Is SUDEP Risk Increased in Insular Epilepsy?
Nuria Lacuey, MD, and Samden Lhatoo, MD, FRCP
The intimate role played by the insula in autonomic control and modulation renders it suspect in sudden unexpected death in epilepsy (SUDEP) pathophenomenology. There are 2 possible types of insular involvement in SUDEP: first, as the epileptogenic zone from where the fatal seizure arises, or second, as the structure, whether damaged or intact, critical to the genesis of autonomic, and/or respiratory seizure features, to which the seizure discharge secondarily spreads. The relative rarity of insular epilepsy accounts for the scant knowledge of SUDEP risk in this condition. Similarly, although the insula is part of the epileptogenic zone in some temporal, frontal, and opercular epilepsies, these too are relatively undercharacterized syndromes.
Among the few reported cases of insular epilepsy related to SUDEP is an SEEG proven case of left insular epilepsy with sleep-related seizures with hyperkinetic automatisms and anterosuperior insular seizure onset. The patient refused resective surgery and died of SUDEP 2 years after assessment.59 MORTality in Epilepsy Monitoring Unit Study (MORTEMUS), a study of SUDEP or near SUDEP in the epilepsy monitoring unit, reported 2 insular cases associated with near-SUDEP.60 Both patients experienced cardiac/cardiorespiratory compromise in the peri-ictal period of seizures with loss of awareness. One 10-year-old female patient had cardiorespiratory arrest in the postictal period and cardiopulmonary resuscitation (CPR) was instituted successfully within a minute of seizure end. The other was a 54-year-old female patient who suffered ictal asystole and underwent CPR. Given current knowledge of the relatively benign, self-limited nature of ictal asystole, the resuscitation instituted within a minute may have been superfluous, and the near-SUDEP label debatable.
The contribution of the insula to seizure-related cardiorespiratory dysfunction and subsequent SUDEP is worthy of discussion. The insula is known to play a central role in the regulation of cardiac functions,61 and a few case reports have suggested that seizures of insular lobe origin, or seizures that spread to the insula, might provoke bradycardia,62,63 an atrioventricular block,64 or asystole.65 Both left and right insular damage are known to affect prognosis and mortality in stroke.66,67 Insular damage, in epilepsies emanating outside this structure, may lead to potentially fatal scenarios. Dysfunctional brain networking, with high insular connectivity, is known to exist in high SUDEP-risk patients.68 Direct structural damage to the insula, whether seizure induced or iatrogenic, has been associated with SUDEP in 2 intractable epilepsy cases.69 In a 33-year-old patient with left hemibody sensory and generalized convulsive seizures, PET hypometabolism in the left posterior parieto-opercular region, and depth electrodes demonstrating unequivocal fast frequency (gamma) discharges in the left posterior insula (Figure 8), posterior insular resection failed to produce seizure freedom. Serial assessments of interictal heart rate variability (HRV) demonstrated significant HRV decrease in the postsurgical period compared with the presurgical period; notably, he had marked sinus tachycardia in the postictal period that continued for more than 25 minutes. The insular resection may have contributed via changes in HRV to a tendency for ventricular arrhythmia and subsequent SUDEP, 2 years after surgery. In a second case, similarly intractable in the postsurgical period, milder left inferior insular damage was noted secondary to a temporal lobectomy. However, increasing HRV was noted over a 3-year period, indicating increased vagal tone and a confirmed tendency to postictal bradycardia. The SUDEP was confirmed 21 months after his last assessment with possible contribution of autonomic dysfunction as described.
Figure 8.  A, Postoperative MRI FLAIR sequence shows evidence of a left posterior temporo-insular resection cavity with surrounding gliosis in a patient with later SUDEP. B, Heart rate plots show ictal sinus tachycardia, followed by sustained postictal sinus tachycardia lasting at least 25 minutes after a nonfatal generalized convulsive seizure. C, Heart rate time and frequency domain parameters calculated during the presurgery (2006) and postsurgery (2011) epilepsy monitoring unit (EMU) evaluations and the results from generalized estimating equation (GEE) analysis. D Extent of insular resection and damage, after 3-dimensional reconstruction of pre- and postoperative MRI is delineated in red. MRI indicates magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; SUDEP, sudden unexpected death in epilepsy; MNN, mean of normal to normal heart beats; SDNN, standard deviation of normal to normal heart beats. Whereas it is easy to speculate on insular contributions to SUDEP, it is less easy to extrapolate anecdotal evidence to larger populations. Thus, cohort studies, with appropriate multimodal seizure assessments, are required to resolve these issues.
In conclusion, insular epilepsy can be difficult to recognize. Surgical treatment of insular epilepsy has it challenges but can be addressed with diligent clinical and electrophysiological investigations. Surgical approaches have to be weighted carefully but can be very successful in treating insular epilepsy.