Timothy E. Welty and Edward Faught
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the epidemiology and social impact of epilepsy.
2. Define terminology related to epilepsy, including seizure, convulsion, and epilepsy.
3. Describe the basic pathophysiology of seizures.
4. Describe the basic pathophysiology of epilepsy.
5. Differentiate and classify seizure types when provided a description of the clinical presentation of the seizure and electroencephalogram.
6. Identify key therapeutic decision points in the treatment of epilepsy.
7. Establish therapeutic goals for pharmacotherapy in a patient with epilepsy.
8. Discuss nonpharmacologic treatments for epilepsy.
9. Recommend an appropriate pharmacotherapeutic regimen for the treatment of epilepsy.
10. Select appropriate monitoring parameters for a pharmacotherapeutic regimen of epilepsy.
11. Devise a plan for switching a patient from one antiepileptic regimen to a different regimen.
12. Recognize complications of pharmacotherapy for epilepsy.
13. Analyze potential drug interactions with antiepileptic drugs (AEDs).
14. Determine when and how to discontinue AED therapy.
15. Educate a patient or caregiver on epilepsy and pharmacotherapy for this disorder.
KEY CONCEPTS
A distinction among convulsions, a single seizure, pseudoseizure, and epilepsy should be made in patients presenting with possible seizures.
Selection of appropriate pharmacotherapy is dependent upon distinguishing, identifying, and understanding different seizure types.
Prior to starting pharmacologic therapy, it is essential to determine the risk of having a subsequent seizure.
Mechanisms of action, effectiveness for specific seizure types, common adverse effects, and potential for drug interactions are key elements in selecting a medication for individual patients.
Antiepileptic drugs (AEDs) therapy should usually be initiated carefully using a titration schedule to minimize adverse events.
Changes in AED regimens should be done in a stepwise fashion, keeping in mind drug interactions that may be present and that may necessitate dosage changes in concomitant drugs.
Discontinuation of AEDs should be done gradually, only after the patient has been seizure-free for 2 to 5 years, and with careful consideration of factors predictive of seizure recurrence.
Children and women with epilepsy have unique problems related to the use of AEDs.
Patients receiving AEDs for seizures should have regular monitoring for seizure frequency, seizure patterns, acute adverse effects, chronic adverse effects, and possible drug interactions.
EPIDEMIOLOGY, SOCIAL IMPACT, AND ETIOLOGY
Epidemiology
Epilepsy is a disorder that afflicts approximately 2 million individuals in the United States, with an age-adjusted prevalence of approximately 4 to 7 cases/1,000 persons.1 The incidence of epilepsy in the United States is estimated at 35 to 75 cases/100,000 persons per year, which is similar to that of other developed countries.23 In developing countries, the incidence is higher at 100 to 190 cases/100,000 persons per year, possibly related to poor health care and prenatal care, increased risk of neurologic trauma, and increased rates of infections. About 8% of the U.S. population will experience a seizure during their lifetime. New onset seizures occur most frequently in infants less than 1 year of age and in adults after age 55.4 However, the largest number of patients suffering from epilepsy is between the ages of 15 and 64 years.
Social Impact
Epilepsy is a disorder with profound impact on a patient’s life. All states limit driving for individuals who have recently had a seizure with impaired consciousness, and restrictions vary from state to state.5Patients who live in communities without adequate public transportation face major impediments to simple activities of life, such as purchasing groceries or getting to a job. Education is also problematic for patients with epilepsy6,7 Individuals with persistent seizures have poor school attendance. Fifty percent of patients with epilepsy complain of cognitive difficulties and believe their seizures interfere with learning. Additionally, patients with epilepsy score 50% lower on standardized examinations and have lower graduation rates from high school and college. Transportation and educational difficulties combine with persistent seizures to cause patients with epilepsy to be unemployed or underemployed. Thus, this group of patients faces multiple financial difficulties and often do not have health insurance.
Finally, patients with epilepsy are often dependent upon caregivers to assist with medications, transportation, and ensuring the patient’s safety. Caregivers should be informed of the patient’s medical needs and how to assist should a seizure occur.
Etiology
For nearly 80% of patients with epilepsy, the underlying etiology is unknown.8 The most common recognized causes of epilepsy are head trauma and stroke. Developmental and genetic defects are the cause of about 5% of cases of epilepsy. CNS tumors, CNS infections, and neurodegenerative diseases are other common causes. Other important causes of epilepsy are HIV infection or neurocysticercosis infection, primarily occurring in Latin America.
Isolated seizures that are not epilepsy can be caused by stroke, CNS trauma, CNS infections, metabolic disturbances (e.g., hyponatremia, hypoglycemia), and hypoxia. If these underlying causes of seizures are not corrected, they may lead to the development of recurrent seizures or epilepsy. Medications can also cause seizures. Some drugs that are commonly associated with seizures include tramadol, buproprion, theophylline, some antidepressants, some antipsychotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, and sympathomimetics or stimulants.
PATHOPHYSIOLOGY
Seizures
Regardless of the underlying etiology, all seizures involve a sudden electrical disturbance of the cerebral cortex. A population of neurons fires rapidly and repetitively for seconds to minutes. Cortical electrical discharges become excessively rapid, rhythmic, and synchronous. This phenomenon is presumably related to an excess of excitatory neurotransmitter action, a failure of inhibitory neurotransmitter action, or a combination of the two. In the individual patient, however, it is usually impossible to identify which neurochemical factors are responsible.
Neurotransmitters
The major excitatory neurotransmitter in the cerebral cortex is glutamate.9 When glutamate is released from a presynaptic neuron, it attaches to one of several receptor types on the postsynaptic neuron. The result is opening of membrane channels to allow sodium or calcium to flow into the postsynaptic neuron, thus depolarizing it and transmitting the excitatory signal.10 Many antiepileptic drugs (e.g., phenytoin, carbamazepine, lamotrigine) work by interfering with this mechanism, either by blocking the release of glutamate or by blocking the sodium or calcium channels, thus preventing excessive excitation.11 These drugs typically do not block normal neuronal signaling, only the excessively rapid firing characteristic of a seizure. For this reason, they do not usually affect normal brain function.
The major inhibitory neurotransmitter in the cerebral cortex is gamma-aminobutyric acid (GABA). It attaches to neuronal membranes and opens chloride channels. When chloride flows into the neuron, it becomes hyperpolarized and less excitable. This mechanism is probably critical for shutting off seizure activity by controlling the excessive neuronal firing. Some antiepileptic drugs (AEDs), primarily barbiturates and benzodiazepines, work by enhancing the action of GABA.
Cortical function is modulated by many other neuro-transmitters. However, their role in the pathophysiology of epilepsy and in the action of AEDs is not yet well known.
Neuronal Mechanisms
Seizures originate in a group of neurons that do not have normal electrical behavior.12 Presumably, this is due to an underlying imbalance of neurotransmitter function as described above. At the level of the individual neuron, firing is excessively prolonged and repetitive. Instead of firing a single action potential, these neurons stay depolarized too long, firing a train of many action potentials. This long, abnormal depolarization is called a paroxysmal depolarizing shift (PDS).
The excessive electrical discharges can spread to other neurons, either adjacent ones or distant ones connected by fiber tracts. The seizure thus spreads to other areas of the brain, recruiting them into the uncontrolled firing pattern. The neurons involved may not be abnormal themselves, but are diverted from their normal functioning to participate in the wildly excessive discharges. The degree of spread and the location of brain areas involved determine the clinical manifestations of the seizure.
Nearly all seizures stop spontaneously, because after seconds to minutes, brain inhibitory mechanisms become strong enough to shut off the abnormal excitation.
Epilepsy
Epilepsy is the tendency to have seizures on a chronic, recurrent basis. This implies that there is a permanent change in cortical function which renders neurons more likely to participate in a seizure discharge. This process is referred to as epileptogenesis, and the exact way in which it occurs is not known. A process thought to be similar to epileptogenesis in humans occurs after prolonged, intermittent electrical stimulation of animal brains and is known as kindling. Epilepsy may develop days, months, or many years after an insult to the cortex. It may be that an originally small group of abnormal neurons causes adjacent or connected neurons to gradually become abnormal as well, by bombarding them over time with frequent, repeated electrical impulses. When the network of abnormal neurons becomes sufficiently large, it becomes capable of sustaining an excessive firing pattern for at least several seconds: a seizure. This hyperexcitable network of neurons is then the seizure focus.
If the change in cortical electrical characteristics is permanent, why don’t seizures occur all the time? This is probably because the occurrence of an individual seizure depends upon an interplay of environmental and internal brain factors that, from time to time, result in loss of the normal mechanisms that contain and control abnormal neuronal firing. Some common factors are sleep loss and fatigue, but it is impossible to determine what sets off a particular seizure in most patients.
Clinical Presentation and Diagnosis of Epilepsy
General
Typically, health care providers are not able to observe a patient’s seizures and for most types of seizures the patient has no memory of the event. It is important to obtain a careful history from the patient and any individuals who witness the seizures.
Common Descriptions of Seizures
The clinical presentation of seizures will vary from patient to patient depending on the portion of brain involved in the seizure. Events will tend to be stereotypical for an individual patient.
Patients who experience seizures may complain of paroxysmal spells of
• Blanking out spells, lapses in memory, periods of altered consciousness
• Warnings or auras consisting of various sensations or automatic, uncontrolled movements
• Daydreaming
• Jerks, shoulder shrugs, sudden chills of spine
• Falling out
Associated Symptoms
• Incontinence, usually of urine
• Tongue biting
• Traumatic injuries, usually associated with falling during a seizure
Diagnosis
Description of events: The patient and any witnesses to the seizures should be carefully interviewed to obtain a full and complete description of typical seizures.
Neurologic examination: Usually, the neurologic physical examination is completely normal. Any neurologic deficits that are identified should be fully investigated because seizures do not usually cause permanent, detectable neurologic deficits.
Electroencephalogram (EEG): A routine EEG can be helpful if epileptiform discharges are seen. However, the EEG may be normal between seizures and most routine EEGs are not performed during a seizure. Maneuvers such as sleep deprivation, photic stimulation, hyperventilation, or prolonged monitoring can help expose EEG changes consistent with epilepsy.
Neuroimaging (preferably an MRI of the brain): Imaging of the brain is important to rule out obvious causes of seizures such as stroke or tumors. An MRI scan is also helpful in detecting mesial temporal sclerosis, a finding often associated with mesial temporal epilepsy and predictive of positive surgical outcomes.
Video EEG monitoring: A procedure consisting of continuous video monitoring of the patient with a simultaneous EEG. Usually a patient is monitored in the hospital for 4 to 5 days. This procedure is used to determine if the patient is truly having seizures, to determine the specific type of seizures the patient is having, and to localize the area of the brain that is the origin of the seizures.
In some patients, epilepsy worsens over time, with the seizures becoming more frequent as patients grow older. This does not occur in most patients with epilepsy. In those so affected, it is possible that the seizures themselves may cause some damage to the cortex; loss of neurons, especially inhibitory neurons, has been demonstrated in tissue from seizure foci. Other changes occur in brain areas affected by seizures: reorganization of connections between groups of neurons may strengthen excitatory connections and weaken inhibitory connections, making the occurrence of future seizures more likely. Additionally, epilepsy is associated with an increased mortality rate.13 For these reasons, an argument can be made for controlling epileptic seizures with medications as early as possible. This may reduce the possibility of permanent changes in brain function, although this hypothesis is unproven.
Genetic Factors
Patients with seizures may be concerned that their children or other family members will inherit epilepsy. This fear is usually unfounded. Patients with acquired causes of seizures, such as head trauma or stroke, will not transmit the problem. There is a group of patients, however, who apparently have epilepsy on a genetic basis. Most of these individuals have primary generalized epilepsy.14,15 Usually these patients develop seizures during childhood. However, the hereditary tendency is not strong. Complex inheritance patterns are usually seen, indicating the likely involvement of several abnormal genes or other factors for seizures to be clinically expressed in offspring. Thus, most patients can be reassured that their children and siblings are unlikely to develop epilepsy. Increasing numbers of epilepsy syndromes are being identified as being of genetic origin, and once the specific genes are identified it may be possible to target drug therapies more specifically toward individual biochemical defects.
SEIZURE CLASSIFICATION AND PRESENTATION
General Principles
Careful diagnosis and identification of seizure types is essential to proper treatment of epilepsy. Numerous schemes and descriptions of seizures exist, but the International League Against Epilepsy (ILAE) has established the currently accepted standard for classifying epileptic seizures (Fig. 30–1) and epilepsies or epilepsy syndromes (Table 30–1).16,17 Classification of epileptic seizures is based upon electroencephalographic (EEG) findings combined with the clinical findings or semiology of the seizure events. Clinical presentations of seizures vary widely depending upon the region and amount of brain involved in the seizure.
Primary Generalized Seizures
If the entire cerebral cortex is involved in the seizure from the onset of the seizure, the seizure is classified as primary generalized. The following are types of primary generalized seizures:
• Tonic-clonic: Characterized by a sudden loss of consciousness accompanied by tonic extension and rhythmic clonic contractions of all major muscle groups. The duration of the seizure is usually 1 to 3 minutes. These seizures are often described as “grand mal.”
• Absence: Characterized by sudden and brief (i.e., several seconds in duration) losses of consciousness without muscle movements. These seizures are often described as daydreaming or blanking out episodes. A common term for these seizures is “petit mal.”
• Myoclonic: Characterized by single and very brief jerks of all major muscle groups. Patients with these seizures may not lose consciousness due to the seizure lasting less than 3 to 4 seconds. Patients may describe these seizures as shoulder shrugs or spinal chills. Myoclonic seizures may cluster and build into a generalized tonic-clonic seizure.
FIGURE 30–1. ILAE classification of epileptic seizures (1981). (From Ref. 16.)
Table 30–1 ILAE Classification Scheme for Epilepsies and Epilepsy Syndromes
|
I. Localization-related (focal, local, partial) epilepsies and epileptic syndromes |
|
A. Idiopathic with age-related onset |
|
1. Benign childhood epilepsy with centrotemporal spikes |
|
2. Childhood epilepsy with occipital paroxysms |
|
B. Symptomatic |
|
II. Generalized epilepsies and epileptic syndromes |
|
A. Idiopathic and age-related onset |
|
1. Benign neonatal epilepsy |
|
2. Childhood absence epilepsy (pyknolepsy) |
|
3. Juvenile myoclonic epilepsy (impulsive petit mal) |
|
4. Juvenile absence epilepsy with generalized tonic-clonic seizure on awakening |
|
B. Secondary (idiopathic or symptomatic) |
|
1. West’s syndrome (infantile spasms) |
|
2. Lennox-Gastaut syndrome |
|
C. Symptomatic |
|
1. Nonspecific etiology (early myoclonic encephalopathy) |
|
2. Specific syndromes (epileptic seizures that may complicate many diseases, e.g., Ramsay-Hunt syndrome, Unverricht’s disease) |
From Ref. 17.
• Atonic: Characterized by loss of consciousness and muscle tone. No muscle movements are typically noted, and the patient falls if not lying down or sitting in a chair. These seizures may be described as “falling out.”
Partial Seizures
When the seizure begins in a localized area of the brain, it is defined as partial. There are three types of partial seizures in the current classification system (Fig. 30–1):
• Simple: The patient has a sensation or uncontrolled muscle movement of a portion of their body without an alteration in consciousness. The type of sensation or movement is dependent upon the location of seizure in the brain.
• Complex: Although the seizure is localized in a specific area of the brain, like a simple partial seizure, there is an alteration in the patient’s level of consciousness.
• Secondarily generalized: The seizure starts as a simple or complex partial seizure and spreads to involve the entire brain. Patients may report a warning or aura, and these are actually the start of the seizure.
Epilepsy Syndromes
Classification of epilepsies and epilepsy syndromes is helpful in determining appropriate pharmacotherapy. This classification scheme is based upon the type of seizures a patient has and an attempt to identify the etiology of the epilepsy or epilepsy syndrome:
• Idiopathic epilepsies: These syndromes are thought to be due to genetic alterations, but the underlying etiology is not identified. Neurologic functions are completely normal apart from the occurrence of seizures.
• Symptomatic epilepsies: There is an identifiable cause for the seizures, such as trauma or hypoxia.
• Cryptogenic epilepsies: In these epilepsies the seizures are the result of an underlying neurologic disorder that is often ill-defined or undocumented. Neurologic functions are often abnormal or developmentally delayed in patients with cryptogenic epilepsies.
A complete description of a patient’s epilepsy should include the seizure type with the epilepsy or syndrome type (e.g., idiopathic, symptomatic, cryptogenic).
Commonly encountered epilepsy syndromes are:
• Juvenile myoclonic epilepsy (JME): A primary generalized epilepsy syndrome that usually starts in the early to middle teenage years and has a strong familial component. Patients have myoclonic jerks and tonic-clonic seizures and may also have absence seizures.
• Lennox-Gastaut syndrome (LGS): Patients with this syndrome have cognitive dysfunction and mental retardation. Their seizures usually consist of a combination of tonic-clonic, absence, atonic, and myoclonic seizures.
• Mesial temporal lobe epilepsy (MTLE): A type of epilepsy that consists of partial seizures arising from the mesial temporal lobe of the brain. Often this type of epilepsy is associated with an anatomical change described as hippocampal sclerosis. Patients with this type of epilepsy often have excellent surgical outcomes.
• Infantile spasms: A seizure syndrome that occurs in infants less than 1 year of age. It is characterized by a specific EEG pattern and spasms or jitters, and is also known as West’s syndrome. Infants with infantile spasms often develop other seizure types and epilepsies later in life.
Other Classifications
The ILAE is proposing a new classification system that improves the description of the seizure type and epilepsy.18,19 The proposed scheme revolves around five axes:
• Axis 1: description of the seizure event
• Axis 2: epileptic seizure type or types
• Axis 3: any syndrome type
• Axis 4: etiology when known
• Axis 5: degree of impairment by the epilepsy
This classification system is undergoing final review and should become the standard in the near future.
DIAGNOSIS
Determining a correct and accurate diagnosis is essential prior to any consideration of pharmacotherapy. When a patient complains of paroxysmal, stereotypical spells that may be seizures, it must be determined if the spells are really seizures. Numerous other disorders, including convulsions, syncope, psychogenic nonepileptic events (i.e., pseudoseizures), anxiety attacks, cardiac arrhythmias, hypoglycemia, transient ischemic attacks, tics, and complicated migraine headaches, are often mistaken as seizures by patients and caregivers. Seizures are typically brief spells, lasting no more than 5 minutes. However, seizures can be prolonged and can last for 15 minutes or more. In this situation the patient is in status epilepticus and requires immediate medical attention.
A proper diagnostic workup of a patient presenting with seizures should include the following elements:
• Thorough neurologic examination
• EEG
• Laboratory tests (complete blood count [CBC], liver function tests [LFTs], serum chemistry)
• Neuroimaging (preferably MRI).
In patients with epilepsy these laboratory findings may be normal. Many of the tests are done to rule out other causes of seizures (e.g., infection, electrolyte imbalance). Often the EEG appears normal between seizures.20 Several manipulations can be done in an attempt to capture seizure or seizure-like activity on the EEG. These include sleep deprivation, photic stimulation, prolonged (greater than 20 minutes) EEG recording, and 24-hour EEG monitoring with video correlation.
TREATMENT
Desired Outcomes
The ultimate outcome goal for any patient with epilepsy is elimination of all seizures without any adverse effects of the treatment. An effective treatment plan would allow the patient to pursue a normal lifestyle with complete control of seizures. Specifically, the treatment should enable the patient to drive, perform well in school, hold a reasonable job, and function effectively in the family and community. However, due to the intractability of the seizures or sensitivity to AEDs, many patients are not able to achieve these outcomes. In these cases, the goal of therapy is to provide a tolerable balance between reduced seizure severity and/or frequency and medication adverse effects that optimizes the individual’s ability to have a lifestyle as nearly normal as possible.
General Approach to Treatment
Once it is concluded that the patient has seizures, the type of seizure and epilepsy syndrome, if any, must be determined. Proper identification and classification of the seizure type is essential in selecting appropriate pharmacotherapy. Without an accurate classification of the seizure type, it is possible to select a medication that is ineffective or even harmful to the patient.
Additionally, the risk of a subsequent seizure must be determined before starting pharmacotherapy. If there is an underlying treatable cause, such as hyponatremia or a CNS infection, the risks of another seizure and the development of epilepsy are very small. In these cases, the only pharmacotherapy that is necessary is to correct the underlying problem and possibly short-term use of an AED. Risk factors for repeated seizures in patients without an underlying disorder include
• Structural CNS lesion
• Abnormal EEG
• Partial seizure type
• Positive family history
• Postictal motor paralysis21
Patient Encounter 1: New Onset Seizures
AG, a 20-year-old male who is a college student, is seen by his physician 4 days after an apparent seizure during finals week. According to his roommate he suddenly fell to the floor and had a generalized tonic-clonic seizure. This seizure lasted for 1 to 2 minutes. The patient was incontinent for urine during the seizure. He was sleepy and confused when the paramedics arrived 10 minutes later. Due to final examinations he reports being sleep deprived.
His physical exam is completely normal and no focal neurologic deficits were observed.
What diagnostic tests should be done at this time?
Should these tests be performed prior to starting medications?
His MRI is normal, and focal epileptiform activity originating from his left temporal lobe is observed on the EEG.
Should an AED be started at this point?
If you decide to treat, what drug and dose would you use?
How should that drug be monitored?
Three months later he has another seizure, but this time it is characterized by a rising feeling in his stomach followed by confused speech, lip smacking, repetitive movements of his right hand, and unresponsiveness. This episode lasts for 2 to 3 minutes, and it takes 15 minutes for his speech to return to normal.
If he is receiving an AED, should a second AED be started at this time?
What tests and evaluations should you do before starting a second AED?
If a second drug is started, what drug and dose would you use?
If no risk factors are present, the risk of another seizure is 10% to 15%. However, if two or more risk factors are present, the risk of another seizure is 100%.
When sufficient evidence is available to determine the patient has real seizures and is at risk for another seizure, pharmacotherapy is usually started (Fig. 30–2). The patient should be in agreement with the plan, be willing to take the medication, and be able to monitor seizure frequency and adverse drug effects in some way. Design of an appropriate pharmacotherapeutic plan is based upon the patient’s seizure type, the common adverse effect profile of possible AEDs, potential drug interactions, and economic factors (e.g., cost of the drug, insurance formulary, ability to pay). Other patient factors such as gender, concomitant drugs, age, and lifestyle also need to be considered.
Nonpharmacologic Therapy
Several nonpharmacologic treatments for epilepsy are available. For some patients, surgery is the treatment approach with the greatest probability of eliminating seizures.22 The most common surgical approach for epilepsy is temporal lobectomy. When the seizure focus can be localized and it is in a region of the brain that is not too close to critical areas, such as those responsible for speech or muscle control, surgical removal of the focus can result in 80% to 90% of patients becoming seizure free. According to a National Institutes of Health Consensus Conference, three criteria should be met for patients to be candidates for surgery.23 These criteria are (a) a definite diagnosis of epilepsy; (b) failure of adequate drug therapies; and (c) definition of the electroclinical syndrome (i.e., localization of the seizure focus in the brain). Other surgical procedures that are less likely to make a patient seizure free include corpus callosotomy and extratemporal lesion removal.
Vagal nerve stimulation is another nonpharmacologic approach to treating all types of seizures.24 In this treatment, a unit that generates an intermittent electrical current is placed under the skin in the chest. A wire is tunneled under the skin to the left vagus nerve in the neck. The unit generates a small electrical current every 5 minutes that stimulates the vagus nerve. Additional stimulations can be initiated by the patient swiping a magnet over the device located in the chest. This treatment approach is essentially equivalent to starting a new medication with regard to efficacy, but the precise mechanism for its effect has not been elucidated. Approximately 25% to 50% of patients who have a vagal nerve stimulator placed will experience at least a 50% reduction in seizure frequency. However, fewer than 10% become seizure free. Adverse effects include hoarseness, swallowing difficulties, tingling or vibration in the neck, infection or bleeding due to surgery, and, rarely, laryngeal spasms. Vagal nerve stimulation is usually reserved for patients who do not respond to several drugs and are not surgical candidates.
FIGURE 30–2. Treatment algorithm for management of seizure disorders.
One of the oldest nonpharmacologic treatments is the ketogenic diet.25 Modern use of the diet was started in the 1920s. This diet produces a keto-acidotic state through the elimination of nearly all carbohydrates. To initiate the diet, patients undergo 24 to 48 hours of fasting until ketones are detected in the urine. The diet consisting of dietary fats (e.g., butter, heavy cream, fatty meats) and protein with no added sugar is started. Daily urinalysis for ketones is performed to ensure the patient remains in ketosis. Any inadvertent consumption of sugar results in the diet needing to be reinitiated. Pharmacists have an important role in maintaining the diet, by determining the sugar or carbohydrate content of medications the patient is taking. This diet is typically used only in children with difficult to control seizures. In certain patients the diet can be extremely effective, resulting in complete seizure control and reduction of AEDs. However, it is hard to maintain a ketotic state, and palatability of the diet is a concern. Additionally, there are concerns about growth retardation in children and hypercholesterolemia with prolonged use of the diet.
Pharmacologic Therapy
Special Considerations
Use of AEDs present some unique challenges, some of which relate to their pharmacokinetic properties, which need to be clearly understood.26
Michaelis-Menten Metabolism
Phenytoin metabolism is capacity limited. Michaelis-Menten metabolism or Michaelis-Menten pharmacokinetics is when the maximum capacity of hepatic enzymes to metabolize the drug is reached within the normal dosage range. The clinical significance is that small changes in doses result in disproportionate and large changes in serum concentrations. The patient is at risk of sudden toxicity if too large a dose increase is made, or a breakthrough seizure may occur if too large a reduction in dose is made. Due to individual differences in metabolism, each patient follows a different curve in the relationship between dose and serum concentrations. These differences can only be defined by careful use of serum concentration and dosing data. There are numerous schemes for determining appropriate dosage adjustments of phenytoin, and these are discussed in pharmacokinetic textbooks. For routine clinical practice, dosage adjustments for adults with normal protein binding of phenytoin and a steady-state serum concentration can be made using the following plan:
• For serum concentrations less than 7 mcg/mL (28 μmol/L), the total daily dose is increased by 100 mg.
• For serum concentrations of 7 to 12 mcg/mL (28–48 μmol/L), the total daily dose is increased by 50 mg.
• For serum concentrations greater than 12 mcg/mL (48 μmol/L), the total daily dose is increased by no more than 30 mg.27
Protein Binding
Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for these drugs.
Normally, 88% to 92% of phenytoin is bound to plasma protein, leaving 8% to 12% as unbound. The unbound component is able to leave the blood to produce the clinical effect in the CNS, produce dose-related side effects in the CNS and at other sites, distribute to other peripheral sites, and be metabolized. Certain patient groups are known to have decreased protein binding, resulting in an increased percentage of drug that is unbound. These patient groups include
• Those with kidney failure
• Those with hypoalbuminemia
• Neonates
• Pregnant women
• Those taking multiple highly protein bound drugs
• Patients in critical care
Due to the Michaelis-Menten metabolism of phenytoin, alterations in its protein binding will result in increased severity of dose-related adverse effects. In patients with suspected changes in protein binding, it is useful to measure unbound phenytoin concentrations.
When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion.
Autoinduction
Carbamazepine is a potent inducer of hepatic microsomal enzymes. Not only does it increase the rate of metabolism for many other drugs, it increases the rate of its own metabolism. Hepatic enzymes become maximally induced over several weeks, necessitating a small initial dose of carbamazepine that is increased over time to compensate for the enzyme induction (Fig. 30–3). Most dosage regimens for carbamazepine call for a starting dose that is 25% to 30% of the typical maintenance dose of 15 mg/kg/day. The dosage is increased weekly until the target maintenance dose is achieved within 3 to 4 weeks. Titration of the carbamazepine dose lessens the risk for severe dose-related adverse effects when carbamazepine is first started.
FIGURE 30–3. Serum concentrations of carbamazepine in the presence and absence of appropriate dose titration.
Drug Selection and Seizure Type
The key to selecting effective pharmacotherapy is to base the decision on the seizure type. Several consensus treatment guidelines from the Scottish Intercollegiate Guidelines Network (SIGN), the National Institute for Clinical Excellence in the United Kingdom (NICE), the American Academy of Neurology (AAN), and ILAE all use determination of seizure type as the basis for selection of pharmacotherapy (Table 30–2).28–30 While the guidelines make recommendations for specific drugs to be used in certain seizure types, the consensus recommendations utilize only data available from the medical literature. In many cases, a recommendation is not made because there are no published data on which to make an evidence-based decision. Therefore, a drug may not currently be recommended for a seizure type simply because it has not been studied for that seizure type. Absence of a recommendation should not be taken to mean the drug is ineffective for a specific seizure type.
Outside of the evidence-based guidelines, other pharmacologic treatments are commonly used or avoided. For initial treatment of absence seizures, ethosuximide and valproate are commonly used, not only in the United Kingdom, but also in the United States. Zonisamide may be also used for initial treatment of absence and myoclonic seizures. In absence and myoclonic seizures, carbamazepine, oxcarbazepine, gabapentin, tiagabine, and pregabalin should be avoided, as they have been associated with an exacerbation of these types of seizures.
Table 30–2 Evidence-Based Guidelines for Initial Monotherapy Treatment of Epilepsy
When an appropriate AED has been chosen, doses are started very low and titrated over several weeks. Usually a moderate target dose is chosen until the patient’s response can be further evaluated in clinic. If seizures continue, the dose should be increased gradually until the patient becomes seizure-free or adverse effects appear. For some drugs like lamotrigine, specific titration guidelines are established by the manufacturer.
Refractory seizure (i.e., unresponsive to at least two first-line AEDs) treatment is somewhat different. According to the AAN Practice Parameter, topiramate is useful as monotherapy for primary generalized tonicclonic seizures, and there is insufficient evidence to make any recommendation regarding gabapentin, lamotrigine, oxcarbazepine, tiagabine, levetiracetam, or zonisamide.31 Combinations of drugs are not addressed by the AAN, but may be useful in patients with difficult to control primary generalized seizures. This practice parameter also gives the highest recommendation to oxcarbazepine and topiramate as monotherapy in patients with refractory partial epilepsy. Additionally, lamotrigine is noted to be effective as monotherapy for refractory partial seizures, but was associated with a high dropout rate in the clinical trials. All AEDs, except ethosuximide, are effective in combination therapy for partial seizures.
Complications of Pharmacotherapy
Adverse effects of AEDs are frequently dose limiting or can cause a drug to be discontinued. Two types of adverse effects occur with AEDs: concentration related and idiosyncratic (Table 30–3). Concentration-related adverse effects happen with increasing frequency and severity as the dose or concentration of a drug is increased. For many AEDs, common concentration-related adverse effects include sedation, ataxia, and diplopia. These adverse effects should be carefully considered and used as one of the AED selection criteria. For example, if a patient has a job that requires mental alertness, it is best to choose an AED that is less likely to cause sedation (e.g., lamotrigine).
Idiosyncratic adverse effects are not dose or concentration related and will almost always result in the AED being discontinued. Rash, hepatotoxicity, and hematological toxicities are the most common idiosyncratic reactions seen with AED. Because many of these adverse effects are life threatening or potentially life threatening, the AED should be discontinued immediately when the reaction is observed. Carbamazepine, phenytoin, phenobarbital, valproate, lamotrigine, oxcarbazepine, and felbamate are most likely to cause these types of reactions. Many of these reactions are thought to occur primarily on an immunological basis, which raises the possibility of cross-reactivity. This is especially true for carbamazepine, phenytoin, phenobarbital, and oxcarbazepine, where 15% to 25% of patients who have an idiosyncratic reaction to one drug will have a similar reaction to the other drugs.
Table 30–3 Characteristics of Common AEDs
Chronic Adverse Effects
Because AEDs are administered for long periods of time, adverse effects due to prolonged drug exposure are of concern. Chronic adverse effects tend to be primarily idiosyncratic in nature. Some chronic adverse effects associated with AEDs include peripheral neuropathy and cerebellar atrophy. Other chronic adverse effects are extensions of acute adverse effects, for example, weight gain.
One chronic adverse effect that is of concern is osteoporosis.32,33 Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, and valproate have all been shown to decrease bone mineral density, even after only 6 months of treatment. Data on the relationship between other AEDs and osteoporosis are not currently available. Multiple studies have shown the risk of osteoporosis due to chronic AED use to be similar to the risk with chronic use of glucocorticosteroids. Patients taking carbamazepine, oxcarbazepine, phenytoin, phenobarbital, or valproate for longer than 6 months should take supplemental calcium and vitamin D. Additionally, routine monitoring for osteoporosis should be performed every 2 years and patients should be instructed on ways to protect themselves from fractures.
Practical Issues
Comorbid Disease States
Patients with epilepsy often have comorbid disease states. Disorders such as chronic headaches and asthma are frequent problems. For patients who also have asthma, care must be taken to identify drug interactions between AEDs and medications used for asthma. These interactions may necessitate close monitoring for changes in efficacy or increased toxicity, and dosage changes of other drugs may be necessary when an AED is added or removed. Patients with chronic headaches need special attention in the selection of an AED. Agents known to prevent headache (e.g., valproate and topiramate) may be preferred among several choices, and agents associated with increased headaches (e.g., lamotrigine and felbamate) may be a secondary or tertiary alternative.
Depression is a common problem in patients with epilepsy, with approximately 30% having symptoms of major depression at some point.34 Patients with epilepsy should be routinely assessed for signs of depression, and treatment should be initiated if necessary. Certain AEDs may exacerbate depression, for example, levetiracetam and phenytoin. Other AEDs (e.g., lamotrigine, carbamazepine, oxcarbazepine) may be useful in treating depression. Changes in mood can be precipitated by the addition or discontinuation of an AED. If treatment for depression is necessary, caution should be exercised in choosing an agent that does not increase seizure frequency and does not interact with AEDs.
Switching Drugs
Changing from one AED to another can be a complex process. If the first drug is stopped too abruptly, breakthrough seizures may occur. Stopping or adding a drug can introduce various problems such as drug interactions which should be considered in any regimen change. Typically the new drug is started at a low initial dose and gradually increased over several weeks. Once the new drug is at a minimally effective dose, the drug to be discontinued is gradually tapered while the dose of the new drug continues to be increased to the target dose. During a transition between drugs, patients should be cautioned about the possibility of increased seizures or adverse reactions.
Patient Encounter 2: Switching a Patient to a Different AED
BC, a 22-year-old woman, was diagnosed 2 years ago with JME. She has been treated with valproate 1,500 mg/day. Since starting valproate she has gained 20.5 kg (45 lb), continues to have occasional myoclonic jerks, had a generalized tonic-clonic seizure 3 months ago, and is sexually active. Additionally, she complains of easily falling asleep during the day. Due to adverse effects, poor seizure control, and the risk of birth defects with valproate, the decision is made to switch to a different AED.
What drug would be the optimal alternative for this patient?
How should the new drug be started and the valproate discontinued?
What instructions should be given to the patient regarding the switch to another drug?
Stopping Therapy
Epilepsy is generally considered to be a life-long disorder that requires ongoing treatment. However, many patients who are seizure-free may desire to discontinue their medications.35 Patients who become seizure free following surgery for their epilepsy may have medications slowly tapered starting 1 to 2 years after their surgery. Many patients will choose to stay on at least one medication, following successful surgery, to ensure they remain seizure free. Five criteria must be met before considering the discontinuation of AEDs.36 They are:
• No seizures for 2 to 5 years
• Normal neurologic examination
• Normal intelligence quotient
• Single type of partial or generalized seizure
• Normal EEG with treatment
Individuals who fulfill all of these criteria have a 61% chance of remaining seizure-free after AEDs are discontinued. Additionally, there is a direct relationship between the duration of seizure freedom while taking medications and the chance of being seizure-free after medications are withdrawn. Withdrawal of AEDs is done slowly, usually with a tapering dose over at least 1 to 3 months.
Dosing
Dosing of AEDs is determined by general guidelines and response of the patient. Serum concentrations may be helpful in benchmarking a specific response. Therapeutic ranges that are often quoted are broad guidelines for dosing but should never replace careful evaluation of the patient’s response. It is not unusual for a patient to be well managed with serum concentrations or doses outside the typical ranges.
Drug Interactions
AEDs are associated with many different drug interactions.37–39 These interactions are primarily in relation to absorption, metabolism, and protein binding. Tube feedings and antacids are known to reduce the absorption of phenytoin and carbamazepine. Phenytoin, carbamazepine, and phenobarbital are potent inducers of various CYP 450 isoenzymes, increasing the clearance of other drugs metabolized through these pathways (Table 30–4). In contrast, valproate is a CYP 450 isoenzyme inhibitor and reduces the clearance of some drugs. Phenytoin and valproate are highly protein bound and can be displaced when taken concurrently with other highly protein-bound drugs. For example, when phenytoin and valproate are taken together, there may be increased dose-related adverse effects within several hours of dosing. This can be avoided by staggering doses or giving smaller doses more frequently during the day. Whenever a change in a medication regimen occurs, drug interactions should be considered and appropriate adjustments in dose of AEDs made.
Patient Encounter 3: Discontinuing AED Therapy
The consultant pharmacist is reviewing the care of AN, who is a 79-year-old male resident of a long-term care facility. According to his records, he has received phenytoin and phenobarbital ever since suffering a stroke 12 years ago. There is no record of a seizure in his chart, and the nursing staff has not observed a seizure since he arrived at the facility 2 years ago. His family recalls that he had one seizure around the time of his stroke, but has not had any more seizures.
Can his antiepileptic medications be discontinued?
What additional information would be helpful to determine the possibility of discontinuing his AEDs?
If the AEDs are stopped, how should they be discontinued?
Table 30–4 Cytochrome P450 and AED Interactions
Special Populations
Children and women present special challenges in the management of epilepsy and use of AEDs. In children, developmental changes occur rapidly, and metabolic rates are greater than those seen in adults. When treating a child it is imperative to control seizures as quickly as possible 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 the rapid metabolic rates seen in children, doses of AEDs are typically higher on a milligram per kilogram basis compared to adults, and serum concentrations are used more extensively to help ensure an adequate trial of a drug has been given.
For women, the treatment of epilepsy poses challenges, including teratogenicity, interactions between AEDs and hormonal contraceptives, and reduced fertility.40,41 Recommendations for managing women of child-bearing potential and who are pregnant have been developed (Table 30–5). Several AEDs have been implicated in causing both minor and serious birth defects.42 Of special concern are neural tube defects (e.g., spina bifida, microcephaly, anencephaly) associated most commonly with valproate and possibly carbamazepine. Additionally, valproate has been associated with impaired cognitive development in children born to women taking valproate during pregnancy. Use of valproate is not absolutely contraindicated in women who may become pregnant, but it is appropriate to use alternative AEDs, if possible, in women of child-bearing potential. All women of child-bearing potential who have epilepsy should take 1 to 4 mg daily of supplemental folic acid to reduce the risk of these defects. Many AEDs are excreted in breast milk. However, infants were exposed to higher concentrations of AED in utero, so it is unclear if drugs in breast milk are harmful to the child. Decisions about breast-feeding should be made on an individual basis.
Table 30–5 Management of AEDs During Pregnancy
|
Give supplemental folic acid 1–4 mg daily to all women of child-bearing potential |
|
Use monotherapy whenever possible |
|
Use lowest doses that control seizures |
|
Continue pharmacotherapy that best controls seizures prior to pregnancy |
|
Monitor AED serum concentrations at start of pregnancy and monthly thereafter |
|
Adjust AED doses to maintain baseline serum concentrations |
|
Administer supplemental vitamin K during eighth month of pregnancy to women receiving enzyme-inducing AEDs |
|
Monitor postpartum AED serum concentrations to guide adjustments of drug doses |
Patient Encounter 4: Hormonal Contraceptives and Interactions With AEDs
LJ, a 25-year-old-woman with complex partial seizures, presents a prescription to the pharmacy for a triphasic oral contraceptive containing ethinyl estradiol and norgestimate. A review of her medication profile shows that she is taking carbamazepine extended release 1,200 mg/day. Her last refill for this prescription was 2 weeks ago. She reports that she has not had a seizure for 1 year and that she just became engaged. She is planning to be married in 4 months.
Is there an interaction between carbamazepine and the oral contraceptive?
If so, what is the cause and clinical outcome of the interaction?
If there is an interaction, how should it be managed?
What AEDs interact with hormonal contraceptives?
What are the clinical implications of these interactions? How should they be managed?
As noted above, many of the AEDs induce hepatic microsomal enzyme systems and thus reduce the effectiveness of hormonal contraceptives. Women taking AEDs that may reduce the effectiveness of hormonal contraceptives should be encouraged to also use other forms of birth control. In contrast to these interactions, hormonal contraceptives induce glucoronidation of lamotrigine and valproate. Oral contraceptives that cycle hormones cause reductions in serum concentrations of lamotrigine or valproate during days of the cycle when hormones are taken; serum concentrations increase during days when hormones are not taken. Due to induction or inhibition of sex hormone metabolism and changes in binding of hormones to sex hormone binding globulin, some AEDs may reduce fertility. For example, valproate has been associated with a drug-induced polycystic ovarian syndrome. Women who experience difficulties with fertility should seek the advice of health care professionals with expertise in fertility.
OUTCOME EVALUATION
Regular reporting and monitoring of seizure counts, changes in seizures, adverse events, and drug interactions are essential to proper management of a patient with epilepsy.
Patient Care and Monitoring
1. Monitor the patient’s seizure frequency and characteristics. The only objective measure of efficacy for AEDs is a count of seizure frequency. Ask patients to keep seizure calendars, noting the numbers and types of seizures that occur, and have them bring the calendars to clinic at every visit for analysis and documentation of seizure frequency.
2. Monitor for acute and chronic adverse effects of AED. Acute adverse effects are best detected by a thorough neurologic examination at clinic visits. Instruct patients to report sedation, ataxia, rash, or other problems immediately. Monitor for chronic adverse effects, including a loss of bone mineral density, which should be measured every 2 years in patients taking phenytoin, phenobarbital, carbamazepine, and valproate.
3. Monitor for comorbid disease states at each clinic visit. Evaluate for depression at every clinic visit. Monitor comorbid disease states when a change in AED therapy is made.
4. Take measures to ensure compliance with medications and access to care. Compliance with medication regimens is a common problem for patients with epilepsy. Ask patients at every visit how they are taking their medications and whether they miss any doses. Identify barriers to care, such as financial issues or transportation problems.
5. Instruct patients, family members, and caregivers on first aid for seizures. First aid for seizures consists primarily of keeping patients from hurting themselves. They should be placed on the floor, if possible, and their head cushioned. First responders to a seizure should never attempt to restrain the patient or force an item into their mouth. If a seizure lasts longer than 5 to 10 minutes, emergency medical assistance should be called.
Efficacy
• Seizure counts are the only reasonable and standard way to evaluate efficacy of treatment.
• Encourage patients to keep a seizure calendar that notes the time and day a seizure occurs and the type of seizure. Compare seizure counts on a monthly basis to determine the level of seizure control.
Toxicity
• Monitor acute toxicity of AEDs at every clinic visit.
• Question patients about common adverse effects of the AEDs they are receiving. Weigh the impact of acute adverse effects against the extent of seizure control achieved from a treatment regimen. If it is determined the adverse effects negatively impact the patient more than the extent of seizure control benefits the patient, adjust the therapeutic regimen. Continuously monitor chronic adverse effects of AEDs.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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