Epilepsy Explained: Causes, Diagnosis, Treatment, and the Future of Care

1. What is epilepsy?

Epilepsy is a brain disorder where there’s an ongoing tendency to have recurrent, unprovoked seizures.

A seizure is a burst of abnormal electrical activity in brain networks. Depending on where it happens and how far it spreads, it can cause:

• Staring or “blanking out”

• Strange sensations (smells, déjà vu, tingling)

• Sudden muscle jerks

• Falling, loss of consciousness, full-body shaking (generalized tonic-clonic seizure)

• Speech problems, confusion, or unusual behaviors

Most modern definitions converge on something like:

A disease of the brain with an enduring predisposition to generate epileptic seizures — usually diagnosed when you’ve had at least two unprovoked seizures more than 24 hours apart, or one unprovoked seizure plus a high (≥60%) risk of more seizures. PubMed+1

The WHO and ILAE (International League Against Epilepsy) both use versions of this definition. World Health Organization+1

Important nuance:

• One seizure ≠ epilepsy, especially if it’s provoked (e.g., severe low blood sugar, alcohol withdrawal, high fever in kids).

• Epilepsy is not always lifelong – some childhood epilepsies are outgrown; others can go into long-term remission. Wikipedia

2. How is epilepsy diagnosed?

Diagnosis is ultimately clinical: a neurologist (often an epileptologist) puts together:

a) Detailed history

• What exactly happens during the events?

• How long do they last?

• Is there a trigger (sleep deprivation, flashing lights, illness, alcohol)?

• Is there tongue-biting, incontinence, injury, confusion afterward?

• Family history of seizures, brain injury, infections, stroke, tumors, etc.

Often a friend or family member’s description is critical, because the person having the seizure may not remember it.

b) Neurological exam

Doctors look for signs of focal brain dysfunction:

• Weakness, asymmetry, speech or visual problems

• Subtle cognitive or coordination issues

c) Electroencephalogram (EEG)

EEG records brain electrical activity from electrodes on the scalp.

• In epilepsy, you may see epileptiform discharges (spikes/sharp waves, spike-and-wave complexes). Wikipedia

• But: a normal EEG does not rule out epilepsy – about half of people with epilepsy will have a normal EEG between seizures.

• Sometimes, prolonged or video-EEG monitoring is used to capture actual events and distinguish epileptic from non-epileptic spells.

d) Brain imaging

Usually MRI (preferably epilepsy-protocol MRI):

• Looks for structural causes:

  • Prior stroke

  • Tumor

  • Scarring (hippocampal sclerosis)

  • Cortical malformations (e.g. focal cortical dysplasia)

  • Old trauma, infections, etc. Wikipedia+1

CT is sometimes used in emergencies (trauma, acute bleeding).

e) Blood tests and other investigations

• To look for metabolic or infectious causes (electrolyte disturbances, autoimmune antibodies, infections, etc.).

• To distinguish provoked seizures from epilepsy.

Bottom line: Epilepsy is diagnosed when the physician is satisfied that:

1. The events are true epileptic seizures, and

2. There is a persistent tendency for them to recur, not just a one-off provoked event.

3. What is acquired epilepsy?

Epilepsy can be broadly split into:

• Genetic / idiopathic – epilepsy arises mainly from genetic factors (even if no single gene is identified).

• Structural / metabolic / immune / infectious – epilepsy arises from an identifiable brain problem.

• Unknown cause – we don’t know yet.

Acquired epilepsy usually means epilepsy that develops after a brain insult that happens post-birth – in contrast to purely genetic/idiopathic epilepsies.

Common causes include: ScienceDirect+2Brieflands+2

• Traumatic brain injury (TBI) – road accidents, falls, violence:

  • TBI accounts for ~15% of all epilepsy and ~30% of acquired epilepsies in young adults. PMC

• Stroke – especially in older adults:

  • Stroke is the most common cause of new-onset epilepsy in older age; about 6% of stroke survivors eventually develop epilepsy. SpringerLink

• Brain tumors – both benign and malignant.

• Brain infections – meningitis, encephalitis, neurocysticercosis, etc.

• Hypoxic injury – cardiac arrest, severe respiratory failure.

• Immune-mediated disorders – autoimmune encephalitis.

• Acquired brain injuries in childhood (infection, trauma, tumors, hypoxia) also create a substantial risk of later seizures and epilepsy. Frontiers

So, acquired epilepsy isn’t “born with it”; it’s epilepsy that develops as a consequence of another brain injury or disease.

4. Why does acquired epilepsy happen?

Not everyone who has a brain injury develops epilepsy. When they do, there’s usually a multi-step process often called epileptogenesis:

1. Initial insult

   • TBI, stroke, infection, tumor, etc. causes acute damage and inflammation.

2. Latent period

   • There’s often a delay of weeks to years before chronic epilepsy emerges.

   • During this time, subtle microscopic and network-level changes accumulate.

3. Chronic epileptic state

   • The brain has now developed an enduring predisposition to generate seizures – i.e., epilepsy.

Risk is influenced by: PMC+2SpringerLink+2

• Severity and location of injury (e.g., cortical involvement, hippocampus, temporal lobe).

• Age (children’s developing brains vs older adults).

• Genetic susceptibility – some people are more prone to becoming epileptic after the same injury. PMC

• Time since insult – early seizures after stroke or trauma raise the risk of later epilepsy, but are not synonymous with it.

5. Chemical & biological mechanisms (epileptogenesis)

Zooming in, what is happening at the cellular and molecular level?

a) Excitation vs inhibition imbalance

The brain is a giant network balancing:

• Excitatory neurotransmission (mostly glutamate)

• Inhibitory neurotransmission (mostly GABA)

In epilepsy, multiple mechanisms shift this balance toward hyperexcitability and hypersynchrony:

• Increased glutamate receptor activity or expression

• Decreased GABAergic inhibition (loss of inhibitory interneurons, altered GABA receptors)

• Changes in ion channels that make neurons more likely to fire (“channelopathies”) Wikipedia+1

b) Structural reorganization

After injuries like TBI or hippocampal damage, neurons die, and others sprout new connections:

• Mossy fiber sprouting in the hippocampus (in temporal lobe epilepsy) can form abnormal recurrent excitatory circuits.

• Loss of certain inhibitory neurons and reorganization of cortical layers create circuits that can easily synchronize into seizures.

c) Glial cells and inflammation

Not just neurons are involved:

• Microglia and astrocytes become activated after injury.

• They release inflammatory mediators (cytokines, chemokines) that can:

  • Alter ion channels

  • Change receptor expression

  • Lower the threshold for seizures PMC+1

Chronic neuroinflammation is now considered a crucial driver of epileptogenesis in acquired epilepsies.

d) Blood–brain barrier (BBB) dysfunction

Damage to blood vessels and BBB can let serum proteins and immune cells into brain tissue:

• This can activate glia, cause further inflammation, and alter local ionic environments.

• BBB leakage is increasingly recognized as both a marker and driver of post-traumatic and post-stroke epilepsy. PMC+1

e) Epigenetic changes

In both genetic and acquired epilepsy:

• DNA methylation, histone modification, and microRNAs can change gene expression in networks over time.

• This can “lock in” a hyperexcitable phenotype long after the original injury.

6. Current treatment lines

Important disclaimer: what follows is general information and not medical advice. Specific treatment choices must be made with a neurologist based on individual context.

Step 1 – Anti-seizure medications (ASMs)

For most people, first-line treatment is medication. Over 20 ASMs are in use; newer ones keep emerging. Thai Epilepsy Society+1

a) Classic mechanisms

Most ASMs work by one or more of:

• Enhancing GABAergic inhibition

  • e.g., benzodiazepines, barbiturates, valproate, tiagabine, vigabatrin

• Reducing excitatory activity

  • Blocking sodium channels (carbamazepine, phenytoin, lamotrigine, lacosamide, etc.)

  • Blocking calcium channels (ethosuximide for absence seizures, some others)

  • Glutamate receptor modulation (e.g., perampanel as an AMPA receptor antagonist)

• Mixed/multi-target effects

  • Levetiracetam, topiramate, valproate, etc.

b) Newer medications and “third-generation” ASMs

Recent attention has focused on drugs like:

• Cenobamate – a new ASM for drug-resistant focal epilepsy that combines sodium channel modulation and positive allosteric modulation of GABA_A receptors; in trials, it produced seizure freedom in a meaningful minority of highly drug-resistant patients, more than most previous ASMs. SpringerLink+2MDPI+2

• Fenfluramine – originally an anti-obesity drug, repurposed and now approved (at much lower doses) for Dravet syndrome, a severe childhood epilepsy. It modulates serotonin and other pathways and has shown impressive seizure reduction in this syndrome. SpringerLink+1

• Other newer ASMs include brivaracetam, perampanel, cannabidiol (for Lennox-Gastaut syndrome, Dravet syndrome, etc.), and several others. Wiley Online Library+1

Overall, about two-thirds of people with epilepsy achieve good seizure control with medications alone. Wikipedia

Step 2 – Epilepsy surgery

For drug-resistant epilepsy (failure of at least two appropriate ASMs), surgery becomes a key option:

• Resective surgery – removing the brain area that generates seizures (e.g., anterior temporal lobectomy for temporal lobe epilepsy).

• Lesionectomy – removing a small lesion like a tumor or cortical dysplasia.

In properly selected patients (especially temporal lobe epilepsy with hippocampal sclerosis), surgery can lead to long-term seizure freedom in a substantial proportion. Wikipedia

Step 3 – Neurostimulation

Several devices stimulate parts of the nervous system to reduce seizures:

• Vagus nerve stimulation (VNS) – a pacemaker-like device in the chest stimulates the vagus nerve.

• Responsive neurostimulation (RNS) – electrodes placed near the seizure focus detect abnormal activity and deliver targeted stimulation in response.

• Deep brain stimulation (DBS) – continuous stimulation of deep nuclei (e.g., anterior nucleus of thalamus). Wikipedia

These are especially valuable for patients with multifocal seizures or those whose seizure focus is in eloquent cortex where resection is risky.

Step 4 – Diet and lifestyle therapies

• Ketogenic diet (very high fat, very low carbohydrate) and modified versions (modified Atkins, low-glycemic index) can significantly reduce seizures in some drug-resistant epilepsies, especially in children. Wikipedia

• Sleep, stress management, and avoiding known triggers (alcohol binges, missed medications, flashing lights for photosensitive epilepsy, etc.) are vital.

• Safety and social support (driving regulations, occupational safety, mental health support) are also part of comprehensive care.

Step 5 – Managing acquired epilepsy specifically

In acquired epilepsy, treatment includes:

• Standard ASM management, tailored to seizure type and comorbidities (e.g., avoiding enzyme-inducing drugs in patients on many other medications).

• Addressing the underlying cause when possible (e.g., tumor removal, immunotherapy for autoimmune encephalitis, infection treatment).

• Rehabilitation – especially after TBI or stroke – because seizures are only one part of a much larger disability profile. Frontiers+1

7. How does the future look?

There’s a lot of work still to do, but the trajectory is cautiously hopeful.

a) Better drugs – but also smarter use of them

The past decade saw ~8 new ASMs, with cenobamate and fenfluramine standing out as unusually effective for certain groups of drug-resistant patients. SpringerLink+1

Current and near-future trends:

• Individualized ASM selection using biomarkers, genetics, and machine learning.

• Combination strategies (e.g., cenobamate plus reduced background ASM load) to improve seizure control while minimizing side effects. MDPI+1

• Refinement of safety labeling and monitoring (like recent updates on cenobamate’s liver injury risk). Default

b) Disease-modifying and anti-epileptogenic therapies

Right now, most treatments are symptomatic — they suppress seizures but don’t cure the underlying tendency.

Active research areas:

• Anti-inflammatory and BBB-stabilizing therapies after trauma or stroke to prevent epileptogenesis.

• Gene therapies for monogenic epilepsies (e.g., Dravet syndrome, other channelopathies).

• Epigenetic drugs targeting maladaptive gene expression changes.

• Cell therapies – transplanting inhibitory interneurons or stem-cell–derived cells to restore inhibition.

Many of these are still in preclinical or early clinical stages, but the explicit goal is to prevent or reverse the development of epilepsy, not just treat seizures when they happen. SpringerLink+1

c) Precision diagnostics and digital health

• High-resolution imaging and advanced EEG analysis help pinpoint seizure networks.

• Wearables and seizure detection algorithms are increasingly used for monitoring, alerting caregivers, and collecting data for treatment optimization.

• Large datasets and AI are being explored to:

  • Predict seizures,

  • Forecast the likelihood of epilepsy after an insult,

  • Optimize medication regimens.

d) Social and global health dimensions

WHO estimates ~50 million people worldwide live with epilepsy. World Health Organization+1

Key shifts happening:

• Greater emphasis on reducing stigma, which remains a huge barrier to quality of life and care.

• Global initiatives to improve access to cheap ASMs, especially in low- and middle-income countries where treatment gaps remain large. World Health Organization+1

8. Take-home points

• Epilepsy is not “just seizures” – it’s a chronic brain disorder with a tendency for recurrent, unprovoked seizures.

• Acquired epilepsy arises after brain injuries like trauma, stroke, infections, tumors, or hypoxia.

• Mechanistically, it reflects long-term changes in brain circuits: imbalance between excitation and inhibition, structural rewiring, inflammation, BBB disruption, and epigenetic shifts.

• Current treatments (medications, surgery, devices, diets) can control seizures in most people, but about a third remain drug-resistant.

• The future is moving toward precision, disease-modifying treatments, better prediction and prevention, and improved global access and stigma reduction.