Researchers in the United States and the Netherlands have reported what appears to be a seizure phenotype in individuals with congenital long QT syndrome (LQTS), a potentially fatal cardiac conduction disorder that can be detected only by electrocardiogram (ECG).
Because fainting and seizures are common symptoms of LQTS, the disorder is often mistaken for epilepsy and treated with antiepileptic drugs (AEDs) while the underlying cardiac risk goes undetected, according to lead author Michael J. Ackerman, MD, PhD, professor and director of the Long QT Syndrome Clinic at the Mayo Clinic in Rochester, MN.
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The findings were published in the Jan. 20 issue of Neurology.
Inherited LQTS results from genetic mutations disrupting normal calcium and potassium ion channel regulation in the heart, resulting in a prolonged Q-T interval — the period between electrically stimulated expansion and contraction of the ventricles. The disruption causes periodic episodes of fast, chaotic heartbeats and fainting due to ventricular arrhythmia. If the heart does not return to a normal rhythm, ventricular fibrillation can occur, with the possibility of sudden cardiac death. Potassium channel defects in the brain, notably in the hippocampus, have been associated with epileptic seizures.
Different genetic mutations have been identified for 10 types of LQTS. LQT1, the most common type, comprises 60 percent of all cases, and is caused by a mutated KCNQ1 gene (See “More about Long QT Syndrome.”) The second most common type, LQT2, which occurs in about 35 percent percent of cases, is caused by mutations of the human ether-a-go-go related gene (HERG) on chromosome 7. The HERG gene is also known as KCNH2.
The disorder can occur in otherwise healthy people, often children or young adults, and especially young women, and half of all cases are asymptomatic.
Dr. Ackerman and his colleagues at the Mayo Clinic and the Academic Medical Center, in Amsterdam, reviewed the charts of 343 unrelated patients who had been clinically evaluated and genetically tested for LQTS. Most (232) were women, diagnosed on average between ages 18 and 27 years. The investigators sought to determine whether seizures were more common in patients with any of the three major subtypes of the disorder and whether there were any genetic signatures indicative of potassium channel defects in the brain.
Twenty-nine percent of the patients had a history of seizures, but they were most common (at 47 percent) among patients with LQTS2. A seizure phenotype was conferred if patients had either a personal of family history of seizures or had used AEDs. Patients with LQTS2 who had the KCNH2 gene were more likely to possess the seizure phenotype than those with LQTS1 or LQTS3.
The authors concluded that people with LQT2 may have alterations in KCNH2-encoded cerebral potassium channels resulting in seizure susceptibility, and that the localization of the gene defect to KCNH-2 encoded potassium channels may reside in the hippocampus, resulting in temporal lobe epilepsy.
“The trademark event for the patient with symptomatic LQTS is the potentially lethal ventricular dysrhythmia known as torsades de pointes (TdP),” the authors noted. “TdP can precipitate syncope, seizures, or sudden death, depending on whether the heart rhythm spontaneously reverts to normal rhythm or if the patient is defibrillated back to normal rhythm before death occurs.”
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Once considered a rare congenital disorder, wider ECG testing for other heart conditions has resulted in an increased rate in the past two decades, Dr. Ackerman told Neurology Today in a telephone interview.
“Just a few years ago the incidence of LQTS was believed to be 1 in 25,000, but we now believe it is much more prevalent, perhaps as common as 1 person in 2,500,” he said. “There is a tremendous need to make neurologists aware of LQTS because it is such a profound mimic of epilepsy. At Mayo, we see [epilepsy misdiagnoses] all the time in LQTS patients.”
Misdiagnosis of LQTS as epilepsy may explain many cases of sudden unexplained death in epilepsy (SUDEP), he cautioned.
Dr. Ackerman noted that just one day before the interview with Neurology Today he saw a 17-year-old patient with a history of seizures. Although the patient had been examined by neurologists and was being treated with antiepilepsy drugs, ECG revealed LQTS.
“If she had died during the seizure, it would have been attributed to SUDEP, when it was really due to her heart condition,” he said. “There is no telling how many cases of SUDEP have actually been caused by long QT syndrome, but neurologists need to be more aware of this possibility.”
Because it is common for arrhythmias and subsequent seizures in LQTS patients to be triggered by exercise, excitement or, notably, sudden noise, neurologists can screen for LQTS by asking whether seizures are precipitated by noise, he continued.
“Door bells, alarm clocks, and telephones. Ask the patient about them. If the seizures are triggered by such sounds, they should have an ECG to check for long QT syndrome — that's the take-home message.”
Orrin Devinsky, MD, professor of neurology and director of the New York University School of Medicine's Comprehensive Epilepsy Center in New York City, said the findings leave some questions unanswered.
In an e-mail to Neurology Today, he and colleague Steven V. Pacia, MD, associate professor of neurology and director of clinical neurophysiology at the Epilepsy Center, cited their own experience with LQTS patients, seizure activity, and epilepsy misdiagnoses, and to a 1994 paper published in Neurology in which they described two such cases and reviewed the medical literature.
“The author's hypothesis that a subset of LQTS patients may also have epilepsy is certainly plausible. However, for the cases we reviewed, there was no suggestion of complex partial seizures, even in patients already treated with AEDs, even though the hippocampus is said to be a likely focus of potassium channel dysfunction.”
At the time of their publication, however, gene-specific sub-typing was unavailable. Nonetheless, they said, “a unifying historical feature was the presence of ‘lifelessness’ before the convulsive movements, thereby facilitating a diagnosis of convulsive syncope and subsequent evaluation for the presence of a LQTS.”
Because the researchers did not provide detailed data about seizure types or EEG changes, comparisons are difficult, they added.
“We look forward to a comprehensive video and electroencephalographic study of patients with LQTS to determine whether they are at higher risk for epileptic seizures or whether the manifestation of cerebral hypoxia is more ‘seizure-like.’”
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Investigators suggest that Long QT syndrome type 2 — a condition that typically involves syncope, seizures, or sudden death — may confer susceptibility for recurrent seizures.
MORE ABOUT CONGENITAL LONG QT SYNDROME
LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion, depending on the subtype; 10 subtypes have been discovered. Investigators have been looking for non-cardiac phenotypic expression in other organs.
The most common type, LQT1, is autosomal dominant and has been associated with profound deafness. Deafness has not been associated with the autosomal recessive LQT2. Patients with LQT3, which comprises fewer than 5 percent of the cases, have had an increased prevalence of gastrointestinal symptoms.
Triggering events differ by genotype. Patients with LQT1 usually have cardiac events preceded by exercise or swimming. Sudden exposure of the patient's face to cold water is thought to elicit a vagotonic reflex. In patients with LQT2, cardiac arrhythmia may be trigged by an emotional event, exercise, or loud sounds. Patients with LQT3 usually have events during night sleep.
For more on LQTS, visit GeneReviews online at www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=rws.