Pharmacologic Considerations in the Treatment of Older Adults With Epilepsy

The incidence and prevalence of epilepsy are highest in older adults, with epilepsy being the third most common neurologic diagnosis in older adults, after dementia and stroke.¹ Treatment with antiseizure medications (ASMs) is the mainstay of therapy for this age group.² We discuss preferred and nonpreferred ASMs for older adults with epilepsy and highlight special considerations for each ASM discussed, including changes in pharmacokinetic and pharmacodynamic responses, risk of adverse effects (AEs), and known drug–disease or drug–drug interactions (DDIs).

Therapy Goals

The aim of pharmacologic therapy in older adults with epilepsy is seizure freedom with minimal drug-related AEs. Because ASM pharmacokinetics and pharmacodynamics in older adults are variable, ASMs are often started at lower-than-normal initiation doses to minimize the occurrence of AEs, with gradual upward titration until seizures are controlled or AEs occur. In comparison with younger individuals, older adults with epilepsy generally respond better to ASMs, often requiring lower doses of ASM monotherapy, with a greater proportion (~80%) achieving seizure freedom.^3-5 This is especially true for individuals with poststroke epilepsy: >80% to 90% of this population achieves seizure freedom with ASMs.^3,6

Evidence for ASM Efficacy

The majority of new-onset epilepsy cases in older adults are focal; therefore, ASMs with efficacy for focal seizures or broad mechanisms of action may be appropriate. Although the data are sparse, lamotrigine (LTG), gabapentin (GBP), and carbamazepine (CBZ) have been identified by the International League Against Epilepsy and the American Epilepsy Society/American Academy of Neurology as efficacious for new-onset focal seizures in older adults.^7,8 A 2019 systematic review and meta-analysis compared levetiracetam (LEV), CBZ, and LTG data from 10 studies and concluded that LEV was more efficacious than LTG in achieving seizure freedom in older adults.⁹ People taking CBZ were almost twice as likely to discontinue their ASM because of AEs compared with people taking LTG. Data from the systematic review of 18 studies also provided evidence for the use of brivaracetam, GBP, lacosamide (LCM), perampanel (Fycompa; Catalyst Pharmaceuticals, Coral Gables, FL), phenytoin (PHT), phenobarbital (PHB), topiramate, valproic acid (VPA), and zonisamide (ZNS) in older adults with epilepsy, although these ASMs were not included in the meta-analysis.⁹

Preferred ASMs

Aligning with available evidence for ASM efficacy in older adults, survey studies, and reviews of prescribing patterns demonstrate that LEV, LTG, and LCM are the most prescribed and preferred ASMs for older adults with epilepsy.^10-13

Levetiracetam

LEV is a preferred agent in older adults for many reasons. LEV can be quickly loaded orally or intravenously to reach immediate therapeutic levels and is available as injectable solution, tablets, and oral solution with similar bioavailability, allowing for easy interchangeability between formulations, characteristics important for a population that may have frequent care transitions where different routes of administration may be required. LEV is primarily eliminated unchanged renally, with no effects on CYP450 or UGT enzymes and, as such, has a relative lack of DDIs overall. However, in people taking concomitant ASM inducers, there may be an inducer-mediated increase in nonrenal (eg, ester hydrolysis) LEV clearance, which may be especially apparent at the oldest ages; increased dosages can be considered if breakthrough seizures occur.^14-16

In general, LEV dosages for older individuals should be 25% to 75% of standard dosages, depending on the individual’s creatinine clearance, because LEV renal clearance correlates with creatinine clearance, which decreases with age; doses of 250 to 500 mg twice daily are often sufficient to achieve long-term seizure control in older adults.^17,18 Dosing adjustments are not necessary in older adults with hepatic impairment, but recent pharmacokinetic/pharmacodynamic modeling suggests that LEV exposure can be increased with Child-Pugh B or C hepatic impairment; LEV dose reduction may be worth considering in older adults with hepatic impairment who seem overly somnolent.¹⁸

Older adults may have varying degrees of declining cognitive, motor, and sensory function and can be particularly susceptible to dose-related neurotoxic AEs associated with ASMs. LEV is preferred because of its minimal motor and sensory neurotoxic effects. Furthermore, LEV has demonstrated beneficial effects on cognitive measures in older adults, including in people with cognitive impairment.^19-24 Behavioral AEs, most notably irritability and anger, are the major drawbacks of LEV, and are an increasing concern in adult and pediatric populations.^25-27 However, behavioral AEs have not emerged as an increased concern in the available data for older adults with epilepsy.^16,27-29 In addition, before its Food and Drug Administration (FDA) approval for epilepsy, LEV was evaluated in numerous trials for cognition, mostly in older adults, and behavioral AEs occurred in only 6% of participants, compared with 13% of adults treated with LEV in epilepsy trials.³⁰ Behavioral AEs in older adults may present as agitation, apathy, or depression, which may be underrecognized; providers should take this into consideration when monitoring for AEs with LEV.

Lamotrigine

LTG is an attractive option for older adults because of its favorable AE profile in relation to cognition, mood, and behavior. Limited data in older adults have shown neutral or positive improvements in cognitive scores in older adults with epilepsy with and without dementia.^19,31,32 Notably, when compared with adults treated with CBZ, adults treated with LTG performed better on certain cognitive tasks.³³ In regard to mood and behavior, improvements in depression, mania, and mood relapses were seen in older adults with epilepsy and bipolar disorder with LTG,³² although direct comparisons with CBZ suggest that CBZ has more favorable psychiatric effects.³³ LTG may also have other psychiatric and behavioral benefits, including improved alertness, attention, learning, and social functioning, and reduced lethargy.³⁴ When compared with people taking LEV, people taking LTG had improved anger and hostility.³⁵

Recently, the FDA issued a warning for risk of arrhythmia and sudden cardiac death with LTG treatment based on in vitro data demonstrating class 1B antiarrhythmic sodium channel–blocking properties of LTG. Several retrospective studies performed since the warning was released have not identified an increased risk of arrhythmia or sudden cardiac death in clinical populations.^36-38 In adults without cardiac disease, high doses of LTG cause mild QT shortening and PR prolongation.³⁹ Whereas the true risk associated with LTG in people with cardiac conditions is uncertain, LTG should be used with caution in older adults with second‐ and third‐degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, or right bundle branch block. An ECG should be considered before LTG initiation, when LTG target doses are reached, and when LTG is used concomitantly with other sodium channel blockers.³⁹ The FDA is requiring investigation of risk of arrythmias with other sodium channel–blocking ASMs as well.

Clinical concerns about rash limit the use of LTG. However, older adults do not appear to be at increased risk for LTG-induced rashes or hypersensitivity reactions.⁴⁰ Rash occurs as much as 2 times more frequently with CBZ than with LTG in randomized controlled trials (RCTs) with older adults.^41-44 LTG use is also limited by the need for slow titration to prevent rash, and this remains true for older adults; however, older adults achieve seizure freedom at lower LTG dosages and reach therapeutic dosages more quickly. For example, 80% of older adults in LTG trials were taking monotherapy dosages of 50 to 100 mg daily,⁴⁰ and average therapeutic LTG dosages in older adults are reported to be as low as 75 mg/d.^32,43,44

LTG is metabolized by the UGT system.⁴⁵ LTG does not interact with other ASMs, but enzyme-inducing or inhibiting medications will affect UGT-mediated LTG clearance; coadministration with inducers PHT, CBZ, or PHB, or inhibitor VPA requires dose modifications.⁴⁶ LTG also requires dose modifications when given with estrogen because of UGT-mediated effects, which may be important in postmenopausal women with epilepsy. Recent LTG pharmacokinetic data suggest that older adults may have lower LTG clearance (~30%), possibly because of reduced UGT expression or liver mass. As such, the half-life of LTG may be extended, which may have implications in reducing dosing frequency, although this has not been evaluated clinically.^45,47 Weight in older adults may also affect LTG clearance and should be taken into consideration when calculating dosages for emaciated or overweight individuals.⁴⁶

Lacosamide

LCM is a third-generation ASM approved as an adjunctive or monotherapy for treatment of focal-onset epilepsy. LCM exerts its anticonvulsant activity by selectively enhancing slow inactivation of voltage-gated sodium channels. LCM is a valuable option for older adults with focal-onset epilepsy because it is well-tolerated. LCM has multiple elimination pathways, primarily renal, and has no clinically relevant interactions with other ASMs or commonly prescribed medications.⁴⁸ However, LCM shares dose-dependent AEs with other sodium channel blockers, including dizziness, drowsiness, and ataxia. A pooled analysis of initial phase 2 and 3 trials and a large multicenter open-label trial indicated dizziness to be one of the most commonly reported AEs.^49,50 This is important in older adults because of the risk of falls. Few observational studies have evaluated the efficacy and tolerability of LCM as monotherapy or add-on therapy in older adults with similar retention rates and seizure freedom rates.^51-53 However, AEs leading to discontinuation in the LCM vs ZNS study differed, with dizziness and gait instability being more prominent with LCM, and cognitive or behavioral AEs with ZNS.⁵¹ The authors reported that concomitant use of a sodium channel blocker was not a predictor of discontinuation of LCM.⁵¹ When LCM was added to 1 ASM with flexible dosing, a subgroup analysis of older adults showed higher rates of seizure freedom (56% at 6 months) and similar rates of AEs compared with younger people at equivalent average doses of 260 mg/d.⁵³

Cardiac arrythmias have also been reported with LCM. They are rare (<1%) and characterized by dose-dependent prolongation of PR interval, bradycardia, atrioventricular block, ventricular tachycardia, syncope, and asystole, especially when given intravenously.^54,55 The prescriber information sheet contains a warning with use of LCM in people with preexisting second-degree or complete atrioventricular block and notes that LCM may be associated with atrial arrhythmias (atrial fibrillation or flutter), especially in people with diabetic neuropathy or cardiovascular disease.⁵⁶ Results of a disproportionality study aimed at examining the association between LCM use and cardiac AEs through data mining of the FDA adverse event reporting system database found 812 cardiac AEs between 2013 and 2022. Of the 812 AEs, 17 were found to be significantly associated with LCM use irrespective of dose and route.⁵⁷

Older Antiseizure Medications

CBZ, PHT, PHB, and VPA initially were the most prescribed ASMs in older adults.^13,58,59 First-generation ASMs are no longer preferred and should only be used after trials when other ASMs have failed. Despite this, these ASMs continue to be prescribed frequently for individuals of all ages, including older adults; providers should be aware of important considerations with their use in older adults.

Carbamazepine

CBZ has demonstrated efficacy in older adults, as well as lower rates of psychiatric and behavioral AEs compared with other ASMs, including LTG.²⁶ However, RCT data show that rash, hypersensitivity syndrome, and hyponatremia drive the overall poor tolerability of CBZ in older adults; CBZ neurotoxicity is similar to that of LTG and GBP.⁴¹ CBZ, along with oxcarbazepine, has been identified in the 2023 Beers Criteria as a drug to be used with caution in older adults because of the risk of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion.⁶⁰ In addition, CBZ is a strong inducer of CYP450 and UGT and interacts with numerous ASMs, most notably PHT, PHB, VPA, and LTG, as well as with other commonly used drugs in older adults.⁶¹ Strong enzyme inducers also increase catabolism of vitamin D, decreasing bone density. The evidence regarding the effect of CBZ on bone density is conflicting, but CBZ is best avoided in older adults, who are at increased risk of osteoporosis, particularly older women with epilepsy, whose risk for this condition may be doubled.^62,63

Phenytoin

PHT, previously the most widely used ASM, is no longer preferred because of its many AEs, including neurotoxicity, gingival hyperplasia, risk of osteoporosis, and numerous DDIs. Older adults are particularly susceptible to these side effects; up to 90% report some side effects on PHT vs 72% with CBZ and 50% with LTG.⁴³ PHT is particularly implicated in increasing osteoporosis and fracture risk through multiple mechanisms beyond enzyme induction.^62,64 Therefore, in older adults in whom PHT cannot be avoided, monitoring of vitamin D levels and bone density scanning along with calcium and vitamin D supplementation may be beneficial;⁶⁵ higher doses of vitamin D at 4000 IU/d may be more effective than low doses at 400 IU/d.⁶⁶

The therapeutic window of PHT may be narrowed in older adults, and AEs can occur at blood levels that are within the standard therapeutic range for younger adults. Further complicating management, PHT is highly protein bound, and measured total PHT levels do not accurately represent the level of pharmacologically active free drug in older adults with low protein states.^67,68 In addition, people living in nursing homes, who are usually older adults, have substantial intraindividual variability in total PHT levels over time, as much as 2- or 3-fold, likely because of altered absorption.⁵⁸ In scenarios where PHT cannot be avoided and accurate levels are needed to guide dosing in people with low protein states, obtaining free PHT levels is the best approach; however, depending on the laboratory, free PHT levels may not be routinely available and may take days to weeks to be completed.⁶⁷

Phenobarbital

PHB is similarly avoided, mostly because of its considerable neurotoxic effects; in addition, similar to CBZ and PHT, it is associated with osteoporosis and numerous DDIs. PHB should be switched to another ASM when possible, although PHB continues to be widely used in older adults in developing countries, where other ASMs may not be available.⁶⁹ In such populations, the cognitive effects of PHB can be lessened by reducing polytherapy with other drugs that may also impair cognition.

Precautions are recommended for using PHB in older adults and with other drugs extending PR interval. Cases of severe third-degree atrioventricular block have been reported only in postmarketing case reports when used at high doses and remain rare.

Valproic Acid

VPA is a broad-spectrum ASM that has been approved for both focal- and generalized-onset epilepsies. VPA is also used in the treatment of bipolar disorder, schizoaffective disorder, and social phobias, and for the prophylaxis and treatment of migraine headaches, and it has been shown to be beneficial in the management of agitation in dementia and refractory anxiety disorders in older adults.⁷⁰ VPA is available in oral delayed-release tablets, immediate-release capsules, oral solution, and an injectable solution. VPA can be titrated rapidly in emergency scenarios, such as status epilepticus. However, its pharmacokinetic properties and side-effect profile limit its use in older adults. VPA is highly protein bound and is a strong inhibitor of the liver microsomal enzymes and some phase 2 metabolizing enzymes, hence its use is associated with considerable clinically relevant interactions with other ASMs and commonly prescribed medications. VPA is generally avoided in older adults because of its side-effect profile. Weight gain and hair loss are common AEs associated with its use. Other substantial AEs observed with use of VPA in older adults include drug-induced parkinsonism, osteoporosis, tremor, and thrombocytopenia.⁷¹

Special Considerations

Cerebrovascular Disease, Cardiovascular Disease, and Cardiac Arrythmias

Nearly half of new-onset epilepsy cases in older adults are caused by stroke, and cerebrovascular disease is a common comorbidity. Cardiovascular disease, cardiac arrythmias, and conduction disorders are also frequent comorbidities of concern in older adults with epilepsy.⁷² Polytherapy for these disorders is common, and ASMs, especially first-generation enzyme-inducing or -inhibiting ASMs, may cause DDIs. Notable DDIs that may occur with enzyme-inducing or -inhibiting ASMs are with antithrombotics (warfarin and all direct oral anticoagulants); antihypertensives, including nondihydropyridine calcium channel blockers (nifedipine and nimodipine), dihydropyridine calcium channel blockers (diltiazem and verapamil), beta blockers, and diuretics; antiarrhythmics (amiodarone and digoxin); and statins. Some, but not all, second- and third-generation ASMs have fewer DDIs. For example, perampanel is a potent CYP3A4 inducer and has numerous DDIs, similar to first-generation ASMs. LEV and LTG are preferred ASMs with minimal DDIs, but DDIs exist; notably, LEV reduces the efficacy of direct oral anticoagulants through P-glycoprotein induction, and LTG may interact with the antiarrhythmic dofetilide, lowering its levels.⁷³

Beyond DDIs, ASMs have also been associated with increasing levels of low-density lipoprotein and accelerating atherosclerosis. Although most associated with enzyme-inducing ASMs, oxcarbazepine, LEV, and topiramate have also been implicated.⁷⁴ People with or at risk for atherosclerosis who are taking ASMs should be monitored for worsening, and lipid-lowering and statin therapy should be optimized appropriately. Some ASMs may have effects on atrioventricular conduction, which may need monitoring; LCM and LTG have already been discussed, but other sodium channel inhibitors such as PHT or CBZ may also cause problems, and providers should be cautious when using them in older adults with cardiac arrythmias.

Alzheimer Disease

Up to 15% of epilepsy cases in older adults are attributable to neurodegenerative disease, including Alzheimer disease (AD).^1,72 ASM use has not been well studied in people with epilepsy and AD. Only 1 RCT has evaluated ASMs in AD, comparing LEV, LTG, and PHB in 95 participants for 1 year. Whereas 60% to 70% of participants in each arm had >50% reduction in seizure frequency, only 25% to 30% of participants in each arm achieved seizure freedom, suggesting that seizures associated with AD may be difficult to control.¹⁹ People taking LEV experienced the fewest AEs (17%) compared with LTG (28%) and PHB (43%), with reports of somnolence, dizziness, headache, and asthenia accounting for most AEs. People taking LEV also showed improvements in Mini-Mental State Examination and Alzheimer’s Disease Assessment Scale–cognitive subscale scores after 12 months compared with people taking LTG and PHB, who had worsened scores. The effect of short-term, low-dose LEV 125 mg twice daily for 4 weeks was also recently evaluated in a small number of participants (n=34) with AD with and without epileptiform activity; the study found that LEV was well tolerated and improved performance on spatial memory and executive function tasks.²² LEV does not interact with AD therapies. Although LEV may worsen agitation, apathy, and depression, as discussed previously, LEV may be a good option for people with AD.