Pathogenesis of early seizures
The early epileptic seizures have been demonstrated to be caused by local metabolic disorders and increased release of excitatory neurotransmitters, leading to the electrophysiological instability and neurotransmitter imbalance, which facilitate the onset of seizure attack.
The acute cerebral hemodynamic changes disrupt the local microenvironment, which reduces the neuronal membrane stability within the lesion, and causes excessive discharges. Ischemia and hypoxic insults are demonstrated to cause a sodium pump failure, which leads to increased intracellular Na+ and cell depolarization. When the accumulation of Na+ reaches a certain extent inside the cell, calcium channels will be activated, leading to a sudden and quick influx of Ca2+ and thus a seizure attack . In addition, neurons within the hippocampus, a region considered to play a crucial role in epileptogenesis, are also susceptible to abrupt ischemic insults and might become an epileptogenic focus . Excessive neuronal excitation is also detected within the surrounding penumbra, which may be due to the disruped blood supply and hypoxia. Besides, reperfusion injury, hemorrhage and vasospasm are all reported to increase the susceptibility to the seizure attack .
The imbalance between excitatory and inhibitory neurotransmitters is another contributor to the early seizures. In the central nervous system, the excitatory neurotransmitter glutamate and the inhibitory gamma aminobutyric acid (GABA) can be converted into each other by certain enzymes. Upon acute disruption of the hemodynamics, excitatory transmitters such as glutamate are increased, while GABA is denatured. As a result, an increased membrane excitability is induced and finally results in a seizure attack . Besides, elevated adrenaline and decreased levels of dopamine are found to impact the calcium influx and decrease the seizure threshold .
It has been reported that early epileptic seizures are less likely to recur compared to the late-onset post-stroke seizures, due to the fact that the epileptogenic factors including ischemia, hypoxia, and brain edema at the early stage after stroke are alleviated as disease progresses. Therefore, the early post-stroke seizures are considered to be self-limited.
Pathogenesis of late seizures
The late-onset post-stroke seizures result from a combination of complex factors including genetic factor, hemodynamic changes, inflammation, neural network reconstitution, glial proliferation, and metabolic disturbance.
It has been established that about 30% of epilepsy syndromes are inherited, but only a few studies have assessed the genetic roles in epileptogenesis after stroke. Yang et al. have reported that the overexpression of aldehyde dehydrogenase 2 (ALDH2) partially blocked the increased level of malondialdehyde, which reduces the neuron apoptosis in the late stage and inhibits epileptic seizures . Other factors such as CD40/−1C/T polymorphism, REST, HCN1, miRNAs, and transcription factors like mSin3A are also proven to play a role in regulating epileptogenesis in the late stage after stroke .
Neurovascular unit imbalance
In the late stage, the neurovascular integrity is disrupted due to the changes of regional cerebral blood flow, disruption of the blood brain barrier integrity, and inflammation. The neurovascular unit is composed of endothelial cells, neurons, and glial cells. Disruptions of the structural and functional integrity of neurovascular unit result in imbalanced micro-environment around neurons, subsequently causing abnormal discharges and the occurrence of late post-stroke seizures .
Discruption of the neuronal network
The epileptic seizures have been defined as a neurologic disorder with neuronal networks involved, rather than a single pathological process. This definition also applies to the post-stroke seizures. The neural network consists of neural circuits, nerve fibers and synapses. The neural repair process occurs in the late stage after stroke, including neurogenesis, integration of new neuronal loops, and synaptic connections. However, maladaptive neurogenesis and synaptic connection may overactivate the neural circuits, thereby increasing the seizure susceptibility .
The post-stroke glial proliferation and activation also play a role in epileptogenesis. In the late stage, the proliferation and activation of astrocytes in the cortex may lead to dysfunctions of ion channels, leading to cell depolarization, increased glutamate, and decreased GABA, all of which contribute to the late post-stroke seizure attack . Particularly, the rise in glutamate levels in the setting of acute stroke was suggested as a potential clinically relevant biomarker for the development of post-stroke epilepsy . In addition to astrocytes, oligodendrocytes and microglia may also proliferate after stroke, though their relations with epileptogenesis remain to be explored.