Genetic Testing in Presurgical Workup for Pediatric Drug-resistant Focal Epilepsy: A Systematic Review
Abstract number :
1.369
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204248
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Chethan Rao, DO, MS – Stanford Children's Health; Douglas Nordli, MD – Child Neurology Resident, Child and Adolescent Neurology, Mayo Clinic Florida; Fernando Galan, MD – Child Neurology Attending Physician, Neurology, Nemours Children's Health; Raj Sheth, MD, FAES – Professor of Neurology, Division Chief, Child and Adolescent Neurology, Mayo Clinic Florida/Nemours Children's Health
Rationale: For children with focal drug-resistant epilepsy, surgical resection and precision therapies can result in seizure reduction or freedom. However, specific genetic etiologies can preclude effective surgical intervention while presenting opportunities for tailored pharmacological intervention. The use of next-generation sequencing in clinical practice holds promise for identifying patients with such diagnoses. In this systematic review, we evaluate the evidence of seizure reduction from resective surgery or precision therapy in pediatric patients with drug-resistant focal epilepsy of genetic etiology identified by next-generation sequencing.
Methods: We systematically searched MEDLINE through PubMed, Embase, Web of Science, and Scopus in December 2021 for all published articles reporting genetic testing in pediatric (age < 18 years) patients with focal drug-resistant epilepsy. We excluded conference proceedings/abstracts, articles not written in English, and reviews. After the initial search, additional eligible articles were identified by hand search. We utilized the Joanna Briggs Institute (JBI) critical appraisal tool to assess risk of bias of all eligible studies. All steps were performed in duplicate by two independent reviewers and a third reviewer as tiebreaker. The study protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (CRD42022298374).
Results: Our search resulted in 1382 unique abstracts, of which 134 were selected for full text screening, and 28 articles met inclusion criteria comprising 549 patients in total. Twelve included studies described seizure outcomes after surgical intervention and 17 after precision pharmacological therapies. Whole exome sequencing (WES) was the most reported method of genetic testing (n=21, 72% of studies) followed by epilepsy gene panel (n=15, 52%), and single gene testing (n=3, 10%). For patients with mTOR pathway pathogenic variants (TSC1, TSC2, DEPDC5, NPRL2, and NPRL3), surgical resection was effective ( >50% seizure reduction) in 105 of 197 (53%) and everolimus was effective in 88 of 253 (35%). Resective surgery was effective in 5 of 9 (56%) patients with SCN1A-associated focal epilepsy, mostly for hippocampal sclerosis. Of 42 patients with KCNT1 pathogenic variants, quinidine was effective in 10 (24%). Sodium channel blockers were effective in 30 of 35 (86%) patients with SCN8A or KCNQ2 pathogenic variants, and 1 KCNQ2 patient treated with retigabine had similar results. Other pathogenic variants including CAD, nicotinic receptor genes, FARS2, and LGI1 were treated with uridine, nicotine, or surgical resection with a total of 12/17 (71%) reported with >50% seizure reduction.
Conclusions: Our findings demonstrate that identification of patients with genetic etiologies through next-generation sequencing allows for seizure reduction from surgical resection and pharmacological precision therapies that would otherwise not be considered. Patients would likely benefit from updated guidelines for the inclusion of next-generation sequencing in presurgical evaluation in pediatric focal epilepsy.
Funding: None
Genetics