The incidence of epilepsy in the elderly increases with age [1]. The annual incidence of new onset epilepsy increases from approximately 28 per 100,000 person-years at the age of 50, to 40 per 100,000 person-years at the age of 60, and 139 per 100,000 person-years at the age of 75. In addition to the increased incidence of epilepsy in the elderly, geriatric epilepsy has some unique features including different etiology, variable clinical presentation and variations in MRI and EEG findings. Pharmacokinetic changes seen with increasing age require special attention in the treatment of epilepsy in the elderly. Elderly patients with epilepsy are usually on polytherapy because of comorbidities, and this can result in pharmacokinetic and pharmacodynamic interactions that affect both drug efficacy and quality of life.
New onset epilepsy in the elderly tends to present with partial seizure types, however their presentation can be atypical and this may delay the diagnosis [2]. This is further complicated because the diagnostic yield of EEG is lower in elderly patients [3]. However, a high index of suspicion for seizures is required in dealing with elderly patients. Epilepsy in the elderly patient is typically symptomatic in nature. Cerebrovascular disease is the most commonly recognized etiology for seizures in elderly patients [4]. Other etiologies of epilepsy in the elderly include neurodegenerative disorders [5], major depression [6], hypertension [7] and sleep apnea [8]. The risk of seizure recurrence in elderly patients in comparison to younger adults is much higher - up to 80% versus 40% in the general population [2].
Several physiological changes occur with aging that may affect medication pharmacokinetics and can result in adverse effects, e.g., altered absorption of drugs, reduction in creatinine clearance and hepatic clearance (resulting in higher serum concentrations of antiepileptic drugs [AEDs]) [9,10] and decreased protein binding (resulting in increased protein-free fraction for drugs such as phenytoin and valproate) [11]. Elderly patients often have concomitant illnesses and are on multiple medications that can interfere with antiepileptic medications. Many elderly patients often are on antihypertensives, anticoagulants, antiarrhythmic agents, lipid-lowering medications, diuretics, and/or psychoactive medications. Enzyme-inducing antiepileptic medications can increase the metabolism of such concomitant medications [12]. Similarly enzyme-inhibiting medications can decrease the metabolism of other concomitant medications resulting in toxicity [13].
Noncompliance is a major issue in elderly patients and is more common than among younger patients with an over threefold increased risk of mortality [14]. Antiepileptic medications with longer half life or extended release formulations may be helpful in elderly patients. The focus of this article is therapeutic choices in the management of epilepsy in old age.
ANTIEPILEPTIC MEDICATION USE IN THE ELDERLY
Once a decision is made to start antiepileptic medication in the elderly, several factors need to be considered in choosing the medication, including seizure type, seizure frequency/severity, comorbid conditions, and concomitant medications.
Older antiepileptic medications
The older antiepileptic medications include phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, clonazepam and valproate. Most of these older AEDs are highly protein bound and are metabolized by the liver through the P-450 system (Table 1). These pharmacokinetic properties make them more likely to result in drug interactions.
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TABLE 1. Pharmacokinetic properties of older antiepileptic medications |
Phenobarbital is the oldest antiepileptic medication that still continues to be widely prescribed due to its low cost, particularly in the developing countries. It is a potent enzyme inducer and has prominent drug-drug interactions. The effect of phenobarbital on cognitive function can be a significant limiting factor in the elderly patients. However its long half life makes once daily dosing possible. This may improve compliance in elderly patients. Phenobarbital was one of the most prescribed AEDs in a study of nursing home elderly patients in the US [15]. A retrospective study evaluating antiepileptic medications use in elderly veterans showed that 80% of 21,435 patients received phenobarbital or phenytoin. Nine percent of patients with newly diagnosed epilepsy received phenobarbital [16]. A follow-up study evaluating trends over five years in antiepileptic medications in older veterans found a small reduction in use of phenytoin (70.6% to 66.1%) and phenobarbital (3.2% to 1.9%) [17]. Phenytoin was still the most commonly used antiepileptic drug and there was little change in its use for elderly patients over 5 years [17].
Primidone is closely related to phenobarbital since it is metabolized to phenobarbital and phenylethylmalonilamide (PEMA), both of which are active. Its use in epilepsy in elderly patients is limited. In the first VA cooperative study conducted by Mattson et al., primidone was poorly tolerated although the study did not specifically target elderly patients [18]. In this multicenter study of veterans with partial epilepsy, 622 adult patients were randomized to carbamazepine, phenobarbital, phenytoin, or primidone. Overall efficacy was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest in the primidone arm. Primidone caused more intolerable acute toxic effects than other antiepileptic medications. In general, it is preferable to avoid primidone for treatment of epilepsy in elderly patients.
Phenytoin is a potent enzyme inducer. Phenytoin does not exhibit linear kinetics but rather zero order kinetics. The phenytoin dose curve is much steeper in elderly patients than younger adults [19]. This may result in significant toxicity with an increase in the phenytoin dose. Considerable variability has been seen in serum phenytoin concentrations in elderly nursing home residents [20]. Phenytoin protein binding decreases with age resulting in more free drug in the serum. If only total phenytoin serum levels are used in dosage adjustments, potential toxicity can be seen at apparently ‘therapeutic’ total phenytoin levels. This is why it is better to avoid phenytoin in the elderly population. However it is still the most widely prescribed AED for seizures in the elderly in the nursing home setting [21]. In healthy elderly patients (without other comorbid conditions), phenytoin pharmacokinetics is very similar to younger adults. In a study of 45 elderly patients, there was no difference between adult and elderly, or men and women in phenytoin clearance, distribution volume, and elimination half-life [22]. Phenytoin may be used in healthy elderly patients for financial reasons if they cannot afford newer AEDs.
Carbamazepine, like phenytoin, is effective against partial onset seizures. However it is a potent inducer of cytochrome P450 enzymes and induces its own metabolism. Carbamazepine shows numerous interactions with other medications. Carbamazepine could result in hyponatremia, especially in the presence of diuretics. This effect can be more troublesome in elderly patients. Being potent enzyme inducers, both carbamazepine and phenytoin can result in a decrease in the level of other concomitant medications, for example, it can decrease lipid lowering medications and result in significant increase in cholesterol and C-reactive protein levels and worsen cardiovascular and cerebrovascular disease. In a study evaluating patients switched from phenytoin and carbamazepine to non-enzyme inducers such as lamotrigine or levetiracetam, a decrease in cholesterol and C-reactive protein levels resulted [23]. In a VA cooperative study, carbamazepine was least tolerated in the elderly compared to gabapentin and lamotrigine [24]. Based on this data, we don’t recommend use of carbamazepine as a first-line AED in the elderly.
Valproate is a broad spectrum antiepileptic medication effective against partial and generalized seizures. It is an enzyme inhibitor and may not result in lowering concomitant medications. However, in the VA cooperative trial comparing valproate with carbamazepine in 480 adult patients with complex partial seizures, valproate was less effective and less well-tolerated than carbamazepine for complex partial seizures but was as effective as carbamazepine for the treatment of generalized tonic-clonic seizures [25]. Like phenytoin, valproate is also highly protein bound and may result in more free drug in the serum than what is reflected by total plasma valproate concentrations in the elderly [26]. Chronic valproate use in the elderly has been reported to result in reversible parkinsonism and cognitive impairment [27]. However, in another prospective study, these cognitive side effects were not seen with valproate in comparison to phenytoin [28]. With the positive behavioral effects of valproate, it may be considered in elderly patients with caution.
Newer antiepileptic medications
Since 1993, approximately ten newer antiepileptic medications have become available. The new antiepileptic medications have the advantage of being better tolerated than the older antiepileptic medications. Their pharmacokinetic properties make them less likely to result in drug interactions (Table 2).
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TABLE 2. Pharmacokinetic properties of newer antiepileptic medications |
Lamotrigine was the first new antiepileptic studied in the elderly patient group. Brodie et al. compared lamotrigine with carbamazepine in a multicenter, double-blind trial involving 150 elderly patients with newly diagnosed epilepsy and noted that in terms of efficacy, they were similar but lamotrigine was better tolerated than the carbamazepine arm [29]. In a VA cooperative study, lamotrigine and gabapentin were compared with carbamazepine in a multicenter, randomized, double-blind, double dummy, parallel study of elderly subjects with newly diagnosed seizures. The seizure control was similar in all three groups but patients taking lamotrigine or gabapentin did better than those taking carbamazepine as far as side effects were concerned [24]. Based on this data, lamotrigine or gabapentin should be considered as initial monotherapy in older patients with newly diagnosed epilepsy. Similarly in another large unblinded, randomized controlled trial in partial epilepsy patients, lamotrigine was found to be better in efficacy than both carbamazepine and gabapentin [30]. An international multicenter, randomized, double-blind, controlled trial of lamotrigine and sustained-release carbamazepine, showed comparable efficacy for both, but there was a trend towards better tolerability with lamotrigine [31].
Gabapentin and lamotrigine have both been approved for initial monotherapy in partial epilepsy patients in the European Union. A panel of the American Academy of Neurology concluded both gabapentin and lamotrigine to be effective as first-line treatments for partial epilepsy [32]. Both of these drugs have the advantage of not affecting other medications. However, lamotrigine requires slow titration, which might not be practical if a rapid onset of action is needed in patients with frequent seizures.
Oxcarbazepine has been studied with good efficacy in partial epilepsy, however data in the elderly is limited. In a open label study of oxcarbazepine in new onset partial epilepsy in 147 adult and elderly patients, 73.6% elderly patients became seizure free for 1 year [33]. Oxcarbazepine has been associated with precipitating hyponatremia in elderly patients, particularly if used concomitantly with diuretics [34]. However hyponatremia is uncommon in otherwise healthy elderly individuals [35]. Oxcarbazepine can be used as a treatment option in healthy elderly patients, but should be used with caution in elderly patients with multiple medical conditions.
Topiramate has been approved as first-line monotherapy in epilepsy. However it has an unfavorable cognitive profile in comparison with lamotrigine [36]. Moreover, patients may not be aware of these cognitive adverse effects [37]. This may be a limiting issue for its use in elderly patients. There have been two studies performed in elderly patients with topiramate. In a double-blind trial, elderly patients were randomized to topiramate 50 mg/day or 200 mg/day as monotherapy or as adjunctive therapy. Though efficacy was similar in the two arms with topiramate as monotherapy, with add-on therapy with topiramate, the 200 mg dose was more effective than the 50 mg dose [38]. Cognitive side effects were seen in only 13% of elderly patients. In an open-label trial in elderly patients with new-onset epilepsy, the drug was titrated up to 100 mg per day, with subsequent dosage adjustments as clinically indicated. A 50% reduction in seizure frequency was seen in 87% patients. Retention rate was low and 14% patients dropped out because of poor tolerability [39]. These studies suggested that low-dose topiramate could be considered for the treatment of epilepsy in the elderly. However topiramate requires slow titration like lamotrigine, making it inappropriate for cases where rapid control of seizures is needed.
Levetiracetam is a broad-spectrum antiepileptic medication with a relatively favorable adverse effect profile. It has shown equal efficacy and tolerability to sustained-release carbamazepine in one trial [40]. One retrospective study reported favorable efficacy and tolerability of levetiracetam in a small group of elderly patients who were either started on or converted to levetiracetam monotherapy [41].
Levetiracetam has been evaluated as initial monotherapy in two studies of elderly patients with late-onset post stroke epilepsy. In one study, seizure freedom was observed in 82.4% of 34 patients at daily doses of 1000–2000 mg. Only seven patients reported adverse effects, and only one patient dropped out of the study due to adverse effects (in this case, somnolence). In the other study, 89.5% of 25 patients became seizure-free after levetiracetam treatment. Adverse effects were reported in 28% of patients, but these effects were mild and did not result in withdrawal from the study [42].
Levetiracetam was also studied as adjunctive therapy in a subset of 78 elderly patients who participated in a large, open-label, community-based trial [43]. Overall, 76.9% showed a 50% or greater reduction in seizures and 40% of patients became seizure-free. Main adverse effects reported were somnolence and dizziness. About 19% of patients dropped out of the study because of these side effects. Overall, levetiracetam was well tolerated [43].
As far as other new antiepileptic medications are concerned, there is limited data available on the use of tiagabine, pregabalin, zonisamide and lacosamide in elderly patients.
Clinical recommendation on using antiepileptic drugs in the elderly
In view of the unique pharmacokinetics in the elderly patient, it is preferable to start with an AED that is not highly protein-bound, not an enzyme inducer and less likely to interact with other concomitant medications. Elderly patients are more susceptible to adverse effects of AEDs than are younger individuals. They should be started on low doses of AED and the dose should be titrated upward slowly. On the same token, the elderly are more likely to respond to lower AED doses [2].
We prefer the new AEDs because of their better tolerability profile [44]. Based on the VA cooperative study, lamotrigine and gabapentin should be considered as first-line monotherapy agents in the elderly. Levetiracetam and pregabalin are also reasonable first choices based on their better tolerability profile. The main advantages of these medications, i.e., levetiracetam and pregabalin, are rapid onset of action, lack of drug interactions, and a favorable safety and tolerability profile.
Oxcarbazepine may also be considered as first-line therapy in healthy elderly patients, though with caution because of the risk of hyponatremia. Topiramate can be used at a low dose, with caution, if indicated by comorbidity. Epilepsy in the elderly patient is amenable to treatment with monotherapy. If a monotherapy is poorly tolerated in elderly patients, the AEDs should be changed to an alternative monotherapy. If, however, the first AED is not effective at the maximum tolerated dose, alternative monotherapy or adjunctive therapy are possible options [45]. On the other hand, if the first AED was efficacious but did not lead to seizure freedom then adjunctive therapy may be a better option, especially with newer AEDs without unfavorable interactions.
In clinical practice, serum concentration of AEDs is helpful in confirming compliance as a reference for achieving effective dose and to investigate poor efficacy or poor tolerability of an AED [46]. We tend to rely more on serum levels of AEDs in the elderly because of the pharmacokinetic changes that occur with age, as well as for possible interactions associated with polypharmacy that is often seen in elderly patients [44]. Since phenytoin and valproate are highly protein-bound, free blood levels rather than total blood level of these AEDs give a more accurate estimate of the drug in the elderly patients. Similarly among the new AEDs, serum level monitoring is very helpful in the case of lamotrigine to help adjust its dose.
SURGICAL TREATMENT
Surgical treatment should be considered in elderly patients who have medically intractable epilepsy, especially if there is a focal epileptogenic lesion. There is limited data available on resective epilepsy surgery in elderly patients. Most of the patients in the studies have had seizure onset earlier in their life that persisted into old age. Some of these studies have included patients who are not elderly i.e., they have included patients younger than age 60, however these studies show a trend of improvement in seizures in these patients [47-50]. In a small retrospective study of seven patients 60 years or older who underwent temporal lobectomy, 4 of these seven patients had hippocampal sclerosis. Of these seven patients, four achieved seizure freedom [47]. Resective epilepsy surgery was found to be effective in older individuals in a subset of another study of temporal lobe resection in a total of 52 patients 50 years of age and older (including 11 patients 60 years of age and older). Thirty-seven older patients out of a total of 52 patients attained complete seizure control (71% class I), and 10 patients had only rare postoperative seizures (19% class II). However there was a slightly higher morbidity rate than for younger patients [48]. Resective epilepsy surgery is a good option in healthy elderly patients with a focal lesion in the noneloquent cortex.
Vagus nerve stimulation (VNS) has not been widely evaluated in the elderly population. Efficacy with VNS therapy was evaluated in a study of 45 patients with refractory epilepsy who were 50 years of age or older. Twelve patients in this study had a 50% decrease in seizure frequency at 3 months, while 21 patients out of 31 (67%) patients had a 50% reduction in seizure frequency noted at one year [51]. There were no complications related to the surgical procedure. Adverse effects were mild and transient, and quality-of-life scores improved significantly over time [51]. In another study evaluating daytime sleepiness in epilepsy patients treated with VNS therapy, it was seen that VNS therapy at low stimulus intensity improves daytime sleepiness, even in subjects without reductions in seizure frequency. However VNS can worsen obstructive sleep apnea in patient with preexisting obstructive sleep apnea [52]. Since obstructive sleep apnea is a common comorbidity in elderly patients, VNS should be used with caution in this population.
CONCLUSIONS
Epilepsy is a common disorder of the elderly. Treatment of epilepsy should be targeted to improve quality of life. In general, new antiepileptic medications such as lamotrigine, gabapentin and levetiracetam are better choices for initial monotherapy. The old dictum of starting low and going slow in increments with the elderly will help in avoiding any adverse effects. Epilepsy surgery may be an alternative choice for management of epilepsy in elderly patients with refractory epilepsy.
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