Pathophysiology of Status Epilepticus Revisited

Abstract

Status epilepticus occurs when a seizure lasts more than five minutes or when multiple seizures occur with incomplete return to baseline. SE induces a myriad of pathological changes involving synaptic and extra-synaptic factors. The transition from a self-limiting seizure to a self-sustaining one is established by maladaptive receptor trafficking, whereby GABA_A receptors are progressively endocytosed while glutamatergic receptors (NMDA and AMPA) are transported to the synaptic membrane, causing excitotoxicity and alteration in glutamate-dependent downstream signaling. The subsequent influx of Ca²⁺ exposes neurons to increased levels of [Ca²⁺]i, which overwhelms mitochondrial buffering, resulting in irreversible mitochondrial membrane depolarization and mitochondrial injury. Oxidative stress resulting from mitochondrial leakage and increased production of reactive oxygen species activates the inflammasome and induces a damage-associated molecular pattern. Neuroinflammation perpetuates oxidative stress and exacerbates mitochondrial injury, thereby jeopardizing mitochondrial energy supply in a state of accelerated ATP consumption. Additionally, Ca²⁺ overload can directly damage neurons by activating enzymes involved in the breakdown of proteins, phospholipids, and nucleic acids. The cumulative effect of these effector pathways is neuronal injury and neuronal death. Surviving neurons undergo long-term alterations that serve as a substrate for epileptogenesis. This review highlights the multifaceted mechanisms underlying SE self-sustainability, pharmacoresistance, and subsequent epileptogenesis.

Keywords: epileptogenesis; pathophysiology; pharmacoresistance; status epilepticus.

Figure 1

Schematic representation of the main models used to study seizure activity. In vivo models of seizures are primarily rodents, in which seizures can be divided into induced or genetic. Seizures are more commonly induced chemically by using agents that promote glutamatergic neurotransmission, either directly, such as KA, or indirectly, such as pilocarpine, or electrically by electrode stimulation of the hippocampus. In vitro preparations are predominantly of brain slices obtained from rodent models in which epileptiform activity can be induced by ionic or pharmacological means.

Figure 2

Schematic of hippocampal dentate gyrus circuitry before and after epileptogenesis: (a) Granule cells project mossy fibers to pyramidal neurons in area CA3, interneurons in the dentate hilus, as well as mossy cells. Mossy cells excite basket cells, which then provide feedback inhibition to granule cells; (b) During epileptogenesis, deafferentation of basket cells in the dentate hilus due to mossy cell death leads to disinhibition of granule cells and is associated with increased neurogenesis and increased mossy fiber sprouting from granule cells and ectopic granule cells resulting in increased connectivity to CA3 pyramidal cells and recurrent excitatory collaterals to granule cells forming monosynaptic interconnections to granule cells in place of the synaptic pathways formerly originating from mossy cells. Mossy fiber sprouting also forms connections to pyramidal cells in CA2 and CA1; (+) and (−) indicate excitatory (glutamatergic) and inhibitory (GABAergic) synapses, respectively.

Figure 3

Schematic representation of the main pathophysiological mechanisms behind status epilepticus. Excessive excitation and activation of glutamate receptors cause excessive influx of Ca²⁺ and efflux of K⁺ followed by internalization of GABAergic receptors and synaptic presentation of glutamatergic receptors, leading to a cycle of synaptic potentiation which is propagated by the release of inflammatory mediators that induce astrogliosis which then stimulates the release of those inflammatory mediators and the release of ET1 which increases BBB permeability and the activation of MMPs. BBB disruption permits the infiltration of immune cells into the brain and propagation of the inflammatory cycle, as well as excitotoxicity through albumin binding to astrocytic receptors. Neurovascular and neurometabolic decoupling associated with seizure prolongation compromises the availability of energy substrates required for homeostatic pump activity and physiologic neurotransmission, exacerbating excitotoxicity and excessive Ca²⁺ influx, which disrupts mitochondrial function and ATP production. This is associated with increased ROS production, which mediates several cytotoxic sequelae, including potentiation of mitochondrial permeability transition pore opening, thereby potentiating Ca²⁺-mediated mitochondrial membrane depolarization leading to further ATP depletion. The aforementioned mechanisms culminate in activated neuronal death pathways and subsequent death of affected neurons by necrosis and apoptosis.