Epilepsy and LQTS: Is there a Genetic Link?

Seizures may be added to the list of comorbidities associated with congenital long QT syndrome (LQTS), according to results published online in Neurology.¹

“Results from this study provided novel insights into the risk factors for seizures… Seizures were the strongest independent positive risk factor for cardiac arrhythmias,” wrote first author David S Auerbach PhD, of the University of Rochester Medical School (Rochester, NY).

The study also identified several potential biomarkers associated with seizure susceptibility in congenital LQTS, including having an LQTS mutation, region of the LQTS mutation, LQTS subtype, LQTS mutation domain, QTc prolongation, and female sex.

Congenital LQTS is a genetic disease that affects 1:2000 people. Several types of LQTS exist, and may be associated with different types of mutations. LQTS 1 and 2 are caused by reduced repolarizing current. LQTS3 is caused by continued depolarizing current, which leads to disruption of the cardiac activation-recovery process.

A subset of patients with LQTS also have seizures. While cardiac arrhythmias associated with LQTS could explain this relationship, the two disorders may also be linked by a genetic mutation expressed in both the heart and the brain.

In the study, researchers used data from the Rochester-based LQTS Registry, which includes clinical and genetic information on 1901 genotyped individuals (61% female). The study included 965 participants with an LQTS mutation and 936 without an LQTS mutation. The cohort included 181 individuals with a history of seizures, or who were on seizure medication. Researchers limited analyses to the three most common LQTS single gene mutations: KCNQ1 (LQTS1), KCNH2 (LQTS2), or SCN5A (LQTS3). QTc prolongation was defined as >470 ms (female) and >450 ms (male).

Key Results:

• Seizure history represented the strongest independent predictor of cardiac arrhythmias (hazard ratio 4.09, 95% confidence interval 2.63–6.36, P<0.001)

• Those with LQTS mutations were 1.7-2.3 more likely to have seizures than those without mutations (P< 0.001)

♦ Those with LQTS mutations and seizures had 5-fold higher rate of lethal cardiac arrhythmias than those without

• Women with LQTS1 and LQTS2 mutations were more likely to have seizures than men with the same mutations (P<0.05)

• Increasing QTc prolongation was associated with higher likelihood of seizures in those with LQTS mutations (P<0.05)

 • The KCNH2/LQTS2 group had the highest percentage of participants with seizures (P<0.05)

♦ The KCNH2 mutation in the pore domain was a positive predictor for arrhythmias and seizures (HR 2.01, 95% CI 1.11–3.61, P<0.021)

• Mutation of the cyclic nucleotide binding domain (cNBD) of KCNH2 was a negative predictor of seizures, but not arrhythmias

• High sensitivity analyses and time-dependent multivariate analyses confirmed that having an LQTS mutation, QTc prolongation, and female sex were independent predictors of seizures

Results also showed that beta blockers decreased the risk of cardiac arrhythmias in those with LQTS mutations (hazard ratio [HR] 0.463, 95% CI 0.273– 0.784, P<0.004), but failed to affect seizure risk (HR 0.787, CI 0.49–1.27, P<0.324). These findings suggest that seizures in patients with LQTS are not entirely of cardiac origin, according to the authors.

They concluded: “This study establishes the basis for future investigations into the mechanisms for neurocardiac pathologies in LQTS. It remains unknown whether the neurocardiac pathologies are the result of (1) mutant gene coexpression in the heart and brain; (2) seizure-induced ANS dysfunction promoting arrhythmias; (3) cardiac arrhythmias leading to cerebral hypoxia/ischemia-induced seizures; or (4) pro- and antiarrhythmic/epileptic effects of medical therapy.”

“These and other studies provide accumulating evidence that in some who experience sudden unexplained death in epilepsy (SUDEP), mutated genes coexpressed in the heart and the brain lead to epilepsy and arrhythmia. In others, however, there may be coincidental predisposition to cardiac death… which may be more likely to manifest in the context of uncontrolled convulsions,” wrote Lina Nashef, FRCP (King’s College Hospital, London UK) and Josemir Sander, FRCP (University College London, and Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands), in a linked editorial.²

However, they also suggested that seizures could have been due to more severe cardiac arrhythmias instead of epilepsy. Seizure status, severity, and etiology were based on patient and physician report without use of neurologic records and EEG reports, raising the possibility of misdiagnosis. However, Drs. Nashef and Sander agreed with the authors that the beta blocker results “strongly” argue for neurocardiac disease in some cases.

“In addition to prevention of convulsions and assistance at the time of a seizure, we now have another potential avenue for SUDEP prevention, one as yet unexplored,” they concluded, “Genes do not recognize the arbitrary divisions of specialization today. Neurologists must consider the heart and cardiologists the brain.”

Take-home Points

• Retrospective study suggests genetic overlap between epilepsy and congenital LQTS.

• LQTS mutations, QTc prolongation, LQTS2 pore/cNBD mutations, and female sex represent independent risk factors for seizures in patients with LQTS.

• Seizure history is a significant predictor of cardiac arrhythmias, which may represent a target for prevention of sudden unexplained death in epilepsy (SUDEP).

The authors report no conflicts of interest.

Dr. Nashef reports being on the editorial board of Epilepsia, serving as a trustee of Epilepsy Research UK, serving on scientific advisory boards and as a speaker for Eisai, attended the American Epilepsy Society meeting as a guest of Bial, and other support from NeuroSigma and UCB Pharma. Dr. Sander reports being on scientific advisory boards for UCB Pharma and Eisai, serving on the editorial board of LancetNeurology and serving on speaker’s bureaus for UCB Pharma, Eisai, Teva, and Lundbeck. He reports research support from UCB Pharma, GSK, Eisai, The Marvin Weil Epilepsy Research Fund, and Nationaal Epilepsie Fonds.

References:

1. Auerbach DS, et al. Genetic biomarkers for the risk of seizures in long QT syndrome. Neurology. 2016 Jul 27.

2. Nashef L, Sander JW. Genes cut across systems: neurologists should think “heart” and cardiologists “brain”. Neurology. 2016 Jul 27.