Abstract
Purpose:
Cardiac abnormalities resulting from chronic epilepsy (“the epileptic heart”) constitute a well-recognized comorbidity. However, the association of cardiac alterations with epilepsy duration remains understudied. We sought to evaluate this association using electrocardiogram (ECG).
Methods:
We prospectively enrolled children between 1 months and 18 years of age without known cardiac conditions or ion channelopathies during routine clinic visits. ECGs were categorized as abnormal if there were alterations in rhythm; PR, QRS, or corrected QT interval; QRS axis or morphology; ST segment or T wave. An independent association between ECG abnormalities and epilepsy duration was evaluated using multivariable logistic regression modeling.
Results:
213 children were enrolled. 100 ECGs (47%) exhibited at least one alteration; most commonly in the ST segment (37, 17%) and T wave (29, 11%). Children with normal ECGs had shorter epilepsy duration as compared to those with ECG abnormalities (46 [18–91] months vs. 73 [32–128 months], p = 0.004). A multivariable logistic regression model demonstrated that increasing epilepsy duration was independently associated with the presence of ECG abnormalities (OR=1.09, 95% CI=1.02–1.16, p = 0.008), adjusted for seizure frequency, generalized tonic-clonic/focal to bilateral tonic-clonic seizures as the predominant seizure type, and number of channel-modifying anti-seizure medications. Increasing epilepsy duration was also independently associated with the presence of ST/T wave abnormalities (OR=1.09, 95% CI=1.01–1.16, p = 0.017), adjusted for the same covariates.
Significance:
Increasing epilepsy duration is independently associated with the presence of minor ECG abnormalities. Additional studies are needed to evaluate whether this finding may represent a manifestation of the “epileptic heart”.
Keywords: Cardiac, Epilepsy, Epileptic heart, Pediatric, ST segment, T wave
1. Introduction
A myriad of ictal and interictal cardiac alterations has been described in individuals with epilepsy, such as rhythm disturbances, increased arrhythmogenic potential, and impaired cardiac function [1–16]. Increasing evidence indicates that adults with epilepsy may be at a higher risk for major cardiovascular events such as myocardial infarction, arrhythmias, and sudden cardiac death [17–21]. Together, these observations in adults support the concept of “the epileptic heart”: cardiac structural and functional abnormalities as result of chronic epilepsy, which may lead to potentially deleterious sequelae [22].
Cardiac electrical and functional abnormalities also have been described in children with epilepsy [10,14,23–28], suggesting that the epileptic heart may similarly affect pediatric patients. Implicit in the concept of the epileptic heart is that the epilepsy chronicity may be associated with an increased risk of developing cardiovascular complications. To date, only few studies with small numbers of patients or highly selective populations have demonstrated the associations between cardiac alterations and longstanding epilepsy [15,24,28].
Using electrocardiogram (ECG) we sought to test the hypothesis that epilepsy duration is associated with cardiac alterations in a prospectively enrolled cohort of pediatric epilepsy patients. Furthermore, we sought to explore additional risk factors associated with the presence of ECG abnormalities in this population.
2. Materials and methods
2.1. Study design and patient selection
The Baylor College of Medicine Institutional Review Board approved the study (H-49517). Children presented to the Texas Children’s Hospital Epilepsy Center for the management or diagnosis of epilepsy were eligible if they were between 1 month and 18 years of age with no history of cardiac conditions or known ion channelopathies. We excluded children with congenital heart disease, simple atrial and ventricular septal defect, cardiomyopathies, heart failure from any etiology, and primary rhythm disorders. We also excluded children with pulmonary hypertension because it has significant secondary effects on the cardiac function. We excluded children with known pathogenic/likely pathogenic mutations, as well as variants of uncertain significance, in sodium, potassium, chloride and calcium channels [29]. Following the enrollment, a standard 12-lead ECG recording (10 s) was obtained and interpreted by a pediatric cardiac electrophysiologist (CM) who was blinded to the subjects’ clinical information using age-based normative values [30]. Based on our prior retrospective study [24], we estimated a sample size of at least 188 children to achieve 90% power to detect a odds ratio of 1.26 for every 5 years increase in epilepsy duration.
2.1. Data collection
From the electronic medical record (EMR), we obtained subject demographics and coexisting medical conditions (Table 1, Appendix 1), including the presence of developmental delays, parental reported behavior concerns and learning concerns. Epilepsy data were also determined from the EMR, including age of seizure onset, epilepsy duration, epilepsy type, presence of an epilepsy syndrome, and epilepsy etiology. In cases where multiple mechanisms potentially contributed to a patient’s seizures, a single mechanism from the inciting event was assigned as the primary etiology. For example, in a patient with structural brain damage due to a remote herpes simplex virus infection, the primary etiology was considered infection. While many epilepsies are thought to have a genetic component, the genetic category included only those patients with known genetic abnormality or highly suspected genetic etiology as described by genetic specialists.
Table 1.
Patient demographics.
| Characteristic | Total N = 213 (100%) | Abnormal ECG N = 100 (47%) | Normal ECG N = 113 (53%) | p1 |
|---|---|---|---|---|
| Gender | ||||
| Male | 114 (54) | 59 (59) | 55 (49) | 0.17 |
| Female | 99 (46) | 41 (41) | 58 (51) | |
| Race | 0.93 | |||
| Non-Hispanic White | 89 (42) | 42 (42) | 47 (42) | |
| Hispanic White | 87 (41) | 40 (40) | 47 (42) | |
| Non-Hispanic Black | 27 (13) | 14 (14) | 13 (12) | |
| Asian/Pacific Islander | 6 (3) | 3 (3) | 3 (3) | |
| Other/unknown | 4 (2) | 1 (1) | 3 (3) | |
| Age at enrollment (months), median [IQR] | 116 [68–162] | 138 [81–180] | 98 [58–147] | <0.005 |
| Comorbidities 2 | 177 (83) | 83 (83) | 94 (83) | 0.99 |
| Developmental Delay | 109 (51) | 56 (56) | 53 (47) | 0.22 |
| Learning difficulties | 59 (28) | 29 (29) | 30 (27) | 0.76 |
| Brain malformations | 47 (22) | 23 (23) | 24 (21) | 0.87 |
| Behavioral concerns | 46 (22) | 23 (23) | 23 (20) | 0.74 |
| Respiratory | 47 (22) | 23 (23) | 24 (21) | 0.87 |
Normal ECG vs. Abnormal ECG.
Each comorbidity is analyzed based on dichotomized “present” vs. “absent” classification between normal and abnormal ECG.
We recorded the following parameters from ECG: heart rate (HR), PR, QRS and corrected QT (QTc) intervals; cardiac rhythm; presence of arrhythmias including premature atrial and ventricular contractions; abnormalities in the PR and QTc intervals, QRS axis and morphology, ST segment and T wave. We collected seizure frequency during the month prior to the ECG study and predominant seizure semiology based on family report, and the name and dosage of antiseizure medications (ASMs) and other antiseizure therapies including vagus nerve stimulator (VNS) at the time of the ECG study. We categorized ASM as channel-modifying or other based on the main mechanism of action (Appendix 2). Enzyme-inducing ASM was similarly classified [31].
2.1. Statistical analyses
The primary analysis was the association of epilepsy duration with the presence of ECG abnormalities. We reported patient demographics and clinical information using descriptive statistics. Univariate associations between clinical characteristics and the presence of ECG abnormalities were analyzed using Fisher exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. We used multivariable logistic regression modeling adjusted for robust standard errors to assess for an independent association between epilepsy duration and ECG abnormalities. We included generalized tonic clonic seizure (GTC)/focal to bilateral tonic-clonic seizure as primary seizure type, seizure frequency, and number of channel-modifying ASMs as pre-specified model covariates. Covariates associated with ECG abnormalities with p < 0.1 in the univariate analyses were also considered for inclusion. We used Pearson correlation coefficients, bivariate linear and logistic regresssion, and variance inflation factors (VIF) to evaluate for potential collinearity with our primary predictor of interest, epilepsy duration; we required our final model to have VIF <2 for all covariates [32]. As expected, age and HR demonstrated meaningful collinearity with epilepsy duration (β=0.63, 95%CI=0.52–0.74, p < 0.005 and β=−2.4, 95% CI=− 2.8 - −2.0, p < 0.005, respectively) and were excluded from the multivariable model. Number of ASM was collinear with number of channel-modifying ASMs and was also excluded (ρ=0.52; p < 0.005, Fisher exact test). Similarly, the presence of VNS was associated with longer epilepsy duration (p < 0.005) and the higher number of channel-modifying ASMs (p = 0.009) and was excluded. Statistical computations were performed using STATA, version 14.2 (StataCorp LP). Data are reported as number (%) or median (interquartile range, IQR). Two-sided P values of < 0.05 were considered statistically significant.
3. Results
3.1. Patient demographics and epilepsy characteristics
Two hundred and thirteen children were enrolled between 8/2021 and 12/2021. Subject demographics are summarized in Table 1. There was a slight male predominance (n = 114, 54%). Non-Hispanic white (n = 89, 42%) and Hispanic white (n = 87, 41%) constituted the most common race/ethnicity. The median age at enrollment was 116 months (IQR 68–162 months). One hundred and seventy-seven patients (83%) had a medical comorbidity, with developmental delays representing the most common comorbidity (n = 109, 51%). Behavioral concerns (n = 46, 22%), and learning concerns (n = 59, 28%) were also common in this cohort.
Epilepsy and seizure characteristics are summarized in Table 2. The median age of seizure onset was 30 months (IQR 7–72 months). The median epilepsy duration at the time of enrollment was 59 months (IQR 22–112 months). Most patients had focal epilepsy (n = 115, 54%). Of the children with known etiology, structural etiologies were most common (n = 58, 27%). Sixty-one patients (29%) had a known epilepsy syndrome, including idiopathic generalized, Lennox Gastaut, infantile spasm, electrographic status epilepticus in sleep (ESES), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Landau Kleffner, Doose, and myoclonic absence epilepsy.
Table 2.
Epilepsy and seizure characteristics.
| Characteristic | Total N = 213 (100%) | Abnormal ECG N = 100 (47%) | Normal ECG N = 113 (53%) | p1 |
|---|---|---|---|---|
| Age of seizure onset (months), median [IQR] | 30 [7 – 72] | 36 [7–68] | 24 [7–72] | 0.72 |
| Age at ECG encounter (years), median [IQR] | 9.7 [5.7–13.5] | 11.6 [6.7–15.0] | 8.3 [4.8–12.3] | <0.01 |
| Epilepsy duration at enrollment (months), median [IQR] | 59 [22 – 112] | 73 [32–128] | 46 [18–91] | 0.004 |
| Epilepsy type | 0.90 | |||
| Focal | 115 (54) | 52 (52) | 63 (56) | |
| Generalized | 54 (25) | 27 (27) | 27 (24) | |
| Focal and Generalized | 34 (16) | 17 (17) | 17 (15) | |
| Undetermined | 10 (5) | 4 (4) | 6 (5) | |
| Epilepsy etiology | 0.73 | |||
| Structural | 58 (27) | 29 (29) | 29 (26) | |
| Genetic/presumed genetic2 | 41 (19) | 16 (16) | 25 (22) | |
| Infectious | 9 (4) | 5 (5) | 4 (4) | |
| Immune | 6 (3) | 2 (2) | 4 (4) | |
| Unknown/other | 98 (46) | 48 (48) | 51 (45) | |
| Epilepsy syndrome | 61 (29) | 31 (31) | 30 (27) | 0.54 |
| Drug-resistant epilepsy | 130 (61) | 67 (67) | 63 (56) | 0.12 |
| Number of seizures per month median [IQR] | 0.5 [0–30] | 1 [0–60] | 0 [0–30] | 0.74 |
| Predominant seizure type at enrollment | 0.65 | |||
| GTC/focal to bilateral tonic-clonic | 29 (14) | 16 (16) | 13 (12) | |
| Generalized onset, motor | 35 (16) | 18 (18) | 17 (15) | |
| Focal onset, motor | 90 (42 | 37 (37) | 53 (47) | |
| Generalized onset, non-motor | 26 (12) | 11 (11) | 15 (13) | |
| Focal onset, non-motor | 14 (7) | 8 (8) | 6 (5) | |
| Unknown/mixed | 13 (6) | 7 (7) | 6 (5) | |
| Number of lifetime seizure types | 0.23 | |||
| 0/not reported | 13 (6) | 10 (10) | 3 (3) | |
| 1 | 78 (37) | 35 (35) | 43 (38) | |
| 2 | 59 (28) | 25 (25) | 34 (30) | |
| 3 | 38 (18) | 17 (17) | 21 (19) | |
| ≥4 | 25 (12) | 13 (13) | 12 (11) | |
| Number of ASM | 0.32 | |||
| 0 | 13 (6) | 4 (4) | 9 (8) | |
| 1 | 68 (32) | 30 (30) | 38 (34) | |
| 2 | 71 (33) | 32 (32) | 39 (35) | |
| ≥3 | 61 (29) | 34 (34) | 27 (24) | |
| Number of channel-modifying ASM | 0.35 | |||
| 0 | 66 (31) | 26 (26) | 40 (35) | |
| 1 | 109 (51) | 55 (55) | 54 (48) | |
| ≥2 | 38 (18) | 19 (19) | 19 (17) | |
| Number of enzyme-inducing ASM | 0.07 | |||
| 0 | 140 (66) | 67 (67) | 73 (64) | |
| 1 | 66 (31) | 27 (27) | 39 (35) | |
| ≥2 | 7 (3) | 6 (6) | 1 (1) | |
| Vagus nerve stimulator | 0.003 | |||
| No | 191 (90) | 83 (83) | 108 (96) | |
| Yes | 22 (10) | 17 (17) | 5 (4) |
ASM = anti-seizure medication. GTC = generalized tonic/clonic. IQR = interquartile range.
Normal ECG vs. Abnormal ECG.
Genetic causes include chromosomal abnormalities and non-ion channel associated epilepsy genes.
Almost half of the patients (n = 103, 49%) had not had self-reported clinical seizures over the preceding month; 31 patients (15%) had not reported clinical seizures over the prior year. On the other hand, 57 patients (27%) had daily seizures. One hundred seventeen children (55%) had experienced one seizure type over the prior year. Most patients had experienced more than one seizure type in their lifetime (n = 132, 63%). Twenty-nine children (14%) had GTC or focal to bilateral tonic-clonic seizures as the predominant seizure type. Overall, patients were on a median of 2 ASMs (IQR 1–2). Sixty-one patients (29%) were on 3 or more ASMs. The most common medications were clobazam (n = 77, 36%), levetiracetam (n = 68, 32%), oxcarbazepine (n = 42, 20%) and lamotrigine (n = 40, 19%) (Appendix 2). One hundred fourty-seven patients (69%) were taking channel-modifying ASMs. Seventy-three patients (34%) were on enzyme-inducing ASMs. Twenty-two patients (10%) had VNS (Table 2).
3.2. Epilepsy duration is an independent risk factor for ECG abnormalities
One hundred ECG studies (47%) exhibited at least one alteration from normal findings (Table 3). ECG abnormalities occurred in all categories examined, with the most common abnormalities occurring in the ST segment (n = 37, 17%) and T wave (n = 29, 11%) (Table 3). Children with normal ECGs had a median epilepsy duration of 46 months (IQR 18–91 months), whereas those with ECG changes had a median epilepsy duration of 73 months (IQR 32–128 months) (Table 2). Age and the presence of VNS at the time of the ECG study were also associated with ECG alterations.
Table 3.
Summary of electrocardiogram (ECG) findings.
| N (%) | |
|---|---|
| Abnormal ECG | 100 (47) |
| Rhythm | |
| normal sinus | 134 (63) |
| sinus arrhythmia | 47 (22) |
| sinus tachycardia | 12 (6) |
| sinus bradycardia | 12 (6) |
| arrhythmias1 | 7 (3) |
| other | 1(<1) |
| PR interval changes | |
| normal | 195 (92) |
| shortened | 16 (8) |
| prolonged | 2 (1) |
| QRS axis | |
| normal | 201 (94) |
| right axis deviation | 11 (5) |
| left axis deviation | 1 (<1) |
| QRS morphology | |
| normal | 188 (88) |
| Incomplete right bundle branch block | 18 (8) |
| Interventricular conduction delay | 6 (3) |
| low voltage | 1 (<1) |
| QTc interval changes | |
| normal | 207 (97) |
| prolonged | 3 (1) |
| shortened | 3 (1) |
| ST segment changes | |
| non-specific | 24 (11) |
| early repolarization | 13 (6) |
| T wave changes | |
| non-specific | 20 (9) |
| inverted | 9 (4) |
Severe sinus arrhythmia with ectopic atrial escape=1, wondering atrial pacemaker=2, premature atrial contraction=1, sinus tachycardia with ectopic atrial rhythm=1, low right atrial rhythm=2.
A multivariable logistic regression model demonstrated that each additional year of epilepsy duration was independently associated with ECG abnormalities (OR=1.09, 95%CI=1.02–1.16, p = 0.008), adjusting for seizure frequency, GTC/focal to bilateral tonic-clonic seizures, and number of channel-modifying ASMs (Table 4). Extrapolating from this model, an epilepsy duration of 5 years longer would have an estimated increased odds of 1.54 (95%CI=1.12–2.11, p = 0.008) of having ECG abnormalities. An epilepsy duration of 10 years longer would have an estimated increased odds of 2.36 (95%CI=1.25–4.45, p = 0.008).
Table 4.
Epilepsy duration is an independent factor for minor electrocardiogram (ECG) abnormalities.
| Any ECG abnormalities | OR | 95% CI | P |
|---|---|---|---|
| Epilepsy duration | 1.09 | 1.02 – 1.16 | 0.008 |
| Seizure frequency | 1.00 | 0.99 – 1.01 | 0.93 |
| GTC/focal to bilateral tonic-clonic seizures | 1.39 | 0.58 – 3.33 | 0.46 |
| Number of channel-modulating ASM | |||
| 0 | Ref | Ref | Ref |
| 1 | 1.33 | 0.68–2.59 | 0.40 |
| ≥2 | 1.58 | 0.67–3.67 | 0.29 |
ASM = anti-seizure medication. GTC = generalized tonic/clonic.
Because changes in the ST segment and T wave were the most common abnormalities, we evaluated whether epilepsy duration was also an independent factor associated with ST segment or T wave abnormalities as a composite outcome using the same multivariable logistic regression model. Each additional year of epilepsy duration was associated with increased odds of having ST/T wave abnormalities (OR 1.09, 95%CI=1.01–1.16, p = 0.017) (Table 5). Every 5 years of additional epilepsy duration would be associated with an estimated increased odds of ST/T wave abnormalities of 1.51 (95%CI=1.08–2.11, p = 0.017); and 10 years would be associated with an estimated increased odds of 2.27 (95%CI=1.16–4.46, p = 0.017).
Table 5.
Epilepsy duration is an independent factor for ST/T wave abnormalities.
| ST/T wave abnormalities | OR | 95% CI | P |
|---|---|---|---|
| Epilepsy duration | 1.09 | 1.01 – 1.16 | 0.017 |
| Seizure frequency | 1.01 | 1.00 – 1.02 | 0.08 |
| GTC/focal to bilateral tonic-clonic seizures | 1.32 | 0.49 – 3.51 | 0.58 |
| Number of channel-modulating ASM | |||
| 0 | Ref | Ref | Ref |
| 1 | 0.89 | 0.49–1.92 | 0.76 |
| ≥2 | 0.54 | 0.18–1.63 | 0.28 |
ASM = anti-seizure medication. GTC = generalized tonic/clonic.
4. Discussion
We found that minor ECG abnormalities are prevalent in a cohort of children with diverse epilepsy etiologies, epilepsy severity, seizure types, and seizure frequency. Nonspecific ST segment and T wave abnormalities represent the most common findings and potentially indicate variations in the normal ventricular depolarization-repolarization cycle. An association between epilepsy duration and ECG abnormalities in children without prior cardiac abnormalities or known ion channelopathies may represent a manifestation of the “epileptic heart”, which may have future clinical implications in children with longstanding epilepsy.
Cardiac autonomic imbalance, increased QTc interval and dispersion, and myocardial strain have been described in children with epilepsy [10–12,14,23,25–28]. However, few studies have focused on the potential association between the observed cardiac changes and the epilepsy duration. For instance, in a small cohort of adults with longstanding and newly diagnosed epilepsy, interictal pathological T-wave alternans, an indicator of cardiac electrical instability and a risk marker for sudden cardiac death, was present only in adults with longstanding epilepsy [15]. Epilepsy duration of five years or greater was associated with longer QTc intervals and worse spatial-temporal ventricular repolarization heterogeneity in children with Dravet syndrome [28]. Similarly, epilepsy duration was independently associated with minor ECG abnormalities in the pediatric epilepsy patients with a history of status epilepticus that required pediatric intensive care unit admission [24]. In this study, cardiac electrical abnormalities were prevalent, with non-specific ST segment (17%) and T wave (11%) abnormalities representing the most common alterations. While we do not have a control group, published normative data show the prevalence of non-specific ST elevation and T wave abnormalities are approximately 10% and 5% in over 48,000 school-age children participating in an ECG screening program [33]. Although these changes do not reach pathological threshold, they may reflect increased complexity in the ventricular depolarization-repolarization cycle [34] and may provide insights into cardiac electrical variations associated with epilepsy. If epilepsy duration is an independent risk factor for the observed ECG abnormalities, this may suggest that cardiac electrical changes emerge over time, supporting the concept of “the epileptic heart” in pediatric patients with epilepsy.
Population-based studies have demonstrated that adults with epilepsy are at a higher risk for major cardiovascular events [17–21]. Similarly, epidemiological studies on sudden cardiac death have demonstrated that epilepsy diagnosis is associated with a three-fold increased risk in adults, with a median epilepsy duration of 10 years at the time of cardiac arrest [20]; and the individuals with epilepsy are younger at the time of sudden cardiac arrest compared to those without epilepsy [20,21]. Interestingly, longitudinal studies in adults revealed minor ST/T wave abnormalities to be independent risk factors for future cardiac mortality [35–37]. Therefore, while these ECG abnormalities are traditionally considered to have indeterminate clinical significance, they may in fact forestall adverse cardiovascular events. Whether minor ST/T wave abnormalities similarly confer future cardiovascular risk in children with epilepsy is currently unknown and merits further study.
Several factors may contribute to the observed ECG changes in our study population. For instance, many ASMs modulate ion channel activity, which could affect cardiac electrical properties [38]. Changes in ventricular repolarization have been described following GTC or focal to bilateral tonic-clonic seizures [3,8,16,27,39–42], suggesting that seizures can adversely affect cardiac electrical properties. Additionally, enzyme-inducing ASMs have been associated with increased risk for major cardiovascular events [17,31], which may be reflected in abnormal ECGs. In this study, we did not observe channel-modifying or enzyme-inducing ASMs, seizure frequency from the preceding month, or the predominant seizure semiology being associated with ECG changes. Therefore, mechanisms underlying the observed ECG alterations in this study remain elusive and require further investigation.
In addition to the indeterminate clinical significance associated with the observed ECG changes, there are other considerations that may influence the interpretation of the findings and pose limitations to this study. A significant limitation is collinearities between epilepsy duration and several variables such as age, HR (which naturally declines as a function of age), and the presence of VNS. Therefore, we are unable to evaluate whether epilepsy duration itself confers increased risk of ECG abnormalities, or whether this is possibly a function of aging, baseline heart rate, or VNS in this cohort. The observed changes could represent simply episodic variations that occur normally in some individuals. Conversely, the brief nature of a standard ECG may miss episodic abnormalities in other subjects. Futhermore, our sample size limits statistical interpretation with additional clinical variables. A majority of patients had medical comorbidities including developmental delays, some of them did not have genetic studies. Therefore, we cannot exclude an undiagnosed genetic etiology contributing to the observed ECG abnormalities. The subjects were recruited in a specialized referral center for pediatric epilepsy, which could limit the generalizability of the findings.
5. Conclusions
Minor ECG abnormalities are common in a cohort of pediatric epilepsy patients without known ion channelopathy or pre-existing cardiac conditions. These abnormalities are associated with longer epilepsy duration, suggesting that the observed ECG abnormalities may reflect changing cardiac electrical properties from chronic epilepsy. This may represent a manifestation of “the epileptic heart”. Prospective long-term studies with serial cardiac assessments are needed to further characterize potential progressive cardiac electrical and functional changes, and to ascertain whether routine ECG surveillance may be indicated in epilepsy.
Acknowledgement
We would like to thank the pediatric epileptologists and neurologists at Texas Children’s Hospital for their assistance in identifying and recruiting patients. We also like to thank the office staff at the Blue Bird neurology clinic and the cardiology clinic, Texas Children’s Hospital, for their logistic support.
Funding
This work was supported by the National Intiture of Neurological Disoders and Stroke (NINDS) as part of the National Institure of Health (NIH) (Grant No.: R21NS119929).
Appendices
Appendix A1.
Co-existing conditions of the study subjects.
| Comorbidities | N (%) |
|---|---|
| Neurologic | |
| Developmental Delay | 109 (51) |
| Learning difficulties | 59 (28) |
| Behavioral concerns | 46 (22) |
| Brain malformations | 47 (22) |
| Cerebral palsy | 43 (20) |
| Psychiatric diagnoses | 41 (19) |
| Acquired brain injury | 34 (16) |
| Respiratory | |
| Obstructive sleep apnea | 22 (10) |
| Asthma | 18 (8) |
| Chronic lung disease | 12 (6) |
| Ventilator dependence | 6 (3) |
| Prematurity | 24 (11) |
| Gastrointestinal | 16 (8) |
| Endocrine | 15 (7) |
| Renal | 8 (4) |
| Hematologic/Oncologic | 4 (2) |
| Immune | 2 (1) |
Medical comorbidities recorded for each patient. An individual patient may have more than one comorbidity.
Appendix A2.
Anti-seizure medications (ASM) and adjunct therapies.
| N (%) | |
|---|---|
| Channel-modifying ASM 1 | |
| Eslicarbazepine | 4 (2) |
| Ethosuximide | 9 (4) |
| Lacosamide | 17 (8) |
| Lamotrigine | 40 (19) |
| Oxcabazepine | 42 (20) |
| Rufinamide | 11 (5) |
| Valproate | 30 (14) |
| Zonisamide | 33 (15) |
| Enzyme-inducing ASM | |
| Eslicarbazepine | 4 (2) |
| Oxcabazepine | 42 (20) |
| Phenobarbital | 10 (5) |
| Rufinamide | 11 (5) |
| Topiramate | 13 (6) |
| Other ASM | |
| Brivaracetam | 5 (2) |
| Clobazam | 77 (36) |
| Clonazepam | 13 (6) |
| Diazepam | 2 (1) |
| Cannabidiol | 26 (12) |
| Felbamate | 5 (2) |
| Levetiracetam | 68 (32) |
| Perampanel | 1 (< 1) |
| Vigabatrin | 13 (6) |
| Other | 5 (2) |
| Adjunct therapy | |
| Immune therapy | 11 (5) |
| Ketogenic diet | 6 (3) |
| Surgery | 16 (7) |
| Laser ablation | 7 (3) |
| Vagus nerve stimulator | 22 (10) |
| Responsive nerve stimulator | 2 (1) |
Channel modifying ASM includes primarily sodium channel modifiers except for ethosuximide, a calcium channel medication.
Footnotes
Declaration of competing interest
None of the authors have any conflict of interest to disclose. We confirm that we have read journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Data statement
The anonymized dataset is maintained by the corresponding author and will be shared with other eligible investigators through academically established means. Request for access to the dataset should be made directly to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The anonymized dataset is maintained by the corresponding author and will be shared with other eligible investigators through academically established means. Request for access to the dataset should be made directly to the corresponding author.