Epilepsy occurs when networks of brain cells become abnormally excitable and fire in synchronized bursts, producing seizures. More than 50 million people worldwide live with the condition, and the causes range from genetic mutations to brain injuries to infections. In roughly 30% of cases, no specific cause can be identified even with modern imaging and testing.
How Seizures Start in the Brain
Your brain runs on a constant balancing act between signals that excite neurons and signals that calm them down. The main excitatory chemical messenger is glutamate, which tells neurons to fire. The main inhibitory one is GABA, which tells them to stop. Epilepsy develops when this balance tips toward too much excitation, too little inhibition, or both. The result is hyperexcitability: large populations of neurons firing together in rapid, synchronized bursts instead of their normal, staggered patterns.
This isn’t always about chemical signaling, though. Potassium levels outside neurons also play a major role in keeping seizure activity going once it starts. Researchers have shown that synchronized firing can continue even when chemical communication between neurons is blocked, meaning the electrical environment around cells matters just as much as the neurotransmitters passing between them.
Genetic Causes
Many forms of epilepsy trace back to mutations in genes that control ion channels, the tiny pores in neuron membranes that let charged particles like sodium, potassium, and calcium flow in and out. These channels are what generate electrical signals in the brain, so even small changes in how they open or close can make neurons too excitable.
The best-studied example involves a gene called SCN1A, which builds one type of sodium channel. Mutations in SCN1A account for roughly 85% of cases of Dravet syndrome, a severe childhood epilepsy, and about 10% of a milder inherited form called genetic epilepsy with febrile seizures plus (GEFS+). In Dravet syndrome, most mutations knock the channel out of commission entirely. In GEFS+, the mutations are subtler, altering when and how the channel opens rather than destroying it. The practical effect in both cases is the same: the inhibitory neurons that normally keep brain activity in check become less active, and seizures result.
Mutations in other sodium channel genes (SCN2A, SCN3A, SCN9A) and in genes for calcium channels and GABA receptors have also been linked to inherited epilepsies. Some of these mutations increase excitatory signaling directly, while others weaken the brain’s built-in braking system. A calcium channel mutation called R468Q, for instance, increases calcium flow into neurons, which can boost the release of excitatory chemical signals and worsen seizures when paired with other genetic vulnerabilities.
Brain Injuries and Stroke
Acquired epilepsy, meaning epilepsy that develops after a specific brain insult, accounts for about one-third of all cases. Stroke is the single leading cause within this group, responsible for nearly one-third of acquired epilepsies. Traumatic brain injury accounts for another 15% overall, and that figure jumps to about 30% of acquired epilepsies in people aged 15 to 34.
What makes these injuries lead to chronic seizures isn’t the damage itself but a process called epileptogenesis that unfolds afterward. Between the initial injury and the first seizure, there’s often a quiet “latent period” during which the brain undergoes invisible changes. Molecular and cellular reorganization takes place: inhibitory neurons in certain brain regions die off, and surviving neurons sprout new connections that create abnormal circuits. Studies have correlated progressive increases in seizure frequency with the loss of specific inhibitory cells and the growth of aberrant fiber connections in the hippocampus, a region involved in memory and commonly affected in temporal lobe epilepsy.
This latent period can last weeks, months, or even years, which is why someone can develop epilepsy long after a head injury or stroke that seemed to heal completely.
Infections and Autoimmune Causes
Brain infections like meningitis and encephalitis can trigger epilepsy both through direct tissue damage and through the immune response they provoke. Central nervous system infections are a particularly common cause of epilepsy in low- and middle-income countries, where nearly 80% of people with epilepsy live.
In autoimmune epilepsy, the immune system itself becomes the problem. The body produces antibodies that attack proteins on the surface of neurons, disrupting normal signaling. About 80% of people with these autoimmune brain inflammations experience repetitive focal seizures. The most well-known example involves antibodies targeting the NMDA receptor, a key player in excitatory signaling, but researchers have now identified antibodies against many other targets: proteins involved in potassium channel function, GABA receptors, glycine receptors, and glutamate receptors, among others. In some cases, these antibodies are triggered by a tumor elsewhere in the body. In others, no tumor is found.
Metabolic and Nutritional Disorders
A number of inherited metabolic conditions cause epilepsy by starving the brain of essential nutrients or allowing toxic byproducts to accumulate. Many of these are rare, but they’re important because some are treatable once identified.
- Glucose transporter deficiency: A genetic defect impairs the brain’s ability to take up glucose from the bloodstream. The brain essentially runs low on fuel. Cerebrospinal fluid glucose levels are abnormally low, and seizures often respond to a ketogenic diet, which provides the brain with an alternative energy source.
- Pyridoxine-dependent epilepsy: Toxic metabolites build up in the central nervous system due to a specific gene mutation, causing seizures that require lifelong vitamin B6 supplementation to control.
- Biotinidase deficiency: The body can’t recycle biotin (a B vitamin), leading to toxic compound accumulation. Oral biotin supplementation treats it effectively.
- Creatine deficiency: Errors in creatine metabolism deprive the brain of a molecule it needs for energy storage, sometimes treatable with creatine supplementation.
- Pyruvate dehydrogenase deficiency: A mitochondrial disorder that impairs the cell’s ability to produce energy, sometimes managed with a ketogenic diet and specific vitamin supplements.
These metabolic epilepsies illustrate an important point: seizures are sometimes a symptom of a deeper problem that, when corrected, can bring them under control.
Who Develops Epilepsy and When
Epilepsy has long been associated with childhood, but the data tells a different story. In a large UK study tracking new epilepsy diagnoses, only 25% of patients were under 15 years old. The incidence in elderly populations in developed countries is now reported at 100 to 140 per 100,000 people, which is significantly higher than the overall population rate. Stroke and neurodegenerative disease are the main drivers of epilepsy in older adults, while genetic and developmental causes are more common in children.
The causes shift with age. Infants and young children are more likely to have genetic, metabolic, or developmental causes. Young adults are more likely to develop epilepsy after a traumatic brain injury. Older adults are more likely to develop it after a stroke or alongside dementia. This pattern means epilepsy isn’t a single disease so much as a shared endpoint that many different brain problems can produce.
When No Cause Is Found
Despite advances in brain imaging and genetic testing, about 30% of all new epilepsy cases are classified as cryptogenic, meaning no identifiable cause turns up on standard evaluation. Among people with focal epilepsy that isn’t clearly genetic, the proportion classified as cryptogenic ranges from 40% to 73% depending on the study and the diagnostic tools used. In many of these cases, there may be subtle structural abnormalities too small for current imaging to detect, or genetic factors that haven’t yet been characterized. The label “unknown cause” reflects the limits of current diagnostic technology more than a true absence of underlying pathology.