Epilepsy is serious neural disorder that causes frequentseizures.1 Seizures are physical changes thatcan be observed during or after abnormal bursts of electrical activity in thebrain that alters brain function..
2 Epilepsymanifestation can be at any age, although it is more common in children and in adultsover 60.3 It is a lifelong disease, but withthe correct treatment, it gets better over time.3 HISTORY Epileptic seizures are caused by the disruption in theelectrical activity of the basic and most primitive components of the nervoussystem.4 A logical conclusion can be drawnfrom this observation that epileptic seizures may have existed in the earlieststages of the human evolution.4 Scientists have associated prehistoric trephined skulls as apossible method by which primitive physicians attempted to solve epilepsy.
5 Many of these trephined skulls atthe time of their discovery had undergone bone apposition signifying survivalover a considerable amount of time6. Trephined skulls with otherfractures were related to traumas and the fracture-free trephined skulls weresaid to belong to epileptic patients since no other explanation of theintervention has been proposed.6 Proving this theory is almostimpossible since no literature has yet been found on it. 6 Literature however indicates thatthe early scientists predicted that seizures were as a result of brain woundsand many thought making holes in the skull could solve the issue7. This can be seen in the earliestHippocratic texts. Hippocrates knew epilepsy as a disease which originates inthe brain and in the second century, one of the early surgeons, Aretaeus theCappadocian suggested trephination as a remedy for the condition.
7 As seen above, scientists tried to use rational thinking toapproach and treat epilepsy; the total contrast of the religious perspective.8 Many religious and superstitiouspeople believed epilepsy was a disorder sent by gods.8 Evidence of this can be found in aBabylonian cuneiform tablet which directly equated epilepsy and associatedseizures to the influence of evil spirits.8 Even in the 21st century, there is still evidence that the confusionin the varying explanations for epilepsy, the religious and scientific, stillexists with numerous people not knowing who to believe.9 This confusion however never affectedHippocrates and in his famous pamphlet on “The sacred disease”, written around450 BC, he was strongly against the religious explanations.9 EARLIERCLASSIFICATION OF EPILEPSYTwo main historical classifications were recorded; One byHippocrates and the other by Galenus.10 Hippocrates classified according tothe multiplicity of natural causes for example climate and moon phases.7,10 Galenus however has an alternativeapproach.
10 Although he agreed that allseizures had something to do with the brain, he believed it was not always theprimary source of the pathology.10 He further divided seizures intoidiopathic and sympathetic.10 The prior referred to conditionsoriginating from the brain and the latter, later renamed symptomatic did notoriginate from the brain.10 Galenus’ classification is stillbeing used even though they have slightly different definitions now.10 CURRENTCLASSIFICATION BASICANATOMY OF THE NEURONSince it has been established that epilepsy is aneurological disorder, a basic understanding of neuroanatomy would betterenable us to dissect the issues.
The nervous system is one of the systems in the human body.The basic working unit of the nervous system is the neuron.11 The brain has as many as 100billion neurons.11 A classic neuron has a cell bodyand processes: an axon and dendrites.
11 The cell body, also known as theperikaryon is the site from which the axon and dendrites arise.11 Dendrites receive stimuli from thesurroundings of the neuron and sends impulses to the cell body while the axontransmits the impulses from the cell body to the surroundings. Neurons areclassified into unipolar, bipolar and multipolar based on the number ofprocesses it has on its cell body. This classification is morphology based.Others classify neurons based on the neurotransmitters they release. A neuronaxon may be myelinated or not and this affects the speed at which impulses aretransmitted. The conduction across a myelinated neuron is said to be saltatory.The cell body has a plasma membrane, a nucleus and other organelles in itscytoplasmic.
11,12 Neurons do not undergo division after initial formation hence theirinability to undergo repair.11 BASICNEUROPHYSIOLOGY OF THE NEURONAs stated earlier, the neuron transmits impulses. It does sothrough its excitable plasma membrane which is an 8nm thick phospholipidmembrane.13 This membrane has proteins whichact as ion channels which allow movement of ions.
At rest, the neuron has a resting membrane potential ofabout -80mV. 13 When the neuron gets excited andthe threshold is reached, the membrane becomes permeable to sodium ions in aprocess called depolarization. The influx of the sodium ions causes an actionpotential to occur during an overshoot. Repolarization occurs after where thereis the efflux of potassium ions. This process allows the transmission ofimpulses down the neuron.
13At the terminal end of the axons, the impulse flowing causesthe influx on calcium ions into the axon. This leads to subsequent exocytosisof the neurotransmitter stored in vesicles at the terminal.13 PATHOGENESISOF EPILEPSYScience is yet to fully understand the various mechanisms bywhich epilepsy develops. Also known as epileptogenesis, the development of epilepsycan be said to be the process by which a normal neuron becomes chronicallyhyper excitable.14–16 This can occur when there is aninjury to the brain slowly reducing the threshold for seizures. For a longtime, the scientific community believed that epilepsy was as a result of alocal area injury15.
But current technology is pointingmore towards multiple hyper-excitable networks even though the local areahypothesis is still relevant.17 These issues may be as a result of idiopathic and geneticcauses. A loss of inhibitory signals or an overstimulation of neurons andgenetic mutations affecting ion channels can lead to the hyper excitablenetworks.15 TREATMENTOPTIONSAs compared to the historical trephination approach oftreating epilepsy, current scientific research has led us to a wide range ofdrugs and surgical procedures used to manage and treat epilepsy. The drugs aregenerally known as anti-epileptic drugs.18 They are also calledanticonvulsants due to their ability to treat other forms of seizures. Moreresearch is being carried out to better the drugs used. Surgery is used inpatients with severe epilepsy.
The various methods will be further discussed inthe subsequent paragraphs. ANTI-EPILEPTICDRUGSThere are many types of anti-epileptic drugs used in themanagement of epilepsy. Out of the anti-epileptic drugs, some are moreeffective and therefore are preferred. Some new drugs which are stillundergoing evaluation to determine its long term effects are being employed.19 Drugs in their various clinical trialphases are also being researched.20 The various classes ofanti-epileptic drugs and how they work will be discussed below. ANTI-SEIZURE BARBITURATES A barbiturate is a drug that acts by slowing down brainactivity.
18,21 The slowing down of neural activityenables barbiturates to have anti-epileptic properties. It also has a sedativeeffect.18 Through research, it has beenobserved that phenobarbital has a maximal anti-epileptic effect. The mechanismof action of phenobarbital involves the increased effect of the inhibitory neurotransmitters,GABA.21 It is an agonist of the GABAreceptors and this allows the GABA response.21 This inhibits neuronal actionpreventing over firing of the neurons. Phenobarbital can be obtained after themetabolism of a drug such as primidone.
21 It having a good anti-epilepticeffect also came with the sedative effect.21 Due to this side effect, manyphysicians do not prefer this drug. Ataxia, irritability and confusion are allside effects of the drug. Mephobarbital is also an anti-epileptic barbiturateand functions similarly to phenobarbital.21 HYDANTOINSHydantoins are anticonvulsants that are used to treat a widerange of seizure types. The most common anti-epileptic drug of the hydantoinsclass is phenytoin. It is known to be effective in partial seizures,tonic-clonic. It is however inactive in absence seizure.
21 Hydantoins and barbiturates arequite similar in structure and chemical properties. Phenytoin works byinhibiting the firing of neuronal action potentials.22 This does so by delaying the sodiumion recovery following an action potential.22 This increases the refractoryperiod of the action potential thereby reducing the transmission of impulses.
22 This in turn greatly reduced theprobability of an epileptic attack. Phenytoins have a wide range of side effects. A low dose canlead to nystagmus, rare hematological toxicity and ataxia.19 A relatively higher dose can leadto confusion and intellectual dysfunction.
19 Sedation is not a side effect. Whenused during pregnancy, the drug can lead to teratogenic effects on the fetus.When it is administered with the intravenous route, it could result in cardiacarrhythmia. Gingival hypertrophy is also a possibility.23 Other hydantoins are ethotoin andpeganone.24 TOPIRAMATE Topiramate is an anti-epileptic drug used for patients betweenthe ages of 2 to 16 with partial-onset seizures.16 It is also effective in seizures associatedwith Lennox–Gastaut syndrome.
16 The anti-seizure mechanism of topiramate is yet to bedetermined. Research however indicates that a certain concentrations, the drug blockssodium channels and interferes in the activities of GABA by acting as GABAreceptor agonist. 16 They enhance the work of GABA bybinding to its receptor. It also inhibits the carbonic anhydrase enzyme.16 Topiramate can cause anorexia, anxiety and loss of appetite.
Confusion, dizziness and diarrhea are adverse effects of the drug.16 IMINOSTILBENESThe most commonly used iminostilbenes is carbamazepine.25 It is so common and effective thatit is used as the primary drug for the treatment of both tonic-clonic andpartial seizures.25 It works similarly to phenytoins.There is a reduction in the recovery period of the sodium channels therebyextending the refractory period.
25 This reduces the firing rate of theneuron. Also 10,11-epoxycarbamazepine, which is the metabolite of carbamazepineplays a role in limiting the firing of action potentials.26 The side effects of carbamazepine vary with dosage. Acutetoxic effects of the drug include hyponatremia, hepatotoxicity and rash.19 The long term side effects include leucopeniaand weight gain.19 This drug has other beneficial usesincluding the treatment of neuropathic pain and manic-depressive illness.19 Other drugs in the iminostilbenesclass are Oxcarbamazepine and Eslicarbamazepine although the latter is still inthe developmental stages.
25 SUCCINIMIDESThe most commonly used succinimide is ethosuximide.27 It is used in the treatment ofabsence seizures and seizures induced by pentylenetetrazol.19 Considering the pharmacokinetics ofthe drug, it can be said to be well absorbed with a plasma half-life of about60 hours.
28 This is how the drug works: Ethosuximide reduces theimpulses from calcium ion channels in the thalamocortical neurons.16,28 This results in the reduction ofthe firing rate of neuron.28 The drug has a number of sideeffects including nausea, vomiting and dizziness.
28 It also exerts a central effectresulting in euphoria and inability to focus.28 Adverse effects includeParkinsonian syndrome and bradykinesia.28 Another drug of this class ismethsuximide, but is less widely used.19 VALPROATE(VPA)Valproic acid and sodium valproate are all forms ofvalproate that is used in the prevention of seizures. It is employed in thetreatment of generalized seizures, partial seizures and complex absenceseizures.16 Valproic acid is also used to treat bipolar disorders, migraine,headache and other psychological conditions.16 Valproic acids mechanism of action is diverse and its anti-epilepticmechanism is yet to be identified.
16 It is however believed that the drugincreases the GABA concentration in the brain.16 The side effects of valproic acid include hepatic damage andpancreatitis.16 When taken during pregnancy, it hasbeen found to be associated with spinal bifida and other developmentalanomalies due to its teratogenicity properties.
16 Using this drug can cause thepatient to be suicidal and experience tremors.16 It also exerts a central effect by acting onthe central nervous system causing ataxia.16 CURRENT RESEARCH & PROSPECTIVE AGENTS Pharmacogenomics Recentscientific research in the U.S. and Europe are primarily pharmacogenomics.19 This involves the search for biomarkersin individual genes that make a person more susceptible to epilepsy. 29 Pharmacogenomics can also predict theseverity and therapeutic response of epilepsy.29 An individual-based treatment, specificto the particular gene responsible for epilepsy is going to be the mosteffective way of managing this disease.
Theexisting drugs are currently ineffective in 1 out of every 3 cases.30 Newer drugs such as Lacosamide,Rufinamide, Perampanel and many others have been found to be more effective inthe management of epilepsy.30 Ganaxolone, another anti-epilepsy drug isstill under review.30Allthese drugs vary in their mode of action. SURGICAL OPTIONS The primary aim of epilepsy surgeries is to pin-point theregion of the brain responsible of the epilepsy.31 A complete removal of this area is goal of thistreatment. Surgeons are very careful and avoid causing cognitive or neurologicdeficit.
31 In situations where the epilepsy-causing lesionis in an important part of the brain, the surgery is stopped in order toprevent irreversible neurologic impairment.31 Temporal lobectomy is the most common surgical treatment.31 Corpus callosotomy is done when the seizures areobserved to spread from one hemisphere to the other.
Implantation of deep brainstimulators is also effective in the treatment of epilepsy. 31