3 Timely referral to presurgical evaluation , with the view that successful curative treatment should offer the most effective protection against SUDEP. Although this conclusion is supported by studies showing higher risk of SUDEP in patients who failed surgery as compared to those who achieved seizure freedom (Sperling et al., 1999 ; Salanova et al., 2002 ; Sperling et al., 2005 ), we still lack definite proof that this difference primarily reflects the impact of epilepsy surgery, rather than preexisting biologic differences between the two groups (Ryvlin et al., 2006 ). For instance, patients failing temporal lobe surgery might have epilepsy involving extratemporal brain regions controlling cardiorespiratory functions, leading to increased risk of SUDEP (Ryvlin & Kahane, 2003 ). This hypothesis supports improving the delineation and surgical management of patients whose epileptogenic zone could represent a risk factor for SUDEP, such as the insular cortex (Ryvlin, 2006 ).

2 Patients' education to promote adherence to treatment, avoidance of seizure triggering factors (lack of sleep, alcohol, medications lowering seizure threshold, abrupt AED changes), and appropriate reaction to seizure clusters (rescue medication), missed medication (redosing), or to any other situations that could lower AEDs levels (gastrointestinal disorders, pregnancy, or prescription of other drugs such as oral contraceptive in patients treated with lamotrigine; (Devinsky, 2012 ).

1 Optimal choice of AED regimen , based on an accurate diagnosis of the epilepsy syndrome to avoid on the one hand, undiagnosed and untreated active epilepsy, and on the other hand, misclassified and mistreated idiopathic generalized epilepsy using aggravating narrow spectrum AEDs. A further and controversial issue is if specific monotherapies or polytherapy can carry an increased SUDEP risk. Regarding monotherapy, a few reports have suggested that lamotrigine and carbamazepine could be associated with a higher risk of SUDEP (Timmings, 1993 ; Langan et al., 2005 ; Aurlien et al., 2010 ). However, these findings were not confirmed by the pooled analysis of case–controlled studies discussed above (Hesdorffer et al., 2012 ). This analysis also demonstrated that the previously reported association between polytherapy and risk of SUDEP reflected higher frequency of GTCS in patients with greater number of AEDs, and vanished after adjusting for seizure frequency (Hesdorffer et al., 2012 ). In fact, a meta‐analysis of all double‐blind randomized placebo controlled trials performed in adult patients with refractory epilepsy showed that patients receiving an add‐on AED had a sevenfold lower risk of SUDEP (0.9/1,000 patient‐years) than those receiving placebo on top of their baseline AED treatment (6.9/1,000 patient‐years; Ryvlin et al., 2011 ). Although these findings cannot readily translate into clinical recommendations, they suggest that review of treatment in patients with refractory epilepsy might have a beneficial impact on the risk of SUDEP.

The strong epidemiologic and pathophysiologic link between seizures, and more specifically GTCS, and SUDEP, suggests that efforts to minimize the risk of seizures should translate into lower rate of SUDEP. A number of general recommendations for optimizing epilepsy therapy deserve to be emphasized in this context, including:

Reducing the risk of postictal respiratory failure

1 Lattice pillows have been proposed to reduce the contribution of the prone position to postictal respiratory distress and thus SUDEP (Devinsky, 2012). Although having the face down in the pillow might not necessarily result in major airways obstruction, the observation that more SUDEP patients are found prone than expected by chance, with 71% found prone in one study (Kloster & Engelskjøn, 1999), suggests that this environmental factor plays a significant role, in as much as patients in postictal coma are unable to correct their position in response to hypoxemia (Nashef et al., 1998). The impact of sleep position upon the risk of sudden infant death syndrome also emphasizes the potential role of such intervention. However, no study has evaluated the benefit of using lattice pillows in epilepsy. It would be worth comparing the impact of using lattice, standard, and no pillow upon ictal/postictal SpO 2 measurements in an epilepsy monitoring unit (EMU) setting.

2 Nocturnal supervision was found to be protective of SUDEP in one case–control study (Langan et al., 2005), a finding supported by another observational study (Nashef et al., 1995). The development of seizure‐detecting devices enable more effective night time supervision, but also raises the issue of false‐positive/false‐negative detection rates as well as that of the risk/benefit balance of such intervention on patients' quality of life. The decision to apply such measures needs to be individualized according to patient preference, seizure profile (nocturnal, generalized, frequency), and overall risk of SUDEP, with the knowledge that seizure‐detecting devices have not been demonstrated to reduce the risk of SUDEP. Although most SUDEP cases are unwitnessed, one must also be aware that the intervention of a witness does not necessarily preclude the occurrence of SUDEP, as illustrated by video recording of patients who died in the EMU while being supervised. Turning the patient from prone to recovery position during the early postictal phase might be sufficient to reverse respiratory distress in some cases, but more active resuscitation procedures are likely to be needed in others. Therefore, families aiming at organizing nocturnal supervision for a relative at significant risk of SUDEP should be educated in order to react promptly and efficiently to ictal/postictal cardiorespiratory distress.

3 Supervision in EMUs raises similar issues, despite the fact that SUDEP in EMUs are extremely rare and its contribution to all SUDEPs in society is minimal. Nevertheless, one could rightly consider that such events should not occur at all in a dedicated medical environment with staff supposedly trained to anticipate the consequences of seizures and GTCS, particularly that the latter are often promoted by tapering AEDs. Therefore, physicians and nurses face clear‐ cut responsibilities in managing SUDEP prevention in EMUs. The MORTEMUS study points to major weaknesses in the general organization of EMU safety with often inadequate supervision, especially at night. Observations from MORTEMUS support the development of safety guidelines in EMUs, with two priorities: (1) systematic monitoring of ECG and SpO 2 with appropriate alarm system in all patients undergoing long‐term video‐EEG monitoring, (2) organization of specific emergency code in EMUs, (3) education of EMU staff to quickly identify ictal/postictal cardiorespiratory distress and start appropriate cardiopulmonary resuscitation.

4 Postictal O 2 therapy is being used systematically in some EMUs, without any evidence that this procedure reduces the risk of postictal respiratory distress or SUDEP. However, in a mice model of seizure‐induced SUDEP, O 2 therapy proved extremely efficacious to prevent death (Venit et al., 2004). Although it remains difficult to extrapolate such experimental findings to humans, it appears reasonable to provide O 2 therapy in patients with postictal decreased SpO 2 or respiratory distress. Studies are also warranted of the impact of postictal O 2 therapy on various outcomes, including the duration of postictal EEG suppression and clinical state.

5 Serotoninergic drug, including selective serotonin reuptake inhibitor (SSRI), might offer a way to decrease the risk of postictal central apnea. Lower brainstem serotoninergic nuclei play an important role in the regulation of respiration (Richter et al., 2003), in particular when recurrent hypoxia leads to a specific plasticity phenomenon called long‐term facilitation (Ling et al., 2001; Mahamed & Mitchell, 2008). Abnormalities of brainstem serotoninergic nuclei have been described in sudden infant death syndrome (SIDS) (Paterson et al., 2006), as well as in mice models of SUDEP (Uteshev et al., 2010; Faingold et al., 2011a). Accordingly, fluoxetine was shown to prevent the occurrence of fatal apnea in these models (Tupal & Faingold, 2006; Faingold et al., 2011b). These experimental data prompted a retrospective study looking at the association between SSRI treatment and pulse oximetry in patients undergoing video‐EEG monitoring (Bateman et al., 2010). Ictal/postictal hypoxemia was significantly less frequent in patients receiving SSRI than in those without such treatment (Bateman et al., 2010). Two double‐blind randomized placebo‐controlled trials are underway to confirm this finding, but whatever the outcome, the relevance for SUDEP prevention remains to be shown.

6 Inhibitors of opiate and adenosine receptors might also contribute, thereby reducing the severity of postictal EEG and neurovegetative dysfunction (Shen et al., 2010). However, this therapeutic strategy carries the risk of aggravating the duration, frequency or severity of seizures, as illustrated by the proconvulsant effect of caffeine, a potent antagonist of adenosine receptors (Shapira et al., 1985). Conversely, naltrexone, an opioid receptor antagonist, is used long term in patients with addiction (Tiihonen et al., 2012), without a known effect on seizure threshold even in patients with alcohol dependence (Volpicelli et al., 1992; Krystal et al., 2001), offering a potential future avenue for SUDEP prevention.