**3. Conclusion**

102 Novel Aspects on Epilepsy

awareness. Recent ECG studies showed that every fifth epilepsy patients experiences abnormally slow heart rhythms during seizures, culminating in 16% with asystolie which is potentially lethal (Rugg-Gunn et al., 2004). For confirmed *KCNQ1* mutation carriers implantable pacemaker therapy should be considered in the context of abnormally slow heart rhythms, and considering the possible changes of brainstem parasympathetic outflow to the heart recently identified in knockin mice with Kv7.1 mutations (Goldman et al., 2009). As β-blockers are therapeutically recommended in LQTS1 in confirmed *KCNQ1* mutation carriers with the potential side effect of slow heart rates, it is important to carefully monitor

In addition, we have developed novel RyR2-specific compounds which permeate the bloodbrain barrier and inhibit both neuronal seizures and cardiac arrhythmias (Lehnart et al., 2008). Different from conventional ion channel blockers, RyR2 stabilizing compounds like S107 have no effect on physiological channel function and do not alter intracellular Ca2+ signaling (Lehnart, 2007). In addition, S107 has not shown any significant side effects against other ion channels or enzymes in large screening panels (Lehnart et al., 2008). Similar to LQTS1, β-blocker therapy is recommended in patients with CPVT1 and confirmed *RYR2* mutation carrier status due to the characteristic dependence of cardiac arrhythmias on sympathetic outflow to the heart. In summary, the neuro-cardiological implications of idiopathic epilepsies are potentially important in mutation carriers, and comprehensive phenotype and genotype risk profiling may lead to improved therapy and prevention of

**2.5 Summary of combined syndromes of neuronal and cardiac ion channelopathies**  Recent studies have for the first time identified previously unrecognized brain ion channelopathies as the neurobiological basis of generalized seizures. While the epilepsy phenotypes represent primary brain discharges, the same molecular defects precipitate lifethreatening cardiac arrhythmias. The following mechanisms have been proposed to underlie

Kv7.1 dysfunction in *KCNQ1* mutation carriers with LQTS1 may alter the propensity of neurons and cardiac myocytes to repolarize following depolarization by an action potential. This results in a decreased repolarization capacity in the brain and heart. In the brain, a decreased repolarization capacity during action potential firing may result in seizures and brainstem autonomic dysfunction of parasympathetic outflow leading to heart rhythm block and asystolie for example at the level of the cardiac AV node. Dysfunction of brain stem parasympathetic outflow to the cardiac sinus and atrioventricular nodes as a cause of asystolie in epilepsy expands previously described arrhythmia mechanisms, since fast ventricular arrhythmias are characteristically triggered by increased sympathetic outflow in *KCNQ1* mutation carriers. Because Kv7.1 mutations can cause dangerous cardiac arrhythmias, *KCNQ1* is a molecular candidate mechanism and risk factor of SUDEP. These findings establish *KCNQ1* in neuronal hyperexcitability and epileptogenesis. Hundreds of *KCNQ1* mutations have been identified mostly leading to loss-of-function phenotypes. However, the correlation between Kv7.1 channel defects and the clinical phenotype in different organs is variable, and not all mutations may cause epilepsy or only when a

*RYR2* mutations appear to cause increased neuronal burst activity of the hippocampal CA3 region and seizure activity as evidenced by synchronous bursting Ca2+ signals of principal

the heart rate behaviour in affected patients (Roden, 2008).

fatal arrhythmias in affected epilepsy patients.

epilepsy in combined neuro-cardiogenic syndromes:

permissive background or environmental condition exists.

Recent advances in ion channelopathy studies related to epilepsy have achieved important new insights about combined neuro-cardiogenic phenotypes, and mechanisms which may link dysrhythmia phenotypes of the brain and heart through the autonomic nervous system. Already, these insights have motivated further research about diagnostic strategies to improve risk prediction and prevention in patients with seizure disorders of unknown origin. In addition, novel therapeutic strategies which target the underlying molecular mechanisms are under development. Despite significant new mechanistic insight about Kv7.1 and RyR2 ion channel mutations as the cause of combined neuro-cardiogenic seizure and arrhythmia syndromes, many questions remain unanswered and require further study. These questions concern the specific brain regions and neuron types, which show a decreased threshold for aberrant network synchronization, such that prolonged depolarization or delayed repolarization may initiate primary brain seizures. In addition, arrhythmias in LQTS1 and CPVT1 are characteristically modulated by the autonomous nervous system. If the autonomous nervous system is also affected by the same gene mutations and exacerbates the cardiac and/or neuronal phenotypes needs further exploration through multidisciplinary research teams. Clearly, the new insights about neuro-cardiogenic dysrhythmias should motivate both clinicians and researchers to critically inquire complex phenotypes beyond the borders of a given research discipline.
