Ictal asystole and increased ictal heart rate variability in PCDH19-related epilepsy

PCDH19 (OMIM 300460) pathogenic variants are associated with a range of neurodevelopmental abnormalities and epilepsy.^{1, 2} This X-linked condition has been referred to as “girls clustering epilepsy,” with the classical phenotype involving infantile onset of recurrent seizure clusters, sometimes lasting several days, in the context of febrile illnesses.^3-5 Seizure semiology is focal in the vast majority, with motor onset described in 85%. Non-motor onset seizures are reported in 59%, with features including behavioral arrest, loss of tone, hypopnea, cyanosis, and desaturation. We describe a girl with PCDH19-related epilepsy who had ictal bradycardia and asystole and report the results of an analysis of peri-ictal heart rate variability (HRV).

At 9 months of age, the proband presented with recurrent focal seizures in the context of a febrile viral illness. While on continuous video EEG monitoring, 27 seizures were recorded over a 49-hour period, 3 focal and 24 focal-to-bilateral. The clinical manifestations usually began after the electrographic onset, and typically involved bilateral arm stiffening and unresponsiveness (Video 1). Based on scalp EEG, 12 seizures had left occipital-temporal onset and 10 right parietal-occipital onset; the region of onset was unclear in three cases. Bradycardia occurred with almost all seizures and ictal asystole (defined as ≥3-second pause between heartbeats) in three instances, lasting as long as 11 s. Seizure duration ranged from 59 to 251 s.

Her past medical history was significant for being a triplet pregnancy and born extremely premature, at 23 weeks, 6 days gestation. She had sequelae of prematurity, including bronchopulmonary dysplasia, retinopathy of prematurity, and metabolic bone disease. An echocardiogram done early in life showed an atrial septal defect (ASD) and ventricular septal defect (VSD). On family history, her mother had autism and was reported to have “generalized epilepsy,” which had started with febrile seizures at age 10 months; she was still on antiseizure medication, lacosamide and clobazam. The patient's father also had autism, as did two paternal half-brothers.

The patient's brain MRI showed periventricular leukomalacia. Genetic testing revealed a maternally-inherited PCDH19 pathogenic variant (NM_001184880.2, c.1201_1202dup, p.(Ser401Argfs*169)).

The proband is now 21 months old and has had 5 more admissions with seizure clusters over the past 12 months; however, ictal bradycardia/asystole has not again been reported. She is currently taking topiramate, carbamazepine, clobazam, and levetiracetam. From a developmental perspective, she can pull to stand and walk one or two steps with support. She babbles and says “dada” and “mama.” There has been no regression.

Using the ECG derivation from the scalp EEG recording, we extracted interbeat intervals during all seizures, as well as for 600 beats prior to electrographic seizure onset. We plotted heart rate based on a moving average over each 4 beats for before and after each seizure onset (Figure S1). A marked heart rate decrease was noted in the first 200 beats after seizure onset. We also calculated the root mean square of successive differences (RMSSD), a time-based HRV measure, and plotted it as a moving average over every 51 beats (Figure 1). A marked increase in RMSSD was seen in the first 200 beats after seizure onset.

This female patient with PCDH19-related epilepsy presented with the classical pattern of clustering seizures in the context of febrile illnesses; however, her seizures during one cluster had the previously unreported ictal features of severe bradycardia and asystole, with associated increase in HRV. These findings add to the autonomic abnormalities that may be seen during seizures in PCDH19-related epilepsy.

One might hypothesize that this pattern suggests an increased risk for sudden unexpected death in epilepsy (SUDEP), particularly given that SUDEP risk is significantly elevated in Dravet syndrome, an epileptic encephalopathy that also initially presents in infancy with seizures in the context of febrile illnesses.⁶ However, while ictal asystole has been discussed as a SUDEP risk factor,⁷ the association is not yet clear. In fact, ictal asystole has been proposed to have protective properties as the consequent cerebral anoxia and ischemia may aid in seizure termination.⁸ Based on the limited available evidence, we suggest that such patients should be referred for a cardiology consultation, though it is not clear that any interventions are necessary if primary cardiac dysfunction is ruled out. Management should be otherwise focused on optimizing seizure control.

This study was supported by funding from Fonds de Recherche du Québec—Santé.

A. Nguyen, R. Eberhard, and E. Simard-Tremblay report no disclosures relevant to the manuscript. K.A. Myers is a site principal investigator for studies sponsored by Ultragenyx and LivaNova, and is on an advisory committee for Jazz Pharmaceuticals.

The patient's mother provided consent for the publication of the video included in this report.