Long QT Syndrome Linked To Higher Seizure Risk

A genetic link between Long QT Syndrome (LQTS), a rare cardiac rhythm disease, and an increased risk for seizures has been discovered by researchers. The findings also show that people with LQTS who experience seizures are at greater risk of sudden cardiac death.

Scientists found a clear association between the heart and the brain of Long QT Syndrome patients. Patients carrying LQTS genetic mutations were three times more likely to have experienced seizures in their past, compared to their family members who did not carry those mutations.

Further, LQTS patients who had a history of seizures also tended to have worse cardiac symptoms.

Seizure status proved to be the strongest predictor of cardiac arrhythmias—the abnormal heart rhythms characteristic of LQTS. In fact, about 20 percent of the Long QT Syndrome patients in the study who had a history of seizures had survived at least one lethal cardiac arrhythmia.

The study sets a new clinical precedence for the link between seizures and LQTS and provides a case for doctors to pay more attention to what is happening in LQTS patients’ brains or, more broadly, to “look outside the classic organ of interest” in any disease, says David Auerbach, senior instructor of medicine in the Aab Cardiovascular Research Institute at the University of Rochester Medical Center.

Long QT Syndrome In Epilepsy

As a postdoctoral fellow, Auerbach studied the heart-brain connection in a severe genetic form of epilepsy, and found that cardiac arrhythmias were one cause of sudden unexplained death in people with epilepsy.

With the new study, he investigates the converse—whether a genetic heart disorder is also associated with issues in the brain.

He tapped into the Rochester-based LQTS Patient Registry to answer this question. The registry, developed 40 years ago by Arthur Moss, professor of medicine and senior author of the current study, contains information about more than 18,000 people including Long QT Syndrome patients and their affected and unaffected family members, who provide a nearly ideal group of controls.

“In essence, they have the same genetic makeup, except theoretically, the LQTS-causing mutation,” Auerbach says.

To ensure that the seizures reported in the registry were not merely misdiagnosed cardiac arrhythmias, Auerbach investigated the effect of beta blockers, drugs often prescribed to LQTS patients to prevent cardiac arrhythmias. While the drugs effectively reduced patients’ arrhythmias, they had no effect on seizures, minimizing the chance that the seizures were simply misdiagnosed cardiac side effects.

LQTS-causing Mutation

Looking at the patients’ genetic information, researchers found that patients with the three different types of Long QT Syndrome (LQTS1-3) showed similar heart rhythm symptoms, but vastly different prevalence of seizures. LQTS1 and LQTS2 patients had much higher prevalence of seizures than LQTS3 or no mutation—with LQTS2 at the greatest risk.

Further investigation of the LQTS-causing mutation showed that the specific location of the mutation greatly affected the risk of cardiac arrhythmias and seizures. In one location on the gene, the mutation protected against these symptoms, but in another location on the same gene, the mutation increased the risk of those symptoms.

Understanding what each of these mutations does may shed new light on a basic mechanism of seizures and may provide viable therapeutic targets to treat LQTS.

There is still a lot more work to do, but Auerbach says

“you could begin applying these findings to patients today by telling physicians treating LQTS patients to look outside the heart.”

Long QT syndrome (LQTS) is a rare inherited or acquired heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsades de pointes (TdP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to fainting and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition.

The condition is named for the appearance of the electrocardiogram (ECG/EKG) on which a prolongation of the QT interval occurs. Normally, the QT interval duration is between 350 and 440 milliseconds. In some individuals, the QT prolongation occurs after the administration of certain medications, which may be dangerous.

In addition to medications, long QT syndrome can be acquired from malnutrition leading to low blood potassium or low blood magnesium, as in anorexia nervosa.

David S. Auerbach, PhD, Scott McNitt, MS, Robert A. Gross, MD, PhD, Wojciech Zareba, MD, PhD, Robert T. Dirksen, PhD and Arthur J. Moss, MD
Genetic biomarkers for the risk of seizures in long QT syndrome
Neurology 10.1212/WNL.0000000000003056

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