Sebagian antikonvulsan (misalnya lamotrigine, topiramate, asam valproat,

zonisamide) memiliki mekanisme kerja lebih dari satu, dan lainnya (misal fenitoin,
karbamazepin) diketahui hanya memiliki satu mekanisme kerja. Antikonvulsan dapat
dibagi menjadi beberapa kelompok berdasarkan mekanisme kerjanya, yaitu:

Blockers of repetitive activation of the sodium channel: Phenytoin, carbamazepine,

oxcarbazepine, eslicarbazepine, lamotrigine, topiramate
Enhancers of slow inactivation of the sodium channel: Lacosamide, rufinamide
Gamma-aminobutyric acid (GABA)�A receptor enhancers: Phenobarbital,
benzodiazepines, clobazam
N -methyl-D-aspartic acid (NMDA) receptor blockers: Felbamate
Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor blockers:
Perampanel, topiramate
T-calcium channel blockers: Ethosuximide, valproate
N- and L-calcium channel blockers: Lamotrigine, topiramate, zonisamide, valproate
H-current modulators: Gabapentin, lamotrigine
Blockers of unique binding sites: Gabapentin, levetiracetam, perampanel
Carbonic anhydrase inhibitors: Topiramate, zonisamide
Neuronal potassium channel (KCNQ [Kv7]) opener: Ezogabine

Kejang absans
Jika hanya terdapat kejang absans, umumnya diobati dengan ethosuximide. Jika kejang
absans diiringi oleh kejang tipe lain (misal kejang umum tonik-klonik, kejang
myoklonik), pilihan pengobatan adalah asam valproat, lamotrigine, atau topiramate.
Jangan gunakan carbamazepine, gabapentin atau tiagabine karena obat-obat tersebut
dapat merangsang kejang absans.

Kejang tonik atau atonik, mioklinik, dan tonik-klonik

Kejang tonik atau atonik dapat muncul pada pasien dengan sindroma Lennox-Gastaut,
dan sebaiknya diobatin dengan obat spektrum luas (asam valproat, lamotrigine,
topiramate) atau felbamate sebagai usaha terakhir. Dapat juga dengan stimulasi
nervus vagal. FDA menyetujui beberapa obat yaitu rufinamide, clobazam, dan
topiramate lepas lambat sebagai terapi adjuvan pada kejang yang berhubungan dengan
sindroma Lennox-Gastaut.
Kejang tonik-klonik umum primer berespon baik terhadap asam valproat, lamotrigine,
dan topiramate. Levetiracepam dan perampanel dapat digunakan sebagai terapi
adjuvant untuk kejang jenis ini.

Kejang mioklonik
Kejang mioklonik memiliki distribusi bimodal. Bayi dengan epilepsi mioklonik
umumnya memiliki prognosis buruk; sedangkan pada akhir masa anak-anak dan remaja,
sindroma mioklonik juvenil (JME) merupakan penyebab kejang mioklonik. Kejang pada
JME umumnya dikendalikan dengan obat antiepilepsi spektrum luas, tetapi angka
rekurensi pasca pemberhentian antikonvulsan tinggi yaitu 80-90%.
Obat terbaik untuk JME dan kejang mioklonik adalah asam valproat, lamotrigine, dan
topiramate. Levetiracetam disetujui FDA sebagai terapi adjuvant untuk JME. Obat-
obatan kejang parsial, seperti fenitoin dan karbamazepin dulunya dipakai untuk
terapi JME, tetapi dinilai tidak efektif, bahkan merangsang kejang.

Kejang onset fokal

Pada kejang onset fokal, terdapat banyak pilihan obat antiepilepsi seperti
karbamazepin, lacosamide, lamotrigine, oxcarbazepine, dan topiramate. Terapi
adjuvant dengan levetiracetam, tiagabine, gabapentin, pregabalin, lacosmide atau
ezogabine dapat dipertimbangkan jika monoterapi pertama atau kedua dengan terapi
lini pertama gagal. Penelitian VA Cooperative menunjukkan keberhasilan terapi
dengan karbamazepin, fenitoin primidone, dan fenobarbital tidak jauh berbeda,
tetapi toleransi karbamazepin dan fenitoin lebih baik pada laki-laki dibanding
perempuan.
Focal-onset seizures
In focal-onset seizures, there are many AED choices with monotherapy indications,
including carbamazepine, lacosamide, lamotrigine, oxcarbazepine, and topiramate.
(see Anticonvulsants in Specific Patient Populations, below). Adjunctive therapy
with levetiracetam, tiagabine, gabapentin, pregabalin, lacosamide, or ezogabine may
be considered if the first or second monotherapy trial with first-line treatments
fails. Discussing the adverse-effect profiles of anticonvulsants with patients is
important, because the efficacies of anticonvulsants appear to be similar. [43]

The VA Cooperative Study I clearly demonstrated similar efficacies for

carbamazepine, phenytoin, primidone, and phenobarbital. [44] However, carbamazepine
and phenytoin were tolerated better by men than women. The VA Cooperative Study II
findings showed that carbamazepine and valproic acid had similar efficacies. [45]
However, subset analysis for complex focal seizures suggested that carbamazepine
may be a better choice than valproate. [45]

In elderly subjects (patients aged =60 years) in the VA Cooperative Study,

lamotrigine and gabapentin were better tolerated than carbamazepine and were
similarly effective. [46] However, gabapentin caused more adverse effects than
lamotrigine. Those results led to the recommendation of lamotrigine as first-line
monotherapy in elderly patients. [46]

The focal seizures arm of the SANAD trial demonstrated that although carbamazepine
is the standard drug treatment, lamotrigine is clinically better with respect to
time to treatment failure. [47] This study also determined that lamotrigine is a
cost-effective alternative to carbamazepine for patients with focal-onset seizures.
Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were included
for comparison. [47] However, the cost-effectiveness of medications has changed, as
many new AEDs also have generic formulations.

All new medications have been tested as adjunctive therapy, and head-to-head
comparisons of new drugs with carbamazepine have been conducted in Europe. In
general, the new drugs have similar statistical efficacies but fewer adverse
effects than carbamazepine; this puts the results of the SANAD trial somewhat in
doubt, as the SANAD investigators did not find any important differences or trends
for scores on the Adverse Events Profile among the drugs.

Of the new anticonvulsants, lamotrigine and topiramate appear to have broad

spectrum of action in many seizure types. [48, 49] The American Academy of
Neurology and the American Epilepsy Society assembled a task force that reviewed
the literature and provided evidence-based recommendations for monotherapy,
adjunctive therapy, treatment of primary generalized seizures, treatment in
children, and treatment of subgroups of new-onset and refractory epilepsy. [48, 49]

If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine,

gabapentin, levetiracetam, oxcarbazepine, pregabalin, and zonisamide are considered
for second- or third-line therapy. Several new anticonvulsants, including
lamotrigine, topiramate, and oxcarbazepine, are indicated as monotherapy. Although
the new anticonvulsants are considered second- or third-line therapy, they can be
used as first-line therapy in some patients, especially as these medications have
become generic.

In October 2013, the FDA approved labeling changes for ezogabine, including a boxed
warning, emphasizing increased risks for potentially permanent adverse effects,
such as retinal abnormalities, vision loss, and skin discoloration. The agency
recommended that the use of ezogabine be limited to patients who have had an
inadequate response to several other therapies and in whom the treatment benefits
outweigh the risks. The FDA also recommended eye examinations for patients before
they start on ezogabine, as well as every 6 months over the course of treatment.
[50, 51, 52]
Medically refractory epilepsy
Although the term medically refractory epilepsy has been used for cases that fail
to respond to three antiepileptic drugs, the International League Against Epilepsy
(ILAE) has proposed defining drug-resistant epilepsy as the failure to achieve
sustained seizure freedom despite adequate trials of two antiepileptic drugs,
either as monotherapy or in combination. [53, 54] The drugs must have been
appropriately chosen and used, and failure must have occurred because of lack of
efficacy and not because of adverse effects.

A study of the ILAE criteria in pediatric epilepsy patients found that the
probability of achieving seizure freedom was 65%, 29%, 27% and 21%, respectively,
with trials of successive therapeutic regimens. [53, 54] Patients with medically
refractory epilepsy should be referred to an epileptologist.

Immunotherapy may be a viable treatment strategy in a subset of epileptic patients

whose seizures are refractory to management with conventional AEDs and whose poor
seizure control may result from the presence of neural-specific antibodies. [55,
56] Iorio et al found autoantibodies specific to neural antigen in 2 of 29 patients
with epilepsy and other neurologic symptoms and/or autoimmune diseases (group 1)
and in 9 of 30 patients with AED-resistant epilepsy (group 2).

Of the patients in group 2 who received (1) immunotherapy with intravenous (IV)
steroids and IV immunoglobulin for 6 months, (2) IV methylprednisolone, IV
immunoglobulin, and rituximab, or (3) IV steroids, 5 cycles of plasmapheresis, and
oral steroids, 75% had a reduction in seizure frequency of 50% or greater. [56] The
remaining patients in group 2 who received immunotherapy were evenly distributed
between those who had a reduction in seizure frequency of 20-50% and those with a
reduction of less than 20%. [56]

Looking ahead
Future advances in AEDs will involve agents that alter the natural history of
epilepsy and modify disease as opposed to providing primarily symptomatic
treatment.

Anticonvulsants in Specific Patient Populations

The use of anticonvulsants is slightly different in several populations of
patients, including the following:

Neonates
Children
Elderly patients
Women on contraceptive agents
Pregnant women [57]
Patients with hepatic or renal insufficiency
Human immunodeficiency virus (HIV) ? infected patients [58]
Neonates, children, and elderly patients
In general, neonates and children require similar loading doses per kilogram of
body weight, but they tend to metabolize the drugs faster than adults. This younger
population also has rapid increases in the total volume of distribution.

In contrast, elderly patients need lower initial and maintenance doses, owing to
the following normal features of the aging process:

Slowed hepatic metabolism

Decreased renal clearance
Decreased volumes of distribution
Women on contraceptive agents
Anticonvulsants that induce hepatic enzymes, such as carbamazepine, phenytoin,
phenobarbital, primidone, felbamate, lamotrigine, topiramate, and oxcarbazepine,
decrease the efficacy of oral contraceptive pills. Some anticonvulsants cause this
drug interaction in a dose-dependent manner, with a negligible effect at low doses.
Some obstetricians use a high-dose estrogen-progesterone contraceptive to
counteract this effect. An alternative and possibly preferable approach is to use a
second method of contraception.

Women of childbearing age and pregnant women

In 2009, the American Academy of Neurology and the American Epilepsy Society issued
new guidelines for the management of antiepileptic drugs (AEDs) during pregnancy.
[57, 59, 60] These guidelines cover obstetric complications and change in seizure
frequency; teratogenesis and perinatal outcomes; and vitamin K, folic acid, blood
levels, and breastfeeding.

Woman of childbearing age should take folic acid, at least 0.4 mg per day, to
decrease the rate of neural-tube malformations in the fetus. In addition, evidence
strongly suggests that, during pregnancy, women should take the medication that
best controls their epilepsy. Switching medications during pregnancy is not
recommended, because of the risk of losing seizure control and because it exposes
the fetus to polypharmacy. Data from multiple studies show an exponential risk of
birth defects as anticonvulsants are added in polytherapy.

Frequent drug serum levels should be obtained because of the many physiologic
changes that take place during pregnancy, including changes in volume of
distribution, protein binding, and hepatic metabolism and erratic absorption. In
particular, decreased serum concentration of lamotrigine in the third trimester is
well documented, and the dose needs to be adjusted after delivery.

Whether to perform amniocentesis is a personal decision between the woman and her
obstetrician. The most important point is to have a clear idea about how the
information obtained will be useful for clinical decision making.

Patients with hepatic and renal insufficiency

Gabapentin, pregabalin, levetiracetam, and lacosamide are excreted mostly by means
of renal clearance, and their doses can be adjusted for renal insufficiency. These
agents are useful in patients with hepatic failure, especially when a drug-induced
etiology is suspected. Lamotrigine, which is metabolized by means of
glucuronidation, a phase II reaction, is also used in some patients with hepatic
insufficiency.

Considerable data are available on the use of phenytoin in the presence of hepatic
and renal insufficiency. However, phenytoin is not a preferred medication because
of its nonlinear kinetics, hepatic autoinduction, numerous drug interactions, and
high degree of protein binding. Among all anticonvulsants, phenytoin,
carbamazepine, valproic acid, and felbamate have been associated with acute hepatic
injury.

Discontinuing Anticonvulsant Agents

After a person has been seizure free for typically 2-5 years, the physician may
consider discontinuing that patient�s medication. Many patients outgrow many
epileptic syndromes of childhood and do not need to take anticonvulsants. The
relapse rate for seizures in adults is about 40-50%; for children, it is about 25%.
This difference probably reflects the different epileptic syndromes that are
prevalent in the 2 populations.

The recurrence rate during adulthood for patients with juvenile myoclonic epilepsy
(JME) is about 80-90% in 2 years, even in patients who have spent many years being
seizure free on low doses of appropriate anticonvulsants.
Risk of seizure recurrence
Many neurologists use the risk factors for new-onset seizures to assess patients
for discontinuation of anticonvulsants. Normal findings on an electroencephalogram
(EEG) and a brain magnetic resonance imaging (MRI) scan lower the risk of relapse
after drug discontinuation, whereas epileptiform or focal abnormalities on an EEG
and/or focal cortical or limbic abnormalities on a brain MRI scan significantly
increase the relapse risk.

Additional factors associated with an increased risk of seizure recurrence after

discontinuation include the following:

Several seizure types (eg, worse if tonic or atonic seizures are present)
High number and frequency of seizures
Long duration of epilepsy before the seizures were controlled
Short duration of seizure freedom
Seizure relapse
About 75% of seizure relapses after medication discontinuation occur in the first
year, and at least 50% of patients who have another seizure do so in the first 3
months. Therefore, advise patients to observe strict seizure precautions (including
not driving) during tapering and for at least 3 months after discontinuation,
depending on state laws. The need to drive is an impediment for some patients, who
may opt to continue therapy for that reason.

Some authors recommend that all anticonvulsants, except primidone, phenobarbital,

and benzodiazepines, be gradually discontinued over 6-10 weeks if they were used
for a long period. Discontinue primidone, phenobarbital, and benzodiazepines over
10-16 weeks.

Nonpharmacologic Management
A ketogenic or modified Atkins diet and vagal nerve stimulation (VNS) are
nonpharmacologic methods for managing patients with seizures that are unresponsive
to antiepileptic drugs. The ketogenic diet is typically used in children. The FDA
has approved VNS stimulation for adolescents and adults with refractory partial
epilepsy, but clinical experience also suggests efficacy and safety in children and
in patients with generalized epilepsies.

Ketogenic diet and modified Atkins diet

The ketogenic diet, which relies heavily on the use of fat, such as hydrogenated
vegetable oil shortening (eg, Crisco), has a role in the treatment of children with
severe epilepsy. Support for the efficacy of these diets comes from large
observational studies rather than from randomized, controlled trials. [61]

Although this diet is unquestionably effective in some refractory cases of seizure,

a ketogenic diet is difficult to maintain; less than 10% of patients continue the
diet after a year. Furthermore, any small carbohydrate intake (eg, lollypop, piece
of candy) resets ketone metabolism for 2 weeks, thereby eliminating antiseizure
efficacy. Consequently, some authors do not consider using this treatment in
teenagers or adults unless all of the patient�s caloric intake is being delivered
by means of a gastric tube.

Preliminary data have been published about improvement of seizure frequency

following a modified Atkins (low-carbohydrate) diet that mimics the ketogenic diet
but does not restrict protein, calories, and fluids. In small studies of children
with intractable epilepsy, seizure reductions of more than 50% have been seen
within 3 months in some children placed on this diet, particularly with
carbohydrate limits of 10 g per day. [62, 63]

Preliminary studies of a modified Atkins diet have also been performed in adults.
For example, Smith et al found that this diet demonstrates modest efficacy as
adjunctive therapy for some adults with medically resistant epilepsy, and it may be
also helpful for weight loss but can pose financial and logistical difficulties.
[64]

Vagal nerve stimulation

VNS is a palliative technique that involves surgical implantation of a stimulating
device. VNS is FDA approved to treat medically refractory focal-onset epilepsy in
patients older than 12 years. Some studies demonstrate its efficacy in focal-onset
seizures and in a small number of patients with primary generalized epilepsy.
Randomized studies showed modest efficacy at 3 months, but postmarketing experience
showed delayed improvement in another group of patients.

Guidelines on vagus nerve stimulation for epilepsy

In August 2013, the American Academy of Neurology issued an update to its 1999
guidelines on the use of VNS for epilepsy. [65, 66] VNS is currently indicated for
patients older than 12 years with medically intractable partial seizures who are
not candidates for potentially curative surgical resections, as well as for the
adjunctive long-term treatment of chronic or recurrent depression in patients older
than 18 years with a major depressive episode not adequately relieved by 4 or more
antidepressant treatments. Recent reports also indicate long-term efficacy and
successful VNS use in pediatric epilepsy and other seizure types and syndromes.

Key recommendations of the updated guidelines include the following [65, 66] :

VNS may be considered for (1) the adjunctive treatment of partial or generalized
epilepsy in children, (2) seizures associated with Lennox-Gastaut syndrome, and (3)
improving mood in adults with epilepsy
VNS may have improved efficacy over time
Children should be carefully monitored for site infection after VNS implantation
According to the manufacturer's registry, efficacy of the stimulating device at 18
months is 40-50%, where efficacy is defined as a seizure reduction of 50% or more.
Many patients report improvement in seizure intensity and general mood. However,
seizure-free rates for pharmacologically intractable focal-onset epilepsy are less
than 10%.

A meta-analysis of VNS clinical studies reported an average reduction in seizures

of at least 50% in approximately 50% of patients at last follow-up. Although VNS
was not initially FDA approved for children or patients with generalized epilepsy,
the authors also found that these groups benefitted significantly from VNS.

Positive predictors of a favorable outcome with VNS therapy include posttraumatic

epilepsy and tuberous sclerosis. Few patients achieve complete seizure freedom with
VNS, and about a quarter of patients receive no benefit in their seizure frequency.
[67] Some patients have clinical improvement in terms of milder and shorter
seizures.

Implantable neurostimulator
The NeuroPace RNS System, a device that is implanted into the cranium, senses and
records electrocorticographic patterns and delivers short trains of current pulses
to interrupt ictal discharges in the brain. The Neurological Devices panel of the
FDA concluded that this device was safe and effective in patients with partial-
onset epilepsy in whom other antiepileptic treatment approaches have failed and
that the benefits outweigh the risks. [68]

In November 2013, the FDA approved the NeuroPace RNS System for the reduction of
seizures in patients with drug-resistant epilepsy. [69, 70] Approval was based on a
clinical trial involving 191 subjects with drug-resistant epilepsy. The
neurostimulator was implanted in all of these patients but activated in only half
of them. After 3 months, the average number of seizures per month in patients with
the activated device fell by a median of 34%, compared with an approximately 19%
median reduction in patients with an unactivated device.

Activity Modification and Restrictions

The major problem for patients with seizures is the unpredictability of the next
seizure. Clinicians should discuss the following types of seizure precautions with
patients who have epileptic seizures or other spells of sudden-onset seizures:

Driving
Ascending heights
Working with fire or cooking
Using power tools or other dangerous equipment
Taking unsupervised baths
Swimming
These lifestyle precautions are clearly more applicable to some patients than to
others. Document on the patient's chart that driving and occupational hazards for
people with seizures were discussed.

Safety must be balanced with the risk for seizures. A patient with many poorly
controlled diurnal seizures may exercise more caution than a patient who has only
nocturnal seizures. Encourage the use of helmets to prevent head trauma while the
patient is biking, skiing, or participating in other high-risk activities.

Driving motorized vehicles

Driving restrictions differ for each patient because of the individual features of
their seizures, their degree of seizure control, and, in the United States, state
laws. US physicians should be aware of the state regulations regarding driving,
which vary considerably among states. If clinicians practice in a state that
requires mandatory reporting of patients with epilepsy to the Department of Motor
Vehicles, they must ensure they are compliant with state laws and have
documentation. International variation regarding reporting is also considerable;
some countries have more permissive or more restrictive laws regarding driving than
does the United States.

Aside from state laws, recommendations regarding driving motorized vehicles also
vary depending on whether the patient has seizures that occur exclusively during
sleep. Consult current state and federal laws and regulations. For example, to
resume commercial driving across state lines, a patient must have a 5-year seizure-
free period. The recommendation for driving cars and trucks extends to the
operation of other motorized vehicles, such as boats and motorcycles. Aircraft
pilots are typically no longer permitted to fly.

Water precautions
Common sense dictates that patients with seizures should not swim alone, and they
should be particularly aware of the importance of the presence of an adult
lifeguard who can pull them out of the water if needed. Wearing a life jacket in a
boat is important. Activities as simple as taking a bath may be risky, because a
person can drown in as little as 1 inch of water during the flaccid postictal
phase. In addition, a patient who has a seizure while waiting for bath water to
warm up may suffer hot-water burns.

Heights, fire, and power tools

Patients with seizures may experience an episode in situations such as being up on
a roof or engaging in some activity at considerable height from the floor. In
addition, burns from injuries related to cooking are not uncommon, and injuries can
occur with the use of power tools and other dangerous equipment. Caution�in
particular, supervision�is advised when power tools are used, and the use of safety
devices, such as an automatic shutoff switch, is recommended.
Medication Summary
Anticonvulsant medication is the mainstay of treatment for seizures, although the
choice of anticonvulsant drug varies with different seizure types and epileptic
syndromes. The number of anticonvulsants has increased, offering many more
medication choices for physicians and their patients. For more information, see
Antiepleptic Drugs.

Anticonvulsants, Other
Class Summary
These agents prevent seizure recurrence and terminate clinical and electrical
seizure activity. Anticonvulsants are normally reserved for patients who are at
increased risk for recurrent seizures.

Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro)

View full drug information
Carbamazepine is indicated for the management of partial seizures and generalized
tonic-clonic seizures. It has an active metabolite, 10-11 epoxide, which has
anticonvulsant activity and can be measured in the serum. This agent works by
binding to voltage-dependent sodium channels and inhibiting the generation of
action potentials. Serum carbamazepine levels should be measured frequently when
initially starting this medication, with a goal of being seizure free. Like
phenytoin, carbamazepine has been associated with osteopenia.

Clobazam (ONFI)
View full drug information
Clobazam is a 1,5-benzodiazepine that possesses potent anticonvulsant properties.
Its mechanism of action is binding to the gamma-aminobutyric acid�A (GABA-A)
receptor. This agent is thought to potentiate GABAergic neurotransmission. The
active metabolite, N-demethylclobazam, is largely responsible for its long duration
of action. Clobazam is indicated for adjunctive treatment of seizures associated
with Lennox-Gastaut syndrome in patients older than 2 years.

Ethosuximide (Zarontin)
View full drug information
Ethosuximide is a succinimide antiepileptic drug (AED) that is effective only
against absence seizures. It has no effect on generalized tonic-clonic, myoclonic,
atonic, or partial seizures.

The mechanism of action is based on reducing current in T-type calcium channels on

thalamic neurons. The spike-and-wave pattern during petit mal seizures is thought
to be initiated in thalamocortical relays by activation of these channels.
Ethosuximide is available in large 250-mg capsules, which may be difficult for some
children to swallow, and as a syrup (250 mg/5 mL).

Blood levels should be measured 1-3 weeks after starting ethosuximide. The
therapeutic concentration of ethosuximide is 40-100 mcg/mL. The major side effects
of the drug include nausea, vomiting, drowsiness, hyperactivity and sleep
disturbance.

Ezogabine (Potiga)
View full drug information
Ezogabine is a neuronal potassium channel opener that stabilizes neuronal KCNQ
(Kv7) channels in the open position, increasing the stabilizing membrane current
and preventing bursts of action potentials during the sustained depolarizations
associated with seizures. It is indicated as adjunctive therapy in partial-onset
seizures uncontrolled by current medications.

Owing to the presence of potassium channels in the bladder, there is a small risk
of urinary retention. In addition, in April 2013 the FDA issued a warning that
ezogabine can cause skin discoloration and abnormalities of the eye characterized
as changes in the pigment in the retina. [50] Whether these changes are permanent
and whether pigment changes in the retina have the potential to cause loss of
vision are unknown.

The FDA recommends that all patients taking ezogabine undergo baseline and periodic
eye examinations and discontinue the medication if changes are observed, unless
there is no other treatment option. Skin discoloration most often appeared as blue
around the lips and nail beds but was also reported to be widespread on the face
and legs. [50] In patients with skin discoloration, alternative treatments should
be considered, but the FDA warns of serious and life-threatening reactions to the
sudden discontinuance of the medication. [50]

Felbamate (Felbatol)
View full drug information
Felbamate is approved by the FDA for medically refractory partial seizures and
Lennox-Gastaut syndrome. This agent has multiple mechanisms of action, including
(1) inhibition of N-methyl-D-aspartate (NMDA)�associated sodium channels, (2)
potentiation of GABAergic activity, and (3) inhibition of voltage-sensitive sodium
channels. Felbamate is used only as a drug of last resort in medically refractory
cases because of the risk of aplastic anemia and hepatic toxicity, which
necessitates regular blood tests.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

View full drug information
Lamotrigine, a triazine derivative, is an antiepileptic drug with a very broad
spectrum of activity, like valproate. It is approved by the FDA for primary
generalized and partial-onset epilepsy. Other indications include adjunctive
therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome,
treatment of juvenile myoclonic epilepsy (JME) and maintenance treatment of bipolar
I disorder. The mechanism of action is based on inhibiting the release of glutamate
and voltage-sensitive sodium channels, leading to stabilization of the neuronal
membrane.

Lamotrigine is quickly absorbed when given orally, and 55% is bound to plasma
proteins. The therapeutic serum levels have not been definitively established.

Side effects of lamotrigine include rash and nausea. The dose has to be increased
very slowly over several weeks to minimize the chance of rash, especially if the
patient is on valproic acid. The risk of developing Stevens-Johnson syndrome, toxic
epidermal necrolysis, and angioedema is 1 in 1000 adults and higher in children,
but this risk is decreased with slower titration.

Levetiracetam (Keppra, Keppra XR)

View full drug information
Levetiracetam is indicated for adjunctive therapy in the treatment of primary
generalized tonic-clonic seizures, JME, and partial-onset seizures in adults and
children. The mechanism of action is thought to be through modulation of synaptic
vesicle proteins. The metabolism of this drug is independent of the CYP450 system,
which limits the potential for interaction with other antiepileptic drugs.

Levetiracetam has a rapid onset of action and is well tolerated. Common side
effects include fatigue, somnolence, dizziness, and irritability. This medication
is available in oral (including extended-release) and intravenous formulations.

Phenytoin (Dilantin, Phenytek)

View full drug information
Phenytoin is used to treat patients with partial, generalized, or mixed seizures,
such as the tonic-clonic (grand mal) type. This agent works by blocking voltage-
dependent neuronal sodium channels. The therapeutic concentration range of
phenytoin in serum is 10-20 mcg/mL for patients who have normal renal function and
serum albumin levels.

The risk of osteopenia and cerebellar ataxia, both of which are long-term adverse
effects associated with phenytoin, now temper the drug's use by neurologists. This
agent is one of the most difficult AEDs to use because of its zero-order kinetics
and narrow therapeutic index. In addition, it can have significant bidirectional
drug interactions.

Primidone (Mysoline)
View full drug information
Primidone is indicated for the management of grand mal, psychomotor, and focal
seizures. In addition, it is commonly used for benign familial tremors. When
metabolized, primidone breaks down to phenobarbital, another active antiepileptic
drug. Primidone decreases neuron excitability and increases the seizure threshold.
Common side effects of this drug include sedation, drowsiness, fatigue, and
depression.

Rufinamide (Banzel)
View full drug information
Rufinamide modulates sodium channel activity, particularly prolongation of the
channel's inactive state. It significantly slows sodium channel recovery and limits
sustained, repetitive firing of sodium-dependent action potentials. Rufinamide is
indicated for adjunctive treatment of seizures associated with Lennox-Gastaut
syndrome. It is well tolerated, with the most common side effects being somnolence
and vomiting.

Topiramate (Topamax)
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Topiramate is an AED with a broad spectrum of antiepileptic activity. This agent is
approved for generalized, primary generalized, tonic-clonic, and partial-onset
seizures. Topiramate has multiple mechanisms of action, including state-dependent
sodium channel ? blocking action, enhancement of the inhibitory activity of the
neurotransmitter GABA, and antagonism of the NMDA-glutamate receptor. It may block
glutamate activity and is a weak carbonic anhydrase inhibitor. Weight loss,
impaired cognition, and mood problems are common side effects of topiramate. The
drug is also approved for migraine prevention.

Valproic acid (Depakote, Depakote ER, Depakene, Depacon, Stavzor)

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Valproate, a broad-spectrum AED, is effective against most seizure types, including
myoclonic seizures. It can also be used alone or in combination for the treatment
of generalized or partial seizures. Valproate has multiple mechanisms of
anticonvulsant action, including increasing GABA levels in the brain, as well as T-
type calcium channel activity. The extended-release (ER) formulation allows for
once-a-day administration. Valproate also has FDA approval for migraine prevention
and prevention of mania in bipolar patients.

Zonisamide (Zonegran)
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Zonisamide has been studied extensively in Japan and Korea and seems to have broad-
spectrum properties. It blocks T-type calcium channels, prolongs sodium channel
inactivation, and is a carbonic anhydrase inhibitor.

Dose adjustments may be required when zonisamide is given with other

anticonvulsants, such as carbamazepine, phenytoin, and phenobarbital. The most
common side effects of this drug include ataxia, anorexia, and fatigue.
Perampanel (Fycompa)
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Perampanel is a noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) glutamate receptor. It is indicated as adjunct
treatment for partial-onset seizures (with or without secondary generalized
seizures) and for primary generalized tonic-clonic seizures in adults and children
aged 12 years or older.

Lacosamide (Vimpat)
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Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels,
resulting in stabilization of hyperexcitable neuronal membranes and inhibition of
repetitive neuronal firing. It is indicated as monotherapy or adjunctive therapy
for partial-onset seizures.

Anticonvulsants, Barbiturates
Class Summary
Like benzodiazepines, barbiturates bind to the gamma-aminobutyric acid (GABA)
receptor, enhancing the actions of GABA by extending GABA-mediated chloride channel
openings and allowing neuronal hyperpolarization. The principal barbiturate used
for status epilepticus is phenobarbital; for refractory cases, pentobarbital is
used.

Phenobarbital (Luminal)
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Phenobarbital works at GABA receptors in the central nervous system (CNS) to
potentiate CNS inhibition. This agent is the best-studied barbiturate for the
treatment of status epilepticus.

In status epilepticus, achieving therapeutic levels as quickly as possible is

important. Intravenous dosing may require approximately 15 minutes to attain peak
levels in the brain. To terminate generalized convulsive status epilepticus,
administer up to 15-20 mg/kg. If the patient has received a benzodiazepine, the
potential for respiratory suppression significantly increases. Ventilation and
intubation may be necessary. Hypotension may require treatment.

In status epilepticus, phenobarbital is generally used after phenytoin or

fosphenytoin fails. However, it can be used in lieu of phenytoin in certain
circumstances. A trend is to recommend agents other than phenobarbital (propofol,
midazolam, other barbiturates) for refractory status epilepticus; however, for
super-refractory status epilepticus, phenobarbital should be used.