Epilepsy in the Elderly

Ann Johnston; Phil EM Smith

Disclosures

Expert Rev Neurother. 2010;10(12):1899-1910. 

In This Article

Management

The overall goals, as in anyone with epilepsy, are the maintenance of seizure freedom without medication side effects and the maintenance of a normal lifestyle with unchanged or improved quality of life.[30] Although antiepileptic drugs (AEDs) are the mainstay of treatment, the overall patient management should encompass other areas that equally concern the patient and family, for example, associated comorbidities, quality of life issues, medication side effects, driving eligibility, social stigmas, taboos and discrimination. A general principle in epilepsy management in the elderly should be to use a multidisciplinary team approach involving epilepsy physicians, epilepsy specialist nurses, primary care clinicians and elderly care physicians. Patient and carer education are crucial, particularly with regard to acute seizure management, medication concordance and accessing advice, counseling and long-term follow-up.

General Prescribing Principles

It is reasonable to assume that antiepileptic treatment will be life-long. Ideally, the AED choice should be that which most likely achieves seizure freedom with the fewest side effects. It should be well tolerated, have a limited side-effect profile, have easy dosing and be free of troublesome drug–drug interactions. The general principle of 'start low and go slow' applies particularly to elderly patients, helping to minimize the intensity and frequency of adverse side effects.

AEDs in the Elderly

Managing AEDs in older people can be complicated and time consuming; the AED choice may depend on associated comorbidities and polypharmacy. The published literature suggests that elderly care clinicians are conservative prescribers, with phenytoin remaining the most commonly prescribed, being the first choice AED for 70% of patients. Second choice drugs were carbamazepine, phenobarbital and sodium valproate; the most common polytherapy regimen was phenytoin and phenobarbital.[35] Of note, ginkgo biloba is the most commonly prescribed herbal remedy in nursing home populations.[36] A recent Italian study on elderly outpatients by Oteri et al. demonstrated that most AEDs were prescribed for neuropathic pain; older AEDs were mostly used for epilepsy whereas newer AEDs were mainly prescribed for neuropathic pain.[37] The authors commented that phenobarbital accounted for over 50% of the total AED volume and was the most frequently prescribed AED between 2004 and 2007.[37]

In 2004, Pugh et al.'s study of prescribing practices using the National Veterans Affairs pharmacy database of all patients diagnosed before 1999 demonstrated that 17% received phenobarbital and 54% phenytoin.[38] Despite the finding that patients classed as having newly diagnosed disease were less likely to receive phenobarbital and were more likely to receive gabapentin (an AED with limited efficacy shown in the Standard and New Antiepileptic Drugs [SANAD] study) or lamotrigine, the authors conclude that most older veterans received potentially inappropriate AED therapy.

There is a very narrow evidence base for managing newly-diagnosed epilepsy in the elderly. Brodie et al. demonstrated that lamotrigine was as effective and better tolerated than standard-formulation carbamazepine.[39] However, a similarly designed study using controlled-release carbamazepine found no advantage.[40] In the Veterans' Administration randomized double-blind study, lamotrigine, gabapentin and carbamazepine each demonstrated similar seizure control. However, carbamazepine was less well tolerated than the other drugs, but notably this was as standard and not a controlled-release preparation and the maintenance doses of gabapentin and lamotrigine were lower than usual.[41] Carbamazepine in clinical practice often seems to be poorly tolerated. However, Seatre et al. found no difference between lamotrigine and carbamazepine in health-related quality of life scores.[42]

Sajatovic et al. reported a literature review in 2007 of lamotrigine in elderly patients with epilepsy, bipolar disorder or dementia.[43] Lamotrigine was effective and well tolerated and also appeared to benefit mood disturbances.[43] Evans et al. also demonstrated in 2007 that lamotrigine as an add-on therapy had good efficacy and tolerability in elderly patients,[44] with further improvement when switched to lamotrigine monotherapy.[44] This confirmed an earlier report by Giorgi et al. in 2001 that lamotrigine prescribed to elderly patients with epilepsy was well tolerated and superior to carbamazepine and phenytoin.[45]

Gilad et al. examined lamotrigine and carbamazepine in patients with post-stroke seizures.[46] It was a small study (n = 64) of symptomatic seizures randomized to either lamotrigine or carbamazepine; seizure freedom was no different, but significantly fewer patients on lamotrigine withdrew owing to adverse events compared with carbamazepine.[46]

There is even less trial information on newer drugs, such as levetiracetam or oxcarbazepine, in elderly populations. In 2010, Cumbo and Ligori evaluated the efficacy, tolerability and cognitive effects of levetiracetam in patients with seizures and Alzheimer's disease.[47] This was a randomized prospective three-arm parallel-group case–control study of levetiracetam, lamotrigine and phenobarbital. Compared with a control group, there were no significant differences in terms of efficacy. Levetiracetam caused fewer adverse events than the other AEDs, lamotrigine had a beneficial effect on mood and not surprisingly phenobarbital produced persistent negative cognitive side effects. The authors suggest that these findings potentially make levetiracetam a cognitively safe drug for seizures in elderly patients with cognitive problems or Alzheimer's disease.[47]

In 2010, Arif et al. retrospectively reviewed the comparative effectiveness of ten AEDs in older adults (aged >55 years) with epilepsy.[48] The study used 12-month study retention and 12-month seizure freedom as the main outcome measures, and found lamotrigine to be the most effective AED, followed by levetiracetam. Oxcarbazepine had the lowest retention rate.[48]

In general, all commonly used AEDs appear similarly effective for seizure control in the elderly; the choice depends more on tolerability than individual AED efficacy. The UK NICE currently recommends carbamazepine as a first-line AED for partial-onset seizures for adults of all ages. However, with the increasing choice of newer AEDs having benefits of inert metabolites and limited drug interactions, certain agents, such as lamotrigine and levetiracetam, should at least be considered as suitable alternative first-line therapies to the older AEDs. Table 1 illustrates some benefits and cautionary notes on using AEDs in the elderly.

The 2007 SANAD study informed clinical prescribing choices for focal and generalized epilepsy.[49,50] Lamotrigine showed similar efficacy to carbamazepine in focal-onset epilepsy, but was better tolerated; sodium valproate was the most effective AED for generalized-onset seizures. Although SANAD showed that gabapentin was less effective than other AEDs, its lack of interactions and dual use for neuropathic pain still make it a reasonable option for elderly people with epilepsy.

Pharmacology in the Elderly

Pharmacokinetics and pharmacodynamics of AEDs differ in old age from younger patients. These differences depend on the physical status of the patient, the presence or absence of comorbidities and the effects of other medications. In general, absorption, protein binding and hepatic metabolism are unchanged in old age except in the very frail or malnourished. As renal function declines with age, care is needed when using renally-excreted drugs; lower doses should generally be prescribed.[51] Table 2 illustrates some pharmacokinetic and pharmacodynamic situations to consider when prescribing for elderly patients.

The half-life and clearance of phenytoin during maintenance therapy in otherwise healthy elderly patients with epilepsy are similar to in younger adults.[52] Therefore, an elderly person's reduced phenytoin dosage requirements may be more due to age-related changes in sensitivity to the therapeutic and toxic effects of the drug, rather than to true pharmacokinetic differences.

Further work by Pugh et al. in 2010 using the National Veterans Affairs databases demonstrated first, that phenytoin was the most commonly prescribed AED and second, that potentially meaningful AED and other drug–drug interactions occurred in 45.5% of records studied.[53] Alongside phenytoin, the most common other prescribed medications were cardiovascular drugs, statins and psychotropic medication. The interaction of enzyme-inducing AEDs with statins may, in theory, increase risks of stroke and myocardial infarction. Therefore, the authors suggested that, despite patients managed in tertiary epilepsy centers being less likely to be exposed to drug–drug interactions, clinicians should nonetheless watch closely for potentially adverse events and avoid co-administering enzyme-inducing drugs with a statin.[53]

Gidal et al. reached similar conclusions: the most commonly prescribed non-AED medications in this study were statins, calcium channel blockers and serotonin selective re-uptake inhibitors.[54] They also emphasized that although polypharmacy is not confined to the elderly, the risk of AED and other drug–drug interactions increases with age, putting the vulnerable elderly at increased risk.[54]

Single Seizure Management in the Elderly

The Multicentre Study of Early Epilepsy and Single Seizures (MESS) study randomized to immediate or delayed AED treatment following a single unprovoked seizure. Its results reinforce current AED prescribing practice – usually to withhold AED treatment until there have been two unprovoked seizures.[55] The immediate treatment group did show fewer recurrences at 1 year, but without longer term benefit. Of note, relatively few older people participated in this study. By contrast, the First Seizure Trial Group (FIRST Group) highlighted old age as a significant predictor of recurrence.[56] Therefore, it is reasonable to consider prescribing an AED to an elderly patient after one unprovoked seizure, especially if there is a structural lesion on neuroimaging (with a consequent high risk of recurrence) or a high risk of injury from a further seizure.

Comorbidities in the Elderly

The comorbidities of epilepsy in elderly patients add to the diagnostic challenge, but also complicate the treatment options.[13] For example, AED-dose alterations may be required in patients with renal failure, and bone protection should be considered in elderly people receiving enzyme-inducing drugs.[57] The comorbidities of mild cognitive impairment and dementia have implications for carers, especially regarding medication concordance.[13] In patients with epilepsy and dementia, it is sensible to select AEDs that do not overly worsen cognitive function. Given the close association of stroke with epilepsy in the elderly, addressing cardiovascular risk factors in elderly patients presenting with new-onset seizures might include an additional prescription of aspirin and a statin;[19] dose adjustments or an alternative cholesterol-lowering agent may be required if the patient is prescribed an enzyme-inducing AED.[58]

In epilepsy populations, the most commonly reported epilepsy-related injuries are contusions and wounds. These are followed by abrasions, fractures, brain concussions, sprains/strains and burns. In patients with associated disability, increased comorbidities and of increased age, especially when side effects of AEDs can impair cognitive ability, there is an increased vulnerability and susceptibility to injury resultant from frequent seizures. A recent study by Lees compared the injuries sustained in an elderly population with epilepsy to that of a control population and demonstrated that falls rather than seizures were the main contributing factor to bony fractures in both groups of elderly patients.[12]

As falls are a common cause of morbidity in the elderly, and given the relatively common adverse effects of dizziness, ataxia and cognitive disturbance with certain AEDs, studies have tried to examine the effects of AEDs on balance and cognition. Fife et al. assessed a small number of patients on stable monotherapy with either moderate doses of gabapebtin, lamotrigine or carbamazapine and found no difference in activity-specific balance rating scales or in quantified tests of vestibular function.[59] When assessed using an ataxia battery, including Romberg testing, those on lamotrigine maintained balance significantly longer than those on carbamazepine.[59] In 1996, Prevey et al. examined the effects of valproate and carbamazepine on cognitive function in a double-blind study of veterans, and found no significant difference in motor speed, coordination, memory and mental flexibility, and no deterioration in neuropsychological testing.[60]

Drug Interactions

The vulnerability of elderly patients and the increased likelihood of multiple prescribed medications make them susceptible to drug interactions. Polypharmacy increases the number of, and risks from drug interactions.[13] A survey of elderly nursing home residents reported by Patsalos et al. in 2002 found that 49% of residents receiving AEDs were prescribed six or more medications.[53,61]

When two or more drugs are prescribed together, clinically important interactions can occur. The older generation AEDs, such as phenobarbital, phenytoin, carbamazepine and primidone, are potent hepatic enzyme inducers and, therefore, can decrease the plasma concentration of many psychotropic, immunosuppressive, antimicrobial, antineoplastic and cardiovascular drugs.[61,62] Most newer generation AEDs have no clinically important enzyme-inducing effects. Perhaps in 6% of patients experiencing AED toxication, a drug interaction was identified as the cause.[61,63] The epilepsy literature on AED–AED interactions and AEDs with other drug interactions has largely been published by Patsalos; a few relevant clinical examples are given in this article.[61,62]

Elderly patients, given their comorbidities, frailty and vulnerability, are susceptible to pneumonias and other infections; for those prescribed AEDs, care is needed in the choice of antibiotic, as certain fluroquinolones and macrolides can result in an increase in plasma concentrations of phenyotin and carbamazepine. Isoniazid can inhibit the metabolism of several AEDs.[61,62]

Particular care is needed in choosing an AED for someone already taking warfarin: older AEDs, such as phenobarbital, phenytoin and carbamazepine, induce the P450 enzyme pathway and so increase warfarin metabolism.

As illustrated by the Veterans Affairs studies, cardiovascular drugs are commonly prescribed in the elderly population. Plasma levels of antiarrhythmic drugs, such as amiodarone, can be decreased by enzyme-inducing AEDs and, therefore, may need to be increased accordingly. There is also a steady-state interaction of amiodarone with phenytoin, giving increased plasma concentrations of phenytoin. Plasma concentrations of digoxin can also be decreased due to concurrent administration of phenytoin. Given the narrow therapeutic index of digoxin, plasma concentrations of digoxin and phenytoin may require dose adjustments and careful monitoring. Care and dose adjustment are also often needed with some antihypertensive drugs; enzyme-inducing AEDs increase the metabolic clearance of β-adrenoreceptor blocking agents, calcium antagonists and verapamil.[61,62]

Owing to the incidence of psychiatric disorders, including depression, anxiety and psychosis, psychotropic and antidepressant drugs are commonly prescribed to elderly people. Enzyme-inducing AEDs can increase the metabolism of antidepressant drugs, such as amitriptyline, and antipsychotics, such as haloperidol, chlorpromazine and clozapine. Enzyme-inducing AEDs also enhance the metabolism of most benzodiazepine drugs.[61,62] Furthermore, concomitant prescription of particular drugs, such as erythromycin, isoniazid, and some cardiac drugs, such as verapamil and diltiazem, inhibit hepatic metabolic pathways and can increase circulating concentrations of AEDs and other drugs.

Adverse drug events are common in elderly people, particularly sedation from drugs such as barbiturates, phenytoin and topiramate. AEDs may also aggravate pre-existing disorders, such as dementia, cardiac arrhythmias, polyneuropathy and osteoporosis.[64] The elderly are more susceptible than younger people to the hyponatremia associated with carbamazepine or oxcarbazepine, especially in those already taking a thiazide or another diuretic.

Although some of the discussed interactions may be theoretical, clinicians should be aware of the potential for harm, and should prescribe AEDs and other drugs in an informed manner in order to minimize the risk. In certain situations, harmful interactions can easily be avoided by prescribing alternative medication or by using one of the new-generation AEDs. In other cases, a simple dose adjustment alongside monitoring the clinical response may be all that is required.

Adherence

Antiepileptic drug adherence may not be as good in elderly patients with epilepsy, a further factor increasing seizure likelihood and healthcare costs.[65]

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