Ictal Hypoxemia in Localization-Related Epilepsy: Analysis of Incidence, Severity and Risk Factors

Lisa M. Bateman; Chin-Shang Li; Masud Seyal

Disclosures

Brain. 2008;131(12):3239-3245. 

In This Article

Discussion

In this group of patients, seizure-associated oxygen desaturation was common and occasionally severe. Pronounced desaturations occurred in some patients with partial seizures that did not progress to generalized convulsions. In a subset of seizures with simultaneous recording of oxygen saturation and ETCO2, an increase in ETCO2 occurred with every seizure that was associated with an oxygen desaturation of 85% or less. The concurrent increase in seizure-associated ETCO2 makes it likely that ictal oxygen desaturation is due to alveolar hypoventilation. In some patients, hypoventilation persisted despite increases in ventilatory rate (Fig. 4A).

Desaturations occurred most commonly with seizures of temporal lobe onset and were uncommon with extra-temporal onset seizures. Seizures occurred more commonly with right rather than left temporal onset seizures. Both the duration of the seizure and electrographic evidence of contralateral spread appeared to influence the degree of desaturation.

Our data suggest that severe desaturations are seen more commonly with seizure spread to the contralateral hemisphere. The descending pathways from limbic areas to the brainstem respiratory centres are primarily ipsilateral (Hopkins and Holstege, 1978). Therefore, seizure-related bilateral impairment of these descending pathways may be a requisite for pronounced respiratory inhibition. There is evidence for significant projections from limbic regions to brainstem areas involved in control of respiratory activity. There are ipsilateral direct projections from the central nucleus of the amygdala to the pontine and medullary tegmentum in the cat (Hopkins and Holstege, 1978). Structures receiving these descending influences include the nucleus of the solitary tract that has neurons projecting to the phrenic motor pool, the parabrachial pontine region that is involved in respiratory phase switching (Bassal and Bianchi, 1982) and the lateral periaqueductal grey that in turn projects to the nucleus retro ambiguous, which modulates upper airway activity and abdominal respiratory muscles (Holstege, 1989). Physiological studies indicate that the hippocampus also influences breathing. Hippocampal neurons include cells that have phase-locked activity with the respiratory cycle (Frysinger and Harper, 1989). Stimulation of the hippocampus entrains the respiratory rhythm (Ruit and Neafsey, 1988). Hippocampal activity is increased before the termination of apnoea, indicating a role in resumption of breathing (Poe et al., 1994).

Obstructive and mixed apnoeas were observed less commonly than central apnoeic events in our group of patients. In a rat model of penicillin-induced seizures, there was reduced activity in the vagal and hypoglossal nerves following a decrease or cessation of phrenic nerve activity. These changes were consistent with seizure-related obstructive apnoea followed by central apnoea. The central apnoeas were profound and could not be reversed by augmentations in ventilatory drive from increasing carbon dioxide (St-John et al., 2006).

Seizure-related arterial PCO2 increases are likely higher than values indicated during ETCO2 recordings. The ETCO2 is lower than arterial PCO2 by 2-4 mm Hg and the capnograph recordings are susceptible to seizure-related displacement and blockage of the nasal prongs, resulting in lowered ETCO2 values. Ictal ETCO2 values > 50 mm Hg were seen with seven of 19 seizures. These data suggest a mechanism for seizure-related cardiac dysfunction. In healthy young adults, acute hypercapnia to 7 kPa (52.5 mm Hg) resulted in prolongation of the QTc interval and QT dispersion (Kiely et al., 1996). This increased QT dispersion, reflecting differences in regional myocardial repolarization, represents a putative substrate for arrhythmia (Kiely et al., 1996). In a sheep model of bicuculline-induced epileptic sudden death, all animals had central apnoeas (Johnston et al., 1997). Animals dying early had pronounced elevations of PaCO2 and drops in PaO2 compared with surviving animals. Hypercarbia contributed to death in these animals. Malignant arrhythmias were not seen and sinus tachycardia persisted until death (Johnston et al., 1997).

Ictal tachyarrhythmia is the most commonly reported arrhythmia associated with seizures (Blumhardt et al., 1986; Maromi et al., 2004). This was also observed in our study, with increases in heart rate above 100 b.p.m. persisting for a median of 70 s. Pronounced tachycardia to 180 b.p.m. occurred with some seizures. Ictal bradycardia and asystole are rare (Rocamora et al., 2003) and in our series, occurred with one seizure that was associated with oxygen desaturation to below 50%.

The patient BMI was associated only with the more severe desaturations accompanying partial seizures, suggesting that a high BMI may exacerbate the level of ictal desaturation in some patients. However, pronounced ictal desaturations did accompany partial seizures in patients with a BMI in the normal range. Ictal oxygen desaturations are more likely to occur in males than in females for reasons that remain unclear.

There was considerable variability in the anti-epileptic drug regimens used by our patients on admission to the epilepsy-monitoring unit. Only 11 patients were on monotherapy. Polytherapy with a variety of anti-epileptic drugs in the majority of patients precluded any determination of whether a particular anti-epileptic drug or class of drugs might influence the degree of ictal-associated hypoxemia. Anti-epileptic drug levels were not monitored; however, since anti-epileptic drugs were reduced or stopped on admission the anti-epileptic drugs' load would be decreased at the tail-end of the monitoring period. We found no difference in the desaturation nadirs between the first and last seizure of each patient. This suggests that the anti-epileptic drug load did not influence the severity of seizure-related oxygen desaturation.

Our data indicate that there is a high probability of recurrent ictal desaturations in a patient who has had a seizure-related desaturation below 85%. Patients with medically refractory epilepsy who have severe seizure-related hypoxemia and hypercapnia identified in epilepsy-monitoring units may be at increased risk for SUDEP. The pursuit of epilepsy surgery to control seizures may be of benefit in this patient population. This would require further study, however, as the role of epilepsy surgery in reducing the risk of SUDEP is still questioned (Ryvlin and Montavont, 2008). Other therapeutic measures to ameliorate hypoxemia in patients with refractory partial seizures could include the use of selective serotonin reuptake inhibitors. Serotonin is implicated in modulating the brainstem respiratory network (Richter et al., 2003). In DBA/2 mice with audiogenic seizures, there is seizure-related respiratory arrest. Fluoxetine reduced respiratory arrest at doses that did not stop seizures (Tupal and Faingold, 2006). Cardiac pacing has been required in patients with ictal bradycardia and asystole (Rugg-Gunn et al., 2004). Nocturnal supervision, including regular checks and the use of listening devices, may be protective against SUDEP (Langan et al., 2005). The potential benefits of other interventions, such as home pulse oximetry monitoring with appropriate alarms or continuous positive airway pressure devices, may be worth evaluating in patients with documented severe seizure-associated oxygen desaturations who are awaiting potentially curative therapies.

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