Download Adverse Effects of Antiepileptic Drugs

Epilepsia, 41(Suppl. 2):S42-S52, 2000
Lippiiicott Williams & Wilkins, Inc., Baltimore
0 International League Against Epilepsy
Adverse Effects of Antiepileptic Drugs
Robert S. Greenwood
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill,North Carolina, U.S.A.
Summary: Because the efficacies of antiepileptic drugs
(AEDs) are often equivalent, selection of an AED is often
determined by adverse effects. Differences in methods for labeling adverse effects and in the adverse effect terms themselves, variations in the populations studied, and inconsistent
classifications of adverse effects make it difficult to know how
to use information on adverse effects to choose an AED. Effort
is underway to develop more extensive and internationally acceptable descriptive terms for adverse effects. Comparison of
adverse effects in patients taking AEDs with adverse events in
control groups is helpful; however, data from controlled studies
are often lacking for most AEDs. Because of these limitations,
the clinician must adopt a preventative and early detection approach based on some general principles. This review outlines
factors to consider for avoiding and detecting AED adverse
effects. The occurrence of weight change with AEDs is reviewed extensively, serving to illustrate how the principle factors can be used to avoid and manage adverse effects and where
there is need for better studies of the short- and long-term
adverse effects of AEDs. Key Words: Antiepileptic drugsEfficacy-Adverse effects-Weight changes-GABA.
Recent attempts to develop better ways of choosing
antiepileptic drugs (AEDs) have placed emphasis on
the inclusion of adverse effects in the analysis. Doctors
who treat patients with epilepsy are now attempting
to develop methods of choosing AEDs that factor in
existing information about efficacy, adverse effects,
cost, and issues of administration (1,2). The efficacies
of AEDs are often found to be equal in comparative
studies; therefore, AED selection is largely determined by adverse effects (3). Definitions and measurements of adverse effects have been inconsistent and,
consequently, the methods by which adverse effects are
defined and detected are changing. The growing list
of new AEDs has also increased the need to compare AED risks. Although the dose-related adverse effects of new AEDs seem to be less, the new AEDs
have introduced new adverse effects that require added
vigilance during the chronic use. Adverse effects have
also become major factors in the overall cost of epilepsy treatment (4). For all of these reasons, it has been
difficult for the physician caring for patients with epilepsy to use adverse effects to help in the choice of an
AED.
DEFINITION OF ADVERSE EFFECTS
The definition and descriptive terms for adverse effects vary among AEDs. Several terms are used to describe health problems that arise in patients taking AEDs,
including “adverse events,” “adverse experiences,”
“problem rates,” “complaint rates,” “adverse effects,”
and “side effects.” The terms “adverse effects” and “side
effects” are often used in publications summarizing AED
adverse events. “Adverse events” and ‘‘adverse experiences” are used interchangeably to refer to the occurrence of an undesirable patient event during use of a
drug. These terms intentionally avoid implying a necessary cause-and-effect relationship between the use of the
drug and the event. The Food and Drug Administration
(FDA) has defined a reportable adverse drug experience
as “any adverse event associated with the use of a drug
in humans, whether or not considered drug related” (5).
They include adverse events that occur during the use of
the drug in professional practice or drug study, during a
drug overdose, as a result of drug withdrawal, and as a
result of the failure of “expected pharmacological action.” The FDA attempts to further classify these adverse
events as possibly, probably, or definitely related to the
use of the AED by using data from many different
sources and attempting to judge the importance of that
data.
The terminology used in the United States to describe
patient reports of adverse experiences in most clinical
trials of new AEDs comes from Coding Symbols for a
Address correspondence and reprint requests to Dr. Robert S. Greenwood at the Department of Neurology, University of North Carolina
School of Medicine, CB# 7025 Burnett-Womack, Chapel Hill, NC
27599, U.S.A.
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ADVERSE EFFECTS OF ANTIEPILEPTIC DRUGS
Thesaurus of Adverse Reaction Terms (COSTART), a
thesaurus of terms for describing patient complaints.
Studies vary widely in the use of COSTART terms and
how the complaints are obtained. The use of COSTART
is not universal, and a list of AED adverse effects may
include terms taken from other sources, such as the
World Health Organization’s Adverse Reaction Terminology (WHO-ART), International Classification of Diseases (ICD) 9, and ICD9-CM. To improve the terminology used to describe adverse effects, the FDA plans to
replace COSTART with the Medical Dictionary for
Regulatory Activities (MedDRA) (6). The International
Conference on Harmonization, an organization made up
of representatives of industry associations and regulatory
authorities in United States, Europe, and Japan, has
agreed upon the structure and content of the MedDRA
so that this terminology may be used internationally.
The descriptive terms used for adverse effects will be
expanded to nearly 10 times the 1,200 terms used in
COSTART, and MedDRA will have a hierarchical structure to allow greater specificity (6). Improvements in the
number of descriptive terms for adverse effects and international use of these terms will make it easier to compare adverse effects when selecting AEDs.
Variations in labeling adverse effects and the use of
different descriptive terms, as noted previously, create
problems in comparing adverse effects of AEDs. Another problem with current reports of adverse effects is
that objective quantifiable measures of most complaints
are not used frequently in studies of drugs. This also
makes comparisons of AED adverse effects among studies difficult. To allow better comparison of adverse effects, the terms “problem rates” and “complaint rates”
have been proposed by some doctors who treat patients
with epilepsy to summarize information on new AEDs
(2). The “problem rate” is the percentage of patients
taking an active drug or placebo that report an adverse
experience. The “complaint rate” is the problem rate for
patients receiving active treatment minus the problem
rate for patients receiving placebo. Use of the complaint
rate helps control for variations in patient populations
and data collection in different studies. The FDA also has
suggested the use of other statistical methods to allow
comparison of adverse effects from different studies.
Recommended statistical methods include relative risk
(cumulative risk on drugkumulative risk on comparison
drug or placebo) or attributable risk (cumulative risk on
drug - cumulative risk on comparison drug or placebo).
Unfortunately, as Cramer et al. (2) have noted, the lack
of uniformity of populations, terminology, methods for
collecting, and patient experiences and the absence of
formal methods for testing for adverse effects make comparisons of complaint rates, relative risks, and attributable risks among studies difficult. In addition, the designs of many studies, especially long-term studies, do
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not include a placebo group or a comparison drug. An
alternative method that may be used to compare adverse
effects when no comparison group is available is the
dropout rate. When the data are available, rate of dropout
due to adverse effects may allow better judgement of the
importance of dose-related or idiosyncratic adverse effects. Unfortunately, often these data are difficult to
compare in many AED studies because doses may be
lower than those used in clinical practice and the length
of study may be too short. Similar to the comparison of
AED efficacy, all of these problems make the comparison of AED adverse effects imperfect.
When considering adverse effects to choose an AED,
the clinician must consider each of the problems confounding the comparison of AED adverse effects. When
available, the difference between rates of adverse effects
in the AED group and placebo group and rates of dropout
may be the most reliable and comparable adverse effect
rates. The clinician should also remember that the true
incidence of adverse effects can be obtained only after
many years of AED use in a varying clinical setting.
CLASSIFICATION OF ADVERSE EFFECTS
The classification systems for AED adverse effects
provide the clinician with ways to remember different
adverse effects. AED adverse effect classification systems may also help the clinician prevent or treat adverse
effects. Table 1 lists several ways in which adverse effects have been classified. The classification “doserelated” or “idiosyncratic” is most commonly used, because it identifies the drug as the cause of the adverse
effect and, in the case of “dose-related,’’ implies that the
adverse effect will improve with dose reduction. Classification of adverse effects by organ system may help
identify organs that must be monitored clinically and
experimentally. Perhaps the most advantageous classification of adverse effects is based on the mechanism involved in the adverse effect. This classification scheme
suggests what organ systems to monitor for adverse effects and how to detect them as well as how adverse
effects may be treated. Unfortunately, the mechanisms
for most of adverse effects are so poorly understood that
most adverse effects can not be classified in this manner.
TABLE 1. Classifications of adverse events
FDA
Dose-related
Organ systems
Mechanism
Life-threatening, serious, unexpected
Dose-related, idiosyncratic
Cardiovascular, gastrointestinal and hepatic,
hematologic and lymphatic, endocrine/metabolic,
musculoskeletal, nervous system, special senses,
respiratory, dermatoiogic, genitourinary,
reproductive
Metabolickoxic, endocrine, immune, teratogenic,
oncogenic, apoptotic
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R. S. GREENWOOD
The confusing descriptive terms and varying classification schemes for adverse effects make it difficult to
know how to use this information to select an AED and
monitor a patient. Table 2 lists AED adverse effects that
are especially common or unique. This list is a starting
point for considering AED adverse effects. An efficient
way to extend the consideration of adverse effects in the
choice of an AED is by being aware of the windows of
susceptibility. Following is a discussion of some of the
most important factors to keep in mind when considering
the potential adverse effects of an AED.
IMPORTANT FACTORS TO CONSIDER IN
EVALUATING ADVERSE EFFECTS
Some AEDs worsen seizures
Many adverse effects of AEDs relate directly to their
therapeutic effects, as noted above. This includes doserelated adverse effects, and even some idiosyncratic adverse effects. AEDS may even increase seizure frequency or severity or change the seizure type (Table 3).
It may be difficult to be certain that an AED exacerbates
or worsens a seizure type, particularly with partial seizures, but accurate counts of seizures preceding the inTABLE 2. Especially common or unique adverse effects
of AEDs
Especially common or
unique adverse effects
Drug
Phenytoin
Barbiturates
Suximides
Carbamazepine and
oxcarbazine
Carbamazepine
Benzodiazepines
Valproate
Felbamate
Gabapentin
Lamotrigine
Topiramate
Tiagabine
Vigabatrin
Zonisamide
Cosmetic changes (gum overgrowth,
coarsening of facies, hirsuitism),
peripheral neuropathy, hypersensitivity
reactions
Behavioral changes and cognitive effects,
Dupytren’s contractures, peripheral
neuropathy
Hiccups, gastrointestinal problems,
visual changes
Hyponatremia
Leukopenia, drug eruptions
Sedation, hypersalivation
Weight gain, endocrine changes, tremor,
hair loss, thrombocytopenia,
hyperammonemia, hepatotoxicity,
pancreatitis
Anorexia and weight loss, insomnia,
aplastic anemia, liver failure
Hyperactivity or aggressive behavior in
children, weight gain
Skin rash
Cognitive problems (speech
disturbance), behavioral abnormalities,
kidney stones, paresthesias, anorexia,
weight loss
Tremor and nervousness, emotional
changes
Behavioral and psychiatric
disturbances: irritability, insomnia,
hyperactivity, psychosis and depression,
visual field defects and blindness
Kidney stones
Epilepsia, Vol. 41, Suppl. 2, 2000
TABLE 3. Antiepileptic drugs reported to increuse seizures
Antiepileptic drugs
Seizure type that increases
Carbamazepine, phenobarbital,
vigabatrin, gabapentin
Carbamazepine, vigabatrin,
gabapentin, lamotrigine
Carbamazepine, phenytoin,
vigabatrin
Carbamazepine
Absence
Myoclonic
Complex partial
Tonic-atonic
Information found in references 7 and 1 1.
troduction of a new AED may help the clinician identify
this adverse effect. AEDs that increase GABA levels
may worsen or exacerbate some generalized seizures (7).
Vigabatrin worsens myoclonic and absence seizures
(7,8), and worsening of myoclonic seizures also has been
noted with gabapentin (9) and with lamotrigine in the
treatment of severe myoclonic epilepsy of infancy (10).
Carbamazepine can increase absence seizures (7). Focal
seizures often increase when vigabatrin controls partial
seizure generalization (1 1). In many patients beginning
treatment with AEDs for control of partial seizures with
secondary generalization or complex partial seizures, seizure manifestations change as the seizures come under
control. Partial seizures with secondary generalization
may become complex partial seizures or simple partial
seizures, and complex partial seizures may evolve to
simple partial seizures. In one study, valproate treatment
of an adult with a hypothalamic tumor and seizures was
reported to result in confusion and increased spike and
wave activity that resolved when the medication was
discontinued (1 2). Pathological laughter, a common feature of seizures associated with hypothalamic tumors,
may occur with intravenous administration of valproate
(13); therefore, use of valproate in the treatment of these
types of seizures must be done with added care. Toxic
levels of some AEDs, such as phenytoin, can increase
seizures that were controlled initially (14). Psychosis as
a treatment-emergent effect with the start of vigabatrin
treatment has been correlated with a right-sided EEG
focus and seizure control and often with complete control of overt seizures (15,16). AED withdrawal, especially when abrupt, and especially with felbamate (17)
and vigabatrin (1 5), can also result in transient increase
in seizures or even status epilepticus. Because AEDs
may worsen seizures, one of the first considerations in
choosing an AED is the efficacy for the patient’s type of
seizure or epilepsy.
Age and sex
Age and sex are important factors in the occurrence of
adverse effects. Some of the endocrine and reproductive
adverse effects are obviously different for men and
women. There are some conspicuous examples of age as
an important factor in the occurrence of adverse effects
with other drugs. Increased drug toxicity in young pa-
ADVERSE EFFECTS OF ANTIEPILEPTIC DRUGS
tients occurs with the use of chloramphenicol in the newborn or tetracycline in infants and children. In contrast,
adults have greater toxicity from aminoglycosides. The
adverse effects of AEDs also vary with age. The growth
effects of AEDs are important in children but not in
adults. Elderly patients are not only more responsive to
AED therapy, but also are more likely to have doserelated adverse effects, often at lower drug concentrations (18). This reflects, in part, the pharmacokinetic
changes and lower serum albumin in elderly adults. Liver
volume, blood flow, and metabolism decrease with age
(19). Elderly adults or neurologically impaired infants
and children also may be more susceptible to some doserelated adverse effects, such as dizziness, because of preexisting neurological problems. Some types of seizures
(but not usually epileptic syndromes) in one age group
may be made worse by the same AED that controls them
in another age group. For example, vigabatrin reduces
myoclonic seizures of infancy (infantile spasms), and
yet worsens myoclonic seizures in older patients with
other types of epilepsy (7). Serious hematological complications are rare with AEDs but seem to be more common in older patients (20). In a cohort study of serious
blood dyscrasias in patients 10 to74 years of age who
were taking AEDs, the overall rate of blood dyscrasias
was 3 to 4 per 100,000 prescriptions. The rate in patients
<60 years of age was 2.0 (range 0.9 to 3.6) per 100,000
prescriptions, compared with 4.0 (range 1.6 to 8.2)
per 100,000 prescriptions for patients >60 years of age
(20). The high rate of aplastic anemia in older patients
treated with felbamate seems to be less in children (21).
Infants and young children, however, are at greater risk
for other adverse effects. The occurrence of StevensJohnson syndrome was higher in patients taking AEDs
who were <18 years of age (22). Children <2 years of
age are at greater risk for hepatotoxicity associated with
valproate (23). Instances where infants and children
have a greater susceptibility to an AED adverse effect
often are related to inherent susceptibility, which is another factor that should be considered when evaluating
AEDs.
Inherent susceptibility
Inherent susceptibility refers to genetic differences in
some patients with epilepsy that predispose them to an
AED adverse effect. Some of the most obvious of these
are found in the contraindications listed in the drug insert
for each AED. One of the most prominent examples of
inherent susceptibility is porphyria. The AEDs that induce hepatic metabolism may precipitate a worsening of
symptoms in patients with porphyria. In some instances,
this may even include exacerbation of seizures. Other
inherent susceptibilities, such as the disorder that increases the rate of valproate hepatotoxicity with the use
of valproate in children <2 years of age, are not as ex-
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plicit. This increased susceptibility to valproate hepatotoxicity in children may in part reflect underlying energy
metabolic defects (24,25). Valproate interferes with mitochondrial metabolism through mechanisms that sequester coenzyme A or inhibit mitochondrial P-oxidation
enzymes. Severe impairment of mitochondrial p-oxidation can lead to microvesicular steatosis, liver failure,
coma, or death (26). Even in adults with fatal hepatotoxicity, proven or suspected mitochondrial disorders have
been more common (27). Variation in the regulation and
expression of the drug-metabolizing enzymes may also
play an essential role in both interindividual variation in
sensitivity to drug toxicity and tissue-specific damage
(28). Genetic or environmental impairment of cytochrome P450 activity may lead to toxicity. Active metabolites produced by cytochrome P450 enzymes may
cause a variety of pathologic effects, including cellular
necrosis, hypersensitivity, teratogenicity, and carcinogenicity (28). The leading hypothesis for the pathogenesis
of AED hypersensitivity reactions is that the AED is
oxidatively metabolized to reactive-cytotoxic intermediates that interact covalently with cellular macromolecules to form haptens (29). In this scheme, the haptens
are immunogenic but the original AED is not. Unfortunately, no identifiable differences in detoxification pathways or immune effectors that predict susceptibility to
hypersensitivity reactions have been identified (30). Efforts to determine the inherent susceptibilities for many
of the serious adverse effects of AEDs are underway.
Continued advances in genetics and molecular biology
may lead to ways of identifying patients susceptible to
AED adverse effects so that we can avoid exposing them
AEDs or take measures to counteract susceptibility to
adverse effects. For now, the clinician must depend on
clues from the patient’s history and family history to
suspect an inherent susceptibility.
Importance of preexisting conditions
Many diseases increase the risk of AED adverse effects. In some cases, preexisting conditions are simply a
version of the propensity wrought by an inherent susceptibility. In other cases, the increased susceptibility comes
from acquired diseases. Dose-related and idiosyncratic
adverse effects may occur at greater rates with preexisting conditions. Patients with hepatic disease that reduces
protein synthesis are more likely to develop adverse effects with drugs that have high protein binding, such as
phenytoin and valproate. In addition, AEDs that are primarily detoxified in the liver, such as barbiturates, phenytoin, suximides, carbamazepine, felbamate, lamotrigine, tiagabine, valproate, and benzodiazepines,
may rise to toxic levels in patients with liver disease. For
patients with liver disease, these drugs offer greater risk
and may not be the first choice, or doses may require
close monitoring. To avoid dose-related adverse effects
Epilepsra, Vol. 41, Suppl. 2, 2000
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R. S. GREENWOOD
in patients with renal disease, doses of AEDs with predominantly renal excretion, such as gabapentin and topiramate, must be reduced or the AED should be avoided.
Some idiosyncratic AED adverse effects have occurred
at high rates in patients with preexisting systemic illnesses. Patients with aplastic anemia during felbamate
treatment frequently have prior histories of immunemediated disorders, drug rashes, and autoimmune disease (31,32). Patients who have had prior drug rashes are
more likely to develop AED rashes. This phenomenon of
cross-reactivity is most obvious in the increased risk of
worsening or recurring AED rash after a drug rash from
a prior AED. Drug allergy cross-reactivity among many
of the aromatic AEDs, such as phenytoin, phenobarbital,
primidone, and carbamazepine, may be as high as 70% to
80% (33). Among the new AEDs, lamotrigine has one of
the highest incidences of immune-mediated drug eruptions. Lamotrigine has an aromatic ring structure. The
drug eruptions with lamotrigine are similar to those that
occur with other AEDs, raising the possibility that there
could be some cross-reactivity between lamotrigine and
aromatic AEDs (34). Valproate has not been reported to
have cross-reactivity with other AEDs and is rarely associated with immune-mediated adverse effects (34) and
thus may be the AED of choice during some immunemediated adverse effects. Some studies have suggested
that patients with brain tumors who receive radiation
therapy may be at greater risk for allergic skin reactions
to AEDs (35,36). In one case, the eruption during phenobarbital treatment was limited to the sites of radiation
(36). Another study of skin eruptions in patients with
brain tumors receiving cranial irradiation suggested that
factors related to the brain tumor may increase the risk of
skin eruptions with the use of AEDs. In this study, mild
rashes occurred in 18% of exposures to AEDs, including
22% of exposures to phenytoin, compared with the expected rate of 5% to 10% (37). Most of these rashes
occurred before initiating cranial irradiation. AED rashes
were especially likely when steroids were being tapered.
These examples represent only a few of the conditions
that increase the frequency or severity of AED adverse
effects. In general, the use of AEDs requires the greatest
caution in the patients with the most preexisting conditions.
Greatest risk for adverse effects is at start
of treatment
Most AED adverse effects occur at the start of AED
treatment, often because of the predisposing factors previously noted. Dose-related adverse effects are more
prominent at the start of treatment and often improve or
even resolve over time without a change in AED dose.
The dose-related adverse experience rates available from
clinical trials are some of the most difficult to interpret.
Not only do the reports vary for reasons cited previously,
but studies of AEDs in early clinical trials were designed
with incomplete knowledge of potential AED adverse
effects or effective AED doses. In controlled trials of
AEDs that study different doses, many adverse effects
have been shown to be dose related. These types of studies may help provide guidance in choosing doses to
avoid adverse effects. Weighing the importance of a
dose-related adverse effect, however, is one of the arts
of medicine. Tolerance and adaptation to dose-related
AED adverse effects will vary widely among patients for
many reasons, which include not only medical factors
but also the patient’s culture, marital status, need for
specific high levels of function, expectations, and financial concerns,
Some of the most important idiosyncratic reactions
also occur at the start of AED treatment. Idiosyncratic
reactions after the start of treatment, such as hypersensitivity reactions and hepatic adverse effects, are most
likely to occur within 2 to 8 weeks (33). Because many
adverse effects occur most frequently at the start of treatment, clinicians should be most vigilant during this time.
Patients and their families should be instructed to be
particularly vigilant about looking for adverse effects
during the first weeks of a new AED treatment and
should be encouraged to contact the physician quickly if
they have concerns about an adverse effect so that the
severity of these complications may be reduced.
Rapid dose changes, high AED doses,
polypharmacy, and other treatments increase risk
of adverse effects
Many AED adverse effects, especially dose-related,
are more frequent and severe when AEDs are initiated
rapidly or administered at high doses. Loading with
AEDs, as occurs during the treatment of status, will invariably increase dose-related adverse effects. Doserelated adverse effects of AEDs may occur in individual
patients even when AED levels are within a therapeutic
range. This problem arises, in part, because therapeutic
blood levels are statistical best estimates of the AED
levels that produce toxic effects and are often derived
from small samples of patients. Even adverse effects that
do not seem directly related to the antiepileptic effect of
an AED, such as thrombocytopenia with valproate treatment, are dose related (38). Dose-related adverse effects
also often increase when multiple AEDs are combined.
The use of other drugs or coadministration of two or
more AEDs may also increase the toxicity of an AED.
Pharmacokinetic interactions and changes in pharmacodynamics are common when antiepileptic drugs are used
together (39) or when coadministered with other medications. Drug interactions are listed in the drug inserts to
warn the physician about the risks of drug interactions.
Many AEDs are metabolized in the liver and cause induction or inhibition of liver enzymes. Carbamazepine,
ADVERSE EFFECTS OF ANTIEPILEPTIC DRUGS
phenobarbital, phenytoin, and primidone induce some
liver enzymes, whereas valproic acid inhibits them (40).
Other drugs (e.g., aspirin, tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine, and
tianeptine) that interfere with mitochondria1 metabolism
in a manner similar to valproate may enhance valproate
hepatotoxicity (26).
Idiosyncratic adverse effects often increase with polypharmacy or rapid dose escalation. Polypharmacy is associated with an increased risk for valproate hepatotoxicity (41) and aplastic anemia during felbamate treatment
(3 1,32). The use of valproate with lamotrigine and rapid
lamotrigine dose escalation greatly increases the risk of
skin eruptions (22). In general, adverse effects can be
avoided or severity can be reduced by slowly increasing
the AED dose and avoiding polypharmacy.
This review of AED adverse effects is only a broad
overview of a very complex topic. The issues and factors
reviewed can be used in conjunction with the lists of
AED adverse effects available from a variety of sources,
such as drug inserts and Physicians’ Desk Reference.
Detailed reviews of AED adverse effects can also be
found in recent volumes of standard epilepsy books (4247). What follows is a description of one adverse effect:
weight changes that accompany the start of treatment
with an AED.
NEW ATTENTION TO WEIGHT CHANGES AS
AED ADVERSE EFFECT
Doctors who treat patients with epilepsy recognize
that limiting AED adverse effects is one of the most
important goals in optimal treatment of epilepsy. Recently, studies of weight changes in patients taking
AEDs and studies attempting to define the mechanisms
that account for these changes have appeared. These
studies are an example of approaches to understanding,
preventing, and managing adverse effects that consider
many of the factors discussed in the preceding section.
These studies also emphasize the importance of age, sex,
drug dose, preexisting conditions, and inherent susceptibility to body weight changes associated with AEDs.
Studies of weight changes show how the antiepileptic
properties of AEDs may play a direct role in an adverse
effect usually considered idiosyncratic. A review of the
mechanisms for regulation of body weight will follow,
providing a framework for understanding how AEDs and
seizures might affect body weight.
Regulation of body weight
Much is known about the control of body weight.
Some mechanisms for weight control implicate pathways, neurotransmitters, and receptors that could be influenced by AEDs. The control of body weight and mass
involves multiple mechanisms. Body weight changes depend on the balance of caloric intake and energy ex-
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pended. The brain integrates information from many afferent inputs and circulating factors to regulate food intake and energy expenditure. The hypothalamus is the
principle site of this integration (Figure 1). Signals arising from food ingestion and metabolism and social and
emotional influences, acting through the brain stem and
limbic system, impinge on the hypothalamus where they
influence eating and energy expenditure. Energy metabolic rate and activity level influence caloric expenditure. Figure 1 illustrates the hypothalamic nuclei involved in regulating food intake, energy expenditure, and
intrinsic and afferent pathways and messengers that influence these nuclei. Afferent pathways and circulating
neuromodulators influencing caloric intake include olfactory and oral special and somatic sensory input, stomach and intestinal stretch receptors input, CCK and other
neuropeptides released from the intestinal tract acting
through the vagal nerve afferents, glucose levels affecting glucose-sensitive neurons in the brain and gut, and
leptin and glycerol released from adipose tissue to act on
the lateral hypothalamus (48). Serum leptin and glycerol
concentrations are correlated with the percentage of body
fat (49). Two areas of the hypothalamus integrate the
afferent signals to regulate feeding patterns: the lateral
hypothalamus and the medial hypothalamic nuclei. Caloric balance may be altered, with ventromedial lesions
causing hyperphagia and lateral hypothalamic lesions
producing a syndrome of aphagia and weight loss in
experimental animals (50). From these types of studies,
the medial hypothalamic region has been designated the
“satiety center” and the lateral hypothalamic region the
“feeding center.”
Neurotransmitters, neuromodulators, and hormones
influence the activity of the neurons in the hypothalamus.
y-aminobutyric acid (GABA) and neuropeptide Y increase carbohydrate consumption and reduce energy expenditure (51). Serotonin acts on the medial hypothalamus to reduce food ingestion. Dietary increases in carbohydrates increase 5-HT levels. Norepinephrine, when
injected in the paraventricular nucleus, elicits eating behavior, whereas injection of dopamine or P-adrenergic
drugs in the lateral hypothalamus reduces feeding.
Caloric expenditure is influenced by basal metabolic
rate, thermogenesis, and physical activity. Basal metabolism is influenced by inherited traits, some of which may
be specific to the caloric substrate (fat, sugar, or protein)
or involve hereditary alterations in leptin or glucoseresponsive neurons. Activity level is affected by social
and emotional factors, level of consciousness, and fatigue. Changes in metabolic rate are also influenced by
circulating hormones and growth factors, especially thyroid hormone and insulin-like growth factors. The satiety
and feeding centers of the hypothalamus and other areas
of the brain important in regulation of body weight can
be affected indirectly or directly by anticonvulsants.
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R. S. GREENWOOD
FIG. 1. This diagram illustrates the hypothalamic nuclei that integrate input from many afferent pathways (solid arrows) and from circulating substance (dashed arrows). The hypothalamus receives and sends messages from
many brain stem and spinal cord nuclei as well
as from the limbic system and cerebral cortex.
The nucleus tractus solitarius in the brain stem
plays a pivotal role in transferring information
from the autonomic system and sensory
stimuli received through cranial nerves (CN) to
the hypothalamus and limbic system. In a simplified view of the hypothalamus, the efferent
activity of the ventromedial nucleus (VMN)
and paraventricular nucleus (PVN) inhibit
feeding, whereas the efferent activity coming
from the lateral hypothalamic nuclei (LHN)
predominantly activates feeding behavior. The
neurotransmitters y-aminobutyric acid
(GABA) and norepinephrine (NE) increase
feeding (t).In the case of NE, intake of carbohydrates (CHO) is primarily increased. The
neurotransmitters, serotonin (5-HT) and dopamine (DA), have been shown to primarily reduce feeding (J). Neuropeptides that affect
the hypothalamus to influence feeding include
vasopressin (VP), proopiomelanocortin(POMC),cholecystokinin (CCK), and gastrin-releasing peptide (GRP) that reduce feeding. Feeding is increased by the neuropeptides, neuropeptide Y (NPY), agouti-related peptide (AGRP), and galanin (GAL), but NPY increases CHO
intake whereas GAL increases fat intake. Leptin is thought to act on the LHN to inhibit feeding behavior, but receptors ( + ) for leptin are
found in many nuclei of the hypothalamic and limbic system. The hypothalamus also contains glucose-sensitive neurons (GSNs) located
predominantly in the LHN and glucose responsive neurons (GRNs) located predominantly in the nuclei of the medial hypothalamus.
Glucose reduces the activity of GSNs ( 0 )and increases the activity of GRNs perhaps thereby leading to a reduction in feeding behavior.
Amino acid-sensitive neurons in the APC also act to inhibit feeding in response to elevation of circulating amino acids (AA). Other
circulating factors that affect feeding behavior include enterostatin, glucagon-like peptide-1 (GLP-l), glucocorticoids, and insulin. APC,
anterior piriform cortex; DMNIVMN, dorsomedial nucleus and ventromedial nucleus; LHN, lateral hypothalamic neurons; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; 3rd Vent, third ventricle.
AED-associated weight changes
Weight gain and weight loss in children and adults are
disturbing general health and cosmetic adverse effects.
Both weight gain and weight loss have been associated
with AEDs (Table 4) and may involve some of the same
pharmacological mechanisms that play a part in seizure
control (Figure 1, Table 5). Weight changes may also
play a role in the occurrence of other adverse effects,
such as polycystic ovaries in women taking valproate
(52). Weight changes are chronic adverse effects that
usually appear slowly, and they can easily be overlooked
by physicians unless careful measurements are done at
regular intervals. Excessive weight gain can be measured
by anthropometric parameters; body mass index (BMI) is
most commonly used. BMI is calculated from the body
weight in kilograms divided by the square of body length
in meters. In persons >19 years of age, obesity is often
defined as BMI equal to or greater than 27.8 for men and
27.3 for women. In adolescent boys, obesity is defined as
BMI equal to or greater than 23.0 for ages 12 to 14 years,
24.3 for ages 15 to 17 years, and 25.8 for ages 18 to 19
years. In adolescent girls, obesity is defined as BMI
equal to or greater than 23.4 for ages 12 to 14 years, 24.8
for ages 15 to 17 years, and 25.7 for ages 18 to 19 years
(53). The 85th percentile is used as the upper limit for
normal weight; obesity is ~ 1 2 0 %of desirable body
weight. Actual measurement of body fat content is a
more precise way to characterize obesity, but this measurement is too difficult to do on a routine basis. Regular
measurements of body weight and length and, in some
cases, calculation of BMI provide a quantitative way to
monitor an adverse effect that has great impact on quality
of life. These measurements should be done as part of the
TABLE 4. A. AEDS associated with weight gain
Patients with weight gain
Drug
Gabapentin
Adults
Children
Adults
Vigabatrin
Adults
Valproate
Children
Carbamazepine
7% to 73% (60)
10% to 44% (60)
8.8% (75)
3% to 46% (76)
7% in clinical trials (4% in
placebo group) (75)
5.7% (77)
29% to 43% (60,78)
B. AEDs associated with weight loss
Patients with weight loss
Drug
Felbainate
Adults
Children
Topiramate
Adults
Children
3.4% (79)
4% (81,82)
6.5% (79)
2% (80)
4.4% to 15% (84)
9.2% (83)
ADVERSE EFFECTS OF ANTIEPILEPTIC DRUGS
TABLE 5. Potential mechanisms of AED-associated
weight gain
Drug
Valproate
Neurotransmitter
mechanisms
GABA
Catecholamines
Gabapentin
Vigabatrin
Carbamazepine
Tiagabine
Metabolic mechanisms
1. Decreased @-oxidation of
FFA and gluconeogenesis,
secondary to carnitine
deficiency
2. Decreased palmitate binding
3. Lower blood glucose
GABA
GABA
GABA
NE 5-HT
GABA
GABA, y-aminobutyric acid; FFA, free fatty acid; NE, norepinephrine.
monitoring of patients with epilepsy to detect changes
before there are serious adverse consequences.
A list of AEDs reported to produce weight gain and
weight loss is given in Table 4. The true incidences of
these complications are hard to determine in most studies. Some data in Table 4A come from studies with small
sample sizes and imprecise measurements and definitions, resulting in a large range of percentage of patients
who gain weight. Even in controlled drug trials, study
duration is usually not sufficiently long to detect anything other than large changes in weight. Conversely,
tolerance to an AED may extend to weight changes,
causing weight to change during the early phases of AED
treatment and then stabilize or return to pretreatment
values. All these factors indicate that values for weight
change must be viewed primarily as relative and applicable only to the populations from which they were derived.
AED weight gain
The drugs most clearly associated with weight
changes are valproate and felbamate (Table 4). Valproate
causes significant weight gain in many patients, and felbamate causes weight loss. Weight loss associated with
felbamate will be discussed below. Weight gain with
valproate exceeds that of any other AED associated with
weight gain in comparative trials (52,54). In one study,
women who gained weight with valproate treatment lost
weight when switched to lamotrigine (55). Weight gain
has been associated with a significant increase in BMI
(52,56) and has been reported in children and adults
treated with valproate (52,57). In children, increase in
weight and BMI has been significantly positively correlated with initial weight (57). Weight gain has been
shown to be significantly greater in prepubertal and pubertal women taking valproate than in age-matched control. In contrast, weight gain in patients taking carbamazepine and oxcarbazepine has not been shown to be significantly greater than that in healthy control girls (58).
s49
In a retrospective study of 260 children taking carbamazepine or valproate, however, no significant difference in
weight gain was noted, although there were more reports
of weight gain as an adverse effect in children treated
with valproate (59,60). Weight gain associated with valproate does not seem to abate with continuation but may
improve with dosing modification or dose reduction
(59,61). No correlation has been found between weight
gain and serum concentration, drug dose, appetite, or
family history (61). In one prospective study, weight loss
and a significant decrease in BMI occurred when patients
treated with valproate changed to lamotrigine (55). In a
study of patients with juvenile myoclonic epilepsy,
weight loss did not occur after changing to lamotrigine
(62). Overall, most studies indicate that valproate can be
expected to cause weight gain that may result in significant obesity. This seems to be especially likely in older
children and adults.
Weight gain with valproate treatment may have additional significant associations or effects, some of which
may be related to the pathogenesis of weight gain.
Isojarvi and colleagues have studied weight change in
women and children taking AEDs (52,55). In one retrospective study, they compared weight gain in women
taking no AEDs, carbamazepine, and valproate (52).
Obesity was found in 59% of women taking valproate,
25% taking carbamazepine, and 21 % of controls. Polycystic ovaries were found in 71% of women with obesity
taking valproate but only 13% of the women without
obesity taking valproate. Isojarvi et al. also found that
these women had high concentrations of fasting serum
insulin and low levels of serum insulin-like growth factorbinding protein 1. In a subsequent study ( 5 3 , Isojarvi et
al. showed that a decrease in weight, body-mass index,
and fasting serum insulin and a reduction of polycystic
ovaries followed a change from valproate to lamotrigine.
In a study by Rattya et al. (58) of prepubertal and pubertal girls taking valproate, carbamazepine, or oxcarbazepine, there was no change in fasting serum insulin,
IGF-binding protein- 1, or IGF-binding protein-3 concentrations. In this same study, plasma insulin-like growth
factor-I (IGF-I) levels were higher in girls treated with
CBZ and OXC than in girls who served as controls, but
these girls did not show excessive growth, which is the
expected effect of elevated IGF- 1.
Other AEDs are associated with less weight gain
(Table 4A) and often only pose a problem at the start of
medication. Weight gain is less common in patients
treated with gabapentin, and previous weight gain in patients taking AEDs does not predict weight gain with
gabapentin. It has been noted that higher dosing increases the likelihood of weight gain. Weight gain with
gabapentin may not plateau and continue beyond the first
year. Weight gain with vigabatrin treatment has been a
consistent finding in most studies. In a study comparing
S50
R. S. GREENWOOD
vigabatrin with carbamazepine (59), vigabatrin was more
likely to be tolerated and had fewer withdrawals, but it
was more frequently associated with weight gain (25 lb
[11%] vs. 12 lb [5%]). The VA comparative study (54)
also showed that weight gain with carbamazepine is less
than that with valproate. In this prospective, blinded
study, weight gain of <5.5 kg (12 lb) was found in 20%
of patients taking valproate versus 8% of patients taking
carbamazepine (p < 0.001). Weight gain with carbamazepine treatment has been a consistent finding in most
studies, however. Weight gain with carbamazepine is
more gradual than with valproate, and increased appetite
and excessive food intake may account for increase in
weight (63). Carbamazepine may cause mild weight
gain, but there is not an untreated group of patients with
seizures to use for comparison, and so it is difficult to be
confident about this conclusion. Weight gain occurs in
patients with seizures who take carbamazepine, gabapentin, and vigabatrin. The weight gain with vigabatrin
seems to be a problem, perhaps exceeding that of carbamazepine. It is still uncertain if the weight gain associated with gabapentin is a significant problem.
AED weight loss
Felbamate and topiramate are the principle AEDs associated with weight loss (Table 4B). Felbamate causes
weight loss more frequently than other AEDs. Weight
loss may occur in most children taking felbamate, but it
may be transient, diminishing over time (64). In one
study of 65 patients, who took felbamate for an average of
23 weeks (65), 75% lost weight. Weight loss was greater
in adults than in children (4.1% vs. 1.8%, respectively).
Weight loss associated with topiramate was greater with
higher doses of topiramate and was usually transient
(66). In one study of topiramate (67), weight loss was
noted early, peaked at 15 to 18 months, and was followed
by a slow weight gain. Weight loss was greatest in
women and patients who weighed the most at the start of
treatment. In summary, weight loss with felbamate and
topiramate can be significant enough to lead to discontinuation of these AEDs, but in most instances, weight
loss is minimal and transient.
Potential AED mechanisms influencing regulation
of body weight
Table 5 lists possible ways AEDs could affect hypothalamic regulation of body weight. Experimental evidence is beginning to appear that addresses the pathogenesis of weight changes in patients taking AEDs. The
weight gain associated with valproate has been studied
most widely. Lower blood glucose in patients taking valproate has been proposed as one mechanism that could
lead to obesity. The elevated insulin levels found in
women could lead to stimulation of eating through the
effect of low glucose on glucose responsive neurons in
the medial hypothalamus (52). Valproate could also
lower glucose through impaired gluconeogenesis. Valproate reduces carnitine levels, which could impair fatty
acid metabolism and gluconeogenesis and increases glucose consumption. According to this hypothesis, the neurons in the medial hypothalamus respond to low glucose
levels, reduce the efferent inhibitory output to the lateral
hypothalamus, and thereby increase feeding (Figure 1).
Hyperinsulinemia has been found in women taking valproate (52), but elevated insulin levels were not found in
pubertal and prepubertal girls who gain weight with valproate (58). These results do not support a role for insulin
and low glucose in the pathogenesis of valproate obesity
in pubertal and prepubertal girls. Valproate could also act
to increase appetite and reduce energy expenditure by
enhancing GABA-mediated inhibition in the medial hypothalamus. Valproate has been shown to enhance
GABA-mediated inhibition, but only at high drug concentrations (68). Valproate also increases whole-brain
GABA levels (68). Circulating catecholamines increase
in patients taking valproate, and this increase could decrease thermogenesis. Breum et al. (69), however, did
not find evidence for greater thermogenesis in their study
of patients taking valproate. Short-term clinical studies
have not provided support for any of the proposed
mechanisms for weight gain in patients taking valproate.
No change in appetite or thirst has been found in patients
who gain weight with valproate (59,61). Breum et al.
(69) did not find any difference in total energy intake or
macronutrient selection, energy expenditure, or thyroid
hormones. The exact mechanism for weight gain with
valproate requires additional study.
Verotti et al. (70) found an increase in serum leptin in
women who began valproate treatment and subsequently
gained weight. Serum leptin increases with increase in
weight and number of fat cells; therefore, this result is
not surprising. Because leptin-receptor defects in animals
are associated with obesity, an alternative explanation
might be that these women were predisposed to obesity
by a preexisting deficient response to leptin. The baseline
leptin levels of women who gained weight with valproate
were not different from those of women who did not gain
weight with valproate. These data, therefore, would not
support a preexisting abnormality in leptin response.
The mechanisms of weight gain with gabapentin and
vigabatrin could reflect enhancement of GABAmediated inhibition in the medial hypothalamus. As
noted in Figure 1, GABA injections in the hypothalamus
seem to increase food ingestion. Opposing this explanation, however, is the finding that weight loss, rather than
weight gain, occurs with tiagabine, another AED known
to increase GABA-mediated inhibition. Similar to the
therapeutic effects of AEDs, the regional variations in
the effects of different AEDs on GABA may influence
their effect on appetite or caloric expenditure. Because
carbamazepine is related to tricyclic antidepressants, the
ADVERSE EFFECTS OF ANTIEPILEPTIC DRUGS
effects of carbamazepine on weight could relate to its
effects on noradrenaline or serotonin neurotransmission.
Weight loss with felbamate and topiramate could relate to the glutamate-blocking effect or their multiple
sites of action to potentiate GABA-mediated responses
and block glutamate neurotransmission (7 1). The effect
of glutamate antagonists on feeding has been variable,
depending on the site tested and the type of glutamate
receptor blocked (72-74). Currently, there are insufficient data about the effects of these drugs on the hypothalamus or other areas of the brain that mediate feeding
and hunger to know how these drugs reduce weight.
These studies of weight change in patients treated with
AEDs illustrate how we can begin to better define the
risk factors for the development of adverse effects and
uncover their mechanisms. These studies have benefited
from quantifiable measures and comparisons of patients
taking different AEDs as well as comparisons with
healthy patients. It is hoped that prospective, comparative studies of other adverse effects will be done in the
future. With a better understanding of the circumstances
in which each adverse effect occurs, we may be able to
determine the mechanisms that mediate the adverse effects and ultimately find ways to prevent them.
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