Assessment of cardiac electrical function and prevalence of electrocardiographic abnormalities in patients diagnosed with Dravet Syndrome and Lennox-Gastaut Syndrome

Lead Investigator: David Auerbach, SUNY Upstate Medical University
Title of Proposal Research: Assessment of cardiac electrical function and prevalence of electrocardiographic abnormalities in patients diagnosed with Dravet Syndrome and Lennox-Gastaut Syndrome
Vivli Data Request: 9739
Funding Source: NIH R01: seeking funding
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Millions of Americans have epilepsy and are at a high risk of sudden death. The cause of death is often unknown, and is termed Sudden Unexpected Death in Epilepsy (SUDEP). Abnormal cardiac (heart) rate/rhythm (i.e., arrhythmias) and abnormalities with electrical activity of the heart are reported surrounding seizures, and are one of several proposed causes of SUDEP. Electrocardiogram measures (ECG – a test that records the electrical activity of the heart, including the rate and rhythm) provide indicators for cardiac arrhythmias and risk of sudden cardiac death.

Some forms of epilepsy, especially SUDEP cases, are associated with changes to genes expressed in both the brain and heart. People with Dravet Syndrome (DS) are at the highest risk of SUDEP. DS is the most severe genetic and difficult to control form of epilepsy (1:30,000 children). More than 80% of people with DS have de novo mutations (changes to genes not inherited from parents) in a gene called SCN1A (voltage gated sodium channel type 1 alpha subunit), which is important for cardiac electrical and contractile function. Lennox-Gastaut Syndrome (LGS) is another severe form of epilepsy, accounting for 1-4% of all pediatric epilepsy. In contrast to DS, LGS arises from multiple causes with no genetic markers. Thus, we will evaluate cardiac electrical function in people with DS vs. LGS.

In order for the heart to contract and push blood around the body, an electrical current passes from cell to cell in the heart muscle changing the cells from a resting state (known as a polarized state) to a depolarized state. This causes the heart muscle to contract. After contraction the cells repolarize back to their resting state. Abnormalities in the spread of electrical waves in the heart (conduction) and electrical activation-recovery intervals (repolarization) increase the risk of potentially lethal cardiac events. Epilepsy is associated with cardiac conduction and repolarization disturbances and arrhythmias. These abnormalities are more evident in severe forms of epilepsy, such as DS, surrounding seizures, and in cases of SUDEP. It remains unclear if ECG pathologies are associated with DS.

Experimental Approach: We will use ECG recordings at the baseline/screening timepoint in people with DS or LGS, who were screened for eligibility to participate in the fenfluramine randomized controlled trials (RCT). Depending on data availability, we will perform standard clinical ECG analysis to evaluate cardiac rate, conduction, and repolarization. Next, or if the measurements have already been performed, we will compare these ECG measures in people with DS vs. LGS. Additionally, we will conduct appropriate statistical analysis to account for other factors that may result in differences in ECG measures (e.g., age, sex, seizure severity, and anti-seizure medications).

Necessity of the Research: Results will provide the most comprehensive assessment of cardiac electrical function in DS and LGS, which will foster the future development and validation of ECG markers for cardiac-mediated SUDEP in these populations.

Requested Studies:

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
Data Contributor: UCB
Study ID: NCT02682927
Sponsor ID: ZX008-1501