Pathophysiology of status epilepticus

Abstract

Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

Mitochondrial diseases and status epilepticus

“…46 Seizure termination may be related to depletion of neurotransmitters and/or ATP, ionic, and/or acid/base changes, and release of adenosine or seizure-terminating peptides. 46 Seizure termination may be related to depletion of neurotransmitters and/or ATP, ionic, and/or acid/base changes, and release of adenosine or seizure-terminating peptides.…”

“…The most obvious explanations, such as bioenergetic failure and/or oxidative stress (overproduction of reactive oxygen species), cannot be the sole cause, since these are common to other mitochondrial disorders that are not associated with epilepsy or status epilepticus. 46,47 An additional possibility is that an immunemediated component of mitochondrial epilepsy drives continuing seizure activity. 11 Mitochondrial abnormalities that follow bioenergetic failure and oxidative stress include the inability to maintain calcium and other ionic gradients, eventually leading to opening of the mitochondrial permeability transition pore and apoptotic cell death.…”

“…Status epilepticus can be viewed as a failure of processes that terminate seizures, or reinforcement of processes that propagate seizure activity. 46 Seizure termination may be related to depletion of neurotransmitters and/or ATP, ionic, and/or acid/base changes, and release of adenosine or seizure-terminating peptides.…”

microRNA‐139‐5p confers sensitivity to antiepileptic drugs in refractory epilepsy by inhibition of MRP1

“…It has been well established that miRNAs could be used as therapeutic biomarkers due to their differential levels in epilepsy, in addition to availability in biofluids . Moreover, the participation of neuronal death in chronic epilepsy and cognitive decline has been previously reported . The further delineation of the regulatory mechanisms of miR‐139‐5p underlying refractory epilepsy is valuable, there is a great potential to translate the findings to clinical applications for patients with refractory epilepsy.…”

“…35,36 Moreover, the participation of neuronal death in chronic epilepsy and cognitive decline has been previously reported. 37 The further delineation of the regulatory mechanisms of miR-139-5p underlying refractory epilepsy is valuable, there is a great potential to translate the findings to F I G U R E 4 miR-139-5p reduces drug resistance of refractory epilepsy via downregulating MRP1. The rats were treated with sh-MRP1, miR-139-5p agomir alone or in the presence of oe-MRP1.…”