Epilepsy is defined as a disorder of the central nervous system (CNS) characterized by recurrent, sudden large increases in electrical activity (electrical seizures) that may be localized or generalized. The prevalence of epilepsy is slightly higher in men than women and it is rarely a life threatening condition. However, the incidence of epilepsy is higher in children and also in the elderly. The average IQ of those who suffer from epilepsy is not different from those who do not.
The symptoms (i.e. the presentation of epilepsy) will depend on:
- The Central nervous system region(s) in which the electrical seizure occurs.
- Whether the seizure is localized or general, i.e if it involves a specific part of the brain or the whole brain
- If localized initially, whether the seizure then spreads to other regions of the CNS.
Types of Seizures
| Absence seizure
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A complex, primarily generalized seizure that is common in children. Characterized by sudden loss of awareness lasting up to about 30 sec.
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| Tonic-clonic seizure
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A complex, primarily generalized seizure lasting 2 – 5 minutes that is characterized by sudden stiffening (‘tonic’) of muscles, a fall, followed by jerking (‘clonic’) movements.
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| Simple partial seizure
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A focal cortical seizure characterized by jerking movements that begin in the extremities and spread throughout the body (Jacksonian march). May be sensory symptoms rather than motor.
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| Status epilepticus
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When a seizure does not spontaneously stop but continues or repeats for a period of 30 min or more the condition is termed status epilepticus and is life-threatening.
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Epilepsy Syndromes
Epilepsies, especially childhood epilepsies, can sometimes be further classified as ‘syndromes’, which are collections of signs and symptoms that more closely identify the particular conditions. Better definition helps to achieve the optimum therapeutic approach.
Factors that are considered on defining a syndrome include the type and pattern of seizures, their frequency, the location of the focus, physical and mental symptoms, the age of onset and gender of the patient and prognosis.
There are at least 40 identified epilepsy syndromes
Causes
In most cases the cause of epilepsy is not known (idiopathic) or cannot be proven (cryptogenic). About 30% of cases are symptomatic i.e. the seizures occur following head injury (often after a delay), stroke, an infection or tumour growth, drug abuse.
There is a 2-3-fold increase in the chances of developing epilepsy if you have a close relative who suffers from the disease but clear genetic links have been difficult to trace suggesting multiple genes or environmental factors are involved.
‘Benign febrile epilepsy’ is linked to mutations in KCNQ2 and KCNQ3 genes that encode voltage-gated potassium channels.
‘Familial generalized epilepsy with febrile seizures plus’ is linked to mutations in SCN1B, a gene that encodes an accessory subunit of the voltage-gated sodium channel.
Drug-induced: many drugs have pro-convulsant effects
Animal models
- Kainic acid (KA) injection. Local (e.g. intrahippocampal) or systemic injections of KA can induce seizures in animals and lead to chronic epileptic behaviour.
- Kindling. Repeated low intensity electrical stimulation (usually in the amydgala or hippocampus) of some brain regions leads, after a delay, to development of chronic epileptic behaviour. The frequency of the kindling stimulus is critical.
“Animal models suggest that the focal synchronous excitation that occurs to initiate a seizure involves (a) increased synaptic transmission and (b) decreased surround inhibition“.
Cellular mechanisms
The cellular event that initiates a focal seizure is called a (paroxysmal depolarizing shift (PDS)
The rise (depolarizing phase) of the cellular PDS depends on activation of ionotropic glu receptors (AMPA and NMDA), and opening of voltage-gated Ca2+channels. Curtailment of the PDS and repolarization depends on opening of voltage-gated K+ channels and activation of ionotropic GABA receptors.
The mechanism by which the PDS is initiated is not known but the ability of the PDS to spread to neighboring cells to generate a synchronous focus implies a failure of inhibitory feedback through local interneurons.
Surround inhibition will localize discharges (e.g due to PDS) and prevent their spread but reduction or loss of surround inhibition will allow spread of excitation.
Use-dependent blockers of sodium channels bind to and stabilize the inactivated state of the channel, which increases the refractoriness of the cell and limits the maximum frequency at which the cell can fire. Some drugs may also have affinity for the open state of the channel and combine an open-channel blocking action with prolongation of inactivation
Therapeutic drug treatment
The main class of drugs enhance the activity of GABAergic systems, these include
- Benzodiazepines (e.g. diazepam, clonazepam) are drugs that enhance the activity of GABA. They bind to a regulatory site on the GABAA receptor and increase the affinity of the receptor for GABA.
- Barbiturates (phenobarbitone) prolong the time that GABA activate Cl- channels stay open when the GABAA receptor is occupied.
- Vigabatrin inhibits GABA transaminase (decreases metabolism of GABA)
- Tiagabin inhibits GABA uptake (increases the concentration of GABA in the extracellular space)
Another class of drugs display a use dependent block of voltage-gated sodium channels such as:
- Carbamazepine, Phenytoin & Lamotrigine:
- These drugs will reduce the likelihood of action potentials firing at high frequencies but have relatively little effect at low frequencies. Their binding (and hence blocking action) to the voltage-gated sodium channels is state-dependent.
- Use-dependent blockers of sodium channels bind to and stabilize the inactivated state of the channel, which increases the refractoriness of the cell and limits the maximum frequency at which the cell can fire. Some drugs may also have affinity for the open state of the channel and combine an open-channel blocking action with prolongation of inactivation
The main two classes of Drugs for treating absence seizures are
- Ethosuximide
- Mechanism of action is uncertain. Thought to work by blocking T-type voltage gated Ca2+ channels in thalamic neurons. These channels are important for the generation of rhythmic activity in the neurons. Not useful for tonic clonic seizures.
- Sodium Valproate
- Mechanism uncertain. Combines a weak blocking action on voltage gated sodium channels with a weak inhibition of GABA transaminase. Useful for both complex and simple seizures.
- Future research strives to further explore epilepsy on a cellular and genetic level, paving the way for creation of novel bespoke therapies based on each individuals needs and biological profile.