Epilepsy is a common neurological problem in the elderly. The incidence of seizure disorders rises steadily after age 60, so the need for antiepileptic drugs (AEDs) increases with age. Etiologies are diverse. A study of 151 patients with new-onset seizures after age 60 reported that 32% of the seizures were caused by strokes, and 14% were caused by brain tumors. Most tumors were metastatic (71%), and 25% of patients had no identifiable cause (Luhdorf et al., 1986). Other studies have found trauma, infectious causes, toxic and metabolic causes, and degenerative diseases, among others.
While similar principles of drug selection apply to elderly individuals and to younger patients, certain factors carry greater weight in the elderly. Selection of the appropriate therapy should be guided by the recognition that older patients often have comorbidity including neurological disease, receive multiple medications that can affect and be affected by AEDs, and have age-related changes in physiology (e.g., decreased gastrointestinal absorption and renal function). Moreover, elderly individuals may be more sensitive to the adverse effects of AEDs (Perucca et al., 2006; Perucca, 2007). In this age group, monotherapy with an AED is desirable, and lifelong therapy may be required.
Features of AEDs that are especially desirable for use in the elderly include the following:
1. Lack of significant interactions with other medications
2. Lack of induction or inhibition of hepatic microsomal enzymes
3. Minimal protein binding
4. Once- or twice-daily dosing
5. No need for laboratory monitoring
6. Side-effect profile with minimal effects on cognitive function and bone metabolism
7. Low cost
These considerations have practical import. For example, AEDs with enzyme-inducing or inhibiting properties, such as phenobarbital, phenytoin, carbamazepine, primidone, and valproate, alter concentrations of other medications and may render them either less effective or toxic. They also are associated with osteoporosis, which is a significant cause of morbidity in the elderly. The elderly are particularly susceptible to sedating or cognitive adverse effects, so drugs with prominent sedation, such as phenobarbital, benzodiazepines, primidone, and topiramate, may cause greater problems. Because elderly patients are apt to take multiple medications, significant drug-drug interactions that occur with some drugs, such as phenytoin, carbamazepine, phenobarbital, primidone, and valproate, pose a problem. Prolonged exposure to AEDs and potentially interacting drugs may be associated with adverse outcomes such as stroke, myocardial infarction, and mortality. Integrating neurology and clinical pharmacy consultation, combined with electronic medical records systems that alert clinicians to significant drug-drug interactions, may improve care quality and outcomes in this vulnerable population (Pugh et al., 2010). Creatinine clearance (CrCl) is reduced in the elderly, so drugs that are primarily cleared by the kidney such as levetiracetam may accumulate in higher serum concentrations than expected in young patients. These considerations do not mean that drugs that might be more complicated in elderly individuals should not be used but rather that careful attention must be paid to potential interactions, toxic levels, and side effects and that the use of some drugs must be limited, if possible.
Few randomized studies have been performed in older adults comparing different AEDs (Rowan et al., 2005; Saetre et al., 2007), so experience and judgment must play a key role when choosing a drug. The comparison studies performed thus far have compared only lamotrigine, carbamazepine, and gabapentin. Lamotrigine and gabapentin may be somewhat better tolerated than carbamazepine, and while efficacy is similar, there may be a slight advantage of carbamazepine in efficacy over the other drugs. No studies have compared levetiracetam or lacosamide with these drugs, and it is the authors’ opinion that these drugs have ideal pharmacological properties and are well suited, perhaps more so than the others, for use in the elderly. The prescribed dose of levetiracetam should be lower in the elderly than in young individuals due to progressively decreasing renal clearance with age.
The following list summarizes features relevant to prescription of AEDs in older patients. Further information regarding relevant pharmacological factors can be found in some of the references (Perucca et al., 2006; Drug Facts and Comparisons, 2007, Drugs’ websites). In general, when prescribing AEDs to the elderly, start with a lower dose than is used in younger patients, titrate upward more slowly, target a lower final dose, and monitor carefully for side effects because these may appear earlier than usual. Therapeutic monitoring of drug levels may be important for these patients to aid in drug management.
Maximum dose in the elderly is similar to that in young adults (Drug Facts and Comparisons, 2007). However, dose reductions should be considered in this age group to compensate for age-related reductions in renal drug clearance. There is potential for renal stone formation and drug interaction.
Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in using these drugs and lower doses are used. Observe for sedating effects, and avoid use if possible.
Hepatic clearance is decreased by 25%–40% in elderly patients compared with younger adults so lower doses are used (Perucca et al., 2006; Kirmani et al., 2014). Due to drug interactions, use with caution.
Although the pharmacokinetics of eslicarbazepine are not affected by age independently, dose selection should take into consideration the greater frequency of renal impairment and medical comorbidities and drug therapies in the elderly patient.
This drug is rarely appropriate for elderly patients, because they rarely have true absence seizures. Drug interactions are sometimes important.
Dosage adjustment is recommended in patients aged 65 years and older. Ezogabine may cause urinary retention. Elderly men with symptomatic benign prostatic hyperplasia (BPH) may be at increased risk for urinary retention.
This is well tolerated and treats concomitant neuropathy and pain. It is often a good choice if these are present. Average decrease in clearance of gabapentin in elderly patients compared with younger adults is about 30%–50%, so lower doses can be used (Perucca et al., 2006). This drug is often a good choice for the elderly, particularly with appropriate comorbidity.
The elderly exhibit a reduced hepatic clearance, higher peak concentrations, and longer elimination half-life compared with young adults. Average decrease in apparent clearance of lamotrigine in elderly patients compared with younger adults is about 35% (Perucca et al., 2006). It is recommended that elderly patients receive lower dosages than would be prescribed for young adults, perhaps 150–200 mg daily. This drug is a good choice.
This drug has ideal pharmacological properties and is a good choice for elderly patients who require AED therapy. Average decrease in renal clearance of levetiracetam in elderly patients compared with younger adults is about 20%–40% (Perucca et al., 2006), so doses of 500–750 mg daily may be sufficient. This dose is often an excellent choice for the treatment of seizures in the elderly.
Average decrease in hepatic clearance of oxcarbazepine in elderly patients compared with younger adults is about 25%–35% (Perucca et al., 2006). Adverse effects and drug interactions are relatively favorable; however, hyponatremia is relatively common in our experience. Use with caution because of the potential for hyponatremia.
In elderly patients, dose titration should be performed with caution. An increased risk of falls occurred in patients being treated with perampanel (with and without concurrent seizures). Elderly patients had an increased risk of falls compared to younger adults.
Average decrease in hepatic clearance of phenobarbital in elderly patients compared to younger adults is about 20% (Perucca et al., 2006). Due to sedation, hepatic enzyme induction, and drug interactions, limit use. However, this drug is quite inexpensive and may be a reasonable choice when cost poses difficulties (Kirmani et al., 2014). Lower doses, perhaps 45–90 mg daily, are effective in elderly patients.
Average decrease in hepatic clearance of phenytoin in elderly patients compared with younger adults is about 25% (Perucca et al., 2006). Due to drug interactions and complicated kinetics, this drug is less than ideal. As a cytochrome P-450 enzyme inducer, it increases clearance of other hepatically metabolized drugs and is therefore suboptimal for that reason as well. This is considered a second-line drug, and better choices are available. Cost and ability to give intravenous doses are its major advantages (Kirmani et al., 2014).
This drug is a reasonable choice for elderly patients, due to minimal drug interactions and treatment of concomitant neuropathy and pain. Reduction of pregabalin dose is required in elderly patients based on CrCl, so that a total dose of 150–200 mg daily may achieve similar levels as higher doses in younger patients.
Decreased hepatic clearance mandates lower doses than in young patients. Due to sedative effects, potential for depression, and drug interactions, it should rarely be used. However, if the patient has essential tremor requiring treatment, this drug may treat both conditions.
In elderly patients, dose titration should be performed with caution. Pharmacokinetics of rufinamide in the elderly is similar to that in young adults.
Average decrease in clearance of tiagabine in elderly patients compared with younger adults is about 30% (Perucca et al., 2006). Elderly patients may be at increased risk for falls while on this drug (Kirmani et al., 2014). This drug is infrequently used.
The possibility of age-associated renal functional abnormalities should be considered. Average decrease in apparent clearance of topiramate in elderly patients compared to younger adults is about 20% (Perucca et al., 2006). Due to cognitive side effects and potential for renal stones, use with precaution (Kirmani et al., 2014). Comorbidity of migraine and obesity may make this a good choice for some patients. Lower doses, perhaps as low as 50–75 mg per day, may be used.
Average decrease in apparent clearance of valproate in elderly patients compared with younger adults is about 40% (Perucca et al., 2006). In addition, a decrease in valproic acid protein binding occurs consequent to hypoalbuminemia, and the half-life of the drug can be prolonged in geriatric patients. In general, use reduced initial dosage and slower dose titration in this age group. Target doses may be as low as 500 mg daily in some patients. Dose reductions or discontinuation should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.
Dosage needs to be reduced in elderly patients because of age-related diminished renal clearance. Adverse effects are sometimes important, and the potential for renal stones should be remembered.
Recommended Antiepileptic Drugs in Elderly Persons With Epilepsy
1. Focal epilepsies: Lacosamide, lamotrigine, levetiracetam, gabapentin. If cost is a factor, carbamazepine is preferred.
2. Generalized epilepsies: These probably do not occur de novo in the elderly but when present consider using lamotrigine or levetiracetam.
Drug Facts and Comparisons. St. Louis: Wolters Kluwer Health/Facts & Comparisons, 2007.Find this resource:
Kirmani BF, Robinson DM, Kikam A, Fonkem E, Cruz D. Selection of antiepileptic drugs in older people. Curr Treat Options Neurol 2014;16(6): 295.Find this resource:
Luhdorf K, Jensen LK, Plesner AM. Etiology of seizures in the elderly. Epilepsia. 1986;27: 458–463.Find this resource:
Perucca E. Age-related changes in pharmacokinetics: predictability and assessment methods. International Review of Neurobiology. 2007;81: 183–199.Find this resource:
Perucca E, Berlowitz D, Birnbaum, et al. Pharmacological and clinical aspects of anti-epileptic drug use in the elderly. Epilepsy Research. 2006;68S: S49–S63.Find this resource:
Pugh MJ, Vancott AC, Steinman MA, Mortensen EM, Amuan ME, Wang CP, Knoefel JE, Berlowitz DR. Choice of initial antiepileptic drug for older veterans: possible pharmacokinetic drug interactions with existing medications. J Am Geriatr Soc. 2010; 58(3): 465–471.Find this resource:
Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology. 2005;64: 1868–1873.Find this resource:
Saetre E, Perucca E, Isojärvi J, Gjerstad L, LAM 40089 Study Group. An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia. 2007;48: 1292–1302.Find this resource: