PGES and HR(V)
We did not find a significant difference in either periictal HR or HRV change between PGES+ and PGES− seizures. We assessed PGES-related HR(V) changes in the immediate postictal phase (within 30 min after seizure end). A small pilot study of six patients and eleven CS suggested that PGES duration is associated with long-term (2 h) effects on autonomic control: a higher electrodermal response and a decrease of HF activity were found indicating sympathetic hyperactivation and parasympathetic suppression (Poh et al., 2012). We could not confirm these findings. As indicated by Figure 3 no trend toward HR increase is seen in our study, even in those with PGES of long duration. It is questionable whether the differences between acute and long-term effects of CS with PGES on autonomic balance can be attributed solely to PGES. In all ictal recordings of SUDEP, signs of cardiac instability appeared within minutes after seizure end, and cardiac function irreversibly ceased within 30 min (Purves et al., 1992; Bird et al., 1997; Lee, 1998; McLean & Wimalaratna, 2007; Bateman et al., 2010; Lhatoo et al., 2010; Tao et al., 2010). We therefore believe acute postictal HRV changes are more relevant to SUDEP pathophysiology.
Figure 3. The difference in HR between the first postictal and the last preictal minute and PGES duration in 50 people with CS. No significant relationship was found between PGES duration and periictal HR change: p = 0.62.
Download figure to PowerPoint
The frequency of PGES is highly variable, with a reported prevalence of 27% (Semmelroch et al., 2011), 40% (Surges et al., 2011), 65% (Lhatoo et al., 2010), and 74% in our study. In children, it seems to be a rarer phenomenon: six (8%) of 200 seizures in children (Kim et al., 2006). This age effect may also explain the relative low prevalence of 27% reported in one study (Semmelroch et al., 2011), as it included children (>8 years old) and adults.
Seizure type is another possible confounder, with a higher prevalence of PGES found after CS than complex partial seizures (Surges et al., 2011). This may in part explain the lower prevalence in the pediatric PGES study, as a mixture of both focal and generalized seizures were studied (Kim et al., 2006).
For this reason, we confined this study exclusively to CS. Another possible confounder is sleep, given the strong relationship between PGES and sleep we found. Our study population had a relatively high percentage (68%) of seizures that started during sleep, which might explain the relatively high prevalence of PGES. The wide variation in prevalence of PGES might also be attributed to the use of different definitions regarding the minimum duration of the PGES: >2 s (Seyal et al., 2012) versus >1 s (Surges et al., 2011) or unspecified (Lhatoo et al., 2010; Semmelroch et al., 2011). To avoid potential interpretation bias in our study, the EEG studies were assessed independently by two observers, resulting in a good interobserver agreement. An additional analysis using quantitative EEG parameters was performed, confirming our findings. Therefore, we believe the overall conclusions of this study are valid.
A high frequency of CS is the strongest risk factor for SUDEP (Hesdorffer et al., 2011), yet even in these people, only a small minority will die. Presumably a complex interplay of various clinical and periictal factors determines whether SUDEP will occur. PGES is the most frequently reported pathomechanism in the few ictal recordings of SUDEP (Purves et al., 1992; Bird et al., 1997; Lee, 1998; McLean & Wimalaratna, 2007; Bateman et al., 2010; Lhatoo et al., 2010; Tao et al., 2010). It usually starts immediately after seizure end and is thought to precede cardiac asystole and apnea. It is, however, important to stress that the precise sequence of events is uncertain, since all reported cases lacked pulse oximetry measurements and only a few cases included video assessment of the respiratory excursions (Bateman et al., 2010; Lhatoo et al., 2010; Tao et al., 2010).
Several theories exist regarding the etiology of PGES (Purves et al., 1992; Bird et al., 1997; Lee, 1998; McLean & Wimalaratna, 2007; Bateman et al., 2010; Lhatoo et al., 2010; Tao et al., 2010). In accordance with previous work we did not find a relationship between seizure duration and PGES, which renders it unlikely that PGES results from neuronal exhaustion (Lhatoo et al., 2010; Semmelroch et al., 2011; Surges et al., 2011; Seyal et al., 2012). It has also been postulated that PGES causes respiratory or cardiac dysfunction (Lhatoo et al., 2010; Surges et al., 2011). We did not, however, find substantial changes in measures of cardiac autonomic instability in PGES. Our study lacked periictal blood pressure assessments so we cannot exclude the possibility that PGES is caused by systemic hypotension as seen in syncope (Wieling et al., 2009). It is unlikely, however, that seizure-induced hypotension occurred in our cases given the fact that PGES was not accompanied by HR changes. If hypotension results from syncope, then hypotension is likely to coincide with either bradycardia/asystole or compensatory tachycardia (van Dijk et al., 2009).
Recently, an association between PGES and severe ictal respiratory hypoxemia was found (Seyal et al., 2012). End-tidal CO2 concentration was also elevated in people with PGES (Seyal et al., 2012). These respiratory changes were already apparent during the ictal phase.
Therefore, as in our study, PGES is unlikely to trigger either postictal respiratory or postictal cardiac dysregulation. Instead, PGES may represent the direct effect of seizure-induced hypoxia on the brain or may result from excessive neuronal inhibition in response to severe hypoxemia. CS with PGES were more likely to arise from sleep. This finding may explain the relationship between SUDEP and sleep; most SUDEP cases are found in or by the bed and a history of nocturnal seizures was found to increase SUDEP risk (Hitiris et al., 2007; Lamberts et al., 2011).
The mechanisms underlying the association between PGES and sleep require further study. It has been postulated that in parallel with sudden infant death syndrome, sleep- and seizure-related dysfunction of serotonergic neurons may facilitate respiratory depression and hereby SUDEP (Richerson & Buchanan, 2011). Dysfunction of these midbrain neurons results in a lack of respiratory increase and a diminished arousal response to hypoxemia (Buchanan & Richerson, 2009). The association between PGES and sleep could thus be explained by a higher frequency of ictal hypoxemia following CS. It is not known, however, whether CS that arise from sleep are associated with more pronounced hypoxemia. An earlier study of seizure-related respiratory dysfunction did not find a higher frequency of ictal hypoxemia during sleep, but this study predominantly analyzed partial seizures (Bateman et al., 2008). It would therefore be of great interest to explore further the association between sleep, PGES, and respiratory measures. Alternatively, excessive neuronal inhibition may explain the relationship between PGES and sleep, since sleep is associated with the activation of inhibitory networks.
Age at onset was higher in those with PGES than in controls. As we did not find a relationship with either age at time of EEG or duration of epilepsy, it seems likely that this is related to etiology. It has previously been suggested that PGES was more frequently seen in children with idiopathic, cryptogenic, or acute symptomatic aetiologies (“normal” brains) than in those with remote or progressive symptomatic etiologies (“abnormal” brains) (Kim et al., 2006). We could not confirm these findings, but it should be noted that most of our cases had a symptomatic etiology and only a few cases had cryptogenic or idiopathic etiologies.
In conclusion, our findings suggest that PGES is not associated with measures of autonomic instability but seems more prevalent in CS arising from sleep. This would support the notion that PGES itself is not a trigger of postictal cardiac dysfunction. Instead, it could be a consequence of severe ictal hypoxemia as has recently been suggested (Seyal et al., 2012). The higher age of seizure onset found in those with PGES might reflect the effect of different epilepsy etiologies on PGES development.