Epilepsy in the Elderly

Ilo E. Leppik

Angela K. Birnbaum

The elderly (persons 65 years of age and older) are the most rapidly growing segment of the population, and onset of epilepsy is higher in this group than in any other group. The incidence of a first seizure is 52 to 59 per 100,000 in persons 40 to 59 years of age but rises to 127 per 100,000 persons in those age 60 years and older (1). Approximately 1.5% of the elderly have active epilepsy, about twice the rate of younger adults. In the United States, of the approximately 181,000 persons who developed epilepsy in 1995, about 68,000 were older than age 65 years (2). In Finland, 34,453 persons had epilepsy during 1986, and 12.8% were older than age 65 years; by 2000, the number had increased to 49,003, of whom 19.7% were elderly. In persons older than age 65 years there were 396 new cases (11.2% of all new cases) in 1986, but in 2000, 597 new cases (22%) were in the elderly group (M. Sillanpaa, personal communication, 2001).

The numbers mentioned above were for the community-dwelling elderly. In nursing homes, epilepsy, seizures, and antiepileptic drug (AED) use are much more prevalent. Among 45,405 elderly residents of U.S. long-term care facilities, 4573 (10.1%) took at least one AED (3). AED use in the nursing-home population varies between 10% and 11% (4, 5, 6). Because approximately 1.5 million elderly reside in nursing homes in the United States, as many as 150,000 may be taking AEDs (7).

Approximately 7% of residents are using AEDs at admission, but approximately 3% receive their first prescription after admission. In a study of 21,551 nursing home residents in 24 states on 1 day during the spring of 1995, 10.5% had an AED order, and 9.2% of them had a seizure or epilepsy indication recorded in the physician’s orders (4). (Information on how the diagnosis was made was not available.) Of the AED prescriptions, 6.2% were for phenytoin (the most commonly used AED in nursing homes), 1.8% for carbamazepine, 0.9% for valproic acid, and 1.7% for phenobarbital; 1.2% were for all other AEDs combined. Phenytoin was the most frequently initiated AED after admission if the current procedural terminology code was for seizures or epilepsy, and valproate or carbamazepine if a psychiatric or behavioral diagnosis was listed (8).

Assessment of AED efficacy and toxicity in elderly patients is challenging because seizures are sometimes difficult to observe, toxic signs and symptoms can be attributed to other causes (e.g., Alzheimer disease or stroke) or to comedications, and patients may not be able to accurately report problems. More so than younger persons, the elderly may experience more side effects, have a higher risk for drug interactions, and be less able to afford medications. Neither the benefits nor the risks of treatment have been investigated in this population, and current practices are not based on evidence.

Stroke accounts for 30% to 40% of all cases of epilepsy in the elderly (9), followed by brain tumor, head injury, and Alzheimer disease. In many cases, however, the precise cause cannot be identified, and the etiology is cryptogenic.

The most important differential diagnosis in the elderly is convulsive syncope in which a seizure is provoked by lack of circulation to the brain. Cardiac causes are common, and in the absence of a known central nervous system disorder (stroke, tumor, degeneration), syncope should be suspected. An electroencephalogram with concomitant electrocardiographic rhythm strip is essential to clarify the diagnosis.

Electrolyte imbalance, febrile illness, hypoglycemia, or hyperglycemia may also provoke seizures, but these conditions should be easily recognized by laboratory tests or physical examination and do not require long-term AED treatment.

Although the diagnosis of epilepsy is generally made only after two or more seizures, persons with a single, unprovoked seizure (no obvious cause external to the central nervous system), especially if a stroke has occurred previously, should be treated with AEDs because of the high risk of a second attack and the catastrophic consequences of a second seizure (fall, fracture, cardiac compromise).

In addition to their use in epilepsy, AEDs are prescribed for neuralgias, aggressive behavior disorders, essential tremor, and restless legs syndrome, all of which are prevalent in the elderly. When clinicians prescribe for the elderly, they must also consider the likelihood of concomitant disorders and the high individual variability in this population. As a cause of adverse reactions among the elderly, AEDs rank fifth among all drug categories (10).

CLINICAL PHARMACOLOGY OF ANTIEPILEPTIC DRUGS

Drug concentration at the site of action determines the magnitude of both desired and toxic responses. The unbound concentration in serum is in direct equilibrium with the concentration at the site of action and correlates best with drug response (11). Total serum drug concentration is useful for monitoring of therapy when the drug is not highly protein bound (<75%) or when the ratio of unbound to total drug concentration remains relatively stable. Phenytoin and valproic acid, which are the most widely used drugs in the elderly, are highly bound, and their binding is frequently altered.

The age-related physiologic changes that have the greatest effect on AED pharmacokinetics involve protein binding and the reduction in liver volume and blood flow (12, 13, 14, 15). Reduced serum albumin and increased α₁-acid glycoprotein (AAG) concentrations in the elderly alter protein binding of some drugs (11,12,14). By age 65 years, many individuals have low-normal albumin concentrations or are frankly hypoalbuminemic (12). Albumin concentration may be further reduced by malnutrition, renal insufficiency, and rheumatoid arthritis. As serum albumin levels decline, the likelihood of reduced drug binding increases. For highly bound drugs, lower albumin levels mean a decrease in total serum drug concentration, while unbound serum drug concentration remains unchanged.

The concentration of AAG, a reactant serum protein, increases with age; further elevations occur during pathophysiologic stresses such as stroke, heart failure, trauma, infection, myocardial infarction, surgery, and chronic obstructive pulmonary disease (14). Administration of enzyme-inducing AEDs also increases AAG (16). When the concentration of AAG rises, the binding of weakly alkaline and neutral drugs such as carbamazepine (and its epoxide metabolite) to AAG can increase, causing higher total serum drug and metabolite concentrations and decreased unbound drug concentrations.

For low-clearance drugs (older AEDs), hepatic clearance is influenced primarily by the extent of protein binding and intrinsic metabolizing capacity (intrinsic clearance) of the liver. Because hepatic clearance affects steady-state drug concentrations, age-related alterations in protein binding or intrinsic clearance can affect serum drug concentrations.

The effect of age on hepatic drug metabolism remains largely unknown owing to the complexity of confounding variables and the lack of correlation between simple measures of liver function and drug metabolism (17,18). Phase I reactions (oxidation, reduction, and hydroxylation) are thought to be affected more than phase II reactions (glucuronidation, acetylation, and sulfation). In the elderly, the decrease in oxidative metabolism of some drugs is believed to be a result of changes in liver blood flow and liver mass with age (15,19). Because the enzymes for glucuronidation are also located in the hepatocytes, which decrease in number with age, a similar decrease in glucuronidation might be expected. However, limited information indicates that glucuronidation reactions appear to be spared with aging. For example, advanced age has little effect on the clearance of lorazepam, which undergoes glucuronidation; whereas, the clearance of diazepam and its active metabolite, both of which undergo oxidative metabolism, is decreased (20).

Despite the theoretical effects of age-related physiologic changes on drug disposition and the widespread use of AEDs in the elderly, few studies on AED pharmacokinetics in the elderly have been published. The available reports generally involve single-dose evaluations in small samples of the young-old (age 65 to 74 years). Data on those older than age 85 years are largely absent, even though this population may face an increased possibility of therapeutic failure and adverse reactions (21). Table 40.1 summarizes pharmacokinetic parameters in the elderly (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39).

CHOOSING ANTIEPILEPTIC DRUGS

The paucity of information on the clinical use of AEDs in the elderly means that the “comfort level” with some drugs may play a larger role in their selection than actual experience or data. Many recommendations in this review will be modified as new knowledge is obtained.

Compared with younger adults, the elderly may represent a much more heterogeneous population. For purposes of simplification, they may be divided into three groups based on health status: the healthy elderly who have epilepsy, the elderly with multiple medical problems (EMMP), and the frail elderly in nursing homes. A drug that is optimal for the healthy elderly may be inappropriate for other groups because of differences among the groups in pharmacokinetics or pharmacodynamics. For example, total phenytoin concentrations vary widely in the frail elderly, who also use many interfering drugs in addition to AEDs (Table 40.2) (5). A study of serial blood levels in elderly nursing home residents receiving constant doses of phenytoin showed an average intrapatient variability from two- to threefold (40), complicating the interpretation of blood level data and therapeutic decisions. This large variability could not be attributed to any one factor and may be a result of absorption, which could not be addressed in the study; newer, more water-soluble drugs may be better in this population, but this possibility needs to be investigated.

TABLE 40.1 PHARMACOKINETICS OF ANTIEPILEPTIC DRUGS IN THE ELDERLY

Drug	Protein Binding (%)	Half-life (h)	Metabolism/Route of Elimination	Comments
Carbamazepine	75-85	^a	Hepatic	Protein binding decreased with reduced serum albumin; estimated dosage requirements 40% less than in younger adults
Felbamate	<10	^a	Hepatic
Gabapentin	<10	^a	Renal	Elimination correlates with creatinine clearance; dosage may need to be reduced by 30%-50%
Lamotrigine	55	˜30	Hepatic glucuronide conjugation	Dosage adjustment may not be necessary, as conjugation reactions only slightly diminished with age
Levetiracetam	<10	˜12-15	Renal	Dosage may need to be reduced in elderly with diminished renal function
Oxcarbazepine	Low	^a	Hepatic
Phenobarbital	50	^a	Hepatic and renal
Phenytoin	80-93	Varies with concentration; e.g., 40-60 h at 15 mg/L	Hepatic	Protein binding decreased with reduced serum albumin; initial dosage 3-4 mg/kg; subsequent increases should be <10% of dose
Primidone		12.1 ± 4.6	Hepatic	Half-life and clearance similar to that of younger adults; dosage adjustments may not be needed
Tiagabine	95	^a	Hepatic
Topiramate	9-17	^a	Hepatic and renal	Dosage may need to be reduced in elderly patients with diminished renal function
Valproic acid	87-95	^a	Hepatic	Protein binding decreased with reduced serum albumin; dosage reduction of 30%-40% may be needed
Zonisamide	Low	^a	Hepatic and renal	Dosage may need to be reduced in elderly with diminished renal function
^aHalf-life is longer in elderly than in younger adults, but few data are available.

Because AEDs may affect balance, falls and fractures might be related to inappropriate use. Cost also may be a factor for many patients. Multiple medical problems intensify these issues, and the physician must be aware of the benefits and shortcomings of all AEDs, as well as the patient’s physical and fiscal health. The benefits and risks of each drug in the healthy elderly and the EMMP is discussed in the following sections (Table 40.3) (41, 42, 43).

TABLE 40.2 USE OF COMEDICATIONS WITH POTENTIAL INTERACTIONS WITH ANTIEPILEPTIC DRUGS IN 4291 RESIDENTS OF NURSING HOMES

Drug Category	Percent Use with Antiepileptic Drugs
Antidepressants	18.9
Antipsychotics	12.7
Benzodiazepines	22.4
Thyroid supplements	14.0
Antacids	8.0
Calcium-channel blockers	6.9
Warfarin	5.9
Cimetidine	2.5
Data from Lackner TE, Cloyd JC, Thomas LW, et al. Antiepileptic drug use in nursing home residents: effect of age, gender, and comedication on patterns of use. Epilepsia 1998;39:1083-1087.

Phenytoin

Phenytoin is effective against localization-related epilepsies and thus has an efficacy profile appropriate for the elderly; however, few studies on its ability to treat seizures in this group have been published. Evidence from the Veterans Affairs Cooperative Study suggests effectiveness equal to that of carbamazepine, phenobarbital, and primidone, although the number of subjects was small (44).

Phenytoin has a narrow therapeutic range and complex pharmacokinetics. It is absorbed slowly, is approximately 90% bound to serum albumin, and undergoes saturable metabolism, which produces nonlinear changes in steady-state serum concentrations.

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