Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure‐induced brain abnormalities and behavioral dysfunction

Abstract

A recent article by Farrell et al. characterizes the phenomenon, mechanisms, and treatment of a local and severe hypoperfusion/hypoxia event that occurs in brain regions following a focal seizure. Given the well-established role of cerebral ischemia/hypoxia in brain damage and behavioral dysfunction in other clinical settings (e.g., stroke, cerebral vasospasm), we put forward a new theory: postictal hypoperfusion/hypoxia is responsible for the negative consequences associated with seizures. Fortunately, inhibition of two separate molecular targets, cyclooxygenase-2 (COX-2) and l-type calcium channels, can prevent the expression of postictal hypoperfusion/hypoxia. These inhibitors are important experimental tools used to separate the seizure from the resulting hypoperfusion/hypoxia and can allow researchers to address the contribution of this phenomenon to negative outcomes associated with seizures. Herein we address the implications of this postictal stroke-like event in acute behavioral dysfunction (e.g., Todd's paresis) and sudden unexpected death in epilepsy (SUDEP). Moreover, anatomic alterations such as increased blood-brain barrier permeability, glial activation, central inflammation, and neuronal loss could also be a consequence of repeated hypoperfusion/hypoxic events and, in turn, underlie chronic interictal cognitive and behavioral comorbidities (e.g., memory deficits, anxiety, depression, and psychosis) and exacerbate epileptogenesis. Thus these seemingly disparate and clinically important observations may share a common point of origin: postictal hypoperfusion/hypoxia.

Seizure‐induced microvascular injury is associated with impaired neurovascular coupling and blood–brain barrier dysfunction

“…Conversely, despite the seizure‐induced neurovascular decoupling, we never observed tissue oxygenation below the normoxic range (>20 mm Hg) during recurrent seizures in vivo. These results are in apparent contradiction to previous studies reporting local postictal hypoxia and vasoconstriction with optical methods (for review, see Suh et al). This discrepancy could be explained by the lower spatial resolution (~60 μm) of the Clark‐style microelectrodes used in our study, by the different models of epileptogenesis, or by the use of the open window technique and perfusion with gassed aCSF.…”

“…Seizure‐induced capillary constriction was accompanied by loss of mitochondrial integrity in pericytes, highlighting the role of energy metabolism in microvascular injury. Our findings may help understand the mechanisms behind the postictal microcirculatory hypoperfusion underlying behavioral and cognitive symptoms associated with seizure disorders …”

“…The balance between metabolic demands and perfusion during seizures remains a matter of debate, with some studies showing that blood supply meets metabolic demands, whereas others suggesting the contrary . More recently, postictal hypoperfusion was highlighted as the potential link between seizures and neurological comorbidities in epilepsy . We thus examined the potential effects of neurovascular decoupling on tissue oxygenation, using Clark‐style pO 2 microelectrodes located adjacent to the responding arterioles (Figure C, n = 4).…”

“…42 More recently, postictal hypoperfusion was highlighted as the potential link between seizures and neurological comorbidities in epilepsy. 24,25 We thus examined the potential effects of neurovascular decoupling on tissue oxygenation, using Clark-style pO 2 microelectrodes 43 located adjacent to the responding arterioles ( Figure 6C, n = 4). Consistent with previous reports, 44 individual seizures induced a characteristic biphasic pO 2 response: a rapid decrease at seizure onset (the "initial dip") followed by a gradual increase that far exceeded the preseizure pO 2 levels (the "overshoot").…”

“…19 Seizures were reported to compromise stimulusinduced vascular reactivity, 20,21 and tissue oxygenation around the epileptic focus 22 and in deep cortical layers. 23 Moreover, several studies implicate postseizure hypoxia and vasoconstriction in seizure-related memory and behavioral deficits 24,25 and point to pericytelike mural cells as the mediators of capillary constriction. 26 This is in line with a recent study showing a correlation between mural cell remodeling, vascular pathology, and seizure severity by monitoring pericytic coverage in vivo over the course of several days after status epilepticus.…”