Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent

Abstract

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.DOI: http://dx.doi.org/10.7554/eLife.19352.001

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

“…By studying the longitudinal changes in the hemodynamic responses to seizures, our study reveals a gradual neurovascular decoupling at both the capillary and the arteriolar level and excludes hypoxia as an immediate cause of microvascular dysfunction and cellular injury. Our findings may explain the reported disturbances in blood flow regulation and mural cell remodeling following recurrent seizures . Furthermore, our in vitro evidence of pericytic injury–associated loss of capillary response and increased microvascular permeability highlights pericyte functionality as a potential therapeutic target for 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).…”

Seven‐tesla susceptibility‐weighted analysis of hippocampal venous structures: Application to magnetic‐resonance–normal focal epilepsy

“…The abnormal vasodynamics coupled with a reduction in functional vessels might further contribute to microscopic hypoxia and ictal neurodegeneration . Thus, ongoing seizures may eventually involve structures and vasculature in the hippocampus even when the region is not implicated as a primary epileptogenic zone.…”

“…This experiment aggregates VD over the entire hippocampus. Measurement of this metric as part of a comprehensive epilepsy imaging protocol may permit us to follow and assess structural changes associated with MTLE and eventually prevent or ameliorate the progression of neuronal damage in patients via the administration of targeted pharmacotherapy …”

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…; Farrell et al . ) and many other disorders characterized as ‘dysautonomia’. These disorders are often associated with breathing disturbances, increased heart rate, decreased heart rate variability and other forms of disturbed cardiorespiratory coupling.…”