SUDEP basic mechanisms: on course to understand, predict, and prevent - Part II: Cardiac and autonomic dysfunction
[Part 2: Questions; Goldman AM. Part 1. Respiratory dysfunction]
Serious periictal and interictal arrhythmias have been observed in up to about 1/3 of epilepsy patients (Nei et al., 2000). Autonomic dysfunction was documented in children affected by Dravet syndrome and in other epilepsy cohorts (Delogu et al., 2011; Lotufo et al., 2012). While a study comparing autonomic function measures between SUDEP cases and epilepsy controls did not identify significant differences (Surges et al., 2009), there was the trend towards abnormal autonomic regulation in the SUDEP group (Surges et al., 2009; DeGiorgio & DeGiorgio, 2010) and this finding was also demonstrated in isolated SUDEP cases (Rauscher et al., 2011; Jeppesen et al., 2014). Findings in a rat model of chronic epilepsy induced by kianic acid parallel human research (Sakamoto et al., 2008; Naggar et al., 2014).
Cardio-autonomic dysfunction in SUDEP physiology
The first link between genetically predisposed cardiac arrhythmias and epilepsy was the discovery that the cardiac voltage-gated sodium channel SCN5A previously linked to the inherited cardiac arrhythmia called the long QT syndrome (LQTS), was expressed in the brain (Hartmann et al., 1999). Subsequently, clinical case reports supported the concept of a combined neuro-cardiac phenotype triggered by a mutation in an ion channel dually expressed in the brain and in the heart (Aurlien et al., 2009; Heron et al., 2010). Then came the report of the complex phenotype of epilepsy, cardiac arrhythmias, and SUDEP in a transgenic mice carrying the human knock-in mutations in another long LQT gene, the potassium channel KCNQ1 (Goldman et al., 2009). The animals displayed several seizure types along with a plethora of cardiac arrhythmias (Goldman et al., 2009). The observed model SUDEP event mirrored a previously-described human case report (Bird et al., 1997) and the study uncovered some of the candidate networks and mechanisms involved in the lethal epilepsy outcome. A link between an epilepsy phenotype and LQTS has been clinically validated (Johnson et al., 2009; Anderson et al., 2014). A seizure phenotype was identified in 28% of cases with clinically evident and genetically confirmed LQTS caused by pathogenic variants in the KCNH2, KCNQ1, and SCN5A genes (Anderson et al., 2014). Molecular survey of these three genes in 68 SUDEP cases uncovered nonsynonymous variants of suspected functional significance in 10% of patients (Tu et al., 2011). Molecular neuro-cardiac connection to SUDEP extends beyond the long QT syndrome and to other cardiac arrhythmias, such as the catecholaminergic polymorphic ventricular tachycardia (CPVT) linked to ryanodine receptor gene RYR2 (Johnson et al., 2010). Moreover, mutational screen in 48 SUDEP cases uncovered several coding variants in the hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels linked to both epilepsy and cardiac arrhythmias (Tu et al., 2011; Benarroch, 2013).
Aside from the genes with ‘primary’ affiliation to cardiac arrhythmias, there is the growing number of primary epilepsy genes with demonstrated connection to cardiac and autonomic dysfunction and SUDEP. For example, the voltage-gated potassium channel KCNA1 is dually expressed in the brain and in the vagus nerve (Glasscock et al., 2010). The Kcna1 null mice have seizures, cardiac arrhythmias, vagal hyperexcitability, and they die prematurely (Glasscock et al., 2010). Pretreatment with atropine and b-blockers ameliorated the AV blocks thus implicating the excessive parasympathetic tone in neuro-cardiac dysfunction (Glasscock et al., 2010). This channel was also clinically validated in a SUDEP case affected by epileptic encephalopathy and suspected cardiac dysrhythmias carrying de novo and novel KCNA1 intragenic duplication (Klassen et al., 2014).
Reports of SUDEP in patients affected by Dravet syndrome implicated the SCN1A gene as the novel candidate SUDEP risk factor (Hindocha et al., 2008; Le Gal et al., 2010) and this finding was corroborated by animal studies (Cheah et al., 2012; Kalume et al., 2013). The Scn1a deficient mice mirror the human autonomic features as they develop spontaneous seizures, episodic ictal bradycardia during the tonic phase of the generalized tonic-clonic seizures, and the evidence for autonomic instability and seizure-driven vagal activation preceding sudden death (Cheah et al., 2012; Kalume et al., 2013). Analogous to the Kcn1a model, administration of parasympatolytics, atropine and scopolamine, reduced the incidence of ictal bradycardia and SUDEP in the model (Kalume et al., 2013). On the other hand, the knock-in scn1a mouse model carrying a human variant SCN1A-R1407X documented the presence of a recurrent seizures and prolonged QT interval that led to a variety of cardiac dysrhythmias, ultimately resulting in ventricular fibrillation and model SUDEP events (Auerbach et al., 2013). Interestingly, the cardiac arrhythmias in this model of Dravet syndrome often preceded the apparent convulsive seizures, thus indicating that that some SCN1A variants might predispose to sudden death through sole cardiac mechanisms (Auerbach et al., 2013).
The SCN1B gene encodes a voltage-gated sodium channel (VGSC) β subunit t (Brackenbury et al., 2013). While human SUDEP linked to SCN1B has not yet been seen, Scn1b mouse model parallels some of the Scn1a animal model features (Chen et al., 2004) and displays spontaneous seizures, prolonged QT and RR intervals on the electrocardiogram, and early mortality (Chen et al., 2004; Lopez-Santiago et al., 2007). The first whole exome sequencing of a nuclear family with a child affected by epileptic encephalopathy and SUDEP (Veeramah et al., 2012) led to discovery of a functionally active de novo variant in the SCN8A channel gene that was previously linked to epilepsy (Hawkins et al., 2011; O'Brien & Meisler, 2013). The recently developed personalized Scn8a mouse model carrying the human mutation p.Asn1768Asp models SUDEP and the mechanisms leading to premature mortality are under study (Wagnon et al., 2014). The recent discovery of Senp2 gene in connection to SUDEP showed that our search for candidate genes will need to consider a larger ion channel network (Qi et al., 2014). Senp2 gene is a modulator of multiple potassium channels and deficiency triggers recurrent seizures, vagally driven arrhythmias, and premature epilepsy related mortality (Qi et al., 2014). Also, there is the preliminary evidence indicating an adenosine role in seizure termination and, possibly, in postictal cardio-respiratory depression (Massey et al., 2014). Recent experiments showed that stimulation of the adenosine receptors may lower seizure threshold and lead to seizure-related death (Fukuda et al., 2011). On the contrary, the administration of caffeine, an adenosine receptor antagonist, increased survival of the animals (Shen et al., 2010).
The wealth of clinical and experimental studies indicates that the biological predisposition to SUDEP is complex and likely a result of an intricate oligogenic molecular network. This was recently illustrated in a case of SUDEP in a child affected by Dravet syndrome (Klassen et al., 2014). The detailed genomic analysis uncovered complex combinations of variants in genes expressed in both neurocardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C. Double gene modulation of SUDEP risk has been already demonstrated experimentally in Cacna1a/Kcna (Glasscock et al., 2007), Kcna1/Mapt (Holth et al., 2013) and Scn1a/Mapt (Gheyara et al., 2014) double mouse mutants.
We have begun unraveling the complex SUDEP mechanisms. Novel technologies in human and experimental science are creating opportunities for unprecedented speed in gene discovery, diagnostics, and development of personalized model systems that are essential in understanding molecular profiles of each individual patient. This in turn will drive implementation of personalized screening procedures or interventions (antiarrhythmic medications, cardiac defibrillators or pacemakers, supplemental oxygen, SSRI class of antidepressants). However, current and future progress in SUDEP detection and prevention is not possible without a broad scientific collaboration in partnership with our patients, families, professional colleagues, and funding bodies. Our effort to preserve the legacy of patients we lost to SUDEP and the research progress are critically dependent on global research participation of all families affected by SUDEP.
Assistant Professor, Department of Neurology
Baylor College of Medicine, Texas, USA
How to cite:
Goldman AM. SUDEP basic mechanisms: on course to understand, predict, and prevent - Part II: Cardiac and autonomic dysfunction. In: Hanna J, Panelli R, Jeffs T, Chapman D, editors. Continuing the global conversation [online]. SUDEP Action, SUDEP Aware & Epilepsy Australia; 2014 [retrieved day/month/year]. Available from: www.sudepglobalconversation.com.