GRACE PEEBLES NEW INVESTIGATOR AWARD 2022 WINNER
Dr. Kenneth Alexis Myers, MD PhD FRCPC, CSCN, Assistant Professor Research Institute of McGill University Health Centre. Centre for Outcomes Research and Evaluation. Pediatric Programs: Developmental & Behavioral Pediatric Services.
Grant Project: Can Epilepsy Surgery Improve Abnormal Heart Rate Variability in Children?
People with epilepsy are known to have dysfunction of their autonomic nervous system, the part of the nervous system responsible for managing unconscious aspects of body function such as digestion, heart rate, sweating, and breathing. This dysfunction is more severe in people with more difficult to control seizures and has been linked to a higher risk for sudden unexpected death in epilepsy (SUDEP). The primary goal of this research is to determine the effect of epilepsy surgery on heart rate variability in children with focal epilepsy. Demonstrating if and how epilepsy surgery can improve autonomic dysfunction and potentially reduce risk for sudden death
Grant: $50,000
From Dr. Kenneth Alexis Myers:
“I am a Pediatric Neurologist, having completed an MD/PhD and Pediatric Neurology residency at the University of Calgary. Early on in my residency, I developed a particular interest in epilepsy as I was struck by the diversity of patient presentations and the fascinating range in which seizures can manifest. Although epilepsy can be a devastating disease, I have also seen many inspiring cases of dramatic improvement. This potential to meaningfully improve quality of life was my main motivating factor in choosing to dedicate my career to treating children with seizures. I completed a 2-year epilepsy fellowship at the University of Melbourne in Australia, which is where I first began to investigate the significance of abnormal heart rate variability.
People with epilepsy are known to have dysfunction of their autonomic nervous system, the part of the nervous system responsible for managing unconscious aspects of body function such as digestion, heart rate, sweating, and breathing. This dysfunction is more severe in people with more difficult to control seizures and has been linked to a higher risk for sudden unexpected death in epilepsy (SUDEP). One way to measure autonomic function is by studying heart rate variability, which may also serve as an indicator of risk for sudden death. In people with epilepsy, heart rate variability is usually abnormally low. If heart rate variability could be normalized in people with epilepsy, this could have a variety of positive effects, including reducing the risk for sudden death. For people with epilepsy whose seizures start in one specific part of the brain, surgically removing the seizure-causing lesion could potentially improve heart rate variability and reduce sudden death risk. However, this has not yet been well-studied in children.
The primary goal of this research is to determine the effect of epilepsy surgery on heart rate variability in children with focal epilepsy. We will collect heart rate data from EEG studies done before and after epilepsy surgery for at least 30 children with drug-resistant focal epilepsy. We will then calculate heart rate variability for 5-minute periods in wakefulness and sleep, for each patient before and after surgery. We will determine the pattern of change of heart rate variability after epilepsy surgery. We will determine whether epilepsy surgery has a significant effect on heart rate variability in children with focal epilepsy.
By demonstrating if and how epilepsy surgery can improve autonomic dysfunction and potentially reduce risk for sudden death, we can provide further motivation for patients and their families to consider epilepsy surgery. The idea of brain surgery can be terrifying for people with epilepsy and their loved ones; however, the knowledge that surgery could reduce the risk for sudden unexpected death may be the extra impetus necessary to help them initiate the evaluation process.
We also expect that our study will shed light on the interplay between epilepsy type and autonomic dysfunction. We will perform some advanced analysis to investigate the relationship between the part of the brain from which seizures start and heart rate variability. This will help us gain an understanding of the underlying causes of autonomic dysfunction in epilepsy. Ultimately, a better understanding of autonomic dysfunction will allow for development of better tools to treat it, with the ultimate result of reducing or eliminating the risk of sudden unexpected death and other related issues in people with epilepsy.”
Interim Report
Can Epilepsy Surgery Improve Abnormal Heart Rate Variability in Children?
Ralf Eberhard, Kenneth A. Myers
Montreal Children’s Hospital (McGill University)
Background: Briefly, heart rate variability (HRV) is a well-established surrogate for the balance of the sympathetic and parasympathetic systems in the human body. This autonomic nervous system regulation has been shown to be altered in persons with epilepsy, commonly towards sympathetic overactivity in wakefulness and abnormal patterns from sleep to awake. Autonomic dysfunction correlates with more difficult-to-control seizures and is associated with an increased risk of sudden unexpected death in epilepsy (SUDEP).
Hypothesis: If autonomic dysregulation is a consequence of seizures or a manifestation of epileptic activity in the brain, suppressing seizures or removing an epileptogenic lesion might reverse abnormal autonomic balance, which should be reflected in a more normal HRV following treatment.
Methods: In this study, we aimed to determine whether HRV patterns are changed in pediatric patients with drug-resistant epilepsy who undergo surgery. Our sample size calculation predicted that – assuming a mean change of HRV measures of 20% – a cohort of 50 children should be sufficient to reach statistical significance for the main analysis and to explore correlations of HRV changes with seizure control following surgery.
Preliminary Results: We reviewed data from 103 pediatric patients that had one or multiple epilepsy-related neurosurgical interventions at the Montreal Children’s Hospital in the last 11 years. The vast majority had anatomical resection of epileptogenic brain tissue, and a smaller proportion dissection of structures considered to communicate the pathologic signals within the brain. About one third had had preceding intracranial EEG diagnostics with temporary implantation of grids or depth electrodes. Seven patients have had only this diagnostic intervention without advancing to resection yet.
In our study, we use the ECG channel that is usually co-registered in electroencephalogram (EEG) recordings. Inherent to the design as a retrospective study, there is no established standard for the timepoints of EEG recordings around a surgical intervention. This diagnostic modality is being indicated on an individual level, based on the variable circumstances that lead up to surgery; postoperatively, a bias exists towards cases with suspicion for persistent seizures, and less examinations are usually performed on subjects with a successful course. Several of the 103 patients had been referred for surgery from outside hospitals and had their follow-up examinations externally, so no EEGs were available for analysis. One patient died postoperatively. With regards to HRV data, a significant proportion of EEG recordings had not included an ECG channel, or it was highly artifactual. Overall, the timepoints of valid EEG/ECG tracings before and after a surgery scattered widely between cases. Additionally, short-term HRV measures fluctuate significantly, which was evident between and even within single EEG recordings. We therefore scrutinized all available EEG recordings from archives on different recording systems to find pre- and post-surgery ECG pairs for each patient with best possibly matching factors such as time from surgery, daytime, and vigilance. We exported the selected 5-min EEG segments to a universal file format for ECG curve extraction and HRV analysis, which involved semiautomated signal detection with manual revision and artifact cleaning. We are integrating the readouts with clinical data from patient charts in a customized database. We have dynamically updated the collection with additional surgeries, newly available EEG recordings, and results from clinical reports.
To date, we have collected pre- and post-surgery HRV data from 86 cases. These were drawn from 71 individual patients (9 patients had data for 2 separate surgeries, 3 patients for 3 sequential surgeries). Age of the patients at surgery was between 8 months and 18 years (median 10.7 years). The patients have been diagnosed with a wide spectrum of epileptogenic lesions, including, in descending order, focal cortical dysplasia and other cerebral malformations; cortical tubers (of tuberous sclerosis); ganglioglioma and other low grade brain tumors; scarred brain tissue from pre- and perinatal insults; or presumptive autoimmune/autoinflammatory encephalitis. In some patients, no well-delineated focus of their seizures or clear etiology of their complex epilepsy has been identified yet. Surgery has been a beneficial treatment for the majority of these patients that suffered from formerly drug-resistant epilepsies. According to the Engel classification, 51 cases reached class 1 (free from disabling seizures), 5 cases class 2 (rare disabling seizures), 22 cases class 3 (worthwhile improvement), and 8 cases class 4 (no significant improvement), which would, in a dichotomic classification, result in 2/3 vs. 1/3 highly successful vs less- or unsuccessful outcomes. To consider with these numbers is a variable observation period and the above-mentioned fact that mainly cases with successful outcomes have been lost to follow-up.
Inspection of the multiple HRV measures on the whole cohort level indicates that there are pre- to post-surgery trends for several of the measures. Since the mean differences are relatively low and on a background with the above-described high variability, we have created a ‘non-intervention’ control group from the same patients by selecting pairs of EEGs/ECGs where both examinations had been performed with a few months’ delay before the surgical intervention. This should give an idea of general trends of HRV measures over time in this patient population and will help to corroborate the additional effects of surgery.
With the outlined challenges arising from non-homogenous data and multiple additional time-consuming technical steps, data read-out and assembly have been somewhat protracted. We are now completing the collection of clinical data along with detailed statistical analyses. Besides judging on a global effect of epilepsy surgery on HRV and the correlation of surgery outcomes and HRV changes, we have collected data from a sufficiently large and diverse cohort to allow for analysis of how variables such as lesion location or lesion type might modulate the HRV changes. Knowing the influence of such factors will help to predict how far a reduction in HRV abnormalities, autonomic dysfunction and eventually SUDEP risk can be expected from a surgical intervention in an individual child or adolescent.
Anticipated Timeline for Completion: We anticipate that data analysis will be completed by December 2023 or January 2024.