Author + information
- aDivision of Cardiology, Duke University Medical Center, Durham, North Carolina
- bDivision of Clinical Pharmacology, Duke University Medical Center, Durham, North Carolina
- cIon Channel Research Unit, Duke University Medical Center, Durham, North Carolina
- ↵∗Reprint requests and correspondence:
Dr. Geoffrey S. Pitt, Ion Channel Research Unit, Box 103030 Medical Center, Duke University, Durham, North Carolina 27710.
In 1856, Meissner described the death of a “deaf-mute girl, who collapsed and died while being publicly admonished” by her school director for a misdemeanor. The girl also had 2 siblings who had hearing loss and died suddenly in the setting of emotional stress (1). This case was likely the first description of Jervell and Lange-Nielsen syndrome (JLNS) (2). An autosomal recessive form of congenital long QT syndrome (LQTS), JLNS was later shown to be caused by mutations in the voltage-activated potassium channel KCNQ1 (Kv7.1) or its subunit KCNE1, both expressed in many organ systems including the heart and the stria of the inner ear (3,4). KCNH2 (Kv11.1), another major LQTS loci, is also expressed in both the central nervous system and heart; mutations in that ion channel would seem likely to also produce a mixed neurocardiac phenotype.
Establishing an association between KCNH2 mutations and neurological symptoms has proven difficult given the clinical overlap between seizures and syncope due to cerebral hypoperfusion during cardiac arrest and that of epileptic seizures related to ion channel–mediated changes in brain excitability (5). In fact, LQTS patients are often initially misdiagnosed with epilepsy (6,7), resulting in both delayed care for LQTS and inappropriate antiepileptic drug therapy. A portion of these patients, however, likely have a true ion channel–mediated neurocardiac syndrome, as recent evidence demonstrated electroencephalography-identified epileptiform activity in 15% of patients with LQTS who presented with seizures or seizure-like episodes (8).
In this issue of JACC: Clinical Electrophysiology, Miyazaki et al. (9) attempt to strengthen the pathogenic link between LQTS and neurological disorders by examining a group of patients with severe cardiac manifestations, perinatal LQTS, for both seizures and developmental disorders. In this small cohort study, 5 of 6 patients (83%) with perinatal LQTS received a diagnosis of epilepsy, and 4 (67%) demonstrated developmental disorders. In contrast, none of the 15 nonperinatal LQTS patients had either epilepsy or developmental delay. In order to help differentiate between seizure-like movements as a result of cerebral hypoperfusion, brain CT or MRI scans and full neurological examinations were performed to assess the presence of imaging findings and/or motor dysfunction consistent with hypoxic brain injury. In the perinatal LQTS cohort, no patients had cerebral palsy or abnormal brain imaging. Further strengthening the case of a true seizure phenotype, electroencephalograms (EEGs) were obtained for all patients with clinical seizures. Ultimately, the authors suggest the possibility of a threshold effect, with a severe cardiac phenotype correlating with a more severe neurological phenotype.
The potential association between LQTS and seizures provides possible insight into mechanisms underlying sudden unexpected death in epilepsy (SUDEP). Patients with epilepsy are more than 20-fold more likely to die suddenly than the general population (10), highlighting an urgent need to identify modifiable risk factors to target susceptible individuals. Analysis of sudden deaths in epilepsy monitoring units (11) and animal studies (12,13) have highlighted respiratory depression and bradycardia accompanying SUDEP events. If patients with an underlying LQTS mutation also experience seizures as an associated neurological syndrome, however, then the life-threatening tachyarrhythmias associated with LQTS suggest an alternative pathogenic mechanism for SUDEP. Patients with a known LQTS mutation are treated with measures to reduce the risk of arrhythmogenic sudden death, thus diminishing the risk of SUDEP if this alternative pathogenic mechanism contributes. Whether patients with epilepsy should be screened for LQTS mutations to identify a subset who might benefit from treatment for LQTS as a means to reduce SUDEP, however, is not known.
Although the study strengthens the association of LQTS and seizures, it does have some significant limitations. First, the author’s definition of perinatal LQTS introduces strong selection bias. By defining perinatal LQTS patients on the basis of the history of life-threatening arrhythmic events such as torsades de pointes or 2:1 atrioventricular block, the authors are essentially comparing patients who, by definition, have had cerebral hypoperfusion with those who have not. Although heart rates and QT intervals did differ among the groups, suggesting an underlying difference in LQTS severity, there was also considerable overlap between the 2 groups. These differences may also be secondary to cerebral insult and not a marker of primary LQTS severity (14). Additionally, a normal neurological exam and CT or MRI scan in affected patients does not necessarily preclude the possibility of hypoxia-induced neurological dysfunction (15,16). Finally, although consistent with previous studies suggesting an increased incidence of seizure disorder in patients with KCNH2 mutations, the classification of 50% of the patients with perinatal LQTS and neurological comorbidities such as LQT3 with SCN5A mutations lacks a clear mechanistic basis. To our knowledge, there is no definitive evidence or established functional role of SCN5A (Nav1.5) in the human brain. Although this study may present a novel finding, it is inconsistent with previous reports of LQT3 and epilepsy (8).
Ultimately, this study adds to the growing body of published data that LQTS patients are at an increased risk of neurological dysfunction. Whether the mechanism is the same for the various genotypes of LQTS, the confirmation of KCNH2 mutations and neurological disorders suggests that new paradigms of epilepsy screening in patients with LQT2 should be considered.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Sun is a consultant for Medtronic, St. Jude Medical, and Biosense Webster; and has received research support from Medtronic and Boston Scientific. Dr. Pitt has reported that he has no relationships relevant to the contents of this paper to disclose.
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