Pediatric Epilepsy Diagnosis and Therapy - part 7 pps

Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomized controlled trial.. Is there some other treatment regimen wit

10% to 20%, which makes it difficult to administer an

effective dose (82)

Oxcarbazepine

Clemens et al performed a study in 10 healthy volunteers

to characterize the bioavailability of rectally administered

oxcarbazepine suspension (300 mg/5 mL) diluted 50%

with water Mean relative bioavailability calculated from

plasma AUCs was 8.3% (SD 5.5%) for monohydroxy

derivative (MHD) and 10.8% (SD 7.3%) for OXC The

MHD excreted in the urine following rectal

administration Oral absorption was consistent with

pre-vious studies The most common side effects were

head-ache and fatigue with no discernable difference between

routes MHD bioavailability following rectal

administra-tion of OXC suspension is significantly less than after oral

administration, most likely because of OXC’s poor water

solubility It is unlikely that adequate MHD

concentra-tions can be reached by rectal administration of diluted

OXC suspension (83)

Paraldehyde

Rectally administered paraldehyde has been widely used

to control severe seizures, particularly in children (84,

85) However, information on the efficacy, toxicity, and

pharmacokinetics is limited Rectal bioavailability is 75%

to 90% versus 90% to 100% for the oral route Time

to peak concentrations after rectal administration is 2.5

hours versus 0.5 hours for oral administration

Paralde-hyde should be diluted with an equal volume of olive oil

or vegetable oil to reduce mucosal irritation

Phenobarbital

There is no commercially available rectal dosage form

for phenobarbital Graves and coworkers gave seven

volunteers phenobarbital sodium parenteral solution

rectally and intramuscularly (86) After rectal

administra-tion absorpadministra-tion was 90% complete, with a time to peak

concentration of 4.4 hours versus 2.1 hours for the IM

injection Suppositories containing phenobarbital sodium

are more rapidly absorbed than phenobarbital acid given

either orally or intramuscularly (87, 88)

Phenytoin

Occasionally, there arises a need to administer phenytoin

rectally, although no commercial rectal dosage form is

available Several studies of investigational suppository

formulations have failed to demonstrate absorption

Rectal administration of phenytoin sodium parenteral solution in dogs produced low but measurable serum concentrations, but absorption was slow (89) Rectal administration of phenytoin is not recommended

Valproic Acid

Valproic acid absorption has been studied after rectal administration of diluted syrup and suppositories Rectal absorption of the commercially available syrup is complete, with peak concentrations occurring approximately 2 hours after a dose (90–92) High osmolality necessitates 1:1 dilu-tion of the syrup to minimize catharsis The syrup has been used to treat status epilepticus when other therapy is ineffective Various suppository formulations are absorbed well, albeit more slowly than the syrup, with time to peak concentration occurring in 2 to 4 hours (93, 94)

Topiramate

Topiramate is also readily absorbed following rectal administration In a study of twelve healthy subjects who received either 100 or 200 mg of topiramate orally and

a 200 mg dose of topiramate given rectally, the relative

bioavailability (Frel), which was determined by ing the dose-normalized areas under the concentration

bio-availability for topiramate administered rectally was

Zonisamide

Nagatomi et al investigated two zonisamide ries compared with IV and oral dosing in rats (96) The bioavailability of the hydrophilic base was 96%, and that

both rectal suppositories was significantly greater than

hydrophilic-based suppository (2 hrs) than after either the lipophilic-based or the oral dose (4 hrs)

STUDIES OF OTHER ADMINISTRATION ROUTES

in 10 healthy adults in a study in which 2 mL of the

IV • GENERAL PRINCIPLES OF THERAPY 530

intravenous preparation of midazolam 5 mg/mL

fla-vored with peppermint was held in the mouth for 5

min-utes, then spat out The researchers found that changes

on electroencephalography were observed within 5 to

10 minutes of administration of the drug, suggesting

rapid absorption and onset of effect (97) In a

random-ized controlled trial conducted in a hospital emergency

department, the safety and efficacy of buccal midazolam

were compared with those of rectal diazepam (98) The

dose used for each drug was determined by the age of the

child, with a target dose of about 0.5 mg/kg (from 2.5

mg for children aged 6 to 12 months; 4 mg for those 1

to 4 years; 7.5 mg for those 5 to 9 years; and 10 mg for

those 10 years or older) A total of 219 episodes of acute

seizures in 177 children were treated Therapeutic success

was defined as cessation of seizure within 10 minutes of

drug administration without respiratory depression and

without seizure recurrence within 1 hour A postivie

out-come was achieved in 56% of patients treated with

buc-cal midazolam, compared with 27% of patients treated

95% CI 2.2–7.6) Median time to seizure termination was

8 minutes (range: 5–20 minutes) for buccal midazolam

and 15 minutes (range: 5–31 minutes) for rectal diazepam

Greenblatt et al compared the pharmacokinetics of

sublingual lorazepam with IV, IM, and oral LZP (99) Ten

healthy volunteers randomly received 2 mg of LZP in the

following five formulations: IV injection, IM injection,

oral tablet, sublingual administration of the oral tablet,

and sublingual administration of a specially formulated

tablet Peak plasma concentrations, time to peak

concen-trations, elimination half life, and relative bioavailability

were not significantly different among the formulations

Peak concentrations were highest for the IM route,

fol-lowed by oral and sublingual; time to peak concentrations

was most rapid for the IM route, followed by sublingual

and oral Mean relative bioavailabilities were high for all

routes: IM (95.9%), oral (99.8%), sublingual of oral

tab-let (94.1%) and sublingual of special tabtab-let (98.2%)

It should be noted, however, that the efficacy, safety,

duration of effect, and ease of buccal/sublingal

adminis-tration by nonmedical caregivers have not been evaluated

in settings outside of hospitals

INTRANASAL

Several benzodiazepines possess the physical, chemical,

and pharmacokinetic properties required of effective

nasal therapies Among the benzodiazepines considered

for intranasal administration, midazolam has been most

extensively studied In one randomized, open-label trial

febrile seizures, the safety and efficacy of intranasal

midazolam (0.2 mg/kg) were compared with those of intravenous diazepam (0.3 mg/kg) administered over

5 minutes (100) Intranasal midazolam was as safe and effective as intravenous diazepam and resulted in earlier cessation of seizures as a result of rapid administration.However, the role of intranasal midazolam in treat-ing seizure emergencies remains to be established There are no adequately controlled trials demonstrating the safety and efficacy of intranasal midazolam for out-of-hospital treatment Moreover, the short elimination half-life of midazolam—especially in patients taking enzyme-inducing drugs—raises concern as to whether its duration

of effect is satisfactory in out-of-hospital settings.Intranasal lorazepam has also been studied (101) Intranasal LZP was absorbed with a mean percent bioavail-

concentration-time curve was observed, indicating possible secondary oral absorption The time to peak concentration was vari-able, ranging from 0.25–2 hours Lorazepam’s relatively limited lipid solubility as compared with that of mid-azolam or diazepam results in a slower rate of absorption and onset of action

Diazepam has a lipid solubility and potency parable with those of midazolam and a much longer elimination half-life, properties that make it a good can-didate for intranasal administration The bioavailability

com-of a novel intranasal diazepam formulation has been compared with that of intranasal midazolam in healthy

were rapidly absorbed, but diazepam’s absorption was more extensive and its half-life longer than that of mid-azolam Compared with rectally administered diazepam, the nasal diazepam formulation is absorbed to the same extent, but appears to be more rapidly absorbed, resulting

in attainment of maximum concentrations as much as

30 minutes earlier (103)

Nasogastric Tubes

A nasogastric (NG) tube offers an alternative route of drug delivery However, drug may adhere to the tubing, clog the tubing, or not be absorbed Occlusion of the tube

by the drug is also a concern Tube occlusions may require replacement of the tube, which is both costly and incon-venient for the patient Recently, it has been demonstrated

be opened, mixed with 0.9% sodium chloride or apple juice as diluents, and reliably delivered through an NG tube or feeding tube 12 French or greater in size (104, 105) Topiramate has also been reported to be effective

in patients with status epilepticus when given through

an NG tube (106)

However, absorption from nasogastric tubes is not always comparable to orally administered formula-tions When patients who are receiving tube feedings are

switched from IV phenytoin (fosphenytoin) to oral

phe-nytoin administered via a nasogastric tube, there appears

to be decreased absorption of the oral formulation This

seems to occur regardless of whether the suspension

or the oral capsule dosage form is used Although the

mechanism has not been clearly documented, it has been

postulated that phenytoin may bind to proteins in the

enteral feeding Also, the enteral feeding may increase

the GI motility, which may decrease the absorption (107)

Sometimes very large oral doses may need to be given to

maintain the desired serum concentrations in patients

receiving phenytoin and enteral feedings via a nasogastric

tube Some practitioners try to stop the enteral feedings

for two hours before and two hours after the dose of

phe-nytoin IM fosphenytoin would be an alternative (3)

SUMMARY

The selection of AED dosage forms is very important in

pediatric epilepsy Patients may be unwilling or unable

to take oral solid dosage forms Therefore, the

avail-ability of alternative oral dosage forms such as

suspen-sions, solutions, and sprinkles is important Patients

who experience concentration-dependent side effects or

breakthrough seizures may realize improved control by

switching to an alternative dosage form For example, a

controlled-release formulation will provide lower peaks

and higher troughs, facilitating better seizure control with

less toxicity

Although it has been the practice to crush oral solids

and mix the contents with food, this is not always

were designed to provide if the structure of the

prepa-ration is disrupted In some cases, the rate or extent of

absorption may be altered when the drug is given with

food It also has been a custom to compound pediatric

dosage forms extemporaneously This is an important way

to provide drug in a form that young children can take

However, clinicians should be cautious about neous compounding of pediatric formulations unless they can determine the amount of drug in the formulation, the stability of the product, and the bioavailability This requires an assay for the compounded product and an assay of the drug in blood In addition, with compounded drugs, someone should taste the preparation before it is given to the patient For example, gabapentin has a very bitter taste when it is put into solution Therefore, when

extempora-a drug is compounded for pediextempora-atric delivery, the new formulation should be tested to ensure that it is being delivered properly Specialized dosage forms generally are more expensive

Caregivers should be thoroughly educated in drug administration techniques for children When carefully instructed, caregivers can properly administer medications (108) Drug administration techniques are summarized

in Tables 38-4, 38-5, and 38-6 When doses are given

as “teaspoonfuls,” caregivers should have a calibrated device for measuring the dose rather than using a com-mon utensil The volume of “standard” teaspoons varies

up to fourfold Drugs given rectally, such as diazepam, require special caregiver education

Clinical assessment, selection of a drug, and mination of the dose require special attention in the

deter-TABLE 38-4

Medication Administration Guidelines for Infants

Use a calibrated dropper or oral syringe.

Support the infant’s head while holding the infant in lap.

Give small amounts of medication to prevent choking.

If desired, crush non–enteric-coated tablets to a powder

and sprinkle on small amounts of food

Provide physical comforting to calm the infant while

Disguise the taste with a small volume of flavored drink

or food Rinse mouth with flavored drink to remove aftertaste.

Use simple commands in the toddler’s jargon to obtain cooperation Allow the toddler to choose which medi cations to take first Allow toddler to become familiar with the oral dosing device.

Use a rinse with a flavored drink to minimize aftertaste Allow child to help make decisions about dosage forms, place of administration, which medication to take first, and the type of flavored drink to use.

IV • GENERAL PRINCIPLES OF THERAPY 532

pediatric patient, as does the selection of the

appropri-ate formulation and dosage form This last step in the

therapeutic plan plays a pivotal role in the ultimate

suc-cess of therapy The objective is to ensure the regular

and consistent delivery of drug to the brain When

con-ventional oral tablets and capsules are inappropriate

or impractical, alternate formulations, dosage forms, and routes of administration should be considered The clinician also must assess the ability of the care-giver to correctly prepare, measure, and administer medications and instruct caregivers about proper drug administration

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107 Au Yeung SC, Ensom MH Phenytoin and enteral feedings: does evidence support an

interaction? Ann Pharmacother 2000 Jul-Aug; 34(7–8):896–905 Review.

108 McMahon SR, Rimsza ME, Bay RC Parents can dose medication accurately Pediatrics

1997; 100:330–333.

Principles of Drug Interactions: Implications for Treatment with

Antiepileptic Drugs

harmacokinetic interactions, times leading to adverse clinical sit-uations, have long been recognized

some-as an occsome-asionally unavoidable facet of antiepileptic drug (AED) treatment (1, 2) Since

the mid-1990s, a number of newer AEDs have entered

the marketplace, both in the United States and globally

One general advantage of these newer medications is an

improved pharmacokinetic profile, including a reduced

potential for participating in drug-drug interactions, as

compared to the older medications

The aim of this chapter is to summarize in-vitro

and in-vivo data regarding drug interactions with both

the newer as well as the older, traditional AEDs in terms

of absorption, distribution, protein binding, and hepatic

induction and inhibition Clinical implications of these

interactions will also be discussed

PATIENTS AT RISK

Patients perhaps at the greatest risk for drug

interac-tions are usually those who are the most severely ill

This includes patients in the intensive care unit, geriatric

patients, premature neonates, and young children Drug

to AED-to-AED interactions, there has been increasing attention to the potential for certain AEDs to interact (perhaps adversely) with other concomitant medica-tions that patients may be receiving

MECHANISMS FOR COMMON DRUG INTERACTIONS

Oral Absorption of Drugs

Most AEDs are well absorbed following oral tion However, absorption of some compounds can be altered by drug-drug or drug-food interactions These

administra-P

39

IV • GENERAL PRINCIPLES OF THERAPY 536

interactions can affect maximum plasma concentration,

time to reach maximum concentration, and even

over-all extent of absorption Among the older, traditional

AEDs, oral absorption of phenytoin appears to be the

most problematic Of particular concern is the issue of

concomitant administration of an AED with an enteral

nutrition supplement Concomitant administration

of phenytoin with these nutritional formulations can

result in marked reductions in oral bioavailablity (4–6)

Because of this interaction, it is commonly suggested

that the administration of phenytoin and enteral

feed-ings be separated by at least 2 hours Unfortunately, this

may not be practical, particularly for patients requiring

continuous feedings Alternatively, clinicians can

over-come this interaction by simply increasing the

phenyt-oin dosage and using serum drug concentrations as a

guide This approach is also problematic If for example,

enteral feedings are discontinued, or interrupted for a

significant period of times, and phenytoin doses are not

readjusted downward, there will likely be a marked rise

in phenytoin concentrations, potentially leading to drug

intoxication If possible, therefore, this drug-nutrient

interaction should be avoided Concomitant ingestion

of food may also delay the rate of absorption of older

agents such as valproic acid but is unlikely to impact

overall absorption (7)

Generally speaking, oral absorption interactions

with the newer-generation AEDs are unlikely to be of

clinical significance in most patients Unlike older,

tradi-tional compounds such as phenytoin or carbamazepine,

the newer-generation AEDs tend to be quite water soluble

and are rapidly and completely absorbed Indeed, in

con-trast to the problems described for phenytoin,

absorp-tion of newer-generaabsorp-tion agents such as gabapentin,

lamotrigine, and levetiracetam does not appear to be

impaired when coadministered with enteral nutritional

supplements (8–9)

When topiramate is administered with food, the rate

of absorption is decreased, delaying time to maximum

concentration by approximately 2 hours and decreasing

mean maximum concentration by approximately 10%,

with no significant effect on overall extent of

absorp-tion Conversely, when oxcarbazepine is given with food,

the mean maximum serum concentrations of the active

monohydroxy metabolite is increased by 23% (10–11)

Whether this is clinically meaningful is unclear

Coadministration of levetiracetam with food

delays the time to peak concentration by approximately

1.5 hours and decreases the maximum concentration by

20%; however, the extent of absorption is not affected

Mixing with enteral feeding formulas does not appear

to result in significant impairment of absorption, over

and beyond that seen with concomitant administration

with food (12)

Role of Drug Transporter Proteins

ATP-dependent drug transporters, including members

of the multidrug resistance protein (MRP) family and P-glycoprotein (Pgp), have been implicated as a major limiting factor in drug pharmacokinetics (13) Pgp and MRP are located on the apical side of capillary endothe-lial cells and are thought to extrude drug molecules back into blood (or intestine) from cells These efflux pumps appear to act in conjunction with drug-metabolizing enzymes such as CYP 3A4 to limit drug access to both the systemic circulation and various cellular compartments (14) This may be clinically important, in that several of the older AEDs, such as carbamazepine, display the abil-ity to induce the activity of CYP 3A4 and Pgp (15) At the intestinal level, induction of both CYP 3A4 and these efflux pumps would serve to significantly reduce the oral bioavailability of a number of medications While most attention has been focused on the role of these trans-porters in modulating oral drug absorption, it has also become clear that these transporter proteins are localized

in a variety of tissues including the liver, kidney, brain barrier, and placenta In addition to potentially limiting oral drug absorption or blood-brain barrier pen-etration, these drug efflux pumps may be important in protecting the fetus from drug/chemical exposure Several studies have now demonstrated that PgP is expressed in the trophoblast layer of the placenta and may provide

blood-an importblood-ant mechblood-anism of protection to the fetus from maternal drug exposure (16)

IS PROTEIN BINDING RELEVANT?

In most cases, changes in protein binding are not clinically significant, but in some situations these alterations, as a result of either changes in protein concentration (e.g., hypo-albuminemia) or protein binding displacement, may lead to misinterpretation of serum drug concentrations (17).Protein binding displacement interactions can occur

administered together and compete for a limited ber of binding sites Typically, the drug with the greater affinity for the binding site displaces the competing agent, increasing the unbound fraction of the displaced drug

num-It is the unbound drug concentration that is responsible for the drug’s pharmacologic activity Unbound drug con-centrations are dependent on the drug dose and drug-metabolizing activity of enzymes (intrinsic clearance) Unbound drug concentrations may rise initially follow-ing the concomitant administration of two competing drugs but should return to preinteraction values fairly quickly In other words, these interactions are transient Total concentrations of drug, however, will be lower than

expected If serum concentrations are being monitored,

this may lead to misinterpretation

Among the AEDs, the potential for protein-binding

interactions is greatest for phenytoin and valproic acid

Both phenytoin and valproic acid are extensively bound

inhibitor of cytochrome P450 2C19, one of the enzymes

responsible for phenytoin metabolism When these two

agents are coadministered, unbound phenytoin

concentra-tions are higher than typically expected and total (bound

unbound) concentrations are lower (16) When using

this combination, it may be prudent to monitor unbound

phenytoin concentrations as well as total

With the exception of tiagabine (96% protein bound),

an advantage of the newer-generation AEDs is that they are

not extensively protein bound, and therefore these types

of pharmacokinetic interactions are not likely

Metabolism: Implications of Enzyme

Induction and Inhibition

Most clinically relevant drug interactions result from

alterations in drug metabolism, either in the liver or in the

gut Drug-metabolizing enzyme induction can result in an

increased rate of metabolism of the affected drug, leading to

both decreased oral bioavailability and increased systemic

clearance of extensively metabolized concomitant

medica-tions The clinical result therefore would be potentially

sub-therapeutic serum concentrations of that drug Conversely, a

number of drugs (including several AEDs) have been shown

to be inhibitors of various drug-metabolizing enzymes, and

concomitant administration of these agents can slow the

rate of metabolism of the affected drug and cause increased

serum levels of drug, leading to toxicity

The metabolic pathways of AEDs can vary; however, most metabolism is achieved via oxidative metabolism and/or glucuronidation (18–20) Oxidative metabolism

is accomplished via the cytochrome P450 (CYP) zyme system This system consists of three main families

isoen-of enzymes: CYP1, CYP2, and CYP3 There are seven primary isoenzymes that are involved in the metabolism

of most drugs: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 Of these, the ones com-monly involved with metabolism of AEDs include CYP2C9, CYP2C19, and CYP3A4 (21) Another important meta-bolic pathway for several AEDs, including valproic acid, lorazepam, and lamotrigine, is conjugation via the enzyme uridine diphosphate glucuronosyltransferase (UGT)

Although they do not necessarily contraindicate AED therapy, these pharmacokinetic interactions can clearly complicate therapy in individuals receiving multi-ple AEDs In some cases, it may be difficult to distinguish whether a change in a person’s clinical state (change in seizure frequency or appearance of toxicity) is due to an additive pharmacologic effect of the added drug or simply due to a change in serum concentration in the original AED One approach to rational polytherapy would be

to combine agents that do not interact with each other

In this way, the confounders of changes in drug tion can be excluded from the evaluation of therapeu-tic response to combined AED treatment Interactions between AEDs and hepatic enzymes are summarized in Table 39-1 and discussed in the following paragraphs

disposi-Hepatic Enzyme Induction Compounds that are hepatic

inducers increase the synthesis of enzyme protein and thus increase the capacity for drug metabolism Induction of hepatic enzymes occurs over a gradual period of days to

TABLE 39-1

Effect of Antiepileptic Drugs on CYP Isoenzymes or Other Enzyme Systems

Phenobarbital, carbamazepine, Inducers Broad CYP, UGT

Valproic acid Inhibitor CYP 2C19, UGT,

Gabapentin, pregabalin No effect

Oxcarbazepine Inducer (modest) CYP3A4

Topiramate Inhibitor (modest) CYP2C19

Inducer (modest) CYP 3A4 Vigabatrin None

IV • GENERAL PRINCIPLES OF THERAPY 538

weeks and is a reversible process Addition of an inducer

will cause a lowering of serum concentrations of the

tar-get drug, conceivably resulting in inadequate therapeutic

response Conversely, removal of an enzyme inducer will

cause a rise in the levels of the target drug, potentially

causing toxicity

Among the older-generation AEDs, carbamazepine,

phenytoin, and the barbiturates phenobarbital and

primi-done are inducers of both the cytochrome P450 (CYP)

and UGT enzyme systems (18) Combining these agents

with other AEDs that are metabolized by either of these

enzyme systems can result in markedly enhanced

sys-temic clearance, and reduced serum concentrations of the

affected drug, requiring higher doses in order to

main-tain comparable (as compared to monotherapy)

steady-state serum concentrations An example of this sort of

interaction would be the combination of phenytoin and

lamotrigine

hepatically by N-glucuronidation via UGT 1A3 and UGT

1A4 Lamotrigine does not appear to significantly alter

concentrations of carbamazepine or carbamazepine

epox-ide (21, 22) nor any of the other AEDs However, the

half-life of lamotrigine is reduced from 24 hours to 15 hours

when administered with enzyme-inducing drugs as just

described Following the withdrawal of the enzyme

induc-ers carbamazepine and phenytoin, lamotrigine plasma

concentrations have been observed to increase by 50%

and 100 %, respectively (23)

Levetiracetam shows limited metabolism in humans,

with 66% of the dose renally excreted unchanged Its

major metabolic pathway is via hydrolysis of the

acet-amide group to yield a carboxylic derivative, which is

mainly recovered in the urine Levetiracetam is not

sig-nificantly metabolized by CYPs or UGTs and appears

to be devoid of pharmacokinetic drug interactions

(24, 25) Similarly, the drugs gabapentin and pregabalin

appear to be devoid of enzyme-inducing (or inhibition)

properties

Oxcarbazepine is converted to

10-hydroxycarbam-azepine (OHCZ), the metabolite primarily responsible for

pharmacologic activity This active metabolite is mostly

excreted by direct conjugation to glucuronic acid

Oxcar-bazepine does not seem to be a broad-spectrum enzyme

inducer, although it does posses modest, specific

induc-tion potential toward the CYP3A subfamily, as evidenced

by the increased metabolism of estrogens and

dihydro-pyridine calcium channel antagonists (1, 2) Clinicians

should be aware that this drug does indeed have modest

potential for causing enzyme induction interactions, but

that this potential may vary among different patients

Topiramate is approximately 60% excreted

unchanged in the urine It is also metabolized by

hydrox-ylation and hydrolysis Two of its metabolites are

con-jugated as glucuronides While not considered a potent

enzyme inducer, topiramate can increase clearance of proate by approximately 13% and may lower oral con-traceptive serum concentrations (26, 27) Whether these changes in valproic serum concentration are clinically meaningful is unclear Topiramate metabolic clearance can be increased when it is administered with enzyme-inducing AEDs, thereby reducing half-life and lowering serum concentrations by up to 40%

val-Zonisamide is a synthetic 1,2-benzisoaxole tive that is metabolized in large part by reduction and conjugation reactions Oxidative reactions involving CYP3A4 and CYP2D6 are also involved Zonisamide elimination can be altered by other drugs Specifically, enzyme-inducing drugs such as carbamazepine and phe-nytoin can significantly increase the clearance of this drug, effectively reducing the half-life of zonisamide by about half

deriva-Hepatic Inhibition deriva-Hepatic enzyme inhibition can occur

when two drugs compete for the same enzyme site, ing the metabolism of the target drug A resultant increase

reduc-in the object drug can occur if a substantial portion of the target drug is prevented from occupying the enzyme site Inhibition is usually a rapid process that is dose/concentration dependent Addition of an enzyme inhibitor may cause a very rapid rise in serum concentrations of the target drug, potentially leading to acute toxicity (18)

In contrast to enzyme induction, inhibition of selected CYP and/or UGT enzymes can be caused by several AEDs of both the older and newer generations These combinations may result in unexpectedly high serum concentrations of the affected AED An exam-ple is the interaction of valproic acid and lamotrigine Lamotrigine’s half-life is increased to approximately 59–70 hours when it is coadministered with valproate, resulting from valproate’s inhibition of glucuronidation Inhibition of lamotrigine clearance can occur at val-proate doses as low as 125–250 mg/day and becomes maximal at dosages approaching 500 mg/day (28) The clinical implication is that lamotrigine dose and dose escalation will need to be substantially reduced in order

to reduce the potential for adverse effects (including perhaps severe rash)

Topiramate may decrease the clearance of oin, suggesting inhibition of CYP2C19 Topiramate has been shown to increase phenytoin serum concentration

phenyt-in some patients While this phenyt-interaction is not clphenyt-inically meaningful in most patients, given the non-linear phar-macokinetics of phenytoin, the potential does exist for this interaction to result in phenytoin intoxication

A significant advancement of oxcarbazepine over

carbamazepine is its lack of susceptibility to inhibitory

interactions Consistent with its differing metabolism (as compared to carbamazepine), oxcarbazepine’s pharmaco-kinetics are not altered by erythromycin Oxcarbazepine

Tolbutamide Acetohexamide Glibenclamide Ciprofloxacin

Erythromycin Fluconazole

PHT

CBZ, BZD, VPA PHT

PB increases metabolism; dosage of adrenergic blockers may need to be increased.

Patients on enzyme inducers such as CBZ, PHT, and PB may be at greater risk of hepatotoxicity following acetaminophen overdose Acetaminophen appears to slightly increase the elimination of LTG.

Enzyme inducers (CBZ, PHT, PB) increase the toxicity and decrease the efficacy of meperidine by increasing the conversation to normeperidine.

Propoxyphene inhibits CBZ elimination and may lead to CBZ toxicity Propoxyphene should be avoided if possible.

High-dose salicylates displace PHT and VPA from protein-binding sites and may decrease VPA elimination.

PB and PHT may increase hepatic metabolism

of disopyramide and require dosage adjustments.

Enzyme inducers can substantially decrease mexiletine serum concentrations.

Enzyme inducers decrease serum concentrations of quinidine.

Inducers increase warfarin metabolism and decrease hypoprothrombinemic effect.

Induction of tricyclic metabolism Dosage may require adjustment.

Enzyme inducers increase elimination and decrease hypoglycemic effects.

Ciprofloxacin increases serum PHT concentrations, probably by decreasing phenytoin elimination.

Erythromycin decreases biotransformation and can markedly increase serum concentrations Fluconazole decreases biotransformation of PHT and can result in marked increase in serum concentrations.

IV • GENERAL PRINCIPLES OF THERAPY 540

is a weak inhibitor of CYP2C19, however, and, like

topiramate, it may increase the plasma concentrations

of phenytoin (1)

Because of their primarily renal clearance, and

absence of substantial hepatic metabolism, levetiracetam,

gabapentin, and pregabalin are not subject to inhibition

In addition, none of these drugs appears to cause

inhibi-tion of metabolism of any other medicainhibi-tion

Interactions Between AEDs and Other Medications

Traditionally, most attention regarding AED cokinetic interactions has been directed toward inter-actions between various combinations of AEDs It is important for the clinician to recognize the potential impact that AEDs may have on concomitant medications that a patient receive For example, many psychotropic

Dichlorphenamide Methazolamide Dexamethasone

Hydrocortisone Methylprednisolone Prednisone

Cimetidine Clozapine Enteral feedings Nafimidone Ritonavir Fluoxetine

PHT

CBZ, PHT, VPA BZD, PHT, VPA TPM

CBZ, PB, PHT

CBZ, PHT, BZD, ESM CBZ

PHT CBZ, PHT BDZ, ESM CBZ

Cytotoxic agents appear to decrease oral absorption of PHT with marked reductions in serum PHT concentrations.

Isoniazid decreases CBZ, PHT, and VPA elimination and may lead to toxicity.

Rifampin increases elimination; dosage adjustments may be necessary.

Concomitant use may lead to increased risk of nephrolithiasis.

Enzyme inducers increase metabolism of steroids and decrease efficacy Decreased PHT absorption and subsequent decrease in serum concentrations.

Cimetidine decreases biotransformation of CBZ and PHT and may lead to toxicity.

May result in increased risk of bone marrow suppression.

Decreased PHT absorption and marked decreased in serum concentration.

May result in CBZ toxicity

Ritonavir decreases biotransformation of BDZ and ESM and may lead to toxicity.

Fluoxetine has been reported to result in CBZ toxicity by inhibiting CYP3A3/4.

BDZ benzodiazepines; CBZ carbamazepine; LTG lamotrigine; PB phenobarbital; PHT phenytoin; PRM primidone; VPA valproic acid; ESM ethosuximide; TPM topiramate; MSM methsuximide

Source: McInnes and Brodie 1988 (39).

agents, including tricyclic antidepressants, selective

serotonin reuptake inhibitors (SSRIs), and antipsychotic

drugs are extensively metabolized by one or more of

the CYP isozymes (29) This would imply that higher

than expected doses of these drugs may be required in

patients receiving enzyme-inducing AEDs such as

phe-nytoin or carbamazepine Conversely, enzyme-inhibiting

drugs such as valproate may inhibit the clearance of

certain psychotropic drugs such as amitriptyline,

nor-triptyline, or paroxetine (1, 2)

For example, AEDs such as carbamazepine and

phenytoin have been reported to increase the clearance,

and consequently markedly lower the serum

concentra-tion, of a number of antipsychotic medications

includ-ing haloperidol, chlorpromazine, clozapine, risperidone,

ziprazidone, and olanzapine (2, 30) Valproate appears

to have minimal pharmacokinetic interactions impact on

these drugs (31, 32)

Antipsychotic drugs are less likely to cause

phar-macokinetic interactions with AEDs, although both

chlorpromazine and thioridazine have been reported to

result in increases in phenytoin serum concentrations

Risperidone has been noted to result in modest decreases

in carbamazepine concentrations (33)

Many commonly used antidepressant agents such

as tricyclics and SSRIs are also metabolized via the CYP

system Consequently, it would be expected that drugs

such as amitriptyline, nortriptyline, imipramine,

desip-ramine, clomipdesip-ramine, protriptyline, doxepin, sertraline,

paroxetine, mianserin, citalopram, and nefazodone may

display reduced serum concentrations in patients

receiv-ing enzyme-inducreceiv-ing AEDs (1, 2, 34, 35) Conversely,

comedication with the enzyme inhibitor valproate may

cause substantial (50–60%) increases in serum

concentra-tions of drugs such as amitriptyline and nortriptyline

AED-antidepressant interactions may be

bidirec-tional, and the clinician should recognize that treatment

with certain drugs may result in increased serum centrations of AEDs, particularly the older, extensively metabolized agents For example, there are data that suggest that SSRIs such as fluoxetine and sertraline can result in increased phenytoin and carbamazepine serum concentrations

con-Examples of other classes of drugs that are sively metabolized and therefore may be influenced by enzyme-inducing AEDs include stimulants (i.e., methyl-phenidate), antineoplastics, immunosuppressants, beta receptor antagonists, oral contraceptives, and many anti-viral agents such as indinavir, retonavir, and saqquinavir (1, 2, 36–38) Table 39-2 provides a representative list of potential AED–non-AED interactions (39)

exten-SUMMARY

Polypharmacy with multiple concomitant medications is common in patients of all ages who suffer from epilepsy Clinicians should be aware that many of the older, tra-ditional AEDs such as carbamazepine, phenytoin and the barbiturates have been consistently associated with pharmacokinetic interactions, both with other AEDs, as well as many commonly used medications In many cases, these interactions may go unrecognized, as routine serum concentration monitoring is not available, or practical in all situations It would seem prudent therefore for clini-cians to monitor clinical response to concomitant medi-cations, and consider potential drug interactions, should sub-optimal patient response (including the appearance

of adverse effects) be noted

Alternatively, clinicians may want to consider using appropriate newer generation AEDs such as that do not seem to interfere, either with drug metabolism, or oral absorption/transport, and thereby avoid these potentially problematic interactions

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ANTIEPILEPTIC DRUGS AND KETOGENIC DIET V

ACTH and Steroids

he efficacy of adrenocorticotropin (ACTH) therapy in childhood sei-zures was first observed by Klein and Livingston in 1950 in a series of children with atypical absence seizures (1) In 1958, Sorel

and Dusaucy-Bauloye reported that ACTH was effective

in children with infantile spasms (IS) These authors not

only reported seizure control in children with IS treated

with ACTH but also observed improvements in

behav-ior and electroencephalogram (EEG) (2) Subsequently,

a number of studies appeared that reported on the

effi-cacy of corticosteroids in IS and confirmed the utility

of ACTH in the treatment of this disorder Both ACTH

and corticosteroids have been used in treating a number

of epilepsy syndromes, including Ohtahara syndrome,

Lennox-Gastaut syndrome and other myoclonic

epilep-sies, and Landau-Kleffner syndrome (3) The epilepsy

syndromes that respond uniquely to ACTH and

cortico-steroid therapy have an age-related onset during a critical

period of brain development, as well as a characteristic

regression or plateau of acquired milestones at seizure

onset, and long-term cognitive impairment (4) In

addi-tion to beneficial effects on the convulsive state, there are

some data to suggest that ACTH, corticosteroids, or both

also can improve the short-term developmental trajectory

and the long-term prognosis for language and cognitive

development in at least some of these patients (5–9)

Rajesh RamachandranNair

O Carter Snead, III

In this review, we will first discuss the evidence in support of the use of steroids in IS This will be fol-lowed by a review of possible mechanisms of the puta-tive anticonvulsant effects of ACTH and corticosteroids This will be followed by a discussion of the use of these compounds in epilepsy syndromes other than IS Finally,

we will review the therapeutic potential of neuroactive steroids in epilepsy

INFANTILE SPASMS

In 1841, William West, an English physician, provided the first description of IS in his own 4-month old son (10) Later, the association of IS with the sequelae of severe mental deficiency emerged In 1952, Gibbs and Gibbs first described the interictal EEG pattern associated with infantile spasms and termed it hypsarrhythmia This pat-tern was unique and described as showing high-voltage, chaotic slowing with multifocal spikes, and marked asyn-chrony (11) Over the years, the triad of infantile spasms, hypsarrhythmia, and mental retardation became known

as West syndrome (12)

After 1958, studies began to appear in the literature reporting the effectiveness of corticosteroids in the treat-ment of this disorder (12) There is a marked variability

of response rates to these therapeutic agents that probably

T

40

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 546

is related to the small cohorts reported and the paucity of

controlled treatment data Another confound is that the

natural history of IS is poorly understood, particularly

the phenomenon of spontaneous remission Moreover,

the literature is replete with marked variations in the

dosage of ACTH and/or corticosteroids given, and in

treatment duration, of both drugs In most studies, an

objective method of documenting spasm cessation has not

been used and response to therapy has been defined in a

graded manner, although there is no convincing evidence

that spasms respond in a graded fashion to any form

of therapy Usually IS respond in an all-or-none fashion

to treatment with ACTH and/or corticosteroids Finally,

most studies have been uncontrolled, unblinded, and

ret-rospective, complicating the establishment of

evidence-based recommendations for optimal treatment (12)

The controversies surrounding the treatment of IS

outnumber the areas of agreement and encompass the

following questions: Which is the most effective therapy:

ACTH or corticosteroid? Are other anticonvulsants such

as vigabatrin, valproic acid, benzodiazepines,

topira-mate, zonisamide, or pyridoxine effective against

infan-tile spasms? Is there some other treatment regimen with

newer antiepileptic drugs that is effective against infantile

spasms? What is the impact of treatment with ACTH

compared with corticosteroids on long-term outcome

in recurrence of spasms, evolution into other forms of

intractable epilepsy, and cognitive or behavioral

func-tion? Does treatment change the outcome for a patient

with preexisting mental retardation and a structurally

abnormal brain? What is the optimal dosage of these

drugs, and how long should treatment last? Does the

ultimate outcome depend on timing of treatment? Does

the efficacy of ACTH depend on the formulation (natural

vs synthetic, sustained vs short-acting)?

Some of these questions were addressed in a recently

published American Academy of Neurology (AAN)/Child

Neurology Society (CNS) Practice Parameter on the

treat-ment of infantile spasms (13) In the following few

para-graphs we will discuss the key issues addressed by this

practice parameter Important studies published

subse-quent to the practice parameter also will be discussed in

the relevant sections

Summary of the AAN/CNS Practice Parameter

on the Treatment of Infantile Spasms

Three major questions were addressed in the practice

parameter

1 What are the most effective therapies for infantile

spasms, as determined by short-term outcome

mea-sures, including complete cessation of spasms,

reso-lution of hypsarrhythmia, and likelihood of relapse

following initial response?

2 How safe are currently used treatments?

3 Does successful treatment of infantile spasms lead

to long-term improvement of neurodevelopmental outcome or a decreased incidence of epilepsy?Articles included for critical analysis pursuant to answer-ing these questions and formulating treatment recommen-dations for infantile spasms had the following inclusion criteria (14–27):

1 A clearly stated diagnosis of infantile spasms

2 An EEG demonstrating hypsarrhythmia or modified hypsarrhythmia

3 Age of 1 month to 3 years

Infantile spasms were classified as either symptomatic

or cryptogenic as defined by the International League Against Epilepsy (ILAE)

Outcome measures included short- and long-term measures Short-term outcome measures were defined as the following:

1 Complete cessation of spasms

2 Resolution of hypsarrhythmia and, where mented, normalization of EEG

in Table 40-1 Depending on the strength of the evidence under this classification system, specific recommenda-tions were made The strength of these recommendations

of IS with oral corticosteroids (level U) ACTH was more effective than oral corticosteroids in causing the cessation

of seizures Side effects reported for ACTH were common and included hypertension, irritability, infection, revers-ible cerebral shrinkage, and, rarely, death due to sepsis

Although vigabatrin (VGB) is not a steroid, its use

in infantile spasms is relevant to this review because roids and vigabatrin are generally considered to be the only two groups of drugs that work in this disorder—an impression borne out by the Practice Parameter (13) In the analysis that led to the AAN/CNS practice parameter, the evidence for the therapeutic efficacy of vigabatrin in

ste-IS was weaker than that for ACTH (level C for vigabatrin

vs level B for ACTH) Hence, vigabatrin was found to be possibly effective for the short-term treatment of IS

As for the efficacy of ACTH in improving the term outcomes in terms of seizure freedom and normal development of children with IS, the data were insuf-ficient (28–31) in that regard (Level U, class III and IV evidence) Similarly, there was insufficient evidence to support the thesis that early initiation of treatment with ACTH improves the long-term outcome of children with

long-IS (Level U, class III and IV evidence)

More recently, the United Kingdom Infantile Spasms Study (32) assessed comparative efficacy of vigabatrin and hormonal treatment of IS in a randomized controlled trial The primary outcome was cessation of spasms on days 13 and 14 Minimum doses were VGB 100 mg/kg per day, oral prednisolone 40 mg per day, or intramuscu-lar tetracosactide depot 0.5 mg (40 IU) on alternate days

Of 208 infants screened and assessed, 107 were randomly

no spasms on days 13 and 14 consisted of: 40 (73%) of

55 infants assigned hormonal treatments (prednisolone 21/30 [70%], tetracosactide 19/25 [76%]) and 28 (54%)

of 52 infants assigned VGB (difference 19%, CI 1–36%,

of 55 infants on hormonal treatments and 28 (54%) of

52 infants on VGB This study concluded that cessation

TABLE 40-1

American Academy of Neurology Evidence

Classification Scheme for a Therapeutic Article

Class I Evidence provided by a prospective,

randomized, controlled clinical trial

with masked outcome assessment, in

a representative population The

following are required: (a) Primary

outcome(s) is/are clearly defined; (b)

exclusion/inclusion criteria are clearly

defined; (c) dropouts and crossovers

are accounted for adequately with

numbers sufficiently low to have

minimal potential for bias; and (d)

relevant baseline characteristics are

presented and substantially

equivalent among treatment groups,

or there is appropriate statistical

adjustment for differences.

Class II Evidence provided by a prospective

matched-group cohort study in a

representative population with

masked outcome assessment that

meets (a)–(d) as defined for Class I

or a randomized controlled trial in a

representative population that lacks

one criterion of (a)–(d).

Class III All other controlled trials (including

well-defined natural history controls

or patients serving as own controls)

in a representative population, where

outcome assessment is independent

of patients’ treatment.

Class IV Evidence from uncontrolled studies,

case series, case reports, or expert

opinion.

TABLE 40-2

American Academy of Neurology System for Translation of Evidence to Recommendations

Level A rating requires at least one convincing class I

study or at least two consistent, convincing class II

studies.

Level B rating requires at least one convincing class II

study or at least three consistent class III studies.

Level C rating requires at least two convincing and

consistent class III studies.

A established as effective, ineffective, or harmful for the given condition in the specified population.

B probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population.

C possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/ predictive) for the given condition in the specified population.

U data inadequate or conflicting Given current knowledge, treatment is unproven.

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 548

of spasms was more likely in infants given hormonal

treatments than in those given VGB

Infants enrolled in the United Kingdom Infantile

Spasms Study were followed up until clinical assessment

at 12–14 months of age (33) Neurodevelopment was

assessed with the Vineland Adaptive Behavior Scales

(VABS) at 14 months of age Of 107 infants enrolled,

five died, and 101 survivors reached both follow-up

assessments Absence of spasms at final clinical

assess-ment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%])

was similar in each treatment group Mean VABS score

did not differ significantly (hormone 78.6 vs vigabatrin

77.5) In infants with no identified underlying etiology,

the mean VABS score was higher in those allocated

hor-mone treatment than in those allocated vigabatrin (88.2

vs 78.9; difference 9.3, 95% CI 1.2–17.3) This study

reported that better initial control of spasms by hormone

treatment in those with no identified underlying etiology

might lead to improved developmental outcome

Kivity and coworkers assessed the long-term

cogni-tive and seizure outcomes of 37 patients with cryptogenic

infantile spasms (onset, age 3 to 9 months) receiving a

standardized treatment regimen of high-dose

tetracos-actide depot, 1 mg intramuscularly (IM) every 48 hours

for 2 weeks, with a subsequent 8- to 10-week slow taper

and followed by oral prednisone, 10 mg/day for a month,

with a subsequent slow taper for 5 months or until the

infant reached the age of 1 year, whichever came later (8)

Cognitive outcomes were determined after 6 to 21 years

and analyzed in relation to treatment lag and

pretreat-ment regression Normal cognitive outcome was found

in all 22 (100%) patients of the early-treatment group

(within 1 month), and in 40% of the late-treatment group

(1–6.5 months) Normal cognitive outcome was found in

all 25 (100%) patients who had no or only mild mental deterioration at presentation, including four in the late-treatment group but in only three of the 12 patients who had had marked or severe deterioration before treatment This study indicated that early treatment of cryptogenic infantile spasms with a high-dose ACTH protocol was associated with favorable long-term cognitive outcomes Once major developmental regression lasted for a month

or more, the prognosis for normal cognitive outcome was poor

Practical Considerations Regarding Dosage

Table 40-3 lists the currently available formulations of ACTH The biologic activity, expressed in international units (IU), permits a comparison of potency in terms of the relative ability of the peptide to stimulate the adrenals, but may not necessarily reflect the ability of the ACTH preparation to affect brain function The biologic activity

of natural ACTH in the brain may differ from that of thetic ACTH as a result of ACTH fragments and possibly other pituitary hormones with neurobiologic activity in the brain that are present in the pituitary extracts (5) These compounds could enhance the therapeutic efficacy

syn-of natural ACTH (34) Any differences in the biologic effects of sustained ACTH levels provided by the depot formulations, as opposed to those of the short-acting preparations, are unknown Given in high doses, how-ever, long-acting depot preparations are associated with

an increased incidence of severe side effects, including death from overwhelming infection

The most effective dose of ACTH for remission

of spasms is controversial Notably, in comparison to prednisone, no major advantage was demonstrated by

TABLE 40-3

Available Preparations of ACTH

Corticotropin (ACTH 1-39): porcine pituitary extract (short-acting)

Acthar gel 80 IU/mL 100 IU* 0.72 mg Acthar lyophylized powder 100 IU* 0.72 mg Cosyntropin/Tetracosactrin (ACTH 1-24): synthetic

*Commercial preparations are described in International Units (IU) based on a potency assay

in hypophysectomized rats in which depletion of adrenal ascorbic acid is measured after neous ACTH injection.

subcuta-low-dose ACTH, whereas high-dose ACTH was reported

to be superior (15, 25) High-dose ACTH (60 IU/day

excel-lent short-term response rates (87–93%) in prospective

studies (14, 25) However; in the only randomized,

pro-spective comparison of ACTH, Hrachovy and coworkers

found no difference between high dose and low dose (16)

A prospective study of synthetic ACTH by Yanagaki and

coworkers compared very low-dose ACTH (0.2 IU/kg per

day) to low-dose (1 IU/kg per day) and found equivalent

efficacy, with response and relapse rates comparable to

other studies (18) Heiskala et al described a protocol

that utilized a stepwise increase in dosage,

demonstrat-ing that some patients can be controlled on lower doses

of carboxymethylcellulose ACTH (3 IU/kg per day) but

others required high doses (12 IU/kg per day) Overall,

spasms were controlled initially in 65% of patients, but

the rate of relapse was high (35)

Some evidence supports a beneficial effect of

high-dose ACTH over low-high-dose ACTH or oral steroids in

cognitive outcome Glaze and coworkers found no

dif-ference between low-dose ACTH (20 to 30 IU/day) and

prednisone (2 mg/kg per day) with regard to the cognitive

outcome (31) However, in a comparison of high-dose

Lom-broso showed a higher rate of normal cognitive outcome

in cryptogenic patients treated with ACTH than in those

treated with prednisone alone (55% vs 17%) (5) Ito and

coworkers also showed a positive correlation between

dose and developmental outcome comparing different

ACTH dosage regimens retrospectively (36)

The optimal ACTH dose may lie between 85 and

250 IU/m2 per day Doses of 400 IU/m2 per day or higher

are contraindicated because of a high incidence of

life-threatening side effects The optimal dose of ACTH

required to enhance short-term response and long-term

cognitive outcome is unknown; however, relatively high

doses given early in the disease, accompanied by a second

course in the event of relapse, appear warranted The

following high-dose ACTH protocol (21, 25) has been

used successfully by us in treating more than 700 children

with infantile spasms

The child is admitted to a day-care unit to initiate

ACTH therapy and to teach parents to give the injection,

measure urine glucose three times daily with Chemstix,

and recognize spasms to keep an accurate seizure

calen-dar Any diagnostic workup indicated by clinical

circum-stances is also performed, including screening for occult

congenital infections Before ACTH is started, an

endo-crine profile, complete blood count, urinalysis, electrolyte

panel, baseline renal function, and calcium, phosphorus,

and serum glucose levels are obtained Blood pressure and

electrocardiogram are also assessed The drug is not given

if any of these studies show abnormal results Diagnostic

neuroimaging is indicated before initiation of ACTH or

steroids because of the association of ACTH treatment with ventriculomegaly The initial dose of ACTH is 150 IU/

in the third week Over the next 6 weeks, the dose is gradually tapered The lot number of the ACTH gel is carefully recorded Usually, a response is seen within the first 7 days; if no response is noted in 2 weeks, the lot

is changed

Blood pressure must be measured daily at home during the first week and three times weekly thereafter Control of hypertension is attempted with salt restriction and amlodipine therapy rather than discontinuation of ACTH The patient is monitored in the outpatient clinic weekly for the first month and then biweekly, with appro-priate blood work at each visit Waking and sleeping EEG patterns are obtained 1, 2, and 4 weeks after the start

of ACTH to assess treatment response As the treatment response is usually all or none, positive results are sug-gested when properly trained parents report no seizures

in a child, whose waking and sleeping EEG patterns are normal If relapse occurs, the dose may be increased to the previously effective dose for 2 weeks and another tapering begun If seizures continue, the dose may be increased to

If prednisone is chosen because of its oral lation and lower incidence of serious side effects, the pretreatment laboratory evaluation described earlier is performed The initial dose is 3 mg/kg per day in four divided doses for 2 weeks, followed by a 10-week taper (25) A multiple-daily-dose regimen is recommended to produce the sustained elevations of plasma cortisol dem-onstrated in high-dose ACTH therapy

formu-Adverse Effects of ACTH and Steroids

ACTH and steroids, particularly at the high doses mended for infantile spasms, can produce dangerous side effects These are more frequent and more pronounced with ACTH (37) Cushingoid features and extreme irri-tability are seen frequently; hypertension is less common but appears to be associated with higher doses Vigilance

recom-is required for signs of sepsrecom-is; pneumonia; glucosuria; metabolic abnormalities involving the electrolytes cal-cium and phosphorus (38–40); and congestive heart failure (41, 42) Cerebral ventriculomegaly, which is not always reversible, can lead to subdural hematoma (43, 44) The cause of the apparent cerebral atrophy is obscure, but its existence emphasizes the importance of diagnostic neuroimaging before initiation of ACTH.Because hypothalamic-pituitary or adrenocortical dysfunction can result from ACTH therapy, morning lev-els of cortisol should be monitored during a taper and any medical stress treated with high-dose steroids (45–47)

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 550

Treatment with ACTH or steroids also can be

immu-nosuppressant and associated with infectious

complica-tions, such as overwhelming sepsis, perhaps as a result

of impaired function of polymorphonuclear leukocytes

(48) Both agents are therefore contraindicated in the face

of serious bacterial or viral infection such as varicella

or cytomegalovirus Because of the potential for fatal

Pneumocystis pneumonia as an infectious complication

of ACTH therapy, prophylaxis with

trimethoprim-sulfamethoxazole, accompanied by folate

supplementa-tion and frequent blood counts, may be prudent in infants

older than 2 months of age In rare cases, ACTH can

exacerbate seizures (49)

Potential Mechanisms of Action of ACTH in

Infantile Spasms

ACTH is a 39-amino-acid peptide hormone produced,

through post-translational modification of the larger

peptide pro-opiomelanocortin (POMC), in the anterior

pituitary POMC expression, processing to ACTH, and

ACTH secretion are stimulated by corticotropin-releasing

factor (CRF) generated in the hypothalamus, and these

processes are under negative feedback control by

gluco-corticoids (50) ACTH secretion is pulsatile and normally

has a pronounced diurnal variation, but secretion also

increases substantially in response to a range of stressors

The effects of ACTH are mediated via stimulation of the

G-coupled cell surface ACTH receptor, which is expressed

primarily on adrenocortical cells This receptor is a

mem-ber of the melanocortin family and is alternatively known

as the melanocortin-2 (MC-2) receptor ACTH acutely

stimulates the synthesis of cortisol in the adrenal gland

ACTH also increases the long-term capacity of the

adre-nal gland to generate cortisol by inducing a range of

ste-roidogenic enzymes and hypertrophy of the cortex (51)

ACTH additionally has the capacity to cross-react with

other melanocortin receptors (52)

The pathogenesis of infantile spasms, and therefore

the mechanism of action of ACTH and steroids in this

condition, are unknown, principally because there is no

available animal model for this disorder Infantile spasms

occur within a narrow developmental window in terms of

age of onset and can be found concurrently with a variety

of congenital abnormalities of brain, which may be

caus-ally linked—so-called symptomatic spasms However, IS

also may occur without apparent cause in children with

no pre-existing neurologic abnormality at the onset of

spasms (i.e., idiopathic spasms) Those children who are

not neurologically normal when the spasms appear, yet

have no demonstrable imaging or metabolic abnormality,

are said to have cryptogenic spasms

The effect of ACTH and corticosteroids in

infan-tile spasms is frequently all or none, and the

steroid-induced seizure-free state is often sustainable even after

drug withdrawal These observations support the theory that due to various etiologies, a significant stress response

is experienced by the developing brain; resulting in this age-dependent epileptic encephalopathy Within this very narrow developmental window, ACTH and steroids may

be able to reset the deranged homeostatic mechanisms of the brain, thereby reducing the convulsive tendency and improving the developmental trajectory

The Brain-Adrenal Axis There is evidence to suggest

that the effects of ACTH in infantile spasms may be independent of steroidogenesis Efficacy studies have demonstrated superiority of ACTH to corticosteroids in treating infantile spasms and also its efficacy in adrenal-suppressed patients Substantial physiologic and phar-macologic data indicate that ACTH has direct effects

on brain function: increasing dendritic sprouting in immature animals; stimulation of myelination; regula-tion of the synthesis, release, uptake, and metabolism

of dopamine, norepinephrine, acetylcholine, serotonin, and gamma-aminobutyric acid (GABA); regulation of the binding to glutamatergic, serotoninergic, muscarinic type 1, opiate, and dopaminergic receptors; and altera-tion of neuronal membrane lipid fluidity, permeability, and signal transduction (53–57) Though activation of glucocorticoid receptors has little direct anticonvulsant effect, it modulates the expression and release of a num-ber of neurotransmitters and neuromodulators, including the proconvulsant neuropeptide corticotropin-releasing hormone (CRH) High brain CRH levels would be pre-dicted to reduce the cerebrospinal fluid ACTH and ste-roids (58) Many authors have reported reduced levels

of ACTH in patients with infantile spasms, compared

to their age-matched controls (59, 60) In infant animal models CRH causes seizures and death of neurons (61) These effects of CRH are most marked in developing brain (62) Suppression of the after-hyperpolarization and activation of the glutamatergic neurotransmission are the possible mechanisms by which CRH may mediate these effects In animals, ACTH appears to down-regulate the CRH expression in amygdala This effect was found

to be independent of glucocorticoid receptor activation but required melanocortin receptors (63) ACTH reduces CRH gene expression in specific brain regions This effect has been demonstrated in the absence of adrenal steroids and resides within the 4-10 fragment of ACTH, a frag-ment that does not release adrenal steroids Melanocor-tin receptor antagonists blocked this effect, suggesting that the melanocortin receptors are the targets of ACTH action (63)

A hypothesis, therefore, can be generated in which a stress response results in enhanced CRH expression, lead-ing to neuronal hyperexcitability and seizures By sup-pressing CRH expression, possibly through the action of peptide fragments of ACTH on melanocortin receptors,

the CRF-induced hyperexcitability may be reduced, hence

ameliorating infantile spasms Clinical trials of ACTH

fragments that have no activity on the adrenal axis have

been disappointing (64); however, these clinical trials

have utilized the 4-9 peptide fragment rather than the

4-10 peptide fragment studied in animal models

The events that precipitate this proposed endocrine

abnormality remain unclear

THE USE OF ACTH AND CORTICOSTEROIDS

IN OTHER SEIZURE DISORDERS

There is limited information concerning treatment of

other intractable seizure disorders with ACTH and/or

steroids The Ohtahara and Lennox-Gastaut syndromes

are believed to represent earlier and later manifestations,

respectively, of a spectrum of infantile epileptic

encepha-lopathies that include infantile spasms These conditions

respond poorly to traditional anticonvulsant drug

ther-apies but are sometimes improved by the antiepileptic

drugs used in infantile spasms: ACTH, steroids,

benzodi-azepines, and valproic acid ACTH or steroids also may

be beneficial in Landau-Kleffner syndrome (65)

Ohtahara Syndrome

The Ohtahara syndrome, also known as early infantile

epileptic encephalopathy (EIEE), is characterized by

spasms beginning within the first three months of life

associated with persistent burst suppression on the EEG

in all stages of the sleep-wake cycle Despite reports of

improvement in seizures in Ohtahara syndrome

follow-ing ACTH, vigabatrin, and/or zonisamide therapy, the

long-term prognosis is usually unchanged by any

treat-ment (66) Mortality in this epilepsy syndrome is high,

and survivors are usually severely handicapped If used,

ACTH should be administered as described for infantile

spasms

Lennox-Gastaut Syndrome and Other

Myoclonic Seizure Disorders

ACTH and steroids have been found to be useful in

younger children with various combinations of severe

and intractable seizures, particularly atypical absence,

myoclonic, tonic, and atonic seizures This group includes

patients with Lennox-Gastaut syndrome, a disorder

characterized by mental retardation, generalized slow

spike-and-wave discharges, intractable atypical absence,

myoclonus, and frequent ictal falls Snead and coworkers

treated 64 children who had myoclonic seizures without

EEG evidence of hypsarrhythmia, or other intractable

sei-zures with either prednisone or ACTH Seventy-three

per-cent of the children treated with ACTH achieved seizure

control, as opposed to none of the prednisone-treated

observed on discontinuation of the ACTH (25)

In 45 cases of Lennox-Gastaut syndrome treated with ACTH, the immediate and long-term effects and the various factors affecting them were investigated by

a follow-up study (67) Twenty-three (51.1%) of the 45 children became “seizure free” for over 10 days Ten children relapsed into Lennox syndrome within 6 months, and in the remaining 13 children, seizures were sup-pressed for over 6 months Of these 13 patients, seizure relapse was observed in eight from 9 months to 7 years later The other five children followed a favorable course without relapse Sinclair treated 10 children with Lennox Gastaut syndrome and intractable seizures with predniso-lone at a dose of 1 mg/kg/day for six weeks followed by withdrawal over the next 6 weeks, and achieved seizure freedom in 7 and seizure reduction in 3 children Long-term outcome was not mentioned (68)

In summary, several uncontrolled, retrospective studies suggest that ACTH is superior to oral steroids

in Lennox-Gastaut syndrome If the decision is made to embark upon such treatment for Lennox-Gastaut syn-drome, the regimen described in this chapter for ACTH

or prednisone is recommended Nevertheless, ACTH and steroids should be reserved for the most severe and intrac-table patients Usually, the best result is temporary relief, because 70% to 90% of patients with multiple seizure types suffer a relapse during the ACTH taper As well, older patients with Lennox-Gastaut syndrome do not tolerate high dose ACTH as well as those children under the age of 2 years who are receiving the same regimen for infantile spasms

Uncontrolled trials of steroids or tropic hormone also have been reported to reduce seizure frequency in severe myoclonic epilepsy of childhood (69), but without a favorable impact on the overall outcome Myoclonic astatic epilepsy, first described by Doose, is another age-dependent epileptic disorder, characterized

adrenocortico-by the onset of myoclonic and astatic seizures between 7 months and 6 years of age in a previously normal child, associated with generalized discharges on the EEG This disorder is resistant to most conventional antiepileptic drugs Oguni and coworkers retrospectively analyzed

81 patients with myoclonic-astatic epilepsy of early hood to investigate the most effective treatment The most effective treatments were ketogenic diet, followed

child-by ACTH and ethosuximide (70)

Landau-Kleffner Syndrome and Related Disorders

Described in 1957, Landau-Kleffner syndrome, also known as acquired epileptic aphasia, is characterized

by regression in receptive and expressive language,

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 552

associated with epileptic seizures (71) The usual

pre-sentation occurs between the ages of 2 and 8 years

Behavioral disturbances are frequent, ranging from

hyperactivity and aggression to autism and global

cog-nitive deterioration Some children display sustained

agnosia and mutism Others show a waxing and

wan-ing course that parallels the EEG changes Spontaneous

resolution also has been reported The

electroencephalo-gram typically shows 1- to 3-Hz high-amplitude spikes

and slow waves; these may be unilateral, bilateral,

unifo-cal, or multifounifo-cal, but often include the temporal region

with or without parietal and occipital involvement, and

are activated during sleep

Valproate and benzodiazepines may control the

clinical seizures but have only a partial and transient

effect on the EEG abnormalities (72) In 1974, McKinney

and McGreal described the beneficial effect of ACTH

on the characteristic seizures, language regression, and

behavioral changes in Landau-Kleffner syndrome (73)

Since then, although no controlled prospective trials of

ACTH or steroids have been published, case reports and

retrospective series have demonstrated improvements in

seizure control and language in children treated with

varying ACTH or corticosteroid regimens Marescaux

and coworkers reported that corticosteroid treatment

resulted in improved speech, suppression of seizures,

and normalization of the EEG in three of three children

with Landau-Kleffner syndrome (74) Four children with

Landau-Kleffner syndrome received early and prolonged

ACTH or corticosteroid therapy, with high initial doses

(75) In all four cases the EEG promptly became normal,

with subsequent long-lasting remission of the aphasia

and improvement of seizure control Three to six years

after discontinuation of hormone therapy the children

were off medication and free from seizures and language

disability Sinclair and Snyder treated 10 children who

had Landau-Kleffner syndrome (8 patients) and

continu-ous spike wave discharge during sleep (2 patients) with

steroids Nine children had significant improvement in

language and behavior (76) Use of ACTH or

corticoste-roids in patients with Landau Kleffner syndrome appears

justified; however, further study of dose and duration of

therapy is warranted If ACTH or corticosteroids are

chosen to treat LKS, a high-dose regimen, as described

in this chapter for infantile spasms, is recommended,

with a longer tapering schedule and concomitant use of

valproic acid

Rasmussen Encephalitis

Rasmussen encephalitis is a focal progressive

inflamma-tory condition of the brain, of unclear etiology Rasmussen

encephalitis is characterized by malignant, progressive,

and intractable partial seizures with a high incidence of

epilepsia partialis continua Treatments advocated in

Rasmussen include anticonvulsants, high-dose steroids, ACTH, intravenous immunoglobulin G (IV IgG), plas-mapheresis, antiviral agents, and hemispherectomy (77) Dulac, in 1992 (78), reported the results of high-dose

prednisone, in seven patients with epilepsia partialis tinua Six of the seven showed an improvement in seizure control, which was variably sustained over a two-year follow-up period Hart (79) reported a benefit of steroids, with 10 of 17 patients showing a reduction of 25–75%

con-in seizure frequency Granata and coworkers reported positive time-limited responses in 11 of 15 patients with Rasmussen encephalitis, using variable combinations of corticosteroids, apheresis, and high-dose IV immuno-globulins (80)

NEUROSTEROIDS

The term neurosteroid was coined by Etienne Baulieu

(81) and Paul Robel (82) to refer to pregnenolone, 20-alphaOH-pregnenolone, and progesterone synthesized

in the brain A more general definition would include all steroids synthesized in the brain The phrase “neuroac-tive steroids” refers to steroids that are active on neural tissue Therefore, they may be synthesized endogenously

in the brain or may be synthesized by classic endocrine tissue but act on neural tissues (83)

Anticonvulsant Properties of Neurosteroids

Grosso and coworkers investigated serum lone levels in 52 children with active epilepsy at pubertal Tanner stage I The interictal serum allopregnanolone levels in the epileptic children were not statistically dif-ferent from those detected in the control group, whereas postictal levels were significantly higher than the interictal ones In this subgroup of patients, allopregnanolone levels decreased to the basal values within 12 hours of the sei-zure Serum allopregnanolone levels may reflect changes

allopregnano-in neuronal excitability, and allopregnanolone appears

to be a reliable circulating marker of epileptic seizures

It is possible that increased postictal serum levels of pregnanolone may play a role in modulating neuronal excitability and represent an endogenous mechanism of seizure control (84)

allo-The brain regulates hormonal secretion and is sitive to hormonal feedback This is particularly true of certain highly epileptogenic mesial temporal lobe regions, such as the amygdala and hippocampus (85) The amyg-dala, in particular, is linked directly to regions of the hypothalamus that are involved in the regulation, pro-duction, and secretion of ovarian steroids (86) Neurons containing corticotropin-releasing factor are particularly prominent in the central division of the extended amyg-

sen-dala (87), which shows structural changes in temporal

lobe epilepsy (88) Seizures, if occurring in a repetitive

manner, are stressful events for the organism, which can

cause lack of inhibitory control in the

pituitary axis system (89, 90) Thus,

hypothalamus-pituitary axis dysfunction might be induced in epileptic

disorders independent of the localization of the focus

Notably, stress and seizures can alter levels of gonadal,

adrenal, and neuroactive steroids, which may then

influ-ence subsequent seizure activity (91)

Anovulatory cycles are associated with greater

seizure frequency (92, 93) This phenomenon may be

due to high serum estradiol-to-progesterone ratios that

characterize the inadequate luteal phases of

anovula-tory cycles and to the opposing neuroactive properties

of these steroids Both adult animal models of epilepsy

and clinical evidence suggest that estrogen has

excit-atory and progesterone has inhibitory effects on

neuro-nal excitability and seizures (93) Progesterone protects

against seizures in animals and in open-label clinical

trials (94, 95) There is also evidence from the work of

Lonsdale and Burnham (96) to suggest that an

inter-mediate product of progesterone reduction,

5[alpha]-dihydroprogesterone, exerts potent antiseizure effects in

the amygdala kindling model of generalized convulsions

in female rats Androgens also have antiseizure effects

Aromatization of testosterone produces estradiol, which

is highly epileptogenic in male rodents (97) Reduction

produces androstanediol, which has potent GABAergic

properties and inhibits seizures (98)

Putative Mechanism of Action

of Neurosteroids

Electrophysiologic and ligand binding experiments

showed that the steroids alphaxolone, allopregnanolone,

pregnanolone, allotetrahydrodeoxycorticosterone, and

tetrahydrodeoxycorticosterone could all interact with the

GABAA receptor It is now clear that these neurosteroids

act as allosteric agonists of the GABAA receptor and act

to enhance GABAergic inhibition in the brain via a single

pregnenolone sulfate and DHEA sulfate, but not

nonsul-fated steroids), act as noncompetitive antagonists of the

result from regionally specific differences in neurosteoid

synthesis, as well as from regionally specific differences in

suggest that the anticonvulsant effects of progesterone

may involve its metabolism to the neuroactive steroid

5-pregnan-3 ol-20-one (3 alpha, 5

alpha-THP) and the subsequent actions of this metabolite at

attributed to the reduced progesterone metabolite

tetrahy-droprogesterone (THP), also known as allopregnanolone,

anti-convulsant properties, a possible role for progesterone receptors also has been raised (100) However, the potent antiseizure properties of progesterone do not require action at the progesterone receptor and can be blocked

by preventing reduction of progesterone to its potent GABAergic metabolite tetrahydroprogesterone Reddy and coworkers used progesterone receptor knockout mice studies to provide strong evidence that the antiseizure effects of progesterone result from its conversion to the neurosteroid THP and not through the actions of proges-terone on its receptor (100) The anticonvulsant effects

of androgens may be mediated, in part, through actions

of the testosterone metabolite and neuroactive steroid

5 alpha-androstane-3 alpha,17 alpha-diol (3 alpha-diol)

at GABAA receptors (91)

Potential for Clinical Use

Since progesterone and 3-reduced pregnane steroids have potent anticonvulsant effects, attempts to develop novel antiepileptic drugs with neurosteroidal properties seem reasonable In preclinical studies, metabolites of proges-terone and deoxycorticosterone, as well as the synthetic neuroactive steroid ganaxolone, exhibit a broad anticon-vulsant profile in different animal models (101, 102) Ganaxolone is a member of a novel class of neuroactive steroids, called epalons, which allosterically modulate

related to progesterone but is devoid of hormonal ity In animal studies, there appears to be no tolerance

activ-to the anticonvulsant activity of ganaxolone when this drug is administered chronically over the course of up

to 7 days In humans, ganaxolone showed a promising pharmacokinetic profile and was well tolerated in a trial with 96 healthy volunteers (103) The steroid proved to

be well tolerated, and effective in clinical studies with lepsy patients (104, 105) Kerrigan and associates (105) found that ganaxolone reduced the frequency of spasms

epi-by at least 50% in 33% of 16 children, with medically intractable infantile spasms, who completed the study Drug-related adverse events (occurring in 10% of the patients) were generally mild and included somnolence, diarrhea, nervousness, and vomiting The tolerability of ganaxolone at doses up to 36 mg/kg per day was accept-able (106) Ganaxolone monotherapy was evaluated in

a randomized, double-blind, presurgical clinical trial Ganaxolone was administered at a dose of 1,500 mg per day on day 1 and 1,875 mg per day on days 2–8 The tolerability of ganaxolone was similar to that of placebo and the drug showed significant antiepileptic activity, which was measured by the duration of treat-ment before withdrawal from the study (104) However, like all GABAergic drugs, ganaxolone has the potential

to exacerbate absence seizures (107)

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 554

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Benzodiazepines

enzodiazepines bind to a site on the neuronal GABAA receptor, a ligand-gated chloride channel, and enhance inhibitory neurotransmission Their high lipid solubility results in rapid central nervous sys-

tem (CNS) penetration and they are particularly useful as

first-line agents in the management of status epilepticus

and seizures occurring repetitively in clusters Their

effec-tiveness in the chronic treatment of epilepsy is limited by

their behavioral effects and their propensity for tolerance

in patients with intractable epilepsy

CHEMISTRY, PHARMACOLOGY, AND

MECHANISM OF ACTION

The base compound is a 5-aryl-1,4-benzodiazepine

structure composed of three ring systems

Modifica-tions in the structure of ring system have resulted in

several compounds with antiepileptic activity but with

different efficacy and side effect profiles

Benzodiaze-pines augment inhibitory neurotransmission by

the opening of the chloride ion channel, which results

in hyperpolarization of the membrane and reduction in

neuronal firing (2) Although benzodiazepines bind to

in a similar fashion to phenytoin and carbamazepine (3) Thus, benzodiazepines raise the seizure threshold, decrease the duration of epileptiform discharges, and limit their spread (3)

The action of benzodiazepines on the GABA receptor may be influenced both by the maturity of the brain and by disease GABA synapses are present before glutamate synapses in early fetal development, and it has been suggested that GABA acts as the primary excitatory neurotransmitter in the immature brain (4) The potassium-chloride transport that removes chlo-ride ions is not expressed until later in development, enabling chloride ions to accumulate intracellularly, resulting in GABA synapses that are excitatory (4) The exact timing of the switch from GABA excitatory action to inhibitory action is not known but is believed

to occur in utero (4) It has been hypothesized that the excitatory action of GABA in early development modulates neuronal migration and differentiation, and

it has been suggested that benzodiazepine use in early

B

41

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 558

pregnancy may have detrimental effects on fetal brain

maturation (4)

ADVERSE EFFECTS Toxicity

Respiratory and cardiovascular depression are the most

common adverse effects of benzodiazepines used

intrave-nously Propylene glycol is a solvent used with intravenous

diazepam and lorazepam, but not midazolam, and plays a

major role in the respiratory depression associated with the

first two drugs (5) Comedication with phenobarbital may

exacerbate the cardiovascular and respiratory depression

Intravenous benzodiazepines may precipitate tonic status

epilepticus in children with epileptic encephalopathies (6)

Chronic treatment with a benzodiazepine may be

associated with sedation, fatigue, ataxia, cognitive

dys-function, drooling, and exacerbation of seizures Abrupt

discontinuation may lead to withdrawal symptoms

Headache and gastrointestinal symptoms can occur but

are uncommon Hematologic abnormalities, hepatic

dys-function, and allergic reactions are uncommon

Tolerance

Although tolerance probably occurs with all

antiepi-leptic drugs (7), it happens more often with

benzodi-azepines The degree of tolerance in animal models is

proportional to the agonist efficacy of the

benzodiaz-epine (8) Tolerance to one benzodiazbenzodiaz-epine does not

necessarily result in tolerance to the others (9) The

mechanisms underlying tolerance are not clear but may

postsynaptic sensitivity to GABA, or modification in

the expression of genes that encode for the various

The incidence of tolerance to the antiepileptic effect

of benzodiazepines is influenced by the type and severity

of the epilepsy Thus, tolerance to clonazepam is observed

much less often in patients with typical absence seizures

than in patients with West syndrome or Lennox-Gastaut

syndrome (11) Similarly, tolerance to clobazam has been

reported in 18% to 65% of patients in open studies

(12–14), whereas in children who had been previously

untreated or who had received only one drug (15), the

incidence of tolerance to clobazam (8%) was similar to

tolerance to carbamazepine (4%) and phenytoin (7%)

INDIVIDUAL BENZODIAZEPINES

The use of benzodiazephines in status epilepticus and in

the prevention of seizures is outlined in Table 41-1 and

Table 41-2 respectively

Diazepam

B i o t r a n s f o r m a t i o n , P h a r m a c o k i n e t i c s , a n d Interactions Rectal diazepam is absorbed via hemor-

rhoidal veins and then rapidly crosses the blood-brain barrier Therapeutic blood levels are achieved within

5 minutes and peak levels within 20 minutes (16) Plasma concentrations of 500 ng/mL of diazepam, which are necessary for acute seizure control, were achieved in infants and children within 2–6 minutes following rec-tal administration of 0.5 to 1 mg/kg (17) Diazepam is absorbed more slowly following oral or intramuscular administration, and these routes are not recommended Plasma levels decrease by as much as 50% within 20–30 minutes after a single bolus injection (16) This short duration of action following intravenous administration relates to its rapid distribution into fat tissue and to the high protein binding of diazepam

Diazepam undergoes demethylation to desmethyldiazepam, a major metabolite that itself has significant antiepileptic and sedative properties (17) Diazepam and N-desmethyldiazepam are both highly protein bound to albumin (17) The elimination half-

hours in older children (17) The elimination half-life of N-desmethyldiazepam is longer than that of diazepam, and serum concentrations are two to five times higher in patients receiving long-term treatment (17) The metabo-lites of diazepam are conjugated with glucuronic acid in the liver and excreted by the kidney

Diazepam does not significantly influence the macokinetics of other drugs Valproate comedication decreases protein binding and inhibits the metabolism of diazepam (18), which may result in increased sedation

phar-Clinical Efficacy Diazepam is effective in the treatment

of both convulsive and nonconvulsive status epilepticus and of acute repetitive seizures Clinical effect is observed usually within 10 minutes of intravenous administration, which is the optimal route for the treatment of status epilepticus (16, 19) The rapid redistribution following

a single dose results in an abrupt decline in brain centration and reduction in the anticonvulsant effect Consequently, a long-acting anticonvulsant, for example, phenytoin, should be administered concomitantly in chil-dren with status epilepticus Rectal diazepam is absorbed rapidly, which may be useful in small children in whom intravenous access may be difficult Limited data sug-gest continuous diazepam infusion may be effective in the treatment of refractory status epilepticus in children (20–22)

con-Rectal diazepam gel has been shown to be effective and safe in the management of children with prolonged

or acute repetitive seizures (23) Sedation was the most common side effect, but no episodes of serious respiratory

TABLE 41-1

The Use of Benzodiazepines in Status Epilepticus

D IAZEPAM

Intravenous 0.2–0.3 mg/kg; max dose 5 mg in infants Administer over 2–5 minutes; rapid

and 10 mg in older children; can be administration increases risk repeated after 15 minutes of apnea

Rectal solution 0.5–1.0 mg/kg; max dose 20 mg

Rectal gel 2–5 years: 0.5 mg/kg Prefixed unit doses of 5, 10, 15, and 20 mg;

6–11 years: 0.3 mg/kg prescribed dose should be rounded to

12 years: 0.2 mg/kg nearest available unit dose

L ORAZEPAM

Intravenous 0.1 mg/kg; max dose 4 mg; can be Administer over 2 min

repeated after 10 minutes Sublingual 0.05–0.15 mg/kg; max dose 4 mg Can be used for serial seizures but should

not be used for tonic-clonic status

M IDAZOLAM

Intravenous bolus 0.15 mg/kg Administer over 2–5 minutes; if not

effective, continuous infusion should be

Continuous infusion 1–5 g/kg/min; max dose 18 g/kg/min Initiate treatment at 1 g/kg/min and

increase rate by that amount

at 15-minute intervals until seizure

Intramuscular, 0.2 mg/kg

intranasal, and buccal

TABLE 41-2

Benzodiazepine Dosages for Prevention of Seizures

Clobazam 2.5 mg/day 2 years; 2.5–5 mg/day every 5–7 days; Doses over 30 mg/day rarely

5 mg/day if 2–10 years; given at night or as improve seizure control

10 mg/day  10 years b.i.d dosing

Clonazepam 0.01–0.03 mg/kg/day 30 kg 0.25–0.5 mg/day every 5–7 days; 0.2 mg/kg/day if on

0.5 mg/day  30 kg b.i.d or t.i.d dosing enzyme-inducing drugs;

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 560

depression have been reported Rectal administration

can be performed by the parent, which permits

treat-ment at home, decreases emergency room visits, and

improves caregivers’ global evaluation (24) This is

of particular value for children with a history of

pro-longed seizures (25)

Both oral (26) and rectal diazepam (27) administered

intermittently at times of fever have been demonstrated in

placebo-controlled studies to be effective in the

preven-tion of recurrent febrile convulsions Rectal diazepam was

as effective as continuous phenobarbital in the prevention

of recurrent febrile seizures (28) The potential toxicities

associated with antiepileptic drug therapy have generally

been considered to outweigh the relatively minor risks

associated with simple febrile seizures (29) However,

intermittent diazepam may be of value in children who

have had a previous prolonged febrile seizure

Childhood-onset encephalopathies associated with

sleep-activated electroencephalographic (EEG)

abnormal-ities may respond to oral diazepam at high doses (30, 31)

Oral diazepam (0.5 mg/kg) for 3 to 4 weeks following

a rectal diazepam bolus of 1 mg/kg has been reported

to be effective in electrical status epilepticus in sleep

(ESES) (32) Oral diazepam at a dose of 0.5 mg/kg given

30 minutes before hemodialysis was effective in

preven-tion of hemodialysis-associated seizures in four children

who had failed to respond to phenobarbital (33)

Adverse Effects Sedation and ataxia occur commonly when

diazepam is used in the treatment of status epilepticus or in

the prevention of recurrent febrile convulsions Respiratory

depression and hypotension may occur following

intrave-nous diazepam, particularly if administered rapidly or used

in combination with phenobarbital (17), but are extremely

rare following rectal diazepam (34) Mild thrombophlebitis

may occur following intravenous administration,

particu-larly if diazepam is mixed with a saline solution or is injected

rapidly (17) Diazepam may induce tonic status epilepticus

in children with epileptic encephalopathies (35) Intermittent

oral diazepam prophylaxis has been associated with ataxia,

sedation, lethargy, and irritability (36)

Clinical Use In the treatment of children with

sta-tus epilepticus, an initial intravenous dose of 0.2 to 0.3

mg/kg (maximum dose, 5 mg in infants and 15 mg in

older children) of diazepam should be given slowly over

2–5 minutes (17) If needed, the dose may be repeated after

15 minutes When intravenous access in not available, a

rectal dose of 0.5 to 0.9 mg/kg has been used to a maximum

of 20 mg (37, 38) In refractory status epilepticus,

continu-ous diazepam infusion has been used successfully (20)

Treatment was initiated at 0.01 mg/kg/min and increased

by 0.005 mg/kg/min every 15 minutes until seizures were

controlled or to a maximum dosage of 0.03 mg/kg/min

A subsequent report has described at an infusion rate up

to 0.08 mg/kg/min (21) Diazepam may precipitate when the intravenous solution is administered in saline solution, and it may adsorb to polyvinyl tubing Consequently, fresh solution should be prepared every 6 hours when continu-ous diazepam infusion is being used (39)

Rectal administration of diazepam should be sidered when intravenous access cannot be obtained and when administration by a caregiver may be helpful, for example, when a child with a history of prolonged sei-zures lives far from medical services The injectable solu-tion can be administered rectally through a soft plastic intravenous catheter, and doses of 0.5 to 1.0 mg/kg have been reported to be effective in a prehospital setting with

con-a mcon-aximum dose of 20 mg (16) Rectcon-al dicon-azepcon-am gel (Diastat®) is available in unit doses of 5, 10, 15, and 20 mg and is easier to handle, faster to administer, and decreases the chance of dosing errors Rectal doses of 0.5 mg/kg for children 2–5 years of age; 0.3 mg/kg between 6 and

11 years of age, and 0.2 mg/kg above 12 years to a mum of 20 mg have been used successfully (40) A second dose may be repeated in 4–12 hours, if needed If admin-istered at home, caregivers should be given instruction as

maxi-to when they should seek medical attention The suggested dosage of oral or rectal diazepam used for febrile seizure prophylaxis is 5 mg every 8 hours when the rectal tem-perature is

doses to avoid drug accumulation (28)

Lorazepam

Biotransformation, Pharmacokinetics, and actions Lorazepam is a 1,4-benzodiazpine that is

Inter-metabolized rapidly through hepatic glucuronidation and

is excreted by the kidneys (41) It is absorbed more rapidly when administered sublingually than orally or intramuscu-larly, and peak plasma levels are achieved within 60 minutes (42) The rectal absorption of lorazepam parenteral solution

is slow and peak concentrations, which may not be reached for 1–2 hours, are much lower than those achieved fol-lowing intravenous administration (43) First-pass hepatic transformation decreases the absolute systemic availability

of oral lorazepam to 29% of that following intravenous administration (44) Lorazepam is 90% protein bound and rapidly crosses the blood-brain barrier The maximal EEG effect of intravenous lorazepam is observed approximately

30 minutes after infusion, which is later than with nous diazepam, probably as a result of slower entry into the brain (45) Following intravenous administration, there is a rapid fall in blood levels because of the distribution phase The elimination half-life is 10.5 2.9 hours in children (46) but is longer in neonates (47) Less than 1% is excreted unchanged in the urine

intrave-The clearance of lorazepam is not influenced by acute viral hepatitis (48) or renal disease (49) However, valproate reduces the clearance of lorazepam, possibly as

a consequence of inhibition of glucuronidation (50) There

are no other significant interactions with antiepileptic drugs

(42), and, in contrast to other benzodiazepines, protein

binding of lorazepam is not influenced by heparin (51)

Clinical Efficacy Intravenous lorazepam is more effective

than intravenous diazepam in the treatment of status

epi-lepticus; it has fewer side effects and has a longer duration

of action (52, 53) Children receiving long-term therapy

with another benzodiazepine are less responsive to

loraz-epam in status epilepticus (54) Sublingual lorazloraz-epam has

also been shown to be a convenient and effective treatment

of serial seizures in children (55) Intravenous or sublingual

lorazepam was completely effective in preventing seizures

in 29 children receiving high dose busulfan treatment (56)

Lorazepam has also been reported to be useful in the

treat-ment of postanoxic myoclonus (57)

Adverse Effects Sedation is the most common side

effect of lorazepam, and ataxia, psychomotor slowing,

and agitation may also occur Respiratory depression may

occur but less often than with diazepam (52) The

treat-ment of serial seizures with lorazepam has been

associ-ated with drowsiness, ataxia, nausea, and hyperactivity

(55) Abrupt discontinuation of lorazepam has been

asso-ciated with withdrawal seizures, which may occur up to

60 hours following its discontinuation (42) Lorazepam

has been reported to cause tonic seizures in patients being

treated for atypical absence status epilepticus (58–60)

Clinical Use The recommended intravenous dose of

lorazepam in children is 0.1 mg/kg (maximum dose,

4 mg) (19) The intravenous rate of administration

should not exceed 2 mg/min The dose can be repeated

if necessary after 10 minutes Sublingual doses of 0.05

to 0.15 mg/kg were effective in 8 of 10 children with

serial seizures (55)

Midazolam

Biotransformation, Pharmacokinetics, and

Inter-actions Midazolam is a 1,4-benzodiazepine with a

fused imidazole ring Prior to administration, the

benzo-diazepine ring of midazolam is open and is water soluble

However, following administration, the benzodiazepine

ring closes at physiologic pH and midazolam becomes

lipid soluble These characteristics permit absorption via

the intramuscular route (with less pain at the injection

site) and rapid transport across the blood-brain barrier

The absorption of intramuscular midazolam is rapid

with 80% to 100% bioavailability (61), and peak blood

levels are obtained after approximately 25 minutes (61)

Pharmacologic effects are observed within 5–15 minutes

but may not be maximal for 20 to 60 minutes (62)

Intranasal absorption of midazolam also occurs rapidly,

with mean time to seizure control of 3.5 minutes (range, 2.5–5.0 minutes) (63) Oral midazolam is absorbed rel-atively rapidly, with peak blood levels being achieved within 1 hour, but first-pass metabolism in the liver limits the availability to 40% to 50% of the oral dose It is distributed rapidly and possesses a short elimination half-life (1.5–3 hours) in children The relatively short half-life makes it less likely to accumulate and therefore more suitable for continuous infusion than diazepam

or lorazepam A longer half-life (6.5 hours) has been observed in critically ill neonates (64)

Midazolam is highly protein bound (96–98%) and

is metabolized extensively by the cytochrome P450 3A4 enzyme system Its metabolism is induced by phenytoin and carbamazepine (65) Medications that inhibit the activity of cytochrome P450 3A4, for example, eryth-romycin and clarithromycin, may prolong the half-life

of midazolam (66) Renal failure does not influence the pharmacokinetics of midazolam (67)

Clinical Efficacy Intravenous midazolam was effective

in the treatment of refractory status epilepticus in 43 of

44 children in two studies (68, 69) The mean infusion rates

appears to be as effective in stopping refractory status lepticus as pentobarbital or thiopental and is associated with fewer adverse effects (70, 71) Continuous intravenous mid-azolam infusion was as effective as continuous diazepam infusion in stopping refractory status epilepticus but was associated with a higher incidence of seizure recurrence (21) Continuous midazolam infusion was also effective in stopping refractory nonconvulsive status epilepticus in 82%

epi-of episodes but breakthrough seizures, which could only

be detected by EEG in most patients, occurred in mately half of the patients (72) Midazolam administered by

effective in controlling seizures refractory to phenobarbital

in four of six neonates and was well tolerated (73)

The high water solubility of midazolam permits administration by a variety of routes Intramuscular midazolam (15 mg) had a comparable effect to intra-venous diazepam (20 mg) in the suppression of interictal spikes in adults within 5 minutes (74) Intramuscular midazolam was effective in stopping 64 of 69 prolonged seizures occurring in 48 children (75) A prospective study reported intramuscular midazolam to be more effi-cacious than intravenous diazepam in the treatment of acute seizures, with a faster cessation of seizures because

of more rapid administration (76) Intranasal tration of midazolam was less effective than intrave-nous diazepam in one study (77) but stopped prolonged febrile seizures more rapidly in another study (78) In addition, the time to seizure cessation was shorter with intranasal midazolam than with rectal diazepam, and

adminis-V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 562

parents felt that the intranasal route was a more

favor-able means of medication administration (79)

Adverse Effects Drowsiness and ataxia are the most

common side effects Apnea and hypotension may occur

following rapid intravenous administration of a bolus

of midazolam, but apnea has been reported in only one

patient following intramuscular midazolam (80)

Throm-bophlebitis occurs less often than with diazepam (80)

Paradoxical reactions including agitation, restlessness,

and hyperactivity have been reported (81)

Clinical Use An initial intravenous bolus dose of 0.15 mg/

kg (68, 69) may be followed by continuous infusion at an

initial rate of 1 g/kg/min, which may be increased

subse-quently by 1 g/kg/min every 15 minutes to achieve seizure

control Seizures are controlled at infusion rates less than

kg/min have been described (69) Intramuscular

admin-istration results in complete and rapid absorption and is

particularly usefully if intravenous access is not available

or is difficult to obtain quickly An intramuscular dose

of 0.2 mg/kg has been used effectively in children (75)

Intranasal and buccal midazolam are safe, effective, and

easy to administer, making these routes particularly useful

in the home setting The usual dose is 0.2 mg/kg

Clonazepam

Biotransformation, Pharmacokinetics, and

Inter-actions Clonazepam is a 1,4-benzodiazepine, and the

bioavailability after oral administration is more than 80%

with peak levels occurring between 1 and 4 hours (82)

The high lipid solubility results in rapid distribution with

easy passage across the blood-brain barrier The protein

binding is 86% Clonazepam is metabolized initially

by reduction to 7-amino-clonazepam and subsequently

by acetylation (83) The metabolites, which are

phar-macologically inactive, are conjugated to glucuronide

and excreted by the kidney Less than 1% is excreted

unchanged in the urine Clonazepam metabolism involves

the hepatic cytochrome P-450 3A4 (84) and comedication

with carbamazepine or phenobarbital lowers blood

clon-azepam levels (82) Acetylation is also a major metabolic

pathway and patients who are rapid acetylators are more

likely to require higher doses to achieve a response (85)

The serum half-life in children is 22–33 hours (86) The

plasma half-life following intravenous administration in

neonates is 20–43 hours (87)

Clinical Efficacy Intravenous clonazepam was effective

in stopping tonic-clonic status epilepticus in all children

in a small open study and was considered to have a longer

duration of action than diazepam (88) The initial dose

was 0.25 mg, which was repeated up to two times

Intra-venous clonazepam was also effective in more than 80%

of children and adults with absence status epilepticus (89) Oral clonazepam has been demonstrated in controlled studies to be effective in the treatment of absence (86, 90, 91), myoclonic (90), and atonic seizures (90) Open stud-ies have suggested that clonazepam is also effective in the treatment of photosensitive epilepsy and of primary gener-alized tonic-clonic seizures, both as monotherapy (92) and

in combination with valproic acid (93) In patients with juvenile myoclonic epilepsy, clonazepam is more effective

in prevention of myoclonic seizures than of tonic-clonic seizures This may result in an increased risk of injury to the patient, who is deprived of the warning jerks that pres-age the onset of the generalized tonic-clonic seizure (94) Clonazepam may also be effective in the treatment of other myoclonic epilepsies, including reflex myoclonic epilepsy, progressive myoclonic epilepsy, posthypoxic intention myoclonus, and epilepsia partialis continua (82) Partial epilepsy may also respond to clonazepam in combination with valproic acid (82) Clonazepam monotherapy is asso-ciated with reduction in interictal rolandic discharges in children with benign rolandic epilepsy (95) and is more effective than valproic acid and carbamazepine in that regard (96) The addition of clonazepam was also effective

in the treatment of children with partial seizures resistant

to carbamazepine (97) Studies have demonstrated mixed results with respect to the efficacy of clonazepam in Len-nox-Gastaut syndrome, where it has been considered as a third line choice (98)

Adverse Effects The most common adverse effects of

clonazepam include drowsiness, ataxia, incoordination, and behavioral changes (34, 99) Comedication with phenobarbital usually exacerbates the drowsiness (100) Diplopia, nystagmus, dysarthria, excessive drooling, and hypotonia may also occur Initiation of therapy at a low dose followed by a slow increase may reduce the neuro-toxicity Increased appetite and weight gain of more than 20% were reported in 9 of 81 children treated with clon-azepam (99) Clonazepam may result in increased seizure frequency (101) and has been reported to induce tonic status epilepticus in Lennox-Gastaut syndrome (6).The development of tolerance to the antiepileptic effect of clonazepam is dependent on the type of epilepsy Thus, tolerance did not develop in 23 children with partial epilepsy who were treated with clonazepam monotherapy

or clonazepam in combination with carbamazepine (97) Similarly, tolerance to clonazepam is observed less often in patients with typical absence seizures than in patients with West syndrome or Lennox-Gastaut syndrome (11) The use

of alternate-day clonazepam has been reported to be ciated with significantly less tolerance in an animal model (102), an effect also observed in children (103) Discon-tinuation of clonazepam may be complicated by transient worsening of seizure control, and status epilepticus may occur with abrupt withdrawal (11) Behavioral changes, including restlessness, dysphoria, sleep disturbance, and

asso-tachycardia, may also occur during clonazepam

with-drawal, which should be done gradually (11)

Clinical Use To minimize side effects, clonazepam

should be started at a dose of 0.01 to 0.03 mg/kg/day in

children under 30 kg and given in two or three daily

dos-ages (104) The dose can be increased by 0.25–0.5 mg/day

every 5–7 days to a total dose of 0.1 mg/kg/day, or 0.2 mg/

kg/day in patients receiving drugs that induce microsomal

metabolism Clonazepam was effective in seven of eight

neonates with seizures when administered by slow

intra-venous infusion in doses of 0.1 mg/kg (87)

Nitrazepam

Biotransformation, Pharmacokinetics, and

Inter-actions Nitrazepam, a 1,4-benzodiazepine, is rapidly

and totally absorbed in the gastrointestinal tract It is

highly protein bound (85–90%) and has an elimination

half-life of 24 to 31 hours (105) Nitrazepam is partially

metabolized in the liver and then excreted in the urine

There are no clinically significant interactions with other

antiepileptic drugs Oral contraceptives, steroids, and

cimetidine reduce nitrazepam clearance, and rifampin

increases nitrazepam clearance (105)

Clinical Efficacy Nitrazepam is generally considered

a third line adjunctive medication in the treatment of

partial and generalized seizures, including the epileptic

encephalopathies of childhood In a randomized control

study in patients with infantile spasms, 75% to 100%

reduction in spasm frequency was observed in 52%

of patients receiving nitrazepam and 57% of patients

receiving adrenocorticotrophin (106), but side effects

were less severe in the patients who received nitrazepam

In open studies, nitrazepam has been reported to be

effective in the treatment of absence and primary

gen-eralized tonic-clonic seizures (107), myoclonic seizures

(108)], and partial seizures (107) Nitrazepam has also

been reported to be effective in the treatment of

Lennox-Gastaut syndrome (105, 109, 110)

Adverse Effects Drowsiness, ataxia and

incoordina-tion, which are common side effects, may be diminished

by initiation of treatment at a low dose followed by slow

increase Increased salivation is a well recognized side

effect of nitrazepam in children and is related to both

hypersecretion of the tracheobronchial tree and

abnor-mal swallowing, due to delay in cricopharyngeal

relax-ation (111) This may also result in feeding difficulties

and aspiration pneumonia, particularly in children (108,

112) Doses of nitrazepam greater than 0.8 mg/kg/day

have been found to be associated with an increased risk

of death in children (112), and the risk appears

high-est in children with intractable epilepsy younger than

3.4 years of age (113) Risk factors included feeding

difficulties, recurrent respiratory tract infections, and aspiration pneumonia

Clinical Use To reduce the risk of side effects,

nitraz-epam should be started in children at a low dose (0.1–0.2 mg/kg/day) and the dosage increased every 5–7 days

to a maximum of 0.8 mg/kg/day (112) Caution should

be taken in patients younger than 4 years of age tinuation of nitrazepam should be gradual to minimize the risk of withdrawal seizures

is 97% protein bound, largely to serum albumin (115) Although N-desmethyldiazepam has an elimi-nation half-life of 55–100 hours, administration of clorazepate once daily is associated with unaccept-able side effects because of the relatively high peak concentrations that follow its rapid absorption (115) N-Desmethyldiazepam is metabolized extensively by the liver and its elimination half-life is prolonged in patients with liver disease Drugs that induce hepatic microsomal metabolism enhance the clearance of N-desmethyldiazepam and patients taking these drugs require higher doses of clorazepate

Clinical Efficacy Clorazepate was introduced in the

1960s and there have been no controlled studies in dren Improvement in seizure control has been reported

chil-in children with partial (116) and generalized seizures (116–118), including children with Lennox-Gastaut syn-drome (116)

Adverse Effects Sedation, ataxia, behavioral changes,

and drooling, which are the most common side effects

of clorazepate in children, often become less pronounced with time Comedication with phenobarbital increases the probability of behavioral problems (119) and should be avoided Idiosyncratic reactions are rare (115)

Tolerance limits the usefulness of clorazepate, but animal studies suggest that tolerance occurs less often with clorazepate than with diazepam or clonazepam (115) With-drawal seizures and behavioral changes may complicate the discontinuation of therapy, which should occur slowly

Clinical Use The initial dose of clorazepate in children

is 0.3 mg/kg/day, and the dose is increased gradually to

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 564

achieve seizure control or until side effects appear, up to

a maximum dose of 3 mg/kg/day (115, 117)

Clobazam

B i o t r a n s f o r m a t i o n , P h a r m a c o k i n e t i c s , a n d

Interactions Clobazam, which differs from the

1,4-benzodiazepines by the presence of a nitrogen atom in

the 1 and 5 positions of the diazepine ring, is relatively

insoluble and cannot be administered intravenously or

intramuscularly Oral clobazam is absorbed rapidly, and

peak concentrations are reached in 1 to 4 hours (120) It is

highly lipophilic, distributed rapidly, and approximately

85% protein bound Factors that influence protein

bind-ing, for example, liver disease, may affect the free and

total levels of the drug (121) Clobazam is metabolized

extensively in the liver to several metabolites including

N-desmethylclobazam, which also has antiepileptic

activ-ity The elimination half-life of clobazam is 18 hours, and

that of N-desmethylclobazam is 42 hours (121) Thus,

blood levels of N-desmethylclobazam are approximately

10 times those of clobazam (122), and

N-desmethylcloba-zam is considered to be responsible for most of the

anti-epileptic effect in patients receiving clobazam (121)

Comedication with phenytoin, phenobarbital, or

carbamazepine increases the N-desmethylclobazam/

clobazam ratio (123) Clobazam increases phenytoin

concentrations (124) and may result in phenytoin

intoxi-cation (125, 126) Clobazam has also been reported to

increase valproate levels, which may remain elevated for

several weeks after the clobazam has been withdrawn

(127), and may result in valproate toxicity (128) Mild

increases in phenobarbital, carbamazepine, and

carba-mazepine epoxide have also been reported (124)

Clinical Efficacy The use of clobazam in the

treat-ment of epilepsy was pioneered by Gastaut and Low,

who reported its effectiveness in patients with partial

seizures, idiopathic generalized epilepsy, reflex epilepsy,

and Lennox-Gastaut syndrome (129) The antiepileptic

effect of clobazam in partial and tonic-clonic seizures has

been demonstrated in several placebo-controlled studies

(121) In addition, clobazam monotherapy has been

dem-onstrated to be as effective as either carbamazepine or

phenytoin in the treatment of children with partial,

tonic-clonic seizures, or both, who were previously untreated or

who had received only one drug (15) Clobazam appears

to have a broad spectrum of antiepileptic activity In a

large retrospective study comprising 1,300 refractory

epileptic patients, including 440 children, more than

50% reduction in seizure frequency was observed for

each seizure type (except tonic seizures) in 40% to 50%

of patients and complete seizure control was obtained

in 10% to 30% (128) It has also been reported to be

effective in the treatment of reflex epilepsies (130–132),

startle epilepsy (133, 134), epilepsy with continuous spike-waves during slow sleep (135), and eyelid myo-clonia with absence (136) Complete seizure control was described in 20% of patients with temporal lobe seizures associated with hippocampal sclerosis, and 75% reduction in seizure frequency in a further 25% (137) Clobazam taken intermittently for 10 days each month around the time of menstruation was effective in the treat-ment of catamenial epilepsy and was not associated with tolerance (138, 139) Administration of intermittent clo-bazam has also been used successfully by the author in the treatment of seizures that occur periodically in clusters Prophylactic clobazam has been used prior to bone mar-row transplantation in the prevention of seizures induced

by high-dose busulfan chemotherapy (140)

Adverse Effects A major advantage of clobazam over

the 1,4-benzodiazepines is the lower incidence of toxicity In a double-blind comparison of clobazam with phenytoin or carbamazepine in children, the incidence of side effects was similar (15) The side effects of clobazam are generally mild and resolve with dosage reduction Drowsiness, short attention span, mood change, ataxia, and drooling may occur These occur less commonly than

neuro-in patients receivneuro-ing 1,4-benzodiazepneuro-ines (13) Marked worsening of behavior has been reported in some patients

in open studies but does not appear to occur any more commonly than with carbamazepine or phenytoin (15) Excessive weight gain, which responds to withdrawal

of the drug, has been reported (13) Hematologic and hepatic side effects have not been reported, and drug-induced skin rash is extremely rare

Open studies in children have reported tolerance in 18% to 65% of patients (12–14, 141, 142), but most of these studies comprised patients who had been intrac-table to several antiepileptic drugs In a controlled study

in children who were previously untreated or who had received only one drug, the incidence of tolerance was similar in patients receiving clobazam (7.5%), carbam-azepine (4.2%), and phenytoin (6.7%) (15)

Clinical Use Clobazam should be started at a dosage of

2.5 mg/day in infants and 5 mg/day in older children The dose can be increased at 5- to 7-day intervals until the sei-zures are controlled or side effects occur Although doses of

up to 3.8 mg/kg/day can be administered to children out undue side effects, dosages greater than 1 mg/kg/day are rarely associated with improved seizure control (13) In teenagers and adults, the initial dose is 10 mg/day The dose can be increased at 5- to 7-day intervals, but those who do not respond to 30 mg/day respond rarely to higher doses (121) Clobazam is usually administered at night or twice

with-a dwith-ay To minimize the risk of withdrwith-awwith-al seizures, continuation should be done gradually over several weeks Drug level monitoring is not clinically useful

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567

Carbamazepine and Oxcarbazepine

CARBAMAZEPINE

Introduced in 1962 for treatment of trigeminal neuralgia,

carbamazepine (CBZ) has emerged as a highly effective

treatment of epilepsy with partial and secondarily

gener-alized seizures It has also been reported to benefit

neu-ropathic pain, certain behavior disorders, and affective

disorders At first, CBZ was used to replace sedating

anti-epileptic drugs, but over time it became the initial therapy

for treatment of localization-related epilepsy with partial

(focal) seizures and epilepsy with generalized tonic-clonic

seizures Although CBZ produces side effects in many

patients, the low incidence of cosmetic, cognitive, and

behavioral side effects are advantages The major

disad-vantages have been its propensity to interact with other

drugs, to cause rashes and to aggravate absence and astatic

seizures in patients with generalized epilepsy

Clinical Efficacy

Carbamazepine is effective in partial (focal seizures),

especially complex partial (psychomotor) seizures and

generalized tonic-clonic (grand mal) seizures (1, 2) It

is ineffective in febrile seizures and absence seizures

Furthermore, children with the Lennox-Gastaut syndrome

sometimes have CBZ-induced worsening of several types

of seizures, especially atypical absence seizures and astatic

W Edwin Dodson

seizures, also called drop attacks (3, 4) Nonetheless, numerous studies have shown that CBZ is just as effec-tive as other major anticonvulsants when prescribed for the appropriate type of seizure (5–14) For example, in benign rolandic epilepsy, a pediatric epileptic syndrome character-ized by partial seizures, CBZ is effective in 94% of patients, producing complete control in 65% Given its comparable efficacy to other first-line anticonvulsants, the somewhat unique spectrum of adverse effects associated with CBZ differentiates it from other antiepileptics Although differ-ent rates of response to CBZ have been linked to age and gender, these differences appear to be small

Carbamazepine has been reported to be more tive in girls than boys, and more effective in older patients than in children (15, 16) The causes for these differences are most likely pharmacokinetic, although they may also relate to distribution of seizure types in various age groups For example, lower CBZ concentrations have been found among nonresponding children (17) Furthermore, young children have accelerated relative clearance of CBZ as com-pared to older children Partial or generalized tonic-clonic seizures are the predominant seizure types in 55% and 90% of children and adults, respectively (18, 19)

effec-The major mechanism of action of CBZ is to limit use-dependent increases in sodium conductance, thereby restricting neuronal high-frequency discharges This mech-anism is shared by phenytoin, oxcarbazepine, lamotrigine,

V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 568

topiramate, and felbamate, but differs from the

mecha-nisms of actions of barbiturates, benzodiazepines,

valpro-ate, and succinimides (20) This mechanism at sodium

channels correlates with clinical efficacy against partial

and generalized tonic-clonic seizures In experimental

ani-mals brain CBZ concentrations of 3.5 to 4.5 g/g prevent

maximal electroshock-induced seizures (21)

Carbamazepine in therapeutic concentrations has few

effects on the electroencephalogram (EEG) It does not

produce frontal low-voltage fast activity like that caused

by barbiturates and benzodiazepines (22) High

concentra-tions of CBZ produce generalized slowing The effect of

CBZ on seizure activity in the EEG varies depending on its

efficacy When CBZ is effective in preventing seizures, focal

spikes at first become more brief and sharp and eventually

may disappear (23) Discontinuation of CBZ is associated

with an increase in the mean dominant rhythm frequency

(24) Generalized spike and spike-wave abnormalities

either are unaffected by CBZ or worsen (16)

Other uses of CBZ include the treatment of chronic

neurogenic pain (25, 26), hemifacial spasm (27), and

affective disorders (28–33), although most of the data

supporting CBZ use in affective conditions are case

reports, retrospective reviews, or open label, uncontrolled

trials Carbamazepine also has been used to treat

atten-tion deficit hyperactivity disorder in children and in other

psychiatric conditions (34–38) In combination with

lith-ium, CBZ has been used to treat refractory depression,

refractory mania, and rapid cycling depression (39–41)

Carbamazepine also may be beneficial in the dyscontrol

syndrome, a disorder characterized by episodic aggressive

outbursts (42, 43) Among impulsive hyperkinetic

chil-dren with attention deficit disorder, the administration of

CBZ is preferred over barbiturates, benzodiazepines and

vigabatrin, and other GABA agonists, because the latter

cause worsening of behavior in a substantial percentage

of patients (18, 44–48)

After patients who have side effects due to other

anticonvulsants are switched to CBZ, overall

function-ing often improves When this occurs, it has been called

a psychotropic action Subjectively, these changes are

described as less dulling of mentation, having a steadier

gait, and improved attention and alertness (47) The

improvement is most dramatic among patients who are

switched from multidrug regimens that include

barbi-turates to monotherapy with CBZ On the other hand,

CBZ does not enhance cognitive function or behavior in

otherwise normal patients unless seizures are occurring

frequently enough to impair thinking

Chemistry

Carbamazepine is a tricyclic compound related to

iminostil-bene (49) Although the two-dimensional structure of CBZ

resembles tricyclic antidepressants, its three-dimensional

conformation is more akin to phenytoin Carbamazepine

is a hydroscopic, neutral, lipophilic chemical that is ble in organic solvents but possesses low water solubility Due to limited aqueous solubility, CBZ has never been formulated for parenteral administration Its crystalline structure and the structure-dependent dissolution rate of CBZ are sensitive to its extent of hydration Exposure to high humidity leads to increasing hydration of CBZ caus-ing the progressive development of a crystalline lattice that resists dissolution and is thereby insoluble Thus patients who take carbamazepine that has been stored in humid and warm environments are at risk to experience drops in carbamazepine levels

solu-Biotransformation, Pharmacokinetics, and

Interactions in Humans

Carbamazepine is eliminated largely by hepatic lism Unique among unsaturated heterocyclic chemicals, the predominant elimination pathway in humans results

metabo-in the formation of a stable epoxide that accumulates

in serum This compound, carbamzepine-10-11-epoxide (CBZE), has actions similar to CBZ but it is less potent

in experimental models of epilepsy (50) The epoxide

is hydrolyzed subsequently to form an inactive 10,11-dihydroxide, the principal urinary metabolite Lesser amounts of CBZ are metabolized by aromatic hydroxyl-ation of the lateral rings Carbamazepine is also a potent broad spectrum inducer of hepatic cytochrome P 450 enzymes, which metabolize other antiepileptic drugs

Pharmacokinetics

Carbamazepine has linear, predictable elimination

kinetics (Table 42-1 and Table 42-2) In individual patients,

TABLE 42-1

Carbamazepine Reference Information

C ARBAMAZEPINE (CBZ)

Molecular weight 236.26 Conversion factor CF 1,000/236.26 4.23 Conversion g/mL or mg/L  4.32 mol/L

C ARBAMAZEPINE -10,11-E POXIDE (CBZE)

Molecular weight 252.3 Conversion factor CF 1,000/252.3 3.96 Conversion: g/mL (or mg/L)  3.96 mol/L

R ATIO OF CBZE TO CBZ

Monotherapy 0.10–0.20 Polytherapy 0.15–0.66

From (22, 50).

92 Naito H, Wachi M, Nishida M Clinical effects and plasma concentrations of long-term

clonaz-epam monotherapy...

anti-epileptic drugs, but over time it became the initial therapy

for treatment of localization-related epilepsy with partial

(focal) seizures and epilepsy with generalized tonic-clonic...

treat-ment of epilepsy was pioneered by Gastaut and Low,

who reported its effectiveness in patients with partial

seizures, idiopathic generalized epilepsy, reflex epilepsy,

and