Cardiovascular autonomic functions in well-controlled and intractable partial epilepsies

Summary

Background

Epilepsy is associated with imbalance of sympathetic and parasympathetic activity which may lead to sudden unexplained death in epilepsy (SUDEP). Well-controlled (WcE) and intractable epilepsy (IE) subjects may present different autonomic profiles, which can be helpful in explaining the predisposition of the latter to SUDEP.

Purpose

To compare inter-ictal cardiovascular autonomic function in subjects with partial WcE and IE.

Methods

Thirty WcE and 31 IE subjects underwent a battery of autonomic function tests: deep breathing, Valsalva maneuver, isometric exercise, cold pressor and tilt-table. Autonomic tone was assessed by heart rate variability (HRV). Their autonomic severity score and anxiety status was also assessed.

Results

IE subjects had elevated low frequency component (52.0 vs. 37.6, p = 0.047) and decremented high frequency component (114 vs. 397, p = 0.013) of HRV and higher diastolic BP (75.62 ± 9.77 vs. 68.64 ± 0.43, p = 0.036). In deep breathing test, they had lesser HR changes (20 ± 10.18 vs. 29.68 ± 11.23, p = 0.007) and lower E:I (1.29 ± 0.16 vs. 1.43 ± 0.21, p = 0.008). IE subjects had higher dysautonomia (chi square 165.0, p < 0.0001).

Conclusions

We observed a higher vasomotor tone, higher sympathetic tone, lower parasympathetic tone, lower parasympathetic reactivity and more severe dysautonomia in the IE subjects. Refractoriness may lead to an alteration in cardiovascular autonomic regulation, which might be a predisposing factor for SUDEP.

Introduction

Seizures are frequently associated with autonomic symptoms, which occur either during the seizure prodrome (aura) or as a predominant part of the seizure manifestation. The abnormal cortical activity underlying a seizure can involve central regions that regulate autonomic activity and present with autonomic symptoms, either initially or during its propagation. Seizure related hypo or hyperactivity modifies the cardiovascular system. In many instances, there is tachycardia and pressor responses preceding or accompanying the seizure discharge, while bradyarrythmias and arterial hypotension are rare (Nashef et al., 1996, Devinsky et al., 1997, Leutmezer et al., 2003). Around a third of simple partial seizures and all generalized seizures are accompanied by autonomic symptoms (Nouri and Marshall, 2006), although in partial seizures, autonomic symptoms often go undetected (Devinsky, 2004).

Studies also suggest interictal autonomic disturbances, mostly showing enhanced sympathetic cardiovascular tone (Frysinger et al., 1993, Devinsky et al., 1994, Faustmann and Ganz, 1994). Changes in parasympathetic heart rate modulation resulting in lower heart rate variability (HRV) have been noticed in temporal lobe epilepsies (Ansakorpi et al., 2000, Ansakorpi et al., 2002, Ansakorpi et al., 2004, Ronkainen et al., 2006) and generalized epilepsies (Harnod et al., 2007, El-Sayed et al., 2007). Anti-epileptic drug therapy, specifically carbamezapine may also influence cardiovascular autonomic functions (Tomson et al., 1998, Ansakorpi et al., 2000).

The mortality rate among people with epilepsy is 2–3 times higher and the risk of sudden death is 24 times greater than in the general population (Ficker et al., 1998). Sudden unexplained death in epilepsy subjects (SUDEP) accounts for deaths in about 2% of population based cohorts with epilepsy and in 18–25% subjects with more severe intractable epilepsy (Walczak, 2003).

The prevailing hypothesis regarding SUDEP involves seizure-induced cardio-respiratory disturbances mediated by the autonomic nervous system (Nashef et al., 1996, Rocamora et al., 2003). It has been proposed that imbalance of sympathetic and parasympathetic cardiovascular activity is a potential cause of SUDEP. It has also been postulated that reduced controls in autonomic nervous system in refractory seizure disorders may be the likely cause for SUDEP (Massetani et al., 1997, Ansakorpi et al., 2000). Among the other causes, some studies have identified anti-epileptic drug (AED) therapy, especially polytherapy as a risk factor independent of seizure control (Nilsson et al., 1999, Walczak et al., 2001, Walczak, 2003), along with frequent dose changes and high serum concentrations of carbamazepine (Nilsson et al., 2001). Other studies have however, not been able to find any specific association between SUDEP and particular AED therapy and hypothesized that SUDEP was linked more to the severity of epilepsy rather than AEDs (Leestma et al., 1997).

Keeping in mind the strong association between cardiovascular autonomic dysfunction and SUDEP and how the latter was linked to seizure severity, we wanted to study autonomic functions in subjects with intractable and well-controlled partial epilepsies. There is only one previous study, in which autonomic functions were compared between well controlled and intractable subjects with temporal lobe epilepsies (Ansakorpi et al., 2000). We hypothesized that the autonomic functions in subjects with intractable epilepsy would be different from those with well-controlled partial epilepsies, irrespective of localization of seizure foci. This is the first study in which heart rate variability, a complete battery of autonomic functions tests and neuropsychological questionnaires are used to compare autonomic and psychological status in subjects with refractory and well-controlled partial epilepsy.