The increased need for drugs to treat PTE led to trials with antiepileptics; these early trials suggested that the drugs could prevent epileptogenesis (the development of epilepsy). It was still thought that antiepileptic drugs could prevent epileptogeneis in the 1970s; in 1973, 60% of physicians surveyed used them to prevent PTE. However, the clinical trials which had supported a protective effect of antiepileptics were uncontrolled; in later, controlled trials the drugs failed to demonstrate an antiepileptogenic effect. Studies did show that antiepileptics prevented seizures occurring within a week after injury, and in 1995 the task force of the Brain Trauma Foundation published a recommendation suggesting their use to protect against seizures early after trauma. However, recommendations were published against the prophylactic use of antiepileptic drugs more than a week after injury by the Brain Injury Special Interest group of the American Academy of Physical Medicine and Rehabilitation in 1998 and by the American Association of Neurological Surgeons in 2000. Research
How epilepsy develops after an injury to the brain is not fully understood, and gaining such understanding may help researchers find ways to prevent it, or make it less severe or easier to treat. Researchers hope to identify biomarkers, biological indications that epileptogenesis is occurring, as a means to find drugs that can target pathways by which epilepsy develops.
The iron from blood also reduces the activity of an enzyme called nitric oxide synthase, another factor thought to contribute to PTE.After TBI, abnormalities exist in the release of neurotransmitters, chemicals used by brain cells to communicate with each other; these abnormalities may play a role in the development of PTE. TBI may lead to the excessive release of glutamate and other excitatory neurotransmitters (those that stimulate brain cells and increase the likelihood that they will fire). This excessive glutamate release can lead to excitotoxicity, damage to brain cells through overactivation of the biochemical receptors that bind and respond to excitatory neurotransmitters. Overactivation of glutamate receptors damages neurons; for example it leads to the formation of free radicals. Excitotoxicity is a possible factor in the development of PTE; it may lead to the formation of a chronic epileptogenic focus. An epileptic focus is the part of the brain from which epileptic discharges originate.In addition to chemical changes in cells, structural changes that lead to epilepsy may occur in the brain. Seizures that occur shortly after TBI can reorganize neural networks and cause seizures to occur repeatedly and spontaneously later on. The kindling hypothesis suggests that new neural connections are formed in the brain and cause an increase in excitability. The word kindling is a metaphor: the way the brains response to stimuli increases over repeated exposures is similar to the way small burning twigs can produce a large fire. This reorganization of neural networks may make them more excitable.