Seizures and Epilepsy: Pathophysiological and Pharmacological Perspectives PDF

Seizures and epilepsy: pathophysiological and pharmacological perspectives Human brain has ~90 billion neurons Typical neocortical neuron has ~7000 synapses Total synapses in human brain = ~0.15x1015, or 0.15 quadrillion! Cultured cortical...

Seizures and epilepsy: pathophysiological and pharmacological perspectives Human brain has ~90 billion neurons Typical neocortical neuron has ~7000 synapses Total synapses in human brain = ~0.15x1015, or 0.15 quadrillion! Cultured cortical neurons with fluorescent reporter of Ca2+: https://www.youtube.com/watch?v=yy994H pFudc  Learning objectives Describe the pathophysiological processes that contribute to hyperexcitability in the brain Outline the classification of seizure types Explain how EEG can be used to differentiate common seizure types and how other investigations are used Describe the mechanism of action and adverse effects of drugs used in the treatment of epilepsy through modulating voltage-gated sodium,calcium and potassium channels, enhancing GABA- mediated inhibition, modifying synaptic processes and modifying glutamate-mediated excitation. Describe the principles, risks and considerations underlying other therapies employed in the treatment of epilepsy List the anti-epileptic drugs that are safe in pregnancy  “Transient occurrence of signs and/or symptoms due to SEIZURE abnormal excessive or hyper-synchronous neuronal activity in the brain” (ILAE) International League Against Epilepsy Clinical features depend on location & extent of neurons affected Can range from disordered thought (deja vu), temporary confusion, staring spells to clonic-tonic convulsions and loss of consciousness http://www.webmd.com/epilepsy/treat-epilepsy-seizures-16/video-seizure-animation Important definitions CLASSIFICATION OF SEIZURE TYPES Seizure originates in Seizure begins networks limited to simultaneously in one hemisphere both hemispheres [partial] (bilaterally distributed networks) Scheffer 2017 Epilepsia ILAE classification of the epilepsies…PMID: 28276062 CLASSIFICATION OF SEIZURE TYPES Seizure manifests with motor symptoms, like jerking of a limb. Seizure begins with non-motor symptoms, such as sensory disturbances begins in a focal area of the brain but then spreads to involve both hemisphere Aware: Patient remains conscious [simple partial] Impaired awareness: Patient loses consciousness [complex partial] Scheffer 2017 Epilepsia ILAE classification of the epilepsies…PMID: 28276062  CLASSIFICATION OF SEIZURE TYPES Tonic phase: Sustained contraction - extension, arching back Motor: [grand mal] Tonic-clonic: loss of consciousness, tonic-clonic convulsions Clonic phase: Myoclonic: sudden, brief, shock-like contractions (muscle jerks) Rhythmic jerking Tonic: not followed by clonic phase movements Clonic: not preceded by tonic phase Atonic: loss of postural tone (‘drop’ attacks) Non-motor (Absence) - brief loss of awareness without loss of postural tone [petit mal] Scheffer 2017 Epilepsia ILAE classification of the epilepsies…PMID: 28276062 Greenberg, Clinical Neurology, 11th ed. Ch 12  Altered Neurological Mood and General Fatigue Duration Consciousness Symptoms Behaviour Changes Confusion and Headache disorientation Agitation or irritability Aphasia difficulty in speech or Lasts from several comprehension minutes to hours; Drowsiness and Physical and varies among potential sleep mental exhaustion individuals and Motor Deficits seizure types Feelings of depression or Amnesia of the anxiety seizure event Visual disturbances (e.g., blurred vision) POST-ICTAL PHASE  Status epilepticus is a condition characterized by continuous seizures that STATUS EPILEPTICUS persist for more than 5 minutes without recovery or the occurrence of repeated seizures without the person regaining consciousness in between. Severe, continuous seizure without recovery (>5 mins) Normal seizure self-termination mechanisms fail Medical emergency – treat aggressively with anticonvulsants Significant morbidity – May cause neuronal death by excitotoxicity > Development of epilepsy > brain damage Significant mortality MRI at 2 & 7 day follow-ups after episode of focal onset impaired awareness status epilepticus. SUDEP - Sudden Unexpected Death in Epilepsy Definition of SUDEP: The sudden, unexpected, non-traumatic, and non- drowning death of a person with epilepsy, where no toxicological or anatomical cause of death is found. Incidence Rates: SUDEP affects about 1 in 1,000 people with epilepsy each year. Risk Factors: 1. Poorly controlled seizures, especially generalized tonic-clonic seizures 2. Seizure frequency 3. Young adult age (20-40 years) 4. Early onset of epilepsy 5. Duration of epilepsy (length of time since the initial diagnosis) 6. Medication non-adherence  Effects of Seizures on the Brain Short Term Neurotransmitter Release Seizures cause a massive release of neurotransmitters, which can lead to changes in neurotransmitter receptor sensitivity and density Metabolic Demand Increase High electrical activity during a seizure increases the brain's metabolic demand for oxygen and glucose, which can lead to transient energy depletion Ionic Imbalance Seizures often involve ionic shifts, particularly of sodium, potassium, and calcium ions, which can disrupt neuronal function and lead to aftereffects such as confusion Risk of Neuronal Injury Intense seizures, or status epilepticus, can cause acute neuronal injury due to excitotoxicity,  Effects of Seizures on the Brain Long Term Epileptogenesis Frequent seizures can lead to changes in brain structure and function that make future seizures more likely Hippocampal Sclerosis Recurrent seizure cause hippocampal sclerosis > loss of neurons and gliosis in the hippocampus > associated with memory impairment Neurocognitive Impairment Repeated seizures and damage can impair neurocognitive function Brain Atrophy Chronic epilepsy can be associated with progressive brain atrophy  Effects of Seizures on the Brain Molecular and Cellular Changes Gliosis Repeated seizures increases the number of astrocytes, forming scar tissue and occupying space for neuronal growth. Inflammatory Responses seizures can promote inflammation in the brain, which can contribute to further neuronal damage Changes in Gene Expression Blood-Brain Barrier Disruption Frequent seizures can disrupt the blood-brain barrier Seizures can have multiple causes Epilepsy Epilepsy can have multiple causes IDIOPATHIC EPILEPSY Epileptogenesis – terms and definitions Epilepsy Vs. Seizures AND CERTAINLY NOT IN THE LONG TERM Types of neuron effected in epilepsy LOCAL CIRCUIT NEURONS HAVE AXONS WHICH DO NOT EXTEND TO OTHER BRAIN AREAS  YOU DON’T HAVE TO LEARN INFORMATION FROM THIS DIAGRAM FOR ANY EXAM Types of Neuron Effected in Epilepsy  YOU DON’T HAVE TO LEARNINFORMATION FROM THIS DIAGRAM FOR ANY EXAM Types of neuron effected in epilepsy  YOU DON’T HAVE TO LEARNINFORMATION FROM THIS DIAGRAM FOR ANY EXAM Types of neuron effected in epilepsy – context  SIGNAL ISOLATION THROUGH SURROUND INHIBITION These discrete signals are maintained within limited neuronal circuits within a defined area Beyond single cell level, neural networks ensure specificity of a signal to a defined area This occurs through surround inhibition which restricts action potentials from reaching adjacent neurons. SIGNAL ISOLATION THROUGH SURROUND INHIBITION A D C GABA ─ GLUT + ─ + GLUT GABA B GLUT + +  Recurrent inhibition GABA At the same time recurrent inhibition can ─ occur when a principal neuron forms synapses on an inhibitory neuron C Which in turn forms synapses back on the + GLUT principal cells to achieve a negative feedback loop B A In this animation, feedback inhibition slows down the firing of A and B GLUT + +  HYPER-EXCITABILITY GLUT In this case a decrease in GABA transmission  Increases projecting neuron  GABA GABA activity GLUT Feedback onto GABA neuron GLUT increased +++  Increased GABA decreases projecting neuron activity  GLUT  Lesions can cause hyperexcitablility by removing negative feedback GLUT LESION LESION    HYPER-EXCITABILITY GLUT A hyper-excitable state can also result from drugs or toxins which  GABA GABA cause GLUT Increased excitatory GLUT synaptic +++ neurotransmission Decreased inhibitory neurotransmission  GLUT Cellular causes of Focal (Partial) Seizures A DECREASE IN GABA MEDIATED INHIBITION CAN PROMOTE SYNCHRONISATION OF A SEIZURE FOCUS. THIS CAN BE CAUSED BY GLUT GABA CONGENITALLY CHANGES AT DERANGED DEGENERATION RECEPTOR LOCAL OF GABAERGIC LEVEL (OFTEN CIRCUITRY NEURONS DUE TO DRUGS (GENETIC OR TOXINS) CAUSE) Epileptogenesis – How seizure activity spreads WHEN EXTRINSIC OR INTRINSIC FACTORS ALTER THE BALANCE OF EXCITATION AND INHIBITION THE INHIBITORY SURROUND BEGINS TO BREAK DOWN AND THE SEIZURE ACTIVITY SPREADS. GLUT GABA THE RING OF CELLS OUTSIDE THE FOCUS, REPRESENTED HERE BY CELL (D) ARE ACTIVATED  Structural Causes of Focal (Partial) Seizures SCAR TISSUE IN THE BRAIN THAT IMPACTS ON THE MOST OFTEN, FOCAL ADJACENT NEURONAL TISSUE SEIZURES RESULT FROM A LOCALIZED ORGANIC A TUMOUR THAT LESION OR COMPRESSES AN AREA OF FUNCTIONAL THE BRAIN ABNORMALITY, SUCH AS A DESTROYED AREA OF BRAIN TISSUE MECHANISMS: Damage to the hippocampus results in hyper-excitable networks Hippocampal sclerosis (shrunken) is the most common pathological finding in temporal lobe epilepsy (TLE)  B hypersynchronization Hypersynchronous discharges begin in a very discrete region of cortex GLUT GLUT GLUT A Spread to neighbouring GLUT regions + + + GLUT B B C C  The synchronized bursts from a sufficient number of neurons result in a so- called spike discharge on the eeg. Seizure propagation, the process by which a partial seizure spreads within the brain, occurs when there is sufficient activation to recruit surrounding neurons. This leads to a loss of surround inhibition and spread of seizure activity Into surrounding areas via local cortical And to more distant areas via long association connections, pathways such as the corpus callosum. The propagation of bursting activity is normally prevented by a region of surrounding inhibition created by inhibitory neurons. SYNCHRONICITY  MECHANISMS OF HYPER-EXCITABILITY Imbalance in excitatory vs inhibitory networks – Too much excitation Neurotransmitters – glutamate, aspartate Ionic current – inward Na+, Ca2+ – Too little inhibition Neurotransmitter – GABA Ionic currents – inward CI-, outward K+ Evidence base Several anti-convulsants work by promoting GABA function GABA antagonists trigger seizures. Glutamate antagonists stop seizures Mutation of genes encoding voltage/ligand-gated ion channels cause brain hyperexcitability (channelopathies)  HYPER-EXCITABILITY A hyper-excitable state can also result from increased excitation through An alteration of intra- or extra- + − − + + − − + cellular ion concentrations in favour of membrane depolarization +  HYPER-EXCITABILITY A hyper-excitable state can also result from increased excitation through An alteration in the structure of voltage-gated ion channels through + − − + genetic mutation + − − + With mutations causing loss of function through a change in structure An example is in Dravet syndrome +  HYPER-EXCITABILITY A hyper-excitable state can also result from increased excitation through Drugs causing prolonged opening in + − − + favour of membrane depolarisation + + − − + this is aconitine, a toxin from the wolfsbane plant, which can make sodium channels open for longer  MECHANISMS: ALTERED FUNCTION OF SUPPORT CELLS (GLIA) Chronic glial dysfunction Ionic imbalance Decreased glutamate uptake Decreased neuronal GABA synthesis Excessive release of pro- inflammatory molecules BBB damage hyper-excitability, seizures, neuronal injury Moshe 2015, Lancet, PMID: 25260236  Hyper-excitability can arise from mutations in genes encoding ion channels CHANNELOPATHIES Chang 2003, NEJM, PMID: 14507951  Paroxysmal Depolarizing Shift Neurons in a seizure focus have characteristic activity Each neuron within a seizure focus has a stereotypic and synchronized electrical response called the paroxysmal depolarizing shift paroxysmal depolarizing shift The paroxysmal depolarizing shift is an intracellular depolarization that is Sudden, Large (20–40 mv), Long-lasting (50–200 ms), Triggers a train of action potentials at its peak The paroxysmal depolarizing shift is followed by an afterhyperpolarization  paroxysmal depolarizing shift The paroxysmal depolarizing shift results from the prolonged depolarization of the neuronal membrane due to influx of extracellular Ca2+ Na+ This leads to the opening of voltage-dependent Na+ channels, influx of Na+, and generation of repetitive action potentials Ca2+ Depolarization-induced activation of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca2+ influx and neuronal activation Paroxysmal depolarizing shift and NMDA receptors Depolarization-induced activation of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca2+ influx and neuronal activation AN INFLUX OF CALCIUM IONS THROUGH THE NMDA RECEPTOR CAUSES DEPOLARISATION  POSITIVELY CHARGED CALCIUM IONS CAUSE VOLTAGE GATED SODIUM CHANNELS TO OPEN + − − + + − − + + THIS PRODUCES MANY ACTION POTENTIALS CALCIUM IS CLEARED SLOWLY FROM THE NEURON – THIS KEEPS THE NEURON DEPOLARISED POTASSIUM CHANNELS OPEN + − − + + − − + + THIS PRODUCES MULTIPLE ACTION POTENTIALS  HYPERPOLARIZING AFTERPOTENTIAL The subsequent hyperpolarizing afterpotential depending on the cell type is mediated by Na+ IN GABA receptors and Cl− influx,  K+ OUT or by K+ efflux or both Ca2+ Cl− K+  Genetics of epilepsy – CONTEXT Gene mutations that affect ion channel function are a major cause of human epilepsies. In the figure the mutations listed near the spike affect the repolarization of the action potential Those listed below affect the after hyperpolarisation  FOCAL ORIGIN The defining feature of focal (and secondarily generalized) seizures is that the abnormal electrical activity originates from a seizure focus. The seizure focus is a small group of neurons, perhaps 1,000 or so, which: HAVE ENHANCED EXCITABILITY THE ABILITY TO OCCASIONALLY SPREAD THAT ACTIVITY TO NEIGHBOURING REGIONS AND THEREBY CAUSE A SEIZURE. FOCAL SEIZURES ORIGINATE IN A SMALL GROUP OF NEURONS (THE SEIZURE FOCUS) DEVELOPMENT AND PROPAGATION OF A FOCAL SEIZURE THE DEVELOPMENT AND PROPAGATION OF A FOCAL SEIZURE CAN BE ARBITRARILY DIVIDED INTO FOUR PHASES:  Primary Generalized seizures Primary generalized seizures begin without an aura or focal seizure and involve both hemispheres from the onset. They usually begin at the thalamus Primary seizures differ from secondary generalized seizures Seizures that begin from a focus and then generalize are secondary generalised seizures  ELECTROENCEPHALOGRAM MEASURES ELECTRICAL ACTIVITY IS THE BRAIN IN DIFFERENT AREAS The most important neurophysiological tool for diagnosis Records the (weak) electrical activity generated by the brain – Currents generated by collective neuronal activity passing through extracellular space Usually recorded from the scalp → cortical electrical activity Good temporal resolution but poor spatial resolution Amplifier PHYSIOLOGICAL BASIS OF THE EEG Extracellular dipole generated by EPSPs Electrical field generated by similarly orientated pyramidal cells in cortex (layer 5) and detected by scalp electrode  F = frontal EEG ELECTRODE Fp = frontopolar T = temporal C = central PLACEMENT P = parietal O = occipital A = auricular Odd numbered leads indicate left, even-numbered right side Paired electrodes record potential between each-other Diagnostic value is in the frequency and amplitude of the waves Fisher (2014) Adv Exp Med Biol, PMID 25012363 EEG: FOCAL ONSET SEIZURE Seizure originates in one or more foci (brain regions) Can spread to involve entire brain – Focal to bilateral tonic-clonic seizures Seizure focus Secondary Generalised Seizures Focal seizures can spread locally from a focus Can also spread to the contralateral cortex and subcortical areas of the brain through projections to the thalamus, The thalamus has widespread connections to both hemispheres This is shown in this EEG where an abnormal pattern is spread to several brain regions  Focal Seizure Activity ONSET OF A CONSCIOUSNESS IS EEG SPIKE-WAVES THE PATIENT COMPLEX PARTIAL ALTERED (C) THE ARE PARTICULARLY LOW-AMPLITUDE SEIZURE, ACTIVITY REPORTED AURA (A SEIZURE ACTIVITY PROMINENT IN BACKGROUND CONFINED TO SENSE OF FEAR) (B) HAS SPREAD TO THE LEADS 9–10 AND 9– RHYTHMS OCCUR AT ELECTRODES IN THERE IS A BUILD UP LEFT HEMISPHERE 14 OVER THE RIGHT THE BEGINNING RIGHT HEMISPHERE OF EEG ACTIVITY ANTERIOR ELECTRODES 9–16 ELECTRODES 1–8 TEMPORAL REGION.  EEG: ACTIVITY DURING SEIZURE (ICTAL) Seizure: repetitive generalised or focal spikes, sharp waves at ≥ 3 Hz lasting > 10 sec Odd-numbered leads indicate electrode placements over the left side of the head; even numbers, over the right side. Greenberg, Clinical Neurology, Ch 12 EEG of a patient with typical absence (petit mal) seizures, showing a burst of generalized 3-Hz spike wave activity (centre of record) that is bilaterally symmetric and bisynchronous  EEG: GENERALISED ONSET SEIZURE Seizure (epileptiform EEG activity) begins simultaneously in both hemispheres [no clear focus]  INTERICTAL EEG ABNORMALITIES IN EPILEPSY Interictal Period: EEG Assessment between seizures. EEG Transient Abnormalities: Indicative of seizure predisposition. Key EEG Features: Clinical Relevance: Spikes: Brief, sharp waves (20-70 Assists in localizing seizure origin. ms), hallmark of epilepsy. Aids in epilepsy syndrome Sharp Waves: Longer duration (70- classification. 200 ms), indicate neuronal Guides treatment strategy. hyperexcitability Monitors therapeutic efficacy. Background Abnormalities: Brain wave frequency slower than expected for alertness level. EEG: EXAMPLE OF INTER-ICTAL ABNORMALITY (EPILEPTIFORM ACTIVITY) EEG of a patient These findings, with idiopathic obtained at a time (primary when the patient generalized) was epilepsy. A burst not experiencing of generalized seizures, support epileptiform the clinical activity (centre) ? diagnosis of is seen on a epilepsy. relatively normal background. Odd-numbered leads indicate electrode placements over the left side of the head; even numbers, over the right side Greenberg, Clinical Neurology, Ch 12  2-minute Neuroscience: Neuroimaging Brain Imaging in Neurological Assessment Structural Imaging: Functional Imaging Purpose: Purpose: Visualize brain activity and metabolism. Detect physical anomalies (e.g., scar tissue, tumours, bleeds). MRI: Higher soft-tissue resolution than CT fMRI: Maps blood flow changes (BOLD signal). Non-invasive, no radioactive tracers. Ideal for detailed structural assessment. Superior spatial resolution to PET. CT/CAT Rapid imaging, good for acute assessment. PET: Uses radiolabelled markers (e.g., O2, 2DG). Scan: Lower soft-tissue contrast compared to MRI. Reflects metabolic activity and neural function Clinical Localization of seizure foci in epilepsy. Clinical Assessment of metabolic brain diseases. Applicatio Applications ns fMRI MRI scan: hippocAMPAl sclerosis CLINICAL SCENARIO: WHAT LOOKS LIKE A SEIZURE BUT ISN’T? Psychogenic non-epileptic seizures (“pseudo seizures”) – Non-epileptic attack disorder (NEAD) – Often manifestations of psychiatric disturbance (patient may/may not be aware) Qs. How would you distinguish psychogenic from real seizure? Long-term video and EEG recording  Anti-epileptic Drug targets EFFICACY OF ANTI EPILEPTIC DRUGS CENTRES IN MANIPULATION OF ION CHANNEL ACTIVITY  ANTI-EPILEPTIC DRUG TARGETS AT THE PAROXYSMAL DEPOLARISING SHIFT DRUGS THAT ENHANCE NA+ CHANNEL MEDIATED INHIBITION Na+ Na+ Na+ DRUGS THAT ENHANCE GABA – MEDIATED VGC-Na+ VGC-Na+ VGC-Na+ VGC-K+ VGC-K+ VGC-K+ INHIBITION K+ K+ K+ AMPA NMDA VGC-Ca+ NMDA GABAA GABAA GABAA GABAA Na+ Ca2+ Ca2+ Ca2+ DRUGS THAT INHIBIT CALCIUM Cl− Cl− Cl− Cl− Ca2+ CHANNELS  Anti-epileptic Drug targets DRUGS THAT GABA DECREASING ACTIVITY OF ─ ENHANCE CELL A THROUGH GABA – INCREASED ACTIVATION C MEDIATED OF CELL C + INHIBITION GLUT B A DRUGS THAT DECREASING ACTIVATION + + GLUT INHIBIT OF CELL B BY CELL A GLUTAMATE DECREASES SEIZURE RECEPTORS PROPAGATION  Na+ Na+ Na+ Pharmacological Targets Decreasing Sodium Influx VGC-Na+ VGC-Na+ VGC-Na+  Inhibition of sodium channel function Depolarisation of a neuron (such as occurs in the paroxysmal discharge) increases the proportion of the sodium channels in the inactivated state. Antiepileptic drugs bind preferentially to channels in this + − − + + + state, − − Preventing them from returning to the resting state, + Thus reducing the number of functional channels available to generate action potentials.  Inhibition of sodium channel function Several antiepileptic drugs carbamazepine, phenytoin, valproate and lamotrigine affect membrane excitability by an action on voltage-dependent sodium channels They block preferentially The excitation of cells that are firing repetitively The higher the frequency of firing, the greater the block produced.  Inhibition of sodium channel function This characteristic, is relevant to the ability of drugs to Block the high-frequency discharge that occurs in an epileptic fit Without unduly interfering with the low- frequency firing of neurons in the normal state  Inhibition of sodium channel function? WHY IS IT NOT DESIRABLE TO USE A VOLTAGE GATED SODIUM CHANNEL BLOCKER? + − − + + − − + CAN YOU NAME ANY VOLTAGE GATED SODIUM CHANNEL BLOCKER? WHAT ARE THEY USUALLY USED FOR? +  CARBAMAZEPINE Carbamazepine, one of the most widely used antiepileptic Carbamazepine stabilizes the deactivated state of voltage- + − − + + − − + gated sodium channels Carbamazepine is also a GABA receptor agonist, as it has also + been shown to potentiate specific GABA receptors  PHENYTOIN Several other antiepileptic drugs exert their effects with similar mechanisms Valproate Phenytoin + − − + Lamotrigine + + − − Topiramate They only differ in their selectivity and half-lives + SODIUM CHANNEL BLOCKERS PHENYTOIN IS WIDELY USED, ALTHOUGH NOT BEING EFFECTIVE AGAINST AGAINST ABSENCE VARIOUS FORMS OF PARTIAL SEIZURES, WHICH IT AND GENERALISED SEIZURES MAY WORSEN PRIMIDONE IS SIMILAR TO PENTABARBITAL PHENYTOIN, EXCEPT IT IS CAUSES MARKED CONVERTED IN SEDATION PENTOBARBITAL  PHENYTOIN AS A NON-SELECTIVE DRUG HAS MANY ADVERSE EFFECTS (MANY NOT LISTED) NYSTAGMUS DIPLOPIA ATAXIA SEDATION LONG-TERM USE IS ASSOCIATED IN SOME GINGIVAL PATIENTS WITH COARSENING OF FACIAL HIRSUTISM HYPERPLASIA FEATURES AND WITH MILD PERIPHERAL NEUROPATHY SODIUM CHANNEL BLOCKERS VALPROATE IS EFFECTIVE AGAINST INCLUDING ABSENCE BOTH PARTIAL AND SEIZURES GENERALISED SEIZURES VALPROATE HAS VG SODIUM CHANNELS T-TYPE CALCIUM MANY OTHER SITES OF CHANNELS ACTION GABA RECEPTORS VALPROATE – ADVERSE EFFECTS NEURAL TUBE RARE BUT FATAL GI DISTRESS DEFECTS (CLASS X HEPATOTOXICITY IN PREGNANCY) TREMOR WEIGHT GAIN SODIUM CHANNEL BLOCKERS CARBAMAZEPINE CAN TREAT CARBAMAZEPINE PARTIAL SEIZURES IS NON SEDATIVE AND IN ITS USUAL THERAPEUTIC GENERALISED RANGE. TONIC-CLONIC SEIZURES Carbamazepine is more selective CARBAMAZEPINE AS A MORE SELECTIVE DRUG HAS FEWER ADVERSE EFFECTS MILD DIPLOPIA (DOUBLE ATAXIA (DISJOINTED GASTROINTESTINAL VISION) MOVEMENT) UPSETS AT MUCH HIGHER ERYTHEMATOUS DOSES, SKIN RASH DROWSINESS Sodium Channel Blockers Commonly Used Mechanism of for Types of Mechanism Fully Drug Action Epilepsy Elucidated? Sodium Channel Phenytoin Focal, Tonic-clonic Yes Blocker Sodium Channel Carbamazepine Focal, Tonic-clonic Mostly Blocker Sodium Channel Oxcarbazepine Focal Mostly Blocker Sodium Channel Eslicarbazepine Focal Mostly Blocker  POTASSIUM CHANNELS OPEN POTASSIUM CHANNEL OPENERS + − − + + − − +  POTASSIUM CHANNEL OPENERS Neuronal membrane excitability is controlled by potassium channel activity. Increasing potassium conductance hyperpolarises neurons making them less VGC-K+ VGC-K+ VGC-K+ excitable K+ K+ POTASSIUM CHANNEL OPENERS RETIGABINE USUALLY AS AN CAN TREAT ADJUNCTIVE TREATMENT – PARTIAL AN ADD-ON TO OTHER SEIZURES THERAPIES  POTASSIUM CHANNEL OPENERS – RETIGABINE Retigabine is an anticonvulsant used as a treatment for focal seizures Retigabine works primarily as a potassium channel activator + − − + It specifically activates a family of + − − + voltage-gated potassium channels in the brain and not peripherally where serious side effects may occur This mechanism of action is unique among antiepileptic drugs RETIGABINE Retigabine interferes with the voltage sensor of the voltage gated potassium channel + − − + This keeps them open for + − − + longer This was withdrawn from use in 2017 due to cognitive side effects High voltage activated calcium channels High voltage activated calcium channels control entry of calcium into the presynaptic terminal (regulating neurotransmitter release) HVA calcium channels  ACTION POTENTIAL CALCIUM ION SODIUM ION Gabapentin and pregabalin partially block voltage gated PRESYNAPTIC TERMINAL calcium channels in synapses This prevents release of vesicles contain neurotransmitters POSTSYNAPTIC DENDRITE Calcium Channel Blockers GABAPENTIN CAN GABAPENTIN HAS TREAT GENERALISED VERY FEW DRUG TONIC-CLONIC SEIZURES INTERACTIONS AND PARTIAL SEIZURES PREGABALIN CAN TREAT PREGABALIN HAS PARTIAL SEIZURES VERY FEW DRUG INTERACTIONS THESE DRUGS HAVE SEVERAL ADVERSE EFFECTS MIXED SODIUM AND HIGH VOLTAGE CALCIUM CHANNEL BLOCKERS Lamotrigine – Mechanisms of Action Prolongs deactivation of voltage gated sodium channels  ACTION POTENTIAL CALCIUM ION LAMOTRIGINE SODIUM ION Lamotrigine blocks voltage gated calcium channels in synapses PRESYNAPTIC TERMINAL This prevent release of vesicles contain neurotransmitters POSTSYNAPTIC DENDRITE SODIUM AND CALCIUM CHANNEL BLOCKERS LAMOTRIGINE CAN TREAT PARTIAL SEIZURES LAMOTRIGINE IS ALSO USED AND ABSENCE IN BIPOLAR AND MYOCLONIC DISORDER SEIZURES IN CHILDREN LAMOTRIGINE AS A LESS SELECTIVE DRUG HAS NUMEROUS DRUG INTERACTIONS  Sodium and Calcium Channel Blockers Commonly Used Mechanism of for Types of Mechanism Fully Drug Action Epilepsy Elucidated? Sodium and Focal, Absence, Lamotrigine Calcium Channel Mostly Lennox-Gastaut Blocker Sodium and Focal, Tonic- Zonisamide Calcium Channel Mostly clonic Blocker A lamotrigine molecule is illustrated in association with its binding site on a VG Sodium channel  ABSENCE SEIZURES ABSENCE EPILEPSY REFERS TO GENERALIZED NON- CONVULSIVE SEIZURES CHARACTERIZED BY A BRIEF AND SUDDEN IMPAIRMENT OF CONSCIOUSNESS. Thalamocortical pathway and sleep INHIBITION OF THALAMOCORTICAL SIGNAL TRANSMISSION MAY PLAY A ROLE IN ACHIEVING SLEEP WHERE THE FIRING RESPONSE OF THALAMIC PROJECTION NEURONS TO VISUAL STIMULATION IS SUPPRESSED DURING SLEEP  T-type calcium channels T-type calcium channels are low voltage gated They are highly concentrated in the thalamocortical system HIGH VOLTAGE LOW VOLTAGE GATED CALCIUM ACTIVATED T-TYPE CHANNELS CALCIUM CHANNELS T-type calcium channels  T-type Calcium Channels – Context YOU DON’T HAVE TO KNOW THIS DIAGRAM FOR ANY EXAM In a waking state, sensory and motor signals are relayed to and from the cerebral cortex through the thalamus T-type calcium channel activity is important in determining the rhythmic discharge of thalamic neurons associated with absence seizures They are responsible for maintaining oscillation of activity between the thalamus and the cortex Current Opinion in Neurobiology, Volume 31, 2015, 133–140 Absence seizures  MARKED INCREASE OF T-TYPE CA2+ CHANNEL- MEDIATED CA2+ ACTIVITY ARE OBSERVED IN THALAMUS DURING SLEEP ABSENCE SEIZURES ABSENCE SEIZURES RESULT FROM ABNORMAL RESULTING IN A SIMILAR SPIKE-AND-WAVE ACTIVATION OF THE T-TYPE CALCIUM EEG PATTERN AS SLOW WAVE SLEEP CHANNEL DURING THE AWAKE STATE  Absence seizures ◉ Where absence seizures result from abnormal activation of the t-type calcium channel during the awake state T-channel gene mutations have been found in patients with childhood absence epilepsy Drugs used to treat absence seizures Ethosuximide, succinimide, valproate and related anticonvulsants block thalamic T-type Ca2 + channels in thalamocortical neurons at therapeutically relevant concentrations ETHOSUXIMIDE SUCCINIMIDE VALPROATE Calcium Channel Blocker Commonly Used Mechanism of for Types of Mechanism Fully Drug Action Epilepsy Elucidated? T-type Calcium Ethosuximide Absence Yes Channel Blocker HVA Calcium Gabapentin Focal Mostly Channel Blocker HVA Calcium Pregabalin Focal Mostly Channel Blocker  GLUTAMATE The major excitatory neurotransmitter in the CNS is the amino acid glutamate There are several subtypes of glutamate receptors Glutamate receptors can be found post-synaptically on excitatory principal cells  NMDA ligand gated ion channel SPECIFIC LIGAND BINDING SITES ION CHANNEL A SINGLE MAGNESIUM ION SITS INSIDE THE CHANNEL THIS CONFORMATION THERE ARE NO THE CHANNEL IS OF THE CHANNEL LIGANDS BOUND TO CLOSED AT THIS DOES NOT PERMIT STAGE THE BINDING SITES THE FLOW OF IONS AT THIS STAGE  NMDA receptors NMDA receptors have ANOTHER UNUSUAL FEATURE IS THAT ACTIVATION OF NMDA RECEPTORS REQUIRES A CO-AGONIST, GLYCINE physiological properties that set them apart from the other ionotropic glutamate receptors. The pore of the NMDA receptor channel allows the entry of Ca2+ in addition to Na+ and K+ Calcium ions are typically used as an intracellular messenger AMPA receptors NMDA AMPA Sodium ions (or at least a positive charge) is required to displace the magnesium ion from the NMDA receptor This influx of sodium ions comes from activation of AMPA receptors which are usually found to coexist with NMDA receptors under conditions of local membrane depolarization, Mg2+ is displaced HOWEVER, THE MAGNESIUM ION IS BLOCKING THE CHANNEL Mg2+ CAN ONLY BE REMOVED IF THE INTERCELLULAR CURRENT IS +++ Activated AMPA receptors permit entry of Na+ ◉ AMPA RECEPTORS ARE ALSO ACTIVATED BY GLUTAMATE  the channel becomes permeable to Ca2+ influx of Ca2+ tends to further depolarize the cell – – – – NOW THE CHANNEL IS OPEN, IONS CAN FLOW THROUGH THE PORE. THIS STREAM OF IONS IS PERMITTED BY ATTRACTION OF POSITIVE IONS TO REPULSION BETWEEN INCOMING ELECTROSTATIC FORCES NEGATIVE AMINO ACIDS IN THE PORE POSITIVE IONS  Functional importance of glutamate IN EPILEPTOGENESIS Glutamate plays a role in the initiation and spread of seizure activity. It also plays a critical role in epileptogenesis. Dependent on activation of n-methyl-d- aspartate (NMDA) receptors AMPA NMDA VGC-Ca+ PAROXYSMAL DEPOLARISING SHIFT CAUSES I Na+ Ca2+ Ca2+ Ca2+  Glutamate receptors AND SEIZURES Experimental studies using animal epilepsy models have shown that NMDA, AMPA and kainate agonists induce seizure activity Antagonists of NMDA, AMPA and kainate suppress seizure activity Glutamate and excitotoxicity This is thought to contribute to Ca2+ mediated neuronal injury under conditions of excessive neuronal activation (such as status epilepticus and ischemia) OVERACTIVATION OF NMDA RECEPTOR HIGH LEVELS OF CALCIUM IONS TO ENTER THE CELL. CA2+ INFLUX INTO CELLS ACTIVATES A NUMBER OF ENZYMES, INCLUDING PHOSPHOLIPASES, ENDONUCLEASES, AND PROTEASES SUCH AS CALPAIN. THESE ENZYMES GO ON TO DAMAGE CELL STRUCTURES SUCH AS COMPONENTS OF THE CYTOSKELETON, MEMBRANE, AND DNA. DRUGS ACTIVE AT THE NMDA RECEPTOR M. Ghasemi, S.C. Schachter / Epilepsy & Behavior 22 (2011) 617–640 EXPECTED SIDE EFFECTS FROM NMDA blockade Blockade of NMDA receptors would be an effective prevention of paroxysmal depolarisation However NMDA receptors are far too widespread in the cns and many side effects would occur. The most major of these effects is a loss of motor function and hallucinations NMDA antagonists in status epilepticus In status epilepticus, a state of continuous seizures, the risk of excitotoxicity and subsequent neuronal death is high. NMDA receptor blockage may be useful in preventing excitotoxicity and seizure in this extreme condition, where side effects may be irrelevant Ketamine has been utilized in refractory status epilepticus. No complications were described. Critical Care Research and Practice (2015) http://dx.doi.org/10.1155/2015/831260  FELBAMATE Felbamate binds to a site within the NMDA receptor channel pore and acts as an open channel blocker The significance of felbamate being an open channel is that it only binds when NMDA receptors are activated This means that it binds where and when there is a high receptor density of open channels (especially preceding paroxysmal depolarisation)  FELBAMATE Felbamate was approved by the U.S. Food and drug administration (FDA) in 1993 Currently, felbamate is not used as a first-line AED and generally is used only for patients with intractable partial seizures Lennox-Gastaut syndrome and infantile spasms AMPA receptors NMDA receptors cannot be activated without an influx of sodium ions Usually, this Na+ influx comes from activation of AMPA receptors can blocking AMPA receptors form a possible drug target for prevention of seizures? Perampanel Perampanel is the first selective AMPA receptor antagonist approved for epilepsy treatment. Perampanel is a potent noncompetitive antagonist of AMPA receptors It does not affect NMDA receptor responses Perampanel is effective at brain concentrations that would produce only low levels of inhibition of AMPA receptors.  Perampanel Perampanel has a black box warning that the drug cause may cause serious psychiatric and behavioral changes it may cause homicidal or suicidal thoughts. aggression and anger Levetiracetam YOU DON’T HAVE TO KNOW THE CONTENTS OF THIS DIAGRAM lev-eh-teer-ASS-eh-tam Levetiracetam is an antiepileptic drug that inhibits glutamate, and thus reduces neuronal hyperactivity. Levetiracetam is known to bind to SV2A (Synaptic Vesicle Glycoprotein 2A); a membrane glycoprotein found on synaptic vesicles in neurons. It plays a crucial role in the regulation of neurotransmitter release, although the exact mechanism remains not fully understood.  Levetiracetam 1. Broad-Spectrum Efficacy: Brivaracetam is a newer Effective for focal and generalized seizures, drug with a similar including tonic-clonic, myoclonic, and atypical mechanism of action absence. 2. Versatile Use: Suitable as both monotherapy and adjunctive therapy across various epilepsy syndromes. 3. Rapid Onset: Quick action onset, beneficial for acute seizure management. 4. Pediatric Approval: Approved for infants and children, with dose adjustments. 5. Low Drug Interaction Risk: Minimal interactions; not metabolized by cytochrome P450. 6. Tolerability: Generally well-tolerated; watch for potential behavioral side effects. YOU DON’T HAVE TO KNOW THE Levetiracetam has been found to inhibit N-type calcium channels, bind to and inhibit AMPA CONTENTS OF THIS DIAGRAM receptors, and modulate SV2A proteins. These interactions are believed to contribute to the antiepileptic effects of levetiracetam Glutamate Modulators and Multi- Mechanism Drugs Commonly used for Mechanism fully Drug Mechanism of action types of epilepsy elucidated? NMDA receptor Refractory epilepsy, Felbamate Mostly inhibition lennox-gastaut Perampanel AMPA receptor inhibition Focal, tonic-clonic Yes Focal, tonic-clonic, Topiramate Multi-mechanism Partially Lennox-Gastaut Focal, myoclonic, tonic- Levetiracetam SV2A binding Partially clonic Multi-mechanism (not Dravet syndrome, Cannabidiol No fully understood) lennox-gastaut  GLUT GABA  GABA GABA GLUT Most inhibitory synapses in the brain and GLUT +++ spinal cord use either y-aminobutyric acid (GABA) or glycine as neurotransmitters.  GLUT  Activation of the GABAergic system ACTIVATION OF THE GABA SYSTEM CAUSES SLEEP & DROWSINESS CAN REDUCE ANXIETY, AND INHIBIT SEIZURES INHIBITION OF THE GABA SYSTEM CAN INCREASE ANXIETY AND AT HIGHER LEVELS OF ACTIVATION CAN CAUSE SEIZURES  PHARMACOLOGICAL TARGETS IN INCREASING GABA ACTIVITY Epileptic activity emerges from the network when GABA-mediated inhibition is deficient GABAA GABAA FEEDBACK INTERNEURON ACTIVATES GABA RECEPTORS AND CL− INFLUX Cl− Cl− Cl− Cl− PHARMACOLOGICAL TARGETS IN INCREASING GABA ACTIVITY Increasing GABA activity can prevent the initial depolarization through activation of GABA receptors and Cl− influx GABAA GABAA Cl− Cl− Cl− Cl− NON-COMPETITIVE LIGANDS AT ALLOSTERIC SITES (NOT AT THE RECEPTOR BIND SITES) AT LIGAND GATED ION CHANNELS CHANNEL MODULATORS – BENZODIAZEPINES  BENZODIAZEPINES | ADVERSE EFFECTS The sedative effect is too Withdrawal syndrome if the pronounced for them to be drug is stopped abruptly used for maintenance therapy Although tolerance to Which results in an sedation develops over exacerbation of 1–6 months seizures CLINICAL USE OF BENZODIAZEPINES Acute seizures, Diazepam often being especially in children administered rectally Status epilepticus where Agents such as lorazepam, they act very rapidly compared with other diazepam, or clonazepam are antiepileptic drugs. administered intravenously. CHANNEL MODULATORS – BENZODIAZEPINES BARBITURATES  Barbiturates have multiple sites of action Barbiturates potentiate inhibitory GABAA receptors However, barbiturates modulate other systems Voltage gated calcium channels Voltage gated sodium channels and ligand gated sodium channels Inhibit excitatory AMPA receptors Given the multiple sites for barbiturates, for example, phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug is often tried for virtually every seizure type Particularly when resistant to other drugs GABA SYNTHESIS GLUTAMIC ACID DECARBOXYLASE (GAD), THE SPECIFIC BIOSYNTHETIC ENZYME FOR GABA, VIT B6 ACTS AS COENZYME FOR GAD 1951 AND 1982 RECALLS OF BABY FORMULA WITH INSUFFICIENT OR NO B6, INFANTS HAD SEIZURES. http://vrn.vanderbilt.edu/2010/Images/Figures/Solis.png  GABA REUPTAKE MECHANISMS TRANSPORTERS PROMOTE THE REUPTAKE OF NEUROTRANSMITTER INTO THE PRESYNAPTIC TERMINAL GABA MAY ALSO BE TAKEN UP BY SURROUNDING GLIAL CELLS IN THE GLIAL CELLS GABA IS CONVERTED INTO GLUTAMATE (GLU) GLUTAMATE IS CONVERTED BY GLIAL GLUTAMINE SYNTHETASE TO GLUTAMINE (GLN). GLUTAMINE IS TRANSPORTED BACK TO THE NERVE TERMINAL SN TRANSPORTERS (SN1/SN2) A TRANSPORTER (SAT) IN THE TERMINAL GABA IS SYNTHESIZED AGAIN FROM GLUTAMINE VIA GLUTAMATE  Drugs acting at GABA Transporter - GAT-1 Tiagabine is a highly selective inhibitor of gat-1 in neurons and glia Inhibition of gat-1 by tiagabine suppresses the reuptake and thus raising extracellular GABA levels. It has a short plasma half-life and is mainly used as an add-on therapy for partial seizures.  GAT-1 GABA Reuptake transporter GABA IS METABOLISED IN THE PRESYNAPTIC TERMINAL PRESYNAPTIC CELL CYTOPLASM SYNAPTIC CLEFT Inhibition of GAT-1 by tiagabine suppresses the reuptake and thus raises extracellular GABA levels. Drugs acting at GABA Transaminase GABA transaminase (GABA-T) is an enzyme that is responsible for the metabolic inactivation of GABA. Vigabatrin, the first ‘designer drug’ in the epilepsy field is an irreversible inhibitor of GABA transaminase Drugs acting at GABA Transaminase Because vigabatrin prevents the metabolism of GABA This increases the amount of GABA released from vesicles and effectively enhances inhibitory transmission. VIGABATRIN Vigabatrin has been reported to be effective in a substantial proportion of patients resistant to the established drugs. However, a drawback of vigabatrin is the development of peripheral visual field defects in a proportion of patients on long-term therapy.  GABA Modulators Commonly Used for Types Mechanism Fully Drug Mechanism of Action of Epilepsy Elucidated? GABA-A Receptor Diazepam Status Epilepticus Yes Modulation GABA-A Receptor Lorazepam Status Epilepticus Yes Modulation GABA-A Receptor Clonazepam Absence, Myoclonic Yes Modulation GABA-A Receptor Phenobarbital Focal, Tonic-clonic Mostly Modulation GABA Transaminase Vigabatrin Infantile spasms, Focal Yes Inhibition Tiagabine GABA Reuptake Inhibition Focal Yes DRUGS ACTING AT MULTIPLE RECEPTORS  DRUGS ACTING AT MULTIPLE RECEPTORS – TOPIRAMATE Topiramate is a drug that appears to do a little of everything, Blocking sodium and calcium channels Enhancing the action of GABA Blocking AMPA receptors Its clinical effectiveness resembles that of phenytoin, and it is claimed to produce less severe side effects, Currently, it is mainly used as add-on therapy in refractory cases of partial and generalised seizures.  BASIS OF COMBINATIONAL TREATMENT Studies have shown that combining newer antiepileptic drugs with different mechanisms of action May have greater effectiveness (a combination of efficacy and tolerability) than combining drugs with similar mechanisms of action  CANNABIDIOLS IN EPILEPSY Since 2014, cannabidiol (CBD) has been administered to patients with treatment- resistant epilepsies, usually as an add-on therapy CANNABIDIOLS IN EPILEPSY In one study, cannabidiol (CBD) administration produced proportions of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures at 52%, 31%, and 11%, respectively, at 12 weeks CBD was generally well tolerated; most common AEs were diarrhoea (29%) and somnolence (22%). (2018 Jul 12. doi: 10.1111/epi.14477) CANNABIDIOLS IN EPILEPSY “CBD is anticonvulsant, but it has a low affinity for the cannabinoid receptors CB1 and CB2; therefore the exact mechanism by which it affects seizures remains poorly understood”. J Pharmacol Exp Ther 357:45–55, April 2016 “studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies”.BMC Pediatr. 2018 Jul 7;18(1):221. THE KETOGENIC DIET The ketogenic diet (KD) is a high fat, low carbohydrate, controlled protein diet It has been used since the 1920s for the treatment of epilepsy. https://www.epilepsysociety.org.uk/ketogenic-diet#.WyX0AiB9hPY  THE Ketogenic diet The ketogenic diet is an established treatment option for children with hard to control epilepsy. The diet is a medical treatment and is usually only considered when at least two suitable medications have been tried and not worked. Some adults may benefit from dietary treatments https://www.epilepsysociety.org.uk/ketogenic-diet#.WyX0AiB9hPY Curr Treat Options Neurol. 2008 Nov; 10(6): 410–419. CONTENTS Antiepileptic drugs often have quite similar adverse effects  Overdose and antiepileptic drugs The most dangerous effect of antiepileptic drugs after large overdoses is respiratory depression Treatment of antiepileptic drug overdose is ◉ supportive – there are not often direct antidotes WITHDRAWAL Withdrawal of antiseizure drugs can cause increased seizure frequency and severity. Some drugs are Withdrawal of anti-absence drugs is easier more easily Withdrawal of drugs needed for partial or withdrawn than generalized tonic-clonic seizures are difficult. others.  Withdrawal from antiepileptic drugsTAPERING 10 9 8 7 6 5 4 3 2 1 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 WEEKS WITHDRAWAL OF DRUGS NEEDED FOR PARTIAL OR GENERALIZED WEEKS OR MONTHS MAY BE TONIC-CLONIC SEIZURES SUCH AS REQUIRED, WITH VERY GRADUAL BARBITURATES AND DOSAGE DECREMENTS BENZODIAZEPINES ARE THE MOST DIFFICULT TO DISCONTINUE  Discontinuance TAPERING 10 if a patient is seizure-free for 9 3 or 4 years, a trial of gradual discontinuance is 8 often warranted. 7 this involves tapering the 6 dose gradually and 5 observing whether seizures take place 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 WEEKS  TERATOGENIC SIDE EFFECTS Many antiepileptic drugs have been implicated as teratogenic, Including phenytoin (particularly cleft lip/palate), Valproate (neural tube defects) Carbamazepine (spina bifida and hypospadias, a malformation of the male urethra)  Risk of major congenital malformations associated with perinatal While no AED is considered antiseizure medication exposure. completely safe for use in pregnancy, some are associated with lower risks of foetal malformations and adverse pregnancy outcomes. Lamotrigine (Lamictal): Studies suggest that lamotrigine is associated with a lower risk of major congenital malformations compared to other AEDs. Levetiracetam (Keppra): This drug is increasingly used in pregnancy and has been associated with lower teratogenic risk in several studies. Omotola A Hope, and Katherine MJ Harris BMJ 2023;382:bmj-2022-074630 ©2023 by British Medical Journal Publishing Group Pregnant Women With Epilepsy Suggested treatment timeline for women with epilepsy planning pregnancy. ASM=antiseizure medication; (ADT???) VPA=valproate; LEV=levetiracetam; LTG=lamotrigine. Omotola A Hope, and Katherine MJ Harris BMJ 2023;382:bmj-2022-074630 ©2023 by British Medical Journal Publishing Group  SUMMARY Known and potential sites of action of anticonvulsant drugs at inhibitory GABAergic synapses: (1) Inhibition of GABA transporters (tiagabine) (2) Inhibition of GABA transaminase (vigabatrin) (3) Facilitation of GABA receptors (benzodiazepines, barbiturates) Known and potential sites of action of anticonvulsant drugs at excitatory glutamatergic synapses: (1) Blocking voltage-gated Phenytoin, carbamazepine, lamotrigine sodium channels (2) Blocking voltage-gated Lamotrigine, gabapentin, pregabalin calcium channels (3) Opening voltage-gated Retigabine potassium channels (4) Synaptic vesicle Levetiracetam glycoprotein 2A Perampanel (6) Inhibiting AMPA Phenobarbital, topiramate, lamotrigine (7) NMDA partial Felbamate (glycine site) antagonist Small circles in the intracellular space represent glutamate molecules. Bibliography