Sudden death in epilepsy, surgery, and seizure outcomes: The interface between heart and brain

EPILEPSY SURGERY AND SUDEP RISK

The above findings make it reasonable to postulate that recurrent uncontrolled seizures may lead to significant cardiac changes—namely, arrhythmias—which may then lead to a higher risk of SUDEP. Successful epilepsy surgery, the treatment of choice for uncontrolled partial epilepsy, would eliminate seizures and would thus be expected to reduce SUDEP risk.

Several studies support this hypothesis. Reductions in all-cause mortality and in SUDEP following successful epilepsy surgery have been observed when patients who became seizure-free after surgery were compared either with patients who had ongoing postoperative seizures or with patients with intractable epilepsy who did not undergo epilepsy surgery.^11,24 In one study with a mean follow-up of 3.82 years, no deaths occurred among 199 patients who were seizure-free following epilepsy surgery, whereas there were 11 deaths—including 6 cases of SUDEP—among 194 patients who had persistent seizures following epilepsy surgery.¹¹ A separate study compared 202 patients who underwent epilepsy surgery with 46 patients with medically treated intractable epilepsy over a mean follow-up period of greater than 5.7 years.²⁴ In this study, death occurred in only 7% of the surgical patients compared with 20% of the medically treated patients, which suggests that epilepsy surgery (or lack thereof) may be an independent predictor of mortality. Favorable outcome was linked closely to seizure control, as 81% of the patients who died had 2 or more seizures per year at last follow-up, compared with only 47% of survivors in the overall cohort.²⁴

Complete seizure resolution—not just reduction—seems necessary for SUDEP risk reduction

In our experience at the Cleveland Clinic Epilepsy Center, we have found that a reduction in seizure frequency following epilepsy surgery is not enough to eliminate SUDEP risk—complete freedom from seizures is required. Of 37 SUDEP cases identified so far in a cohort of 3,481 patients evaluated in our epilepsy monitoring unit between 1990 and 2005 (Jehi et al, in preparation), 7 patients had undergone epilepsy surgery. None of these 7 patients was seizure-free at the time of death; four had a greater than 50% reduction in seizure frequency. No cases of SUDEP occurred in patients who were seizure-free after surgery.

Our findings mirror earlier results reported by Sperling et al,¹¹ who also found that epilepsy surgery improves mortality only when seizures resolve completely, not when they merely “improve.” It seems plausible, therefore, that elimination of seizures postoperatively eliminates the risk for the several seizure-related cardiac arrhythmogenic changes discussed above, thereby eliminating the risk for the series of events that eventually leads to SUDEP.

A role for stabilized baseline autonomic control?

Alternatively, some data suggest that the “autonomic” impacts of epilepsy surgery may extend beyond the immediate seizure-related manifestations to the baseline interictal period in epilepsy patients. One study found that surgery for temporal lobe epilepsy is followed by a reduction of sympathetic cardiovascular modulation and baroreflex sensitivity.²⁵ The authors proposed that this finding may be attributable to decreased influences of interictal epileptogenic discharges on brain areas involved in cardiovascular autonomic control. These researchers continue to postulate that surgery for temporal lobe epilepsy seems to stabilize cardiovascular control in epilepsy patients by reducing the risk of sympathetically mediated tachyarrhythmias and excessive bradycardiac counterregulation, potentially lowering SUDEP risk.²⁵

CARDIAC FINDINGS, SUDEP, AND SEIZURE OUTCOMES

Whether it is the elimination of seizure-related cardiac arrhythmias achieved by rendering patients seizure-free after surgery, or whether it is the stabilization of baseline autonomic cardiac control by reducing interictal epileptiform discharges, this line of thought assumes that the autonomic dysfunction contributing to SUDEP is caused by epilepsy and that freedom from seizures following epilepsy surgery should therefore be responsible for reducing the risk of death. An alternative hypothesis for the infrequent occurrence of SUDEP in seizure-free patients may be that seizure outcomes following epilepsy surgery and SUDEP risk are actually both governed by the same underlying biologic process. This would suggest that the same patient cohort is at a higher baseline mortality risk and in a prognostically poorer seizure outcome group following epilepsy surgery.

This idea is supported by a recent prospective study among 21 consecutive candidates for temporal lobe epilepsy surgery in which spectral analysis of heart rate variability performed preoperatively was correlated with seizure control 1 year after surgery.²⁶ The study found that patients with poor seizure outcomes (Engel class II to IV, signifying ongoing postoperative seizures) had significantly lower power in all domains of heart rate variability than did patients with favorable seizure outcomes.²⁶

In another study, heart rate was recorded in 16 patients before and after temporal lobe epilepsy surgery, and sympathetic and parasympathetic cardiac modulation was determined as powers of low-frequency (LF, 0.04–0.15 Hz) and high-frequency (HF, 0.15–0.5 Hz) heart rate oscillations.²⁷ The LF/HF ratio was calculated as an index of sympathovagal balance. Cardiac MIBG uptake was measured with MIBG single-photon emission computed tomography and compared with control data. Baseline sympathetic LF power and LF/HF ratio were higher in patients who eventually had persistent seizures than in those who became seizure-free. Following surgery, both measures decreased in seizure-free patients but increased in patients with persistent seizures. MIBG uptake was lower in patients than in controls and even lower yet in patients who had persistent seizures. In this subgroup, MIBG uptake declined further after surgery.

Essentially, both of the above studies^26,27 demonstrate findings of autonomic cardiac abnormalities that predated epilepsy surgery and reliably predicted the eventual surgical outcome in terms of seizure continuance. This suggests that “poor candidates” for epilepsy surgery—ie, those with lower chances of achieving seizure freedom with surgery—may a priori have a higher SUDEP risk. A possible explanation for these findings may be epileptogenic zones, including the insula and other components of the central autonomic network, or molecular/genetic diffuse abnormalities that extend beyond a limited surgically removable seizure focus and involve the heart, increasing the risk for cardiac conduction abnormalities.

CONCLUSIONS

SUDEP is the most common cause of death in epilepsy patients. A significant body of literature suggests that a cardiac mechanism contributes to its occurrence. Although the exact relationship between seizure outcomes following epilepsy surgery and SUDEP risk is still being investigated, it is accepted that seizure control correlates with reduced mortality. Cardiac changes and autonomic dysregulation seem to be at the “heart” of the problem.