Last updated on March 1, 2021 at 15:41
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Introduction to epilepsy
An epileptic seizure occurs when there is abnormal electrical activity in the brain. This electric activity is often comprised of synchronous high frequency discharges in groups of neurons in the brain.
Epilepsy is an umbrella term for multiple conditions that cause recurring, unprovoked epileptic seizures. When an epileptic seizure is provoked by a stroke, brain injury, metabolic or electrolyte disturbances etc., the condition is not called epilepsy.
If a one or more seizures last for more than five minutes, without the affected person recovering their consciousness between the seizures, the condition is called status epilepticus. Unlike most other seizures, status epilepticus is a medical emergency.
There are two types of epileptic seizures; partial (or focal) seizures and generalized seizures.
Partial seizures:
In a partial seizure there is abnormal activity in only one hemisphere. These seizures can be simple or complex.
In simple partial seizures there is no impairment of consciousness. The patient can experience jerking of a single limb or localized sensory disturbances like paraesthesia.
In complex partial seizures the consciousness is impaired, but the person can still stand upright or walk around. An affected person can appear drunk or confused. These seizures most commonly arise from the temporal lobe and move to other areas of the brain. An affected person can suddenly stop moving and just stare into space, they can begin smacking their lips, chewing or swallowing. The person usually doesn’t remember the seizure afterwards.
Generalized seizures:
In a generalized seizure there is abnormal activity in both hemispheres. A partial seizure can progress into a generalized seizure.
The most common type of generalized seizure is the tonic-clonic seizure (“grand mal” seizure), which is the where the affected person experiences convulsions while being unconscious. The extensor muscles in the body spasm, and muscles contract and relax alternately. During this seizure the affected person may bite their tongue or lose bladder control.
Another type is the absence seizure (“petite mal” seizure). In this type the affected person briefly loses consciousness and stops talking or doing whatever they’re doing, but still standing or sitting upright.
The most common cause of epilepsy in adults is alcohol withdrawal.
Pathomechanism:
The mechanism behind epileptic seizures is poorly understood. Facilitation of excitatory neurotransmission, diminishment of inhibitory neurotransmission or enhanced neuronal excitability are potential mechanisms.
Special considerations:
Withdrawal from antiepileptics may trigger seizures. This must be kept in mind when switching between drugs.
These drugs have narrow therapeutic windows, so their plasma level must be routinely monitored to prevent toxicity.
Antiepileptics
We can distinguish three types of antiepileptic drugs, according to which types of seizures they’re useful against:
| Seizure type | Treated by narrow spectrum drugs | Treated by ethosuximide | Treated by broad spectrum drugs |
| Simple partial seizure | Yes | No | Yes |
| Complex partial seizure | Yes | No | Yes |
| Generalized tonic-clonic seizure | Yes | No | Yes |
| Generalized absence seizure | No | Yes | Yes |
Mechanism of action:
Many antiepileptics work by stabilizing voltage-gated Na+ channels in their “inactive” or closed state. This prolongs the refractory period of neurons, causing them to fire less frequently.
This effect is use-dependent, meaning that the more overactive a Na+ channel is, the more strongly these drugs bind to the channel. During a seizure the Na+ channels at the area of the seizure are overactive, so the drugs target overactive neurons during a seizure. Na+ channels are mostly unaffected when a seizure is not currently happening.
Some antiepileptics work by other mechanisms as well:
- By blocking T-type voltage-gated Ca2+ channels
- By potentiating endogenous GABA activity
- By potentiating voltage-gated K+ channels
Narrow spectrum antiepileptics
- Carbamazepine
- Oxcarbamazepine
- Phenytoin
- Gabapentin
- Pregabalin
- Vigabatrin
These antiepileptics are used for focal or partial seizures.
Indications:
- Partial seizures (both types)
- Tonic-clonic generalized seizures
Carbamazepine can also be used to treat trigeminal neuralgia. Gabapentin and pregabalin are also used to treat neuropathic pain.
Mechanism of action:
Phenytoin and carbamazepine inhibit voltage-gated Na+ channels by the mechanism outlined above.
Gabapentin blocks calcium channels, attenuating neurotransmitter release.
Vigabatrin irreversibly inhibits GABA transaminase, the enzyme that inactivates GABA. This increases levels of GABA in the CNS.
Pharmacokinetics:
Elimination of phenytoin follows a special pattern called mixed-order or non-linear pharmacokinetics. Non-linear pharmacokinetics mean that Elimination is unsaturated (follows first-order kinetics) when the dose is less than 300 mg/day. When the daily dose exceeds 300 mg the enzymes metabolising phenytoin become saturated, causing it to switch to zero-order kinetics above this daily dose.
Interactions:
Phenytoin, carbamazepine, and oxcarbazepine induce CYP450 enzymes, which is important to know. Phenytoin has significant plasma protein binding and therefore interacts with other drugs with the same property.
Side effects:
Phenytoin
- Diplopia
- Ataxia
- Gingival hyperplasia
- Decreased bone density
- Hirsutism
- Teratogenic
Carbamazepine
- Diplopia
- Ataxia
- Syndrome of inappropriate ADH
- Aplastic anaemia
- Agranulocytosis
- Teratogenic
Ethosuximide
Ethosuximide can only treat generalized absence seizures, but it’s the preferred drug for these seizures.
Indications:
- Generalized absence seizures
Mechanism of action:
Ethosuximide blocks T-type Ca2+ channels in neurons in the thalamus.
Side effects:
- GI symptoms
Broad spectrum antiepileptics
- Antiepileptics
- Valproate (or valproic acid)
- Lamotrigine
- Levetiracetam
- Topiramate
- Benzodiazepines
- Barbiturates
- Phenobarbital
These antiepileptics are useful for treating almost all types of seizures.
Valproate is a first-line drug in treating generalized seizures, except in pregnant women. Lamotrigine is a newer broad spectrum antiepileptic which has fewer side effects.
Indications:
- Partial seizures (both types)
- Generalized tonic-clonic seizures
- Generalized absence seizures
Valproate is also used in migraine prophylaxis and as a mood stabilizer. Lamotrigine is also used as a mood stabilizer.
Mechanism of action:
Valproate, topiramate and lamotrigine inhibit voltage-gated Na+ channels by the mechanism outlined above. Valproate also increases levels of GABA in the CNS.
Topiramate binds to an allosteric site on the GABAA receptor, increasing its activity.
Valproate and lamotrigine also block T-type Ca2+ channels.
Pharmacokinetics:
These drugs are metabolized by CYP450 enzymes in the liver.
Valproate is highly plasma protein bound.
Side effects:
Valproate
- Sedation
- Nausea
- Hepatotoxicity
- Teratogenicity
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