Monday, October 31, 2016

The heart of epilepsy

S. Shmuely, M. van der Lende, R.J. Lamberts, J.W. Sander and R.D. Thijs.  The heart of epilepsy: current views and future concepts.  Seizure: European Journal of Epilepsy.  Article in press.


• Cardiovascular (CV) comorbidities are common in people with epilepsy.

• Epilepsy and CV disorders have a complex relationship.

• Shared risk factors, causal and resultant mechanisms may play a role.

• Great progress in clinical profiles has been made.

• Further studies are needed to aid early identification of CV disorders in epilepsy.

Cardiovascular (CV) comorbidities are common in people with epilepsy. Several mechanisms explain why these conditions tend to co-exist including causal associations, shared risk factors and those resulting from epilepsy or its treatment.

Various arrhythmias occurring during and after seizures have been described. Ictal asystole is the most common cause. The converse phenomenon, arrhythmias causing seizures, appears extremely rare and has only been reported in children following cardioinihibitory syncope. Arrhythmias in epilepsy may not only result from seizure activity but also from a shared genetic susceptibility. Various cardiac and epilepsy genes could be implicated but firm evidence is still lacking. Several antiepileptic drugs (AEDs) triggering conduction abnormalities can also explain the co-existence of arrhythmias in epilepsy.

Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease and a poorer CV risk profile than those without epilepsy. Shared CV risk factors, genetics and etiological factors can account for a significant part of the relationship between epilepsy and structural cardiac disease. Seizure activity may cause transient myocardial ischaemia and the Takotsubo syndrome. Additionally, certain AEDs may themselves negatively affect CV risk profile in epilepsy.

Here we discuss the fascinating borderland of epilepsy and cardiovascular conditions. The review focuses on epidemiology, clinical presentations and possible mechanisms for shared pathophysiology. It concludes with a discussion of future developments and a call for validated screening instruments and guidelines aiding the early identification and treatment of CV comorbidity in epilepsy.

From the article:

Various arrhythmias have been described, occurring during (ictal) or after (postictal)
seizures. Sinus tachycardia is the most common ictal pattern, seen in up to 80% of all
seizures and in 82% of people with epilepsy, but usually without symptoms. The most
frequent clinically relevant arrhythmia is ictal asystole, occurring in 0.318% (95% CI 0.316%
to 0.320%) of people with refractory focal epilepsy admitted for video-EEG. Ictal asystole,
bradycardia and AV block predominantly occur in people with temporal lobe epilepsy. 
Clinically, ictal asystole is characterised by sudden loss of tone during a dyscognitive
seizure. The circulatory pattern resembles vasovagal syncope with a transient,
progressive and self-limiting slowing of the heart rate and decrease of blood pressure.
For many years, ictal asystole was thought to be a possible mechanism underlying sudden 
unexpected death in epilepsy (SUDEP). This appears to be unlikely: all but one reported case
so far of ictal asystole were self-limiting. In this one case successful resuscitation was
started after 44 seconds of asystole and the event was classified as near-SUDEP. The
longest ictal asystole reported so far, however, lasted 96 seconds and appeared self-limiting.
Whether an event is classified as near-SUDEP or not will depend on interventions of
medical personnel: prompt resuscitation in response to ictal asystole will likely lead to more
classified as near-SUDEP cases. While there are no reports of fatal ictal asystole, it remains
debatable whether ictal asystole can cause SUDEP…

Another mechanism explaining the association between arrhythmias and epilepsy is a shared
genetic risk factor. A rapidly increasing number of genes potentially linking epilepsy to
cardiac arrhythmias has been identified. Here we discuss some relevant examples; starting
with the genes predominantly known for their cardiac functions and then the ‘epilepsy

Several genetic ion channel mutations are thought to be expressed in the brain as well as in
the heart, and might thus cause seizures and cardiac arrhythmias. The first reported genetic
link between epilepsy and cardiac arrhythmias was the discovery of cardiac sodium channel
gene SCN5A in the brain. Subsequently, more pathogenic variants in the long QT (LQT)
gene family (i.e. KCNQ1, KCNH2 and SCN5A) were associated with a “seizure phenotype”
(e.g. self-reported diagnosis of epilepsy and AED use). Mice models indicated that
other, non-LQT, cardiac channelopathy genes including RYR2 (associated with
catecholaminergic polymorphic ventricular tachycardia), and HCN1-4 potentially
predispose to epilepsy…

Several AEDs, particularly those with sodium blocking properties are known to trigger
conduction abnormalities or arrhythmias. Atrioventricular (AV) conduction is the most
frequent reported complication. ST changes, Brugada-like patterns, atrial fibrillation and QTc
prolongation have also been reported but the association with AED treatment is less well
established. Most clinically relevant arrhythmias were related to AED overdose.
Carbamazepine is, however, known to cause AV conduction blocks at low or therapeutic
levels; this is almost exclusively reported in elderly women. Rapid administration
of phenytoin may also cause sinus arrest and hypotension; elderly people and those with
pre-existing heart disease seem most vulnerable to these adverse effects. IV administration
should, therefore, be undertaken slowly, with continuous cardiac monitoring.
The above-mentioned AED effects do not seem to play a role in ictal arrhythmias.
Nevertheless, it is important to take these effects into consideration in the selection of an
AED and to monitor adverse effects closely especially in elderly people and those with
cardiovascular comorbidities.

1 comment:

  1. Ammar Hussain, Syndi Seinfeld, Lawrence Morton. Genetic Association with Ictal Cardiorespiratory Phenomena: SCN8A Case Series. J Pediatr Neurol 2016; 14(04): 151-155


    Increased availability of genetic testing has led to identification of expanding SCN8A phenotypic spectrum ranging from early-infantile epileptic encephalopathy (EIEE) to developmental and cognitive disabilities, movement disorders, and a possible high incidence of sudden unexplained death in epilepsy patients (SUDEP). Children with SCN8A mutations may also have dysfunction of cardiac voltage gated sodium channels, resulting in ictal cardiac symptoms with associated respiratory distress. We report a case series of two patients with de novo SCN8A mutation. These patients presented with recurrent tonic seizures at 4 and 6 months of age, along with ictal bradycardia and asystole respectively. Interictally both patients had normal EEG and cardiac evaluation. The antiepileptic drug treatment choice was made prior to known genetic abnormality, with resultant decrease in seizure frequency and severity of cardiorespiratory symptoms in both patients. The association of SCN8A mutation–related rare epilepsy with ictal cardiac symptoms has not been well described in the literature. The association of ictal cardiac phenomena with this mutation is important in patient treatment, family education, and risk of complications such as SUDEP. The role of SCN8A in the mechanism of SUDEP requires future studies.