Laboratory Tests

Ilo E. Leppik

Introduction

Laboratory testing for persons with epilepsy is needed for two reasons: (a) measuring antiepileptic drug (AED) concentrations and (b) monitoring for adverse side effects. Therapeutic drug management is based on the rationale that knowledge of the AED concentrations is necessary to identify the appropriate dose and concentration for an individual patient and monitor treatment to maintain stable therapeutic levels. Measurements of AED concentrations can improve care by avoiding breakthrough seizures, and unnecessary toxicity. AED concentrations can be influenced by a number of factors: (a) pharmacologic, such as changes in product formulation and use of comedications; (b) alterations in physiologic states, such as pregnancy, illnesses, and aging; and (c) noncompliance with AED treatment. The rationale for routine laboratory monitoring for systemic adverse events is based on the assumption that subclinical hepatitis or hematopoietic dysfunction can be detected in asymptomatic patients. However, the cost of performing routine laboratory testing is considerable. As the public becomes increasingly concerned about the cost of health care, physicians can expect to feel more pressure to cut expenses, especially in the area of routine laboratory testing. In facing these pressures, physicians must also consider the overall cost to both patients and society of not performing laboratory tests when they are necessary. This chapter describes a rational approach to the use of laboratory testing in patients with epilepsy.

Monitoring Antiepileptic Drug Treatment

Measurement of antiepileptic drug concentrations is necessary to manage the treatment of epilepsy. Routine measurement of AEDs without a specific purpose is not cost effective and not recommended. There must be a reason for ordering each test. One useful approach is to obtain an AED level when the patient has been titrated to his or her therapeutic goal—no or the fewest seizures with no toxicity. This level then serves as that individual’s therapeutic range and is much more useful than the published ranges, which are population derived. Serial AED concentrations in compliant, healthy patients usually do not vary by more than 20%. Thus, if a person has a therapeutic target of 13 mg/L, a level of 10.4 to 15.6 mg/L would fall within this range. However, a level of 18 mg/L, although within the published therapeutic range, may be unnecessarily high. Measurement of a level during a breakthrough seizure can then be very informative. If the level was <10 mg/L, a cause for the decreased concentration must be identified. However, if the breakthrough was associated with a level of 13 mg/L, a lowering of the patient’s seizure threshold by worsening of the epileptogenic process or a lowering of the seizure threshold (i.e. use of excitatory substances, sleep deprivation) must be considered, and appropriate changes in management can be initiated. Table 1 lists appropriate times at which to measure AED concentrations.

A number of devices exist for measuring drug concentrations in plasma, serum, saliva, and other biologic samples.⁹^,¹²^,³⁰ To be approved by the U.S. Food and Drug Administration (FDA), a device for therapeutic drug monitoring must be able to perform with a coefficient of variation of <5%. Although all marketed devices meet this standard under strict testing conditions, the potential for error exists, and unusual results should be repeated.

In the United States, there are laboratories within clinics and within hospitals, as well as central national laboratories. Clinics and hospitals can usually measure concentrations of the older AEDs, usually within hours for emergency situations. Tests are available for all of the new AEDs through central laboratories, but results are usually not available for a few days. Every laboratory in the United States has relations with national laboratories, and so physicians in, say, Minot, North Dakota, or other remote locations can have access to these laboratories. Routine tests measure only the total (bound plus unbound) concentrations. For some highly bound AEDs such as valproate (VPA) and phenytoin (PHT), unbound or “free” levels may be more informative.

The rationale behind measuring levels is that the serum concentration, specifically the unbound (free) fraction, is in equilibrium with the receptor-site concentrations. This has been verified for the older AEDs, for which serum levels and brain concentrations in animal and human specimens (obtained during surgery) showed close relationships.¹⁰^,¹⁸^,²⁴ However, these relationships have not been established for the newer AEDs. Indeed, for some of these, there appears to be very strong, and in some cases irreversible, binding with the pharmacologically active site. This appears to be the case for vigabatrin and perhaps levetiracetam, for which the pharmacodynamic half-life appears to be much longer than the plasma half-life.

Although a single measurement at steady state when the person with epilepsy has attained the therapeutic goal sets the individual’s therapeutic range, subsequent monitoring is for the purpose of assuring that these levels are being maintained in this range. Serial measurements are needed to identify variations from the target AED concentration over time. These can be attributed to pharmacokinetics, changes in physiology, and/or compliance issues.

Table 1 Use of blood tests in monitoring patients with epilepsy

For antiepileptic drugs

At steady state, good seizure control, and no toxicity, to obtain a target level^a
Annually, to monitor compliance
When a patient has a breakthrough seizure
When a patient experiences toxicity
When a substance known to affect metabolism is added or removed
When there is a change in a patient’s physiologic state (pregnancy, burns, renal failure)

Hematologic/hepatic

At initiation of therapy
Once during the first few months
Whenever clinical symptoms occur
Annually or less often

^aTrough measurements are primarily useful for pharmacokinetic studies. Levels drawn for target levels and compliance should be obtained at similar times of day, within 1 to 2 h of each other.

Variability Due to Pharmacokinetics

A number of pharmacokinetic factors can influence the absorption and elimination of antiepileptic drugs. For example, changes in product formulation can markedly alter the absorption of phenytoin. If the preparation is more bioavailable, phenytoin concentrations can increase to levels at which toxic reactions occur.²¹^,³⁰ Alteration of gastric or intestinal absorption by food or other drugs may influence the time or extent of absorption. If a product’s bioavailability is affected by food,
lowered levels and seizures may occur. This appears to be the case for phenytoin as well.³^,³² Changes in hepatic or renal blood flow can modify the rate of clearance and affect drug concentrations only to a small degree.⁶

Time of sampling can contribute to variability for some AEDs. In general, AEDs with long absorption and elimination characteristics vary little, regardless of time of sampling. Phenytoin has a relatively long absorption time (time to maximal concentration of 9 to 12 hours) because it is absorbed only in the small intestine. It also has a long half-life and nonlinear kinetics (slower elimination at higher concentrations). Thus, the absorption and elimination phases overlap during one dosing cycle, and the concentration differences are small, usually <2 mg/L, between peak and trough levels. On the other hand, carbamazepine and valproate both have shorter absorption times and, during long-term therapy, have elimination half-lives of 6 to 14 hours. This can lead to differences between peak and trough concentrations of as much as 50% or more. Sustained-release preparations for these products have lengthened the absorption phase and have decreased the peak and trough variations.

To be most useful, blood samples should be drawn at the same time relative to dosing. In a clinical setting, this can be accomplished by always scheduling appointments for the same time of day. A reasonable limit is ±1 hour, which can be attained most of the time. For example, a person with a 3 PM examination usually has blood drawn by 3:30 PM, but any time between 2:30 PM and 4:30 PM is acceptable. Trough concentrations can be quite misleading, especially for AEDs with short serum half-lives. In one institution, it was mandated that carbamazepine levels needed to be >4 mg/L for carbamazepine, and physicians were requested to increase its dose if levels were below this value. Unfortunately, all levels were measured as morning fasting or trough levels, and the mandated dose increases sometimes led to toxicity. The problem was solved by simply changing the time of sampling to approximately 2 hours post morning dose. Through levels for AEDs are widely used, but for therapeutic management of AEDs they can be misleading for agents with short half-lives such as carbamazepine, valproate, and levetiracetam.

Concentrations of AEDs that are metabolized can be altered by the addition or removal of other drugs that are also processed by the liver. These may be other AEDs, drugs used for other disorders, or herbal supplements and foods. For example, St. John’s wort, a popular herbal purported antidepressant, is a powerful inducer of cytochrome P3A4, the major isozyme responsible for carbamazepine metabolism, and can significantly lower concentrations of prescription drugs.

Variability Due to Altered Physiology

Any change in homeostasis can alter the absorption or elimination of AEDs. The most commonly encountered situation is that of a woman who becomes pregnant. Of the older AEDs, phenytoin concentrations decrease the most, beginning in the first trimester and decreasing to the lowest levels before labor. Carbamazepine and valproate levels also decrease but to a lesser degree. Of the newer AEDs, lamotrigine levels decrease dramatically, by as much as 200%.³⁰ There are no specific guidelines for monitoring AED concentrations during pregnancy, but it may be reasonable to obtain a minimum of one measurement at the onset of pregnancy, during the second trimester, and near the time of delivery, or at any time that breakthrough seizures occur or there are symptoms of toxicity.

Phenytoin clearance can be accelerated during various febrile illnesses and also after vaccination.¹⁴^,¹⁶ Because many AEDs are metabolized by the liver, any condition affecting this organ can influence the concentrations of AEDs. Very little research has been done in this area, and so knowledge of basic principles of metabolism and clinical judgment rather than evidence-based medicine must be relied on when caring for patients with hepatic disease. Burns extensive enough to require admission to a burn unit significantly influence phenytoin, phenobarbital, and diazepam levels.² Valproate concentrations can be influenced by head injury.¹ The newer AEDs have not been studied in this regard.

Renal disease or the normal decline in renal function in the elderly necessitates the measurement of AEDs whose elimination is mainly through the kidneys. The formulas that are given to calculate creatinine clearance to adjust doses for gabapentin and levetiracetam cannot substitute for actual measurement of levels. This is because in the elderly, decreases in muscle mass lower the amount of creatinine in the blood, and levels may be in the normal range even when the kidney function is less than in younger persons. In addition, protein binding is greatly affected by renal disease, and the unbound (free) concentration must be measured for highly bound AEDs (phenytoin, valproate).

Table 2 Types of behavior in noncompliance

Medication ingestion

Consistent overcompliance
Consistent undercompliance
Irregularity
Irregularly irregular
Sporadically irregular
Cyclically irregular
Filling prescriptions
Medical appointments

Lifestyle

Sleep patterns
Alcohol use
Psychological stress
Exposure to music, strobe lights
Drug abuse
Adherence to regulations

Intentionality of compliance (patient controlled)

Rational
Pregnant women afraid of teratogenicity
Compensation related
Irrational
Fear of medicine
Superstition

Structural

Memory deficit
Financial problems

Variability Due to Compliance Issues

Noncompliance with antiepileptic drug treatment is a major factor in the recurrence of seizures in patients with epilepsy (Table 2). As many as 50% of all patients with epilepsy are noncompliant to a degree that interferes with optimal treatment.¹⁷^,²⁷ Studies using electronic monitors to measure compliance indicate that what might appear to be sporadic seizures can be attributed to missed doses of prescribed drugs.⁵ Consequently, proper management of epilepsy requires physicians to identify noncompliant patients, determine the extent of the problem, and devise and monitor an appropriate intervention strategy.

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