Genetic epilepsies, such as KCNQ2 gene variants, although uncommon, are potential causes of neonatal seizures in infants with complex congenital heart disease (CHD). KCNQ2-related seizures commonly present as tonic posturing with autonomic changes and a distinctive amplitude-integrated EEG (aEEG) pattern with increase in amplitude, immediately followed by background suppression. Seizures are typically refractory to commonly used antiepileptics in this age group and respond best to sodium channel blockers such as carbamazepine and fosphenytoin. We report the cases of 2 neonates with complex CHD who presented with seizures secondary to KCNQ2 gene variation and discuss how early recognition of clinical and EEG features led to early treatment and improved seizure burden. When investigating the etiology of neonatal seizures in the perioperative complex cardiac infant, genetic etiologies such as KCNQ2 variants should be considered, particularly in the absence of clinical examination and neuroimaging features consistent with brain injury. These 2 cases highlight the importance of a precision medicine approach using clinical examination and seizure semiology, bedside aEEG monitoring, genetic testing, and targeted treatments to improve patient care and outcomes.
A 4-day-old male infant born at 39 + 2 weeks gestation with antenatally diagnosed unbalanced atrioventricular septal defect (AVSD) presented with 4 acute paroxysmal episodes of tonic posturing of the arms bilaterally associated with apnea and desaturations. Each episode lasted 30 seconds and occurred over 12 hours. Neurologic examination revealed mild encephalopathy with decreased responsiveness to handling and inability to orally feed. The brain MRI was normal. Continuous EEG (cEEG) over 24 hours captured a single electroclinical seizure, and the interictal background was excessively discontinuous for gestational age. He continued to have frequent refractory clinical seizures despite treatment with loading doses of phenobarbital, levetiracetam, and fosphenytoin, and initiation and optimization of maintenance therapy with phenobarbital, levetiracetam, and pyridoxine. Seizures continued on an almost weekly basis until he was 3 months of age, at which time trio whole-exome sequencing using PGxome assay by Prevention Genetics revealed a heterozygous de novo pathogenic variant in KCNQ2 c.794C>T, p.Ala265Val. He was switched to carbamazepine and subsequently had good seizure control. At 2 years of age, he was weaned off carbamazepine after a 2-year period of seizure freedom and normal EEG. Since then, he has remained seizure-free and apart from a mild expressive language delay, his development has been age appropriate.
A 6-week-old female infant born at 33 + 2 weeks gestation (postmenstrual age of 39 + 4 weeks) with antenatally diagnosed double outlet right ventricle with pulmonary atresia, balanced AVSD, left-sided unobstructed total anomalous pulmonary venous connection, and right atrial isomerism presented with 5 paroxysmal episodes of tonic posturing, followed by apnea, bradycardia, and desaturations, 3 days after patent ductus arteriosus stenting. Each episode lasted approximately 30 seconds and occurred over an 8-hour period. Neurologic examination was normal for gestational age. The brain MRI was normal. Bedside aEEG recorded over 12 hours captured 4 seizures with a distinctive pattern concerning for KCNQ2-related epilepsy consisting of high-amplitude fast rhythmic activity on the raw EEG trace, followed by a period of background suppression. This was confirmed with cEEG capturing 2 additional seizures with prolonged background discontinuity for gestational age over a period of 12 hours (Figure). As a result of rapid identification of the distinctive seizure pattern on aEEG, this infant was immediately started on carbamazepine and had resolution of her seizures. She underwent next-generation trio whole-genome sequencing by The Rady Children’s Institute for Genomic Medicine, which revealed a likely pathogenic heterozygous de novo variant in KCNQ2 c.920T>C p.Leu307Pro. Her development up until 2 months of age was appropriate for gestational age. Unfortunately, she died at 4 months of age secondary to complications of her complex CHD and limited cardiovascular surgical options.
Neonates with complex CHD have a seizure incidence of 11.5%, most commonly presenting as acute symptomatic seizures secondary to brain injury including ischemic stroke, hypoxia ischemia, and intraparenchymal hemorrhage.1,2 Neonatal-onset epilepsies are an uncommon etiology of neonatal seizures representing approximately 13% of all neonatal seizures, many of which have a genetic etiology.3 Pathogenic or likely pathogenic variants in the KCNQ2 gene are responsible for more than one-third of genetic neonatal onset epilepsies.3 When investigating the etiology of neonatal seizures in the perioperative complex cardiac infant, genetic epilepsies such as KCNQ2 variants should be considered, particularly in the absence of clinical and neuroimaging features consistent with brain injury. Genetic testing using epilepsy gene panels and next-generation sequencing, such as whole-exome and genome sequencing, are among the recommended tools in diagnosing genetic epilepsies.3
KCNQ2-related epilepsy causes neonatal seizures secondary to impaired function of potassium channels.4,5 Seizures typically present in the first few days of life and can present as 2 phenotypes: self-limited familial neonatal epilepsy (SLFNE) or developmental and epileptic encephalopathy (DEE).4,–,6 Infants with SLFNE usually have positive long-term neurodevelopmental outcomes, and seizures respond well to treatment with sodium channel blockers.4,5 Infants with the DEE phenotype can often present with pharmacoresistant seizures and unfavorable neurodevelopmental outcomes.4,5,7 The brain MRI is typically normal or can show diffuse cerebral atrophy, and neonatal neurologic examination features include axial hypotonia and encephalopathy.5,7 Seizures secondary to KCNQ2-related epilepsy most commonly present as tonic posturing with autonomic changes, typically heart rate and respiration changes, with multifocal epileptiform abnormalities and suppression burst pattern on EEG.5,7 Recently, seizure semiology and EEG patterns typical for KCNQ2 gene variants were reported in SCN2A and KCNQ3-related epilepsies, showing that these may be features more consistent with genetic epilepsies as a whole, rather than KCNQ2 variants specifically.8 By contrast, acute symptomatic seizures secondary to brain injury more commonly present with clonic movements.6 Various studies have shown that seizures secondary to KCNQ2 gene variants respond best to carbamazepine and fosphenytoin, resulting in complete resolution of seizures in 65%–92.5% of infants.4,7
Both infants described in this report had either pathogenic or likely pathogenic KCNQ2 gene variants and complex CHD; there is currently no known association between KCNQ2 variants and non-neurologic defects such as CHD.4,–,7 Both infants in this case report likely represent a clinical presentation of SLFNE based on the available data; (1) neither infant presented with severe encephalopathy as would be expected with DEE; (2) both achieved complete cessation of seizures with initiation of carbamazepine; (3) case 1 achieved normal EEG background on repeat recording; (4) and both had overall favourable developmental outcomes, although long-term data are not available for the infant in case 2. It is particularly challenging to determine the etiology of developmental delays in infants with KCNQ2 gene variants and complex CHD. Children with complex CHD have increased incidence of mild-to-moderate developmental delays, even in the absence of known brain injury or genetic syndromes.9 Hence, it is unclear whether the mild language delays present in the child in case 1 are secondary to his KCNQ2 gene variant or his complex CHD.
aEEG is a tool used in many neonatal intensive care units and is starting to gain popularity in cardiac intensive care units. Using 2 channels of EEG, bedside providers are able to screen for seizure activity and abnormal background brain activity in critically ill neonates. There is a specific ictal aEEG pattern in KCNQ2-related epilepsy consisting of increased amplitude immediately followed by suppression.8,10 More recently, this ictal aEEG pattern has also been found in SCN2A and KCNQ3-related epilepsies.8 Using aEEG as a bedside tool for identifying abnormal brain activity and knowledge of the distinctive ictal pattern associated with KCNQ2-related epilepsy has been helpful in the early identification of seizures secondary to KCNQ2 gene variants, allowing for early initiation of optimal treatment with sodium channel blockers.7,10
aEEG can be a helpful bedside tool in the early recognition of seizures secondary to neonatal genetic epilepsies in infants with CHD. As outlined in case 2, this patient benefitted from early application of aEEG, which not only helped determine that the paroxysmal episodes were seizures but also helped recognition of the aEEG pattern as consistent with KCNQ2-related epilepsy. This resulted in immediate initiation of carbamazepine and cessation of seizures. By contrast, the infant in case 1 was not connected to aEEG and the pattern was not clear on cEEG, resulting in poor control of seizures until genetic diagnosis of KCNQ2 gene variation was confirmed at 3 months of age and he was switched to carbamazepine therapy.
Neonatal genetic epilepsies are an important cause of seizures in infants with complex CHD, which has not been widely explored in the literature. This case report links 2 areas of research; neonatal genetic epilepsies and neurologic comorbidities in CHD to enhance awareness of genetic epilepsies in patients with complex CHD. Clinical and aEEG features of genetic epilepsies in CHD are important to recognize because targeted seizure therapies, such as sodium channel blockers in infants with KCNQ2-related epilepsy, are recommended for optimal seizure management and can be initiated before genetic testing results are available. The comparison of these 2 cases brings attention to the need for precision medicine approaches in the care of the complex cardiac infant with seizures through the use of bedside aEEG monitoring, genetic testing, and targeted treatments to improve patient care and outcomes.