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

https://doi.org/10.1016/j.ejpn.2015.12.005Get rights and content

Highlights

  • Overactivation of the mTOR pathway may lead both to epilepsy and to encephalopathy.

  • Early seizures negatively contribute to worsening the final developmental outcome.

  • Early signs of altered developmental trajectories may be unrecognized.

  • Controlling seizures is crucial to reduce profound learning disability.

  • Seizure onset may precede neurodevelopmental problems without any causal relationship.

Abstract

Background

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.

Methods

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.

Results/Conclusion

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.

Introduction

Epileptic encephalopathy embodies the notion that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation).6

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by a mutation in one of the two genes, TSC1 or TSC2, leading to a overactivation of the mammalian target of rapamycin (mTOR).18 mTOR is a serine/threonine kinase playing a crucial role in cell growth and proliferation, and it exerts its activity in response to nutrients and growth factors.15 “mTORopathies” are a group of conditions in which TSC is best known, but also includes focal cortical dysplasia and hemimegalencephaly, and are characterized by a disruption of the brain architecture.14 mTOR dysregulation in TSC 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.36 Also neurodevelopmental deficits may be the result of signaling abnormalities, deriving from the alteration of the cascade of events subsequent to the TSC gene mutation, and the severity of symptoms may depend on which structural and functional sites are impaired by an individual mutation.21 Indeed, mTOR overactivation is also responsible of altered long term potentiation and connectivity abnormalities, which might be responsible per se of neurodevelopmental problems.29

TSC is frequently associated with seizures, which are present in up to 85% of patients. Seizure onset is observed in the first year of life in about 67% of affected children. About half of the children remain resistant to the current available treatment options.13 Furthermore, learning disability is present in about half of patients affected by TSC, with a considerable proportion with severe/profound ID.33 A higher tuber burden is associated with a higher risk of ID, and the presence of tubers in the temporal lobes may increase the risk for autism spectrum disorders.16, 8, 31

A significant relationship between early age at seizure onset and poor developmental outcomes has been established.25, 31 However, it is still unclear whether epilepsy in TSC is simply a marker of infants who are destined to develop an encephalopathic process or seizures play a causal role in developing an encephalopathy.

A European workshop in the context of a Steering Committee Meeting of a multicenter trial (EPISTOP project) was held in Rome on June 19th 2015 with the aims of discussing the current knowledge on early onset epilepsy and encephalopathy in TSC, including the possible relationship between seizures and neurodevelopmental phenotype – cause or consequence. This paper reports the main points discussed at this workshop, and review the experimental evidences in support of the two theories.

Section snippets

Brain consequences of mTOR activation

mTOR is an ubiquitously expressed protein, mainly localized into cytoplasm, that modulates cell growth and proliferation, autophagy, and protein synthesis and acts as a key regulator of neural network activity.52 mTOR activity and TSC proteins are also important for the regulation of synaptic organization and function, axonal polarization and myelination.12, 37 mTORC1 signaling has been demonstrated to be activated early during brain development,46, 56 and pathological neural networks with

Is epilepsy the cause of encephalopathy?

From a clinical point of view, TSC most of time well illustrates the concept of epileptic encephalopathy since the majority of affected children exhibit normal early development with learning and behavioral deficits becoming evident only after early seizure onset. Treating clinicians might encounter children with TSC presenting a normal development in the first two or three years of life, and going toward a regression after the onset of seizures.28 In these cases a causal relationship between

Can we predict the TSC associated epileptic encephalopathy?

About 5% of children with TSC will develop their first seizures in the first 4 weeks of life.35 Neonatal onset of epilepsy is frequently observed in the presence of a large cortical dysplasia,35 however no accurate predictors of early onset seizures or developmental delay have been identified currently.

The predictive role of interictal EEG findings is of paramount importance to the clinical understanding of the epileptogenesis. Early detection of EEG abnormalities during EEG monitoring in the

Can we prevent the TSC associated epileptic encephalopathy with early targeted treatment?

Today, TSC is increasingly more frequent diagnosed in the prenatal period or in the early infancy, prior to the onset of epilepsy, thus raising the possibility of monitoring children before the onset of seizures and/or neurodevelopment delay.17 To study the effects of prenatal treatment with mTOR inhibitors, aiming to prevent mTOR activation, different experimental models have been undertaken with significant results in terms of histological rescue and prolonged survival.3, 62, 53 However,

Conclusions and future directions

The key points of the workshop have been summarized in Panel 1. The concept of the role of early onset of epilepsy in cognitive outcome is challenged as the sole factor in TSC related encephalopathy. The role of the genetic defect is recently raising. Although a definite conclusion is still difficult to be made, the current evidence suggests that both early onset seizures as well as encephalopathy in TSC are genetically determined through a cascade of events involving an early mTOR

Conflict of interest

None.

Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC: key points agreed during the workshop.

  • -

    Infants with TSC have a genetic and neurobiological basis for the early onset seizure appearance and for the encephalopathic process

  • -

    Mutation in one of the two TSC genes is directly responsible for both encephalopathy and early onset epilepsy

  • -

    The overactivation of the same mTOR pathway may lead both to epilepsy and to

Acknowledgments

All authors of this manuscript participate in the EPISTOP study (www.epistop.eu) which is funded under the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement n° 602391.

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