE: Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants. METHODS: The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated. RESULTS: Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77). SIGNIFICANCE: VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms.

Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Rome Italy

Department of Child Neurology Charité University Medicine Berlin Berlin Germany

Department of Pathology Amsterdam Neuroscience Amsterdam University Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pediatric Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatric Neurology Katholieke Universiteit Leuven Belgium

Department of Pediatric Neurology Reference Center for Rare Epilepsies Necker Enfants Malades Hospital Paris Descartes University Imagine Institute Paris France

Department of Pediatric Neurology University Medical Center Utrecht Brain Center Utrecht The Netherlands

Department of Radiology University Medical Center Utrecht The Netherlands

Developmental Neurology Unit Bambino Gesù Children's Hospital Scientific Institute for Research Hospitalization and Health Care Rome Italy

Epilepsy Center Department of Pediatrics Medical University of Vienna Vienna Austria

Genetics Reproduction and Development Research Group Vrije Universiteit Brussel Brussels Belgium

Image Sciences Institute Division Imaging and Oncology University Medical Center Utrecht Utrecht The Netherlands

Neurosciences Unit Queensland Children's Hospital South Brisbane Queensland Australia

Research Department Department of Neurology and Epileptology Children's Memorial Health Institute Warsaw Poland

Transition Technologies Advanced Solutions Children's Memorial Health Institute Warsaw Poland

Transition Technologies Science Children's Memorial Health Institute Warsaw Poland

Translational Neurosciences University of Antwerp Antwerp Belgium

Zobrazit více v PubMed

Salussolia CL, Klonowska K, Kwiatkowski DJ, Sahin M. Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex. Annu Rev Genomics Hum Genet. 2019;20:217–240. PubMed

Northrup H, Krueger DA, International tuberous sclerosis complex consensus G . Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49(4):243–254. PubMed PMC

Chu‐Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51(7):1236–1241. PubMed PMC

Nabbout R, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, et al. Epilepsy in tuberous sclerosis complex: findings from the TOSCA study. Epilepsia Open. 2019;4(1):73–84. PubMed PMC

Capal JK, Bernardino‐Cuesta B, Horn PS, Murray D, Byars AW, Bing NM, et al. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav. 2017;70(Pt A):245–252. PubMed PMC

Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14(7):733–745. PubMed

Koo B, Hwang PA, Logan WJ. Infantile spasms: outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology. 1993;43(11):2322–2327. PubMed

Bombardieri R, Pinci M, Moavero R, Cerminara C, Curatolo P. Early control of seizures improves long‐term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol. 2010;14(2):146–149. PubMed

Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P. Long‐term neurological outcome in children with early‐onset epilepsy associated with tuberous sclerosis. Epilepsy Behav. 2011;22(4):735–739. PubMed

Jambaque I, Chiron C, Dumas C, Mumford J, Dulac O. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res. 2000;38(2–3):151–160. PubMed

Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol. 1999;14(2):71–74. PubMed

Curatolo P, Verdecchia M, Bombardieri R. Vigabatrin for tuberous sclerosis complex. Brain and Development. 2001;23(7):649–653. PubMed

Curatolo P, Bombardieri R, Cerminara C. Current management for epilepsy in tuberous sclerosis complex. Curr Opin Neurol. 2006;19(2):119–123. PubMed

Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. 2013;6:CD001770. PubMed PMC

Zhang B, McDaniel SS, Rensing NR, Wong M. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS One. 2013;8(2):e57445. PubMed PMC

Hussain SA, Tsao J, Li M, Schwarz MD, Zhou R, Wu JY, et al. Risk of vigabatrin‐associated brain abnormalities on MRI in the treatment of infantile spasms is dose‐dependent. Epilepsia. 2017;58(4):674–682. PubMed

Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, et al. Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial. Ann Neurol. 2021;89(2):304–314. PubMed PMC

Bebin EM, Peters JM, Porter BE, McPherson TO, O'Kelley S, Sahin M, et al. Early treatment with vigabatrin does not decrease focal seizures or improve cognition in tuberous sclerosis complex: the PREVeNT trial. Ann Neurol. 2023;95:15–26. PubMed PMC

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. PubMed

Biswas A, Yossofzai O, Vincent A, Go C, Widjaja E. Vigabatrin‐related adverse events for the treatment of epileptic spasms: systematic review and meta‐analysis. Expert Rev Neurother. 2020;20(12):1315–1324. PubMed

Desguerre I, Marti I, Valayannopoulos V, Bahi‐Buisson N, Dulac O, Plouin P, et al. Transient magnetic resonance diffusion abnormalities in west syndrome: the radiological expression of non‐convulsive status epilepticus? Dev Med Child Neurol. 2008;50(2):112–116. PubMed

Dracopoulos A, Widjaja E, Raybaud C, Westall CA, Snead OC 3rd. Vigabatrin‐associated reversible MRI signal changes in patients with infantile spasms. Epilepsia. 2010;51(7):1297–1304. PubMed

Harini C, Yuskaitis CJ, Libenson MH, Yang E, DeLeo M, Zhang B, et al. Hippocampal involvement with vigabatrin‐related MRI signal abnormalities in patients with infantile spasms: a novel finding. J Child Neurol. 2021;36(7):575–582. PubMed

Milh M, Villeneuve N, Chapon F, Pineau S, Lamoureux S, Livet MO, et al. Transient brain magnetic resonance imaging hyperintensity in basal ganglia and brain stem of epileptic infants treated with vigabatrin. J Child Neurol. 2009;24(3):305–315. PubMed

Pearl PL, Vezina LG, Saneto RP, McCarter R, Molloy‐Wells E, Heffron A, et al. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia. 2009;50(2):184–194. PubMed

Wheless JW, Carmant L, Bebin M, Conry JA, Chiron C, Elterman RD, et al. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia. 2009;50(2):195–205. PubMed

Xu Y, Wan L, He W, Wang YY, Wang QH, Luo XM, et al. Risk of vigabatrin‐associated brain abnormalities on MRI: a retrospective and controlled study. Epilepsia. 2022;63(1):120–129. PubMed

Reyes Valenzuela G, Crespo A, Princich J, Fassulo L, Semprino M, Gallo A, et al. Vigabatrin‐associated brain abnormalities on MRI and other neurological symptoms in patients with west syndrome. Epilepsy Behav. 2022;129:108606. PubMed

Arezzo JC, Schroeder CE, Litwak MS, Steward DL. Effects of vigabatrin on evoked potentials in dogs. Br J Clin Pharmacol. 1989;27(Suppl 1):53S–60S. PubMed PMC

Butler WH. The neuropathology of vigabatrin. Epilepsia. 1989;30(Suppl 3):S15–S17. PubMed

Butler WH, Ford GP, Newberne JW. A study of the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and lister‐hooded rats. Toxicol Pathol. 1987;15(2):143–148. PubMed

Gibson JP, Yarrington JT, Loudy DE, Gerbig CG, Hurst GH, Newberne JW. Chronic toxicity studies with vigabatrin, a GABA‐transaminase inhibitor. Toxicol Pathol. 1990;18(2):225–238. PubMed

Graham D. Neuropathology of vigabatrin. Br J Clin Pharmacol. 1989;27(Suppl 1):43S–45S. PubMed PMC

Jackson GD, Williams SR, Weller RO, van Bruggen N, Preece NE, Williams SC, et al. Vigabatrin‐induced lesions in the rat brain demonstrated by quantitative magnetic resonance imaging. Epilepsy Res. 1994;18(1):57–66. PubMed

Schroeder CE, Gibson JP, Yarrington J, Heydorn WE, Sussman NM, Arezzo JC. Effects of high‐dose gamma‐vinyl GABA (vigabatrin) administration on visual and somatosensory evoked potentials in dogs. Epilepsia. 1992;33(Suppl 5):S13–S25. PubMed

Weiss KL, Schroeder CE, Kastin SJ, Gibson JP, Yarrington JT, Heydorn WE, et al. MRI monitoring of vigabatrin‐induced intramyelinic edema in dogs. Neurology. 1994;44(10):1944–1949. PubMed

Yarrington JT, Gibson JP, Dillberger JE, Hurst G, Lippert B, Sussman NM, et al. Sequential neuropathology of dogs treated with vigabatrin, a GABA‐transaminase inhibitor. Toxicol Pathol. 1993;21(5):480–489. PubMed

Cohen JA, Fisher RS, Brigell MG, Peyster RG, Sze G. The potential for vigabatrin‐induced intramyelinic edema in humans. Epilepsia. 2000;41(2):148–157. PubMed

Peters JM, Sahin M, Vogel‐Farley VK, Jeste SS, Nelson CA 3rd, Gregas MC, et al. Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex. Acad Radiol. 2012;19(1):17–25. PubMed PMC

McKavanagh A, Kreilkamp BAK, Chen Y, Denby C, Bracewell M, Das K, et al. Altered structural brain networks in refractory and nonrefractory idiopathic generalized epilepsy. Brain Connect. 2022;12(6):549–560. PubMed

Jin B, Lv Z, Chen W, Wang C, Aung T, Chen W, et al. Perilesional white matter integrity in drug‐resistant epilepsy related to focal cortical dysplasia. Seizure. 2021;91:484–489. PubMed

Cohen J. A coefficient of agreement for nominal scales. Educ Psychol Meas. 1960;20:37–46.

Grant RL. Converting an odds ratio to a range of plausible relative risks for better communication of research findings. BMJ. 2014;348:f7450. PubMed

Wan L, He W, Wang YY, Xu Y, Lu Q, Zhang MN, et al. Vigabatrin‐associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable? Ther Adv Neurol Disord. 2022;15:17562864221138148. PubMed PMC