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Eur J Paediatr Neurol. 2016 Mar;20(2):203-211. doi: 10.1016/j.ejpn.2015.12.005. Epub 2015 Dec 23.

Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC.

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Systems Medicine Department, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital of Rome, Italy. Electronic address:
Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; SEIN - Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:
Pediatric Neurology Unit - UZ Brussel, Brussels, Belgium. Electronic address:
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands. Electronic address:
Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland. Electronic address:
Department of Development and Regeneration-Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium. Electronic address:
Systems Medicine Department, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital of Rome, Italy; Department of Neuroscience and Neurorehabilitation, Pediatric Neurology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:
Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland. Electronic address:



In tuberous sclerosis complex (TSC) a relationship has been shown between early and refractory seizures and intellectual disability. However, it is uncertain whether epilepsy in TSC is simply a marker in infants who are destined to develop an encephalopathic process or if seizures play a causal role in developing an encephalopathy.


This paper summarizes the key points discussed during a European TSC workshop held in Rome, and reviews the experimental and clinical evidence in support of the two theories.


There are many factors that influence the appearance of both early seizure onset and the encephalopathy resulting in neurodevelopmental deficits. Experimental studies show that as a consequence of the TSC genes mutation, mammalian target of Rapamycin (mTOR) overactivation determines an alteration in cellular morphology with cytomegalic neurons, altered synaptogenesis and an imbalance between excitation/inhibition, thus providing a likely neuroanatomical substrate for the early appearance of refractory seizures and for the encephalopathic process. At the clinical level, early signs of altered developmental trajectories are often unrecognized before 12 months of age. Evidence from experimental research shows that encephalopathy in TSC might have a genetic cause, and mTOR activation caused by TSC gene mutation can be directly responsible for the early appearance of seizures and encephalopathy.


Epileptic encephalopathy; Genetics; Tuberous sclerosis; Vigabatrin; mTOR

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