THIS ARTICLE WILL HELP YOU TO:
- 1. Define and distinguish between seizure and epilepsy
2. Classify seizures
3.Explain the physiology of excitatory and inhibitory neurotransmitters in CNS
4.Explain the molecular mechanism of seizure initiation and propagation
5.Explain the mechanism of epileptogenesis
6.Discuss the basic pharmacology of antiepileptic drugs
· Seizure: the clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons
· Epilepsy: two or more recurrent seizures unprovoked by systemic or acute neurologic insults
Definitions and Epidemiology
A. Seizure
A seizure is the manifestation of an abnormal, hypersynchronous discharge of a population of cortical neurons. This discharge may produce subjective symptoms or objective signs, in which case it is a clinical seizure, or it may be apparent only on an electroencephalogram (EEG), in which case it is an electrographic (or subclinical) seizure. Clinical seizures are usually classified according to the International Classification of Epileptic Seizures. Although all classification schemes have limitations, this is the best one currently available. The incidence of new-onset seizures in the general population is approximately 80 per 100,000 per year; approximately 60% of these patients will have epilepsy, a tendency toward recurrent unprovoked seizures. The diagnosis of a particular seizure type, and of a specific type of epilepsy (epilepsy syndrome), directs the diagnostic workup of these patients and their initial therapy.
B. Epilepsy
At least two unprovoked seizures are required for the diagnosis of epilepsy. In the past, physicians were reluctant to make this diagnosis even after repeated seizures, because of the adverse consequences including social stigmatization and limitations on driving and employment. Despite advances in public understanding of the condition, these issues remain active.
Epilepsy is an umbrella term, under which many types of diseases and syndromes are included. The current classification of the epilepsies and epileptic syndromes attempts to separate these disorders according to their putative brain origins, that is, whether they arise in a circumscribed portion of the brain (partial), or appear to begin diffusely in the cortex and its deeper connections (generalized).
The syndrome is idiopathic when the disorder is not associated with other neurologic or neuropsychologic abnormalities; symptomatic indicates that such an abnormality is present and the cause is known. Cryptogenic refers to syndromes that are presumed to be symptomatic but the cause in a specific patient is unknown. Many idiopathic epilepsies occur in children and adolescents, and often remit in adolescence or adulthood. There is evidence that most or all of these syndromes have a genetic basis, and that when this basis becomes known, they will move from the idiopathic to the symptomatic category.
Some authors distinguish between epilepsies and epileptic syndromes, depending on whether seizures are the only neurologic disorder (an epilepsy) or are one of a group of symptoms (an epileptic syndrome). Some of the epilepsies (e.g., juvenile myoclonic epilepsy) have well-defined genetics, clinical courses, and responses to medication. Others (e.g., temporal lobe epilepsy) have natural histories which are highly variable, and which reflect differences in pathology as well as in host response to that pathologic process and to the treatments administered.
CLASSIFICATION OF SEIZURES
I. Partial seizures (seizures beginning locally)
A. Simple partial seizures (consciousness not impaired)
1.with motor symptoms
2.with somatosensory or special sensory symptoms
3.with autonomic symptoms
4.with psychic symptoms
B. Complex partial seizures (with impairment of consciousness)
1.beginning as simple partial seizures and progressing to impairment of consciousness
a.without automatisms
b.with automatisms
2.with impairment of consciousness at onset
a.without automatisms
b.with automatisms
C. Partial seizures (simple or complex), secondarily generalized
II. Generalized seizures (bilaterally symmetric, without localized onset)
1.Absence seizures
a.true absence (`petit mal')
b.atypical absence
2.Myoclonic seizures
3.Clonic seizures
4.Tonic seizures
5.Tonic-clonic seizures (`grand mal')
6.Atonic seizures
III.Unclassified seizures
CELLULAR MECHANISMS OF SEIZURE GENERATION
· Excitation (too much)
o Ionic-inward Na+, Ca++ currents
o Neurotransmitter: glutamate, aspartate
· Inhibition (too little)
o Ionic-inward CI-, outward K+ currents
o Neurotransmitter: GABA
The cortex includes two general classes of neurons. The projection, or principal, neurons (e.g., pyramidal neurons) are cells that "project" or send information to neurons located in distant areas of the brain. Interneurons (e.g., basket cells) are generally considered to be local-circuit cells which influence the activity of nearby neurons. Most principal neurons form excitatory synapses on post-synaptic neurons, while most interneurons form inhibitory synapses on principal cells or other inhibitory neurons. Recurrent inhibition can occur when a principal neuron forms synapses on an inhibitory neuron, which in turn forms synapses back on the principal cells to achieve a negative feedback loop.
Recent work suggests that some interneurons appear to have rather extensive axonal projections, rather than the local, confined axonal structures previously suggested. In some cases, such interneurons may provide a very strong synchronization or pacer activity to large groups of neurons.
BASIC NEUROPHYSIOLOGY AND NEUROCHEMISTRY GOVERNING EXCITABILITY
Given that the basic mechanism of neuronal excitability is the action potential, a hyperexcitable state can result from increased excitatory synaptic neurotransmission, decreased inhibitory neurotransmission, an alteration in voltage-gated ion channels, or an alteration of intra- or extra-cellular ion concentrations in favor of membrane depolarization. A hyperexcitable state can also result when several synchronous subthreshold excitatory stimuli occur, allowing their temporal summation in the post synaptic neurons.
Neurotransmitters are substances that are released by the presynaptic nerve terminal at a synapse and subsequently bind to specific postsynaptic receptors for that ligand. Ligand binding results in channel activation and passage of ions into or out of the cells. The major neurotransmitters in the brain are glutamate, gamma-amino-butyric acid (GABA), acetylcholine (ACh), norepinephrine, dopamine, serotonin, and histamine. Other molecules, such as neuropeptides and hormones, play modulatory roles that modify neurotransmission over longer time periods.
The major excitatory neurotransmitter is the amino acid glutamate. There are several subtypes of glutamate receptors. Glutamate receptors can be found postsynaptically on excitatory principal cells as well as on inhibitory interneurons, and have been demonstrated on certain types of glial cells. The ionotropic subclasses are the alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA), kainate receptors, and N-methyl-D-aspartate (NMDA); these allow ion influx upon activation by glutamate. They are differentiated from one another by cation permeability as well as differential sensitivity to pharmacological agonists/antagonists. All ionotropic glutamate receptors are permeable to Na+ and K+, and it is the influx of Na+ and outflow of K+ through these channels that contribute to membrane depolarization and generation of the action potential. The NMDA receptor also has a Ca++ channel that is blocked by Mg++ ions in the resting state, but under conditions of local membrane depolarization, Mg++ is displaced and the channel becomes permeable to Ca++; influx of Ca++ tends to further depolarize the cell, and is thought also to contribute to Ca++ mediated neuronal injury under conditions of excessive neuronal activation (such as status epilepticus and ischemia), potentially leading to cell death, a process termed excitotoxicity. The other major type of glutamate receptor is the metabotropic receptor, which functions by means of receptor-activated signal transduction involving membrane-associated G-proteins
There are at least 3 subtypes of metabotropic receptors, based on differential agonist potency, mechanism of signal transduction, and pre- versus post-synaptic localization.
Experimental studies using animal epilepsy models have shown that NMDA, AMPA and kainate agonists induce seizure activity, whereas their antagonists suppress seizure activity. Metabotropic agonists appear to have variable effects likely dependent upon their different location and mechanisms of signal transduction.
The major inhibitory neurotransmitter, GABA, interacts with 2 major subtypes of receptor: GABAA and GABAB receptors. GABAA receptors are found postsynaptically, while GABAB receptors are found presynaptically, and can thereby modulate synaptic release. In the adult brain, GABAA receptors are permeable to Cl− ions; upon activation Cl− influx hyperpolarizes the membrane and inhibits action potentials. Therefore, substances which are GABAA receptor agonists, such as barbiturates and benzodiazepines, are well known to suppress seizure activity. GABAB receptors are associated with second messenger systems rather than Cl− channels, and lead to attenuation of transmitter release due to their presynaptic location. The second messenger systems often result in opening of K+ channels, leading to a hyperpolarizing current. Certain GABAB agonists, such as baclofen, have been reported to exacerbate hyperexcitability and seizures.
Relevant to epilepsy, glutamate and GABA both require active reuptake to be cleared from the synaptic cleft. Transporters for both glutamate and GABA exist on both neurons and glia (primarily astrocytes). Interference with transporter function has also been shown to activate or suppress epileptiform activity in animal models, depending on which transporter is being blocked.
FACTORS GOVERNING EXCITABILITY OF INDIVIDUAL NEURONS
· Intrinsic factors
· Extrinsic factors
The complexity of neuronal activity is partly due to various mechanisms controlling the level of electrical activation in one or more cellular regions. These mechanisms may act inside the neuron or in the cellular environment, including other cells (e.g., neighboring neurons, glia, and vascular endothelial cells) as well as the extracellular space, to modify neuronal excitability. The former may be termed "neuronal" or "intrinsic," and the latter "extra-neuronal" or "extrinsic."
1. Examples of neuronal (intrinsic) factors include:
The type, number and distribution of voltage- and ligand-gated channels. Such channels determine the direction, degree, and rate of changes in the transmembrane potential, which in turn determine whether an action potential occurs. Voltage-gated sodium channels, for example, form the basis of the rapid depolarization constituting the action potential. Among ligand-gated channels, the GABA receptor complex mediates inflow of chloride ions which hyperpolarize the cell, forming the basis of neuronal inhibition, as described previously.
Biochemical modification of receptors. For example, phosphorylation of the NMDA receptor increases permeability to Ca++, resulting in increased excitability.
Activation of second-messenger systems. Binding of norepinephrine to its alpha receptor, for example, activates cyclic GMP, in turn activating G-proteins which open K+ channels, thereby decreasing excitability.
Modulating gene expression, as by RNA editing. For example, editing a single base pair of mRNA encoding a specific glutamate receptor subunit can change the ion selectivity of the assembled channel.
2. Examples of extra-neuronal (extrinsic) factors include:
Changes in extracellular ion concentration due to variations in the volume of the extracellular space. For example, decreased extracellular volume leads to increased extracellular K+ concentration, resisting the outward movement of K+ ions needed to repolarize the cell, thereby effectively increasing excitability.
Remodeling of synaptic contacts. For example, movement of an afferent axon terminal closer to the target cell body increases the likelihood that inward ionic currents at the synapse will bring the target neuron to threshold. The coupling between the pre- and post-synaptic elements can be made more efficient by shortening of the spine neck. In addition, previous synaptic experience such as a brief burst of high frequency stimulation (e.g., long-term potentiation-LTP) also increases the efficacy of such synapses, increasing their excitability.
Modulating transmitter metabolism by glial cells. Excitability increases, for example, if glial metabolism or uptake of excitatory transmitters such as glutamate or ACh decreases.
PATHOPHYSIOLOGY OF SEIZURES: AN ALTERATION IN THE NORMAL BALANCE OF INHIBITION AND EXCITATION
A. Basic Mechanisms of Focal Seizure Initiation and Propagation
The hypersynchronous discharges that occur during a seizure may begin in a very discrete region of cortex and then spread to neighboring regions. Seizure initiation is characterized by two concurrent events: 1) high-frequency bursts of action potentials, and 2) hypersynchronization of a neuronal population. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG. At the level of single neurons, epileptiform activity consists of sustained neuronal depolarization resulting in a burst of action potentials, a plateau-like depolarization associated with completion of the action potential burst, and then a rapid repolarization followed by hyperpolarization. This sequence is called the paroxysmal depolarizing shift.
The bursting activity resulting from the relatively prolonged depolarization of the neuronal membrane is due to influx of extracellular Ca++, which leads to the opening of voltage-dependent Na+ channels, influx of Na+, and generation of repetitive action potentials. The subsequent hyperpolarizing afterpotential is mediated by GABA receptors and Cl− influx, or by K+ efflux, depending on the cell type.
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 contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum.
The propagation of bursting activity is normally prevented by intact hyperpolarization and a region of surrounding inhibition created by inhibitory neurons. With sufficient activation there is a recruitment of surrounding neurons via a number of mechanisms. Repetitive discharges lead to: 1) an increase in extracellular K+, which blunts the extent of hyperpolarizing outward K+ currents, tending to depolarize neighboring neurons; 2) accumulation of Ca++ in presynaptic terminals, leading to enhanced neurotransmitter release; and 3) depolarization-induced activation of the NMDA subtype of the excitatory amino acid receptor, which causes more Ca++ influx and neuronal activation. Of equal interest, but less well understood, is the process by which seizures typically end, usually after seconds or minutes, and what underlies the failure of this spontaneous seizure termination in the life-threatening condition known as status epilepticus.
B. Current Theories as to How Inhibition and Excitation Can Be Altered at the Network Level
Our understanding of the CNS abnormalities causing patients to have recurrent seizures remains limited. It is important to understand that seizures and epilepsy can result from many different pathologic processes that upset the balance between excitation and inhibition. Epilepsy can result from processes which disturb extracellular ion homeostasis, alter energy metabolism, change receptor function, or alter transmitter uptake. Despite major differences in etiology, the outcome of synchronous bursting of cortical neurons may superficially appear to have a similar phenotype. Seizure phenotype may be modified more by the location and function of the neuronal network recruited into the synchronous bursting than by the underlying pathophysiology.
Because of the well organized and relatively simple circuits within the entorhinal-dentate-hippocampal loop, the limbic system has been intensively studied in experimental models of epilepsy. These investigations have led to two theories regarding the cellular network changes which cause the hippocampus, among the most common sites of origin of partial seizures, to become hyperexcitable. The first proposes that a selective loss of interneurons decreases the normal feed-forward and feedback inhibition of the dentate granule cells, an important group of principal neurons. The other theory suggests that synaptic reorganization follows injury and creates recurrent excitatory connections, via axonal "sprouting," between neighboring dentate granule cells. More recently, it has been proposed that the loss, rather than being of GABAergic inhibitory neurons, is actually of excitatory neurons which normally stimulate the inhibitory interneurons to, in turn, inhibit the dentate granule cells. These mechanisms of hyperexcitability of the neuronal network are not mutually exclusive, could act synergistically, and may coexist in the human epileptic brain.
Seizures may also appear to arise from widespread cortical areas virtually simultaneously. The mechanisms underlying such generalized seizures are uncertain. One type of generalized seizure, the absence seizure, (also called petit mal) is a generalized seizure consisting clinically of a brief staring spell in conjunction with a characteristic burst of spike-wave complexes on the EEG. Generalized spike-wave discharges in absence seizures may result from aberrations of oscillatory rhythms that are normally generated during sleep by circuits connecting the cortex and thalamus. This oscillatory behavior involves an interaction between GABAB receptors, Ca++ channels and K+ channels located within the thalamus. Pharmacologic modulation of these receptors and channels can induce absence seizures, and there is speculation that genetic forms of absence epilepsy may be associated with mutations of components of this system.
C. Epileptogenesis: The Transformation of a Normal Network Into a Hyperexcitable Network
Clinical observations suggest that certain forms of epilepsy are caused by particular events. For example, approximately 50% of patients who suffer a severe head injury will develop a seizure disorder. However, in a significant number of these patients, the seizures will not become clinically evident for months or years. This "silent period" after the initial injury indicates that in some cases the epileptogenic process involves a gradual transformation of the neural network over time. Changes occurring during this period could include delayed necrosis of inhibitory interneurons (or the excitatory interneurons driving them), or sprouting of axonal collaterals leading to reverberating, or self-reinforcing, circuits. In the future, patients at risk for developing epilepsy due to an acquired lesion may benefit from treatment with "anti-epileptogenic" compounds that could prevent these network changes.
An important experimental model of epileptogenesis is kindling, discovered by Goddard and coworkers in the 1960s. Daily, subconvulsive stimulation (electrical or chemical) of certain brain regions such as the hippocampus or amygdala result in electrical afterdischarges, eventually leading to stimulation-induced clinical seizures, and in some instances, spontaneous seizures. This change in excitability is permanent and presumably involves long-lasting biochemical and/or structural changes in the CNS. A variety of changes have been measured in kindling models, including alterations in glutamate channel properties, selective loss of neurons, and axonal reorganization.
MECHANISMS OF ANTI-EPILEPTIC DRUG (AED) ACTIVITY
A seizure is the clinical manifestation of a hyperexcitable neuronal network, in which the electrical balance underlying normal neuronal activity is pathologically altered—excitation predominates over inhibition (see Basic Mechanisms syllabus). Effective seizure treatment generally augments inhibitory processes or opposes excitatory processes. Since the normal resting neuronal membrane potential is intracellularly negative, inhibitory processes make the neuron more electrically negative, hyperpolarizing the membrane, while excitatory processes make the intracellular potential less negative or more positive, depolarizing the cell. On an ionic level, inhibition is typically mediated by inward chloride or outward potassium currents, and excitation by inward sodium or calcium currents. Drugs can directly affect specific ion channels or indirectly influence synthesis, metabolism, or function of neurotransmitters or receptors that control channel opening and closing. The most important central nervous system inhibitory neurotransmitter is gamma-amino-butyric acid (GABA). The most important excitatory neurotransmitter is glutamate, acting through several receptor subtypes.
Blocking voltage-gated sodium channels during rapid rates of neuronal discharge appears to be the primary mechanism of action of several AEDs, particularly the two first-line drugs for partial epilepsies, phenytoin and carbamazepine; this mechanism also appears to be at least partly responsible for the antiepileptic effects of newer drugs such as lamotrigine and topiramate. This rate-dependent action is crucial, addressing the requirement that AEDs should affect pathologic more than physiologic neuronal excitation, since a drug with similar effects on all excitation would produce deep coma as an inevitable side effect.
The GABA system and its associated chloride channel is a target of many old and new AEDs effective against many seizure types. Barbiturates and benzodiazepines act directly on subunits of the GABA receptor-chloride channel complex. Barbiturates increase the duration of chloride channel openings, while benzodiazepines increase the frequency of these openings. Tiagabine inhibits GABA re-uptake from synapses. Vigabatrin, a drug not available in the U.S., elevates GABA levels by irreversibly inhibiting its main catabolic enzyme, GABA-transaminase. Gabapentin was designed as a lipophilic GABA analogue, but does not function as a receptor agonist; its mechanism of action is unknown.
Calcium current into the neuron is another important excitatory mechanism. There are several different calcium channel types, but nonselective calcium channel blockers have low antiepileptic efficacy. Ethosuximide selectively blocks transient ("T-type") calcium currents in thalamic neurons, which inhibits the thalamocortical circuits responsible for generating the EEG spike-wave complex underlying absence seizures.
Excitatory neurotransmission mediated by calcium and sodium currents through glutamate receptors has been a tempting target for new AEDs, because these currents may contribute not only to seizure generation but also to neuronal damage from status epilepticus and stroke. Direct glutamate receptor antagonists are effective against experimental seizures, but frequently cause psychosis and other neuropsychiatric adverse effects, preventing clinical use. However, several newer, better tolerated drugs, including lamotrigine and topiramate, may act on this system indirectly.
AED PHARMACOKINETICS
Pharmacokinetics is the quantitative description of what happens to a drug when it enters the body, including drug absorption, distribution, metabolism and elimination/excretion).
A. Absorption
This is determined by route of intake. Most AEDs are available for oral administration, although some have formulations that are also available for intravenous, intramuscular or rectal administration.
Oral Absorption:
Most AEDs undergo complete or nearly complete absorption when given orally. Most often, administration of AEDs with food slows absorption and can help avert peak dose related side effects. Calcium containing antacids may interfere with phenytoin absorption. Gabapentin is absorbed by a saturable amino acid transport system and does not get absorbed after a certain dose.
Intramuscular Administration:
Fosphenytoin may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures.
Rectal administration:
Diazepam (available as a rectal gel) has been shown to terminate repetitive seizures and can be administered by family members at home.
Intravenous administration:
This route is used for emergencies. Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproic acid are available as IV preparations (see section on status epileptics for side effects related to intravenous use).
B. Distribution
Following absorption into the bloodstream, the drug is distributed throughout the body. Lipid solubility and protein binding affect CNS availability. Drugs can displace others from albumin and protein binding is responsible for many pharmacokinetic interactions between AEDs. An example of this is the interaction between phenytoin and valproic acid. If valproic acid is added to a patient who is already taking phenytoin, the phenytoin is displaced from albumin binding sites, resulting in a higher free fraction and toxicity.
C. Metabolism
Most AEDs are metabolized in the liver by hydroxylation or conjugation. These metabolites are then excreted by the kidney. Some metabolites are themselves active (carbamazepine, oxcarbazepine, primidone). Gabapentin undergoes no metabolism and is excreted unchanged by the kidney.
Most AEDs are metabolized by the P450 enzyme system in the liver. Different AEDs either induce or inhibit certain isoenzymes of this system and can result in changes of the pharmacokinetic properties of different medications
In general enzyme inducers decrease the serum concentrations of other drugs metabolized by the system and enzyme inhibitors have the opposite affect. Valproic acid is metabolized by a combination of conjugation by uridine glucuronate (UDP)-Glucuronyltranferase (UGT) via conjugation and by mitochondrial beta-oxidation.
D. Elimination
Drug elimination rate is usually expressed as the biological half-life and is defined as the time required for the serum concentration to decrease by 50% following absorption and distribution.
This changes for some drugs based on serum concentration e.g. phenytoin has a longer half-life at high serum levels. The half-life also determines the dosing frequency required for a drug to be maintained at a steady state in the serum. Most drugs are eliminated by the kidneys and dosage adjustments are required in cases of renal impairment.
ADDITIONAL PHARMACOKINETIC AND PHARMACODYNAMIC ASPECTS OF AEDs
A. Therapeutic Index
AEDs can have a narrow range within which seizures are controlled without toxicity. This concept is quantified as the "therapeutic index" (TI). TI is the ratio of the drug concentration effective for 50% of subjects (ED50) to the concentration toxic to 50% of subjects (TD50) – TI=ED50/TD50. The "therapeutic range" of AED serum concentrations is an attempt to translate the experimental concept of therapeutic index to the clinic. These ranges are broad generalizations which are of limited use and can be misleading when applied to individual patients. Many patients tolerate and need serum concentrations above the usual therapeutic range, while others achieve complete seizure control, or even experience adverse effects, at concentrations below it.
B. Pharmacodynamic Interactions
Drug interactions based on pharmacokinetics, or "what the body does to the drug," must be distinguished from those based on pharmacodynamics, or "what the drug does to the body." Pharmacodynamic effects include both wanted and unwanted drug effects on the brain and other organs. Gabapentin, for example, has no important pharmacokinetic interactions with other AEDs. Because gabapentin and many other drugs can cause sedation and dizziness, however, pharmacodynamic interactions can occur. Ideally, drug combinations should produce additive or synergistic (supra-additive) therapeutic effects and sub-additive toxicities. Drug combinations with different mechanisms of action may help achieve this goal.
C. Adverse Effects
Most AEDs have a narrow therapeutic window—a small range of serum concentrations within which seizure prevention is achievable without significant toxicity or side effects. This concept applies primarily to dose-related, reversible, short-term side effects. However, risk of idiosyncratic effects such as allergic reactions and organ damage must also be considered. Serious idiosyncratic effects are rare but can be life threatening. They generally occur within several weeks or months of starting the drug, tend to be dose-independent (except possibly for skin rash with lamotrigine), and unpredictable.
Intermittent or frequent monitoring of biochemical (e.g., liver functions such as ALT, AST) or hematologic (e.g., CBC) laboratory tests may not detect changes in time to alter prognosis. In addition, frequent monitoring may detect changes or abnormalities which are not clinically significant (e.g., usually transient alterations in liver function tests associated with valproate therapy or commonly-observed, usually transient reductions in leukocyte counts associated with carbamazepine). Education of patients or caregivers to promptly report relevant symptoms of possibly serious idiosyncratic effects accompanied by appropriate laboratory follow-up are currently regarded as mainstays of detection.
Many idiosyncratic reactions likely result from inherited genetic susceptibilities to a particular drug or metabolite. The most common target organs are skin, liver, bone marrow, and occasionally pancreas. Skin rashes are common, immunologically mediated, and usually minor and reversible. Skin rashes, can however, progress to Stevens-Johnson syndrome. The more serious organ toxicities occur in less than 1 in 10,000–100,000 treated patients. Felbamate-related aplastic anemia appears to occur more commonly (approximately 1:5,000). For some AEDs, the presence of predisposing risk factors may increase the risk of serious idiosyncratic reactions. Valproate-related hepatotoxicity is more common in very young children receiving multiple AEDs; lamotrigine-induced skin rashes are more common in patients receiving valproate and/or who are treated with aggressively-titrated lamotrigine doses.
The third type of adverse drug effect is cumulative toxicity, usually occuring over years of treatment. Because most AEDs other than phenobarbital and phenytoin have been in use for less than 25 years, data regarding these types of adverse effects are limited.
