A seizure is the clinical expression of an abnormal, excessive, and hypersynchronous discharge of a population of neurons. Understanding why seizures occur requires understanding both why individual neurons become hyperexcitable and why that hyperexcitability spreads to recruit neighboring neurons into a synchronized, self-reinforcing discharge. These two problems, excitability and synchrony, are the targets of essentially all anti-seizure drug (ASD) mechanisms currently in clinical use.
At the cellular level, seizure generation depends on an imbalance between excitatory and inhibitory neurotransmission. The principal excitatory neurotransmitter in the central nervous system (CNS) is glutamate, which acts at ionotropic receptors including the N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate subtypes, as well as at metabotropic glutamate receptors. Activation of NMDA receptors, which are voltage-gated and ligand-gated, allows calcium influx that can trigger long-lasting changes in neuronal excitability. The principal inhibitory neurotransmitter is gamma-aminobutyric acid (GABA), which acts at GABA-A receptors, which are ligand-gated chloride channels, and at GABA-B receptors, which are G protein-coupled receptors linked to potassium channel opening and calcium channel closure.1 Under normal conditions, the balance between glutamatergic excitation and GABAergic inhibition maintains neuronal firing within physiological limits.
Seizure initiation requires that this balance shift sufficiently to allow runaway excitatory activity. Several distinct mechanisms can produce this shift. Increased glutamatergic drive, through excess glutamate release, reduced reuptake, or upregulation of AMPA or NMDA receptor expression, lowers the threshold for neuronal firing. Reduced GABAergic inhibition, through loss of interneurons, reduced GABA-A receptor expression, or altered receptor subunit composition that changes chloride conductance, impairs the feedback braking that normally terminates excitatory activity. Intrinsic membrane changes, including increased persistent sodium currents, increased T-type calcium currents in thalamocortical circuits, and reduced potassium conductances that normally repolarize neurons after firing, also promote repetitive high-frequency discharge.2 In many forms of epilepsy, several of these mechanisms operate simultaneously and are mutually reinforcing.
The transition from a single hyperexcitable neuron to a synchronized seizure discharge requires network recruitment. Lateral inhibition, the normal mechanism by which inhibitory interneurons suppress the firing of surrounding pyramidal neurons, is overwhelmed when the excitatory drive is sufficiently intense. Gap junctions between neurons allow direct electrical coupling that can synchronize firing independent of synaptic transmission. Ephaptic coupling, the influence of local field potentials on neighboring neurons, can also contribute to synchronization in dense cortical tissue. Once a critical mass of neurons enters synchronous discharge, the field potential that results further depolarizes adjacent neurons through ephaptic mechanisms, creating a self-propagating wave of excitation that characterizes the ictal (seizure) state.3
The concept of the seizure threshold is clinically important: it refers to the level of excitatory stimulus required to generate a seizure in a given individual at a given moment. The seizure threshold is not fixed; it is lowered by sleep deprivation, fever, metabolic disturbances (hyponatremia, hypoglycemia, hypocalcemia), alcohol withdrawal, and many drugs that either enhance glutamatergic transmission or reduce GABAergic transmission. It is raised by adequate ASD plasma concentrations and by the physiological state of wakefulness, which is why some patients experience seizures predominantly during sleep or in the immediate post-awakening period. This dynamic nature of the seizure threshold has direct implications for counseling patients about seizure triggers and for understanding breakthrough seizures in patients otherwise well-controlled on ASDs.
Between seizures, the electroencephalogram (EEG) of a patient with epilepsy often shows interictal epileptiform discharges (IEDs), which are brief spikes or sharp waves reflecting focal or generalized cortical hyperexcitability without clinical manifestation. IEDs confirm the diagnosis of epilepsy but do not define seizure type. During a seizure, the EEG shows ictal activity: rhythmic, evolving patterns including spike-wave discharges in generalized epilepsies or focal rhythmic activity in focal onset seizures. The transition from interictal to ictal activity on EEG corresponds to the critical recruitment of surrounding neurons that converts subthreshold hyperexcitability into a self-sustaining synchronized discharge.
Seizure termination involves active processes rather than simply the exhaustion of excitatory drive. As an ictal discharge continues, several feedback mechanisms engage: potassium accumulates in the extracellular space, hyperpolarizing neurons through potassium conductance; sodium accumulates intracellularly, reducing the driving force for further sodium-dependent depolarization; and inhibitory interneurons, if not themselves silenced by excessive excitation, can eventually overcome the ictal drive. Adenosine, released from metabolically active neurons during the ictal discharge, acts at A1 adenosine receptors to inhibit neuronal firing and contribute to seizure termination and the post-ictal refractory state that follows.3 The post-ictal state, characterized clinically by confusion, somnolence, and in some patients by a Todd paralysis (a transient focal neurological deficit reflecting neuronal exhaustion in the region of seizure onset), reflects this combination of active inhibitory processes and metabolic recovery.
The International League Against Epilepsy (ILAE) revised its seizure and epilepsy classification in 2017, replacing the older 1981 and 1989 frameworks that had become misaligned with contemporary understanding of seizure biology and clinical practice. The 2017 classification operates at three levels: seizure type, epilepsy type, and epilepsy syndrome. For the prescribing clinician, the most immediately actionable level is seizure type, because several ASDs are effective across a broad range of seizure types while others are narrowly indicated, and some agents that are effective for one seizure type will aggravate another.
The 2017 ILAE classification divides seizures at the first level by onset: focal onset, generalized onset, and unknown onset.4 This first step reflects the most important pharmacological distinction. Focal onset seizures (previously called partial seizures) arise in a network limited to one cerebral hemisphere. They may remain focal or may spread to involve both hemispheres through a secondary generalization, now termed focal to bilateral tonic-clonic seizure. Generalized onset seizures arise simultaneously in networks distributed across both hemispheres from the outset, as reflected by the bilateral synchronous ictal pattern on electroencephalography (EEG). Unknown onset seizures are classified as such when the onset cannot be determined from available information, a common situation in patients whose seizures are unwitnessed or begin during sleep.
Focal onset seizures are further classified by the level of awareness during the event. Focal aware seizures (previously called simple partial seizures) are those in which the patient retains full awareness and can recall the event. Focal impaired awareness seizures (previously called complex partial seizures) involve any alteration of awareness or responsiveness during the event; the patient may appear confused, perform automatisms such as lip-smacking or hand-wringing, and will typically not recall the ictal period. This distinction matters clinically because focal impaired awareness seizures carry greater safety implications, including driving restrictions, and are more likely to be associated with mesial temporal sclerosis or other structural pathology that may be surgically addressable.4
Focal onset seizures are additionally classified by their motor or non-motor characteristics. Motor onset types include tonic (sustained muscle contraction), clonic (rhythmic jerking), myoclonic (brief, shock-like muscle jerks), epileptic spasms (sudden brief flexion or extension of the trunk and limbs, seen in infantile spasms), hyperkinetic (proximal limb and trunk movements resembling pedaling or thrashing), and automatisms. Non-motor onset types include autonomic (tachycardia, piloerection, epigastric rising sensation), behavioral arrest (cessation of activity without other features), cognitive (disturbance of language, memory, or thought), emotional (fear, laughter, or other affective change), and sensory (visual, auditory, olfactory, or somatosensory phenomena). An aura is a focal aware seizure that precedes a focal impaired awareness or bilateral tonic-clonic event and serves as a localizing signal of the cortical region of seizure onset.
Generalized onset seizures are classified by their predominant motor or non-motor characteristics. Motor types include tonic-clonic (the classic grand mal, with an initial tonic phase of stiffening followed by a clonic phase of rhythmic jerking), tonic, clonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, and epileptic spasms. Non-motor generalized onset seizures include absence seizures, which are brief (typically 5–30 seconds), abrupt lapses of awareness with behavioral arrest and a characteristic 3 Hz generalized spike-wave discharge on EEG, without a post-ictal phase; and atonic seizures, which are sudden losses of postural muscle tone causing head drops or falls (drop attacks).4 The distinction between typical absence seizures, which have the classic 3 Hz spike-wave and respond well to ethosuximide and valproate, and atypical absence seizures, which have slower spike-wave and are associated with Lennox-Gastaut syndrome (LGS), is pharmacologically important because these two types require different treatment strategies.
Several anti-seizure drugs (ASDs) that are effective for focal onset and generalized tonic-clonic seizures will aggravate absence, myoclonic, and atonic seizures. Carbamazepine, oxcarbazepine, phenytoin, and gabapentin are among the agents that can paradoxically worsen generalized seizure types, particularly absence and myoclonic seizures, when administered to patients with idiopathic generalized epilepsies (IGEs). This aggravation occurs because these drugs selectively target sodium channel or calcium channel mechanisms that are not the primary drivers of generalized spike-wave discharges, and in some cases may reduce overall cortical inhibition at the network level. Misclassifying a generalized epilepsy as focal and initiating carbamazepine is a well-recognized clinical error with preventable harm. Accurate seizure classification is therefore not an academic exercise; it is the essential first step in selecting a drug that will help rather than harm.
At the second classification level, epilepsy type is designated as focal, generalized, combined generalized and focal, or unknown. At the third and most specific level, epilepsy syndrome refers to a cluster of features, including seizure type, EEG characteristics, neuroimaging findings, age of onset, natural history, and genetic associations, that together define a recognizable condition with specific prognostic and therapeutic implications. Syndrome diagnosis, where achievable, provides the most precise guide to drug selection and is discussed further in Section 3.
Focal onset: arise in one hemisphere; classified as aware or impaired awareness; may have motor or non-motor onset features; may secondarily generalize to bilateral tonic-clonic.
Generalized onset: arise in bilateral networks simultaneously; include tonic-clonic, absence (typical and atypical), myoclonic, atonic, tonic, and clonic types.
Unknown onset: insufficient information to classify; does not prevent treatment but should prompt further diagnostic evaluation including video-EEG monitoring when seizures recur.
Clinical rule: always determine seizure type before selecting an ASD. Broad-spectrum agents (valproate, lamotrigine, levetiracetam, topiramate) cover both focal and generalized types. Narrow-spectrum agents (carbamazepine, oxcarbazepine, phenytoin, gabapentin) cover focal and tonic-clonic but must be avoided in idiopathic generalized epilepsies.
Epilepsy syndrome diagnosis, when achievable, is the most clinically precise guide to anti-seizure drug (ASD) selection. Several syndromes have specific first-line agents supported by strong evidence, specific agents that are contraindicated because they reliably worsen seizure control, and well-defined natural histories that determine the appropriate duration of therapy. This section focuses on the syndromes most likely to be encountered in general clinical practice and most relevant to the ASD pharmacology covered in subsequent modules.
Childhood absence epilepsy (CAE) is one of the most common pediatric epilepsy syndromes, typically presenting between ages 4 and 10 years with multiple daily absence seizures. Each seizure consists of an abrupt, brief (5–30 second) lapse of awareness with behavioral arrest, often accompanied by subtle eye flickering, and an immediate return to full consciousness without post-ictal confusion. The electroencephalogram (EEG) shows the pathognomonic pattern of 3 Hz generalized spike-wave discharges arising from and returning to a normal background. Ethosuximide is the first-line agent for pure CAE and is superior to valproate in cognitive tolerability and to both ethosuximide and lamotrigine when considering absence seizure control without generalized tonic-clonic seizures, as demonstrated in the Childhood Absence Epilepsy trial.5 Lamotrigine is a reasonable alternative. Carbamazepine, oxcarbazepine, phenytoin, tiagabine, and gabapentin are contraindicated in CAE, as they reliably aggravate absence seizures. The prognosis of CAE is generally favorable, with remission in the majority of patients by mid-adolescence, though a subset develop juvenile myoclonic epilepsy (JME).
Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy (IGE) syndrome in adolescents and young adults, accounting for approximately 5–10% of all epilepsy. The hallmark is myoclonic jerks occurring predominantly in the morning within an hour of awakening, often causing patients to drop objects or spill liquids. Most patients also have generalized tonic-clonic seizures (GTCs), and approximately one-third have absence seizures. The EEG characteristically shows 4–6 Hz generalized polyspike-wave discharges, with marked sensitivity to photic stimulation and eye closure. Valproate has historically been the most effective agent for JME, providing control of all three seizure types in the majority of patients, but its teratogenicity makes it a problematic first choice for women of reproductive age.6 Levetiracetam and lamotrigine are widely used alternatives; lamotrigine may paradoxically worsen myoclonic jerks in some patients with JME despite being effective for other seizure types in the syndrome. JME requires lifelong treatment in most patients, as relapse rates after drug withdrawal are high.
Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic encephalopathy characterized by multiple seizure types, intellectual disability, and a characteristic slow spike-wave EEG pattern of less than 2.5 Hz. The seizure types most characteristic of LGS are tonic seizures (during sleep), atonic seizures (drop attacks causing falls and injury), and atypical absence seizures. LGS is pharmacologically challenging because no single agent controls all seizure types, and many patients continue to have frequent seizures despite polytherapy.7 Valproate is typically the backbone of therapy. Clobazam, rufinamide, lamotrigine, topiramate, and felbamate each have evidence for adjunctive efficacy in LGS. The cannabidiol preparation Epidiolex has regulatory approval specifically for LGS and Dravet syndrome. Drug-drug interactions are particularly important in LGS because of polytherapy: rufinamide levels are substantially reduced by enzyme-inducing ASDs, and clobazam levels are increased by several co-administered agents.
Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adults and the epilepsy type most frequently associated with drug resistance. Most cases are associated with mesial temporal sclerosis (MTS), a pattern of hippocampal neuronal loss and gliosis visible on magnetic resonance imaging (MRI). Seizures in TLE typically begin with an aura (rising epigastric sensation, fear, or a deja vu phenomenon), progress to a focal impaired awareness seizure with behavioral arrest and oro-alimentary automatisms (lip-smacking, swallowing, hand automatisms), and may secondarily generalize. TLE associated with MTS is the form of epilepsy with the strongest evidence for surgical benefit: temporal lobectomy achieves seizure freedom in approximately 60–70% of appropriately selected patients, a substantially better outcome than additional ASD trials in drug-resistant cases.8 For medical management, carbamazepine and oxcarbazepine are traditional first choices for focal epilepsy, with levetiracetam and lamotrigine increasingly preferred due to their more favorable drug interaction profiles.
Dravet syndrome is a severe childhood epileptic encephalopathy caused predominantly by loss-of-function variants in SCN1A, the gene encoding the Nav1.1 sodium channel subtype expressed preferentially on inhibitory interneurons. Loss of Nav1.1 in interneurons reduces GABAergic inhibition, promoting seizures despite the paradoxical sodium channel deficit. Sodium channel-blocking ASDs (carbamazepine, lamotrigine, phenytoin) aggravate Dravet syndrome by further reducing the residual Nav1.1 function in interneurons, worsening inhibitory deficits. First-line agents include valproate, clobazam, and stiripentol. Cannabidiol (Epidiolex) and fenfluramine have regulatory approval as adjunctive treatments. The Dravet syndrome example illustrates the principle that pharmacogenetic knowledge of a syndrome's molecular basis directly determines which drugs are contraindicated, not merely which are preferred.
West syndrome, also known as infantile spasms, deserves mention because its pharmacological management is entirely distinct from other epilepsy syndromes and relies on agents that have no other major role in adult epilepsy practice. The syndrome presents in infancy (typically before 12 months) with epileptic spasms (brief flexion or extension of the trunk and limbs), developmental regression, and a chaotic high-amplitude EEG pattern called hypsarrhythmia. First-line treatments are adrenocorticotropic hormone (ACTH) and vigabatrin, an irreversible inhibitor of GABA transaminase. Vigabatrin is particularly effective in West syndrome associated with tuberous sclerosis complex (TSC). The distinction between West syndrome and other infantile seizure types requires EEG confirmation of hypsarrhythmia and carries important prognostic implications, as early effective treatment correlates with better developmental outcomes.
CAE and JME (idiopathic generalized epilepsies): avoid carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, tiagabine. These agents worsen absence and myoclonic seizures.
Dravet syndrome: avoid sodium channel blockers (carbamazepine, lamotrigine, phenytoin). Use valproate, clobazam, stiripentol, cannabidiol, fenfluramine.
LGS drop attacks: rufinamide, clobazam, and cannabidiol each have specific approval or strong evidence. Lamotrigine and valproate are backbone agents but rarely sufficient alone.
TLE with drug resistance: always evaluate for surgical candidacy before cycling through additional ASDs; the probability of seizure freedom with a third ASD trial is approximately 5% or less.
Anti-seizure drugs (ASDs) act by reducing the excitability of individual neurons, impairing the synchronization of neuronal networks, or both. The major mechanistic categories correspond to the principal drivers of seizure generation discussed in Section 1: voltage-gated sodium channel blockade, enhancement of GABAergic inhibition, reduction of T-type calcium channel activity, modulation of high-voltage-activated calcium channels through the alpha-2-delta subunit, glutamate receptor antagonism, and modulation of synaptic vesicle release through the SV2A protein. Most currently used ASDs act predominantly through one of these mechanisms, though several have multiple actions that collectively contribute to their clinical profile.
Voltage-gated sodium channel blockers represent the largest mechanistic category of ASDs. These drugs bind to the inactivated state of the voltage-gated sodium channel (Nav), stabilizing it in the inactivated conformation and reducing the availability of channels for repetitive high-frequency firing. This state-dependent mechanism means that the drug has greater effect on neurons firing at high frequencies, as occurs during a seizure, than on neurons firing at normal rates, providing a degree of selectivity for ictal over normal neuronal activity. Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, and zonisamide all act primarily through this mechanism on the fast inactivation state. Lacosamide differs by selectively enhancing slow inactivation of sodium channels, a distinct conformational state that is engaged at depolarized membrane potentials maintained over longer periods.2 This mechanistic distinction may account for lacosamide's activity in some sodium channel-blocker-resistant seizure populations.
Enhancement of GABA-A receptor-mediated chloride conductance is the mechanism of benzodiazepines, barbiturates, and several other ASDs. GABA-A receptors are heteropentameric ligand-gated ion channels assembled from alpha, beta, gamma, delta, and other subunits. Benzodiazepines bind to the interface between alpha and gamma subunits and act as positive allosteric modulators, increasing the frequency of chloride channel opening in response to GABA without activating the channel directly. Barbiturates bind to a distinct site and at therapeutic concentrations prolong the duration of chloride channel opening; at high concentrations they can activate the channel directly, independent of GABA, which contributes to their greater toxicity relative to benzodiazepines.1 Vigabatrin irreversibly inhibits GABA transaminase, the enzyme responsible for GABA catabolism, increasing synaptic GABA concentrations. Tiagabine blocks the GABA transporter GAT-1, reducing GABA reuptake from the synapse.
T-type calcium channels, low-voltage-activated calcium channels found at high density in thalamic relay neurons, are the target of ethosuximide and contribute to the action of valproate and zonisamide. These channels underlie the rhythmic burst firing of thalamic neurons that generates the 3 Hz spike-wave oscillations of absence seizures. The thalamocortical circuit in absence epilepsy operates as an abnormally synchronized oscillator between thalamic relay neurons and reticular thalamic neurons, with the cortex both receiving and reinforcing the thalamic rhythm.9 Ethosuximide reduces T-type calcium current in thalamic neurons, dampening the oscillatory drive and specifically suppressing absence seizures. Its selectivity for this mechanism explains why it is effective for absence but not for focal or generalized tonic-clonic seizures, and why it can safely be used in typical absence without concern for aggravating other seizure types in isolated CAE.
The alpha-2-delta (alpha2delta) subunit of high-voltage-activated calcium channels is the binding site for gabapentin and pregabalin. Despite their names, these drugs are not GABAergic; they do not bind to GABA-A or GABA-B receptors. The alpha2delta subunit is an auxiliary subunit that regulates the trafficking of calcium channels to the presynaptic membrane and modulates calcium-dependent neurotransmitter release. By binding to this subunit, gabapentin and pregabalin reduce presynaptic calcium influx and consequently reduce neurotransmitter release, particularly in dorsal horn neurons relevant to neuropathic pain. Their CNS penetration is adequate for anticonvulsant and analgesic effects but is subject to saturable transport, as discussed further in Module 05.
Blood-brain barrier (BBB) penetration is a critical pharmacokinetic determinant of ASD efficacy. The BBB, formed by tight junctions between cerebral capillary endothelial cells and further regulated by astrocytic end-feet and pericytes, restricts passage of hydrophilic and protein-bound molecules into brain tissue. Most ASDs are sufficiently lipophilic to cross the BBB by passive diffusion; however, P-glycoprotein (P-gp) and other efflux transporters expressed on the luminal surface of BBB endothelium actively pump certain drugs back into the bloodstream, reducing central nervous system (CNS) concentrations relative to plasma concentrations.10 The drug resistance hypothesis of epilepsy proposes that overexpression of P-gp in the epileptic focus, driven by seizure activity itself, is one mechanism by which seizures become drug-resistant over time, an area of active research but without established clinical interventions to date.
Therapeutic drug monitoring (TDM) is most valuable for ASDs with narrow therapeutic indices, nonlinear pharmacokinetics, or significant pharmacokinetic variability. Phenytoin is the paradigm case: its zero-order (Michaelis-Menten) kinetics at therapeutic concentrations mean that small dose increases can produce disproportionately large plasma level increases and toxicity. Carbamazepine requires TDM because of autoinduction and the active epoxide metabolite. Valproate TDM is useful for safety monitoring (liver function, platelet count) and for detecting interactions. Phenobarbital has a long half-life that facilitates monitoring. By contrast, levetiracetam, lamotrigine, and oxcarbazepine have broad therapeutic windows and more linear kinetics; TDM is used selectively for these agents rather than routinely. For all ASDs, trough plasma concentrations (drawn just before the next dose) are standard; the published therapeutic ranges are population averages and individual patients may require concentrations outside these ranges for optimal control.
Pharmacogenomics has identified several clinically actionable genetic associations in ASD prescribing, most prominently the HLA allele associations with severe cutaneous adverse reactions (SCARs) to aromatic ASDs. These associations are now incorporated into regulatory labeling and clinical guidelines in multiple countries, and pre-treatment screening is recommended for specific drugs in specific high-prevalence populations. Understanding these relationships is necessary for safe prescribing, particularly in ethnically diverse patient populations.
The most well-established pharmacogenomic association in epilepsy pharmacotherapy is between the HLA-B*1502 allele and Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by carbamazepine. SJS and TEN are severe, potentially life-threatening mucocutaneous reactions in which extensive epidermal detachment occurs, with mortality rates of 5–10% for SJS and 25–35% for TEN. HLA-B*1502 is found at high frequency in populations of Han Chinese, Thai, Malaysian, Vietnamese, and other Southeast Asian ancestry (allele frequency 5–15%), and is uncommon in populations of European or Japanese ancestry (frequency less than 1%).11 The association between HLA-B*1502 and carbamazepine-induced SJS/TEN in Han Chinese populations is extremely strong (odds ratio greater than 1000 in some studies), and the U.S. Food and Drug Administration (FDA) labeling for carbamazepine recommends HLA-B*1502 testing before initiation in patients of Asian ancestry. The same allele association extends to phenytoin and oxcarbazepine in Asian populations, though the evidence is somewhat less extensive.
A second HLA association, HLA-A*3101, has been identified primarily in populations of European and Japanese ancestry and is associated with a broader spectrum of carbamazepine hypersensitivity reactions, including maculopapular exanthema, hypersensitivity syndrome (drug reaction with eosinophilia and systemic symptoms, DRESS), SJS, and TEN.12 HLA-A*3101 has an allele frequency of approximately 5–6% in Northern European populations. The magnitude of the association is more modest than HLA-B*1502, with an odds ratio in the range of 5–25 depending on the reaction phenotype studied. European regulatory agencies have recommended consideration of HLA-A*3101 testing before carbamazepine initiation, and it is included in some national prescribing guidelines.
CYP2C9 and CYP2C19 polymorphisms are clinically relevant to phenytoin pharmacokinetics. Phenytoin is metabolized primarily by CYP2C9 (approximately 90%) and to a lesser extent by CYP2C19. CYP2C9 poor metabolizers (individuals carrying two loss-of-function alleles, such as CYP2C9*2/*2, *2/*3, or *3/*3) have substantially reduced phenytoin clearance, reaching toxic plasma concentrations at doses that would be subtherapeutic in normal metabolizers. The prevalence of CYP2C9 poor metabolizer status is approximately 1–3% in European populations and lower in East Asian populations. The Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines recommend considering CYP2C9 genotype when initiating phenytoin, particularly in patients who show early signs of dose-dependent toxicity such as nystagmus or ataxia at apparently conservative doses.13 CYP2C19 rapid metabolizers may require higher lamotrigine doses when lamotrigine is metabolized via this pathway, though glucuronidation (UGT1A4) is the primary elimination route for lamotrigine.
UGT (UDP-glucuronosyltransferase) enzyme polymorphisms affect the metabolism of lamotrigine, valproate, and other ASDs that undergo glucuronidation. UGT1A4 and UGT2B7 polymorphisms can alter lamotrigine clearance, though the clinical impact is generally less dramatic than CYP2C9 effects on phenytoin because lamotrigine has a wider therapeutic index. Valproate undergoes glucuronidation by multiple UGT enzymes and mitochondrial beta-oxidation, with the toxic metabolite 4-en-valproate formed by CYP2C9 contributing to valproate-associated hepatotoxicity. Patients with mitochondrial disorders or POLG mutations (encoding the mitochondrial DNA polymerase gamma) are at extreme risk of valproate-induced hepatic failure and are a contraindication to valproate use.14
Severe cutaneous adverse reactions (SCARs) to ASDs share an early phase that can be mistaken for a benign drug rash. Features that indicate potential SJS or TEN rather than benign maculopapular exanthema include mucosal involvement (oral, ocular, or genital erosions), target lesions with blistering centers, skin tenderness, fever above 38.5 degrees Celsius, and a positive Nikolsky sign (epidermal detachment with lateral pressure). DRESS (drug reaction with eosinophilia and systemic symptoms) presents later, typically 2–8 weeks after drug initiation, with facial edema, exanthema, lymphadenopathy, eosinophilia, atypical lymphocytosis, and internal organ involvement (hepatitis, nephritis, pneumonitis). Any suspected SCA should prompt immediate ASD discontinuation and urgent dermatology or hospital referral. The offending drug should never be rechallenged, and cross-reactivity exists among aromatic ASDs (carbamazepine, phenytoin, phenobarbital, lamotrigine), requiring caution when selecting an alternative.
Practical implementation of pharmacogenomic screening for ASDs depends on the clinical setting, patient ancestry, and the urgency of treatment. In elective settings, HLA-B*1502 screening before carbamazepine or phenytoin initiation in patients of Southeast Asian ancestry is recommended by FDA labeling, is cost-effective in high-prevalence populations, and should be considered standard of care. In emergent settings such as status epilepticus, HLA screening is not practical and should not delay treatment; the risk of the untreated seizure disorder substantially outweighs the risk of a SCAR in the acute setting. When HLA-B*1502 is positive, carbamazepine and phenytoin should be avoided if alternatives exist; if no alternative is feasible, the decision requires a careful risk-benefit discussion. The same HLA allele is not a contraindication to lamotrigine use (a different molecular interaction is involved), but lamotrigine still carries its own SCAR risk that is managed primarily through slow titration rather than genetic screening.15
HLA-B*1502 + carbamazepine/phenytoin: extreme SJS/TEN risk in Southeast Asian populations. Screen before initiation. Allele frequency 5–15% in Han Chinese, Thai, Vietnamese ancestry; less than 1% in European ancestry.
HLA-A*3101 + carbamazepine: increased risk of maculopapular exanthema, DRESS (drug reaction with eosinophilia and systemic symptoms), SJS, TEN in European and Japanese populations. Allele frequency approximately 5% in Northern Europeans. Consider screening per national guidelines.
CYP2C9 poor metabolizers + phenytoin: toxic concentrations at standard doses. Prevalence 1–3% European ancestry. Consider genotyping when early dose-dependent toxicity appears.
POLG mutations + valproate: contraindication. POLG-related disorders include Alpers syndrome and other mitochondrial epilepsies; valproate causes fulminant hepatic failure in this population.
Aromatic ASD cross-reactivity: carbamazepine, phenytoin, phenobarbital, and primidone share structural features; SCAR to one increases risk with the others. Lamotrigine is not aromatic in the classic sense but carries independent SCAR risk managed by slow titration.
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