T.D.’s parents should be informed that nausea or sedation may occur with
initiation of ethosuximide. Tolerance to these effects usually develops, although
temporary dose reductions may be necessary.
Generalized Tonic–Clonic Seizures Accompanying
CASE 60-7, QUESTION 3: Three months later, T.D.’s absence seizures have been reduced to a frequency
of one every 2 weeks with an ethosuximide dosage of 750 mg/day. Her initial drowsiness has almost
confusion and drowsiness were significant. Physical examination and laboratory testing showed no
It is commonly believed, and often stated in the literature, that ethosuximide may
precipitate or worsen tonic–clonic seizures;
however, this effect has not been clearly demonstrated. As many as 50% of
patients who initially present with absence seizures also experience tonic–clonic
128 Historically, it had been common practice to add another AED (e.g.,
phenobarbital or phenytoin) to ethosuximide therapy to prevent this.
routine use of drugs for prophylaxis of tonic–clonic seizures may increase the risk of
toxicity and potentially reduce adherence with medication regimens. Sedative drugs,
especially phenobarbital, actually may aggravate absence seizures in some
In summary, subsequent generalized tonic–clonic seizures are common in patients
who initially experience absence spells. It is unlikely that ethosuximide played a
causative role for this development in T.D.
ASSESSMENT REGARDING NEED FOR ALTERATION IN
ANTIEPILEPTIC DRUG THERAPY AND CHOICE OF ALTERNATIVE
of generalized tonic–clonic seizures?
Drug therapy for prevention of further tonic–clonic seizures is indicated.
Phenytoin, carbamazepine, or valproate might be considered for use in T.D. Owing to
her age and sex, many clinicians would avoid using phenytoin because of its
dysmorphic and cosmetic side effects. Carbamazepine is widely used for secondarily
generalized tonic–clonic seizures and some cases of tonic–clonic seizures in
children. It lacks many of the troublesome, common side effects associated with
phenytoin. Carbamazepine, however, is not effective for control of absence seizures.
Therefore, it is likely that both ethosuximide and carbamazepine would be needed by
T.D. Carbamazepine also has been associated with exacerbation of seizures
(including atonic, myoclonic, and absence seizures) in children with mixed seizure
disorders who exhibit bilaterally synchronous 2.5- to 3-Hz discharges on the
132 The need for polytherapy and the possible risk of seizure exacerbation
make carbamazepine a less attractive treatment option for T.D.
Valproate is effective for controlling both absence and primary generalized tonic–
51 T.D. appears to have primary generalized tonic–clonic
convulsions; focal signs (e.g., unilateral or single limb involvement) were not
observed, and focal discharges (e.g., isolated abnormal electrical activity localized
to one portion of the brain) were not found on the EEG. Although neither observation
completely rules out secondarily generalized tonic–clonic seizures, the likelihood
seems low. Therefore, valproate may offer advantages over carbamazepine in terms
of efficacy. In addition, both of T.D.’s seizure types potentially could be controlled
Techniques used by clinicians to substitute one AED for another depend largely on
experience and judgment. Generally, it is best to attain a potentially therapeutic dose
of a new medication before attempting to discontinue the previous drug. Serum
concentration monitoring may be helpful for some AEDs. Ethosuximide has a
relatively long half-life, whereas valproate’s half-life is short. Therefore, if
necessary, steady state serum concentrations of valproate can be established and
evaluated rapidly; evaluation of the effect of decreases in the ethosuximide dosage
must await the prolonged elimination of this drug. Once a desired valproate dose or
serum concentration has been achieved, the ethosuximide dosage can be reduced
gradually by 250 mg/day every 2 to 4 weeks.
Valproate should be initiated at 125 to 250 mg twice daily. Valproic acid syrup or
capsules or divalproex sodium can be used. Divalproex often is preferred because it
may cause fewer GI side effects than valproic acid. Syrup forms of valproate
probably should be avoided unless extremely small doses are required (e.g., infants)
or patients cannot swallow. Valproate syrup has an unpleasant taste, and its rapid
absorption increases the likelihood of acute, dose-related side effects such as nausea.
Lower initial valproate doses are less likely to cause acute side effects (e.g.,
drowsiness and GI upset). Weekly dosage increases of 5 to 10 mg/kg/day usually are
well tolerated and would be appropriate for T.D. More rapid increases may be
desirable if tonic–clonic seizures occur frequently. The maximal recommended
dosage of valproate is 60 mg/kg/day. Many patients, especially those receiving
enzyme-inducing drugs, require higher-than-recommended doses to achieve adequate
clinical effect; other patients may respond at much lower doses. Valproate can be
titrated in T.D. to produce a “target” serum concentration of approximately 75
mcg/mL. Because ethosuximide is withdrawn, the valproate dose can be further
adjusted on the basis of seizure frequency and side effects.
CASE 60-7, QUESTION 6: T.D. has been taking valproic acid capsules, 250 mg TID, for 3 weeks.
T.D.’s dosing regimen to relieve these symptoms and possibly improve seizure control?
T.D. appears to be a candidate for the use of an enteric-coated valproate
preparation or extended-release divalproex. Divalproex tablets are available as an
enteric-coated delayed-release preparation, which causes delayed rather than
extended absorption of valproate; therefore, these tablets are not a sustained-release
product formulation. When patients are switched from nonenteric-coated
formulations to divalproex tablets, the frequency of administration should not be
decreased. Valproic acid and enteric-coated dosage forms of valproic acid or
divalproex are completely absorbed; these can be interconverted at the same total
134 An extended-release formulation of divalproex
135 When equal doses are administered, the ER formulation
produces serum concentrations that are approximately 89% of those produced by
other valproate dosage forms. Accordingly, when patients are converted to
divalproex ER from other forms of valproate, the manufacturer recommends an
increase of 8% to 20% in the administered dose. T.D.’s valproic acid capsules can
be replaced with an equal daily dose of divalproex tablets. Divalproex should be
administered on a 3-times-daily dosing schedule. Alternatively, T.D. could be given
1,000 mg of divalproex ER once daily. The results of this change should be apparent
within approximately 1 week. By that time, significant relief from GI side effects
should have occurred. It may then be possible to increase the dose of divalproex in
an effort to improve seizure control.
Capsules containing enteric-coated beads of divalproex also are available; the
125-mg capsule contents can be dispersed in food for administration to children or
others who have difficulty swallowing tablets or capsules. In addition, use of the
“cap” end of the capsule to measure half of the contents can approximate doses of
Pharmacokinetics and Serum Concentration Monitoring
CASE 60-7, QUESTION 7: Two weeks later, T.D. returns for follow-up. Her GI symptoms have resolved.
dose-dependent pharmacokinetics?
The observed changes in T.D.’s valproate serum concentrations are probably not
the result of dose-dependent metabolism as is seen with phenytoin; instead, these
changes are more readily explained by the absorption characteristics of divalproex
tablets. Peak serum concentrations of valproate after administration of divalproex
may be delayed for 3 to 8 hours, and administration of food may further delay
In addition, diurnal fluctuation in both the rate and extent of absorption
divalproex doses administered in the evening.
32 Twelve to 15 hours probably
elapsed between the administration of T.D.’s last dose and blood sampling;
therefore, the currently reported blood level may more closely approximate a peak
concentration. Previous blood levels, determined while she was receiving rapidly
absorbed valproic acid capsules, are more likely to have been trough concentrations.
T.D.’s adherence to her prescribed dosage regimen also may have increased because
of the change in dosage form and reduced side effects; her previous serum
concentrations may not have reflected administration of the prescribed dose.
Other pharmacokinetic factors may have actually moderated this unusual increase
in valproate concentrations. Valproate concentrations may fluctuate throughout the
day in a pattern that does not reflect the timing of doses.
partially related to changes in serum concentrations of endogenous fatty acids that
displace valproate from protein-binding sites. Valproate’s hepatic clearance is
restrictive (i.e., valproate has a low extraction ratio and its clearance is limited by
the free fraction of drug in plasma); therefore, when protein-binding displacement
occurs, free fraction of drug in plasma and clearance increase. As a result, free serum
concentrations of valproate increase only transiently, whereas total serum
concentrations decrease persistently. Valproate also exhibits dose dependency in its
binding to serum proteins. As concentrations approach 70 to 80 mcg/mL, binding
sites on albumin molecules become saturated, and the free fraction of drug in plasma
133 This effect also increases valproate clearance and reduces total serum
concentrations. Both of these effects may actually “dampen” the apparent increase in
plasma concentrations seen in T.D. When also considering the poorly established
“therapeutic range” for this drug, it becomes apparent that monitoring serum
concentrations is a less useful tool in valproate therapy than with some other
The clinical significance of T.D.’s elevated valproate serum concentrations is
minimal. She is not experiencing symptoms suggestive of valproate toxicity, and it is
too soon after the dosage increase to assess the effect of this change on her seizure
frequency. Therefore, alteration in her drug therapy is unnecessary at present and
might only confuse evaluation of her response to this drug. She should be observed
for an additional 4 to 6 weeks to evaluate seizure frequency before further alterations
in her dosing regimen are considered. Further increases in her dosage are not
contraindicated as long as she is tolerating the medication and such increases are
justified on the basis of seizure frequency.
CASE 60-7, QUESTION 8: Two months later, T.D. is taking 375 mg of divalproex TID with meals. She has
were normal. T.D.’s LFTs have been monitored monthly since she began taking valproate, and they were
Liver damage related to valproate therapy appears to be caused by accumulation
of hepatotoxic metabolites of valproate (probably 4-en-valproate) in certain
139 These metabolites may be formed in larger quantities in patients who
also receive enzyme-inducing drugs such as phenobarbital. Most cases of fatal
hepatotoxicity have occurred in young (<2 years of age) patients with neurologic and
metabolic abnormalities who also had severe, difficult-to-control seizures and who
It is important to recognize, however, that severe
hepatotoxicity is not limited to this population.
144 Liver damage occurs early in
therapy and symptomatically resembles fulminant hepatitis with hepatic failure.
Patients may experience vomiting, drowsiness, lethargy, anorexia, edema, and
jaundice; these symptoms often precede laboratory evidence of hepatic damage.
Liver biopsies in affected patients show evidence of hepatic necrosis and steatosis.
Death results from hepatic failure or a Reye-like syndrome.
Asymptomatic elevations in liver enzymes (such as those found in T.D.) occur
commonly during the first 6 months of treatment with valproate and usually are not
associated with severe or potentially fatal valproate-induced hepatotoxicity. These
changes in aminotransferase usually disappear without alteration in therapy; in some
cases, temporary dosage reduction is followed by normalization of laboratory tests
141 Without systemic symptoms or other signs of significant
liver damage, it is unlikely that the laboratory abnormalities observed in T.D.
represent severe liver toxicity from valproate. Because T.D. is responding well to
valproate therapy, no change in therapy is warranted at this time. Laboratory testing
probably can be repeated in 4 to 6 weeks. T.D. and her family should be educated
regarding the possible signs and symptoms of valproate-induced liver damage and
instructed to consult their physician if these symptoms are noted.
CASE 60-7, QUESTION 9: What is the usefulness of routinely monitoring LFTs in patients receiving
Serious hepatotoxicity related to valproate therapy is extremely rare. Historically,
the rate of fatal hepatotoxicity decreased significantly (despite substantial increases
in the use of valproate) after the use of the drug in high-risk patients (e.g., the very
young) decreased and its use as monotherapy increased. Hepatotoxicity is estimated
to occur in less than 0.002% of patients treated with valproate.
younger than 2 years of age who receive AED polytherapy, the incidence of this
complication is 1 in 500 to 1 in 800. Because asymptomatic, apparently benign
elevations in liver enzymes are common early in therapy with valproate and
symptoms of liver damage often precede laboratory changes, frequent LFTs during
early valproate therapy are unlikely to detect serious hepatotoxicity.
Education of caregivers or patients regarding potential symptoms of hepatotoxicity,
with careful observation and follow-up by health care professionals, is
recommended as the most effective method to monitor for this drug-induced illness.
In predisposed patients (i.e., very young children with associated neurologic
abnormalities and those receiving polytherapy), significant increases in LFT values
that are noted early in therapy may be clinically significant. At the onset of symptoms
suggesting this condition, laboratory testing may help confirm its presence.
Acute Repetitive (Cluster) Seizures
Although he regains consciousness between these “flurry” seizures, he remains lethargic. During ED
Frequent ED visits resulting from cluster seizures are expensive and frightening for
many patients and their families. B.N. continues to experience seizure flurries despite
carbamazepine therapy. He responds well to IV diazepam and has a caregiver who
can identify the onset of seizure clusters. His seizure clusters appear to be distinct
from the other seizures that he experiences. All of these factors indicate that a trial of
caregiver-administered treatment to abort these cluster episodes is likely to be
helpful and should be initiated.
Rectal diazepam gel is available for home administration to patients with acute
episodes of repetitive seizure activity.
147 When diazepam gel is administered
rectally, peak plasma concentrations occur in approximately 1.5 hours,
seizures are often terminated within 15 minutes. Use of diazepam rectal gel is
recommended only when caregivers can recognize the onset of cluster seizures,
which are different from a patient’s usual seizure activity, and when the caregivers
can be trained to administer the preparation safely and to monitor the patient’s
response (e.g., respiratory status) after administration. Caregivers should be
informed that this preparation is not for as needed use with every seizure; it should
be used only for identifiable cluster seizures or prolonged seizures.
B.N.’s mother should administer rectal diazepam gel at the onset of identifiable
cluster seizure activity. A dose of approximately 0.3 mg/kg (10 mg) should be given
and repeated, if necessary, within 4 to 12 hours of the first dose. B.N.’s mother
should be counseled on the administration of this product and given the patient
package insert, which gives complete instructions for the administration of rectal
diazepam. After administration, B.N. should be monitored for at least 4 hours to
ensure that no respiratory depression or other adverse side effects are occurring and
to assess the effect of the medication on his seizures. The most common adverse
effect seen with rectal diazepam is somnolence, occasionally accompanied by
dizziness and ataxia. Respiratory depression is very uncommon. IM, buccal, and
intranasal formulations of benzodiazepines are currently being investigated for their
utility in aborting cluster seizures and their use may address some of the barriers
associated with rectal drug administration.
QUESTION 1: J.J., a 14-month-old girl, is brought to the ED after having a generalized tonic–clonic
Her 7-year-old brother suffers from both absence and generalized tonic–clonic seizures. What is the
Up to 8% of children have a febrile seizure between 6 months and 6 years of
151 Simple febrile seizures occur with a fever of greater than or equal to 38°C
in previously normal children younger than 5 years of age. They last less than 15
minutes and have no focal features. The associated seizure does not arise from CNS
pathology. Complex febrile seizures show focal characteristics or are prolonged
longer than 15 minutes. The child may or may not have previous neurologic
abnormalities. The risk of occurrence of unprovoked afebrile seizures after a febrile
seizure is 4 times greater than in the general population. A family history of afebrile
seizures, complex febrile seizures, and pre-existing neurologic abnormality is a risk
factor associated with the later development of chronic epilepsy.
J.J.’s seizure appears to be a typical simple febrile seizure that developed in
association with her upper respiratory tract infection. The lack of previous
neurologic abnormality and normal findings on lumbar puncture and laboratory
evaluation help confirm this assessment.
CASE 60-9, QUESTION 2: How should J.J.’s febrile seizures be treated?
Because J.J. is not having a seizure at present, AED therapy is not required.
Measures to reduce her elevated temperature should be initiated; however, these
measures may not reduce the risk of further seizures. Acetaminophen and tepid
sponge baths usually are helpful.
If patients experience prolonged or repeated febrile seizures, either diazepam or,
less commonly, midazolam may be administered.
151–153 Rectal diazepam gel can be
PROPHYLAXIS AND CHOICE OF ANTIEPILEPTIC DRUG
CASE 60-9, QUESTION 3: On the basis of the subjective and objective data available for J.J., is AED
Long-term treatment or prophylaxis with AED for simple febrile seizures is not
recommended. Up to 54% of affected patients will have recurrent febrile seizures,
and the risk of recurrence is even greater when the first episode occurs before 13
months of age. Nonetheless, recurrent febrile seizures are not associated with brain
damage or development of epilepsy.
150 Although administration of continuous AED
treatment may reduce the recurrence rate of febrile seizures, published guidelines
recommend against this practice due to the associated adverse effects.
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