Pathogenesis of epilepsy

The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain m...

Epilepsy: Pathogenesis Genetic susceptibility Angelman syndrome, Fragile X syndrome, Tuberous sclerosis, neurofibromatosis Chromosomal abnormalities cause abnormal neural patterns Neural Cerebral palsy, focal cortical dysplasia Malformation of cortical development Cerebrovascular Intracranial hemorrhage, ischemic stroke Other Acquired Head trauma, cerebral infection (i.e., HSV1, VZV, cysticercosis) Neoplasm Metabolic Inborn errors of metabolism Inherited enzyme deficiencies Neurodegenerative Alzheimer’s Disease Protein-rich plaque build-up and brain atrophy Inflammation and formation of scar tissue irritates neural tissue Infiltration of mass, grey matter irritation Damage to the brain and subsequent alteration of neuronal circuitry Neurotransmitter imbalances (i.e. ↑ glutamate, ↓ GABA, ↓ serotonin, ↓ dopamine, ↓ noradrenaline) Abbreviations: • HSV1 – Herpes Simplex Virus 1 • VZV – Varicella Zoster Virus ↑ Inflammatory cytokines (e.g. interleukin-6, tumor necrosis factor-α) Altered neurogenesis and gliosis Ion channel and receptor dysfunction causes imbalance of ion channel charges Authors: Keerthana Pasumarthi Christopher Li Reviewers: Negar Tehrani, Ephrem Zewdie, Ran (Marissa) Zhang, Carlos R. Camara-Lemarroy* * MD at time of publication Neurons fire in burst activity (referred to as paroxysmal depolarization shift) and often in groups (hypersynchrony) Abnormal neural activities eventually create self-reinforcing circuits and transform neural network over time Injuries ...