Electrophysiological and Molecular Basis of Novel Biomarkers for Epileptogenesis and Post-Traumatic Epilepsy
Introduction. Epilepsy is a chronic neurological disorder characterized by repeated, unprovoked seizures and affects 65 million people worldwide. Epileptogenesis occurs when the brain undergoes molecular and cellular changes and gains the ability to initiate spontaneous, recurrent seizures.1 The lack of available biomarkers for epileptogenesis prevents the early detection and prevention of epilepsy in people at risk.1 High frequency oscillations (HFOs) can be observed using electroencephalogram (EEG) between 80-500 Hz.2 HFOs are separated into two categories: ripples (80-200 Hz) and fast ripples (200-500 Hz).2 Fast ripples are only present in epileptic foci, providing a way to distinguish between normal and epileptic zones.3 HFOs have the potential to be the first electrophysiological biomarker for post-traumatic epilepsy (PTE) following TBI. Brain inflammation also plays an important role in the development of PTE. Translocator protein, TSPO, is a biomarker of inflammation and activated microglia and is upregulated in patients with epilepsy.3 Using ligands that bind TSPO, Positron Emission Topography (PET) scans may provide a non-invasive way to predict the development of epilepsy, based on severity of brain inflammation.3 Methods. 1) A lateral fluid percussion injury model was used and HFO tracings were recorded for 2 weeks post-TBI.4 2) A kainic acid (KA) model was utilized to induce status epilepticus (SE), a period of repetitive seizures without recovery. HFO readings were recorded extrahippocampally for 5 weeks.5 3) A PET scan was performed 2-weeks post KA-induced SE (KASE) to determine severity of brain inflammation using [18F]-PBR111 ligand and TSPO.6 Results. 1) Pathologic high frequency oscillations (pHFOs) occurred in and next to TBI areas in all rats that developed late seizures.4 pHFOs were present in none of the control animals, but were present in 58% of the TBI animals.4 2) Widespread ripples and fast ripples were only found in animals that developed spontaneous, recurrent seizures.5 3) Ligand uptake was higher in KASE animals than controls.6 PET imaging at 2 weeks post-SE accurately predicted spontaneous recurrent seizure (SRS) frequency at the onset of epilepsy.6 Conclusions. Presently, there is no validated biomarker for predicting or estimating PTE development in patients with brain injury or acquired risk factors.1 In the future, HFOs and TSPO represent two associated biomarkers that may have potential use as clinically non-invasive indicators of epileptogenesis. Stratification of subjects with TBI who would be at high risk for PTE is extremely helpful for early intervention to mitigate the long-term cognitive dysfunction and neurological impact of brain injury.
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