Traumatic brain injury (TBI) affects millions of people worldwide each year.
The consequences of TBI can be severe, leading to a range of neurological and psychological disorders. Among these, post-traumatic epilepsy (PTE) is a significant and debilitating condition that can arise following TBI.
This article explores the epidemiology, risk factors, mechanisms and treatment options for PTE, providing a thorough understanding of this complex relationship.
Epidemiology of TBI and epilepsy
TBI is a leading cause of morbidity and mortality globally, with millions of cases reported annually.
The incidence of TBI is particularly high among young adults, military personnel and the elderly due to factors such as falls, vehicle accidents and sports injuries.1
PTE accounts for approximately 10-20% of symptomatic epilepsy cases and 5% of all epilepsy cases in the general population.2
The risk of developing epilepsy after TBI is influenced by the severity of the injury, with higher rates observed in patients with severe TBI.
Studies have shown that the incidence of PTE is higher in military veterans, with about 50% developing epilepsy 10 or more years after the injury.1 This highlights the long-term nature of the risk and the need for ongoing monitoring and management of TBI patients.
Risk factors for developing PTE
Several risk factors contribute to the development of PTE, including the severity of the TBI, the patient's age, the type of injury, genetic predisposition and the occurrence of early post-traumatic seizures.
Severity of TBI
The likelihood of developing PTE increases with the severity of the injury. Patients with severe TBI have a significantly higher risk of seizures compared to those with mild or moderate TBI.1 A study showed the five-year cumulative probability of unprovoked seizures is 0.7% for mild TBI, 1.2% for moderate TBI and 10% for severe TBI.5
Age
Younger individuals and the elderly are more susceptible to developing PTE. The developing brain in children and the ageing brain in the elderly are more vulnerable to the effects of TBI.2 In children, the risk is particularly high due to the plasticity and ongoing development of the brain.
Type of injury
Penetrating head injuries, which involve the dura mater, are associated with a higher risk of PTE compared to closed head injuries. Intracranial haemorrhages, such as subdural and subarachnoid haemorrhages, also increase the risk.1
Genetic factors
Genetic predisposition can influence the likelihood of developing PTE. Variations in genes involved in neuronal excitability and inflammation may play a role.1 For example, the presence of the ApoE ε4 allele has been linked to a higher risk of developing late post-traumatic seizures.3
Early post-traumatic seizures
The occurrence of seizures within the first week after TBI is a strong predictor of subsequent PTE.2 Early seizures indicate a more severe initial brain injury and a higher likelihood of ongoing neurological dysfunction.
Mechanisms linking TBI to epilepsy
The pathophysiological mechanisms linking TBI to epilepsy are complex and multifaceted. Key mechanisms include glutamate excitotoxicity, neuroinflammation, blood-brain barrier disruption, oxidative stress, synaptic reorganization and tau pathology.
Glutamate excitotoxicity
Following TBI, excessive release of glutamate can lead to overactivation of NMDA receptors, resulting in neuronal injury and death. This excitotoxicity contributes to the development of hyperexcitable neuronal networks that can generate seizures.1
Neuroinflammation
TBI triggers an inflammatory response involving the activation of microglia and astrocytes. This inflammation can lead to the release of pro-inflammatory cytokines, which contribute to neuronal damage and increased seizure susceptibility.2 Neuroinflammation is a critical factor in the development of PTE, as it can create a persistent pro-epileptogenic environment.
Blood-brain barrier disruption
TBI can cause a breakdown of the blood-brain barrier (BBB), allowing immune cells and other substances to enter the brain tissue. This disruption can promote neuroinflammation and epileptogenesis.1 The integrity of the BBB is crucial for maintaining the homeostasis of the brain microenvironment.
Oxidative stress
The production of reactive oxygen species (ROS) following TBI can lead to oxidative damage to neurons and glial cells, contributing to the development of epilepsy.2 Oxidative stress can exacerbate neuronal injury and promote epileptogenesis.
Synaptic reorganization
TBI can induce structural changes in the brain, such as axonal sprouting and synaptic reorganization. These changes can create abnormal neural circuits that are prone to generating epileptic activity .1 Synaptic reorganization is a hallmark of the epileptic brain, leading to the formation of new and hyperexcitable connections.
Tau proteins
Hyperphosphorylated tau proteins, often associated with neurodegenerative diseases, have been linked to acquired epilepsy. Tau pathology can disrupt normal neuronal function and contribute to the development of PTE.2 Tau protein aggregates can interfere with synaptic function and stability.
Signs and symptoms of PTE
PTE can present with various types of seizures, including generalized seizures, focal seizures and focal seizures with secondary generalisation.
Generalized seizures
These involve both hemispheres of the brain and can result in loss of consciousness, convulsions and tonic-clonic movements. Generalized seizures are often more dramatic and can significantly impact the patient's quality of life.1
Focal seizures
These seizures originate in a specific area of the brain and can present with localized symptoms such as sensory disturbances, motor abnormalities or altered consciousness. Focal seizures may be subtle and harder to recognize, especially in the early stages.2
Focal seizures with secondary generalization
These start in one area of the brain and then spread to involve both hemispheres, leading to generalized seizure activity.1 This progression can complicate diagnosis and treatment.
The majority of individuals with PTE experience their first seizure within the first year post-injury, with over 90% having their initial seizure within two years.1 PTE is often associated with other neuropsychiatric conditions such as depression, anxiety and cognitive impairments, which can complicate the management of the disorder.
Current treatment options for PTE
The primary treatment for PTE involves the use of anti-epileptic drugs (AEDs). Commonly used AEDs include phenytoin, carbamazepine, valproate and levetiracetam.
Phenytoin
Often used in measures to stop seizures in the acute phase of TBI. However, its use for long-term prevention of PTE is controversial due to potential side effects and lack of efficacy in preventing late seizures.1
Carbamazepine
Effective for controlling partial and generalized seizures but may cause side effects such as dizziness, drowsiness and gastrointestinal disturbances.2
Valproate
Broad-spectrum AED is effective for various seizure types but associated with significant side effects, including weight gain, and liver toxicity and causes fetal abnormalities in pregnant women.1
Levetiracetam
Preferred for its favourable side effect profile and effectiveness in controlling seizures, especially in the acute post-TBI phase.2
Despite the availability of these medications, a significant proportion of TBI patients continue to experience chronic seizures. Approximately 4-53% of patients develop chronic epilepsy despite prophylactic treatment.1
Novel therapeutic approaches and future directions
Future research
Research is ongoing to develop novel therapeutic approaches targeting the underlying mechanisms of epileptogenesis in TBI.
Some promising areas of research include:
- Neuroinflammation modulation
- Oxidative stress reduction
- Tau pathology inhibition
- Synaptic reorganization prevention genetic modulation
Controlling inflammation of the brain
Targeting inflammatory pathways using agents such as minocycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential to reduce seizure susceptibility in preclinical models.2
Oxidative stress reduction
Antioxidants such as N-acetylcysteine (NAC) are being investigated for their ability to reduce oxidative damage and prevent the development of epilepsy post-TBI.1
Tau pathology inhibition
Therapies aimed at reducing tau hyperphosphorylation and aggregation, such as tau-targeting antibodies are being explored as potential treatments for PTE.2
Synaptic reorganization prevention
Modulating synaptic plasticity and preventing aberrant synaptic reorganization through agents like BDNF (brain-derived neurotrophic factor) mimetics and modulators of synaptic signalling pathways.1
Epigenetic modulation
Epigenetic changes following TBI can contribute to the long-term risk of epilepsy. Epigenetic modulators, such as histone deacetylase inhibitors, are being studied for their potential to modify gene expression and reduce seizure susceptibility.2
Summary
Traumatic brain injury is a significant risk factor for developing epilepsy, with the potential for long-term neurological consequences. Understanding the epidemiology, risk factors, mechanisms, and treatment options for post-traumatic epilepsy is crucial for improving patient outcomes. While current treatments focus on managing seizures with anti-epileptic drugs, ongoing research is exploring novel therapeutic approaches targeting the underlying mechanisms of epileptogenesis. Future advancements in this field may lead to more effective prevention and treatment strategies for PTE, ultimately improving the quality of life for individuals affected by TBI.
In summary, traumatic brain injury can lead to the development of post-traumatic epilepsy through complex mechanisms involving excitotoxicity, inflammation, oxidative stress and synaptic reorganization. While current treatment options focus on controlling seizures with anti-epileptic drugs, ongoing research into novel therapeutic approaches holds promise for more effective prevention and management of PTE. Understanding the risk factors and underlying mechanisms of PTE is essential for developing targeted interventions and improving the long-term outcomes for TBI patients.
FAQs
What is post-traumatic epilepsy (PTE)?
Post-traumatic epilepsy (PTE) is a type of epilepsy that develops after a traumatic brain injury (TBI). It is characterized by recurrent, unprovoked seizures that occur months to years after the injury.
How common is epilepsy after TBI?
The incidence of PTE varies depending on the severity of the TBI. Severe TBIs have a higher likelihood of leading to epilepsy, with studies indicating that up to 50% of military veterans with severe TBI may develop epilepsy 1
What are the main risk factors for developing PTE?
Key risk factors for PTE include the severity of the TBI, age (with higher susceptibility in younger and older individuals), the type of injury (with penetrating head injuries posing a higher risk), genetic predisposition and the occurrence of early post-traumatic seizures.2
What are the current treatments for PTE?
The primary treatment for PTE involves the use of anti-epileptic drugs (AEDs) such as phenytoin, carbamazepine, valproate and levetiracetam. Despite these treatments, a significant proportion of patients continue to experience chronic seizures.1
What future treatments are being explored for PTE?
Future research is focused on targeting the underlying mechanisms of epileptogenesis, such as neuroinflammation, oxidative stress and tau pathology. Novel therapeutic approaches include the use of anti-inflammatory agents, antioxidants and epigenetic modulators.2
References
- Ding K, Gupta PK, Diaz-Arrastia R. Epilepsy after Traumatic Brain Injury. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury [Internet]. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016 [cited 2024 Aug 10]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK326716/.
- Fordington S, Manford M. A review of seizures and epilepsy following traumatic brain injury. J Neurol [Internet]. 2020 [cited 2024 Aug 10]; 267(10):3105–11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501105/.
- Diaz-Arrastia R, Gong Y, Fair S, Scott KD, Garcia MC, Carlile MC, et al. Increased Risk of Late Posttraumatic Seizures Associated With Inheritance of APOE ϵ4 Allele. Archives of Neurology [Internet]. 2003 [cited 2024 Aug 10]; 60(6):818–22. Available from: https://doi.org/10.1001/archneur.60.6.818.
- Lucke-Wold BP, Nguyen L, Turner RC, Logsdon AF, Chen Y-W, Smith KE, et al. Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure. Seizure [Internet]. 2015 [cited 2024 Aug 10]; 33:13–23. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1059131115002332.
- Annegers JF, Hauser WA, Coan SP, Rocca WA. A population-based study of seizures after traumatic brain injuries. N Engl J Med. 1998; 338(1):20–4.