Epilepsy

Susan J. Rogers and Jose E. Cavazos

KEY CONCEPTS
1. Patient-specific treatment goals should be identified as early as possible.
2. Accurate diagnosis and classification of seizure/syndrome type is critical to selection of
appropriate pharmacotherapy.
3. Patient characteristics such as age, comorbid conditions, ability to comply with the
prescribed regimen, and presence or absence of insurance coverage can also influence
the choice of antiepileptic drugs (AEDs).
4. Pharmacotherapy of epilepsy is highly individualized and requires titration of the dose to
optimize AED therapy (maximal seizure control with minimal or no side effects).
Approximately 50% to 70% of patients can be maintained on one AED.
5. If the therapeutic goal is not achieved with monotherapy, a second drug can be added or
a switch to an alternative single AED can be made. If a second AED is added it should
have a different mechanism of action from the first, although there is no clear evidence
in humans to support this.
6. Some patients eventually can discontinue AED therapy. Several factors predict successful
withdrawal of AEDs.
7. Surgery is the treatment of choice in selected patients with refractory focal epilepsy.
8. The appropriate use of AEDs requires a thorough understanding of their clinical
pharmacology, including mechanism of action, pharmacokinetics, adverse reactions, and
drug interactions, as well as available dosage forms.

Epilepsy is a disorder that is best viewed as a symptom of disturbed electrical activity in the
brain, which may have many etiologies. It is a collection of many different types of seizures that
vary widely in severity, appearance, cause, consequence, and management. Seizures that are
prolonged or repetitive can be life-threatening. Epilepsy is defined by the occurrence of at least
two unprovoked seizures separated by 24 hours. The effect epilepsy has on patients’ lives can be
significant and extremely frustrating. It is also important to recognize that seizures can be just
one (albeit the most obvious) symptom of an epileptic disorder. Not uncommonly, patients have
other comorbid disorders, including depression, anxiety, and potentially neuroendocrine
disturbances. Patients with epilepsy also may display neurodevelopmental delay, memory
problems, and/or cognitive impairment. Although, by convention, the focus of drug treatment is
on the abolition of seizures, clinicians must also try to address these common comorbidities.

EPIDEMIOLOGY
Each year, 120 per 100,000 people in the United States come to medical attention because of a
newly recognized seizure. At least 8% of the general population will have at least one seizure in
a lifetime.
However, it is common to have a seizure and not have epilepsy. The rate of recurrence of a first
unprovoked seizure within 5 years ranges between 23% and 80%. Children with an idiopathic
first seizure and a normal electroencephalogram (EEG) have a particularly favorable prognosis.
Some seizures occur as single events resulting from withdrawal of CNS depressants (e.g.,
alcohol, barbiturates, and other drugs) or during acute neurologic illnesses or systemic toxic
conditions (e.g., uremia or eclampsia). Some patients will have seizures only associated with
fever. These febrile seizures do not constitute epilepsy. The age-adjusted incidence of epilepsy is
44 per 100,000 person-years. Each year, approximately 125,000 new epilepsy cases occur in the
United States; only 30% are in people younger than 18 years of age at the time of diagnosis.
There is a bimodal distribution in the occurrence of the first seizure, with one peak occurring in
newborn and young children and the second peak occurring in patients older than 65 years of
age. The relatively high frequency of epilepsy in the elderly is now being recognized.

ETIOLOGY
Seizures occur because a group of cortical neurons discharge abnormally in synchrony. Anything
that disrupts the normal homeostasis or stability of neurons can trigger hyperexcitability and
seizures.
Thousands of medical conditions can cause epilepsy, from genetic mutations to traumatic brain
injury.
A genetic predisposition to seizures has been observed in many forms of primary generalized
epilepsy.
Patients with mental retardation, cerebral palsy, head injury, or strokes are at an increased
risk for seizures and epilepsy. The more profound the degree of mental retardation as measured
by the intelligence quotient (IQ), the greater is the incidence of epilepsy. In the elderly, the
onset of seizures is typically associated with focal neuronal injury induced by strokes,
neurodegenerative disorders (e.g., Alzheimer’s disease), and other conditions. In some cases, if
an etiology of seizures can be identified and corrected, the patient may not require chronic
antiepileptic drug (AED) treatment.
Patients can also present with unprovoked seizures that do not have an identifiable cause, and
thus by definition have idiopathic or cryptogenic epilepsy. Idiopathic etiology is the term used
for suspected genetic cause, whereas cryptogenic etiology is used if no obvious cause is found
for focal-onset seizures. Many factors have been shown to precipitate seizures in susceptible
individuals. Hyperventilation can precipitate absence seizures. Excessive sleep, sleep eprivation,
sensory stimuli, emotional stress, and hormonal changes occurring around the time of menses,
puberty, or pregnancy have been associated with the onset of or an increased frequency of
seizures. A careful drug history should be obtained from patients presenting with seizures
because theophylline, alcohol, high-dose phenothiazines, antidepressants (especially
maprotiline or bupropion), and street drug use have been associated with provoking seizures.
Perinatal injuries and small gestational weight at birth are also risk factors for the development
of partial-onset seizures. Immunizations have not been associated with an increased risk of
epilepsy.

PATHOPHYSIOLOGY
Seizures result from excessive excitation, or in the case of absence seizures, from disordered
inhibition of a large population of cortical neurons.2 This is reflected on EEG as a sharp wave or
spike. Initially, a small number of neurons fire abnormally. Normal membrane conductances and
inhibitory synaptic currents break down, and excess excitability spreads, either locally to
produce a focal seizure or more widely to produce a generalized seizure. This onset propagates
by physiologic pathways to involve adjacent or remote areas. The clinical manifestations depend
on the site of the focus, the degree of irritability of the surrounding area of the brain, and the
intensity of the impulse. There are multiple mechanisms that might contribute to synchronous
hyperexcitability, including:
(a) alterations in the distribution, number, type, and biophysical properties of ion channels in
the neuronal membranes; (b) biochemical modifications of receptors; (c) modulation of second
messaging systems and gene expression; (d) changes in extracellular ion concentrations; (e)
alterations in neurotransmitter uptake and metabolism in glial cells; and (f) modifications in the
ratio and function of inhibitory circuits. In addition, local neurotransmitter imbalances could be
a potential mechanism for focal epileptogenesis. Transitory imbalances between the main
neurotransmitters, glutamate (excitatory) and γ-aminobutyric acid (GABA) (inhibitory), and
neuromodulators (e.g., acetylcholine, norepinephrine, and serotonin) might play a role in
precipitating seizures in susceptible patients.
Control of abnormal neuronal activity with AEDs is accomplished by elevating the threshold of
neurons to electrical or chemical stimuli or by limiting the propagation of the seizure discharge
from its origin. Raising the threshold most likely involves stabilization of neuronal membranes,
whereas limiting the propagation involves depression of synaptic transmission and reduction of
nerve conduction.
Prolonged seizures and continued exposure to glutamate can result in neuronal injury in
vulnerable neuronal populations resulting in functional deficits, primarily in memory, and in
permanent changes of wiring of the neuronal circuitry. Sprouting and reorganization of neuronal
projections might lead to a chronic susceptibility to seizures, neuronal destruction, and brain
damage.
However, limited degree of neurogenesis in the hippocampal pathways has been induced by
epileptic seizures. The role of these newly born neurons is not well understood.

CLINICAL PRESENTATION
The International League Against Epilepsy has proposed two major schemes for the
classification of seizures and epilepsies: the International Classification of Epileptic Seizures and
the International Classification of the Epilepsies and Epilepsy Syndromes.3,4 The International
Classification of Epileptic Seizures (Table 40-1) combines the clinical description with certain
electrophysiologic findings to classify epileptic seizures. Seizures are divided into two main
pathophysiologic groups— partial seizures and generalized seizures—by EEG recordings and
clinical symptomatology.
CLINICAL PRESENTATION Epilepsy
General
In most cases, the healthcare provider will not be in a position to witness a seizure. Many
patients (particularly those with CP or GTC seizures) are amnestic to the actual seizure event.
Obtaining an adequate history and description of the ictal event (including time course) from a
witness is critically important. With treatment the typical clinical presentation of the seizure
may change

Symptoms
Symptoms of a specific seizure will depend on seizure type. Although seizures can vary between
patients, they tend to be stereotyped within an individual
• CP seizures can include somatosensory or focal motor features
• CP seizures are associated with altered consciousness
• Absence seizures can be almost nondetectable with only very brief (seconds) periods of
altered consciousness
• GTC seizures are major convulsive episodes and are always associated with a loss of
Consciousness

Signs
Interictally (between seizure episodes), there are typically no objective or pathognomonic signs

Laboratory Tests
There are currently no diagnostic laboratory tests for epilepsy. In some cases, particularly
following GTC (or perhaps CP) seizures, serum prolactin levels can be transiently elevated.
Laboratory tests can be done to rule out treatable causes of seizures (e.g., hypoglycemia,
altered electrolyte concentrations, infections, etc.) that do not represent epilepsy

Other Diagnostic Tests

• EEG is very useful in the diagnosis of various seizure disorders
• An epileptiform EEG is found in only approximately 50% of the patients who have epilepsy
• A prolactin serum level obtained within 10 to 20 minutes of a tonic–clonic seizure can be
useful in differentiating seizure activity from pseudoseizure activity but not from syncope 5
• Although magnetic resonance imaging (MRI) is very useful (especially imaging of the temporal
lobes), a computed tomography (CT) scan typically is not helpful except in the initial
evaluation for a brain tumor or cerebral bleeding

Partial (focal) seizures begin in one hemisphere of the brain and—unless they become
secondarily generalized—result in an asymmetric motor manifestation. Partial seizures manifest
as alterations in motor functions, sensory or somatosensory symptoms, or automatisms. Partial
seizures with no loss of consciousness are classified as simple partial (SP). In some cases,
patients will describe somatosensory symptoms as a “warning” prior to the development of a
generalized tonic– clonic (GTC) seizure. These warnings are, in fact, SP seizures and frequently
are termed auras.
Partial seizures with an alteration of consciousness are described as complex partial (CP). With
CP seizures, the patient can have automatisms, periods of memory loss, or aberrations of
behavior.
Some patients with CP epilepsy have been mistakenly diagnosed as having psychotic episodes.
CP seizures also can progress to GTC seizures. Patients with CP seizures typically are amnestic to
these events. A partial seizure that becomes generalized is referred to as a secondarily
generalized seizure.
Generalized seizures have clinical manifestations that indicate involvement of both
hemispheres. Motor manifestations are bilateral, and there is a loss of consciousness.
Generalized seizures can be further subdivided by EEG and clinical manifestations. Generalized
absence seizures are manifested by a sudden onset, interruption of ongoing activities, a blank
stare, and possibly a brief upward rotation of the eyes. They generally occur in young children
through adolescence. It is important to differentiate absence seizures from CP seizures. With
GTC seizures there is a sudden sharp tonic contraction of muscles followed by a period of
rigidity and clonic movements. During the seizure, the patient may cry or moan, lose sphincter
control, bite the tongue, or develop cyanosis. After the seizure, the patient may have altered
consciousness, drowsiness, or confusion for a variable period of time (postictal period) and
frequently goes into a deep sleep. Tonic and clonic seizures can also occur separately.

Brief shock-like muscular contractions of the face, trunk, and extremities are known as
myoclonic jerks. They can be isolated events or rapidly repetitive. A sudden loss of muscle tone
is known as an atonic seizure, which may present as a head drop, the dropping of a limb, or a
slumping to the ground. These patients often wear protective head ware to prevent trauma.
The International Classification of Epilepsies and Epilepsy Syndromes adds components such as
age of onset, intellectual development, findings on neurologic examination, and results of
neuroimaging studies to define epilepsy syndromes more fully. Syndromes can include one or
many different seizure types (e.g., Lennox–Gastaut syndrome). The syndromic approach
includes seizure type(s) and possible etiologic classifications (e.g., idiopathic, symptomatic, or
unknown). Idiopathic describes syndromes that are presumably genetic but also those in which
no underlying etiology is documented or suspected. A family history of seizures is commonly
present, and neurologic function is essentially normal except for the occurrence of seizures.
Symptomatic cases involve evidence of brain damage or a known underlying cause. A
cryptogenic syndrome is assumed to be symptomatic of an underlying condition that cannot be
documented. Unknown or undetermined is used when no cause can be identified. This
syndromic classification requires more information and is more important for prognostic
determinations and response to treatment than for a classification based simply on seizure
type

TREATMENT
Desired Outcomes
The ideal goal of treatment for epilepsy is complete elimination of seizures and no side effects
with an optimal quality of life (QOL). Data from a large systematic review found that optimal
QOL in epilepsy patients is defined by decreasing their seizure frequency and severity as well as
addressing comorbid conditions, especially anxiety and depression.6 A large multicenter study
found that in pharmacoresistant epilepsy patients, the adverse effects of their AEDs and
depressive comorbidity were far more important in determining QOL than reducing the
frequency of their seizures when seizure freedom cannot be obtained.7 In addition, other
factors that can impact QOL in epilepsy patients include issues about driving, economic security,
forming relationships, safety, social isolation, and social stigma.
The American Academy of Neurology (AAN) has developed eight quality performance measures
for the clinician that define a high quality of care of these patients.8 In a recent survey of
practicing neurologists, poor performance was found on three of these eight—counseling
patients about AED side effects, discussion about depression, and their knowledge about
referral of the intractable epilepsy patient for surgery.9 Lastly in helping to address QOL in
epilepsy patients, an international consensus group has recently developed evidenced-based
and practice-based statements to provide guidance on the management of neuropsychiatric
conditions associated with epilepsy including depression.

Clinical Controversy…
A significant amount of accumulating data suggests that treatment-resistant epilepsy may be
intertwined with the presence of anxiety and/or depression in many epilepsy patients. In some
patients the presence of bilateral hippocampal atrophy, diffuse cortical atrophy, or both in those
persons with a history of depressive disorder at time of onset of epilepsy may provide a possible
explanation for a very poor treatment response to AEDs. In addition, the issue of increased
suicide rate seen in patients on AEDs may be influenced by the presence of these conditions.
Until more valid data are collected in this area, it is the responsibility of the clinician treating the
patient to make sure these conditions are carefully taken into account when selecting the
appropriate AED therapy.
General Approach to Treatment
The general approach to treatment involves assessment of seizure type and frequency,
identification of treatment goals, development of a care plan, and a plan for followup
evaluation. During the assessment phase, it is critical to establish an accurate diagnosis of the
seizure type and classification in order to select the appropriate initial AEDs. Patient-specific
treatment goals must be identified, and these can change over time. Despite appropriate AED
treatment, approximately 30% to 35% of patients are refractory to treatment. In this setting,
seizure freedom may not be obtained, and more obtainable goals should be established (e.g.,
decrease in the number of seizures and minimized drug adverse effects).
Patient characteristics such as age, medical condition, ability to comply with a prescribed
regimen, and insurance coverage also should be explored because these can influence AED
choices or help to explain nonadherence to the regimen, a lack of response, or unexpected
adverse effects.
Once the assessment is complete, for patients with new-onset seizures, the choice is whether to
use drug therapy and, if so, which one. For a patient with long-standing epilepsy, adequacy of
the current medication regimen must be evaluated. An AED should not be considered
ineffective unless the patient has experienced unacceptable adverse effects with continued
seizures.
If a decision is made to start AED therapy, monotherapy is preferred, and approximately 50% to
70% of all patients with epilepsy can be maintained on one drug.11 However, many of these
patients are not seizure free. The percentage of patients who are seizure free on one drug varies
by seizure type. After 12 months of treatment, the percentage who are seizure free is highest
for those who have only GTC seizures (48% to 55%), lowest for those who have only CP seizures
(23% to 26%), and intermediate for those with mixed seizure types (25% to 32%).11 Combining
AEDs with different mechanisms of action to achieve freedom from seizures may be
advantageous, although this approach is as yet unproven. Approximately 65% of patients can be
expected to be maintained on one AED and be considered well controlled, although not
necessarily seizure free.
Of the 35% of patients with unsatisfactory control, 10% will be well controlled with a twodrug
treatment. Of the remaining 25%, 20% will continue to have unsatisfactory control despite
multiple drug treatment. There may be a genetic predisposition to epilepsy that is refractory to
drug therapy. Some of these patients may become candidates for surgery or vagal nerve
stimulator.

Once the care plan is established, an AED is selected. Patient education and assurance of patient
understanding of the plan are essential. Detailed directions regarding titration, what to do in the
event of a treatment-emergent side effect, and what to do if a seizure occurs must be provided
to patients.
Documentation of the assessment, care plan, and educational process is essential. Providing the
patient with a seizure and side-effect diary will assist in the followup and evaluation phase. At
the followup stage of treatment (which can be done in the hospital, clinic, pharmacy, or by
phone), the treatment goals must be reviewed. If the goal has been achieved, new goals should
be identified. For example, if the GTC seizures are now controlled, the goal may be to control
partial seizures. If a patient fails to respond to the first AEDs, trials with other AEDs should be
attempted as appropriate.
Completion of the evaluation often requires a reassessment of the patient and development of
a new care plan taking into account patient compliance, efficacy, and safety of the initial
treatment. Medication noncompliance can be the single most common reason for treatment
failure. It is estimated that up to 60% of patients with epilepsy are noncompliant.12 The rate of
noncompliance is increased by the complexity of the drug regimen and by doses taken three
and four times a day.
Frequent uncontrolled seizures can also predispose a patient to noncompliance secondary to
confusion over whether the drug was taken. Noncompliance is not influenced by age, sex,
psychomotor development, or seizure type.

Difference of opinion exists on the most appropriate time to initiate AED therapy. Treatment
decisions vary depending on individual patient clinical characteristics and circumstances. Some
clinicians start AED treatment after the first seizure, whereas others do not initiate treatment
until a second, unprovoked seizure has occurred. Still others initiate prophylactic treatment
following a CNS insult thought likely to cause epilepsy eventually (e.g., stroke or head trauma).
Drug treatment may not be indicated when seizures have minimal impact on patients’ lives or
when there has been only a single seizure. If a patient presents after a single isolated seizure,
one of three treatment decisions can be made: treat, possibly treat, or do not treat. These
decisions are based on the probability of the patient having a second seizure (Table 40-2). For
patients with no risk factors, the probability of a second seizure is less than 10% in the first year
and approximately 24% by the end of 2 years. If risk factors are present, the recurrence rate can
be as high as 80% after 5 years.13 The decision on whether to start AED therapy often depends
on patient-specific factors such as epilepsy syndrome, seizure etiology, presence of a
neuroanatomic defect, and the EEG, as well as, the patient’s lifestyle and preferences. Patients
who have had two or more seizures generally should be started on AEDs.

When to Stop Antiepileptic Drugs

The AEDs used to control seizures may not need to be given for a lifetime. Polypharmacy can be
reduced, and some patients can discontinue AEDs altogether. The drug considered less
appropriate for the seizure type (or the agent deemed most responsible for adverse effects)
should be discontinued first. In some cases, decreasing the number of AEDs can decrease side
effects and increase cognitive abilities. This improvement in cognition may be small, especially if
the patient is on a drug that primarily affects psychomotor speed with less effect on higher-
order cognitive functioning.
Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years,
complete seizure control within 1 year of onset, an onset of seizures after age 2 but before age
35, and a normal neurologic examination and EEG. Factors associated with a poor prognosis in
discontinuing AEDs, despite a seizure-free interval, include a history of a high frequency of
seizures, repeated episodes of status epilepticus (SE), a combination of seizure types, and
development of abnormal mental functioning. A 2-year seizure-free period is suggested for
absence and rolandic epilepsy, whereas a 4-year seizure-free period is suggested for SP, CP, and
absence seizures associated with tonic–clonic seizures. AED withdrawal generally is not
suggested for patients with juvenile myoclonic epilepsy (JME), absence with clonic–tonic–clonic
seizures, or clonic–tonic–clonic seizures. The AAN has issued guidelines for discontinuing AEDs
in seizure-free patients.14 After assessing the risks and benefits to both the patient and society,
AED withdrawal can be considered in a patient meeting the following profile: seizure free for 2
to 5 years, a history of a single type of partial seizure or primary GTC seizures, a normal
neurologic exam and normal IQ, and an EEG that has normalized with treatment. When these
factors are present, the relapse rate is expected to be less than 32% for children and 39% for
adults.
AED withdrawal should be done gradually, especially in patients with profound developmental
disabilities. Some patients will have a recurrence of seizures as the AEDs are withdrawn. Sudden
withdrawal is associated with the precipitation of SE. Withdrawal seizures are of particular
concern for agents such as benzodiazepines and barbiturates. Seizure relapse has been reported
to be more common if these AEDs are withdrawn over 1 to 3 months compared to over 6
months.
The risk of seizure relapse has been estimated at 10% to 70%. A meta-analysis determined that
the relapse rate was 25% after 1 year and 29% after 2 years. Recurrence of seizures tends to
occur early with at least one-half of the recurrences within 6 months of AED withdrawal and
60% to 90% within 1 year. Patients who relapse will generally become seizure free and in
remission after AEDs are restarted although not necessarily immediately. The underlying
epilepsy syndrome appears to determine prognosis for long-term remission.

Pharmacologic Therapy
Optimal management of epilepsy requires that AED treatment be individualized. Different
patient groups (e.g., children, women of child-bearing potential, and the elderly) may be better
suited to receive one AED than another by virtue not only of seizure type but also of
susceptibility or relative risk for certain adverse effects. These issues are highlighted further
below.
Selection and optimization of AED therapy require not only an understanding of drug
mechanism(s) of action and spectrum of clinical activity, but also an appreciation of
pharmacokinetic variability and patterns of drug-related adverse effects. An AED must be
effective for the specific seizure type being treated. The drug treatments of first choice depend
on the type of epilepsy, drugspecific adverse effects, and patient preferences. Ultimately, AED
effectiveness is the result of the interaction of each of these factors. A suggested algorithm for a
general approach to the treatment of epilepsy is shown in Figure 40-1.
The mechanism of action of most AEDs can be categorized as (a) affecting ion channel kinetics,
(b) augmenting inhibitory neurotransmission, or (c) modulating excitatory neurotransmission.
Augmentation in inhibitory neurotransmission includes increasing CNS concentrations of GABA,
whereas efforts to decrease excitatory neurotransmission are primarily focused on decreasing
(or antagonizing) glutamate and aspartate neurotransmission. AEDs that are effective against
GTC and partial seizures probably reduce sustained repetitive firing of action potentials by
delaying recovery of sodium channels from activation. Drugs that reduce corticothalamic T-type
calcium currents are effective against generalized absence seizures. Myoclonic seizures respond
to drugs that enhance GABAA-receptor inhibition. In addition to mechanism of action,
awareness of pharmacokinetic properties (Table 40-4), adverse effects (Table 40-5), and AED
metabolic pathway as well as inducer or inhibitory effects on liver (Table 40-6) can aid in the
optimization of AED therapy.
Pharmacokinetic interactions are a common complicating factor in AED selection.
Interactions can occur in any of the pharmacokinetic processes: absorption, distribution,
metabolism, or elimination. Caution should be used when AEDs are added to or withdrawn
from a drug regimen.
Adverse effects of AEDs can be divided into acute and chronic (see Table 40-5). Acute
effects can be dose/serum concentration-related or idiosyncratic. Concentration-dependent
effects are common and troublesome but not usually life-threatening. Neurotoxic adverse
effects are encountered commonly and can include sedation, dizziness, blurred or double vision,
difficulty with concentration, and ataxia. In many cases, these effects can be alleviated by
decreasing the dose or avoided in some cases by titrating the dose upward very slowly. Most
idiosyncratic reactions are mild, but they can be more serious if the hypersensitivity involves
one or more organ systems. Other idiosyncratic side effects including hepatitis or blood
dyscrasias are serious but rare.
Acute organ failure, when it occurs, generally occurs within the first 6 months of AED
therapy.
Unfortunately, laboratory screening evaluations of blood and urine typically are not
helpful in predicting or detecting the early stage of severe reactions and generally are not
recommended in asymptomatic patients. An exception to this is in the screening of patients of
Southeast Asian heritage for HLA-B*1502 antigen who are to receive carbamazepine and
possibly phenytoin, lamotrigine, and oxcarbazepine. There is a strong association between the
presence of this antigen and Stevens– Johnson syndrome as well as toxic epidermal necrolysis.
In addition the HLA genotype HLAA* 3101 has been found to be associated with multiple
carbamazepine-induced cutaneous reactions in Chinese, Japanese, and European populations.
In any patient, laboratory assessment, including white blood cell (WBC) counts and liver
function tests, may be reasonable if the patient reports an unexplained illness (e.g., lethargy,
vomiting, fever, or rash).7 It is important to note that patients dosed and maintained within
“therapeutic ranges” are also capable of experiencing toxicities to AEDs.
Another potential long-term adverse effect of AED treatment is osteomalacia and osteoporosis.
The bone disorders associated with AED use are a heterogeneous group of disorders,
ranging from asymptomatic high-turnover disease, with findings of normal bone mineral
density, to markedly decreased bone mineral density sufficient to warrant the diagnosis of
osteoporosis. While the etiology of these osteopathies is uncertain, it has been hypothesized
that certain drugs, including phenytoin, phenobarbital, carbamazepine, oxcarbazepine,
felbamate, and valproic acid, may interfere with vitamin D metabolism; at least for the CYP3A4
inducers this activity may be explained by recent findings of an inducible CYP3A4-dependent
vitamin D pathway. Whether the other AEDs cause these effects is unknown, however, current
evidence suggests that lamotrigine does not. Common laboratory findings in these patients
include elevated bone-specific alkaline phosphatase concentration, intact parathyroid hormone,
and decreased serum calcium and 25-OH vitamin D concentrations. Patients receiving these
drugs should receive supplemental vitamin D and calcium, as well as bone mineral density
testing if other risk factors for osteoporosis are present.
Comparative data now exist between some of the older AEDs, carbamazepine,
phenytoin, and valproic acid and the newer agents, levetiracetam, lamotrigine, and topiramate
(low dose) that suggest the older agents increase circulatory vascular risk markers, which may
contribute to acceleration of atherosclerosis and that this effect is treatment duration
dependent.
The comparative effects of AEDs on cognition have been difficult to evaluate because of
differences or inconsistencies in study design, seizure types studied, control for serum drug
concentrations, and the neuropsychologic tests used. In general, there are not large differences
between the older drugs, although the barbiturates, phenobarbital and primidone, appear to
cause more cognitive impairment than other commonly used AEDs.44,45 Phenytoin,
particularly when serum concentrations are above the commonly accepted therapeutic range,
may have a greater effect on motor function and speed. Among the older AEDs, valproic acid
may cause less impairment of cognition. Improvement in cognition has been reported in
patients switched from phenytoin or phenobarbital to valproic acid. However, these
improvements are subtle if patients are in the same relative area of the therapeutic range.
Patients changed from polytherapy to monotherapy also may demonstrate improvement in
cognition. Some of the newer agents are believed to cause fewer neurobehavioral or cognitive
effects. Among the newer AEDs, gabapentin and lamotrigine have been shown in several studies
to cause fewer cognitive impairments compared with older agents, such as carbamazepine.
Conversely, topiramate may cause substantial cognitive impairment, particularly when used at
high doses or during rapid dose escalation.48 In addition, these patients may not be fully aware
of their deficits. AED treatment itself may sometimes worsen seizures due to improper AED
selection for a specific seizure type or syndrome or can represent a paradoxical toxic effect of
the drug.
Because most adult patients have localization-related (partial-onset) seizures, the most
widely used AEDs traditionally have been carbamazepine, phenobarbital, phenytoin, and
valproic acid. For CP seizures, these AEDs have similar efficacy.52,53 Of these, carbamazepine
and phenytoin are the most commonly prescribed AEDs for partial seizures in the United States.
This preference is largely based on data derived from two landmark trials conducted through
the Veterans Administration (VA) Epilepsy Cooperative Study Group. In the first of these trials,
patients with new-onset partial or generalized epilepsy were randomized to receive either
carbamazepine, phenobarbital, phenytoin, or primidone. After 3 years, patients who received
either carbamazepine or phenytoin were equally likely, and patients on phenobarbital or
primidone were least likely to have remained on their originally assigned treatment. Thus,
carbamazepine and phenytoin were considered the drugs of first choice in patients with new-
onset partial or generalized seizures. Carbamazepine was associated with fewer side effects. A
followup study using almost identical methods compared carbamazepine and valproic acid.53
Carbamazepine- and valproic acid-treated groups had equal retention rates for tonic–clonic
seizures. Carbamazepine was superior to valproic acid for efficacy in the treatment of partial
seizures. Valproic acid caused slightly more adverse effects.
Based primarily on these trials, carbamazepine has been recognized as the AED of first
choice for partial seizures. Several of the newer generation AEDs are now proving to be
reasonable alternatives. The newer AEDs were first approved as adjunctive therapy for patients
with refractory partial seizures. Monotherapy trials with several of these newer agents including
lamotrigine, gabapentin, topiramate, oxcarbazepine, and levetiracetam have now been
completed.
Comparisons between lamotrigine and older agents, including carbamazepine and
phenytoin as initial monotherapy for partial seizures have been conducted in Europe, and the
results suggest comparable effectiveness and perhaps better tolerability for lamotrigine,
particularly in elderly patients. In a large, unblinded, randomized, controlled trial in hospital-
based outpatient clinics in the United Kingdom, lamotrigine was found to be clinically better
than carbamazepine for time to treatment failure outcomes in newly diagnosed patients with
partial seizures; lamotrigine was determined to be a cost-effective alternative to
carbamazepine. Other drugs studied in this trial were gabapentin, oxcarbazepine, and
topiramate. Results from a VA cooperative trial designed to compare gabapentin, lamotrigine,
and carbamazepine in newly diagnosed elderly patients with partial seizures found that
lamotrigine efficacy is comparable with that of both gabapentin and carbamazepine, and is
better tolerated than carbamazepine but equal to gabapentin in this population.58 Clinical data
suggest that in newly diagnosed patients, oxcarbazepine is as effective as phenytoin, valproic
acid, and immediate-release carbamazepine, with perhaps fewer adverse effects. Close
examination of the conversion to monotherapy trials suggests that oxcarbazepine demonstrates
efficacy even in patients who previously had an inadequate response to carbamazepine, in spite
of their structural similarity.
Lastly, levetiracetam in a 1-year study was found to have equal efficacy and tolerability
when studied against controlled-release carbamazepine.59
In addition, several monotherapy trials using an active control or pseudoplacebo design
also have been conducted. Although these study designs provide evidence of efficacy for the
newer drugs, because the comparison is between active drug and placebo in patients who
continue to have seizures in spite of current treatment with standard AEDs, it is difficult to
compare the efficacy of the newer drugs directly with the older AEDs. Generally speaking, the
newer AEDs appear to have comparable efficacy to the older agents and are perhaps better
tolerated. A recent systematic review and metaanalysis attempted to compare the efficacy and
tolerability of the newer AEDs in treatment of refractory partial epilepsy as add on therapy with
another AED or placebo; although the results provided indirect evidence, the authors found
topiramate and probably levetiracetam more efficacious in controlling seizure frequency and
gabapentin less efficacious compared to all other new AEDs. In addition, tolerability was poorer
with oxcarbazepine and topiramate whereas gabapentin and levetiracetam were better
tolerated with the most common side effects comparable between the new AEDs.60
 To date, among the newer generation agents, lamotrigine, oxcarbazepine, and
topiramate have received FDA approval for use as monotherapy in patients with partial seizures.
Phenobarbital and primidone are also useful in partial seizures, but sedation and cognitive
adverse effects limit their utility. Felbamate, which has monotherapy approval, is effective but
has been associated with some significant side effects. Interpretation of monotherapy trials with
the newer AEDs can be daunting owing to the unique study designs and specific patient
populations employed. Withholding an effective AED (i.e., giving placebo) in patients with
epilepsy is generally considered unethical.
Primarily generalized seizures such as absence seizures may respond differently
pharmacologically than other seizure types. Phenytoin, phenobarbital, and carbamazepine,
although effective in GTC and partial seizures, are ineffective for absence seizures, and in some
cases, can precipitate an increase in seizure frequency. Absence seizures are best treated with
ethosuximide, valproic acid, and perhaps lamotrigine. For levetiracetam, topiramate, and
zonisamide, additional data are needed to confirm efficacy. Oxcarbazepine, gabapentin, and
tiagabine do not appear to be effective in treating absence seizures, and can worsen this
condition in some patients. If the patient has a combination of absence and other generalized or
partial seizures, valproic acid or lamotrigine is the preferred first choice because they are
effective for absence and other seizure types. If valproic acid is ineffective in treating a mixed
seizure disorder that includes absence, ethosuximide could be used in combination with
another AED.
The traditional treatment of tonic–clonic seizures is phenytoin; however, carbamazepine
and valproic acid are increasingly used because these AEDs have a lower incidence of side
effects with equal efficacy. Valproic acid generally is considered the drug of first choice for
atonic seizures and for JME. Lamotrigine and perhaps topiramate and zonisamide can be
alternative agents for these seizure types. Levetiracetam is FDA approved as adjunctive
treatment of myoclonic seizures in patients with JME.
Results of a large, unblinded, randomized, controlled trial conducted in patients with
new-onset generalized and unclassified epilepsy outpatients in the United Kingdom has helped
to define the role of the newer generation drugs. These researchers found that for idiopathic
generalized epilepsy, valproic acid was significantly better tolerated than topiramate and more
efficacious than lamotrigine.61 A post hoc analysis of this trial delineated clinical factors
significant in influencing treatment failure and in achieving a 12 month remission.62
Serum concentrations of the older AEDs should be viewed as a tool with which to optimize
therapy for an individual patient, not as a therapeutic end point in itself. The serum
concentration is a target that should be correlated with clinical response. The desired outcome
is the cessation of seizures without side effects. Seizure control can occur before the
“minimum” of the published therapeutic range is achieved, and side effects can appear before
the “maximum” of the range is achieved. Some patients may need and tolerate concentrations
beyond the maximum. The therapeutic range for AEDs can be different for different seizure
types. Serum concentrations may need to be higher to control CP seizures than to control tonic–
clonic seizures. Clinicians should define a therapeutic range for an individual patient above
which there are side effects and below which the patient experiences seizures. Then serum
levels can be useful to document lack of efficacy, loss of efficacy, noncompliance, and to
determine how much room there is to increase a dose based on expected toxicity. Depending
on the AED, serum levels can also be useful in patients with significant renal and/or hepatic
disease, patients taking multiple drugs, and women who are pregnant or taking oral
contraceptives (OCs). Therapeutic concentration ranges have not been clearly defined for some
of the second-generation AEDs.

Therapeutic Considerations in the Elderly and Young

Use of AEDs in the elderly and young can pose special challenges.32 Avoidance of AEDs that
interact with other medications that the elderly are often taking is of upmost importance. Many
of the AEDs are inducers or inhibitors of the cytochrome P450 (CYP450) system, which can
adversely affect the drug level of concomitantly administered drugs. Hypoalbuminemia is
common in the elderly, and can make monitoring and adjustment of serum drug levels of highly
albumin-bound AEDs, such as phenytoin, valproic acid, and tiagabine, problematic. The elderly
also experience body mass changes, such as an increase in fat to lean body mass or decrease in
body water, which can affect the volume of distribution of some drugs, and therefore possibly
the elimination half-life. In addition, declining renal and/or hepatic function can occur in the
elderly, which can require a lower dose of the AED.
Lastly, the pharmacodynamic response to AEDs can change with aging such that elderly
patients may be more sensitive to various neurocognitive adverse effects. Also, elderly patients’
seizures may be controlled at relatively lower total serum concentrations.
For neonates and infants, an increase in the total body water to fat ratio and a decrease
in serum albumin and α-acid glycoprotein can result in volume of distribution changes that can
affect the elimination half-life of the AEDs. In addition, newborns up to the age of 2 to 3 years
display decreased efficiency in renal elimination, with newborns being the most affected.
Hepatic activity is also reduced in this population. However, by age 2 to 3 years, hepatic activity
is more robust than that seen in adults. Therefore, children require higher doses of many of the
AEDs than adults, whereas neonates and infants require lower doses. Lastly, rapidly changing
and sometimes inconsistent metabolism in the patient groups above make therapeutic drug
monitoring especially important even though the definition of therapeutic blood level is less
certain in these patients than in adults.

Therapeutic Considerations in Women (and Men)

Many hormones influence brain electrical excitability, and estrogen and progesterone may
interact in complex ways to alter neuronal excitability and protein synthesis. Estrogen has a
slight proconvulsant effect, whereas progesterone exerts a mild anticonvulsant effect. Estrogen
has a mild inhibitory effect on GABA receptors, potentiates excitatory glutaminergic activity, and
can promote the development of kindling. Progesterone has the opposite effect and appears to
potentiate GABA receptor activity and reduce neuronal discharge rates. AEDs, especially hepatic
metabolizing enzyme inducers, increase the metabolism of these hormones and induce the
production of sex hormone-binding globulin. This may lead to decreases in the unbound
fraction of the hormone. Enzyme-inducing AEDs, including topiramate and oxcarbazepine at
higher doses, can cause treatment failures in women taking OCs owing to induction of the
metabolism of ethinyl estradiol and progestin. This may also be an issue with rufinamide,
lamotrigine, clobazam, and felbamate, all which have a small effect in decreasing the
bioavailability of OCs. A supplemental form of birth control, in addition to OCs, is advised if
breakthrough bleeding occurs. However medroxyprogesterone depot injection, copper
intrauterine devices, and hormone-releasing intrauterine systems are not affected by AEDs.
There are no data available on the efficacy of the transdermal contraceptive patch or the
emergency contraceptive pill in patients taking these AEDs, but it has been suggested that
women use twice the normal dose of the postcoital pill.63 Valproic acid, benzodiazepines,
except clobazam, and most of the newer AEDs, such as gabapentin, levetiracetam, tiagabine,
zonisamide, vigabatrin, and lacosamide, are not enzyme inducers and have not been implicated
in reducing contraceptive effectiveness. Of note, OCs lower lamotrigine’s serum level
significantly and lower valproic acid’s level about 20%.
In some women, vulnerability to seizures is highest just before and during the menstrual flow
(catamenial seizures) and at the time of ovulation. The increased susceptibility to seizures
during those catamenial periods is associated with a slight increase of estrogen relative to
progesterone. The risk of catamenial epilepsy is estimated at 12.5%, but it may be as high as
50% in women with epilepsy. This pattern of seizure exacerbation can also be related to
progesterone withdrawal and changes in the estrogen-to-progesterone ratio. Conventional AEDs
should be used as primary agents but intermittent supplementation with higher dose of AED or
benzodiazepines should be considered.
Acetazolamide also has been used during catamenial periods but with variable and
limited success. Hormonal therapy with progestational agents, particularly cyclic natural
progesterone therapy, may be effective.
Reproductive endocrine disorders are common in women with epilepsy and include
menstrual irregularity, infertility, sexual dysfunction, and in some patients polycystic ovary
syndrome (PCOS).
Potential mechanisms for these disturbances include disruption of the hypothalamic–
pituitary–adrenal (HPA) axis via seizure discharges in limbic structures and/or AEDs.64 AEDs,
particularly the enzyme-inducing agents (e.g., carbamazepine, phenytoin, and phenobarbital),
also may affect HPA function by altering the metabolism of the neuroactive sex hormones,
including testosterone.
Valproic acid is associated with increasing changes in sex hormone concentrations that
causes hyperandrogenism and polycystic changes regardless if the patient has epilepsy,
especially in women who have gained weight or those who start valproic acid at age less than
20 years.
During pregnancy there may be increased maternal seizures, pregnancy complications,
and adverse fetal outcome.65 Approximately 25% to 30% of pregnant women have increased
seizures, whereas seizures decrease in a similar number. However, the risk of seizures is
significantly less if the patient has been seizure free 12 months prior to the pregnancy.66
Increased seizure frequency may result from either a direct effect on seizure threshold or a
reduction in AED concentration. An increase in clearance has been reported for phenytoin,
carbamazepine, phenobarbital, ethosuximide, lamotrigine, oxcarbazepine, levetiracetam,
topiramate, and clorazepate during pregnancy. Protein binding may also be reduced. The
altered disposition of AEDs can begin as early as the first 10 weeks of pregnancy, and may
require up to 4 weeks postpartum to normalize (longer for carbamazepine and phenobarbital
than for phenytoin).
Women with epilepsy have a higher incidence of adverse pregnancy outcomes. Although the
risk of congenital malformations is 4% to 6% (twice as high as in nonepileptic women), more
than 90% of pregnancies in epileptic mothers have satisfactory outcomes. Older data, much of
which included AED polytherapy, indicated that barbiturates and phenytoin may cause
congenital heart malformations, orofacial clefts, and other malformations. From these data the
risk of neural tube defect with valproic acid and carbamazepine was estimated to be 0.5% to
1%, respectively, and appeared to be related to drug exposure during gestational days 0 to 28.
Other adverse pregnancy outcomes associated with maternal seizures, but not necessarily
caused by AEDs, are growth, psychomotor, and mental retardation. Women with epilepsy are
also more likely to have miscarriages, and 10% to 20% of infants are born with low birth weight.
Updated practice parameters are available to aid in the counseling and management of
pregnant women with epilepsy.
Although data exist which question the effectiveness of folic acid supplementation, it is
currently believed that some teratogenic effects may be prevented by adequate folate intake;
therefore, prenatal vitamins with folic acid (0.4 to 5 mg/day) should be given to any woman of
child-bearing potential who is taking AEDs.65 Also, that higher folate doses should be used in
women with a history of a previous pregnancy with a neural tube defect or taking valproic acid.
Higher AED doses and serum concentrations, polytherapy, and a family history of birth defects
appear to increase the teratogenic risk of AEDs. Deciding on the most effective single-drug
treatment prior to conception is vitally important. Current data strongly suggest that an
increased risk of adverse outcomes in women with epilepsy is due to teratogenic effects of AEDs
and not epilepsy since studies show that epileptic women who do not take AEDs have the same
risk of birth defects as infants born to control, seizure free women. The most concerning effects
are found with the use of valproic acid in the pregnant patient. Data gathered from pregnancy
registries and long-term studies suggest that valproic acid exposure is associated with a 1% to
2% risk of neural tube defects, a 10- to 20-fold increase over the general population, and an
increased risk of neurodevelopmental deficits, reduced verbal abilities,
and poorer attentional tasks; it appears that these effects are dose-dependent with major
congenital malformation risk significantly increasing at 600 mg/day and largest risk observed at
doses that exceed 1,000 mg/day. However, individual susceptibility is genetically determined,
and teratogenicity can occur at much lower doses in some persons. Data are still limited on the
newer agents, although topiramate may have a negative effect on birth weight and cause an
increase risk in oral cleft and hypospadias in the fetus.70 Some AEDs can cause neonatal
hemorrhagic disorder, which can be prevented by administrating 10 mg/day vitamin K orally to
the mother during the last month of pregnancy and/or administering parenteral vitamin K to
the newborn at delivery.
Most AEDs pass into the breast milk, and concentrations are measureable in breastfeeding
infants. In general, the degree of protein binding of a given AED allows for prediction of its
concentration in breast milk. AEDs with less protein binding accumulate more in breast milk.
Treatment with AEDs is not necessarily a reason to discourage breastfeeding. In fact, an
argument could be made that since AEDs should rarely be discontinued abruptly, breastfeeding
is a reasonable way to allow for a downward titration of a medication that the baby was
exposed to for the past 9 months. Infants born to women taking any AED (particularly
barbiturates or benzodiazepines) should be closely observed for signs of excess sedation,
irritability, or poor feeding.65 An ongoing multicenter observational study of breastfeeding
women taking AED monotherapy has failed to show significant cognitive effects in children
exposed in utero to various AEDs—carbamazepine, lamotrigine, phenytoin, or valproic
acid, although there was some negative effect on cognition noted for phenytoin.
The perimenopausal period can be associated with worsening of seizures. At menopause,
seizures often improve in frequency, particularly in women with a catamenial seizure pattern.
According to current data, conjugated equine estrogens plus 2.5 mg of medroxyprogesterone
acetate may increase the frequency of epileptic seizures. It is suggested that a combination of
single estrogenic compound such as 17-β-estradiol along with a natural progesterone should be
considered in women who need hormone replacement therapy for disruptive menopausal
symptoms.72 Data suggest that men with epilepsy have reduced fertility, and that
carbamazepine, oxcarbazepine, and valproic acid are associated with sperm abnormalities in
these men while levetiracetam appears to slightly increase serum testosterone.73 In addition,
valproic acid seems to cause testicular atrophy resulting in reduced testosterone volume.

Antiepileptic Drugs Dosing and Target Serum Concentration Ranges

Carbamazepine
Dosing and Administration The variable contributions of the 10,11-epoxide metabolite
and freecarbamazepine concentrations have restricted a precise definition of the therapeutic
range. Loading doses of carbamazepine are indicated only for critically ill patients. During
dosage titration, it must be remembered that carbamazepine clearance increases with time.
Doses may be started at one-fourth to one-third the anticipated maintenance dose and
increased every 2 to 3 weeks. Because of the autoand heteroinduction of carbamazepine
metabolism, it is necessary to administer the drug two to four times per day. Carbamazepine
tablets should not be stored in places where they would be exposed to high heat or high
humidity.
Advantages
Carbamazepine has been well studied. Oral solid and liquid dosage forms are available.
The oral solid dosage form is available as an immediate-release tablet, as a sustained-release
capsule, and a controlled-release tablet. The sustained-and controlled-release dosage forms
allow for twice-daily dosing to reduce the peak-to-trough fluctuations. Compared with other
first-generation AEDs, carbamazepine causes minimal cognitive impairment.
Disadvantages
Carbamazepine has an active metabolite that can contribute to efficacy and toxicity.
Other drugs can alter the concentration of this metabolite without changing the concentration
of theparent carbamazepine. It induces its own metabolism, which complicates dosage titration.
It also induces the metabolism of other medications, and other drugs may interact with it
and/or its active metabolite. There is no parenteral formulation. There are clinically meaningful
CNS side effects including sedation and nausea. One prospective study, however, found fewer
side effects with the sustained-release formulation compared to the immediate-release
formulation. When ingested during the first trimester of pregnancy, carbamazepine has been
associated with a slight risk of spina bifida. Chronic carbamazepine use has also been associated
with decreases in bone mineral density and 25-hydroxy (OH) vitamin D. The generic
formulations of immediate-release tablets have been associated with breakthrough seizures
when brands have been switched.
Place in Therapy
Carbamazepine is considered a first-line therapy for patients with newly diagnosed
partial seizures and for patients with primary generalized convulsive seizures who are not in an
emergent situation.

Clobazam
Dosing and Administration
Dosing is weight based, so patients who are less than or equal to 30 kg are started at 5 mg/day
and increased slowly to 20 mg/day, while those weighing more than 30 kg are started at 10
mg/day and increased slowly to 40 mg/day; doses greater than 5 mg should be given in two
divided doses. Dosing in geriatric patients is initiated as in patients weighing less than or equal
to 30 kg, but increased up to 40 mg depending on the weight of the patient. Poor metabolizers
of CYP2C19 are dosed like geriatric patients.
Advantages
Clobazam is a potent chlorinated benzodiazepine that is more efficacious than clonopin in the
treatment of Lennox–Gastaut. As with other benzodiazepines, tolerance can develop to its
effectiveness in treatment of epilepsy, however 30% of patients do not develop tolerance, so
the drug can often be used for years.
Disadvantages
It is a class IV controlled substance. Patients must be carefully weaned off the drug to avoid a
significant withdrawal symptoms. The drug is much less effective than clonazepam in treatment
of myoclonic jerks and absence seizures. There is no liquid or parenteral formulation available.
Place in Therapy
Adjunctive treatment of seizures associated with Lennox–Gastaut syndrome.

Gabapentin
Dosing and Administration
Typical starting doses of gabapentin are 300 mg at bedtime on the first day, increasing to 900
mg/day over 3 days. Faster titration rates (e.g., starting at 300 to 900 mg three times daily) have
been well tolerated.87 Data suggest gabapentin should be given at least four times a
day when the total daily dose is 3,600 mg or greater.88 It does not appear to be absorbed
rectally.
Patients with end-stage renal disease maintained on hemodialysis should receive an initial 300-
to 400-mg dose with 200 to 300 mg gabapentin given after every 4 hours of hemodialysis.
Advantages
Gabapentin has multiple mechanisms of action and is mechanistically different from first-
generation AEDs. It is not metabolized and is excreted unchanged by the kidney. It has a broad
therapeutic index with minimal CNS adverse effects and few drug interactions. Doses can be
escalated rapidly. It is available in liquid dosage form.
Disadvantages
Gabapentin is absorbed by an active process that saturates at higher doses. This may require
more frequent daily dosing for patients who need doses greater than 3,600 mg/day. Doses
exceeding the 3,600 mg/day maximum listed in the package insert may be required in some
patients to achieve seizure remission. There is no parenteral formulation.
Place in Therapy
Gabapentin is a second-line agent for patients with partial seizures who have failed initial
treatment. In addition, although monotherapy has no proven efficacy in previously diagnosed
refractory patients, it may have a role in patients with less severe seizure disorders, such as
new-onset partial epilepsy, particularly in the elderly. Gabapentin also has been shown to be
useful for chronic pain and other nonepileptic conditions.

Phenytoin
Dosing and Administration
Four oral dosage forms are available, and changing dosage forms can lead to changes in
phenytoin serum concentrations. Whether or not a dosage form uses the parent drug or salt
form should be considered when changing from one dosage form to another. One hundred
milligrams of phenytoin acid is equal to 92 mg of phenytoin sodium. Phenytoin capsules are
designated as immediate-release or extended-release. Only the extended-release capsules
should be used in once-daily dosing. Particle size rather than formulation may determine the
rate of absorption. If oral administration is not feasible, IV administration of phenytoin is
preferred, as IM administration can cause tissue necrosis. Fosphenytoin is a prodrug for
phenytoin and is available as a parenteral dosage form. Fosphenytoin is ordered in phenytoin
equivalents (PE), the actual dose of phenytoin acid desired. It is very water-soluble and is
converted rapidly to phenytoin systemically.
Fosphenytoin can be given rapidly IV and IM with reliable absorption and minimal pain. It is
significantly better tolerated than phenytoin. Because of saturable absorption, an oral loading
dose, such as 20 mg/kg, should be divided into four equal doses and given at 6-hour intervals.
Subsequent dosage adjustments should be done cautiously owing to its nonlinear elimination.
One author has suggested that if the serum concentration is less than 7 mcg/mL (28 μmol/L),
the daily dose should be increased by 100 mg; if the serum concentration is between 7 and 12
mcg/mL (28 and 48 μmol/L), the daily dose can be increased by 50 mg; and if the serum
concentration is greater than 12 mcg/mL (48 μmol/L), the daily dose can be increased by 30 mg
or less. These increases are reported to result in less than 10% of patients achieving a phenytoin
serum concentration greater than 25 mcg/mL (99 μmol/L).
Advantages
After more than 66 years, phenytoin’s risk-to-benefit ratio is well established. It is
available in oral solid, oral liquid, extended-release oral solid, and parenteral (phenytoin and
fosphenytoin) dosage forms, allowing flexibility in dosing and use in emergent situations. In
some patients, the extended-release dosage form can be given once a day with good seizure
control.
Disadvantages
Phenytoin displays Michaelis–Menten pharmacokinetics, meaning that the metabolism
saturates at doses given clinically thus complicating dose titration. Also, phenytoin is an inducer
of CYP450 isozymes, is metabolized by CYP450 enzymes, and is highly protein bound. Therefore,
many drug interactions are associated with coadministration of this agent. It also has multiple
significant adverse effects.
Place in Therapy
Phenytoin has long been a first-line AED for primary generalized convulsive and partial seizures.

Pregabalin
Dosing and Administration
Starting doses of pregabalin are divided into twice or thrice daily intervals. The manufacturer
recommends that patients with end-stage renal disease maintained on hemodialysis receive a
25 to 75 mg daily dose with 25 to 75 mg given after every 4 hours of hemodialysis.
Advantages
Pregabalin is somewhat more potent than gabapentin without the dose-limited GI absorption
properties. It has minimal CNS side effects and no drug interactions.
Disadvantages
It is a class V controlled substance. Like gabapentin it can cause weight gain and peripheral
edema, especially as the dose is increased. There is no parenteral formulation available.
Place in Therapy
Pregabalin is a second-line agent for patients with partial seizures who have failed initial
treatment. It is also useful for chronic neuropathic pain and generalized anxiety disorder

Valproic Acid/Divalproex Sodium

Dosing and Administration
Valproic acid in some patients may have a half-life long enough for
once-daily dosing with enteric-coated divalproex, but more frequent dosing is the norm. Based
on half-life data, twice-daily dosing is feasible with any valproic acid dosage form; however,
children and patients taking enzyme inducers can require dosing three to four times daily. The
serum concentration–dose relationship is curvilinear (e.g., the concentration–dose ratio
decreases with increasing dose) probably because of increasing free concentrations and a
resulting increase in clearance.
Valproic acid is available as a soft gelatin capsule, an enteric-coated tablet, a syrup, a “sprinkle
capsule,” an extended-release formulation designed for once-daily dosing, and an IV
formulation for replacement of oral therapy or in situations where rapid loading is necessary.
This parenteral formulation must not be given IM because it can cause tissue necrosis. The
sprinkle capsule, designed to be opened and mixed with food, has a slower rate of absorption,
which results in fewer fluctuations in the peak-to-trough ratio. The syrup is absorbed more
rapidly than any solid dosage form. The enteric-coated divalproex tablet is not sustained
release. It must be metabolized in the gut to valproic acid. The enteric coating reduces GI
distress. The enteric coating causes delayed absorption, although once the enteric coating
dissolves, sodium divalproex has absorption, metabolism, and elimination rates similar to those
of the gelatin capsule. If a patient is switched from Depakote to Depakote-ER, the dose should
be increased by 14% to 20%. Depakote-ER may be given once daily.
Advantages
Valproic acid is available in multiple dosage formulations. The IV formulation is especially well
tolerated. It has a wide therapeutic index and is considered a broad-spectrum AED. It is also
used in other neurologic or psychiatric disorders (e.g., migraine headache, bipolar disorder).
Disadvantages
Some patients report significant weight gain with valproic acid, which may limit compliance. It
has other side effects, such as alopecia, tremor, pancreatitis, PCOS, and thrombocytopenia. It
has been associated with hepatic necrosis in young children. As an enzyme inhibitor, it is
involved in multiple drug–drug interactions.
Place in Therapy
Valproic acid is first-line therapy for primary generalized seizures, including myoclonic, atonic,
and absence seizures. It can be used as both monotherapy and adjunctive therapy for partial
seizures, and it can be very useful in patients with mixed seizure disorders.