FIGURE 7.

Time course of pathophysiological brain alterations after an initial brain insult. Initial brain injuries comprise traumatic brain injury, stroke, hypoxic-ischemic encephalopathy, brain infections, or prolonged seizures such as complex febrile seizures or status epilepticus. The complex molecular, structural and functional alterations, which underlie the motor, cognitive, and behavioral abnormalities and the spontaneous recurrent seizures (i.e., epilepsy) that may develop after brain injury, exhibit commonalities across different brain insults, thus providing an opportunity for therapeutic intervention. Following brain injuries as illustrated here, the cascade of events that are primarily suggested by experimental evidence can be classified temporally following the initial insult into 1) early changes (including post-translational modification of receptor and ion-channel related proteins), which occur within seconds to minutes; 2) more retarded changes (e.g., neuronal death, inflammation, altered transcriptional regulation of genes), which occur within hours to days; and 3) later changes (including morphological alterations such as mossy fiber sprouting, gliosis, and neurogenesis), occurring days to weeks to months after the initial insult. These molecular, structural and functional alterations eventually lead to structural and functional changes in neurons and neuronal networks, which are eventually manifested as abnormal hyperexcitability and spontaneous seizures. Note that acute symptomatic (early) seizures that may occur in the first week after brain injury are not considered spontaneous seizures. Current drug therapy of spontaneous seizures is symptomatic in that available antiseizure medications inhibit seizures, but neither effective prophylaxis nor cure is available. The complexity of the alterations illustrated in this figure indicates that multi-targeted drug combination therapy is needed for disease modification. However, please note that part of the multiple changes after brain injury may be aimed to repair or reverse the detrimental consequences of the insult. For instance, secondary neuroinflammation both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery (Jayakar et al., 2019). For details see Rakhade and Jensen (2009), Clossen and Reddy (2017), Klein et al., 2018), Somayaji et al. (2018), Campbell et al., 2019, and Löscher (2020).