Search This Blog

468x60.

728x90

 


Prophylactic administration of various fast-acting agents, given during fever

episodes, has been studied as an alternative to continuous treatment for the

prevention of febrile seizures. Agents in both the AED and antipyretic drug classes

have been studied in this regard, but no clinically important benefits have been

found.

155–159 Thus, AED prophylaxis for febrile seizures is probably not warranted for

J.J., even though she is at risk for both development of epilepsy and recurrence of

febrile seizures. No evidence supports that medication will significantly affect her

later development of epilepsy. Close medical follow-up of J.J. is warranted. Her

parents should be counseled to contact a physician if J.J.’s febrile seizure is

accompanied by focal features or last longer than 15 minutes; or, if J.J. experiences

afebrile seizures. Although antipyretic measures (tepid sponge baths, acetaminophen

or ibuprofen) are of questionable benefit, they can be considered at the onset of fever

because these interventions are usually safe and well tolerated. Many febrile seizures

occur early in the course of an illness before fever is detected

160

; nevertheless,

vigilance by her parents and early antipyretic therapy may help prevent further febrile

seizures.

Skin Rash: Hypersensitivity Reactions to Antiepileptic

Drugs

CASE 60-10

QUESTION 1: R.S., a 34-year-old man, has been taking phenytoin 200 mg BID for the past 7 weeks to

control complex partial and secondarily generalized tonic–clonic seizures. Seizures began approximately 4

months ago after surgical evacuation of a subdural hematoma. Today he appears at the walk-in clinic and

complains of an “itchy rash” that began 2 days ago. He describes “feeling lousy” for the past week. On

examination he is febrile (38.5°C orally). A maculopapular, scaly, erythematous rash covers his upper

extremities and torso, and the mucous membranes of his mouth appear to be mildly inflamed. Cervical

lymphadenopathy is noted, and the liver is found to be enlarged and tender. R.S. also relates that his urine has

become very dark in the past 2 days and that his stools are light colored. What is the significance of R.S.’s skin

rash and other signs and symptoms? Are these likely to be related to his phenytoin therapy?

Skin-related adverse reactions (e.g., rash, urticarial) are relatively common (2%–

3% of patients) side effects related to AED therapy. Skin rash is most commonly

associated with phenytoin, lamotrigine, carbamazepine, and phenobarbital. Most

cases are relatively mild, but severely affected patients may exhibit Stevens–Johnson

syndrome or a systemic hypersensitivity syndrome accompanied by severe hepatic

damage. In R.S.’s case, signs and symptoms suggesting hepatic involvement

accompany the skin rash. Fever, lymphadenopathy, and apparent inflammation of

mucous membranes also suggest a hypersensitivity reaction to phenytoin with

multisystem involvement and the potential for progression to Stevens–Johnson

syndrome. Viral infection (e.g., hepatitis, influenza, infectious mononucleosis) should

be considered and ruled out as a possible cause of R.S.’s symptoms before they are

attributed to phenytoin therapy.

161–164

DRESS syndrome (which stands for Drug Reaction with Eosinophilia and

Systemic Symptoms) is a type of hypersensitivity syndrome that can occur with some

drugs, including phenytoin and other AEDs, that is most commonly seen in adults.

Typically, patients with this syndrome present with complaints of fever, skin rash,

and lymphadenopathy during the first 2 months of AED therapy. Hepatomegaly,

splenomegaly, jaundice, or bleeding manifestations may occur. Laboratory

manifestations often include leukocytosis with eosinophilia, elevated serum bilirubin,

and elevated AST and ALT. When a phenytoin hypersensitivity reaction includes

significant hepatotoxicity, fatality may occur in as many as 38% of affected

patients.

161

A high likelihood exists that R.S. has developed a severe reaction to phenytoin; the

clinical manifestations and the timing of their appearance are typical of this reaction.

Phenytoin should be discontinued immediately pending diagnostic clarification. R.S.

should be hospitalized for evaluation of other possible causes of his symptoms such

as viral illness and treatment. Treatment of phenytoin-related hypersensitivity and

hepatotoxicity is symptomatic and supportive. Intensive therapy with corticosteroids

has commonly been used, although little objective evidence exists for beneficial

effects of this treatment. Potential complications of this reaction include sepsis and

hepatic failure; these conditions should be treated specifically.

CASE 60-10, QUESTION 2: R.S. was hospitalized and treated with oral prednisone and topical

corticosteroids. Other potential causes for his condition were ruled out, and his signs and symptoms were

attributed to cutaneous and systemic phenytoin hypersensitivity. His fever resolved within 5 days; the skin rash

became exfoliative but resolved without infectious complications. Laboratory parameters began to normalize

after 10 days. While he was hospitalized, R.S. experienced three generalized tonic–clonic seizures that were

treated acutely with administration of IV lorazepam. R.S. was afebrile at the time these episodes occurred.

What information regarding the pathogenesis of phenytoin hypersensitivity and hepatotoxicity can be used to

guide selection of an alternative AED for R.S.?

Further administration of phenytoin to R.S. is contraindicated on the basis of his

history of a severe hypersensitivity reaction to this drug. Although the mechanism of

this reaction is not fully understood, research implicates reactive arene oxide

metabolites

p. 1295

p. 1296

of phenytoin (and other chemically similar AEDs) as possible causative agents for

hypersensitivity reactions. Affected patients purportedly are predisposed genetically

to the development of hypersensitivity, possibly because a relative deficiency of

epoxide hydrolase enzymes allows the accumulation of toxic concentrations of

reactive epoxide metabolites. These metabolites are believed to exert a direct

cytotoxic effect and to interact with cellular macromolecules, thereby functioning as

haptens that stimulate an immunologic reaction.

165

,

166 Carbamazepine, phenytoin, and

phenobarbital all are metabolized by similar pathways and converted to reactive

arene oxides. It is hypothesized that carbamazepine-induced liver damage also may

result from the effects of accumulation of reactive epoxide metabolites; these reactive

metabolites differ from the 10,11-epoxide metabolite that accumulates during

carbamazepine therapy. For this reason, these drugs potentially cross-react in

susceptible patients. Cases of apparent cross-reactivity between phenytoin and

phenobarbital or carbamazepine have been documented.

167–169

In addition, both

carbamazepine and phenobarbital can produce hypersensitivity reactions similar to

those seen with phenytoin. This potential for cross-reactivity should be considered

when an alternative AED is selected for R.S. An analysis of cases of AED-related

skin rashes found that the most significant nondrug predictor of skin rash was the

occurrence of a rash with another AED.

170

Valproate has been suggested as the preferred alternative AED for patients who

have exhibited hypersensitivity reactions to phenytoin.

168 Valproate is not

metabolized to arene oxides and also is chemically dissimilar to all other AEDs.

Because valproate often shows good efficacy for complex partial seizures with

secondary generalization, it would seem to be a safe and potentially effective

alternative AED for R.S. Of the newer AEDs, lamotrigine should probably be

avoided in R.S. because of its likelihood of causing skin rash and apparent

hypersensitivity reactions. Oxcarbazepine is potentially an alternative AED for R.S.

because it is not metabolized through the arene oxide pathway. Nevertheless, 25% to

30% of patients who experience a rash in response to carbamazepine will also

experience a rash with oxcarbazepine.

171 Therefore, many clinicians would avoid

oxcarbazepine. Gabapentin, lacosamide, levetiracetam, pregabalin, tiagabine,

topiramate, or zonisamide could be considered as alternative medications for R.S.

These medications appear less likely to cause skin rash or hypersensitivity

reactions.

170

,

172

It is suggested that R.S. be advised to add phenytoin to his list of medication

allergies.

Additional recognized genetic risk factors for AED-related hypersensitivity

reactions in specific populations are presented in Table 60-6.

WOMEN’S ISSUES IN EPILEPSY

Although epilepsy affects men and women equally, many health issues are of specific

importance to women, such as contraceptive interactions with AEDs, teratogenicity,

pharmacokinetic changes during pregnancy, breast-feeding, menstrual cycle

influences on seizure activity (catamenial epilepsy), AED impact on bone, and sexual

dysfunction.

173

,

174

It is noteworthy that the latter two issues can also occur in men. A

great need exists to educate both health care professionals and patients about the

many complex issues facing women with epilepsy.

175

For women of childbearing potential, prepregnancy planning and counseling are

important, because significant AED exposure of the fetus often occurs by the time

pregnancy is confirmed. This is especially important because of the potential for

unplanned pregnancies from the AED–contraceptive drug interactions. Prepregnancy

counseling also should include the importance of at least 0.4 mg/day of folic acid

supplementation and medication adherence. Patients should be informed about the

risk of teratogenicity and the importance of prenatal care.

Although complete seizure control is desirable for all patients with epilepsy, it is

especially favorable for a woman’s seizures to be well controlled before conception.

Monotherapy is preferred whenever possible, because the relative risk of birth

defects dramatically increases with AED polytherapy.

160

,

176 Monotherapy also

improves patient adherence. The AED should be given at the lowest effective dose to

reduce the possibility of birth defects.

154 Gradual discontinuation of AED before

pregnancy may be considered if a woman has been seizure-free for 2 years or longer.

Antiepileptic Drug–Oral Contraceptive Interaction

CASE 60-11

QUESTION 1: P.Z., a 26-year-old woman, experiences complex partial and secondarily generalized tonic–

clonic seizures. She is taking phenytoin 400 mg/day and divalproex 2,000 mg/day. She reports having two or

three partial seizures and one generalized seizure every 3 to 4 months. Despite taking Lo/Ovral (norgestrel 0.3

mg with ethinylestradiol 30 mcg), she has just learned she is pregnant. Her last menstrual period was 6 weeks

ago. What is the relationship between P.Z.’s apparent contraceptive failure and her AED therapy?

There have been several reports of reduced efficacy of oral contraceptives in

patients receiving various AEDs.

177

,

178 These reports describe both breakthrough

bleeding and pregnancy. Phenobarbital, phenytoin, carbamazepine, oxcarbazepine,

eslicarbazepine, perampanel, and felbamate have been shown to increase the

metabolism of ethinylestradiol and progestogens.

179 This effect is not associated with

valproate, lamotrigine, gabapentin, tiagabine, zonisamide, levetiracetam, lacosamide,

or pregabalin.

179 Topiramate in polytherapy and at high dosages (200–800 mg/day)

appears to have a mild, though measurable, effect on oral contraceptive

pharmacokinetics; apparent clearance of the estrogen component of combined oral

contraceptives is increased in patients taking topiramate.

180

In contrast, topiramate

monotherapy in lower dosages (50–200 mg/day) has a lesser impact on the

pharmacokinetics of the oral contraceptive.

181

A lack of contraceptive efficacy may present as irregular or breakthrough

menstrual bleeding. Decreased efficacy is not always associated with breakthrough

bleeding, however. Oral contraceptive doses can be increased to compensate for the

effect of an AED.

182 However, estrogens also may exacerbate seizures in some

women.

183 Women older than 35 years of age and those who smoke must consider the

risk of thromboembolic complications associated with higher doses of

contraceptives. A second contraceptive method (e.g., condoms, intrauterine devices,

or spermicide) is recommended to avoid contraceptive failure.

170 Tubal ligation is

also an alternative. An additional alternative that could be considered is injectable

depot medroxyprogesterone acetate. Although there is a lack of clinical studies

substantiating its effectiveness in patients on enzyme-inducing AED, the

pharmacokinetic characteristics of this agent suggest that its effect is not reduced by

enzyme induction. Medroxyprogesterone is a high-clearance drug; its clearance is

directly dependent on hepatic blood flow. Thus, enzyme induction would have little

effect on the metabolism of this drug when it is administered by injection. Depot

medroxyprogesterone acetate may, however, have other negative effects that would

limit its choice as an alternative contraceptive in this situation.

184

p. 1296

p. 1297

Assuming P.Z. was taking her contraceptive pills on a regular basis, it is possible

that her enzyme-inducing AED (phenytoin) is responsible for their failure. Patients

receiving enzyme-inducing AED should be prospectively informed that this

interaction can occur and advised concerning the use of alternative contraceptives

(see Chapter 47, Contraception).

Interestingly, a different drug interaction exists between oral contraceptives and

lamotrigine. The estrogen component in oral contraceptives increases the clearance

of lamotrigine. Lamotrigine clearance may increase twofold when contraceptive

steroids are begun and fall by 50% when contraceptive steroids are discontinued.

Changes in lamotrigine levels associated with initiation and discontinuation of

contraceptive steroids can result in increased seizure activity in some patients and

toxicity in others.

185

Teratogenicity

CASE 60-11, QUESTION 2: What are the risks of teratogenic effects from P.Z.’s medications? What steps

might be taken to minimize these risks?

P.Z.’s child is at risk of congenital malformations because of exposure to several

potentially teratogenic drugs: estrogen–progestin combination oral contraceptives,

valproate, and phenytoin (also see Chapter 49, Obstetric Drug Therapy).

Many AEDs have teratogenic effects.

186 Animal data regarding the teratogenic

potential of the new AEDs are encouraging, but conclusions regarding the teratogenic

potential of these AEDs cannot be made because of limited experience in pregnant

women. A good resource for clinicians to educate women is the American Epilepsy

Society and the American Academy of Neurology series of three Practice Parameter

updates on management issues for women with epilepsy focused on pregnancy. They

deal with obstetric complications and change in seizure frequency; teratogenesis and

perinatal outcomes; and vitamin K, folic acid, blood levels, and breast-feeding.

187–189

The authors evaluated the available evidence based on a structured literature review

and provide recommendations.

Most AEDs are believed to exert their teratogenic effects (and possibly other

adverse effects such as hepatotoxicity) partly via reactive epoxide metabolites.

160

Enhancement of the formation of these metabolites via hepatic enzyme induction (e.g.,

by carbamazepine or phenobarbital) or inhibition of their breakdown (e.g., through

inhibition of epoxide hydrolase by valproate) would increase the risk of

teratogenicity. Combined administration of enzyme inducers and valproate

(specifically the combination of carbamazepine, phenobarbital, and valproate with or

without phenytoin) is associated with an especially high risk of teratogenicity.

190

In

addition, each of the present major AEDs has been associated with congenital

malformations when administered alone. Meador et al.

191 provide data from 333

pregnancies in women with epilepsy taking an AED in monotherapy and enrolled in

the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. Serious

adverse outcomes (major malformations and fetal death) were significantly more

likely to occur with exposure to valproate (20.3%) than with carbamazepine (8.2%),

phenytoin (10.7%), or lamotrigine (1%). In addition to physical malformations, AED

exposure in utero has an adverse effect on neurodevelopment.

192 The NEAD study

evaluated age-6 IQ and found that valproate-exposed children had significantly lower

scores (mean 97), even after controlling for the mother’s IQ and seizure type.

193 The

age-6 IQ scores were significantly lower for children exposed in utero to valproate

compared with scores of children exposed to carbamazepine (mean 105), phenytoin

(mean 108), and lamotrigine (mean 108) monotherapy. A European task force of

epilepsy experts recommends that, where possible, valproate should be avoided in

women of childbearing potential.

194

Several strategies can be used to reduce the potential adverse effects of AEDs on

pregnancy outcomes. If feasible, before conception, seizure control should be

optimized using the AED of first choice for the prospective mother’s seizure type or

epilepsy syndrome. Monotherapy at the lowest effective dose is the goal.

Maintenance of adequate folic acid stores before conception and during fetal

organogenesis is also important. Folic acid supplementation can reduce the risk of

congenital neural tube malformations in infants at risk who are born to women

without epilepsy, but folate supplementation does not reliably reduce the teratogenic

effects of AED. Nevertheless, supplementation of folic acid (and ensuring adequate

folate levels) is recommended. Because about half of pregnancies are unplanned and

not evident until weeks after conception, folate supplementation should be given

routinely to women of childbearing age with epilepsy. No study has been conducted

to determine the optimal dose of folic acid supplementation in patients taking AEDs.

Clinicians engage in much discussion of this topic, but the current practices are not

evidence-based. Even though this is the case, P.Z. should start taking 4 mg of folic

acid supplementation each day.

Physiologic changes in pregnant women may affect the pharmacokinetics of

AEDs.

171 Absorption can be influenced by nausea and vomiting. Hepatic metabolism

and renal function both increase during pregnancy. The binding capacity of albumin is

decreased during pregnancy, resulting in decreased protein binding for highly bound

drugs. Unbound fractions of phenobarbital, phenytoin, and valproate increase with

decreased concentrations of albumin.

195–197 For drugs predominately metabolized by

the liver with a restrictive clearance (e.g., carbamazepine and valproate), decreased

protein binding without changes in intrinsic clearance should result in a decrease in

total drug concentrations; unbound drug concentrations usually remain unchanged. For

drugs with both increased hepatic metabolism and decreased protein binding (e.g.,

phenytoin and phenobarbital), both total and unbound plasma concentrations

decrease, but not necessarily proportionately.

The clearance of lamotrigine increases as pregnancy progresses, presumably

related to the impact of estrogen on lamotrigine metabolism.

198 This alteration in

clearance changes immediately postpartum. Preliminary data suggest that

oxcarbazepine concentrations may also decrease as pregnancy progresses.

199

The effects of changes in renal function during pregnancy on AED concentrations

are not well known.

199 Renal blood flow and glomerular filtration rate increase

during pregnancy. Thus, the renal clearance of drugs that are predominately excreted

through the kidneys, such as gabapentin, levetiracetam, and pregabalin, may increase

during pregnancy.

During pregnancy, serum levels of AEDs (including free serum levels for highly

protein-bound drugs) can be monitored. In this case, a prepregnancy level would be

optimal for comparison. Dosage adjustments may help to prevent the increase in

seizure frequency that is seen in approximately 25% of pregnant women with

epilepsy. Because falls and anoxia associated with uncontrolled generalized tonic–

clonic seizures may increase the risk to the unborn baby, P.Z. should be educated on

the value of adherence to her AED regimen.

For P.Z., it can be presumed that significant exposure of the fetus to any teratogenic

influence of AED has already occurred. Optimization of seizure control is now the

primary concern for her. Any major alterations in P.Z.’s AED regimen should be

made cautiously to avoid precipitating seizures. In addition, she should be instructed

to contact the AED pregnancy registry at Massachusetts General Hospital (1-888-

233-2334 or www.aedpregnancyregistry.org). Information provided to the registry

will aid in the ongoing monitoring of outcomes of babies born to mothers taking

AEDs. Reports from this registry have provided

p. 1297

p. 1298

risk information on many AEDs and regular visits to their website is helpful to

learn the latest.

VITAMIN K SUPPLEMENTATION

Babies born to women with epilepsy who are taking enzyme-inducing AED are at

risk of hemorrhage owing to decreased vitamin-K-dependent clotting factors.

Although some question the evidence, women taking carbamazepine, phenobarbital,

primidone, or phenytoin should receive vitamin K 10 mg orally every day from 36

weeks of gestation until delivery, and babies should also receive vitamin K 1 mg IM

at birth.

200

BREAST-FEEDING

In a lactating woman who is taking medications, the risk of drug exposure to the

infant needs to be weighed against the benefits of breast-feeding.

201 All drugs transfer

into milk to some extent. The extent of protein binding of the drug is the most

important predictor of drug passage into milk.

202

,

203 For the AEDs, a large

intersubject variability in the milk/plasma (M/P) ratio exists, presumably owing to a

difference in volume and composition of the milk. Thus, the M/P ratio is not useful

for predicting infant AED exposure. Reviews on AED and breast-feeding are

available.

204 For most first-generation AEDs (carbamazepine, phenytoin, valproic

acid), breast-feeding results in negligible AED plasma concentrations in the infants.

For the newer AEDs, breast-feeding should be done cautiously and the infant should

be monitored for excess AED plasma concentrations and toxicity, if possible. This

information should be presented to P.Z. in an appropriate manner. Once she delivers

her baby, re-evaluation and optimization of P.Z.’s AED therapy should occur.

STATUS EPILEPTICUS

Characteristics and Pathophysiology

CASE 60-12

QUESTION 1: V.S., a 22-year-old, 85-kg man, was recently diagnosed as having idiopathic epilepsy with

generalized tonic–clonic seizures. For the past 3 months, he has been treated with 600 mg/day of

carbamazepine, which completely eliminated his seizures. His steady state carbamazepine serum concentration

was 10 mcg/mL. While at his parents’ home, he had two tonic–clonic seizures, each lasting 3 to 4 minutes. On

arrival at the hospital (~30 minutes after the first seizure began), he was noted to be only semiconscious. His

blood pressure was 197/104 mm Hg, his pulse was 124 beats/minute, respirations were 23 breaths/minute, and

his body temperature was 38°C rectally. Shortly after his arrival, another generalized tonic–clonic seizure

began. How does V.S.’s current condition meet accepted diagnostic criteria for status epilepticus? What risks

are associated with status epilepticus?

Status epilepticus (SE) is operationally defined as “either continuous seizures

lasting at least 5 minutes or 2 or more discrete seizures between which there is

incomplete recovery of consciousness.”

205 Because V.S. has had three seizures within

slightly more than 30 minutes and did not return to his baseline level of

consciousness between seizures, his present condition meets this definition. V.S. is

experiencing generalized convulsive SE; this is the most common type and it is

associated with the greatest risk of systemic and neurologic damage. SE also may be

characterized by nonconvulsive seizures that produce a persistent state of impaired

consciousness, or by partial seizures (with or without impaired consciousness).

These forms of SE are associated with much lower morbidity and mortality than

generalized convulsive SE.

Uncontrolled, convulsive SE can cause severe metabolic and hemodynamic

alterations. V.S.’s vital signs (tachycardia, elevated blood pressure, increased

respiratory rate, and elevated body temperature) are typical for a patient in SE.

Prolonged, severe muscle contractions and CNS dysfunction from uncontrolled

seizure discharges result in hyperthermia, cardiorespiratory collapse, myoglobinuria,

renal failure, and neurologic damage. Even in the absence of convulsive muscle

movements, neurologic damage can occur from excessive electrical activity and the

resultant alterations in brain metabolism. When seizure activity persists longer than

approximately 30 minutes, failure of mechanisms that regulate cerebral blood flow is

more likely; this failure accompanies dramatic increases in brain metabolism and

demand for glucose and oxygen. Failure to meet the metabolic demands of brain

tissue results in accumulation of lactate and cell death. Peripherally, lactate

accumulates and serum glucose and electrolytes are altered. After 30 minutes of

seizure activity, the body often fails to compensate for increased metabolic demands,

and cardiovascular collapse can occur.

206

,

207 For these reasons, SE is considered a

medical emergency that requires immediate treatment to prevent or lessen both

systemic and neurologic damage. Mortality in adults with SE is approximately

20%205

; fatal outcome is often the result of the condition that precipitated SE (e.g.,

acute symptomatic causes, such as cardiopulmonary arrest, stroke). Long-term

neurologic consequences of severe SE may include cognitive impairment, memory

loss, and worsening of seizure disorders.

General Treatment Measures and Antiepileptic Drug

Therapy

CASE 60-12, QUESTION 2: Describe a general treatment plan for V.S.’s episode of status epilepticus.

The immediate therapeutic concern in V.S. is to ensure ventilation, stabilize vital

signs, and terminate current seizure activity. If possible, an airway should be placed

for airway protection and if ventilatory support is needed; however, this may not be

possible while he is convulsing. Objects (e.g., spoons, tongue blades) should never

be placed into the mouth of a patient during a seizure. If airway placement is

impossible, V.S. should be positioned on his side to allow drainage of saliva and

mucus from the mouth and prevent aspiration. An IV line should be established using

normal saline, and blood should be obtained for serum chemistries (especially

glucose and electrolytes), AED serum concentrations, and toxicology screens.

Glucose, 25 g (50 mL of 50% dextrose solution) by IV push should be administered

to correct any hypoglycemia, which may be responsible for SE. Glucose

administration should be preceded by IV thiamine 100 mg or vitamin B complex to

prevent Wernicke encephalopathy.

208

IV administration of rapid-acting anticonvulsant medication should begin as soon

as possible to terminate V.S.’s seizure activity. Status epilepticus becomes more

resistant to treatment the longer the seizure continues; thus, treatment is more likely to

stop seizures the sooner it is administered.

205 For in-hospital treatment of SE, IV

medication administration is usually preferred.

CASE 60-12, QUESTION 3: Which anticonvulsants are available for IV administration? Evaluate the

available drugs and recommend a drug, dosage, and regimen for initial treatment of SE in V.S.

Lorazepam, phenytoin, and fosphenytoin are the agents most commonly used as IV

therapy in the initial treatment of SE.

205

,

209 Phenytoin and fosphenytoin are indicated

for treatment of SE, but owing to limitations on their rates of infusion, the onset of

their

p. 1298

p. 1299

peak effect may be delayed. Therefore, phenytoin or fosphenytoin is usually used

after initial treatment with lorazepam.

IV sodium valproate (Depacon) is available, but it is not FDA-approved for the

treatment of SE. Although the manufacturer recommends that Depacon be

administered slowly (<20 mg/minute), it has been administered safely at high doses

and faster infusion rates.

208 There is growing experience with the use of IV valproate

for SE that fails to respond to lorazepam and phenytoin, and for patients in whom

phenytoin is contraindicated (e.g., phenytoin allergy).

209 An IV form of levetiracetam

is available. This drug also is FDA-approved only for patients who cannot receive

oral dosage forms of levetiracetam. Rapid IV administration of levetiracetam has

been used; however, experience with this agent is limited.

210 Lacosamide is also

available in an IV formulation and there are several case reports of its successful use

for refractory nonconvulsive SE.

211

,

212

IV phenobarbital is usually reserved for SE

that does not respond to benzodiazepines and phenytoin.

205

Four IV regimens for generalized convulsive SE were directly compared in one

randomized controlled trial.

213 The study evaluated diazepam followed by phenytoin,

lorazepam alone, phenobarbital alone, and phenytoin alone. For initial IV treatment

of overt generalized SE, lorazepam was more effective than phenytoin alone.

Lorazepam was as effective as the other two regimens, and it was easier to use.

IV administration of either diazepam or lorazepam is usually effective for rapid

termination of seizure activity in SE.

214 Owing to diazepam’s higher lipid solubility,

it redistributes from the CNS to peripheral tissues rapidly after administration; this

results in a short duration of action (<60 minutes).

215 Lorazepam’s lower lipid

solubility prevents rapid redistribution and accounts for its longer duration of

action.

215 Lorazepam may be effective for up to 72 hours.

216

,

217 Owing to this longer

duration, lorazepam is the preferred benzodiazepine for immediate treatment of

SEs.

208

,

209

Lorazepam 0.1 mg/kg given intravenously at 2 mg/minute would be appropriate

initial therapy for V.S.

208 Lorazepam may cause significant venous irritation, and the

manufacturer recommends dilution with an equal volume of normal saline solution or

water for injection before IV administration. Lorazepam may be repeated after 5

minutes if seizures continue. The efficacy of lorazepam depends on rapid

achievement of high serum and CNS concentrations. Although lorazepam can be

administered IM, this route should not be used for treatment of SE because it is

unlikely that it would achieve serum concentrations necessary for termination of

seizure activity and there is little experience with its use for terminating SE.

Midazolam given IM has been shown to quickly and effectively terminate SE when

used in out-of-hospital settings. This treatment is an acceptable alternative for inhospital use when IV access is not feasible.

218

,

219 The most common adverse effects

after IV administration of benzodiazepines are sedation, hypotension, and respiratory

arrest.

215 These side effects are usually short-lived and, when adequate facilities are

available for assisted ventilation and administration of fluids, they usually can be

managed without major risk to the patient. Respiratory depression occurs most

commonly in patients who receive multiple IV medications for control of SE.

INTRAVENOUS PHENYTOIN AND FOSPHENYTOIN

CASE 60-12, QUESTION 4: V.S. was given lorazepam 8 mg IV. Seizure activity ceased 2 minutes after the

injection was completed. What drug should be administered to V.S. for prolonged control of seizures?

Recommend a dose, route, and method of administration.

Continued effective seizure control is important for patients who experience SE.

Previously, when diazepam was the benzodiazepine predominantly used for

immediate control of SE, a long-acting AED such as phenytoin was routinely

administered at the same time to ensure continued suppression of seizure activity.

Routine use of phenytoin has been somewhat de-emphasized with increased use of

lorazepam208

; lorazepam’s apparent longer duration of effect may make routine use of

IV phenytoin less necessary. Nevertheless, many centers still use phenytoin in

conjunction with lorazepam.

The availability of fosphenytoin for IV administration has provided an additional

option for administration of phenytoin in the treatment of SE, and in most centers,

fosphenytoin is preferred over phenytoin. Use of this phenytoin prodrug allows more

rapid administration of large IV loading doses of phenytoin with less risk of injection

site complications. Fosphenytoin is also better tolerated than phenytoin.

219

Fosphenytoin itself is inactive; the therapeutic effect results from its conversion to

phenytoin.

100

,

101

In the U.S., phenytoin (administered as either sodium phenytoin injection or as

sodium fosphenytoin injection) is considered the long-acting anticonvulsant of choice

for most patients with generalized convulsive SE.

209 Phenytoin causes much less

sedation and respiratory depression than drugs such as phenobarbital when it is used

in conjunction with IV benzodiazepines.

208 V.S.’s maintenance carbamazepine

therapy was previously effective. Without obvious precipitating factors such as head

trauma, CNS infection, and drug or alcohol abuse, SE, in a patient with a history of

epilepsy, most commonly results from poor adherence with maintenance AED

medication. Therefore, IV fosphenytoin is a good choice for re-establishing effective

AED therapy for V.S. Phenytoin is an acceptable alternative if fosphenytoin is

unavailable.

No comments:

Post a Comment

اكتب تعليق حول الموضوع

mcq general

 

Search This Blog