Epilepsy

Ruba Shaheen
Introduction
• Epilepsy is a common neurologic condition in which a person is prone to recurrent
seizures. Epilepsies are characterized by different seizure types, ranging in
severity and etiologies often with neurobiological, cognitive, psychological, and
social consequences.
• Status epilepticus can occur when the length of the continuous seizure activity
extends past 5 minutes or time of ongoing seizure activity extends past 30
minutes, after which there is a risk of long-term consequences. It is a neurologic
emergency.
Epidemiology
• Epilepsy is the fourth most common neurologic disorder globally.
• In the US: 3.4 million people have epilepsy with a prevalence of 1.2%.
• While epilepsy is a chronic disease that can present at all ages: highest incidence in childhood
(especially < 5years) and the older adult population (esp. >65)
• Usually has good prognosis (able to attain seizure freedom) but the mortality rate is 2-3x higher
and life expectancy is shorter than general population.
• All individuals with epilepsy experience seizures; however, not all individuals who experience
seizures will be diagnosed with epilepsy.
• Some seizures are provoked and occur as a result of systemic, toxic, or metabolic insults such as
substance use; alcohol, barbiturate, or benzodiazepine withdrawal; or acute neurologic (eg, brain
hemorrhage) or systemic illnesses (eg, hypocalcemia, hypoglycemia, uremia, and eclampsia).
Furthermore, some patients will have seizures only associated with fever (eg, febrile seizures).
Etiology
• The most common causes vary depending on the population of interest (e.g in childhood-onset:
genetic and/or developmental structural abnormalities, older ages: acquired structural injury)
• Genetic:
• In childhood: Dravet syndrome (mutations in sodium channel (SCN1A)), childhood absence
epilepsy (CAE) (mutations in T-type Ca2+ channels and GABA-receptor subunits) and Juvenile
Myoclonic Epilepsy (JME) (mutations in the EF-hand containing protein-1 (EFHC1) and intestinal
cell kinase (ICK).
• Genetic etiologies usually pass from generation to generation but can also arise from sporadic
mutations, and cannot be acquired after birth.
• Structural:
• Common epilepsies caused by structural abnormalities include cortical dysplasia (childhood
onset), mesial temporal lobe epilepsy (adult onset), and posttraumatic epilepsy.
Etiology
• Infectious:
• Most common etiology worldwide
• Not seizures associated w/ acute infections such as meningitis or encephalitis
• Most common acquired infectious epilepsy is from neurocysticercosis.
• Metabolic, Immune, and Unknown Etiology:
• Less common causes
• Examples of metabolic include Lafora disease
• Examples of immune include anti-NMDA receptor encephalitis
• Unprovoked seizures
Etiology
• Risk Factors:
• known epilepsy risk factors include premature birth with small gestational weight, perinatal
injury (eg, anoxia), history of alcohol withdrawal seizures, history of febrile seizures, and family
history of seizures.
• Seizure Triggers:
• Most common triggers: hyperventilation and photostimulation
• Others include: physical/emotional stress, sleep deprivation, sensory stimulation, hormonal
changes.
• Medications: theophylline, high-dose phenothiazines, antidepressants (especially bupropion),
alcohol, and substance use > lower Sz threshold
Pathophysiology
• The underlying general pathophysiologic process for all epilepsies is neuronal hyperexcitability
and hypersynchronization.
• Seizures result from excessive excitation or disordered inhibition of neurons.
• Initially, a small number of neurons fire abnormally. Normal membrane conductances and
inhibitory synaptic currents then break down, and excitability spreads locally (focal seizure) or
more widely (generalized seizure).
• This may occur as the result of multiple mechanisms, alterations in the number, type, and
biophysical properties of voltage- or ligand-gated K+, Na+, Ca2+, and Cl– ion channels in neuronal
membranes are thought to play a significant role
• Epileptic seizures result only when there is also synchronization of excessive neuronal firing.
• Seizure initiation is likely caused by an imbalance between excitatory (eg, glutamate, calcium,
sodium, substance P, and neurokinin B) and inhibitory (γ-aminobutyric acid [GABA], adenosine,
potassium, neuropeptide Y, opioid peptides, and galanin) neurotransmission.
• Sustained depolarization can result in neuronal death.
Clinical presentation
• Many patients, particularly those with focal onset seizures with dyscognitive features or generalized
tonic–clonic (GTC) seizures, are amnestic to the actual seizure event.
• Symptoms depend on seizure type and where the abnormal firing occurs. Although seizures can vary
between patients, they tend to be stereotyped within an individual.

• Focal (partial) seizures:

• begin in one hemisphere of the brain
• result in an asymmetric seizure
• manifest as alterations in motor functions (eg, twitching or shaking), sensory (eg, numbness or
tingling) or somatosensory symptoms, aberrations in behavior, or automatisms.
• Focal seizures without dyscognitive features (formerly called simple partial seizures) are associated
with no impairment of consciousness.
• In focal seizures with dyscognitive features (formerly called complex partial seizures), there is
impairment of consciousness and awareness and no memory of the event > postictal period and
deep sleep
Clinical presentation
• Absence seizures:
• generally occur in young children or adolescents and exhibit a sudden onset, interruption of
ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes.
• There is only a very brief (seconds) period of altered consciousness.
• Absence seizures have a characteristic 2- to 4-cycles per second spike and slow-wave EEG pattern.
• Generalized Tonic Clonic (GTC) seizures:
• GTC seizures are major convulsive episodes and are always associated with a loss of consciousness.
• Motor symptoms are bilateral.
• GTC seizures may be preceded by premonitory symptoms (ie, an aura).
• Tonic–clonic seizures begin with a short tonic contraction of muscles followed by a period of
rigidity and clonic movements.
• The patient may lose sphincter control, bite the tongue, or become cyanotic. The episode is
frequently followed by a deep sleep.
Clinical presentation
• Myoclonic seizures:
• Brief shock-like muscular contractions (jerks) of the face, trunk, and extremities.
• They may be isolated events or rapidly repetitive.
• There is no alteration of consciousness.

• Atonic seizures:
• The hallmark of Lennox–Gastaut syndrome
• There is a sudden loss of muscle tone that may be described as a head drop, dropping of a
limb, or slumping to the ground.

• Interictally (between seizure episodes), there are typically no objective, pathognomonic signs of
epilepsy.
Clinical presentation

ILAE 2017 Classification of seizure types—expanded

version. (Reprinted, with permission, from Fisher RS,
Cross JH, French JA, et al. Operational classification of
seizure types by the International League Against
Epilepsy: Position paper of the ILAE Commission for
Classification and Terminology. Epilepsia.
2017;58(4):522–530.)
Clinical presentation
• Classification of Epilepsies and Epilepsy Syndromes:
• The starting point of epilepsy classification is identification of the seizure type, understanding
that some patients may have multiple different seizure types.
• After seizure types are determined, the epilepsy should be classified into one of four
categories:
1. focal epilepsy in which a patient only has focal-onset seizures;
2. generalized epilepsy in which a patient displays evidence of only generalized-onset
seizures;
3. combined generalized and focal epilepsy; and
4. unknown in which the epilepsy type is unknown
Clinical presentation

ILAE framework for classification

of the epilepsies. (Reprinted, with
permission, from Scheffer IE,
Berkovic S, Capovilla G, et al.
ILAE classification of the
epilepsies: Position paper of the
ILAE Commission for
Classification and Terminology.
Epilepsia. 2017;58(4):512–521.)
Diagnosis
• Epilepsy is a clinical diagnosis, meaning that it is made on the basis of medical signs and patient-
reported symptoms, rather than any one diagnostic test.
• A person is considered to have epilepsy if they meet any of the following conditions:
1. at least two unprovoked (or reflex) seizures occurring greater than 24 hours apart;
2. one unprovoked (or reflex) seizure and a probability of further seizures similar to the
general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the
next 10 years; or
3. diagnosis of an epilepsy syndrome.
Diagnosis
• Ask the patient and family to characterize the seizure for signs/symptoms, triggers, frequency,
duration, precipitating factors, time of occurrence, presence of an aura, impairment of consciousness,
ictal activity, and postictal state.
• Accurate diagnosis also depends on the neurologic examination and diagnostic techniques such as
EEG and brain imaging.
• In some cases, particularly following GTC seizures, serum prolactin levels may be transiently elevated.
• Laboratory tests may rule out treatable causes of seizures (hypoglycemia, altered serum electrolyte
concentrations, infections, etc.) that are not epilepsy.
• EEG is very useful in the diagnosis of various seizure disorders, but epileptiform activity is found in only
about 50% of patients with epilepsy > Golden standard is video EEG but is not standard practice
• Brain imaging with either a CT scan or MRI can detect structural lesions that can aid in the diagnosis of
seizures and epilepsy types.
• Physical, neurologic, and laboratory examinations may identify an etiology.
Treatment
Goals of therapy
• Anti-seizure medications (ASM) therapy is the mainstay of epilepsy treatment > all available
ASMs are symptomatic treatments and none are curative >> Lifelong use
• Surgery is the only possibly curative therapy and only a select number of patients qualify for
surgery.
• The goal of ASM therapy is eliminating the occurrence of seizures within the shortest possible
duration of time and with minimal impact on QOL.
• In most patients the desired outcome is complete seizure freedom with little to no medication
adverse effects > not always achievable
General Approach to Treatment
• After an isolated seizure, assess whether to: treat, possibly treat or not to treat.
• Assess the risk of recurrence: high vs. low risk.
• The probability of recurrent seizures is higher if certain findings are present, including:
• brain imaging abnormalities (eg, stroke, trauma, CNS infection, cerebral palsy, and other cognitive developmental
disabilities)
• Abnormal neurologic examination beyond the postictal period, including focal findings or intellectual disability
• EEG with epileptiform abnormalities (characterized by spikes or sharp waves)
• First presentation of an epilepsy syndrome
• or a nocturnal seizure.
• For patients with any of the above findings present, the probability of seizure recurrence may be 2 to 2.5 times that of
those without those findings.
• The decision on whether to start ASM therapy after a single seizure depends on clinician judgment and available clinical
evidence.
• Some clinicians choose to start ASM treatment after one seizure with a definite abnormal MRI or epileptiform EEG while
others do not initiate treatment until a second seizure has occurred.
• In general, patients who have had two or more unprovoked seizures should be started on ASMs
General Approach to Treatment
• Once the decision to initiate therapy has been determined, accurate identification of seizure
type and epilepsy diagnosis is critical for treatment, as an ASM must be effective for the specific
seizure type and epilepsy, or epilepsy syndrome, being treated.
• Pharmacokinetics and metabolism pathways should be taken into consideration
• Start with a ASM monotherapy> if it fails > switch to a different agent with a different MOA > if
that fails >> dual therapy
• Assess for adherence
• Start with a low dose of ASM and uptitrate over weeks.
• In patients with multiple recent seizures, a therapeutic dose needs to be reached much more
quickly, and a rapid titration over days instead of weeks is appropriate >> choose medications
with LD options.
• Optimize the dose in accordance with up titration guidelines and clinical response
Non pharmacologic treatment
• Approximately 20% to 35% of patients will not achieve adequate seizure control and seizures may
be considered medication-resistant.
• Nonpharmacologic therapies are available for these medication-resistant seizures, as well as for
individuals with medication-responsive seizures in whom the benefits of nonpharmacologic
therapies outweigh its risk.
• Diet: Ketogenic diet
• Vagus nerve stimulation:
• The most common adverse reactions associated with stimulation are hoarseness, voice
alteration, increased cough, pharyngitis, dyspnea, dyspepsia, and nausea. Serious adverse
reactions reported include infection, nerve paralysis, hypoesthesia, facial paresis, left vocal
cord paralysis, left facial paralysis, left recurrent laryngeal nerve injury, urinary retention,
and low-grade fever
Non pharmacologic treatment
• Surgery:
• The treatment of choice in select patients with refractory focal epilepsy, especially those
with seizures originating from the temporal lobe.
• Certain factors have been found to predict positive outcomes in surgical patients including
presence of a focal brain lesion on MRI, presence of unilateral mesial temporal sclerosis,
presence of a localized temporal lobe positron emission tomography (PET) abnormality
(even if brain MRI is normal), concordant EEG data showing location of ictal onset and
shorter preoperative seizure duration.
• Epilepsy surgery is not without risk, as learning and memory can be impaired
postoperatively, and general intellectual abilities have also been affected in a small
number of patients
Pharmacologic treatment
Pharmacologic treatment
• There are more than 27 FDA-approved ASMs for the treatment of epilepsy in the United States.
Only a subset of these are approved for monotherapy, and many are approved as add-on
treatment only
Pharmacologic treatment: general considerations
• Most antiseizure medications (ASMs) affect channel (sodium and Ca) kinetics, augment
inhibitory neurotransmission (increasing central nervous system [CNS] GABA), and modulate
excitatory neurotransmission (decreasing or antagonizing glutamate and aspartate).

• ASMs are effective against GTC and focal seizures and probably work by delaying recovery of
sodium channels from activation. Medications that reduce corticothalamic T-type Ca currents
are effective against generalized absence seizures.

• Begin with monotherapy, as ~65% of patients can be maintained on one ASM, although not
necessarily seizure free.

• Up to 60% of patients with epilepsy have adherence issues, commonly leading to treatment
failure.
Pharmacologic treatment: general considerations
• Carbamazepine, ethosuximide, gabapentin, levetiracetam, oxcarbazepine, phenytoin valproic
acid, and zonisamide have strong enough evidence to be labeled efficacious or effective or as
probably efficacious or effective as initial monotherapy in certain seizure types.

• Some ASMs may possibly precipitate or aggravate certain seizure types, and it is suggested that
they be used with caution in those patients. Examples are carbamazepine, gabapentin,
oxcarbazepine, phenytoin, tiagabine, and vigabatrin in children with absence or juvenile
myoclonic epilepsy.
Pharmacologic treatment: general considerations
• Initiate ASMs with a low dose (ie, one-fourth to one-third of the anticipated maintenance dose),
and titrated gradually over 3–4 weeks to a moderate dose. If seizures continue, titrate to a
maximum dose.
• If the first ASM is ineffective or causes intolerable adverse effects, add a second ASM (preferably
with a different mechanism of action), and then taper and discontinue the ineffective or
intolerable ASM. If the second ASM is ineffective, then polytherapy may be indicated.
• The therapeutic range for ASMs may be different for different seizure types

• Medication resistance occurs if there is inadequate seizure control after two trials of tolerated
and appropriately chosen and scheduled ASMs (whether as monotherapies or in combination).
Pharmacologic treatment: Geriatric considerations
• Lower doses of ASMs are often required in older individuals due to compromised renal or
hepatic function and some patients have increased receptor sensitivity to CNS medications,
making the accepted therapeutic range invalid.
• Older persons often take many medications, and thus are more prone to experience
neurocognitive effects and medication interactions involving ASMs that affect the CPY450
system (eg, carbamazepine, phenytoin, valproic acid, and phenobarbital).
• Hypoalbuminemia is common in older individuals, and highly bound ASMs (eg, valproic acid) can
be problematic.
• They also experience body mass changes which can affect the elimination half-life and volume
of distribution.
• Lamotrigine is often considered a medication of choice for older patients with focal onset
seizures because of effectiveness and tolerability.
Pharmacologic treatment: Paediatric considerations
• Neonates and infants display decreased efficiency in renal elimination and may metabolize
medications more slowly, but by age 2 or 3 years they may metabolize medications more rapidly
than adults.
• Thus, neonates and infants require lower ASM doses, but children may require higher doses
than adults.
Pharmacologic treatment: Withdrawal
• ASM withdrawal can be considered if:
1. the patient is seizure free for 2–5 years,
2. has a history of a single type of focal seizure or primary generalized seizures with a normal
neurologic exam and normal IQ,
3. and an EEG that has normalized with treatment.

• Factors favoring an unsuccessful ASM withdrawal include a high seizure frequency history,
repeated episodes of status epilepticus, combination seizure types, and abnormal cognition.
Always withdraw ASMs gradually
Pharmacologic treatment: PK considerations
• Measure free rather than total serum concentrations of highly protein-bound ASMs if
suspected altered protein binding.
• Example situations include chronic renal failure, liver disease, hypoalbuminemia, burns,
pregnancy, malnutrition, displacing medications, and in neonates and older persons.
• Unbound concentration monitoring is especially useful for phenytoin.
• Concentration-dependent effects can often be alleviated by decreasing the dose or avoided by
slow dose titration.
Pharmacologic treatment: AE considerations
• CNS adverse medication effects are frequent and include sedation, dizziness, blurred vision,
poor concentration, and ataxia.
• Barbiturates can cause more cognitive impairment than other ASMs, but in children can cause
paradoxical excitement. The newer agents have less effect on cognition in general, except
topiramate.
• The most widely recognized idiosyncratic reactions are ASM-induced rashes, which can
progress to Stevens–Johnson syndrome/toxic epidermal necrolysis.
• The HLA-B*1502 variant has been associated with increased risk of developing Stevens–
Johnson syndrome as well as toxic epidermal necrolysis with carbamazepine (and possibly
phenytoin, lamotrigine, and oxcarbazepine) and occurs in ~15% of individuals of Asian,
southeast Asian, and south Asian origin >> Patients with this variant should not use these
ASMs.
• The HLA genotype HLA-A*3101 is associated with carbamazepine-induced skin reactions in
individuals of Chinese, Japanese, and European populations and this ASM should also be
avoided in those with this variant.
Pharmacologic treatment: AE considerations
• Other reactions include hepatitis and blood dyscrasias. (Fatal aplastic anemia with felbamate)
• ASM treatment itself may sometimes worsen seizures as a paradoxical toxic effect of the medication
• Acute organ failure usually happens within the first 6 months of ASM therapy.
• Any patient taking an ASM who complains of lethargy, vomiting, fever, or rash should have a
laboratory assessment, including white blood cell counts and liver function tests.

• An adverse effect of long-term use of ASMs is osteomalacia or osteoporosis as phenytoin,

phenobarbital, carbamazepine, oxcarbazepine, felbamate, and valproic acid may interfere with
vitamin D metabolism.
• Patients taking these medications should receive vitamin D supplementation and calcium and bone
mineral density testing if other risk factors for osteoporosis are present.
• Laboratory tests may reveal elevated bone-specific alkaline phosphatase and decreased serum Ca
and 25-OH vitamin D, as well as intact parathyroid hormone

• A warning on suicidal behavior and ideation also accompanies all ASMs.

Pharmacologic treatment: Interactions
• Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome
P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme
systems.

• Valproic acid inhibits many hepatic enzyme systems and displaces some medications from
plasma albumin.

• Felbamate and topiramate can act as inducers with some isoforms and inhibitors with others.
Pharmacologic
treatment
Pharmacologic
treatment
First-Generation ASMs
First-Generation ASMs
1. Carbamazepine
2. Clonazepam
3. Ethosuximide
4. Phenobarbital
5. Phenytoin (and its esterified prodrug fosphenytoin)
6. Primidone
7. Valproate (available as valproic acid and divalproex)

These ASMs are considered amongst the most efficacious

First-Generation ASMs: MoA
• GABAergic Activity (Promotes Inhibition):
• Phenobarbital, Primidone (prodrug of phenobarbital), Clonazepam: Bind to sites at the GABAA receptor
as agonists, increasing chloride channel opening and promoting hyperpolarization, which results in cells
that are less susceptible to electrical impulses.

• Sodium Channel Blockers (Reduce Excitability):

• Phenytoin, Carbamazepine: bind to voltage-gated sodium channels in their inactive form preventing
repetitive and sustained firing of sodium-dependent action potentials and stabilizing the threshold
against hyperexcitability.

• Unique Mechanism:
• Ethosuximide: inhibits t-type calcium channels in cells of the thalamus and the cortex, preventing the
abnormal firing of these cells, used in absence seizures.
First-
Generatio
n ASMs:
Doses
First-Generation ASMs: PK
• Phenytoin:
 90% protein bound in individuals with normal protein status and 10% being unbound as free phenytoin.
Only unbound free phenytoin is pharmacologically active.
 Reference ranges: total phenytoin level in the therapeutic range of 10 to 20 mg/L (mcg/mL; 40-79 µmol/L)
corresponding to a pharmacologically active free phenytoin level of 1 to 2 mg/L (mcg/mL; 4-8 µmol/L).
 Monitoring of free phenytoin levels better reflect the true therapeutic levels in patients with
hypoalbuminemia. (Results not readily available and may take weeks)
 Equations are available to normalize the phenytoin concentration in patients with hypoalbuminemia or
renal failure. (e.g. Winter–Tozer equation).

• Valproate: extensively bound to albumin, and due to saturable binding, the valproate free fraction will
increase as the total serum concentration increases. (free valproate levels are not commonly ordered)
• Therefore, it is also important to know the patient’s serum albumin level and protein status to aid in
interpretation of total phenytoin and valproate serum levels.
• Valproate levels are not routinely corrected for low protein status in clinical practice, although it is still
important to be aware of its possible effect.
First-Generation ASMs: PK
• Carbamazepine, ethosuximide, and phenobarbital are also highly protein bound, but this has less of a
clinically meaningful impact in practice.
• Phenytoin:
• Zero-order kinetics occurs within the usual therapeutic range (≥300 mg), so any change in dose may
produce disproportional changes in serum concentrations >> Increase in increments of 30 mg instead of
100 mg

• Carbamazepine, ethosuximide, phenobarbital, and valproate: linear pharmacokinetics at clinically relevant

doses.
• An exception to this is ethosuximide which displays some evidence of nonlinear kinetics at higher
concentrations.
• Carbamazepine is a particularly strong inducer of CYP metabolism and induces its own metabolism in a
process known as autoinduction, where its half-life starts decreasing 3 to 5 days after therapy initiation with
autoinduction being complete within 21 to 28 days.
• Carbamazepine, ethosuximide, phenobarbital, phenytoin, and valproate all have narrow therapeutic ranges
and require monitoring of serum concentrations
First-Generation ASMs: Medication Interactions
• All first-generation ASMs are metabolized via CYP450 enzymes, leading to significant interactions.
• Carbamazepine, Phenobarbital, and Phenytoin: act as both substrates and inducers of CYP enzymes.
• Valproate: Inhibits CYP450 and UGT metabolism, increasing levels of phenobarbital and lamotrigine (30–
50%), potentially causing toxicity.
• Oral Contraceptives (OCs):
• Enzyme-inducing ASMs (e.g., carbamazepine, phenytoin) increase OC clearance, reducing efficacy.
• Valproate does not compromise OC efficacy but may experience increased metabolism when used with
OCs, risking seizure recurrence.
First-Generation ASMs: Adverse Reactions
• The first-generation ASMs are, in general, associated with a higher incidence of dose-related and
idiosyncratic adverse reactions including neurotoxic effects, hepatotoxicity, and SJS/TEN.
• Unique adverse effects associated with first-generation ASMs:
• hyponatremia with carbamazepine
• hyperactivity with phenobarbital in children
• gingival hyperplasia and osteoporosis with chronic use of phenytoin.
• Valproate especially has a number of unique adverse effects including concentration-dependent
thrombocytopenia at serum levels above 100 mg/L (mcg/mL; 693 µmol/L), hyperammonemia related to
carnitine deficiency that may or may not lead to encephalopathy, idiosyncratic pancreatitis, and well-known
teratogenicity.
First-Generation ASMs: Advantages and Disadvantages
First-generation ASMs are highly effective for epilepsy, with notable examples including:
• Valproate: A broad-spectrum ASM effective for both focal-onset and generalized-onset seizures, as well as
various epilepsy syndromes. It also benefits conditions like migraine and bipolar disorder.
• Phenobarbital: The longest-used ASM, widely available globally.
• Carbamazepine and Phenytoin: Effective for focal-onset and tonic-clonic seizures but may worsen some
generalized seizures (e.g., atypical absence seizures).
• Ethosuximide: The first-line treatment for absence seizures but limited for other epilepsy types.

While effective, first-generation ASMs are generally reserved for cases where second-generation ASMs fail, due
to better tolerability, fewer interactions, and broader availability of second-generation options.
Second-Generation ASMs
Second-Generation ASMs
1. Felbamate
2. gabapentin
3. Lamotrigine
4. Levetiracetam
5. Oxcarbazepine
6. Tiagabine
7. Topiramate
8. Zonisamide

In general, these medications are considered to have similar efficacy in controlling seizures as
first-generation ASMs, have relatively simple pharmacokinetics with fewer interactions, and
have an overall lower incidence of adverse effects.
Second-Generation ASMs: MoA
The second-generation ASMs have mechanisms of action that include enhancement of GABAergic activity
(eg, tiagabine) and sodium channel inhibition (eg, lamotrigine, oxcarbazepine, zonisamide) but also expand
beyond that:
• Felbamate: modulates neurotransmission via inhibition of the N-methyl D-aspartate (NMDA) glutamate
receptor
• Topiramate: inhibits the kainate/α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate
receptor
• Levetiracetam: may modulate both glutamergic and GABAergic neurotransmission through modulation of
presynaptic neurotransmitter release via inhibition of SV2A protein, considered the master regulator
molecule of neurotransmitter release.
• Gabapentin: binds to presynaptic α2δ subunit of calcium channels, possibly resulting in decreased release
of the excitatory neurotransmitters glutamate, noradrenaline, substance P, and calcitonin gene-related
peptide).
• Topiramate and zonisamide are also carbonic anhydrase inhibitors
• Oxcarbazepine: structurally similar to carbamazepine and exhibits a similar mechanism of action, but with
an improved pharmacokinetic and adverse reaction profile.
Second-Generation ASMs: PK
• Second-generation ASMs generally have simpler pharmacokinetics than first-generation ASMs.
• Most are well absorbed and not significantly protein-bound, with some exceptions
• Gabapentin: Saturable transport system at doses ≤1,200 mg per single dose
• Topiramate, Gabapentin, levetiracetam, oxcarbazepine: renal dose adjustment
• felbamate, lamotrigine, oxcarbazepine, tiagabine, and zonisamide are all hepatically metabolized
• Oxcarbazepine doesn’t undergo autoinduction
Second-Generation ASMs: Medication Interactions
• Gabapentin and levetiracetam exhibit minimal interactions due to the lack of significant hepatic
metabolism.
• Hepatically metabolized ASMs (e.g., oxcarbazepine, topiramate) can interact with the CYP450 system, but
to a lesser extent than first-generation ASMs.
• Lamotrigine has notable interactions with valproate and first-generation ASMs, requiring careful titration
due to the risk of severe rashes (e.g., Stevens-Johnson syndrome).
• Hormonal contraceptives can affect or be affected by ASMs such as lamotrigine, oxcarbazepine, and
topiramate.
Second-Generation ASMs: Adverse Reactions
• Second-generation ASMs are generally better tolerated than first-generation drugs, but some (e.g.,
topiramate, zonisamide) can cause cognitive slowing and sedation, particularly with rapid titration or high
doses.
• Serious Risks:
• Felbamate has severe risks, including fatal liver failure and aplastic anemia, and requires signed
consent.
• Lamotrigine can cause severe rashes, particularly with improper dosing or in combination with
valproate.
• Specific Reactions:
• Oxcarbazepine can cause hyponatremia, especially in older adults or those on diuretics.
• Gabapentin discontinuation can lead to withdrawal symptoms
• levetiracetam may cause irritability.
Second-Generation ASMs: Adv. And Disadv.
• Second-generation ASMs are as effective as first-generation drugs but with improved tolerability and
fewer interactions.
• Levetiracetam: Broad-spectrum efficacy with minimal CNS effects (irritability being a notable exception),
widely used for focal-onset epilepsy.
• Lamotrigine: Well-tolerated with minimal cognitive effects, suitable for older adults, but requires slow
titration due to rash risks.
• Both lamotrigine and oxcarbazepine may be a good ASM for patients with comorbid bipolar disorder,
with oxcarbazepine not requiring very slow dose titration
• Topiramate and Zonisamide: Effective but limited by cognitive side effects and slow titration; useful for
patients with migraines and weight loss (Topiramate) or poor adherence (Zonisamide)
• Gabapentin: Limited efficacy but well-tolerated; primarily used for comorbid conditions like neuropathic
pain.> could exacerbate generalized onset seizures
• Felbamate: Effective but reserved for severe cases due to serious adverse effects> for treatment resistant
• Tiagabine: after treatment failure
Third-Generation ASMs
Third-Generation ASMs
Categorized into ASMs for typical seizures and ASMs for specific epilepsy syndromes
For typical seizures:
1. Brivaracetam
2. Cenobamate
3. eslicarbazepine
4. Lacosamide
5. Perampanel
6. Pregabalin
Third-Generation ASMs
Categorized into ASMs for typical seizures and ASMs for specific epilepsy syndromes
For specific epilepsy syndromes:
1. Cannabidiol for LGS and dravet syndrome
2. Clobazam for LGS
3. Rufinamide for LGS
4. Stiripentol for dravet syndrome
5. Vigabatrin for focal onset seizures as well as infantile spasms.
Third-Generation ASMs: MoA
Sodium Channel Inhibition:
• Eslicarbazepine: Enhances slow inactivation of sodium channels, targeting overactive neurons.
• Lacosamide: Similar to eslicarbazepine, also has slow sodium channel inactivation properties.
• Rufinamide: Prolongs sodium channel inactivation.

GABAergic Mechanisms:
• Vigabatrin: Irreversible inhibitor of GABA-transaminase, increasing GABA levels.
• Clobazam: A partial agonist of GABA𝐴A​ receptors, reducing sedative effects compared to
traditional benzodiazepines.
• Stiripentol: Enhances GABAergic activity and inhibits CYP450 enzymes to increase clobazam
levels.
Third-Generation ASMs: MoA
Dual Mechanisms:
• Cenobamate: Inhibits sodium channels and acts as an allosteric modulator of GABA𝐴A​
channels.
Novel Mechanisms:
• Perampanel: Non-competitive AMPA receptor antagonist, reducing excitatory
neurotransmission.
• Cannabidiol and Fenfluramine: Mechanisms are unclear; fenfluramine increases serotonin and
has efficacy in Dravet Syndrome.
Second-Generation Derivatives:
• Pregabalin: Similar to gabapentin, binds to calcium channels, reducing excitatory
neurotransmitter release.
• Brivaracetam: A selective SV2A modulator with higher affinity than levetiracetam.
Third-Generation ASMs: PK
Simple PK:
• Pregabalin and vigabatrin: Good absorption, low protein binding, renal clearance, and linear elimination
kinetics.
• Rufinamide and Eslicarbazepine (prodrug): Hepatically metabolized but bypass CYP450 pathways,
minimizing drug interactions. Eslicarbazepine requires renal dose adjustment.
• Lacosamide: 40% renally eliminated and 60% hepatically metabolized by CYP3A4, CYP2C9, and CYP2C19,
requiring dose adjustment in renal and hepatic impairment

Complex PK:
• Brivaracetam and Clobazam: Hepatically metabolized with CYP2C19 polymorphisms influencing their
pharmacokinetics > hepatic dose adjustments
• Perampanel: Highly protein-bound, long half-life (~100 hours), and CYP3A4 metabolism> avoid in severe
renal/hepatic impairment
• Fenfluramine and Stiripentol: Involve multiple CYP enzymes, necessitating careful monitoring for
interactions.
Third-Generation ASMs: Interactions
Little to no interactions
• Pregabalin and Vigabatrin: Limited hepatic metabolism; few drug interactions.

Fewer Interactions:
• lacosamide, rufinamide, and fenfluramine.
Significant Interactions:
• Brivaracetam: Affected by CYP2C19 inducers and inhibitors; may increase levels of carbamazepine
metabolites and phenytoin.
• Clobazam: Affected by CYP3A4 and CYP2C19 modifiers; can reduce oral contraceptive efficacy.
• Eslicarbazepine: substrate and inhibitor of CYP2C19. CYP3A4 inducer> OCs levels reduced
• Perampanel: Enzyme-inducing ASMs decrease its levels; high doses may reduce oral contraceptive
efficacy.
• Stiripentol: Induces and inhibits multiple CYP enzymes, inhibitor of p glycoprotein
Third-Generation ASMs: Adverse reactions
• Brivaracetam and Lacosamide: Well-tolerated
• Lacosamide: CNS side effects (less than other ASMs), may lengthen PR intervals but typically not clinically
significant.
• Pregabalin: Common side effects include sedation and weight gain.
• Clobazam: CNS effects; risk of withdrawal syndrome upon abrupt discontinuation.
Serious Effects:
• Eslicarbazepine: Hyponatremia (less than carbamazepine or oxcarbazepine) , rash (SJS/TEN),
hepatotoxicity, and hematologic issues.
• Perampanel: Aggression and psychiatric changes, requiring close monitoring (FDA warning).
• Fenfluramine: Cardiac effects at higher doses; boxed warning for valvular heart disease and pulmonary
hypertension.
• Vigabatrin: Irreversible visual field loss, seizure aggravation, psychiatric effects, intramyelinic edema.
• Cenobamate: Risk of DRESS syndrome and QT interval shortening.
• Stiripentol: Neutropenia and thrombocytopenia.
Third-Generation ASMs: Adv. and Disadv.
• Comparable efficacy to first- and second-generation ASMs for focal-onset epilepsies, but limited long-term
data.
• Syndrome-Specific Benefits: Cannabidiol, fenfluramine, stiripentol, and vigabatrin are highly effective for
LGS, Dravet Syndrome, and infantile spasms.
• Lacosamide: Favorable pharmacokinetics and minimal interactions make it a preferred second- or third-
line agent despite its cost.
• Clobazam: Broad utility for focal and generalized epilepsies.
Special Considerations in Patients of Reproductive Age
Females:
• Estrogen has a seizure-activating effect, and progesterone has a seizure-protective effect.
• Enzyme-inducing ASMs (eg, phenobarbital, phenytoin, carbamazepine, topiramate, oxcarbazepine, and
perhaps rufinamide, lamotrigine, clobazam, and felbamate) may cause oral contraceptive failures;
supplemental birth control is advised if breakthrough bleeding occurs.
• Individuals taking these ASMs should take twice the usual dose of emergency contraception.

• For catamenial epilepsy (seizures just before or during menses) or seizures that occur during ovulation,
conventional ASMs should be tried first, but intermittent supplementation with higher-dose ASMs or
benzodiazepines should be considered. Acetazolamide has been used with limited success. Progestational
agents may also be effective.

• Seizures often improve in frequency at menopause.

Special Considerations in Patients of Reproductive Age
Pregnancy:
• Individuals with epilepsy who are seizure free for 9–12 months before becoming pregnant, have an 84%–
92% chance of being seizure free during pregnancy.
• Fluctuations in ASM serum concentrations during pregnancy may be due to reduced gastric motility,
nausea and vomiting, increased medication distribution, increased renal elimination, altered hepatic
enzyme activity, or changes in protein binding.
• ASM monotherapy is preferred in pregnancy.
• Clearance of phenytoin, carbamazepine, lamotrigine, oxcarbazepine, and levetiracetam increases during
pregnancy, and protein binding may be reduced. Serum concentrations of phenobarbital, primidone,
ethosuximide, and valproic acid may also fluctuate during pregnancy.
• Serum concentrations of ASMs should be monitored closely during pregnancy.
• There is a higher incidence of adverse pregnancy outcomes in individuals taking ASDs, including an
increased risk of major congenital malformation (MCMs).
Special Considerations in Patients of Reproductive Age
Pregnancy:
• Although data are insufficient to show that folate is effective in preventing MCM in pregnant individuals
with epilepsy, there is no evidence of harm.
• Therefore, the American Association of Neurology recommends that all females of childbearing potential,
take at least 0.4 mg of folic acid prior to conception and during pregnancy.
• Higher folate doses should be used for those who have previously delivered a child with a neural tube
defect and who are taking valproic acid.
• Valproic acid is associated with a risk of MCMs 3.5–4 times that of offspring of nonepileptic individuals.
There is also an increased risk of neurodevelopmental effects including effects on cognition in children.
• Valproic acid should not be used in pregnancy, but when it is used, doses should not exceed 500–600
mg/day.
• Topiramate use during pregnancy has been associated with cleft palate and possibly low birth weight and
hypospadias.
Special Considerations in Patients of Reproductive Age
Pregnancy:
• ASMs with low protein binding will accumulate in human milk.

• Other adverse outcomes of maternal seizures are growth, psychomotor, and intellectual delays.
• Vitamin K, 10 mg/day orally, given during the last month of pregnancy may prevent neonatal hemorrhagic
disorder. Alternatively, parenteral vitamin K can be given to the newborn at delivery.
Special Considerations in Patients of Reproductive Age
Males:
• Data suggest that males with epilepsy have reduced fertility, and that carbamazepine, oxcarbazepine, and
valproic acid are associated with sperm abnormalities.
• Valproic acid seems to cause testicular atrophy resulting in reduced testosterone volume, whereas
levetiracetam appears to slightly increase serum testosterone.
Refer to Table 75-5
 felbamate, and valproic acid may interfere with vitamin D metabolism. Patients taking these medications should receive vitamin D
Birzeit University
supplementation and calcium and bone mineral density testing if other risk factors for osteoporosis are present. Laboratory tests may reveal
Access Provided by:
elevated bone­specific alkaline phosphatase and decreased serum Ca and 25­OH vitamin D, as well as intact parathyroid hormone.

Table 54­3 shows ASM elimination pathways and major effects on hepatic enzymes. Use caution when ASMs are added to or discontinued from a
regimen. Pharmacokinetic interactions are a common complicating factor in ASN selection.

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine
diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some medications from
plasma albumin.

Felbamate and topiramate can act as inducers with some isoforms and inhibitors with others.

TABLE 54­1
Antiseizure Medication Dosing and Target Serum Concentration Ranges

Medication (Brand Name) Initial Total Daily Dose (TTD) Target Serum
Concentration Range

First Generation

Carbamazepine (Tegretol, Tegretol XR) 400 mg (>12 yrs) 4–12 mcg/mL (mg/L; 17–51
200 mg (6–12 yrs) μmol/L)
10–20 mg/kg (<6 yrs)

Clonazepam (Klonopin) Up to 1.5 mg (≥18 yrs) 20–70 ng/mL (mcg/L; 63–222

0.01–0.03 mg/kg (<10 yrs or <30 kg) nmol/L)

Ethosuximide (Zarontin) 500 mg (≥6 yrs) 40–100 mcg/mL (mg/L; 283–708

250 mg (3–6 yrs) μmol/L)

Phenobarbital (Various) 300 mg (≥18 yrs) 10–40 mcg/mL (mg/L; 43–172

5 mg/kg (<18 yrs) μmol/L)
(15–20 mg/kg LD)

Phenytoin (Dilantin) 300 mg (≥18 yrs) Total: 10–20 mcg/mL (mg/L; 40–
5 mg/kg (<18 yrs) 79 μmol/L)
(15–20 mg/kg LD) Unbound: 0.5–3 mcg/mL (mg/L;
2–12 μmol/L)

Primidone (Mysoline) 100–125 mg (≥8 yrs) 5–10 mcg/mL (mg/L; 23–46

μmol/L)

Valproic acid, Divalproex, Valproate (Depakene, Depakote 10–15 mg/kg (≥10 yrs) 50–100 mcg/mL (mg/L; 347–693
DR, Depakote ER, Depacon) μmol/L)

Second Generation

Felbamate (Felbatol) 1200 mg (≥14 yrs) 30–60 mcg/mL (mg/L; 126–252

15 mg/kg (2–14 yrs) μmol/L)

Gabapentin (Neurontin) 300–900 mg (≥12 yrs) 2–20 mcg/mL (mg/L; 12–117

10–15 mg/kg (3–11 yrs) μmol/L)

Lamotrigine (Lamictal, Lamictal XR) 25 mg (>12 years) 4–20 mcg/mL (mg/L; 16–78
0.3 mg/kg (2–12 yrs) μmol/L)

Downloaded 2024­12­23
Levetiracetam (Keppra,6:30 A Your
Keppra XR) IP is 1000 mg (≥16 yrs) 12–46 mcg/mL (mg/L; 70–270
Chapter 54: Epilepsy, Page 5 / 25
20 mg/kg (6–15 yrs) μmol/L)
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Varies by age (<6 yrs)
 Gabapentin (Neurontin) 300–900 mg (≥12 yrs) 2–20 mcg/mL (mg/L; 12–117
10–15 mg/kg (3–11 yrs) μmol/L) Birzeit University
Access Provided by:

Lamotrigine (Lamictal, Lamictal XR) 25 mg (>12 years) 4–20 mcg/mL (mg/L; 16–78
0.3 mg/kg (2–12 yrs) μmol/L)

Levetiracetam (Keppra, Keppra XR) 1000 mg (≥16 yrs) 12–46 mcg/mL (mg/L; 70–270
20 mg/kg (6–15 yrs) μmol/L)
Varies by age (<6 yrs)

Oxcarbazepine (Trileptal, Oxtellar XR) 600 mg (>17 yrs) 3–35 mcg/mL (MHD) (mg/L; 12–
8–10 mg/kg­max 600 mg (2–16 yrs) 138 μmol/L)

Tiagabine (Gabitril) 4 mg if on other ASMs that are inducers and <4 mg if 0.02–0.2 mcg/mL (mg/L; 0.05–
not on inducers (≥12 yrs) 0.5 μmol/L)

Topiramate (Topamax, Trokendi XR) 25–50 mg (≥10 yrs) 5–20 mcg/mL (mg/L; 15–59
25 mg (2–9 yrs) μmol/L)

Zonisamide (Zonegran) 100 mg (>16 yrs) 10–40 mcg/mL (mg/L; 47–188

μmol/L)

Third Generation

Brivaracetam (Briviact) 100 mg (≥16 yrs) Not defined

50–100 mg if >50 kg or 1–3 mg/kg if <50 kg (1 mo – 15
yrs)

Cenobamate (Xcopri) 12.5 mg (≥18 yrs) Not defined

Eslicarbazepine (Aptiom) 400 mg (≥18 yrs) Not defined

200–400 mg (4–17 yrs)

Lacosamide (Vimpat) 100–200 mg (>17 yrs) Not defined

100 mg if >50 kg and 2 mg/kg if <50 kg (4–17 yrs)

Perampanel (Fycompa) 2 mg Not defined

Pregabalin (Lyrica) 150 mg (≥17 yrs) Not defined

2.5 mg/kg if >30 kg and 3.5 mg/kg between 11–29 kg (4–
17 yrs)

Third Generation with Indications for Specific Epilepsy Syndromes

Cannabadiol (Epidiolex) 5 mg/kg (≥2 yrs) Not defined

Clobazam (Onfi) 5 mg if ≤30 kg and 10 mg if >30 kg (≥2 yrs) 0.03–0.3 ng/mL (mcg/L; 0.1–1.0
nmol/L)

Fenfluramine (Fintepla) 0.2 mg/kg if not on STP and 0.1 mg/kg if on STP and Not defined
CLB (≥2 yrs)

Rufinamide (Banzel) 400–800 mg (≥17 yrs) Not defined

10 mg/kg (1–16 yrs)

Stiripentol (Diacomit) 50 mg/kg (≥2 yrs) 4–22 mg/L (mcg/mL; 17–94

µmol/L)

Downloaded 2024­12­23 6:30 A Your IP is

Vigabatrin
Chapter (Sabril)
54: Epilepsy, 1000 mg (≥17 yrs) 0.8–36 mcg/mL (mg/L; 6–279
Page 6 / 25
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy
350–500 • Notice • on
mg depending Accessibility
weight (2–16 yrs) μmol/L)
50 mg/kg (Infants)
 Rufinamide (Banzel) 400–800 mg (≥17 yrs) Not defined
Birzeit University
10 mg/kg (1–16 yrs)
Access Provided by:

Stiripentol (Diacomit) 50 mg/kg (≥2 yrs) 4–22 mg/L (mcg/mL; 17–94

µmol/L)

Vigabatrin (Sabril) 1000 mg (≥17 yrs) 0.8–36 mcg/mL (mg/L; 6–279

350–500 mg depending on weight (2–16 yrs) μmol/L)
50 mg/kg (Infants)

CLB, clobazam; CBZ, carbamazepine; DR, delayed­release; FDA, Food and Drug Administration; ER, extended­release; LD, loading dose; LGS, Lennox–Gastaut
Syndrome; MHD, 10­monohydroxycarbazepine derivative; PB, phenobarbital; PHT, phenytoin; PI, prescribing information; PRM, primidone; STP, stiripentol; TDD,
total daily dose; yrs, years; VPA, valproate; XR, extended­release.

TABLE 54­2
Antiseizure Medications (ASMs)

ASM and Advantages/Disadvantages Interactions Adverse Medication Reactions

Available
Formulations

First­Generation ASM

Carbamazepine Advantages: Useful in comorbid bipolar disorder and Effect of CBZ on ASMs: BOXED WARNING: Increased risk of
(CBZ) trigeminal neuralgia Potent inducer of CYP3A4, SJS/TEN with HLA­B*1502 allele;
Chewable tablet, Disadvantages: Worsens other seizure types in CYP1A2, CYP2B6, CYP2C9/19; aplastic anemia and agranulocytosis
ER tablet, liquid patients with absence epilepsy; HLA­B*1502 and HLA­ CBZ decreases or possibly C o m m o n: CNS effects including
suspension A*3101 may be a risk factor for the development of decreases levels of diplopia, dizziness, drowsiness;
SJS/TEN in patients of Asian ancestry; avoid if prior rash brivaracetam, clonazepam, unsteadiness, lethargy;
with other ASMs due to possible cross­reaction auto­ eslicarbazepine, ethosuximide, hyponatremia from SIADH
inducer; active metabolite carbamazepine­10,11 epoxide felbamate, lacosamide, Serious but rare: Other blood
contributes to idiosyncratic adverse reactions; avoid if lamotrigine, oxcarbazepine, dyscrasias including
history of bone marrow depression or sensitivity to perampanel, phenytoin, thrombocytopenia, leukopenia;
tricyclic compounds; cannot use within 14 days of MAO rufinamide, stiripentol tiagabine, DRESS; increased intraocular
inhibitor; can cause fetal harm topiramate, valproate, pressure; cardiovascular effects
zonisamide including second and third degree
Effect of ASMs on CBZ: AV heart block; hepatotoxicity
Cenobamate, eslicarbazepine, Long term: Hyponatremia from
felbamate, phenobarbital, SIADH; metabolic bone disease
phenytoin, primidone, including osteoporosis, osteopenia,
rufinamide may decrease CBZ osteomalacia
levels; brivaracetam, felbamate,
valproate may increase
carbamazepine­10,11 epoxide
levels; vigabatrin may increase
CBZ levels
Others (partial list): CYP3A4
inhibitors/inducers may
increase/decrease CBZ levels;
CBZ may decrease levels of
hormonal contraceptives; do
not administer with other liquid
agents due to possibility of
precipitate occurrence
Downloaded 2024­12­23 6:30 A Your IP is
Chapter 54: Epilepsy, Advantages: Useful when there is a need for a
Clonazepam Effect of clonazepam o n Page 7 / 25
BOXED WARNING: Concomitant
©2024(Schedule
McGrawIV)Hill. All Rights Reserved. Terms of Use
benzodiazepine with long half­life
• Privacy Policy • Notice • Accessibility
ASMs: Clonazepam may affect use with opioids may result in
Tablet, ODT Disadvantages: May increase TC seizures when used in levels of phenytoin profound sedation, respiratory
 increase/decrease CBZ levels;
CBZ may decrease levels of Birzeit University
hormonal contraceptives; do Access Provided by:

not administer with other liquid

agents due to possibility of
precipitate occurrence

Clonazepam Advantages: Useful when there is a need for a Effect of clonazepam o n BOXED WARNING: Concomitant
(Schedule IV) benzodiazepine with long half­life ASMs: Clonazepam may affect use with opioids may result in
Tablet, ODT Disadvantages: May increase TC seizures when used in levels of phenytoin profound sedation, respiratory
mixed seizure types; tolerance and dependence may Effect of ASMs on depression, coma, and death
occur; risk of respiratory depression which is increased clonazepam: Carbamazepine, C o m m o n: CNS effects including
when used with other CNS depressants including lamotrigine, phenobarbital, impairment of cognitive and motor
opioids; contraindicated in acute narrow angle glaucoma phenytoin may decrease performance due to sedation and
and severe hepatic impairment; metabolites may clonazepam levels; vigabatrin ataxia; behavior problems;
accumulate with impaired renal function and may increases clonazepam, paradoxical reactions such as
require dose adjustment; some loss of effect may occur clonazepam may be affected by agitation, irritability, aggression,
after 3 months; withdrawal symptoms including status other enzyme inducing or anxiety, anger, nightmares,
epilepticus may occur after discontinuation; may enzyme­inhibiting ASMs hallucinations and psychoses
increase hypersalivation; no adequate data in pregnancy Other (partial list): Use with Serious but rare: Respiratory
—may cause fetal harm opioids increases risk of depression; hepatomegaly; muscle
respiratory depression weakness
Long term: Physiologic
dependence; hair loss; hirsutism;
ankle and facial edema

Ethosuximide Advantages: Medication of choice for absence seizures Effect of ETX on ASMs: ETX C o m m o n: GI distress including
(ETX) Capsule, Disadvantages: May worsen generalized TC seizures may affect levels of nausea/vomiting, cramps diarrhea;
liquid solution and other seizure types when used alone in mixed types carbamazepine, phenobarbital, epigastric and abdominal pain;
of epilepsy; contraindicated in those with allergies to phenytoin, primidone, valproate anorexia and weight loss; CNS effects
succinimides; may cause fetal harm; use with caution in Effect of ASMs on ETX: including lethargy, fatigue,
hepatic/renal dysfunction Valproate may increase or drowsiness, dizziness, ataxia
decrease ETX levels Serious but rare: Blood dyscrasias
including leukopenia,
agranulocytosis, pancytopenia,
eosinophilia; rash including SJS;
DRESS; hepatic/renal dysfunction;
lupus erythematosus; psychiatric
abnormalities including night terrors
and paranoid psychosis
Long­term: Behavioral changes

Phenobarbital Advantages: Easily available world­wide; extensive Effect of PB on ASMs: PB is C o m m o n: CNS effects including
(PB) (Schedule III) knowledge and experience with PHB use; not FDA­ inducer of CYP1A2, CYP2C9, residual sedation or “hangover,”
Tablet, elixir, approved as PHB developed in early 1900s prior to CYP2C19, CYP3A4; PB may impaired cognition, drowsiness,
injectable establishment of FDA and current regulatory practices decrease levels of dizziness, vertigo, ataxia, headache,
solution Disadvantages: Tolerance and dependence may occur; carbamazepine, eslicarbazepine, sleep disturbance; paroxysmal
slow taper needed when discontinuing after prolonged ethosuximide, felbamate, effects including excitement,
use; use with other CNS depressants may produce lacosamide, lamotrigine, irritability and hyperactivity in older
additive CNS effects; may cause respiratory depression; oxcarbazepine, perampanel, adults and children; GI effects
can cause fetal harm phenytoin, rufinamide, including epigastric pain, nausea,
stiripentol, tiagabine, vomiting, diarrhea, and constipation
topiramate, valproate, Serious but rare: Respiratory
zonisamide depression and apnea; rash (SJS,
Effect of ASMs on PB: TEN); cardiac effects including
Downloaded 2024­12­23 6:30 A Your IP is Cenobamate, felbamate, bradycardia, hypotension with IV
Chapter 54: Epilepsy, rufinamide, valproate may administration, syncope; Page 8 / 25
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
increase PB levels; phenytoin hepatotoxicity; megaloblastic
may increase or decrease PB anemia; apnea and hypoventilation
levels Long term: Behavioral changes;
 can cause fetal harm phenytoin, rufinamide, including epigastric pain, nausea,
Birzeit University
stiripentol, tiagabine, vomiting, diarrhea, and constipation
Access Provided by:
topiramate, valproate, Serious but rare: Respiratory
zonisamide depression and apnea; rash (SJS,
Effect of ASMs on PB: TEN); cardiac effects including
Cenobamate, felbamate, bradycardia, hypotension with IV
rufinamide, valproate may administration, syncope;
increase PB levels; phenytoin hepatotoxicity; megaloblastic
may increase or decrease PB anemia; apnea and hypoventilation
levels Long term: Behavioral changes;
Other (partial list): PB may connective tissue disorder;
decrease levels of oral intellectual blunting; metabolic
contraceptives bone disease (Rickets, osteopenia,
osteoporosis, osteomalacia); folate
deficiency (with megaloblastic
anemia)

Phenytoin (PHT) Advantages: May be orally or intravenously loaded in Effect of PHT on ASMs: PHT C o m m o n: CNS effects including
ER capsule; liquid patients who require rapid steady­state serum levels; ER may decreases levels of ataxia, nystagmus, slurred speech,
suspension; formulation useful in nonadherence as dosed once daily brivaracetam, carbamazepine, decreased coordination, mental
injectable; Disadvantages: May aggravate seizures in patients with cenobamate, clonazepam, confusion, dizziness, insomnia,
chewable tablet absence seizures; can increase blood sugar levels in eslicarbazepine, felbamate, transient nervousness, headaches
(Fosphenytoin, a diabetes; HLA­B*1502 may be a risk factor for the ethosuximide, felbamate, Serious but rare: Blood dyscrasias
prodrug development of SJS/TEN in patients of Asian ancestry; lacosamide, lamotrigine, including thrombocytopenia,
desterified by CYP2C9*3 carriers may increase development of SCARS; oxcarbazepine, perampanel, leukopenia, granulocytopenia,
esterases in the monitoring of free phenytoin levels required in renal, rufinamide, stiripentol, agranulocytosis, pancytopenia;
blood to hepatic impairment, hypoalbuminemia, and pregnancy; tiagabine, topiramate, valproate, lymphadenopathy; rash
phenytoin, also compromised absorption with concomitant tube feeds; zonisamide (SJS/TEN/SCARS); DRESS;
available as dose adjustments required to switch between free acid Effect of ASMs on PHT: hepatotoxicity; angioedema;
injectable and sodium salt formulations; phenytoin dose Carbamazepine, eslicarbazepine, bradycardia/cardiac arrest; purple
solution only) adjustments needed in older adults due to decreased vigabatrin may decrease PHT glove syndrome with IV
clearance; may exacerbate porphyria levels; brivaracetam, administration
cenobamate, ethosuximide, Long term: Connective tissue
felbamate, methsuximide, changes including skin thickening,
oxcarbazepine, rufinamide, gingival hyperplasia, coarsening of
topiramate may increase PHT facial features, enlargement of lips;
levels; phenobarbital, valproate hirsutism; metabolic bone disease
may increase or decrease PHT (osteoporosis, osteopenia,
levels osteomalacia); peripheral
Other (partial list): PHT can neuropathy; cerebellar atrophy;
substantially reduce delavirdine folate deficiency (with megaloblastic
concentrations and cause loss of anemia)
virologic response and
resistance; may decrease
contraceptive levels, may
increase/decrease PT/INR when
given with warfarin

Primidone Advantages: Useful in patients with essential tremor Effect of PRM on ASMs: PRM C o m m o n: CNS effects including
(PRM) Disadvantages: Contraindicated in porphyria may decrease levels of ataxia, vertigo, nystagmus, diplopia,
Tablet carbamazepine, eslicarbazepine, drowsiness, fatigue; GI effects
ethosuximide, felbamate, including nausea/vomiting, anorexia,
lacosamide, lamotrigine, fatigue; emotional disturbances
oxcarbazepine, perampanel, including hyperirritability
phenytoin, rufinamide, Serious but rare: Blood dyscrasias
Downloaded 2024­12­23 6:30 A Your IP is stiripentol, tiagabine, including granulocytopenia,
Chapter 54: Epilepsy, Page 9 / 25
topiramate, valproate, agranulocytosis; rash (SJS, TEN);
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
zonisamide liver dysfunction
Effect of ASMs on PRM: Long term: Behavioral changes;
 (PRM) Disadvantages: Contraindicated in porphyria may decrease levels of ataxia, vertigo, nystagmus, diplopia,
Tablet carbamazepine, eslicarbazepine, Birzeit University
drowsiness, fatigue; GI effects
ethosuximide, felbamate, including nausea/vomiting, anorexia,
Access Provided by:

lacosamide, lamotrigine, fatigue; emotional disturbances

oxcarbazepine, perampanel, including hyperirritability
phenytoin, rufinamide, Serious but rare: Blood dyscrasias
stiripentol, tiagabine, including granulocytopenia,
topiramate, valproate, agranulocytosis; rash (SJS, TEN);
zonisamide liver dysfunction
Effect of ASMs on PRM: Long term: Behavioral changes;
Valproate may increase PRM intellectual blunting; connective
levels; phenytoin may increase tissue disorder; metabolic bone
or decrease PRM levels; disease (rickets, osteomalacia);
carbamazepine, eslicarbazepine folate deficiency (with megaloblastic
may affect levels anemia)

Valproate (VPA) Advantages: Useful in comorbid bipolar disorder and Effect of VPA on ASMs: VPA BOXED WARNING: Hepatotoxicity
Divalproex DR migraine; commonly used in all age groups including may increase levels of especially for children <2 years of
sprinkle capsule ages <10 years eslicarbazepine, ethosuximide, age and with mitochondrial
and tablet, Disadvantages: Contraindicated in significant hepatic felbamate, lamotrigine, disorders; fetal risk including neural
Divalproex ER 24­ dysfunction, mitochondrial disorders caused by DNA oxcarbazepine, phenytoin, tube defects, other major
hour tablet, polymerase γ (POLG) mutations, urea cycle disorders; phenobarbital, rufinamide, malformations, and decreased IQ;
valproic acid IR use with caution in pancreatitis, bleeding and other tiagabine, topiramate, pancreatitis including fatal
capsule, hematopoietic disorders; risk of hyperammonemia with zonisamide hemorrhagic pancreatitis
valproate sodium and without encephalopathy associated with Effect of ASMs on VPA: C o m m o n: GI effects including
injectable concomitant topiramate use; pregnancy category D— Carbamazepine, phenobarbital, abdominal pain/GI upset (worse
solution contraindicated in females of childbearing potential and phenytoin, primidone may with valproic acid IR), constipation,
pregnancy category X for pregnant patients treated for decrease VPA levels; felbamate diarrhea, anorexia, increased
migraine prophylaxis may increase VPA levels appetite, weight gain,
Other (partial list): Estrogen nausea/vomiting; CNS effects
OCP may affect VPA levels including blurred vision, ataxia,
dizziness, headache, insomnia,
nystagmus, somnolence, thinking
abnormal, tremor; dose­dependent
thrombocytopenia (>100 mg/mL)
Serious but rare:
Hyperammonemia with and without
encephalopathy; hypothermia with
and without hyperammonemia;
DRESS; bleeding and other
hematopoietic disorders
Long­term: Hair and nail changes
including alopecia, hirsutism, hair
texture and color changes, nail and
nail bed disorders; irregular menses
and polycystic ovary­like syndrome;
weight gain; cerebral
pseudoatrophy; osteoporosis and
osteopenia

Second­Generation ASMs

Gabapentin Advantages: Useful in post­herpetic neuralgia, chronic Effect of GBP on ASMs: No C o m m o n: CNS effects including
(GBP) pain, and neuropathy; few interactions significant effects somnolence, dizziness, ataxia,
Tablet, capsule, Disadvantages: Considered weakly efficacious; Effect of ASMs on GBP: No fatigue, nystagmus; peripheral
oral solution
Downloaded 2024­12­23potential
6:30 A abuse when
Your IP is taken with opioids; withdrawal significant effects edema and weight gain; GI effects
Chapter 54: Epilepsy, reaction characterized by anxiety, insomnia, nausea, including nausea/vomiting Page 10 / 25
©2024 McGraw Hill. All Rights Reserved.
sweating, Terms
and increased pain;ofabsorption
Use • Privacy
may bePolicy • Notice • Accessibility Serious but rare: Anaphylaxis,
impaired for single oral doses >1200 mg; no adequate angioedema, DRESS;
data in pregnancy—may cause fetal harm neuropsychiatric symptoms in
 Second­Generation ASMs
Birzeit University
Access Provided by:
Gabapentin Advantages: Useful in post­herpetic neuralgia, chronic Effect of GBP on ASMs: No C o m m o n: CNS effects including
(GBP) pain, and neuropathy; few interactions significant effects somnolence, dizziness, ataxia,
Tablet, capsule, Disadvantages: Considered weakly efficacious; Effect of ASMs on GBP: No fatigue, nystagmus; peripheral
oral solution potential abuse when taken with opioids; withdrawal significant effects edema and weight gain; GI effects
reaction characterized by anxiety, insomnia, nausea, including nausea/vomiting
sweating, and increased pain; absorption may be Serious but rare: Anaphylaxis,
impaired for single oral doses >1200 mg; no adequate angioedema, DRESS;
data in pregnancy—may cause fetal harm neuropsychiatric symptoms in
children 3–12 years of age
Long­term: Weight gain, peripheral
edema

Lamotrigine Advantages: Useful in bipolar disease; XR useful in Effect of LTG on ASMs: No BOXED WARNING: Rash including
(LTG) nonadherence as dosed once daily significant effects SJS, TEN with increased risk if given
Tablet, chewable Disadvantages: Slow titration required to avoid rash Effect of ASMs on LTG: with valproate, exceeding
tablet,a ODT,a XR including SJS; rash more likely to occur if patient with Carbamazepine, cenobamate, recommended initial dose or dose
prior rash to other ASM and concomitant use of valproic oxcarbazepine, phenytoin, escalation
tableta
acid; rash incidence higher in children; may exacerbate phenobarbital, primidone, C o m m o n: CNS effects including
myoclonus; dosage adjustment required in patients with rufinamide may decrease LTG dizziness, headache, diplopia, ataxia,
moderate and severe liver impairment; no adequate levels; Cannabidiol increases blurred vision, somnolence, tremor;
data in pregnancy—may cause fetal harm LTG and valproate increases GI effects including
LTG levels by 2­fold nausea/vomiting, abdominal pain,
Other (partial list): Estrogen diarrhea; other effects including
OCPs may decrease LTG by 50% rhinitis, pharyngitis, infection, fever;
rash
Serious but rare: DRESS; blood
dyscrasias; hemophagocytic
lymphohistiocytosis (HLH). Rash
usually appears after 3–4 weeks of
therapy and is typically generalized,
erythematous, and morbilliform but
can progress to SJS

Levetiracetam Advantages: Minimal interactions; XR useful in Effect of LEV on ASMs: No C o m m o n: CNS effects including
(LEV) nonadherence as dosed once daily significant effects somnolence, fatigue; behavior
Tablet, XR Disadvantages: May worsen depression, PTSD, anxiety, Effect of ASMs on LEV: No effects including aggression,

tablet,a injectable thought disorders; must dose adjust in dialysis/renal significant effects agitation, anger, anxiety, apathy,

solution failure; pregnancy category C depersonalization, depression,

emotional liability, hostility,
irritability
Serious but rare: Psychosis,
hallucinations

Oxcarbazepine Advantages: Useful in bipolar disorder; ER useful in Effects of OXC on ASMs: OXC C o m m o n: CNS effects including
(OXC) nonadherence as dosed once daily is inhibitor of CYP2C19 and dizziness, somnolence, diplopia,
Tablet, tablet Disadvantages: Higher incidence of hyponatremia, (as inducer of CYP3A4/5; OXC may fatigue, ataxia, abnormal vision,

ER,a liquid high as 25%); HLA­B*1502 in Asians may increase SJS or decrease lamotrigine levels headache, nystagmus, tremor; GI
TEN risk; may require slower titration in renal through UGT induction and effects including nausea, vomiting;
suspensiona
impairment; active MHD metabolite may decrease in decrease perampane levels; OXC hyponatremia due to SIADH; rash
pregnancy; no adequate data in pregnant patients—may may increase phenytoin levels Serious but rare: SJS, TEN; DRESS;
cause fetal harm Effect of ASMs on OXC: blood dyscrasias
Carbamazepine, phenobarbital,
phenytoin, primidone may
Downloaded 2024­12­23 6:30 A Your IP is decrease levels of OXC active
Chapter 54: Epilepsy, metabolites; valproate may
Page 11 / 25
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
increase levels of OXC
Other (partial list): OXC may
 TEN risk; may require slower titration in renal through UGT induction and effects including nausea, vomiting;
suspensiona
impairment; active MHD metabolite may decrease in decrease perampane levels; OXC Birzeit
hyponatremia due to SIADH; rashUniversity
pregnancy; no adequate data in pregnant patients—may may increase phenytoin levels Serious but rare: SJS, TEN; DRESS;
Access Provided by:

cause fetal harm Effect of ASMs on OXC: blood dyscrasias

Carbamazepine, phenobarbital,
phenytoin, primidone may
decrease levels of OXC active
metabolites; valproate may
increase levels of OXC
Other (partial list): OXC may
decrease estrogen OCP levels

Tiagabine (TGB) Advantages: None noted Effect of TGB on ASMs: TGB C o m m o n: CNS effects including
Tablet Disadvantages: Has been associated with new onset may decrease VPA levels by 10% dizziness, lightheadedness,
seizure, status epilepticus, and exacerbation of EEG Effects of ASMs on TGB: somnolence, thinking abnormal;
abnormalities in those with existing epilepsy; dosage Carbamazepine, phenobarbital, behavior effects including asthenia,
reduction may be necessary in patients with liver phenytoin, primidone increases lack of energy, nervousness,
disease; pregnancy category C TGB clearance by 60% and may irritability, difficulty with
decrease TGB levels; valproate concentration or attention; GI
may increase TGB levels by 40% effects including abdominal pain,
nausea, and vomiting
Serious but rare: Increase in
generalized seizures and non­
convulsive SE in patients with
refractory epilepsy; occurrence of
seizures and SE in patients without
epilepsy; moderately severe to
incapacitating generalized weakness;
exacerbation of EEG abnormalities;
rash including SJS
Long­term: Possibility of long­term
ophthalmologic effects

Topiramate Advantages: Useful in comorbid migraine and obesity; Effect of TPM on ASMs: TPM is C o m m o n: CNS effects including
(TPM) ER useful in nonadherence as dosed once daily weak inhibitor of CYP2C19 and fatigue, difficulty concentrating,
Sprinkle capsule, Disadvantages: Avoid in patients with preexisting inducer of CYP3A4; TPM may confusion, language problems,
tablet, ER capsule cognitive issues; renally dose adjust with CrCl <70 increase or decrease ASMs tremor, paresthesias; behavioral
mL/min (1.17 mL/s); can cause fetal harm metabolized by CYP2C19 and effects including nervousness,
3A4 including felbamate and anxiety
topiramate Serious but rare: Renal stones,
Effect of ASMs on TPM: glaucoma, hypo/hyperthermia,
Carbamazepine, phenobarbital, oligohidrosis, metabolic acidosis,
phenytoin, primidone may SJS, TEN, and hyperammonemia
decrease TPM levels; valproate with and without encephalopathy
may increase TPM levels when used with valproate
Other (partial list): TPM at Long term: Weight loss; renal
higher doses may decrease stones; metabolic acidosis
estrogen OCP levels

Zonisamide Advantages: Useful in tremor; useful in nonadherence Effect of ZON on ASMs: No C o m m o n: CNS effects including
(ZON) as dosed once daily significant DDIs sedation, ataxia, confusion,
Capsule Disadvantages: Contraindicated in those with sulfa Effect of ASMs on ZON: depression, difficulty concentrating,
allergy; dose efficacy may plateau at 400 mg; should not CYP3A4 inhibitors or inducers word­finding difficulties
be used in renal failure due to increases in SCr and BUN may alter ZON levels; Serious but rare: Oligohidrosis
and possible effects on GFR; pregnancy category C carbamazepine, phenobarbital, and hyperthermia; renal stones;
Downloaded 2024­12­23 6:30 A Your IP is phenytoin, valproate may metabolic acidosis; rash (SJS, TEN);
Chapter 54: Epilepsy, decrease ZON levels Page 12 / 25
DRESS; fulminant hepatic necrosis;
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility blood dyscrasias
Long term: Weight loss; renal
stones; metabolic acidosis
 (ZON) as dosed once daily significant DDIs sedation, ataxia, confusion,
Birzeit University
Capsule Disadvantages: Contraindicated in those with sulfa Effect of ASMs on ZON: depression, difficulty concentrating,
Access Provided by:
allergy; dose efficacy may plateau at 400 mg; should not CYP3A4 inhibitors or inducers word­finding difficulties
be used in renal failure due to increases in SCr and BUN may alter ZON levels; Serious but rare: Oligohidrosis
and possible effects on GFR; pregnancy category C carbamazepine, phenobarbital, and hyperthermia; renal stones;
phenytoin, valproate may metabolic acidosis; rash (SJS, TEN);
decrease ZON levels DRESS; fulminant hepatic necrosis;
blood dyscrasias
Long term: Weight loss; renal
stones; metabolic acidosis

Third­Generation ASMs

Brivaracetam Advantages: Can consider converting well­controlled Effect of BRV on ASMs: BRV C o m m o n: CNS effects including
(BRV, Schedule V) patients from levetiracetam if intolerable psychiatric may increase carbamazepine sedation, fatigue, ataxia, nystagmus;
Tablet, oral adverse reactions metabolite; BRV may increase behavioral effects including
solution, Disadvantages: Dosage adjustments required in phenytoin levels; no added irritability, aggressive behavior,
injectable hepatic impairment; no adequate data in pregnancy— therapeutic benefit when given anxiety, agitation, restlessness,
solution may cause fetal harm with levetiracetam tearfulness, apathy, altered mood,
Effect of ASMs on BRV: mood swings, hyperactivity,
CYP2C19 inhibitors may alter adjustment disorder; GI effects
BRV levels including nausea, vomiting
Other (partial list): rifampin Serious but rare: Angioedema;
will reduce BRV levels bronchospasm; decreased
neutrophils; psychosis and
depression; hematologic
abnormalities including leukopenia
and neutropenia

Cenobamate Advantages: None Effect of CBM on ASMs: CBM is C o m m o n: CNS effects including
(CBM, Schedule V) Disadvantages: Must be slowly titrated every 2 weeks a CYP2C19, CYP2B6, CYP3A somnolence, dizziness, fatigue,
Tablet to avoid DRESS; contraindicated in familial short QT inhibitor and may increase diplopia, headache; dizziness and
syndrome; caution when administering with other substrate levels; CBM is a CY2B6, disturbance in gait and coordination;
medications that shorten QT interval; use with caution CYPC8, CYP3A4 inducer and may cognitive dysfunction including
and dose reduce in hepatic and renal impairment; use decrease substrate levels; CBM memory impairment, disturbance in
not recommended in end­stage hepatic or renal disease; may increase phenytoin, attention, confusional state,
no adequate data in pregnancy—may cause fetal harm phenobarbital, clobazam slowness of thought; vision changes
concentrations; CBM may including diplopia, blurred vision,
decrease lamotrigine, and impaired vision; laboratory
carbamazepine concentrations; abnormalities including hepatic
CBM does not affect valproic transaminases, potassium elevation
acid, levetiracetam, or Serious but rare: DRESS with fast
lacosamide titration (weekly intervals); QT
Effect of ASMs on CBM: interval shortening; appendicitis
Phenytoin may decrease CBM;
valproate, phenobarbital,
carbamazepine do not
significantly impact CBM
Other (partial list): CBM may
decrease estrogen OCP levels;
additive risk with other
medications that shorten the QT
interval; use with CNS
depressants increases CNS
toxicity
Downloaded 2024­12­23 6:30 A Your IP is
Chapter 54: Epilepsy, Advantages: Useful in nonadherence as dosed once
Eslicarbazepine Effect of ESL on ASMs: Page 13 / 25
C o m m o n: CNS effects include
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
(ESL) Tablet daily Inhibitor of CYP2C19; ESL may dizziness, somnolence, nausea,
Disadvantages: Avoid in severe hepatic impairment; affect carbamazepine, headache, diplopia, fatigue, vertigo,
 decrease estrogen OCP levels;
additive risk with other Birzeit University
medications that shorten the QT Access Provided by:

interval; use with CNS

depressants increases CNS
toxicity

Eslicarbazepine Advantages: Useful in nonadherence as dosed once Effect of ESL on ASMs: C o m m o n: CNS effects include
(ESL) Tablet daily Inhibitor of CYP2C19; ESL may dizziness, somnolence, nausea,
Disadvantages: Avoid in severe hepatic impairment; affect carbamazepine, headache, diplopia, fatigue, vertigo,
dose adjustment in renal failure; avoid concomitant use perampanel, phenytoin, ataxia, blurred vision, tremor;
with carbamazepine and oxcarbazepine; no adequate phenobarbital, primidone levels hyponatremia due to SIADH; rash
data in pregnancy—may cause fetal harm Effect of ASMs on ESL: Serious but rare: SJS; anaphylaxis,
Carbamazepine, phenobarbital, angioedema, DRESS; cardiac effects
primidone, and phenytoin may including prolonged PR interval, AV
decrease ESL levels block; hepatotoxicity; blood
Other (partial list): ESL dyscrasias
decreases estrogen OCP levels Long­term: Hyponatremia

Lacosamide Advantages: Minimal interactions Effect of LCM on ASMs: LCM is C o m m o n: CNS effects including
(LCM) (Schedule Disadvantages: Avoid in third degree heart block; must a potential CYP2C19 inhibitor diplopia, headache, nausea,
V) Tablet, oral obtain ECG prior to intravenous infusion; use with but no clinically significant somnolence, dizziness, ataxia; GI
solution, caution in patients with underlying proarrhythmic effects of LCM on other ASMs effects including constipation,
injectable conditions or on concomitant medications that affect have been observed Effect of diarrhea, nausea, vomiting,
solution cardiac conduction; not recommended in severe hepatic ASMs on LCM: LCM is a dyspepsia, dry mouth, oral
impairment; requires dose adjustment in renal substrate of CYP3A4, CYP2C9, hypoesthesia/paresthesia;
impairment; oral solution contains phenylalanine and is and CYP2C19; carbamazepine, laboratory abnormalities including
a risk in patients with phenylketonuria no adequate data phenytoin, phenobarbital, LFT elevations
in pregnancy—may cause fetal harm primidone may decrease LCM Serious but rare: Cardiac effects
levels by 15%–20% including AV conduction
Other (partial list): LCM may abnormalities, prolonged PR
increase levels of strong CYP3A4 interval, atrial arrhythmias, syncope
or CYP2C9 inhibitors in renal or (especially in patients with diabetes);
hepatically impaired patients; DRESS and hypersensitivity
risk of cardiac abnormalities reactions; blood abnormalities
increased with concomitant including neutropenia and anemia
medications that affect cardiac
conduction

Perampanel Advantages: Useful in mixed seizure types; useful in Effect of PER on ASMs: PER is BOXED WARNING: Aggression,
(PER) (Schedule nonadherence as dosed once daily a modest enzyme inducer at hostility, irritability, anger, and
III) Tablet, oral Disadvantages: Avoid in active psychosis or unstable high doses homicidal ideation
suspension recurrent affective disorders with significant hostility or Effect of ASMs on PER: C o m m o n: CNS effects including
aggressive behavior; avoid in severe hepatic/renal Carbamazepine, eslicarbazepine, dizziness, somnolence, fatigue, falls,
impairment or hemodialysis; no adequate data in oxcarbazepine, phenobarbital, vertigo, ataxia, headache, confusion;
pregnancy—may cause fetal harm phenytoin, primidone, GI effects including nausea, weight
topiramate decrease PER levels; gain, vomiting, abdominal pain;
valproate has no effect on PER behavioral effects including
levels irritability anxiety; weight gain; falls
Other (partial list): PER sometimes leading to serious head
decreases estrogen OCP levels injuries
Serious but rare: DRESS

Pregabalin Advantages: Useful in patients with diabetic peripheral Effect of PGB on ASMs: No C o m m o n: CNS effects including
(PGB) (Schedule neuropathy, postherpetic neuralgia, fibromyalgia, significant effects dizziness, somnolence, blurred
V) Capsule,
Downloaded tablet
2024­12­23neuropathic
6:30 A Your pain
IPwith
is spinal cord injury; minimal DDIs Effect of ASMs on PGB: No vision, difficulty with concentration
Chapter
CR,54:
oralEpilepsy,
solution due to renal excretion significant effects Page 14 / 25
and attention; dry mouth; edema
©2024 McGraw Hill. All Rights Reserved.Caution
Disadvantages: Terms of Use • Privacy
in preexisting Policy • Notice • Accessibility
cognitive and weight gain
disorders; no adequate data in pregnancy—may cause Serious: Potential for misuse when
fetal harm taken with opiates
 decreases estrogen OCP levels injuries
Birzeit University
Serious but rare: DRESS
Access Provided by:

Pregabalin Advantages: Useful in patients with diabetic peripheral Effect of PGB on ASMs: No C o m m o n: CNS effects including
(PGB) (Schedule neuropathy, postherpetic neuralgia, fibromyalgia, significant effects dizziness, somnolence, blurred
V) Capsule, tablet neuropathic pain with spinal cord injury; minimal DDIs Effect of ASMs on PGB: No vision, difficulty with concentration
CR, oral solution due to renal excretion significant effects and attention; dry mouth; edema
Disadvantages: Caution in preexisting cognitive and weight gain
disorders; no adequate data in pregnancy—may cause Serious: Potential for misuse when
fetal harm taken with opiates
Long term: Weight gain

Third­Generation ASMs with FDA Approval for Specific Epilepsy Syndrome Indications

Cannabidiol Advantages: Useful for refractory seizures in LGS and Effect of CBD on ASMs: CBD C o m m o n: CNS effects including
(CBD, Schedule V) Dravet Syndrome increases lamotrigine levels; somnolence, fatigue, malaise,
Oral solution Disadvantages: Avoid in patients with hypersensitivity CBD increase levels of asthenia; sleep disorders including
reactions to cannabis, THC; liver function and bilirubin clobazam's active metabolite 3­ insomnia, poor quality sleep; GI
monitoring before and at 1, 3, and 6 months of fold effects including decreased appetite;
treatment specially if given with valproate; no adequate Effect of ASMs on CBD: diarrhea; transaminase elevations
data in pregnant woman—may cause fetal harm CYP3A4 and CYP2C19 inhibitors Serious but rare: Hepatotoxicity;
will increase CBD levels; CYP3A4 hypoxia; respiratory failure
and CYP2C19 inducers will
decrease CBD levels

Clobazam (CLB, Advantages: Despite FDA approval for LGS only, may Effect of CLB on ASMs: CLB is BOXED WARNING: Concomitant
Schedule IV) be useful in all types of epilepsy; less sedating inhibitor of CYP2C9 and inducer use with opioids increases risk of
Tablet, oral benzodiazepine of CYP3A4; CLB may affect levels death
suspension Disadvantages: Monitor patients with history of of CYP2C9, CYP3A4 substrates C o m m o n: CNS effects including
substance use; use with other CNS depressant may Effect of ASMs on CLB: somnolence, sedation, lethargy;
produce additive CNS effects; may cause respiratory Carbamazepine, felbamate, pyrexia; constipation; drooling
depression, coma, and death; no adequate data in phenobarbital, phenytoin, Rare but serious: Rash (SJS, TEN);
pregnant patients—may cause fetal harm primidone may decrease CLB anemia; liver enzyme elevations;
levels; cannabidiol, cenobamate, respiratory depression
stiripentol increase CLB levels
Other (partial list): CLB
decreases estrogen OCP levels

Fenfluramine Advantages: Useful for refractory seizures in Dravet Effect of FEN on ASMs: No BOXED WARNING: Risk of valvular
(FEN, Schedule IV) Syndrome significant effects heart disease and pulmonary
Oral solution Disadvantages: Contraindicated within 13 days of MAO Effect of ASMs on FEN: arterial hypertension;
inhibitors due to risk of serotonin syndrome; may CYP1A2, 2B6 inducers will echocardiograms required before,
increase blood pressure; not recommended in severe decrease FEN; stiripentol + during, and after treatment
hepatic or renal impairment; available only through clobazam will increase FEN C o m m o n: GI effects like decreased
FINETPLA REMS; no adequate data in pregnancy—may concentrations (max daily dose appetite/weight, vomiting, diarrhea,
cause fetal harm of FEN is reduced to 17 mg); constipation; CNS effects like
cyproheptadine and potent 5­ somnolence, sedation, lethargy;
HT serotonin receptor binding fatigue, malaise, asthenia; ataxia,
agents may decrease efficacy of balance disorder, gait disturbance;
FEN blood pressure increase; salivary
Other (partial list): Rifampin effects like drooling, hypersecretion;
will decrease FEN, strong pyrexia; falls; status epilepticus;
CYP1A2 and CYP2B6 inducers abnormal echocardiogram
will decrease FEN Rare but serious: increased blood
pressure including hypertensive
Downloaded 2024­12­23 6:30 A Your IP is crisis; risk of valvular disease and
Chapter 54: Epilepsy, pulmonary arterial hypertension;Page 15 / 25
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility mydriasis precipitating acute angle
closure glaucoma
 Other (partial list): Rifampin effects like drooling, hypersecretion;
Birzeit University
will decrease FEN, strong pyrexia; falls; status epilepticus;
Access Provided by:
CYP1A2 and CYP2B6 inducers abnormal echocardiogram
will decrease FEN Rare but serious: increased blood
pressure including hypertensive
crisis; risk of valvular disease and
pulmonary arterial hypertension;
mydriasis precipitating acute angle
closure glaucoma

Rufinamide Advantages: Useful for refractory seizures in LGS Effect of RFN on ASMs: RFN is C o m m o n: CNS effects including
(RFN) Tablet, oral Disadvantages: Contraindicated in severe liver a weak inhibitor of CYP2E1 and somnolence, fatigue, coordination
suspension impairment or in familial short QT syndrome; use weak inducer of CYP3A4; RFN abnormalities, dizziness, gait
caution with other drugs that shorten QT interval; no modestly decreases levels of disturbances, ataxia; GI effects
adequate data in pregnancy—may cause fetal harm carbamazepine, lamotrigine; including nausea
RFN increases levels of Rare but serious: DRESS; rash
phenobarbital, phenytoin (SJS); status epilepticus; leukopenia;
Effect of ASMs on RFN: QT interval shortening
Carbamazepine, phenobarbital, Other (partial list): RFN decreases
phenytoin decrease RFN levels estrogen OCP levels
by 19%­46%; valproate
increases RFN levels up to 70%

Stiripentol Advantages: Useful for refractory seizures in Dravet Effect of STP on ASMs: STP is C o m m o n: Somnolence, decreased
(STP) Capsule Syndrome inhibitor and inducer of CYP1A2, appetite/weight, agitation, ataxia,
Disadvantages: Must be used as adjunctive therapy 2B6, 3A4 and possible inhibitor hypotonia, nausea, tremor,
with clobazam; hematologic testing is required prior to of CYP2C8, 2C19, P­gp dysarthria, insomnia
first dose and q6months after due to risk of neutropenia transporter, BCRP transporter; Rare but serious: Neutropenia
and thrombocytopenia; powder formulation contains STP increases clobazam and thrombocytopenia; monitor
phenylalanine and is a risk in patients with concentration 2­fold and
phenylketonuria; not recommended in moderate or clobazam active metabolite 5­
severe hepatic or renal impairment; no adequate data in fold (must decrease clobazam
pregnancy—may cause fetal harm dosage when used together)
Effect of ASMs on STP: STP is
substrate of CYP1A2, CYP2C19,
CYP3A4 and phenytoin,
phenobarbital, carbamazepine
may decrease stiripentol levels

Vigabatrin (VGB) Advantages: Useful in infantile spasms for whom Effect of VGB on ASMs: VGB is BOXED WARNING: Progressive and
Tablet, powder potential benefit outweighs risk of vision loss; renally inducer of CYP2C9; VGB permanent bilateral peripheral
packet cleared and has less DDIs than other ASMs decreases levels of phenytoin by visual loss including tunnel vision
Disadvantages: Permanent vision loss in most patients 20%; VGB possibly increases and decrease in visual acuity
after a certain duration of exposure requiring eye exams levels of carbamazepine by 10%; C o m m o n: CNS effects including
Q3 months; requires REMS program registration; no VGB increases Cmax of fatigue, somnolence, nystagmus,
adequate data in pregnancy—may cause fetal harm clonazepam tremor, blurred vision, memory

Effect of ASMs on VGB: impairment, abnormal coordination,

Carbamazepine, primidone, confusion; weight gain; edema;

valproate have no effect on VGB peripheral neuropathy; laboratory
Other (partial list): Unlikely abnormalities including decreases in
to affect estrogen OCP levels ALT/AST in pediatric patients;
aggression; infection including upper
respiratory tract infection,
bronchitis, ear infection, and acute
otitis media constriction; vision loss
Downloaded 2024­12­23 6:30 A Your IP is Serious but rare: Seizure
Chapter 54: Epilepsy, Page 16 / 25
exacerbation, particularly absence
©2024 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
and myoclonic seizures in patients
with generalized epilepsies; anemia;