Epilepsy
Rani R. Sarkis
Christelle Moufawad El Achkar
Barbara A. Dworetzky
BACKGROUND
History
1. The term “epilepsy” is derived from Greek epilepsia: a taking hold of or seizing.
2. Ancient accounts more than 2,500 years ago by Babylonians and Egyptians. Detailed descriptions in On the Sacred Disease attributed to Hippocrates in the fifth century BC. The use of “sacred” possibly meant to be ironic, as Hippocrates is regarded as wishing to replace the earlier, supernatural explanations of epilepsy with a natural one dependent on brain function.
3. Late 19th century:
a. Jackson: Model of focal seizure beginning as aura and evolving to focal seizure with impaired awareness or convulsive seizure and use of aura symptoms to localize seizure onset within gray matter of the brain.
b. Gowers: Detailed descriptions of epileptic syndromes and related disorders; concept that “seizures beget seizures.”
4. Mid-20th century:
a. Berger, Walter, and Lennox: Ability to record human electroencephalogram (EEG) from scalp and correlate with epilepsy.
b. Penfield and Jasper: Surgical resection facilitated by identification of epileptic focus on the basis of clinical manifestations and electrocorticography (EEG recorded from the brain surface) and identification of functional cortical regions by cortical electrical stimulation.
c. Merritt and Putnam: Determination that phenytoin (PHT) was an antiseizure medication (ASM) using an animal seizure model.
d. Gastaut: Advances in syndromic classification and treatment.
5. Late 20th century:
a. Widespread use of simultaneous video-EEG (vEEG) recording, allowing accurate correlations of EEG and behavior.
b. Neuroimaging, allowing visualization of lesions responsible for seizure generation and facilitating surgical treatment of epilepsy.
c. Development of many new ASMs by screening and synthesis based on knowledge of seizure mechanisms.
d. Emergence of epileptology as a defined specialty within neurology and the development of comprehensive epilepsy management programs, including long-term vEEG monitoring and epilepsy surgery.
6. 21st century:
a. Identification of genetic mechanisms behind many epilepsies.
b. Implantable stimulation techniques (eg, vagal nerve stimulation, responsive neurostimulation, deep brain stimulation) for treatment-resistant epilepsy.
c. Use of laser interstitial thermal therapy (LITT) in epilepsy surgery.
Definitions
1. Epileptic Seizure: a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain
a. Provoked (acute symptomatic): a seizure occurring in the setting of a reversible cause, or at the time of or in close proximity to a central nervous system insult.
b. Unprovoked: a seizure occurring in the absence of a potentially reversible cause.
2. Epilepsy: A brain disease characterized by an enduring predisposition to have recurrent epileptic seizures. The International league against epilepsy (ILAE) practical definition includes:
a. At least two unprovoked seizures >24 hours apart
b. One unprovoked seizure and probability of recurrence at least 60% over the next 10 years, which is similar to the risk after two unprovoked seizures.
c. Diagnosis of an epilepsy syndrome
3. Aura: The earliest part of a seizure and typically the only subjective experience recalled by the patient.
4. Postictal period: Time between the end of the seizure and recovery to the baseline state.
5. Status epilepticus (SE): Five or more minutes of continuous or recurrent seizures without recovery to baseline.
6. Sudden unexpected death in epilepsy (SUDEP): Sudden, unexpected, witnessed or unwitnessed, nontraumatic, and non-drowning death of patients with epilepsy with or without evidence of a seizure and in whom postmortem examination does not reveal a structural or toxicologic cause.
7. Functional or nonepileptic seizure: Functional neurological disorder (FND) is a common conversion disorder and top differential for epileptic seizure. Functional seizures/attacks are the most common subtype (aka psychogenic nonepileptic seizure [PNES]). These episodes do not have electrical discharges in the brain.
Classification
Seizure Types
The main types of seizures are (a) focal onset (“partial” in the old terminology) seizures that are presumed to originate in a specific lobe or hemisphere of the brain and (b) generalized onset seizures that originate at some point within, and rapidly engage, bilaterally distributed networks. A further distinction is made between focal seizures without impairment in awareness (previously simple partial) now termed “focal aware” and those with impaired awareness (previously complex partial) now termed “focal impaired awareness”. Awareness is defined as the knowledge of self or environment.
Seizure semiology terms:
a. Myoclonic: Brief, involuntary single or multiple contractions of muscles lasting <100 msec.
b. Clonic: Series of regular and repetitive myoclonic jerks usually 0.2 to 5 Hz in frequency of variable duration.
c. Tonic: Stiffening or contraction in a fixed posture usually causing extension; usual duration seconds to minutes.
d. Tonic-clonic: Stereotyped sequence of bilateral stiffening followed by clonic contractions; duration seconds to minutes.
e. Atonic: Sudden loss of postural tone; duration 1 to 2 seconds.
f. Automatisms: a repetitive insuppressible motor behavior that often looks voluntary.
g. Epileptic spasms: sudden flexion or extension of the head, appendicular and truncal muscles. Usually consisting of repetitive episodes of arm abduction and extension.
The following is a summary of the 2017 seizure classification system of the ILAE:
1. Focal onset seizures (seizures beginning within networks limited to one hemisphere).
With or without impaired awareness
a. Motor onset: automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic
b. Nonmotor onset: autonomic, behavior arrest, cognitive, emotional, sensory
c. Can progress from focal to bilateral tonic-clonic
2. Generalized seizures originate at some point within and rapidly engage bilaterally distributed networks
a. Motor: tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, spasms
b. Nonmotor (absence): typical, atypical, myoclonic, eyelid myoclonia
c. Unknown onset:
1) Motor: tonic-clonic, spasms
2) Nonmotor: behavior arrest
d. Unclassified.
Epilepsy Syndromes
1. Epilepsy syndromes are characterized by a cluster of features incorporating seizure types, EEG, and imaging that tend to occur together.
2. A syndrome can have an age-dependent onset, age-dependent remission, specific triggers, prognosis, and comorbidities.
Etiology
1. Genetic: If it is the result of a known genetic abnormality (eg, SCN1A, KCNQ2), or presumed genetic based on history despite no clear monogenic etiology found (eg, genetic generalized epilepsies such as juvenile myoclonic epilepsy [JME]). This also includes metabolic disorders (eg, pyridoxine-dependent epilepsy, GLUT-1 deficiency syndrome, etc.).
2. Structural: There is a distinct structural abnormality demonstrated on neuroimaging known to be substantially associated with the increased risk of developing epilepsy (eg, stroke, tumors). Structural abnormalities can be genetic in origin (eg, malformations of cortical development).
3. Infectious: epilepsy is a result of an infectious process that involves the (eg,.HSV, neurocysticercosis, toxoplasmosis)
4. Immune: epilepsy is the result of an autoimmune-mediated process affecting the brain (eg, anti-LGI-1 encephalitis, anti-NMDA encephalitis).
5. Unknown cause.
Epidemiology
1. Seizures have a 9% to 10% cumulative lifetime incidence (3%-4% febrile, 3% due to other acute triggers [eg, hypoglycemia, post-concussive, etc.], 2%-3% epileptic) in almost all populations.
2. The incidence of epilepsy is 30 to 50/100,000; with a cumulative incidence of 2% to 3% by age 75 years and prevalence 0.5% to 0.8%.
3. There is a bimodal incidence for both seizures and epilepsy with the highest rate in the first year of life and increasing again after age 60.
PATHOPHYSIOLOGY
The hypersynchronous neuronal discharge that characterizes a seizure is the result of an imbalance between excitation and inhibition. Genetic epilepsies caused by channelopathies typically affect the structure and function of neurotransmitter receptors and their associated ion channels. Other genetic etiologies can affect cortical development. The mechanisms by which cortical injuries produce epilepsy are unknown but probably are related to alterations in the neurochemical environment within and surrounding the lesion in addition to connectivity changes between the lesion and brain networks. Glia, astrocytes, and neuroinflammation also likely play a role in this process.
Physiologic Mechanisms
1. Cellular: Alterations in distribution or function of ion channels, or in neurotransmitter synthesis, metabolism, or uptake.
2. Extracellular: Alterations in ionic environment (partially mediated by glial cells) or synaptic structure.
3. Network: Alterations in synaptic organization; alterations in number or function of inhibitory or excitatory neuronal populations. There is evidence that absence seizures result from aberration in the thalamocortical network that underlies sleep spindle generation.
Molecular Mechanisms
1. Main inhibitory neurotransmitter: γ-aminobutyric acid (GABA), which is a pleomorphic class of receptors linked to the chloride channel, activation of which hyperpolarizes neurons
2. Main excitatory transmitter: Glutamate acts via several ionotropic (creating ion pores) receptors that are often divided into three groups on the basis of experimental agonists (N-methyl D-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid [AMPA], and kainic acid). Glutamate also acts on metabotropic receptors affecting intracellular processes more slowly via G-proteins.
Genetics
1. In general, and even for nongenetic causes of epilepsy, the current view is that a collection of genes and polymorphisms, coding mainly for neurotransmitter receptors and their associated ion channels, determine an individual’s “seizure threshold”. This threshold influences the likelihood that an individual will develop epilepsy after a brain injury, infection, or from a systemic or neurologic derangement.
2. There are also monogenic causes of epilepsy whereby pathogenic variants in a gene affect ion channels (eg, sodium and potassium channels), cellular receptors (eg, nicotinic acetylcholine receptor in some autosomal dominant frontal lobe epilepsies, etc.). Other genetic abnormalities affect early brain development and can lead to malformations (eg, Tuberous Sclerosis, hemimegalencephaly, etc.).
3. Outside of the recognized monogenetic causes of epilepsy, certain syndromes are presumed to have a genetic etiology based on population data. The mechanisms include monogenic variants in undiscovered genes, multigenetic, or epigenetic factors (eg, Genetic Generalized Epilepsies such as Childhood Absence Epilepsy [CAE] and JME).
PROGNOSIS
Natural History
1. A single unprovoked seizure has a 2-year recurrence rate of 23% to 71%. The recurrence rate after a second seizure is 60% to 90%; risk factors for recurrence include seizures occurring out of sleep, abnormal brain imaging, or EEG consistent with decreased seizure threshold. Recurrent seizures or a single seizure and the presence of some of these additional features implicate a diagnosis of epilepsy in the correct clinical context.
2. Many childhood-onset epilepsy syndromes remit spontaneously after a certain age (eg, about 2/3 of patients with CAE, nearly all patients with Self-limited Epilepsy with Centro-temporal Spikes [SeLECTS], etc.).
3. Adolescent-onset genetic or idiopathic generalized epilepsies (eg, JME, juvenile absence epilepsy [JAE]), as well as epilepsy associated with structural abnormalities are less likely to remit.
Data are limited as to whether ASMs have an effect on the natural history of the epilepsy and its comorbidities beyond seizure control. This is one of the reasons the terminology has switched from antiepileptic drugs to ASMs.
Response to Medical Treatment
1. Approximately half of new cases respond to the first well-tolerated ASM.
2. Drug-resistant epilepsy is defined as failure of adequate trials of two tolerated and appropriately chosen and used ASMs.
3. Prevalence of drug-resistant epilepsy is around 33% to 36% in clinic-based studies, but around 14% in community-based studies.
Nonpharmacological Treatment
1. Ketogenic diet (KD)
a. A diet with high fat to carbohydrate + protein ratio can result in marked seizure reduction in 30% to 50% of children with various seizure types. The mechanism of action is yet to be fully elucidated, but possibilities include a role of ketones in alteration of neuronal metabolic activity and neuroprotection, as well as potentially anti-inflammatory effects, and more recently a postulated connection with alterations in the gut microbiome.
b. In the classic KD, a typical ratio is 2.5:1 up to 4:1. Short-term side effects can include dehydration, acidosis, weight loss, renal stones, and elevated liver function tests; treatment should be initiated under the direct supervision of an epileptologist and dietician specialized in KD. Depending on the age, health status, and social and environmental contexts, KD can be initiated in-patient, or more gradually out-patient. The level of ketosis (or amount of ketones produced from fat breakdown) is usually measured for titration and safety, either in blood (through beta-hydroxybuterate levels), or urine (urine ketones measured at home using dipsticks).
c. Less restrictive and more practical options include diets with lower fat to carbohydrate + protein ratios. These include the modified Atkins diet, where the ratio is 1:1, as well as the Low Glycemic Index Treatment (LGIT), which consists of avoiding high glycemic index foods. Although compliance tends to be better with modified Atkins diet and Low Glycemic Index Treatment, seizure response in general is superior in classic KD.
d. Compared to pediatric data, much less is known about the feasibility, effectiveness, and safety of dietary treatments in adults. In general, the KD is less tolerated in adults.
e. KD should be considered as a first-line treatment in patients with GLUT1-DS secondary to abnormalities in the SLC2A1 gene. It can also be quite effective in children with Myoclonic Astatic Epilepsy, regardless of whether it is associated with GLUT1-DS.
f. KD is contraindicated in certain metabolic conditions, such as pyruvate carboxylase deficiency. Caution should be taken in patients with a history of kidney stones, hypercholesterolemia, or swallowing difficulty/aspiration.
2. Resective surgery
a. Drug-resistant patients with an identifiable seizure focus (focal epilepsy) should be considered for resection of the epileptic focus.
b. In appropriately selected candidates, long-term seizure-free rates range from 60% to 80%. The best prognosis is for those with structural lesions, even subtle ones, especially mesial temporal sclerosis, cavernomas, and low-grade tumors.
3. Palliative procedures
a. For those who are not candidates for resective surgery, several procedures have been shown to produce meaningful benefit in many patients, although complete seizure remission is less common. These include disconnection procedures such as corpus callosotomy (section of the major interhemispheric commissures, which can be complete, or only include the anterior two-thirds or posterior one-third of the corpus callosum) used most successfully for atonic seizures.
b. Other treatments include neurostimulation including insertion of a vagus nerve stimulator (VNS), insertion of a responsive neurostimulator, or deep brain stimulator (DBS).
c. All neuromodulation techniques require time to show efficacy, with benefits starting at 6 months after implantation with continued improvement in seizure reduction the longer the device is maintained.
d. The VNS, which delivers controllable stimulations at programmable intervals to the left vagus nerve, can result in a 50% decrease in seizure frequency in 25% to 45% of patients. It is U.S. Food and Drug Administration (FDA)-approved for patients 12 years of age or older with focal seizures, but younger patients and those with generalized epilepsies may respond. It is rare for patients to become seizure free with VNS alone.
e. Neurostimulation of deep gray nuclei (deep brain stimulation) such as the anterior nucleus of the thalamus (FDA-approved for adults older than 18) are associated with a median seizure reduction of 56% at year 1 and up to 70% by year 3 in patients with focal epilepsy. Other thalamic targets are also being explored off-label such as the centromedian nucleus for generalized epilepsies.
f. Responsive neurostimulation involves the implantation of one or two intracranial (depth or surface) electrodes that stimulate the seizure focus on detection of seizures using an automated algorithm. Median percent reduction at 2 years is 53% with higher rates noted with longer follow-up. Some of the data obtained from the device may lead to a resective surgery if a single “active” focus is identified with chronic monitoring.
4. Complementary and alternative therapies: Such activities as relaxation techniques, yoga, and exercise are under investigation, as are some herbal medicines
and dietary supplements. Although some of these may prove beneficial, and relaxation and related techniques appear safe, caution must be exercised with herbal preparations, because some have potentially harmful effects (including lowering the seizure threshold) or may interact with ASMs.
Medication Withdrawal
1. In general, patients who have had no seizures for at least 2 years can be considered for medication withdrawal, although the recurrence rate ranges between 20% and 40%.
2. Those patients with only one seizure type, who responded promptly and were controlled for many years on modest doses of one medication, have the best prognosis, particularly if they have normal neurologic examinations, normal imaging studies, and normal EEG. Even a small risk of recurrence may be unacceptable to people with certain lifestyles or occupations that put them at risk for brief loss of consciousness.
3. Specific epilepsy syndromes have different recurrence risks than the overall statistics quoted in list item 1 discussed hereinbefore, such as SeLECTS (vast majority will remit in adolescence) or JME (vast majority will have life-long epilepsy thus requiring indefinite treatment)
4. The epilepsy is considered in remission or resolved if the patient has been seizure free for 10 years and off medications for 5 years.
Mortality in Epilepsy
1. Patients with epilepsy have a standardized mortality ratio of 1.6 to 9.3 times higher than the general population, with SUDEP accounting for 10% to 15% of these deaths. Seizure-related injuries (trauma, drowning), status epilepticus, and suicide are some of the other contributors to mortality.
2. The exact pathophysiology of SUDEP is unclear but likely involves cardiac, respiratory, or autonomic compromise, and it tends to afflict patients aged 40 or younger.
3. Risk factors include generalized tonic-clonic seizure frequency especially if nocturnal, drug-resistant epilepsy, being in a prone position at the time of a seizure, and medication nonadherence. The duration of postictal generalized EEG suppression (PGES) has been considered a risk factor for SUDEP, but it remains controversial as some additional research has shown no correlation.
4. Preventive measures to address SUDEP are unclear, but seizure control seems to be crucial, and other measures such as nocturnal supervision, sharing a room, and seizure detection technology may also play a role. It is very important to start counseling patients about the SUDEP risk and seizure precautions as soon as possible after the diagnosis of epilepsy.
DIAGNOSIS
Differential Diagnosis
1. Transient events that mimic focal or generalized seizures:
a. Syncope, especially “convulsive syncope” with clonic shaking or tonic extension with pallor after the patient has fallen to the ground.
b. Functional neurological disorder-attack/seizures (PNES).
c. Migraine (migraine with aura or basilar migraine).
d. Transient ischemic attack (TIA) (carotid or vertebrobasilar, particularly the uncommon carotid syndrome of “limb-shaking” TIA) or amyloid spells.
e. Movement disorder (tremor, nonepileptic myoclonus, dyskinesia, tics).
f. Sleep disorders (specifically narcolepsy-cataplexy syndrome, rapid eye movement [REM] behavior, and somnambulism).
g. Toxic-metabolic disturbances (distinct from those that can cause seizures), particularly with tremulousness or asterixis.
h. Panic attacks
Evaluation
1. History: Helpful aspects are recent or remote serious brain injury or illness; sleep deprivation or fever; presence, nature, and duration of warning before seizure and whether either the entire event or the warning was ever experienced before; witness accounts including level of responsiveness, motor manifestations, duration of event and recovery; patient and witness assessment of functioning afterward, particularly focal symptoms, incontinence, mouth/tongue biting, muscle soreness. Also, family history especially of epilepsy in a first degree relative increases the risk for the patient.
2. Physical examination: Mental status, focal features, signs of infection or trauma.
3. Laboratory studies: Electrolytes, calcium, magnesium, glucose, renal and liver function tests, toxic screen, and complete blood count (CBC), creatine phosphokinase.
4. Ancillary tests: Neuroimaging (MRI preferred to CT), EEG (as soon as available), lumbar puncture if infection suspected. Specific MRI epilepsy protocols are available at different centers. More advanced noninvasive imaging and neurophysiologic tests are pursued during presurgical evaluations: functional MRI, magnetoencephalography (MEG), positive emission tomography (PET), single-photon emission computed tomography (SPECT).
TREATMENT
ASMs
1. Principles of use:
a. Several ASMs have similar efficacies and work well in any given clinical seizure type or epilepsy syndrome.
b. Cenobamate is unique among ASMs because seizure freedom was achieved in 20% of patients with drug-resistant epilepsy, as compared to 1% to 3% with other drugs.
c. Unless a rapid therapeutic effect is essential, choose a low-starting dose and slow upward titration. This is especially true when treating elderly, frail, or medically ill patients.
d. In general, increase the dose until an adequate observation period establishes that seizures are controlled or until dose-related side effects develop. In the latter case, decrease back to the previous dose and monitor response. If seizures are not controlled, another appropriate ASM should be initiated and titrated, usually while weaning the patient off the first drug (ie, monotherapy is always preferable to polytherapy unless there is no alternative).
e. Sometimes, increases in dose result in increased seizures. The dose should be reduced and the drug is replaced by an alternative ASM.
f. Off-label use is justifiable if approved ASMs are not successful or the risk with the off-label alternative appears lower than that with the approved ASM.
g. The most common drug interactions involving ASMs are based on induction, or, less commonly, inhibition, of the hepatic mixed-function oxidase or P450 enzyme system or other interactions that involve glucuronidation pathways. As a group, the older ASMs have much stronger effects on these systems than do the newer ones, although several of the latter are substrates whose metabolism is affected by addition or withdrawal of the older drugs. Chronic enzyme induction in the setting of ASMs has been associated with a decreased efficacy of chemotherapeutic, immunosuppressive, and antiretroviral therapy. In addition, enzyme induction affects sex hormones and can lead to sexual dysfunction, osteopenia or osteoporosis (increased risk of fractures), and increased serologic markers of vascular risk including elevated cholesterol and cardiovascular disease.
h. Serum drug concentrations (drug levels) can be useful in pregnancy, in verifying adherence, or in providing an initial target for patients with infrequent seizures, but if used mechanically as a guide to dosing, these can hinder rather than help in achieving the goal of treatment: no seizures and no side effects (and ultimately, optimizing quality of life). Even for the older ASMs, published therapeutic ranges have limited scientific support, and individuals may have therapeutic responses or adverse effects either below or above this range. For the newer ASMs, therapeutic ranges are even more provisional, but these are included in the following discussions for completeness.
2. Specific ASMs: The common medications for seizures are categorized in several ways. Classifications based on biochemical mechanism are logical but of limited clinical value in that several drugs work by more than one mechanism and, for many, the mechanisms are poorly understood. We find it more useful to group the drugs by their spectrum of action for specific seizure types:
a. The first and the largest group of ASMs is effective against focal seizures, including those evolving into bilateral tonic-clonic seizures. Most, if not all, of these also can prevent generalized onset tonic-clonic seizures; however, they are not effective against, and may worsen, other generalized seizure types, including absence and myoclonic seizures. Drugs in this class include carbamazepine (CBZ), cenobamate (CNB), eslicarbazepine (ESL), gabapentin (GBP), lacosamide (LAC), oxcarbazepine (OXC), phenobarbital (PHB), phenytoin (PHT), pregabalin (PGB), primidone (PRM), tiagabine (TGB), and vigabatrin (VGB).
b. The second group is the “broad-spectrum” ASMs with activity against a variety of generalized onset and focal onset seizures. This group includes brivaracetam (BRV), clobazam (CLB), felbamate (FBM), lamotrigine (LTG), levetiracetam (LEV), perampanel (PER), rufinamide (RUF), topiramate (TPM), valproic acid (VPA), and zonisamide (ZNS).
c. The third group includes drugs that do not easily fit in the above categories, including ethosuximide (ESX), a narrow-spectrum ASM with established efficacy against only typical absence seizures.
d. A fourth group of drugs includes those FDA approved for specific epilepsy syndromes: Cannabidiol (CBD) for Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or Tuberous Sclerosis Complex (TSC), Stiripentol (STP) for DS, and Fenfluramine (FFA) for DS and LGS.
e. Finally, there are medications used in seizure clusters and SE, alcohol or drug-related seizures/withdrawal seizures. These include intravenous (IV), sublingual, intranasal, and rectal benzodiazepines, fosphenytoin (fos-PHT), midazolam, propofol, and anesthetic agents.
f. Polytherapy: When adding a second agent to a first one, medications with similar mechanisms of action should be avoided (eg, PGB + GBP, ESL + OXC, ESL + OXC, OXC + CBZ, ZNS + TPM). There is some evidence for synergism with VPA + LTG and VPA + ESX, as well as CLB + CBD
3. Newer ASMs have a black box warning of increased suicidality. There has been criticism of the warning as the data did not account for prior psychiatric history and drugs were grouped together. Psychiatric comorbidities are common in epilepsy with a prevalence of 25% to 40% of mood disorders and 20% to 30% anxiety disorders. Medications that can worsen mood include barbiturates, LEV, TPM, and ZNS.
Drugs Predominantly Used for Focal Epilepsy
Carbamazepine
1. Advantages: Effective against focal seizures, may help with tonic-clonic seizures or either focal or generalized onset. Well established ASM, slow-release preparations allow twice a day (bid) dosing. It is also a mood stabilizer.
2. Disadvantages: Need to titrate slowly to avoid dose-related adverse effects, pharmacokinetic interactions (P450 enzyme inducer and substrate). Ineffective against absence or myoclonic seizures and may worsen seizures or trigger SE in these patients. Weight gain.
3. Major adverse effects:
a. Dose-related: dizziness, diplopia, nausea, sedation, mild leukopenia, hyponatremia, and bradyarrhythmias (elderly).
b. Idiosyncratic: rash (including Stevens-Johnson syndrome [SJS] especially in HLA-B*1502 carriers, highest risk in patients of Asian descent), agranulocytosis, hepatic failure, pancreatitis, lupus-like syndrome
c. Chronic: effects of chronic enzyme induction (drug-drug interactions), effects on hormones, osteopenia/osteoporosis (possibly mitigated by vitamin D supplementation), elevated cholesterol, and serum vascular risk markers/increased cardiovascular risk.
4. Teratogenicity: Dose-dependent, low doses (<400 mg) are less teratogenic with a rate of 3.4%, whereas rates with higher doses (>1,000 mg) are 8.7%.
5. Initiation and titration: 100 to 200 mg at night (hs) or 100 mg bid; increase after 3 to 7 days to 200 mg bid. Can check blood tests after 1 week on this dose: CBZ level, CBC/differential, electrolytes (Na), and perhaps albumin and aspartate aminotransferase (AST) levels. Dose can be increased at 3- to 7-day intervals to obtain a level of 4 to 12 mg/L; level is typically rechecked in 4 to 6 weeks, as autoinduction of enzymes may necessitate further increases. Usual maintenance doses in adults are as follows: 600 to 1,600 mg/d, up to 2,400 mg/d. In children, start at 5 to 10 mg/kg/d, maintenance 15 to 20 mg/kg/d, up to 30 mg/kg/d.
6. Pharmacokinetics: Half-life: 12 to 20 hours (shorter with enzyme-inducing drugs; autoinduction also occurs, with level falling after 2 to 6 weeks on stable dose), protein binding: 70% to 80%.
7. Usual therapeutic range: 4 to 12 mg/L.
8. Preparations: 100- and 200-mg tablets; suspension 100 mg/5 mL (can solidify in tube feedings); slow-release preparations including brand Tegretol-XR 100-,
200-, and 400-mg caplets and Carbatrol 200- and 300-mg capsules. Carnexiv-IV carbamazepine has FDA approval as replacement therapy for oral formulations when oral administration is not feasible.
Oxcarbazepine
1. Advantages: Allows for more rapid titration than CBZ, bid dosing, minor interactions, no known hepatic or hematologic adverse effects; approved as initial monotherapy for focal seizures. It is also a mood stabilizer.
2. Disadvantages: Dose-related effects similar to those of CBZ; although induces P450 only weakly, it can lower hormone (eg, contraceptive) levels. Ineffective against and can worsen absence and myoclonic seizures. Weight gain.
3. Comment: Very similar chemically to CBZ but not converted into epoxide metabolite, which accounts for many adverse effects of CBZ.
4. Major adverse effects:
a. Dose-related: dizziness, diplopia, hyponatremia (more common than with CBZ), somnolence, ataxia, gastrointestinal (GI) upset
b. Idiosyncratic: rash (25% cross-reactivity with CBZ)
c. Chronic: Effects of chronic enzyme induction (drug-drug interactions), effects on hormones, osteopenia/osteoporosis (possibly mitigated by vitamin D supplementation), elevated cholesterol, and serum vascular risk markers/increased cardiovascular disease.
5. Teratogenicity: Limited data but appears lower than carbamazepine and possibly similar to lamotrigine.
6. Initiation and titration: Adults—150 to 300 mg bid, increasing by 300 to 600 mg every 1 to 2 weeks to target of 1,200 to 2,400 mg/d; children (older than 4 years)—8 to 10 mg/kg/d titrated to 20 to 40 mg/kg/d or higher (to effect and therapeutic level). Note: Conversion from CBZ can be rapid, over 1 day to 2 weeks, at a ratio of 300 mg OXC to 200 mg CBZ.
7. Pharmacokinetics: Half-life of 2 hours but converted into active monohydroxy-derivative (MHD) with half-life of 8 to 10 hours; protein binding: 40%.
8. Therapeutic range: 10 to 35 mg/L (MHD).
9. Preparations: Trileptal or generic tablets 150, 300, 600 mg; syrup 300 mg/5 mL. Extended release also available (Oxtellar) 150, 300, 600 mg.
Eslicarbazepine
1. Advantages: Milder enzyme induction compared to CBZ and OXC. Once daily dosing, lower risk of rash and hyponatremia. Approved for conversion to monotherapy in refractory epilepsy.
2. Disadvantages: Weak cytochrome P450 induction. Ineffective against or may worsen absence or myoclonic seizures, oral contraceptives may need to be adjusted. Mood stabilization properties less well established compared to CBZ, OXC.
3. Comment: Very similar chemically to CBZ and OXC but not converted into epoxide metabolite and exclusively to (S) enantiomer believed to be better tolerated.
4. Major adverse effects:
a. Dose-related: dizziness, diplopia, somnolence, ataxia, GI upset
b. Idiosyncratic: none
c. Chronic: effects of chronic enzyme induction
5. Teratogenicity: Unknown.
6. Initiation and titration: 400 mg once daily (qd), increase by 400 mg every week. Aim for 800 to 1,200 mg in monotherapy, up to 1,600 mg with polytherapy.
Pediatrics: (11-21 kg: start 200 mg, max 600, 22-38 kg: start 300 mg max 800 to 900, >38 kg: start 400 mg max 1,200 mg.
7. Pharmacokinetics: Hepatic clearance. Half-life of 13 to 20 hours; protein binding: <40%.
8. Therapeutic range: 5 to 35 mg/L
9. Preparations: Aptiom 200, 400, 600, 800 mg.
Phenytoin
1. Advantages: Effective against focal seizures, physician familiarity, and long history in medical use; long duration of action, especially with slow-release preparations—usually bid dosing but can be qd; parenteral loading options.
2. Disadvantages: As the dose of PHT increases, plasma levels rise to a disproportionate degree because of saturation of metabolic pathway, referred to as nonlinear or zero-order kinetics; pharmacokinetic interactions (strong P450 inducer); chronic cosmetic and other adverse effects. Levels can vary on a day-to-day basis and adjustments can lead to toxicity and breakthrough seizures.
3. Major adverse effects:
a. Dose-related: dizziness, ataxia, diplopia, nausea
b. Idiosyncratic: rash, including SJS; blood dyscrasias; hepatic failure; lupus-like syndrome
c. Chronic: gingival hyperplasia, hirsutism, neuropathy, pseudolymphoma, and controversially, lymphoma, cerebellar atrophy; effects of chronic enzyme induction (drug-drug interactions), effects on hormones, osteopenia/osteoporosis (possibly mitigated by vitamin D supplementation), elevated cholesterol, and serum vascular risk markers/increased cardiovascular risk.
4. Teratogenicity: 3%. Risk of fetal hydantoin syndrome (distinctive dysmorphic features, risk of developmental delay, microcephaly) 2.4% risk of major congenital malformations.
5. Initiation and titration: Adults—in nonemergent situations, can load orally; two doses of 500 mg or three doses of 300 mg can be taken 4 to 6 hours apart. Parenteral loading can be achieved IV (15 mg/kg, or 20 mg/kg for SE, not more than 50 mg/min; precursor drug fos-PHT may be preferable for status). When loading is not needed, can initiate estimated maintenance dose of 300 to 400 mg/d, usually in two doses, checking levels in 1 to 2 weeks. Because of zero-order kinetics, increases must be proportionately less as the level rises; for example, if the steady-state level on 300 mg/d is 12 mg/L, then 330 mg/d, a 10% dose increase, may be sufficient to raise the level to 18, a 50% increase. Pediatrics: 4 to 5 mg/kg/d, up to 8 mg/kg or more depending on level.
6. Pharmacokinetics: Half-life depends on the serum concentration and is longer at higher concentrations, for example, 20 to 30 hours when in usual therapeutic range; protein binding: 90% (lower with renal failure or hypoalbuminemia).
7. Usual therapeutic range: 10 to 20 mg/L (arguably 5-25 mg/L).
8. Preparations: Dilantin tablets 50 mg, Dilantin and generic extended-release capsules 30 and 100 mg, and suspension 125 mg/5 mL (must be adequately mixed in bottle); Phenytek capsules 200 and 300 mg. Fos-PHT used for rapid loading IV.
Gabapentin
1. Advantages: Rapid titration, relatively well tolerated, no pharmacokinetic interactions, additional uses (neuropathic pain, restless leg, migraines).
2. Disadvantages: Three or four times daily (tid and qid, respectively) dosing recommended (although it can be given bid); less efficacious than other ASMs except perhaps in elderly.
3. Major adverse effects:
a. Dose-related: sedation, dizziness, ataxia
b. Idiosyncratic: weight gain, rash (rare), behavioral changes in children, myoclonus
c. Chronic: none known
4. Teratogenicity: Limited data but likely low
5. Initiation and titration: 300 mg hs, increasing by 300 mg every 1 to 7 days to target of 1,800 to 3,600 mg/d; in elderly, 100 mg hs or bid, increasing in 100- to 200-mg increments; pediatrics (older than 3 years), 10 to 20 mg/kg/d increasing to target of 30 to 60 mg/d; adjust for renal impairment.
6. Pharmacokinetics: Half-life: 5 to 7 hours (but brain kinetics likely slower); protein binding: none.
7. Therapeutic range: 4 to 16 mg/L.
8. Preparations: Neurontin or generic capsules 100, 300, 400 mg; tablets 600 and 800 mg; solution 250 mg/5 mL. XR formulation (Horizant) is only approved for restless leg syndrome.
Pregabalin
1. Advantages: No pharmacokinetic interactions, additional uses (neuropathic pain, migraines).
2. Disadvantages: Relatively slow titration owing to sedation, weight gain.
3. Major adverse effects:
a. Dose-related: sedation (may potentiate ethanol, benzodiazepine effects), dizziness, ataxia, peripheral edema.
b. Idiosyncratic: weight gain, rash (rare)
c. Chronic: none known
4. Teratogenicity: Limited data but likely low
5. Initiation and titration: 75 to 100 mg hs, increasing by a similar amount mg every 1 to 2 weeks to target of 300 to 600 mg/d in two divided doses; adjust for renal impairment. Pediatrics: (<4 years) 3.5 mg/kg/d tid, max 14 mg/kg/d. (4-17 years) <30 kg 3.5 mg/kg/d bid or tid max 14 mg/kg/d >30 kg 2.5 mg/kg/d bid or tid max 10 mg/kg/d or 600 mg.
6. Pharmacokinetics: Half-life: 4 to 7 hours (but brain kinetics likely slower); protein binding: none.
7. Provisional therapeutic range: 4 to 16 mg/L.
8. Preparations: capsules 25, 50, 75, 100, 150, 200, 225, 300 mg.
Tiagabine
1. Advantages: May have antianxiety or analgesic effects; can sometimes be given bid.
2. Disadvantages: Sedating; risk of nonconvulsive SE (NCSE); P450 induction.
3. Major adverse effects:
a. Dose-related: dizziness, somnolence, nausea, cognitive slowing
b. Idiosyncratic: rash, mood changes, generalized NCSE (doses 48 mg/d or greater)
c. Chronic: unknown
4. Teratogenicity: Unknown.
5. Initiation and titration: 2 to 8 mg/d, increasing by 2 to 8 mg/d at weekly intervals to target of 24 to 56 mg/d in two to four doses; pediatrics (older than 12 years): 4 mg/d, increasing by 4 mg/wk to target of 20 to 32 mg/d.
6. Pharmacokinetics: Half-life: 4 to 9 hours, protein binding: 96%.
7. Provisional therapeutic range: 0.1 to 0.3 mg/L.
8. Preparations: Gabitril film tabs 2, 4, 12, 16, 20 mg.
Phenobarbital
1. Advantages: Long half-life (daily dosing), inexpensive.
2. Disadvantages: Drowsiness, cognitive and behavioral side effects, interactions (induces P450).
3. Major adverse effects:
a. Dose-related: sedation, depression, cognitive impairment
b. Idiosyncratic: rash, hyperactivity (children), hepatic failure (rare), aplastic anemia (rare)
c. Chronic: connective tissue disorders (eg, frozen shoulder, Dupuytren contractures); effects of chronic enzyme induction (drug-drug interactions), effects on hormones, osteopenia/osteoporosis (possibly mitigated by vitamin D supplementation), elevated cholesterol and serum vascular risk markers/increased cardiovascular risk
4. Teratogenicity: Yes, 5.5% rates of major malformations.
5. Initiation and titration: 90 to 250 mg/d, can load IV with up to 20 mg/kg (<100 mg/h for SE), but sedation is universal; check steady-state levels in 2 to 3 weeks (4-5 weeks in presence of VPA); pediatrics: 3 to 6 mg/kg/d.
6. Pharmacokinetics: Half-life: 72 to 168 hours (less in children; more when co-administered with VPA).
7. Usual therapeutic range: 10 to 40 mg/L.
8. Preparations: Tablets 15, 30, 60 (or 62.5), 100 mg; suspension 15 or 20 mg/5 mL; parenteral 30, 60, 130 mg/mL.
Primidone
1. Advantages: Parent compound may have efficacy beyond that of PHB metabolite, at least against myoclonic seizures; effective against tremor at low doses.
2. Disadvantages: Possibly more sedating than PHB alone; must be taken in divided doses, usually tid or qid; strongly induces P450.
3. Comment: Metabolized to PHB.
4. Major adverse effects:
a. Dose-related: same as PHB
b. Idiosyncratic: same as PHB
c. Chronic: same as PHB
5. Teratogenicity: Yes, but rate unclear.
6. Initiation and titration: 100 to 125 mg hs, increasing by 125 to 250 mg every 2 to 7 days to target of 500 to 1,500 mg/d; pediatrics: 50 mg/d increasing to 10 to 25 mg/kg/d.
7. Pharmacokinetics: Half-life: 6 to 22 hours (72-168 hours for PHB metabolite); P450 inducers promote conversion to PHB.
8. Usual therapeutic range: 5 to 12 mg/L (10-40 mg/L for PHB).
9. Preparations: Mysoline and generic tablets 50 and 250 mg; suspension 250 mg/5 mL.
Lacosamide
1. Advantages: Rapid titration, relatively well tolerated, low pharmacokinetic interactions (limited metabolism by CYP2C19), availability of IV and oral solution. Also seems to work for generalized onset seizures.
2. Disadvantages: Dizziness and gait instability can limit tolerability.
3. Major adverse effects:
a. Dose-related: dizziness, headache, diplopia/blurred vision, ataxia, tremors, nausea/vomiting; Dose dependent increase in P-R interval on EKG, therefore should be avoided or used with extreme caution in patients with any type of A-V block, or in patients on other medications that can affect P-R interval.
b. Idiosyncratic: none
c. Chronic: unknown
4. Teratogenicity: Unknown.
5. Initiation and titration: Start 50 mg p.o./IV bid and increase by 50 mg bid up to 100 to 200 mg bid to maximum of 400 mg/d unless severe hepatic or renal impairment. In the acute setting, a loading dose of 100 to 300 mg can be used, with a maintenance dose of up to 600 mg. Pediatrics: p.o 1 mg/kg bid, increase by 1 mg/kg/dose bid typically up to 10 mg/kg/d, but can titrate further for effect and therapeutic serum level. ≥50 Kg: 50 mg bid, increase by 50 mg bid weekly, recommended maximum of 200 mg bid.
6. Pharmacokinetics: Renal clearance. Half-life: 13 hours; protein binding: less than 15%.
7. Provisional therapeutic range: 2.5 to 18 mg/L.
8. Preparations: Vimpat 50-, 100-, 150-, 200-mg tablets; 200 mg/20 mL solution IV; 10 mg/mL solution p.o.
Vigabatrin
1. Advantages: Efficacious for infantile spasms especially in context of TSC or brain malformations; and for focal seizures.
2. Disadvantages: Risk of dose and duration dependent peripheral, irreversible vision loss in children and adults. Use of the medication necessitates frequent ophthalmologic evaluations to avoid further progression.
3. Major adverse effects:
a. Dose-related: somnolence, headache, dizziness, sedation
b. Idiosyncratic: Reversible MRI changes in about 20% to 30% of infants (hyperintensities and restricted diffusion in basal ganglia, corpus callosum, and brainstem). Clinical significance is unclear as this is not associated with specific symptoms although it is difficult to detect subtle neurological changes in some infants.
c. Chronic: unknown
4. Teratogenicity: Unknown.
5. Initiation and titration: Adults: 500 mg bid, increase by 500 mg weekly until 1.5 g bid. In children, 250 mg bid with a maximal dose of 1 g bid. For infantile spasm treatment, starting dose is 50 mg/kg/d divided into two doses, increase by 25 to 50 mg/kg every 3 days up to 150 mg/kg/d.
6. Pharmacokinetics: Renal clearance. Half-life: 5 to 10 hours.
7. Usual therapeutic range: 0.8 to 36 mg/L.
8. Preparations: Sabril and Vigadrone, 500-mg tablets and 500 mg powder packets.
Cenobamate
1. Advantages: A very effective ASM for focal epilepsy with higher seizure freedom rates compared to other drugs.
2. Disadvantages: Requires a slow titration over several weeks.
3. Major adverse effects:
a. Dose-related: fatigue, diplopia, dizziness.
b. Idiosyncratic: drug reaction with eosinophilia and systemic symptoms occurred with rapid titrations. QT shortening, increased serum potassium.
c. Chronic: unknown, has some enzyme inducing properties.
4. Teratogenicity: Unknown.
5. Initiation and titration: Adults: weeks 1 to 2: 12.5 mg, weeks 3 to 4: 25 mg, weeks 5 to 6: 50 mg, weeks 7 to 8: 100 mg, weeks 9 to 10: 150 mg, weeks 11 to 12: 200 mg. Maximal dose 400 mg, therapeutic benefits can be seen starting 50 mg. Proactive lowering of clobazam, phenytoin, and phenobarbital recommended prior to initiation.
6. Pharmacokinetics: Renal clearance. Half-life: 50 to 60 hours.
7. Usual therapeutic range: To be determined.Related posts:
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