There are lots of sudden unexplained death in patients with epilepsy in clinical practice, and no evidence of epileptic seizures before death presents in some patients. So far, the argument on the relationship between epilepsy and sudden death continue until now. A study of 22 cases of SUDEP revealed that both hot shock protein and immediate early gene increased significantly in the SUDEP group, while remained normal in the non-epileptic group or sudden cardiac death group [11]. These results have implied that epileptic patients had cerebral dysfunction even before sudden death, and the dysfunction becomes a pathological basis of SUDEP. The investigation of death cases (including epileptic sudden death cases) showed that the sudden unexpected death in patients with epilepsy was 3.5 to 8 times than that in normal control group [12, 13], suggesting that SUDEP is associated with epilepsy. Because the cause of SUDEP still remains unclear, the pathological examination is necessary for the patients to reveal the enigma. Furthermore, the risk factors would be analyzed to discover the etiology of SUDEP.
Pathological characteristics of SUDEP
Cerebral pathology
The brain sections of our eleven cases showed significant brain edema with unknown reasons. CT scan of brain has shown that epileptic seizure may lead to brain edema, and brain edema may last for weeks to months [14]. However, another study showed only two of 107 SUDEP cases had seizures several hours before death [15], which did not support the hypothesis that epileptic seizure caused brain edema. In our study, death occurred after a seizure in eight patients; therefore, brain edema in pathological examination might be induced by epileptic seizure. However, brain edema caused by the metabolism termination after death cannot be excluded in the present study. All cases in our study presented brain edema, but no case showed brain hernia, significant displacement of brain or status epileptic caused by brain edema. Therefore, brain edema is not considered as a cause of SUDEP.
Loss of neurons was found in three cases. The exact incidence of neuronal loss and its relationship to SUDEP are unknown. Our previous study has found that neuron specific enolase, a neuronal marker, significantly increases after seizure activity, which suggests that epileptic seizures contribute to neuronal necrosis [14]. Seizures occurred before death in patients with neuronal loss, we then postulate that neuronal loss in SUDEP is associated with seizure. Researches of SUDEP animal models have revealed that dysfunction of neurons may result to lethal cardiac arrhythmia and central apnea. Therefore, loss of neuron becomes one cause of sudden epileptic death. However, seven cases in our study showed no neuronal loss; thus, other reasons could contribute to SUDEP besides neuronal loss.
Gliosis is common in SUDEP patients. Our results presented perivascular oligodendroglia, oligodendroglial clusters and Bergmann’s gliosis. However, gliosis has been also observed in the surgical specimens of non-SUDEP; therefore, gliosis is not be a cause of SUDEP.
Pulmonary pathology
Pulmonary congestion and edema, which is common in SUDEP, are the strong evidence of SUDEP. All cases in our study have presented pulmonary edema, enlarged pulmonary interstitial and alveolar hydrops on microscopic examination. It is believed that the underlying mechanism for pulmonary edema is due to the dysfunction of the central nervous system [16]. This neurogenic pulmonary edema is regarded as a possible cause of SUDEP. However, the metabolism stopping after death can also cause pulmonary edema. Therefore, we cannot draw a conclusion that pulmonary edema is a specific pathological change of SUDEP.
The pulmonary fibrosis with moderate inflammatory cell infiltration in one case show possible chronic pulmonary infection. However, the patient had no respiratory failure before death, and no severe hypoxia features after death. Then, his sudden death could not be a result of the pulmonary problem. Moreover, no similar pulmonary pathological changes were found in other SUDEP patient, thus we think the pulmonary changes might co-exist with SUDEP in this individual.
Cardiac pathology
Fatal arrhythmia is another possible cause of sudden death [17, 18]. No significant morphologic abnormality of the hearts were found in eleven patients with SUDEP. The result have suggested that the cardiac morphologic changes could not be the cause of SUDEP in the present study. Lack of the record of the electrocardiogram at the time of death, we cannot corfirm whether or not the SUDEP subjects developed fatal cardiac arrhythmia before death. But all electrocardiogram examinations were normal in follow-up before death. Therefore, it is less possible that the cardiac dysfunction induces SUDEP in our group.
Others
One case showed dearrangement of the nephric cell with immersion of inflammatory cells, suggesting possible chronic nephritis, whereas, it was not a cause of SUDEP. Of eleven cases, the hepatic configuration was normal in ten, slightly bigger than expected in one. Although two cases presented hepatic blood sinuses dilation and congestion with disorderedly arranged hepatic lobules and inflammatory cell infiltration, the hepatic changes could not explain SUDEP.
Risk factors of SUDEP
The most effective way of SUDEP prevention is to investigate risk factors. Recent study has shown that SUDEP associated factors included poor seizure control, in particular generalized tonic-clonic seizures (GTCS), absence of treatment with AEDs, polytherapy with AEDs, onset of epilepsy at a young age, long duration of epilepsy, male sex [1]. Risk factor identification can assist doctors in educating patients and family members about SUDEP, and to take some measures to reduce risk. After analyzing the clinical data in our cohort, several possible risk factors are discussed.
Sleep asphyxia
In an eleven-year investigation of sudden death of patients with epilepsy, 69% of SUDEP has died in sleep [19], another report indicates the great majority of 103 SUDEP patients in their study has died in bed [20]. In our group, four cases of eleven have also died in sleep with a prone position. Given the association between SUDEP and prone position, we can hypothesize that these cases of SUDEP may have been due to airway obstruction. The prone position may be dangerous if epilepsy patients remain immobile despite hypoxemia during the postictal period. These studies have showed that SUDEP is prone to occur at night, so the asphyxia during postictal confusion might be a possible risk factor of SUDEP.
Trepidation and emotional disturbance
It is supported in clinics that trepidation and emotional disturbance can induce epileptic seizures. Five SUDEP cases in our study have suddenly died during trepidation or after quarreling with others. The results suggest that trepidation and emotional disturbance are probably the risk factors for SUDEP. Therefore, it may reduce SUDEP by reminding the patients and their relatives to control their mood.
Antiepileptic drugs (AEDs)
Although the relationship of AEDs with SUDEP is still controversial, sub-therapeutic level of AEDs and polytherapy with more than two AEDs have been considered to be risk factors for SUDEP [21]. Phenytoin, valproate, carbamazepine, gabapentin, lamotrigine and tiagabin were rarely associated with SUDEP [18]. It is reported that the fluctuation of serum levels of carbamazepine leads to cardiac arrhythmias and vegetable neural dysfunction, which then contribute to the sudden death in epileptic patients [18]. Six cases in our study took carbamazepine, one took carbamazepine and valproate combined, this suggests that carbamazepine is possibly related to SUDEP. It is regretful that the serum levels of AED(s) had not been tested due to practical reasons; however, the overdose of AED(s) cannot explain sudden death because no AED(s) dosage was altered recently or no clinical manifestation of AEDs toxicity was presented before death. In addition, irregular AED(s) treatment is a possible risk factor for SUDEP because AEDs were terminated in two patients.
Pattern and frequency of seizure
In general, GTCS is associated with SUDEP, and at least 90% of SUDEP patients had a history of primary or secondary generalized tonic-clonic seizure [22]. 90% of these patients with GTCS or GTCS component demonstrate that SUDEP occurred easily in GTCS epilepsy. It is reported that frequent GTCS increased the risk of SUDEP [23]. However, at least 50% of patients in our study showed infrequent seizures (< 2 seizures per year), thus, our results do not support that SUDEP is a seizure-associated event.