Author + information
- Received September 10, 2015
- Revision received October 22, 2015
- Accepted October 29, 2015
- Published online June 1, 2016.
- Aya Miyazaki, MDa,∗ (, )
- Heima Sakaguchi, MDa,
- Takeshi Aiba, MDb,
- Akira Kumakura, MDc,
- Michio Matsuoka, MDa,
- Yosuke Hayama, MDa,
- Yuriko Shima, MDa,
- Nobuyuki Tsujii, MDa,
- Osamu Sasaki, MDa,
- Ken-ichi Kurosaki, MDa,
- Jun Yoshimatsu, MDd,
- Yoshihiro Miyamoto, MDe,
- Wataru Shimizu, MDb,f and
- Hideo Ohuchi, MDa
- aDepartment of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
- bDepartment of Cardiovascular Medicine, Division of Arrhythmias and Electrophysiology, National Cerebral and Cardiovascular Center, Osaka, Japan
- cDepartment of Pediatrics, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan
- dDepartment of Perinatology, National Cerebral and Cardiovascular Center, Osaka, Japan
- eDepartment of Preventive Cardiology, Department of Preventive Medicine and Epidemiologic Informatics, National Cerebral and Cardiovascular Center, Osaka, Japan
- fDepartment of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
- ↵∗Reprint requests and correspondence:
Dr. Aya Miyazaki, Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Objectives Given the association of long QT syndrome (LQTS) and neurological disorders, we speculated that the more severe LQTS phenotype, perinatal LQTS, would exhibit more frequent comorbid neurodevelopmental anomalies than LQTS without perinatal arrhythmias (nonperinatal LQTS).
Background Congenital LQTS with life-threatening perinatal arrhythmias (perinatal LQTS) has a poor life prognosis.
Methods Twenty-one consecutive LQTS patients diagnosed before 1 year of age at our institution and 3 previously reported perinatal LQTS patients with neurological seizures were enrolled. In total, the clinical course was evaluated in 24 patients.
Results Among 21 infantile LQTS patients, 5 of 6 with perinatal LQTS (83%) were diagnosed with epilepsy and 4 (67%) with developmental disorders, but none with nonperinatal LQTS were. The total development quotient by Kinder Infant Development Scale scores was 17 to 72 (median 67) in 5 epileptic perinatal LQTS. In the 8 perinatal LQTS patients with neurological disorders, including 3 previously reported cases, epileptic seizures occurred at 2 days to 2.5 years of age and 5 had developmental disorders. Mutations in these 8 patients were located in the transmembrane loop of KCNH2, and D3/S4-S5 linker, D4/S4, or the D4/S6 segment of SCN5A.
Conclusions A high comorbidity of neurodevelopmental anomalies was observed in perinatal LQTS. Mutations in patients with neurological comorbidities were in loci linked to LQTS with a severe cardiac phenotype. These observations indicate the possibility that neurological disorders in perinatal LQTS are manifested as neurological phenotypes associated with severe cardiac phenotypes, while we could not completely exclude another possibility that those were caused by a brain perfusion injury.
Congenital long QT syndrome (LQTS) patients who experience aborted cardiac arrest in the first year of life are at very high risk for near-fatal or fatal cardiac events during the next 10 years of life (1). Especially, LQTS cases with torsade de pointes (TdP) and 2:1 atrioventricular block (AVB) during the perinatal period have poorer prognoses than LQTS cases without these arrhythmias (2–5). Current therapies, such as β-blockers, mexiletine, and pacemaker device implantations, have reduced the mortality and resulted in relatively favorable prognoses for perinatal LQTS (1,3,6). However, aborted cardiac arrest and sudden death still occur in this group despite treatment (1,3,4).
As with LQTS, Mendelian epilepsies and cardiac arrhythmias may also arise from mutations in ion channels or related signaling molecules, some due to mutations in the same genes associated with LQTS (7). In the brain, as in the myocardium, inherited dysfunction of ion channels (channelopathies) can destabilize excitable tissue, leading to paroxysmal clinical events (7). The possible association of epilepsy arising from the same channelopathies as LQTS was recently examined (8–10). Abnormal cortical electroencephalographic (EEG) activity was identified more frequently in subjects with LQTS secondary to potassium channel mutations than in healthy controls (8). In addition, 15% of the patients with LQTS who presented with seizures or seizure-like episodes had EEG-identified epileptiform activity (9). Furthermore, mutations in KCNH2 or SCN5A were identified in 6 of 68 patients with sudden unexpected death in epilepsy (10).
A comorbidity of epilepsy and/or developmental disorders has been observed in perinatal LQTS patients who survived life-threatening ventricular arrhythmias. However, to the best of our knowledge, only 3 case reports have been previously published (11–13). Therefore, we hypothesized that perinatal LQTS patients, the most severe phenotype of LQTS (1,3,4), would have higher incidences of neurological manifestations of channelopathies, such as epilepsy or developmental disorders. In this study, we evaluated the clinical and neurological findings in infantile LQTS patients with or without perinatal arrhythmias.
Twenty-four consecutive patients diagnosed with LQTS before 1 year of age at the National Cerebral and Cardiovascular Center from November 1998 to August 2015 were considered for this study. LQTS was diagnosed by genetic testing or a corrected QT (QTc) interval ≥470 ms with a family history of LQTS, calculated with Bazett’s formula (14) on the resting electrocardiogram (ECG). Three patients who were less than 1 year old at the last follow-up were excluded and the remaining 21 were enrolled in this study. Four sibling pairs were included, and 1 patient was previously described (Patient #3) (15). Among the 21 patients, 6 had life-threatening arrhythmic events during the perinatal period, such as TdP or 2:1 AVB due to QTc prolongation. We classified these 6 patients as perinatal LQTS, and the other 15 as nonperinatal LQTS. Further, we added the data of the clinical features and genetic analyses from 3 previously reported cases with perinatal LQTS and epileptic seizures (11–13). A total of 24 patients were examined. We assert that all procedures contributing to this work complied with the relevant national guidelines on human experimentation (Japan) and with the Helsinki Declaration of 1975 (as revised in 2008), and were approved by the institutional ethics committees (M25-132).
The following parameters were assessed: gender, age at the initial presentation, family history of LQTS, gene mutations, ECG findings at the initial presentation, syncope or life-threatening arrhythmias during follow-up, medical treatments for LQTS, comorbid epilepsy, developmental outcomes, and other neurological disorders. Syncope was distinguished from epileptic seizures by a rapid onset without warning, shorter duration, and no postictal phase.
The ECG findings at the initial presentation were compared between 9 perinatal and 15 nonperinatal LQTS patients, including the 3 previously reported cases. The incidence of life-threatening arrhythmias, epilepsy, and developmental disorders during the follow-up was evaluated in our 6 perinatal LQTS and 15 nonperinatal LQTS patients.
The developmental outcomes were assessed using the Kinder Infant Development Scale (KIDS) (16,17) in 14 patients from our institution. In the perinatal LQTS group, the KIDS was available only in 5 patients with comorbid epileptic seizures. KIDS type B, C, and T were used as appropriate. Type B was designed for assessing infant children 12 to 23 months of age. It included 142 items and yields subscales for 9 developmental domains: physical motor, manipulation, language reception, language expression, concept, social relationships with children, social relationships with adults, training, and feeding. Type C was designed for children 36 to 83 months of age. It included 133 items and yield subscales for the same developmental domains except for feeding. Type T was designed for assessing developmentally delayed children 36 to 83 months of age. It included 282 items and yield subscales for the 9 developmental domains of type B. Type T was also useful for assessing severe developmentally delayed children of up to 12 years old. Each item was scored as pass (1 point) or fail (0) by the parents and the scores were summed for each subscale. The overall developmental age from the total score and those for all subscales were determined using a conversion chart (16). Development quotients (DQs) for the total and all subscales were then calculated using the following formula.
A total DQ under 70 was defined as a developmental disorder. DQs were compared between 5 epileptic perinatal LQTS and 9 nonperinatal LQTS patients.
Epilepsy was diagnosed by pediatric neurologists, based on the definitions of a seizure and epilepsy by the Task Force of the International League Against Epilepsy in 2005 (18). An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by and enduring a predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequence of this condition. The definition of epilepsy requires the occurrence of at least 1 epileptic seizure. We evaluated the neurological examination, blood tests, and electroencephalograms to diagnose epilepsy in all our patients with clinical seizures. We eliminated the possibility of epilepsy imitators such as syncope due to arrhythmias by monitoring the electrocardiograms during the seizures. Computed tomography (CT) or magnetic resonance imaging (MRI) was performed in patients with epilepsy or syncope to determine the presence and extent of hypoxic ischemic encephalopathy, brain hemorrhages, and cerebral infarctions. For the 3 previously reported cases, the data concerning the neurological findings were obtained from their reports.
The protocol for the genetic analysis was approved by the Institutional Ethics Committee and performed under its guidelines (M24-031-4). The genomic DNA was isolated from whole blood using a DNA analyzer (QIAGEN GmbH, Hilden, Germany) (19). Genetic screening for KCNQ1, KCNH2, and SCN5A (and if necessary KCNE1, KCNE2, and KCNJ2) mutations was performed by direct sequencing (ABI 3730 DNA Analyzer, Life Technologies, Carlsbad, California). The cDNA sequence numbering was based on the GenBank reference sequence.
Statistical analysis was not performed to compare the clinical findings between perinatal LQTS and nonperinatal LQS, because of the small number population (n = 24) including 4 sibling pairs.
The clinical characteristics are shown in Table 1. Patients #1 to #6 were perinatal LQTS patients from our institution, and 22 to 24 were previously reported perinatal LQTS patients with neurological seizures. Three of the 9 perinatal LQTS cases had TdP in utero as documented by magnetocardiography. One patient was delivered in our hospital because of maternal LQTS and the other 5 were transferred from other institutions or consulted because of frequent premature ventricular contractions, nonsustained ventricular tachycardia, or fatal arrhythmias. All 15 nonperinatal LQTS patients (Patients #7 to #21) were examined because of maternal or paternal LQTS but presented without symptoms. Thirteen patients in total were transplacentally administered antiarrhythmic agents, 2 for fetal TdP (Patient #5 and #6) and 11 for maternal LQTS.
The heart rate and QTc at the initial presentation were compared between 9 perinatal and 15 nonperinatal LQTS patients in Figure 1. The heart rate was 58 to 158 (median 104) beats/min and 97 to 150 (median 130) beats/min, and the QTc was 513 to 686 (median 582) ms and 452 to 582 (median 509) ms in perinatal and nonperinatal LQTS, respectively. The ECGs from our 6 perinatal LQTS patients are shown in Figure 2.
Clinical course of infantile LQTS
Twenty-two patients were alive at the last follow-up and 2 patients with perinatal LQTS (Patients #4 and #23) died suddenly due to arrhythmias (Table 2). All 9 perinatal LQTS cases have been taking antiarrhythmic agents since their perinatal periods. Conventional pacemaker devices were implanted during the neonatal period in 5 patients (Patients #2, #5, #6, #22, and #24) and 4 were later upgraded to an implantable cardioverter-defibrillator. Patient #3 was implanted with an implantable cardioverter-defibrillator at 0.9 years old. Despite treatment, syncope or life-threatening arrhythmias still occurred after the neonatal period in 7 patients. In the nonperinatal LQTS group, 1 unmedicated patient (Patient #8) had syncope at 13.5 years of age.
Comparison of the clinical findings and KIDS between perinatal LQTS and nonperinatal LQTS in 21 infantile LQTS patients from our institution
Among our 21 infantile LQTS patients, the age at the last follow-up was 1.0 to 16.8 (median 8.1) years in the 6 perinatal LQTS and 1.0 to 16.6 (median 3.8) years in the 15 nonperinatal LQTS patients. During the follow-up, syncope or life-threatening arrhythmias occurred in 5 perinatal LQTS patients (83%) and 1 nonperinatal LQTS patient (7%). Further, 5 perinatal LQTS patients (83%) were diagnosed with epilepsy and 4 (67%) with developmental disorders, while neither disorder was observed in the nonperinatal LQTS group. Among the perinatal LQTS patients, Patients #2, #3, #5, and #6 had all symptoms, such as syncope or life-threatening arrhythmias, epilepsy, and developmental disorders, while Patient #1 had no symptoms during the follow-up (Figure 3). There were no family members with epilepsy or developmental disorders.
A type B KIDS was performed in 4 patients, type C in 5 patients, and type T in 5 patients (Table 2). The total and 9 subscales were compared between perinatal LQTS patients with epilepsy and nonperinatal LQTS cases in Figure 4. The total DQ was 17 to 72 (median 67) in 5 epileptic perinatal LQTS, while it was 73 to 129 (median 100) in 9 nonperinatal LQTS.
No patients in either group had symptoms of cerebral palsy except for 2 previously reported cases without any information about it (Patients #23 and #24). The neurological findings of 8 perinatal LQTS patients with neurological disorders are shown in Table 3. The age at the onset of the epileptic seizures ranged from 2 days to 2.5 years of age and 5 had developmental disorders (Table 3). Epileptic seizures occurred under mexiletine or lidocaine in 7 patients, excluding Patient #22. Five patients had interictal EEG abnormalities (Figure 5), while 2 had none (Patients #2 and #24) and the remaining 1 had no data. Six patients had unremarkable findings on cerebral imaging (CT in 3 rather than MRI due to device implantations), while there were no data for 2 previously reported cases.
The LQT genotype was either LQT2 or LQT3 in all perinatal LQTS patients. In the nonperinatal LQTS patients, the genotype was more variable, either LQT1, LQT2, LQT3, or LQT7 (Table 1). Among 9 perinatal LQTS cases, 7 were probands. Five had a de novo mutation and 4 had inherited mutations.
The locations of the gene mutations in 8 perinatal LQTS patients with neurological disorders are shown in Figure 6. The KCNH2 mutation in Patients #2, #6, and #24 (T613M, T623I) was previously reported without functional assays (20,21), and the S624R in Patient #5 was a novel mutation. The other 4 SCN5A mutations (P1332L, R1623Q, G1631D, M1766L) in the perinatal LQTS patients were previously reported with detailed functional assays (12,15,22,23). In the 6 perinatal LQTS cases with epileptic seizures, the mutations were located in the transmembrane loop of KCNH2 (T613M, T623I, S 624R) and the D4/S4 segment of SCN5A (R1623Q, G1631D).
We showed a high incidence of comorbid epilepsy and/or developmental disorders in perinatal LQTS patients, while neither disorder was observed in the nonperinatal LQTS patients. In addition, the total DQ was 17 to 72 (median 67) in 5 epileptic perinatal LQTS. In the 8 perinatal LQTS patients with neurological disorders including 3 previously reported cases, epileptic seizures occurred between 2 days and 2.5 years of age and 5 had developmental disorders. We found no evidence of hypoxic ischemic brain injury in any of these patients. The mutations in patients with neurological comorbidities were in loci previously linked to LQTS with a severe cardiac phenotype. These findings indicate the possibility that neurological disorders are observed in perinatal LQTS as a neurological phenotype associated with the most severe cardiac phenotype of LQTS, life-threatening arrhythmias, during the perinatal period.
Clinical characteristics and clinical course in perinatal and infantile LQTS
Life-threatening cardiac events are rare during infancy in LQTS patients. Of 3,323 LQTS patients in an international registry, sudden cardiac death occurred in only 20 (0.6%), aborted cardiac arrest in 16 (0.4%), and syncope in 34 (1%) during the first year of life (1). However, these patients are known to be at a very high risk of aborted cardiac arrest or sudden death in the years to come, especially those with LQTS plus TdP or 2:1 AVB during the perinatal period (1–5).
In the present study, during the follow-up, more arrhythmic events were observed in the perinatal LQTS patients despite more intensive treatment. Notably, perinatal LQTS had a high incidence of epilepsy (83%) and developmental disorders (67%), while neither disorder was observed in the nonperinatal LQTS patients. Moreover, the total DQ by KIDS was revealed to be low, 17 to 72 (median 67), in 5 epileptic perinatal LQTS.
Previous relatively large-scale studies on perinatal LQTS did not report the rates of epilepsy and/or developmental disorders (1,3,4,6), possibly because of the brief follow-up data in patients with rare phenotypes associated with early mortality. In addition, these reports were mostly retrospective analyses from registry data or questionnaire surveys rather than prospective studies with clinical monitoring.
While the channelopathy could lead directly to neurological dysfunction, an alternative possibility is that the neurological disorder in perinatal LQTS arises secondary to hypoxic ischemic injury from perinatal arrhythmias. However, the clinical manifestations of the patients in the present study differed from that of the patients with intrapartum hypoxic ischemia. The main symptom of the patients with intrapartum hypoxic ischemia is cerebral palsy, and learning difficulties in these patients generally occur in conjunction with CP associated with severe motor disability and extensive brain damage observed by cerebral imaging (24). In this study, none of perinatal LQTS patients with neurological disorders had cerebral palsy and or any remarkable findings in the cerebral imaging. MRI is the most sensitive and specific imaging modality for examining infants with hypoxic-ischemic brain injuries (25). Also, cerebral CT can reveal the atrophic changes of the brain in the chronic phase of hypoxic-ischemic encephalopathy, but it is hard to detect small brain damage (25). In the present study, at least 3 patients were confirmed to have no findings of hypoxic ischemic brain injury by MRI, and another 3 did not exhibit any atrophic changes of the brain observed on CT. These finding support our hypothesis that neurological disorders in perinatal LQTS are manifested as a neurological phenotype. Nevertheless, still we could not completely deny the possibility that these were caused by a hypoxic ischemic brain injury, because childhood survivors of perinatal hypoxic ischemia was reported to be at risk for cognitive deficits even in the absence of functional motor disorders (24).
Another possibility is additional mutations at epilepsy susceptibility loci (26). While genetic testing for known epilepsy-associated mutations was not performed, in our 5 patients no family members had any neurological symptoms, and Patient #21 was reported to have no mutations of epilepsy susceptibility genes (11).
Genotype-neurological phenotype correlation
LQTS patients with arrhythmias during the perinatal period have predominantly LQT2 or LQT3 (3). Indeed, all 9 perinatal LQTS patients in the present study had LQT2 or LQT3, 8 of which exhibited neurological comorbidities.
A clinical association between LQTS and epilepsy was recently reported in older LQTS patients. EEG abnormalities were found in 71% of individuals with LQT1 or LQT2 (8). Further, the seizure incidence was significantly higher in LQT2 than LQT1 or LQT3 patients (9). In a large cohort of Australian cases of sudden unexpected death in epilepsy, genetic analyses revealed 6 nonsynonymous variants in KCNH2 and SCN5A among 68 patients (10).
KCNH2 and SCN5A are expressed not only in the heart, but also in brain. A correlation between mutations in these genes and neurological phenotypes has been proposed but there have been no molecular investigations. LQT2 is caused by loss-of-function mutations in KCNH2, encoding the α-subunit of the Kv11.1 potassium channel that conducts the IKr current (27). Expression of KCNH2 transcripts have been detected within hippocampal astrocytes, cerebellar Purkinje cells, and vestibular nucleus neurons (28). These IKr currents are important for spatial buffering of extracellular potassium ions by astrocytes during high neuronal activity. Kv11.1 mutations could affect the potassium ion buffering properties of astrocytes, leading to epilepsy (9,28). Alternatively, LQT3 is caused by mutations in the Nav1.5 sodium channel α-subunit gene SCN5A, which increase the persistent inward sodium current (27). SCN5A expression has been detected in the rat limbic forebrain (29). Persistent depolarization by abnormally prolonged sodium currents in limbic cortex neurons due to SCA5A mutations would elicit epileptiform bursting, synchronous network activation, and seizures (11,29).
Among 7 mutations in 8 perinatal LQTS patients with neurological disorders, T613M in KCNH2, and R1623Q and G1631D in SCN5A were reported as mutations in life-threatening perinatal LQTS (4,15,20,23). Further, in 6 of 8 patients, the mutations were located in the transmembrane loop of KCNH2 (T613M, T623I, S 624R) and the D4/S4 segment (R1623Q, G1631D) of SCN5A. Mutations in the transmembrane loop of KCNH2 are correlated with a severe LQTS cardiac phenotype (30), and mutations in the SCN5A D4/S4 segment, a component of the voltage-sensor important for activation and inactivation, are correlated with severe perinatal LQTS (15). Another 1 of the remaining 2 mutations, the P1332L mutation in the D3/S4-S5 linker, was also correlated with a severe cardiac phenotype, but with a good response to mexiletine (22). Based on these findings, we speculated that the channelopathy associated with the most severe cardiac phenotype also conferred susceptibility to a “neurological phenotype,” such as epilepsy and/or developmental disorders.
There were several limitations to this study. First, the static analysis was not available because of the small sample size. Second, 5 perinatal LQTS patients with comorbid neurological disorders were not examined by MRI because of device implantations. Even when the findings of the present study are supported our hypothesis, still the possibility that the neurological disorders were the result of a perfusion injury due to hemodynamically compromising arrhythmias could not be completely excluded. Third, functional assays were not available for the 3 KCNH2 mutations. Fourth, the EEG and KIDS were performed at various ages. Finally, we did not test for mutations in epilepsy susceptibility genes. Nevertheless, these findings strongly suggest that certain mutations associated with severe LQTS (with life-threatening cardiac arrhythmias in the perinatal period) may also enhance the susceptibility to neurological disorders, such as epilepsy and/or developmental disorders.
In this study of LQTS patients diagnosed in infancy, 8 with perinatal arrhythmias, including 3 previously reported cases, exhibited a comorbid neurological phenotype. We found no evidence of hypoxic ischemic brain injury in any of these patients. In addition, the total DQ scores on the KIDS was revealed to be low, 17 to 72 (median 67), in 5 epileptic perinatal LQTS. The mutations in the perinatal LQTS with epilepsy cases were located in ion channel gene loci associated with a severe cardiac phenotype. Although we could not completely deny the possibility that the neurological disorders were the result of a brain perfusion injury, our findings suggested that channel dysfunction leading to a most severe cardiac phenotype may also confer susceptibility to a neurological phenotype. Further study is needed to define the etiology of the neurodevelopmental anomalies in perinatal LQTS.
COMPETENCY IN MEDICAL KNOWLEDGE: Current therapies have resulted in relatively favorable life prognoses in perinatal LQTS. Based on our findings that they have a high comorbidity of neurological disorders, the improvement of their developmental prognoses should be considered as the next step of the medical treatment.
TRANSLATIONAL OUTLOOK: Further larger prospective studies with a more detailed neurological evaluation are needed to define the etiology of comorbid neurological disorders in perinatal LQTS.
The authors wish to express their gratitude to Mr. John Martin for his assistance in preparing the manuscript.
Drs. Aiba, Miyamoto, and Shimizu were supported in part by the Research Grant for Cardiovascular Diseases (H26-040) from the Ministry of Health, Labour and Welfare, Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrioventricular block
- computed tomography
- development quotient
- Kinder Infant Development Scale
- long QT syndrome
- magnetic resonance imaging
- corrected QT
- torsade de pointes
- Received September 10, 2015.
- Revision received October 22, 2015.
- Accepted October 29, 2015.
- American College of Cardiology Foundation
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