Chapter 49. Epilepsy

S. Scott Sutton; Holly J. Watson

Foundation Overview

Epilepsy is a chronic disease of disturbed electrical activity in the brain, resulting in recurrent seizures with or without convulsions. The age-adjusted prevalence of epilepsy is 4 to 7 cases per 1,000 persons, with approximately 125,000 new cases of epilepsy annually. Developing countries have higher rates of epilepsy related to poor health care and prenatal care, increased risk of neurologic trauma, and increased rates of infection.

Epilepsy is a disorder with profound impact on lifestyle and patients are often dependent upon caregivers to assist with medications and transportation. All states impose limitations on driving for individuals who have recently had a seizure with impaired consciousness.1

The pathophysiology of a seizure is due to an unstable cell membrane in the gray matter of the brain. The cause of the unstable cell membrane has been linked to three causes: an abnormality in potassium conductance, an abnormality in voltage-sensitive ion channels, or a deficiency in membrane ATPases linked to ion transport. Excitatory neurotransmitters (glutamate, aspartate, acetylcholine, norepinephrine) enhance the propagation of seizures while inhibitory neurotransmitters (GABA, dopamine) decrease the propagation of seizure activity in the brain. The spread can be local (partial seizure) or throughout the entire brain (generalized seizure). The different types of epilepsies are due to the different pathophysiologic abnormalities.1

Epilepsy is classified by the seizure presentation (Table 49-1).2-3 The classification system is based on how the seizure begins; therefore, obtaining an adequate description from a third party is important. The classifications of epilepsy are:

TABLE 49-1 International Classification of Epileptic Seizures

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TABLE 49-1 International Classification of Epileptic Seizures

I. Partial seizures (seizures begin locally)
- A. Simple (without impairment of consciousness)
  - 1. With motor symptoms
  - 2. With special sensory or somatosensory symptoms
  - 3. With psychic symptoms
- B. Complex (with impairment of consciousness)
  - 1. Simple partial onset followed by impairment of consciousness, with or without automatisms
  - 2. Impaired consciousness at onset, with or without automatisms
- C. Secondarily generalized (partial onset evolving to generalized tonic-clonic seizures)
II. Generalized seizures (bilaterally symmetrical and without local onset)
- A. Absence
- B. Myoclonic
- C. Clonic
- D. Tonic
- E. Tonic-clonic
- F. Atonic
- G. Infantile spasms
III. Unclassified seizures
IV. Status epilepticus

Absence seizures (petit mal)—sudden interruption of activities and a blank stare.
Myoclonic seizures—brief shock-like contraction of a muscle group.
Clonic seizures—jerking motion while tonic seizures involve a sustained muscle contraction.
Tonic-clonic seizures (grand mal)—alternating muscle contraction and jerking.
Atonic seizures involve a sudden loss of muscle tone known as "drop attacks."

Epilepsy syndromes are another classification system of epilepsies based on seizure type and etiology. The syndrome approach provides a tool to aid clinical management and provide prognosis.3

Idiopathic epilepsy—no underlying etiology and is presumed genetic.
Symptomatic epilepsy—an underlying cause which is usually brain damage.
Cryptogenic epilepsy—presumed to have an underlying etiology that cannot be identified.

Epilepsy is a clinical diagnosis made when the patient has recurrent seizures. An isolated seizure does not justify the diagnosis of epilepsy. Laboratory tests are evaluated to rule out treatable causes of seizures such as hypoglycemia, altered electrolytes, and infections. A seizure produced by treatable causes does not represent epilepsy. Electroencephalogram (EEG) can be useful to confirm a seizure and identify seizure types based on the spike and wave pattern generated; however, the EEG may be normal in some patients.4

The underlying etiology of epilepsy is unknown in 80% of patients. The most common recognized causes of epilepsy are head trauma and stroke. Developmental and genetic defects represent 5% of epilepsy cases. Central nervous system tumors, infections, metabolic disturbances (hyponatremia and hypoglycemia), neurodegenerative diseases, and medications represent other causes. Medications associated with causing seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsychotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, sympathomimetics, and stimulants.

Prevention

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Epilepsy cannot be prevented, but the seizures experienced by the patient can be minimized in both number and duration. There is a positive association between early initiation of antiepileptic drug (AED) therapy and seizure control. The inability to control seizures early can lead to increased frequency in seizure activity and the generation of other seizure types. External factors known to precipitate seizures in patients with epilepsy include hyperventilation, sleep deprivation, sensory stimuli, emotional stress, and hormonal fluctuations during pregnancy/menses/puberty. These external factors should be minimized in the epilepsy population.

Treatment

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The goal of epilepsy treatment is complete elimination of seizures with no drug side effects. This is not always possible and the patient should be involved in deciding the balance between frequency of seizures and occurrence of side effects. In certain situations, some seizure control may be sacrificed to improve the patient's day to day functioning. Optimal quality of life requires balancing seizures, side effects, and addressing life issues (eg, driving, safety, relationships, and social stigma). Epilepsy patients may have neuropsychiatric diseases such as depression, anxiety, and sleep disturbances which require treatment to optimize quality of life.5-7

Initial therapy is initiated with one AED and up to 70% of patients are controlled on monotherapy. Initial management of seizure disorders depends upon the type of seizure (Table 49-2). Combination AED therapy is required in 30% of patients in order to achieve seizure control; however, combination therapy increases the chance of side effects and drug interactions. Combination AED therapy is achieved by combining seizure medications with different mechanisms of action.5-7Table 49-3 lists key AED properties that impact medication selection, dosing, and adverse reactions.

TABLE 49-2 Evidence-Based Guidelines for Initial Monotherapy Treatment of Epilepsy

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TABLE 49-2 Evidence-Based Guidelines for Initial Monotherapy Treatment of Epilepsy

Seizure Type

American Academy of Neurology

Scottish Intercollegiate Guidelines Network

United Kingdom National Institute for Clinical Excellence

Primary generalized tonic-clonic

Carbamazepinea

Lamotriginea

Oxcarbazepinea

Phenobarbitala

Phenytoina

Topiramatea Valproatea

Valproate

Valproate

Second line:

Clobazamb

Levetiracetam

Oxcarbazepine

Absence

Lamotrigine (children)

Valproate

Valproate

Second line:

Clobazamb

Clonazepam

Topiramate

Myoclonic

Not mentioned

Lamotrigine

Valproate

Topiramate (children with severe myoclonic epilepsy of infancy)

Second line:

Clobazamb

Clonazepam

Lamotrigine

Levetiracetam Piracetamb

Topiramate

Tonic

Not mentioned

Lamotrigine

Valproate

Second line:

Clobazamb

Clonazepam

Levetiracetam

Topiramate

Atonic

Not mentioned

Lamotrigine

Valproate

Second line:

Clobazamb

Clonazepam

Levetiracetam

Topiramate

Partial with or without secondary generalization

Valproate

Valproate

Valproate

Second line:

Clobazamb

aBased upon data from newly diagnosed epilepsy patients of multiple seizure types.

bNot currently available in the United States. Reproduced with permission from: Welty TE, Faught E. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, et al, eds. Pharmacotherapy Principles & Practice. New York, NY: McGraw-Hill; 2008: 443-460.

TABLE 49-3 Characteristics of Common Antiepileptic Drugs

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TABLE 49-3 Characteristics of Common Antiepileptic Drugs

Drug

Mechanism of Action

Dose

Pharmacokinetic Parameters

Usual Serum Concentration Range

Dose-Related Adverse Effects

Idiosyncratic Adverse Effects

Carbamazepine

Modulate sodium channels

Loading dose: Not recommended due to excessive dose-related toxicity

Maintenance dose: Titrate dosage to target over 3-4 wk

Adults: 10-20 mg/kg/d as a divided dose

Children: 20-30 mg/kg/d as a divided dose

Half-life: 10-25 h with chronic dosing

Apparent volume of distribution: 0.8-1.9 L/kg

Protein binding: 67%-81%

Primary elimination route: Hepatic

4-12 mg/mL (17-51 μmol/L)

Diplopia, drowsiness, nausea, sedation

Aplastic anemia, hyponatremia, leukopenia, osteoporosis, rash

Clonazepam

Enhance GABA activity

Loading dose: Not recommended due to increased adverse effects

Maintenance dose: Initiate at 0.5 mg one to three times daily, titrate dose to effectiveness usually 3-5 mg daily in 2-3 divided doses

Half-life: 30-40 h

Apparent volume of distribution: 3.2 L/kg

Protein binding: 47%-80%

Primary elimination route: Hepatic

Not established

Ataxia, memory impairment, sedation, slowed thinking

Ethosuximide

Modulate calcium channels

Loading dose: Not recommended due to increased adverse effects

Maintenance dose: Initiate at 250 mg twice daily and titrate to 500-1000 mg twice daily

Half-life: 60 h

Apparent volume of distribution: 0.6-0.7 L/kg

Protein binding: None

Primary elimination route: Hepatic

40-100 mg/mL (283-708 mmol/L)

Ataxia, sedation

Hepatotoxicity, neutropenia, rash

Felbamate

Inhibit glutamate activity

Loading dose: Not recommended due to increased adverse effects

Maintenance dose: 1200-3600 mg/d in 3-4 divided doses

Half-life:

Monotherapy: 20 h

Concurrent enzyme inducers: 11-16 h

Apparent volume of distribution: 0.7-0.8 L/kg

Protein binding: 25%-35%

Primary elimination route: Hepatic

Not established

Anxiety, insomnia, nausea

Anorexia, aplastic anemia, headache, hepatotoxicity, weight loss

Gabapentin

Modulate calcium channels and enhance GABA activity

Loading dose: Not recommended due to short half-life

Maintenance dose: 900-3600 mg/d in 3-4 divided doses (doses up to 10,000 mg/d have been tolerated)

Half-life: 5-7 h (proportional to creatinine clearance)

Apparent volume of distribution: 0.6-0.8 L/kg

Protein binding: >10%

Primary elimination route: Renal

Not established

Drowsiness, sedation

Peripheral edema, weight gain

Lamotrigine

Modulate sodium channels

Loading dose: Not recommended due to increased risk of rash

Maintenance dose: 150-800 mg/d in 2-3 divided doses.

Doses should be initiated and titrated according to the manufacturer's recommendations to reduce the risk of rash

Half-life:

Monotherapy: 24 h

Concurrent enzyme inducers: 12-15 h

Concurrent enzyme inhibitors: 55-60 h

Apparent volume of distribution: 1.1 L/kg

Protein binding: 55%

Primary elimination route: Hepatic

Not established

Ataxia, drowsiness, headache, insomnia, sedation

Rash

Levetiracetam

Unknown

Loading dose: Not recommended due to excessive adverse effects

Maintenance dose: 1000-3000 mg/d

Start at 1000 mg/d and titrate upward as indicated by response

Half-life: 6-8 h

Apparent volume of distribution: 0.5-0.7 L/kg

Protein binding: >10%

Primary elimination route: 70% renal 30% hepatic

Not established

Somnolence, dizziness

Depression

Oxcarbazepine

Modulate sodium channels

Loading dose: Not recommended due to excessive adverse effects

Maintenance dose: 600–1200 mg/d

Start at 300 mg twice daily and titrate upward as indicated by response

Half-life: Parent drug ∼2 h 10-monohydroxy metabolite ∼9 h

Apparent volume of distribution: 0.5–0.7 L/kg

Protein binding: 40%

Primary elimination route: Hepatic

Not established

Diplopia, dizziness, somnolence

Hyponatremia, 25%-30% cross sensitivity in patients with hypersensitivity to carbamazepine

Phenobarbital

Modulate sodium channels

Loading dose: 10-20 mg/kg as single or divided intravenous infusions or orally in divided doses over 24-48 h

Maintenance dose:

Adults: 1-4 mg/kg/d as a single or divided dose

Children: 3-6 mg/kg/d as divided dose

Neonates: 1-3 mg/kg/d as divided dose

Half–life:

Adults: 49-120 h

Children: 37-73 h

Neonates: ∼115 h

Volume of distribution: 0.7-1 L/kg

Protein binding: ∼50%

Primary elimination route: Hepatic

15-40 mg/mL (65-172 μmol/L)

Ataxia, drowsiness, sedation

Attention deficit, cognitive impairment, hyperactivity, osteoporosis, passive-aggressive behavior

Phenytoin

Modulate sodium channels

Loading dose:

Adults: 15-20 mg/kg single intravenous dose or divided oral dose

Infants > 3 mo: 10-15 mg/kg single intravenous dose

Neonates: 15-20 mg/kg single intravenous dose

Maintenance dose:

Adults: 5-7 mg/kg/d as single or divided dose

Children: 6-15 mg/kg/d as divided dose

Neonates: 3-8 mg/kg/d as divided dose

Half-life: Follows capacity-limited or Michaelis-Menten pharmacokinetics

Half-life increases as the dose and serum concentration increases

Volume of distribution:

Adults: 0.7 L/kg

Children: 0.8 L/kg

Neonates: 1.2 L/kg

Protein binding:

Adults, children: 88%-92%

Neonates: 65%

Primary elimination route: Hepatic

10-20 mg/mL (40-79 mmol/L) total concentration

1-2 mg/mL (4-8 mmol/L) unbound concentration

Ataxia, diplopia, drowsiness, sedation

Anemia, gingival hyperplasia, hirsutism, lymphadenopathy, osteoporosis, rash

Pregabalin

Modulate calcium channels

Loading dose: Not recommended due to increased adverse effects

Maintenance dose: Initiate at 150 mg/d in 2-3 divided doses and titrate to a maximum dose of 600 mg/d

Half-life: 6.3 h, proportional to creatinine clearance

Apparent volume of distribution: 0.5 L/kg

Protein binding: Negligible

Primary elimination route: Renal

Not established

Ataxia, blurred vision, dizziness, dry mouth, somnolence

Edema, weight gain

Tiagabine

Enhance GABA activity

Loading dose: Not recommended due to excessive adverse effects

Maintenance dose: 32-56 mg/d in four divided doses

Doses should be titrated upward over 6 wk, starting at 4 mg/d

Half-life:

Monotherapy: 7-9 h

Concurrent enzyme inducers: 2.5-4.5 h

Apparent volume of distribution: 0.6-0.8 L/kg

Protein binding: 96%

Primary elimination route: Hepatic

Not established

Dizziness, somnolence, irritability, slowed thinking

Topiramate

Modulate sodium channels; inhibit glutamate activity; enhance GABA activity

Loading dose: Not recommended due to excessive adverse effects

Maintenance dose: 100-400 mg/d in 2-3 divided doses

Doses should be started at 25-50 mg/d and gradually titrated upward over 3-6 wk to avoid excessive adverse effects

Half-life:

Monotherapy: 21 h

Concurrent enzyme inducers: 11-16 h

Apparent volume of distribution: 0.55-0.8 L/kg

Protein binding: 13%-17%

Primary elimination route: 60% renal 40% hepatic

Not established

Ataxia, dizziness, drowsiness, slowed thinking

Acute glaucoma, metabolic acidosis, oligohidrosis, paresthesias, renal calculi, weight loss

Valproic acid/divalproex sodium

Modulate sodium channels

Loading dose: 20-40 mg/kg

Maintenance dose:

Adults: 15-45 mg/kg/d in 2-4 divided doses

Children: 5-60 mg/kg/d in 2-4 divided doses

Half-life:

Adults: 8-15 h

Children: 4-15 h

Infants > 2 mo: 65 h

Volume of distribution: 0.1-0.5 L/kg

Protein binding: 90% (decreases with increasing serum concentrations)

Primary elimination route: Hepatic

50-100 mg/mL (346-693 μmol/L); children may require concentrations up to 150 mg/mL (1040 mmol/L)

Drowsiness, nausea, sedation, tremor

Hepatotoxicity, osteoporosis, pancreatitis, weight gain

Zonisamide

Modulate sodium and calcium channels

Loading dose: Not recommended due to excessive adverse effects

Maintenance dose: 100-600 mg/d; start at 100 mg/d and titrate upward as indicated by response

Half-life: ∼63 h

Apparent volume of distribution: 1.45 L/kg

Protein binding: 40%

Primary elimination route: Hepatic

Not established

Dizziness, somnolence

Metabolic acidosis, oligohidrosis, paresthesias, renal calculi

Abbreviation: GABA, γ-aminobutyric acid.

Reproduced with permission from: Welty TE, Faught E. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, et al, eds. Pharmacotherapy Principles & Practice. New York, NY: McGraw-Hill; 2008: 443-460.

Special Considerations

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Complications of Therapy

Adverse effects of AEDs are often dose limiting or cause a drug to be discontinued. AED adverse reactions are classified as dose related or idiosyncratic (see Table 49-3). Dose-related adverse reactions are associated with the dose or concentration. Dose-related adverse effects include sedation, ataxia, and diplopia. Idiosyncratic adverse reactions are not related to the dose of the AED and often lead to discontinuation of the AED. Examples of idiosyncratic reactions include rash, hepatotoxicity, and hematologic toxicities. Because idiosyncratic reactions may be life threatening, the AED should be discontinued. Idiosyncratic reactions are associated with an immunologic reaction; therefore cross-reactivity among AEDs is possible.6-7

Switching AEDs

Switching AEDs requires a titration process, because abrupt discontinuation of an AED may lead to breakthrough seizures. The process requires starting the new AED at a low dose and titrating up to the minimal effective dose. Once the minimal effective dose is reached, the drug to be discontinued is gradually tapered, while the dose of the new AED continues to be increased to the target dose.

Discontinuing AEDs

Epilepsy is considered a lifelong disorder; however, patients who are seizure-free may desire to discontinue their medication. Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 but before age 35, and a normal neurologic examination and EEG. Withdrawal of AEDs is done slowly with a dose tapered over at least 3 months.8

Drug Interactions

AEDs are associated with numerous drug interactions related to absorption, metabolism, and protein binding. Tube feedings and antacids reduce the absorption of phenytoin and carbamazepine. Phenytoin, carbamazepine, and phenobarbital are potent inducers of the cytochrome P-450 (CYP-450) isoenzyme system and valproic acid is an inhibitor of the P-450 isoenzyme system (Table 49-4).9

TABLE 49-4 Drug Interaction Properties with Antiepileptic Drugs

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TABLE 49-4 Drug Interaction Properties with Antiepileptic Drugs

Enzyme

Substrate

Inducers

Inhibitors

CYP 1A2

Carbamazepine

Carbamazepine Phneytoin Phenobarbital

CYP 2C9

PhenobarbitalPhenytoinCarbamazepineValproic acid

CarbamazepinePhenytoinPhenobarbital

Valproic acid

CYP 2C19

PhenobarbitalPhenytoinValproic acid

FelbamateTopiramateZonisamide

CYP 2D6

Zonisamide

Carbamazepine

CYP 3A4

Carbamazepine

CarbamazepinePhenytoinPhenobarbital

Uridine diphosphate glucuronyl-transferase

LamotrigineCarbamazepine

LamotriginePhenobarbitalPhenytoin

Valproic acid

Special Populations

Children require prompt control of seizures to avoid interference with development of the brain and cognition. AED doses are increased rapidly and frequent changes in the regimen are made to maximize control of seizures. Due to high metabolic rates in children, doses of AEDs are higher on a milligram per kilogram basis compared to adults.

Women of child-bearing potential or who are pregnant have recommendations for AED management (Table 49-5). Several AEDs have been implicated in minor and serious birth defects. Valproic acid and carbamazepine are associated with neural tube defects (eg, spina bifida). The majority of pregnant epileptic patients receiving AEDs produce a normal infant, but special recommendations must be followed. AEDs induce hepatic CYP-450 isoenzymes and decrease the effectiveness of hormonal contraceptives. Epileptic women taking AEDs and hormonal contraceptives are recommended to use other forms of birth control.10

TABLE 49-5 Management of Antiepileptic Drugs During Pregnancy

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TABLE 49-5 Management of Antiepileptic Drugs During Pregnancy

• Give supplemental folic acid 1-4 mg daily to all women of child-bearing potential

• Use monotherapy when possible

• Use lowest dose possible to control seizures

• Monitor AED serum concentrations at the start of pregnancy and monthly thereafter

• Administer supplemental vitamin K during the eighth month of pregnancy to women receiving enzyme-inducing AEDs

Michaelis-Menten Metabolism

Phenytoin exhibits dose-dependent capacity-limited (Michaelis-Menten) pharmacokinetics, meaning the maximum capacity of hepatic enzymes to metabolize the drug is reached within the normal dosage range. Therefore, small changes in doses result in disproportionate and large changes in serum concentrations. Due to individual differences in metabolism, each patient follows a different curve in the relationship between dose and serum concentrations.4,6

Protein Binding

Phenytoin and valproic acid are highly protein bound and only unbound medication is able to produce clinical and adverse effects. When interpreting serum concentrations for highly protein-bound AEDs, it is important to remember that the value represents the total concentration (bound and unbound). Patients with decreased protein (albumin) will have the same total concentration of AEDs, but the unbound concentration (active component) will be increased. Also, certain diseases states and medications may displace AEDs from protein, thereby increasing the unbound concentration. Examples of patients with low protein or disease states/medications that increase the unbound concentration of AEDs include:

Patients with renal failure
Patients with hypoalbuminemia
Neonates
Pregnant women
Patients taking other highly protein bound medications
Critical care patients

Alterations in protein binding of phenytoin will result in increased dose-related side effects. In patients with suspected changes in protein binding, it is useful to measure or calculate unbound (free) phenytoin concentrations.6

Autoinduction

Carbamazepine is a potent inducer of the CYP-450 isoenzyme system, leading to increased clearance of many medicines and itself. Carbamazepine displays autoinduction of its own metabolism.

Serum Concentration Monitoring

A therapeutic range should be established for each patient and this range should define concentrations that result in minimal side effects and optimal seizure control. Table 49-3 lists usual serum concentrations for the AEDs.

Status Epilepticus

Status epilepticus (SE) is a neurologic emergency that can lead to permanent brain damage or death. SE is defined as any seizure lasting more than 30 minutes, with or without a loss of consciousness; or having recurrent seizures without regaining consciousness between seizure episodes.11 The goals for treatment of SE include the cessation of any seizure activity and the prevention of further seizures. Ideally, this is accomplished through directed pharmacotherapy with minimization of adverse reactions. Treatment of SE includes benzodiazepines and anticonvulsants (Table 49-6).

TABLE 49-6 Parenteral Medications Used in Status Epilepticus in Adults

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TABLE 49-6 Parenteral Medications Used in Status Epilepticus in Adults

Drug Name (Brand Name)

Loading Dose

Administration Rate

Therapeutic Level

Side Effects

Comments

Diazepam (Valium)

0.15 mg/kg

5 mg/min (IVP)

N/A

Hypotension, respiratory depression

Rapid redistribution rate; can be given rectally

Lorazepam (Ativan)

0.1 mg/kg

2 mg/min (IVP)

N/A

Hypotension, respiratory depression

May be longer-acting than diazepam

Midazolam (Versed)

0.2 mg/kg

2 mg/min (IVP)

N/A

Sedation

Can also be given IM, buccally, intranasally; expensive

Phenytoin (Dilantin)

15-20 mg/kg

Up to 50 mg/min

10-20 mg/mL (39.6-79.2 μmol/L)

Arrhythmias, hypotension,

Hypotension, especially in elderly

Fosphenytoin (Cerebyx)

15-20 mg PE/kg

Up to 150 mg PE/min

10-20 mg/mL

Paresthesias, hypotension

Can be given IM; less CV side effects than phenytoin; expensive

Phenobarbital (Luminal)

20 mg/kg

50-100 mg/min

15-40 mg/mL (64.7-172.4 μmol/L)

Hypotension, sedation, respiratory depression

Long-acting

Valproate sodium (Depacon)

15-20 mg/kg (up to 40 mg/kg)

3-6 mg/kg/min

50-150 mcg/mL (346.5-1039.5 μmol/L)

Less CV side effects than phenytoin

Propofol (Diprivan)

1-2 mg/kg

∼ 40 mg/10 s

N/A (typically titrated to EEG)

Hypotension, respiratory depression

Requires mechanical intubation; high lipid load (increased calories); propofol infusion syndrome

Pentobarbital (Nembutal)

10-15 mg/kg

Up to 50 mg/min

10-20 mg/mL (typically titrated to EEG)

Hypotension, respiratory depression, cardiac depression, infection, ileus

Requires mechanical intubation, pressors, hemodynamic monitoring

Abbreviations: CV, cardiovascular; EEG, electroencephalogram; IM, intramuscular; IVP, intravenous push; N/A, not applicable; PE, phenytoin equivalents.

Reproduced with permission from Brophy GM, Tesoro EP. Status epileptieus. In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, et al, eds. Pharmacotherapy Principles and Practice. New York, NY: McGraw-Hill, 2008;461-471.

Phenytoin and Fosphenytoin in Status Epilepticus

Phenytoin is administered intravenously as a loading dose (for patients not previously on phenytoin) of 15 to 20 mg/kg. The loading dose is infused no faster than 50 mg/min due to risks of hypotension and arrhythmias. Continuous monitoring of ECG and blood pressure is recommended. Maintenance dosing can be started in 12 hours after the loading dose. Phenytoin should not be administered via the intramuscular route due to alkaline nature. Extravasation of the drug can cause local discoloration, edema, pain, and sometimes necrosis.

Fosphenytoin is a water-soluble, prodrug of phenytoin that is rapidly converted to phenytoin in the body. Unlike phenytoin, fosphenytoin is compatible with most intravenous solutions and is tolerated as an intramuscular injection. Fosphenytoin is dosed on phenytoin equivalents (PE), and it can be infused up to 150 mg PE/min. The loading dose for patients not taking phenytoin is 15 to 20 mg PE/kg. Although fosphenytoin has fewer cardiovascular side effects compared to phenytoin, blood pressure and ECG should still be monitored.12

AED Brand Names and Formulations

Table 49-7 lists brand/generic names and formulations of antiepileptic drugs.

TABLE 49-7 Brand/Generic Names and Formulations of AEDs

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TABLE 49-7 Brand/Generic Names and Formulations of AEDs

Generic

Brand

Formulations

Sodium Channel Modulators

Carbamazepine

Tegretol, Tegretol XR Epitol Equitro

Tablet Chewable tablet Extended release tablet Extended release capsule Suspension

Lamotrigine

Lamictal

Tablet Chewable tablet Disintegrating tablet

Oxcarbazepine

Trileptal

Tablet Suspension

Valproic acid

Depacon Depakene Stavzor

Softgel capsule Solution

Divalproex

Depakote Depakote ER

Delayed release capsule Extended release tablet Delayed release/enteric coated tablet

Phenytoin

Dilantin Phenytek

Capsule Extended release capsule Chewable tablet Suspension IV solution for injection

Fosphenytoin

Cerebyx

IV/IM solution for injection

Phenobarbital

Luminal

Tablet Elixir IV solution for injection

Calcium Channel Modulators

Ethosuximide

Zarontin

Liquid-filled capsule Syrup

Pregabalin

Lyrica

Capsule

GABA Modulators

Clonazepam

Klonopin Klonopin Wafers

Tablet Disintegrating tablet

Glutamate Modulators

Felbamate

Felbatol

Tablet Suspension

Combination Modulators

Gabapentin

Neurontin

Capsule

Tablet

Solution

Topiramate

Topamax

Capsule/sprinkles

Tablet

Zonisamide

Zonegran

Capsule

Unknown Mechanism of Action

Levetiracetam

Keppra Keppra XR

Tablet

Extended release tablet

IV solution for injection

Solution

Takeaway Points

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Epilepsy is a chronic disease of disturbed electrical activity in the brain resulting in recurrent seizures with or without convulsions.
The pathophysiology of a seizure is due to an unstable cell membrane in the gray matter of the brain.
The classifications of epilepsy are: absence seizures (petit mal)—sudden interruption of activities and a blank stare; myoclonic seizures—brief shock-like contraction of a muscle group; clonic seizures—jerking motion while tonic seizures involve a sustained muscle contraction; tonic-clonic seizures (grand mal)—alternating muscle contraction and jerking; atonic seizures involve a sudden loss of muscle tone know as "drop attacks."
Laboratory tests are evaluated to rule out treatable causes of seizures, such as hypoglycemia, altered electrolytes, and infections. A seizure produced by treatable causes does not represent epilepsy.
Medications associated with causing seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsychotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, sympathomimetics, and stimulants.
The goal of epilepsy treatment is complete elimination of seizures with no drug side effects. This is not always possible and the patient should be involved in deciding the balance between frequency of seizures and occurrence of side effects.
Initial therapy is initiated with one AED and up to 70% of patients are controlled on monotherapy.
Adverse effects of AEDs are often dose limiting or cause a drug to be discontinued. AED adverse reactions are classified as dose related or idiosyncratic.
Dose-related adverse effects include sedation, ataxia, and diplopia. Idiosyncratic adverse reactions are not related to the dose of the AED and often lead to discontinuation of the AED.
AEDs are associated with numerous drug interactions related to absorption, metabolism, and protein binding.
Phenytoin exhibits dose-dependent capacity-limited (Michaelis-Menten) pharmacokinetics, meaning the maximum capacity of hepatic enzymes to metabolize the drug is reached within the normal dosage range.
Phenytoin and valproic acid are highly protein bound and only unbound medication is able to produce clinical and adverse effects.
A therapeutic range should be established for each patient and this range should define concentrations that result in minimal side effects and optimal seizure control.
Status epilepticus (SE) is a neurologic emergency that can lead to permanent brain damage or death.

References

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1. Armijo JA, Shushtarian M, Valdizan EM, Cuadrado A, de las Cuevas I, Adín J. Ion channels and epilepsy. Curr Pharm Des. 2005;11:1975-2003.

2. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981;22:489-501.

3. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399.

4. Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion. Epilepsy Behav. 2005; 7:S1-S64.

5. Perruca E. An introduction to antiepileptic drugs. Epilepsia. 2005;46(suppl 4):31-37.

6. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy, report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2005;62:1252-1260.

7. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of new onset epilepsy, report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2005;62:1261-1273.

8. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: a guideline for discontinuing antiepileptic drugs in seizure free patients [summary statement]. Neurology. 1996;47:600-602.

9. Patsalos PN, Froscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia. 2002;43: 365-385.

10. Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia. 2005;46(suppl 9):117-124.

11. Commission on Classification of Terminology, International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981;22;489-501.

12. Pryor FM, Gidal B, Ramsay RE, DeToledo J, Morgan RO. Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses. Epilepsia. 2001:42(2):245-250.

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Chapter 49. Epilepsy

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Foundation Overview

Prevention

Treatment

Special Considerations

Complications of Therapy

Switching AEDs

Discontinuing AEDs

Drug Interactions

Special Populations

Michaelis-Menten Metabolism

Protein Binding

Autoinduction

Serum Concentration Monitoring

Status Epilepticus

Phenytoin and Fosphenytoin in Status Epilepticus

AED Brand Names and Formulations

Takeaway Points

References

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