Abstracts

Rationale: The pathogenesis of seizures in persons with epilepsy (PWE) varies, from structural, infectious, metabolic, immune, to genetic causes. Initial seizure management may be difficult with imprecise seizure semiology, clinical history, and nondiagnostic testing. This hinders early, accurate diagnosis of patients’ specific epilepsy type, and often necessitates a “trial and error” approach with anti-seizure medications (ASM). Additionally, there may be unforeseeable side effects from ASMs, delaying time to seizure freedom, and increasing morbidity and mortality from poorly treated epilepsy. The cost of genetic testing has rapidly declined, and recent advancements in pharmacogenomic panels make this a promising tool to help guide treatment. Our institution is developing epilepsy-specific pharmacogenomic panels, and here we highlight a patient where pharmacogenomic testing helped optimize seizure control after he failed 2 ASMs. 

Methods:
A 51-year-old man with a history of hearing loss, major depression with prior suicide attempt, cardiac abnormalities, and dysmorphic facial features presented with new onset of convulsive seizures. In retrospect, the patient reported lifelong non-motor seizures, which were never diagnosed and attributed to anxiety. His first convulsive seizure occurred at the age of 50. He was prescribed Levetiracetam, but the patient self-discontinued it due to severe depression/suicidal ideation. He experienced a second convulsive seizure, after which he was started on Oxcarbazepine. Unfortunately, this caused visual changes, worsening of hearing loss, and hyponatremia, prompting transition to Zonisamide. Zonisamide 400 mg daily led to seizure freedom but caused severe tinnitus. Pharmacogenomic testing was ordered to help guide treatment.




Results:
Pharmacogenomics testing showed the patient is a poor metabolizer of CYP3A5, a rapid metabolizer of both CYP2C19 and CYP1A2, positive for a SCN1A homozygous AA genotype polymorphism(rs3812718), and negative for both HLA-A*31:01 and HLA-B*15:02 genotypes. A poor metabolizer of CYP3A5 can increase the risk of toxicity/side effects of Carbamazepine, Oxcarbazepine, and Phenytoin. Rapid metabolizers of CYP2C19 can increase metabolism of Oxcarbazepine, Phenytoin, and Clobazam leading to subtherapeutic levels, while being a CYP1A2 rapid metabolizer may lead to subtherapeutic levels of Carbamazepine. The SCN1A homozygous AA polymorphism (rs3812718) is associated with unresponsiveness to Valproic Acid and Carbamazepine, but no effect on Lamotrigine.




Conclusions:
Given the patient’s pharmacogenomics testing, Lamotrigine was selected. The combination of Lamotrigine (titrated to 50 mg twice daily) and Zonisamide 300 mg daily led to seizure freedom and resolution of side effects. Additionally, his mood and quality of life improved with these ASM changes. This case demonstrates the significance of pharmacogenomic testing in guiding ASM selection in PWE, helping reduce reliance on the “trial and error” approach. Further studies are needed to evaluate the efficacy of pharmacogenomics gene testing in the management of PWE. 




Funding: None