Neuroimaging and genetic characteristics of malformation of cortical development due to mTOR pathway dysregulation: clues for the epileptogenic lesions and indications for epilepsy surgery

ABSTRACT

Introduction: Malformation of cortical development (MCD) is strongly associated with drug-resistant epilepsies for which surgery to remove epileptogenic lesions is common. Two notable technological advances in this field are identification of the underlying genetic cause and techniques in neuroimaging. These now question how presurgical evaluation ought to be approached for ‘mTORpathies.’

Area covered: From review of published primary and secondary articles, the authors summarize evidence to consider focal cortical dysplasia (FCD), tuber sclerosis complex (TSC), and hemimegalencephaly (HME) collectively as MCD mTORpathies. The authors also consider the unique features of these related conditions with particular focus on the practicalities of using neuroimaging techniques currently available to define surgical targets and predict post-surgical outcome. Ultimately, the authors consider the surgical dilemmas faced for each condition.

Expert opinion: Considering FCD, TSC, and HME collectively as mTORpathies has some merit; however, a unified approach to presurgical evaluation would seem unachievable. Nevertheless, the authors believe combining genetic-centered classification and morphologic findings using advanced imaging techniques will eventually form the basis of a paradigm when considering candidacy for early surgery.

KEYWORDS:

• Cortical development
• developmental disorders
• epilepsy
• focal cortical dysplasia
• hemimegalencephaly
• MRI
• mTORpathies
• neuroimaging
• tuberous sclerosis complex

Article highlights

• FCD, TSC, and HME share a common dysregulation of mTOR signaling due to somatic ‘second hit’ mutation, either during neurogenesis or de novo within cerebral lesion tissue, resulting in focal cortical epileptogenic lesions.

• The later a mutation occurs during cortical development, the more restricted will be its distribution within the formed brain, underlying the varied characteristics of the conditions.

• Development of high-resolution neuroimaging techniques has enabled visualization of subtle clues to epileptogenic lesions, such that imaging and genetics should be included in the routine clinical assessment for all patients with epilepsy when considering candidacy for early surgery.

• No single neuroimaging modality has yet provided universal definition of the epileptogenic zone and subsequent seizure outcome following surgical resection, so we believe specific selection of one or more imaging techniques for a patient should be guided by the genetic-centered etiology and electro-clinical features.

Acknowledgments

The authors would like to thank Dr David Macari for the English editing of the final version of the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.