Introduction

Epilepsy is a condition that affects patients in all age groups. Estimates of prevalence vary, in part due to differing classifications and definitions of epilepsy and seizures, study methodologies, and the patient populations studied. A recent WHO publication on the public health aspects of neurological disorders estimated that approximately 50 million people worldwide have epilepsy, with about 85 % of those living in developing countries [1]. Epilepsy is more prevalent in patients over age 60, affecting close to 1 % of this group, and the prevalence appears to increase with age 0 [2, 3]. Most studies suggest that there is an increase in both incidence and prevalence of epilepsy in older patients [2, 4, 5]. An investigation of treated epilepsy in the UK General Practice Research database suggested that the incidence of treated epilepsy rises from 85.9 per 100,000 in patients aged 65–69 to 135.4 per 100,000 in patients over 85 years of age [2]. Several studies suggest that epilepsy is the third most common neurological diagnosis in elderly patients after dementia and stroke [2].

The treatment of elderly patients with epilepsy presents a unique series of challenges and opportunities. Most new-onset seizures in elderly patients are focal and often resulted from new underlying neurologic disease, such as cerebrovascular disease, neurodegenerative disorders, trauma, and neoplasm, though as with other age groups, a specific etiology cannot be identified in a large proportion of patients [5, 6]. The presentation of seizures can also differ in this population. Descriptions of the symptoms and semiologies may be variable or lacking, in part due to memory issues or lack of witnesses. Elderly patients are more likely to present with subtle or non-characteristic symptoms of seizures, such as syncope, memory problems, and confusional episodes or mental status changes, and classic auras and automatisms are less common [7, 8]. The relatively nonspecific nature of the symptoms often leads to a delay in diagnosis. In the VA Cooperative Study 428, epilepsy was on the initial differential diagnosis in only a small proportion of elderly patients who were eventually diagnosed with epilepsy [7]. It is also important to note that a subset of elderly patients will experience acute seizures provoked by severe medical/metabolic abnormalities, abrupt medication changes, or direct medication effects (acute symptomatic seizures). These seizures do not always require long-term treatment. In those patients who are diagnosed with epilepsy and require ongoing treatment, consideration should be given to a number of factors. This article will review some of the general principles of treatment in elderly patients with epilepsy.

Medication Choice

When the diagnosis of epilepsy has been established, the primary treatment recommendation is typically an anti-epileptic drug (AED). While in some cases, the choice of AED is closely tied to a specific syndrome (for example, ethosuximide for childhood absence epilepsy), the majority of new-onset epilepsy in elderly patients is likely to be focal, and thus, many AED options may be appropriate, and medication selection focuses on those AEDs with efficacy in treating focal (and often secondarily generalized) seizures or those with a broad mechanism of action. In all patients with epilepsy, the choice of an appropriate medication involves an evaluation of several factors, including efficacy, potential adverse effects (both short and long term), interactions with other medications, feasibility/ease of use, and, increasingly, cost to the patient. There are limited head-to-head studies comparing efficacy of the AEDs and even less data specific to older patients. Evidence for best AED treatment for all adults has been extrapolated to the treatment of elderly patients, but only a few studies specific to this population have been performed. In a large randomized study of new-onset epilepsy among elderly patients in the Veteran’s Administration, Rowan et al. compared the use of lamotrigine, carbamazepine, and gabapentin [9]. All three medications demonstrated similar effectiveness in treating seizures; however, lamotrigine and gabapentin were better tolerated than carbamazepine (possibly due in part to the use of standard release carbamazepine rather than sustained release). Several other studies have also suggested that lamotrigine is as effective as carbamazepine in this population and better tolerated than standard formulation carbamazepine [10, 11]. A recent updated review of the evidence for AED efficacy in the treatment of newly diagnosed epilepsy conducted by the International League Against Epilepsy (ILAE) noted that there have been a total of four randomized controlled trials examining monotherapy for partial onset seizures in elderly adults, only one of which produced class I data [12•]. On the basis of this data, it was concluded that lamotrigine and gabapentin were established (level A evidence) as effective initial monotherapy for treatment of partial onset seizures in elderly adults, whereas carbamazepine was possibly effective (level C), and topiramate and valproate (level D) were potentially effective. There are also studies that suggest that some of the newer generation AEDs such as oxcarbazepine, levetiracetam, and zonisamide may be safe and effective in elderly patients; however, few head-to-head or randomized trials exist [13–15]. Some limited randomized trials and subgroup analyses suggest that some of the newer AEDs, including levetiracetam, may be effective and have favorable pharmacokinetic profiles in elderly patients; considering these early in the course of treatment may be beneficial [16, 17]. More recently, a blinded clinical comparator trial compared retention rates in elderly patients with epilepsy randomized to carbamazepine (controlled release), lamotrigine, and levetiracetam. Seizure freedom rate (a secondary outcome measure) was similar among the three AEDs; however, patients randomized to levetiracetam had significantly higher retention rates (the primary outcome) compared with carbamazepine. Patients randomized to lamotrigine also demonstrated higher retention compared with carbamazepine, though this difference did not meet statistical significance [18•].

In general, anti-epileptic medications that are effective in the overall adult population are likely to be effective when used in elderly patients, and there are an increasing number of studies in the literature addressing efficacy in this age group. Newer generation AEDs appear in many cases to be comparable in terms of effectiveness, and may have several advantages over older generation medications, including more favorable side effect profiles, retention rates, and pharmacokinetic profiles, and often have fewer drug-drug interactions. Some of these considerations will be further discussed below.

Pharmacokinetic and Pharmacodynamic Considerations

The pharmacokinetic properties (absorption, distribution, metabolism, elimination) of AEDs are variable and often complex (Table 1). In elderly patients, there can be additional considerations which may necessitate adjustment of medication doses. Commonly, a decline in renal function and filtration/clearance is seen with age, resulting in decreased clearance and elimination. Many AEDs are metabolized by the hepatic cytochrome P-450 system. In some elderly patients, particularly those with other significant medical illnesses, hepatic function can decline, leading to decreased metabolism and the potential for elevated serum levels. Elderly patients commonly have lower lean body mass and increased body fat, which can affect both water and lipid soluble drugs. Older patients also commonly have lower serum protein and albumin levels, which can result in an increased free fraction of protein bound drugs and potential toxicity [19, 20]. The pharmacodynamic profiles of AEDs can also be challenging in elderly patients. In particular, effects on balance and cognition are important to monitor. Elderly patients can be more sensitive to medication side effects at doses normally tolerated by younger individuals; therefore, it is often advisable to begin initial titrations at lower doses and to proceed more slowly with titration schedules (following the common adage “start low and go slow”). The idiosyncratic effects of individual AEDs are also important to consider. An example is the increased risk of hyponatremia associated with oxcarbazepine (and to a lesser extent carbamazepine) use. Hyponatremia is more common in the elderly population in general compared with younger adults, and thus, closer monitoring may be necessary.

Table 1 Commonly available anti-epileptic drugs and some features to consider when treating elderly patients. Not all drug effects are listed
Full size table

Medication Interactions

AEDs with strong enzyme-inducing properties (such as phenytoin, carbamazepine, phenobarbital, and primidone) can increase the metabolism of other medications, including cardiovascular medications (anti-arrhythmics, anti-hypertensives), psychotropic medications and anti-depressants, cancer treatments, antibiotics/antimicrobials, other seizure medications, and anticoagulants (such as warfarin). This is not only the case with initiation of these AEDs but also with dose adjustment and withdrawal, necessitating close communication between the patient’s neurologist and other treating physicians. In elderly patients who are often on multi-drug regimens, this can be challenging, particularly if other care providers are not familiar with these interactions. The newer generation of AEDs (including levetiracetam, lacosamide, and lamotrigine) are less likely to be associated with potent enzyme-inducing activity, or may do so only at higher doses. Inhibitors of hepatic metabolism (such as valproic acid) are somewhat less problematic but nevertheless require close monitoring.

Comorbid Conditions

Many elderly patients with epilepsy have underlying medical conditions which should be taken into consideration when treating seizures. As described previously, many AEDs have interactions with medications used to treat other disorders, often by their enzyme-inducing effects on the hepatic cytochrome system (phenytoin, carbamazepine, phenobarbital, mysoline). In patients who are required to take several drugs, several of the newer generation AEDs with no significant drug-drug interactions are attractive options (levetiracetam, lacosamide, gabapentin), as are those with enzyme-inducing properties that typically occur only at higher doses (lamotrigine, oxcarbazepine).

A particular concern in the elderly is the issue of decreased bone density (osteoporosis), particularly in women. Many of the AEDs, especially those with strong enzyme-inducing properties, have been associated with decreased bone density (osteoporosis) with chronic use, likely from induction of vitamin D metabolism, which may lead to an increased risk of fractures [21, 22]. Interestingly, non-enzyme-inducing AEDs (such as valproate) have also been implicated in bone density loss [23, 24]. While there are no specific practice parameters or dosing guidelines regarding treatment, several prospective trials have been published suggesting that supplementation with calcium and vitamin D (and possibly risedronate) may result in improved bone mineral density in patients with epilepsy on AEDs; higher doses of vitamin D at 4000 IU/day may be more effective than low doses at 400 IU/day [25, 26]. In some cases, physicians and patients may elect to transition to newer generation AEDs, which generally have fewer negative effects on bone density; however, for various reasons this may not always be possible. For those patients on higher risk AEDs, many clinicians and professional societies suggest regular monitoring of vitamin D levels, along with supplementation of calcium and vitamin D, regular exercise, and healthy meal choices. Regular bone density screening (DEXA scans) may also be considered, particularly for patients on strong enzyme-inducing AEDs, though no clearly defined screening intervals have been established. Finally, evaluation by an endocrinologist can be helpful in patients who continue to have decreases in bone density despite these recommendations.

In the recent years, the association between mood disorders and epilepsy has been increasingly recognized. Mood and psychiatric issues are very common in patients with epilepsy, and there is some evidence to suggest that mood-related symptoms may even precede onset of epilepsy, suggesting a possible bidirectional relationship [27–29]. Recognizing the symptoms of mood disorders and treating them appropriately may have a variety of beneficial effects, including helping to improve mood, overall quality of life, medication adherence, and perception of medication side effects [30]. Treatment of mood may even improve seizure control and may affect surgical success [31]. There have been fewer studies focusing specifically on the role of mood in elderly patients with epilepsy; however, it has been reported widely that elderly patients in general are at higher risk for mood problems. Historically, a variety of screening instruments have been used to identify patients with depression. However, relatively few are validated for use in the epilepsy population. The most commonly used tools are the Beck Depression Inventory, which is a self-reporting instrument screening for depression, and the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E), which screens for current episodes of depression [32, 33]. Recent research has validated use of the Hamilton Rating Scale for Depression, one of the most common screening tools for depression worldwide, in the epilepsy population [34].

Epilepsy Surgery

The literature regarding success rates of resective surgery in elderly patients is relatively limited. There are several published studies, though the number of participants tends to be small, and age ranges vary considerably [35–38]. Overall, published reports and subgroup analysis suggest that efficacy rates are relatively similar compared with younger adults, and that the factors which portend better outcomes are also comparable. Several of the studies suggest that while surgical outcomes may be comparable, the rates of neurologic complications such as cognitive deficits may be slightly higher in the elderly population.

Devices

There are two FDA approved devices for treatment of focal epilepsy in adults: vagal nerve stimulation (VNS) and responsive neurostimulation (RNS). There is a relative paucity of data regarding efficacy and tolerability in the elderly population; however, both may be considered as treatment options, and there is some data to suggest that the age of epilepsy onset or VNS implantation may not affect long-term efficacy of the device, and that the likelihood of VNS success in older patients is comparable to that in younger adults [39, 40].

Conclusions

Epilepsy is a common disorder in elderly patients, with increased incidence and prevalence in later life. The diagnosis itself can be challenging, as many elderly patients with epilepsy may present with symptoms that are somewhat nonspecific or subtle. The majority of new-onset epilepsy in older patients is focal in nature and results from a variety of etiologies. The primary treatment option for most patients is an anti-seizure medication. There are limited data available regarding comparative efficacy of these medications in older patients; however, most AEDs that are effective in younger adults are likely to show similar benefits in the elderly, and there are a few recently published studies in the literature which suggest that this is the case. In clinical practice, the comparative efficacy of anti-seizure medications in this population is sometimes less critical than the pharmacodynamic side effects and interactions that these medications can produce. Anti-seizure medications can be associated with a variety of short- and long-term side effects. Some of these can also exacerbate underlying comorbid medical conditions, which are often present in greater prevalence in elderly patients. The pharmacokinetic profiles and drug-drug interactions of these medications can also be complex. These factors must all be considered in the selection of an appropriate anti-seizure medication. For all of these reasons, consideration of a newer-generation AED as initial monotherapy may be advantageous. Finally, although relatively less data exists in the elderly population for the use of non-medication treatments such as resective surgery and devices, these are also viable options and should not be excluded from consideration.