Epilepsy: Causes And Medications
It is imperative to differentiate between epilepsy and seizures; epilepsy is a chronic and complex neurological disorder which increases the susceptibility of individuals having gratuitous and recurring seizures. A seizure is warranted when normal electrical brain function is temporarily interrupted by burst of abnormal electrical signals. (University, 2015) Fundamentally not all seizures are due to epilepsy however, epilepsy is characterised by recurrent seizures. Epilepsy affects 450,000 people in the UK which accounts for 0.5-1% of the population, with 30,000 cases being diagnosed every year. The neurons in our brain possess a balance between synaptic inhibition and synaptic excitation, this balance of synaptic excitation and inhibition is modified with individuals who have suffer from epileptic seizures resulting in pathological synchronization of neurons in the brain or abnormal excessive activity in the brain. Glutamate is the main excitatory neurotransmitter which propagates the firing of an action potential, comparatively GABA in an inhibitory neurotransmitter which counteracts glutamate and reduces the activity of the neural cells.
A single neurone is linked via a synapse to hundreds of other neurones, and hundreds of other neurones are interlinked via an exceedingly complex network of neurones. Neurones communicate with each other via chemical and electrical signals. Electrical signals also referred to as action potential stimulate the neurones to release a neurotransmitter which can be either excitatory or inhibitory. Thus, the neurotransmitter can either excite or inhibit its neighbouring neurone. Excitatory neurones can either excite and activate the neurone it is connected to; conversely an inhibitory neurone will decrease excitation and activation of the neurone. A typical neuron releases frequently at a low baseline, regular low-frequency discharges. Regular low-frequency discharges in the case of epilepsy are accompanied by bursts of high-frequency discharges typically preceded by periods of inactivity (Mormann, Jefferys, 2013). An abnormally charging single neurone typically has no profound clinical significance. It is just when an entire populace of neurones releases synchronously in an irregular way that an epileptic seizure may be activated. The region from which irregular discharge stems from is referred to as the epileptic focus.
Potential causes of epilepsy include brain tumours, stroke, infection or head injury. (What is epilepsy, 2020) Epilepsy can be classified into several subgroups. Generalised seizures and partial seizures are the two broad categories of epileptic seizures. Generalised seizures are also known as generalised whole cortex bilateral seizures as the whole cortex is involved. Generalised seizures can be further subdivided into absence seizures and tonic clonic seizures. As the name implies tonic clonic seizures are manifested by a period of muscle contraction and loss of consciousness followed by a period of relaxation where the muscles will commence to jerk rapidly and rhythmically. Salivation, urination and excretion can occur either during the seizure or after (Bromfield et al., 2006). Absence seizures where the patient will experience perhaps a staring episode or altered state, brief consciousness. Patients will not recall absence seizures and essentially the individual ‘blanks out’ for approximately less than 15 seconds (Appleton, 2019).
If consciousness is not lost, it can result in a partial seizure, as the name implies only one portion of the brain is experiencing a seizure. Partial seizures are also referred to as focal or localised seizures. They have a location dependent aspect to them, if the seizure occurs in an area associated with language such as: Broca’s area, Wernicke’s area patients may experience visual or auditory hallucinations (Duke et al., 2012). However, some partial seizures can result in a loss of consciousness when they manifest the patient and spread, also referred to as secondary generalised seizures.
The fundamental way of managing epileptic seizure is through the utilisation of anti-epileptic drugs (AEDs). Antiepileptic (often referred to as anti-convulsant) drugs are incredibly diverse; these drugs essentially restore the balance between inhibition and excitation by reducing the glutamate concentration or increase the GABA concentration. Many AED’s act via several mechanisms of action, very few antiepileptic drugs act via a singular, specific pathway. Antiepileptic drugs can be categorised into first generation or second generation. First generation AED’s include phenobarbital, valproic acid, phenytoin and carbamazapine; they were introduced into the market several decades ago. However, in the last two decades several newer anti-epileptic drugs such as: levetiracetam lamotrigine, pregabalin, vigabatrin etc have entered the market. Second generation anticonvulsants preferred as they are generally higher tolerated and possess a wide therapeutic range than classic anti-convulsants.
Unfortunately, AEDs are unable to cure epilepsy, they just attempt to reduce the frequency of seizures from occurring. Although anti-epileptics are a lifeline for many individuals who suffer from epileptic seizures, approximately two thirds of patients are unresponsive to AED’s and often have to adopt other forms of therapeutic management. Optimal therapy is profoundly desired whereby patients are prescribed the fewest types of anti-epileptic drugs at lowest dose possible and experience the fewest side effects. However, combination therapy is often adopted to enhance tolerability and efficaciousness when monotherapy first line treatment and second line treatment has failed (Joint Formulary Committee (2020)). Various factors must be taken into consideration when selecting an anti-epileptic drug such as: type of seizure, cost, co-morbidities, efficacy, expected adverse effects. If medication has failed other interventions can be practised such as vagal nerve stimulation, surgery or for children a ketogenic diet.
Carbamazepine is a sodium channel blockade and is the first line treatment for treat focal seizures and generalised tonic clonic seizures for adults and young people. Carbamazepine acts via three mechanisms of action, however the primary mechanism of action is blocking voltage gated sodium ion channels in the presynaptic neurone (G Harkin*, 2010). Sodium ions play a critical role in an action potential, when a stimulus travels down an axon, voltage gated sodium ion channels open, sodium ions diffuse into the negatively charged axon down their electrochemical gradient. When the threshold potential is reached, depolarisation occurs. It has been suggested that carbamazepine bind to the alpha subunit of the voltage gated sodium ion channels, resulting in the sodium channels entering an inactivated state and reducing the excitability of neurons. Ergo inhibiting the orchestration of the action potential and inhibiting the release of glutamate into the synaptic cleft (Gambeta 2016). Thus, elevating the seizure threshold. Carbamazapine is indicated to be used in the treatment of trigeminal neuralgia, bipolar disorder and diabetic neuropathy (Joint Formulary Committee (2020)).
Sodium valproate is another primary medication which is has been utilised for multiple decades to treat epilepsy. It is offered to young adults and children who have been newly diagnosed with generalised tonic clonic seizures. Women and young females of child-bearing age have been strongly advised against taking sodium valproate due to the detrimental risks of birth defects in children whose mothers took valproate while pregnant (Shakespeare, Sisodiya 2019). Sodium valproate acts on the GABA synapse thus affecting potentiation of GABA activity. Sodium valproate is a GABA transaminase inhibitor; it inhibits succinic semialdehyde dehydrogenase which consequently increases the concentration of succinic semialdehyde which inhibits GABA transaminase. This blocks GABA breakdown, enhances GABA concentration and enhances GABA release resulting in the reduced excessive excitability of neurons.
Levetiracetam is one of the newest AED’s available on the market with a novel pharmacological profile. It is frequently utilised as a first line treatment in seizures for individuals in palliative care (Howard et al., 2018). The specific physiological role of SV2A remains ambiguous (Sills) however it is understood levetiracetam binds to SV2A. SV2A (synaptic vesicle glycoprotein 2A) is an ever-present synaptic vesicle protein located in the secretory vesicles of neurons (Bartholome et al., 2017). Levetiracetam selectively binds to SV2A, with minute affinity for SV2B and SV2C which are members of the SV protein family (Sills). It is understood levetiracetam effects vesicle exocytosis, a study conducted in laboratory mice exhibited a reduction in the frequency of inhibitory postsynaptic transmissions suggesting a detrimental effect of presynaptic neurons on GABA release (Crowder et al., 1999). Levetiracetam decreases excitatory and inhibitory post synaptic transmissions in an activity dependent method, with the greatest impact witnessed with the highest stimulation frequency (Meehan et al., 2012). This reduces the amount of neurotransmitters available to transmit the electrical signal thus reducing the electrical signal and enables the stabilisation of electrical conductance in the brain.
Tiagabine exerts its action by selectively inhibiting the reuptake of GABA. It is utilised to treat focal seizures with or without secondary generalisation. Tiagabine binds to the specific receptor sites related to the GABA uptake carrier (GAT-1), this prevents the reuptake of GABA into the presynaptic neurone and increases the concentration of GABA in the synaptic cleft and more GABA is available to bind to the receptors on the post synaptic neurone therefore, reducing the electrical signal and in the brain conduction is stabilised (Bauer, Cooper-Mahkorn, 2008). A study conducted on humans and rodents have displayed an increase in extracellular concentration of GABA as a result of tiagabine is several areas of the brain. With individuals experiencing refractory partial seizures with or without generalisation, tiagabine has been recommended as adjuvant therapy. It has proved to be incredibly effective, between January and December 2000, an experiment was conducted where 20 patients who had been diagnosed with refractory partial epilepsy were administered tiagabine, they were required to take a dose of 5mg or 10mg per day, and increased the dose by either 5 or 10mg on a weekly basis until the patients had established a maintenance dose. 35% of patient who were administered tiagabine had respectively experienced a reduction in the frequency of seizures by ≥50% (Paul McKee, 2004).
Voltage gated calcium channels have become an appealing target for anti-epileptic drugs. Gabapentin binds to the alpha2delta1 regulatory subunit present on the presynaptic neurone. This inhibits the influx of calcium ions into the presynaptic neurone down their electrochemical gradient consequently depolarisation of the cell membrane is unable to occur preventing the release of neurotransmitters into the synaptic cleft. As opposed to blocking the voltage gated calcium ion channels directly, gabapentin redistributes the ion channels away from the surface of the cell. Moreover, gabapentin has displayed an effect on the potassium and sodium ion channels.
Like almost all drugs, despite their therapeutic benefits, they also responsible for adverse effects. Adverse effects of AEDs can be divided into acute dose related, idiosyncratic and chronic. Many acute dose related adverse effects are reversible, neurological adverse effects are the most prominent and are often manifested by tremor, changes in behaviour or mood, paraesthesia, blurred vision etc. Idiosyncratic adverse effects rash, Stevens-Johnson syndrome, agranulocytosis as a result of haematologic damage. Long term adverse effects include neuropathy and endocrine/metabolic effects.
In conclusion, epilepsy can severely impair an individual’s life and daily routine. Fundamental activities such as driving can manifest into a major safety and personal issue. Nonetheless, we have witnessed incredible progression and substantial advancement in the treatment of epileptic seizures with hopes of a cure being developed.
