New Insights Into Postictal Paresis: An Epilepsy-Associated Phenomenon That may not be as Benign as Long Thought

Commentary

Postictal Behavioural Impairments are Due to a Severe Prolonged Hypoperfusion/Hypoxia Event That is COX-2 Dependent.

Farrell JS, Gaxiola-Valdez I, Wolff MD, David LS, Dika HI, Geeraert BL, Wang XR, Singh S, Spanswick SC, Dunn JF, Antle MC, Federico P, Teskey GC. Elife 2016;22;5;pii e19532.

Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable.

Postictal paresis commonly occurs in epilepsy and has long been thought of as a benign manifestation of the disease process. This phenomenon is often referred to as Todd's paresis after the Irish neurologist who is typically credited with first characterizing it (1). Despite being described nearly 200 years ago, the mechanism(s) underlying postictal paresis remain unknown (1). Prior to the preclinical article described below, a number of competing hypotheses have been proposed to explain postictal paresis, each with its own historical origin. Contemporaries of Todd such as John Hughlings Jackson (for whom the ‘Jacksonian March’ is named) described an exhaustion of the nervous tissue, while Sir William Richard Gowers (namesake of the ‘Gower's sign’) referred to a compensatory inhibition of the affected tissue (1). Even in modern reviews, these ideas have remained in vogue, although more recently it has been suggested that a reduction in blood flow could also explain the phenomenon (2). Until now, the lack of basic science investigations into postictal paresis combined with a small number of case reports had created a confusing landscape with evidence supporting and opposing each of these hypotheses (2).

In a recent report published in eLife, Farrell and colleagues successfully demonstrated that postictal paresis is the result of a sustained cerebral hypoperfusion that occurs in the postictal state. Impressively, they observed that this mechanism occurred in a variety of animal models of epilepsy and confirmed some of their basic findings in a small series of human patients. Although this is not the first study to ascribe postictal paresis to hypoperfusion (3, 4), it is the first to rigorously establish a link between a seizure, hypoperfusion, and postictal weakness in an animal model.

In order to study postictal paresis, the authors employed state of the art experimental techniques. In particular, they used indwelling probes in the hippocampus to simultaneously measure the partial pressure of oxygen (pO₂) and blood flow in the surrounding area. Following both evoked and spontaneous seizures, they observed a profound drop in pO₂ and blood flow beginning within minutes after the seizure ended and lasting for up to 1 hour.

The authors next employed a series of pharmacological experiments to determine if the postictal hypoperfusion could be prevented and to try to disentangle the effects of the seizure itself from the subsequent hypoperfusion. Toward that end, the authors pretreated the animals with nifedipine, a calcium channel blocker. This was sufficient to limit the postictal hypoperfusion without affecting seizure severity (an important potential confound). Farrell et al. then screened a series of drugs that affect vasodilation and vasoconstriction to try to elucidate the pathway through which epileptic discharge was producing hypoperfusion and found evidence that pretreatment with inhibitors of cyclooxygenase function (i.e., with acetaminophen) produced similar results and limited postictal hypoperfusion.

Although pretreatment with either nifedipine or acetaminophen limited postictal hypoperfusion, Farrell et al. also noted important differences between these two compounds. In separate experiments, they administered the drugs immediately after seizure onset, in order to determine if they would still be capable of preventing hypoperfusion. While post seizure administration of nifedipine blocked hypoperfusion, acetaminophen did not. As such, the authors concluded that cyclooxygenase function during the seizure ultimately leads to vasoconstriction and hypoperfusion.

While their experimental evidence suggests the importance of pathways relevant to hypoperfusion, they ultimately sought to link their observation of hypoperfusion to postictal weakness. Toward that end, the authors next engaged the animals in a task of grip strength before and after a seizure and with or without nifedipine treatment. Fascinatingly, untreated animals were indeed weaker after a seizure (consistent with their model of Todd's paresis), but animals treated with nifedipine did not show a deficit. Similarly, animals pretreated with acetaminophen were also protected from weakness following a seizure. In both cases, the authors were careful to demonstrate that the seizure itself was not affected by pretreatment with either nifedipine or acetaminophen, allowing them to conclude that the postictal weakness they observed was the specific result of hypoperfusion.

Farrell and colleagues have made an important step in demonstrating a mechanism for postictal paresis. Using an animal model of the phenomenon, they were able to elucidate key signaling pathways involved in the phenomenon. Although their study is an exciting one, there remain several caveats that yet limit the clinical utility of such a study. First, their most convincing work was performed in animal models and it is premature to extend these findings into clinical practice. While nifedipine and acetaminophen are in widespread clinical use, neither is approved for the treatment of postictal paresis, and no evidence was provided that such therapies would be useful in human patients. A second caveat is that while the authors established that similar hypoperfusion occurs in a subset of human patients (8 of 10 subjects), it may not be the case that all postictal weakness can be explained by the same mechanism (3).

While caution is important whenever interpreting basic science results, the experiments presented in this paper have compelling implications for understanding epileptogenesis more generally. Hypoxic insults to the brain frequently lead to seizures and injury that can provide the substrate for subsequent epileptogenesis (5, 6). Under the paradigm that “seizures beget seizures” (7), it is not unreasonable to speculate that hypoxic insults resulting from postictal hypoperfusion might lead to tissue damage that promotes future seizures. Such a mechanism might play a role in the progressive hippocampal atrophy often seen in temporal lobe epilepsy (8). Thus, by establishing that seizures initiate COX signaling and lead to hypoxia, the work done by Farrell et al. not only explain a common neurological consequence of seizures but also raises the possibility that postictal hypoxia may be an important contributor to epileptogenesis. If this proves to be the case, the long-held belief that Todd's paralysis is a benign manifestation of seizures would likely be abandoned and new initiatives to find novel therapeutics to eliminate postictal neurological abnormalities would ensue.