OBJECTIVE: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80-150 mg/kg/day). METHODS: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). RESULTS: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. INTERPRETATION: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

Brigham and Women's Hospital Harvard Medical School Boston MA 02115

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Via Montpellier 1 Rome 00133 Italy

Child Neurology Unit Neuroscience and Neurorehabilitation Department Bambino Gesù Children's Hospital IRCCS P zza S Onofrio 4 Rome 00165 Italy

Department of Biomedicine and Prevention Tor Vergata University of Rome Via Montpellier 1 Rome 00133 Italy

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

Department of Child Neurology Charité University Medicine Berlin Augustenburger Platz 1 Berlin 13353 Germany

Department of Child Neurology Medical University of Warsaw Warsaw Poland

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven Leuven Belgium

Department of Neurology and Epileptology The Children's Memorial Health Institute Al Dzieci Polskich 20 Warsaw 04 730 Poland

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

Department of Pathology Amsterdam UMC University of Amsterdam Amsterdam Neuroscience Meibergdreef 9 Amsterdam The Netherlands

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

Department of Pediatrics Medical University Vienna Vienna Austria

Diagnose und Behandlungszentrum für Kinder und Jugendliche Vivantes Klinikum Neuköln Berlin Germany

Neuroscience Unit Queensland Children's Hospital 501 Stanley Street South Brisbane QLD 4101 Australia

Pediatric Neurology Unit UZ Brussel Brussels Belgium

School of Clinical Medicine University of Queensland St Lucia QLD 4072 Australia

Stichting Epilepsie Instellingen Nederland Heemstede The Netherlands

Transition Technologies ul Pawia 5 Warsaw 01 030 Poland

Warsaw University of Technology Institute of Heat Engineering Warsaw Poland

Zobrazit více v PubMed

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

de Vries PJ, Wilde L, de Vries MC, et al. A clinical update on tuberous sclerosis complex‐associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet 2018;178:309–320. PubMed PMC

Curatolo P, Moavero R, van Scheppingen J, Aronica E. mTOR dysregulation and tuberous sclerosis‐related epilepsy. Expert Rev Neurother 2018;18:185–201. PubMed

Ruppe V, Dilsiz P, Reiss CS, et al. Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and perituberal cortex. Epilepsia 2014;55:539–550. PubMed

Chu‐Shore CJ, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010;51:1236–1241. PubMed PMC

Nabbout R, Belousova E, Benedik MP, et al. Epilepsy in tuberous sclerosis complex: findings from the TOSCA Study. Epilepsia Open 2019;4:73–84. PubMed PMC

Bolton PF. Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Ment Retard Dev Disabil Res Rev 2004;10:126–131. PubMed

Curatolo P, Aronica E, Jansen A, et al. Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC. Eur J Paediatr Neurol 2016;20:203–211. PubMed

Cusmai R, Moavero R, Bombardieri R, et al. Long‐term neurological outcome in children with early‐onset epilepsy associated with tuberous sclerosis. Epilepsy Behav 2011;22:735–739. PubMed

Numis AL, Major P, Montenegro MA, et al. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 2011;76:981–987. PubMed PMC

Benova B, Petrak B, Kyncl M, et al. Early predictors of clinical and mental outcome in tuberous sclerosis complex: a prospective study. Eur J Paediatr Neurol 2018;22:632–641. PubMed

Dragoumi P, O'Callaghan F, Zafeiriou DI. Diagnosis of tuberous sclerosis complex in the fetus. Eur J Paediatr Neurol 2018;22:1027–1034. PubMed

Curatolo P, Jozwiak S, Nabbout R. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 2012;16:582–586. PubMed

Curatolo P, Nabbout R, Lagae L, et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol 2018;22:738–748. PubMed

Whitney R, Jan S, Zak M, McCoy B. The utility of surveillance electroencephalography to guide early antiepileptic drug therapy in infants with tuberous sclerosis complex. Pediatr Neurol 2017;72:76–80. PubMed

Wu JY, Peters JM, Goyal M, et al. Clinical electroencephalographic biomarker for impending epilepsy in asymptomatic tuberous sclerosis complex infants. Pediatr Neurol 2016;54:29–34. PubMed PMC

Domanska‐Pakiela D, Kaczorowska M, Jurkiewicz E, et al. EEG abnormalities preceding the epilepsy onset in tuberous sclerosis complex patients ‐ a prospective study of 5 patients. Eur J Paediatr Neurol 2014;18:458–468. PubMed

Wu JY, Goyal M, Peters JM, et al. Scalp EEG spikes predict impending epilepsy in TSC infants: a longitudinal observational study. Epilepsia 2019;60:2428–2436. PubMed PMC

Bombardieri R, Pinci M, Moavero R, et al. Early control of seizures improves long‐term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol 2010;14:146–149. PubMed

Jozwiak S, Kotulska K, Domanska‐Pakiela D, et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011;15:424–431. PubMed

Jozwiak S, Slowinska M, Borkowska J, et al. Preventive antiepileptic treatment in tuberous sclerosis complex: long‐term, prospective trial. Pediatr Neurol (2019); 101: 18–25. PubMed

Northrup H, Krueger DA; G International Tuberous Sclerosis Complex Consensus . Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:243–254. PubMed PMC

Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069–1077. PubMed

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

Tye C, McEwen FS, Liang H, et al. Long‐term cognitive outcomes in tuberous sclerosis complex. Dev Med Child Neurol 2020;62:322–329. PubMed PMC

Goorden SM, van Woerden GM, van der Weerd L, et al. Cognitive deficits in Tsc1+/‐ mice in the absence of cerebral lesions and seizures. Ann Neurol 2007;62:648–655. PubMed

Ehninger D, Han S, Shilyansky C, et al. Reversal of learning deficits in a Tsc2+/‐ mouse model of tuberous sclerosis. Nat Med 2008;14:843–848. PubMed PMC

Boronat S, Shaaya EA, Doherty CM, et al. Tuberous sclerosis complex without tubers and subependymal nodules: a phenotype‐genotype study. Clin Genet 2014;86:149–154. PubMed

Farach LS, Pearson DA, Woodhouse JP, et al. Tuberous sclerosis complex genotypes and developmental phenotype. Pediatr Neurol 2019;96:58–63. PubMed PMC

Spurling Jeste S, Wu JY, Senturk D, et al. developmental trajectories associated with ASD in infants with tuberous sclerosis complex. Neurology 2014;83:160–168. PubMed PMC

McDonald NM, Varcin KJ, Bhatt R, et al. autism symptoms in infants with tuberous sclerosis complex. Autism Res 2017;10:1981–1990. PubMed PMC

Moavero R, Benvenuto A, Emberti Gialloreti L, et al. Clinical Predictors of autism spectrum disorder in infants with tuberous sclerosis complex: results from the EPISTOP study. J Clin Med 2019;8:788. PubMed PMC

Prohl AK, Scherrer B, Tomas‐Fernandez X, et al. white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder. J Neurodev Disord 2019;11:36. PubMed PMC

Moavero R, Napolitano A, Cusmai R, et al. White matter disruption is associated with persistent seizures in tuberous sclerosis complex. Epilepsy Behav 2016;60:63–67. PubMed

Peters JM, Struyven RR, Prohl AK, et al. White matter mean diffusivity correlates with myelination in tuberous sclerosis complex. Ann Clin Transl Neurol 2019;6:1178–1190. PubMed PMC

Bolton PF, Clifford M, Tye C, et al. Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study. Psychol Med 2015;45:2321–2331. PubMed

Jansen FE, Vincken KL, Algra A, et al. Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology 2008;70:916–923. PubMed

Humphrey A, MacLean C, Ploubidis GB, et al. Intellectual development before and after the onset of infantile spasms: a controlled prospective longitudinal study in tuberous sclerosis. Epilepsia 2014;55:108–116. PubMed

Jambaque I, Cusmai R, Curatolo P, et al. Neuropsychological aspects of tuberous sclerosis in relation to epilepsy and MRI findings. Dev Med Child Neurol 1991;33:698–705. PubMed

Tye C, Thomas LE, Sampson JR, et al. Secular changes in severity of intellectual disability in tuberous sclerosis complex: a reflection of improved identification and treatment of epileptic spasms? Epilepsia Open 2018;3:276–280. PubMed PMC

Prabowo AS, Anink JJ, Lammens M, et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 2013;23:45–59. PubMed PMC

van Eeghen AM, Black ME, Pulsifer MB, et al. Genotype and cognitive phenotype of patients with tuberous sclerosis complex. Eur J Hum Genet 2012;20:510–515. PubMed PMC

Dickinson A, Varcin KJ, Sahin M, Nelson CA, Jeste SS. Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex. Autism Res 2019;12:1758–1773. PubMed PMC

Nguyen LH, Mahadeo T, Bordey A. mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical dysplasia. J Neurosci 2019;39:2762–2773. PubMed PMC

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex