Seizure disorder is one of the most common neurological conditions affecting 2% of the population worldwide, and almost 2 million people in the USA alone. The incidence of seizures rises sharply after the age of 60 years, and among all age groups, those over the age of 60 years have the highest incidence of acute symptomatic seizures and epilepsy Citation[1,2]. While many studies have examined the impact of epilepsy in the general population, little attention has been focused on older patients with epilepsy Citation[3]. In this editorial we will consider why we need more studies in order to better understand the differences in clinical pharmacology and treatment approaches for older patients with epilepsy.
First of all, pharmacokinetics and pharmacodynamics of antiepileptic drugs (AEDs) may be altered by advancing age. For example, decreased plasma protein binding, decreased renal drug clearance, decreased hepatic oxidation and longer elimination half-life may occur, all of which influence a patient‘s overall tolerability and susceptibility to AEDs. In addition, older patients are also more likely to be receiving multiple medications for concurrent diseases, thereby increasing the possibility of drug interactions and possibly affecting the effectiveness of the treatment Citation[4]. For example, hepatic enzyme-inducing AEDs (i.e., phenytoin, phenobarbital and carbamazepine) can cause concurrent antihypertensive or cholesterol-lowering agents to be less effective, and interaction with narrow therapeutic index medications, such as warfarin or digoxin, is a significant concern for elderly patients with epilepsy. Conversely, commonly used medications, such as cimetidine and fluoxetine, inhibit the metabolism of carbamazepine, phenytoin and valproate, possibly causing significant drug toxicity Citation[5].
Second, in comparison to younger adults, older individuals tend to be more susceptible to cognitive and cardiac side effects of AEDs Citation[6–8]. The elderly population may already have declining cognitive and memory function, which may make them more susceptible to the cognitive side effects of AEDs. The conventional assumption is that elderly patients experience more exaggerated cognitive side effects of AEDs, but it is not well understood whether older patients experience different types of cognitive side effects than younger adults and, if so, how they would differ. Although many comparative studies have been performed in younger patients Citation[9–11], very few clinical studies compared the cognitive side effects of AEDs in older patients with epilepsy. In a multicenter, double-blind, parallel-group, randomized study involving 150 elderly patients (mean age: 77 years) with newly diagnosed epilepsy, lamotrigine was superior to carbamazepine on the basis of patient completion, ability to minimize seizures, fewer side effects and better patient outcome Citation[12]. However, more studies are needed and it would be useful to ascertain which AEDs may cause less cognitive or memory deficits in older patients with epilepsy.
Third, there are growing concerns for osteoporotic changes and pathologic fractures in the elderly population with epilepsy, which could be caused by AED therapy and associated side effects leading to falls and accidental injury. Ensrud et al. examined the relationship between CNS medications and fractures in nearly 8000 elderly community-dwelling women Citation[13]. The risk of any fall was found to be increased by 175% in women taking AEDs. Another study found that patients taking phenytoin had a three- to four-fold increased risk of any fracture Citation[14]. This is a very concerning finding, particularly considering the fact that phenytoin is the most commonly prescribed AED in the elderly and is used in almost 70% of previously and newly diagnosed patients Citation[15].
Finally, older patients have different etiologies of epilepsy and may present with different diagnostic problems and treatment responses. Cerebrovascular disease is the most commonly identified etiology for epilepsy in the elderly Citation[16], followed by dementia, head injury, tumors and systemic and metabolic diseases. Differences in underlying etiology may warrant not only a different approach to diagnostic evaluation but also different treatment considerations. Ticlopidin is widely used among patients who have cerebrovascular disease; however, it is a known inhibitor of CYP2C19, which can cause phenytoin and carbamazepine toxicity with concomitant administration Citation[17,18].
Thus, the pressing question remains: should we treat elderly seizure patients differently? Absolutely. Since many AEDs commonly prescribed in geriatric patients may cause significant adverse side effects and interactions, it is imperative that we treat elderly patients with AEDs that cause less drug interactions and are better tolerated. Considering their more favorable efficacy, linear kinetics and minimal or no drug interactions, newer AEDs, such as levetiracetam, lamotrigine, gabapentine and lacosamide, would be better tolerated by elderly patients and should eventually replace older AEDs. Newer AEDs also cause less significant bone density loss and may result in less pathologic fractures and mobility issues. In addition, since new onset seizures in the elderly population are mostly due to underlying parenchymal lesions, early treatment even after the first seizure is recommended for prophylaxis. In fact, more than 90% of elderly patients have been demonstrated to have subsequent seizures Citation[16], compared with only 50% in younger patients.
In summary, tolerance, drug interactions and bone health concerns are therapy-limiting factors in older patients with epilepsy, and optimal treatment outcomes for seizure control with minimal or no adverse events is highly dependent upon well-informed AED selection by the treating physician.
Financial & competing interests disclosure
Steve Chung, MD, is a consultant for Medtronics, Inc., GlaxoSmithKline plc. and UCB S.A., is on the speaker‘s bureau of Cyberonics, Inc., GlaxoSmithKline plc., and UCB S.A and receives grant and research support from Schwarz Pharma A.G., GlaxoSmithKline plc., UCB S.A., Valeant, Eisai Inc., Ortho-McNeil and Medtronics, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Additional information
Funding
Bibliography
- Annegers JF , HauserWA, LeeJet al.: Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935–1984.Epilepsia36, 327–333(1995).
- Hauser WA , AnnegersJF, KurlandLT: Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984.Epilepsia34, 453–468(1993).
- Wagner AK , BungayKM, KosinskiMet al.: The health status of adults with epilepsy compared with that of people without chronic conditions.Pharmacotherapy16, 1–9(1996).
- Martin R , MeadorK, TurrentineLet al.: Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults.Epilepsia42, 764–771(2001).
- Grimsley SR , JannMW, CarterJGet al.: Increased carbamazepine plasma concentrations after fluoxetine coadministration.Clin. Pharmacol. Ther.50, 10–15(1991).
- Turnheim K : When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly.Exp. Gerontol.38, 843–853(2003).
- Motamedi GK , MeadorKJ: Antiepileptic drugs and memory.Epilepsy Behavior5, 435–439(2004).
- Ortinski P , MeadorKJ: Cognitive side effects of antiepileptic drugs.Epilepsy Behavior5, 60–65(2004).
- Chung S , WangN, HankN: Comparative retention rates and long-term tolerability of new antiepileptic drugs.Seizure16, 296–304(2007).
- Blum D , MeaderK, BitonVet al.: Cogntive effects of lamotrigine compared with topiramate in patients with epilepsy.Neurology67, 400–406(2006).
- Labiner D , EttingerA, FakhouryTet al.: Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.Epilepsia50(3), 434–442(2009).
- Brodie MJ , OverstallPW, GiorgiL: Multicentre, double-blind, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.Epilepsy Res.37, 81–87(1999).
- Ensrud KE , BlackwellT, MangioneCMet al.: Central nervous system-active medications and risk for falls in older women.J. Am. Geriatr. Soc.50, 1629–1637(2002).
- Bohannon A , HanlonJT, LandermanLRet al.: Association of race and other potential risk factors and nonvertebral fractures in community dwelling elderly women.Am. J. Epidemiol.149, 1002–1009(1999).
- Pugh MV , CramerJ, KnoefelJet al.: Potentially inappropriate antiepileptic drugs for elderly patients with epilepsy.J. Am. Geriatr. Soc.52, 417–422(2003).
- Ramsay RE , RowanAJ, PryorFM: Special considerations in treating the elderly patient with epilepsy.Neurology.62(Suppl. 2), S24–S29 (2004).
- Brown RI , CooperTG: Ticlopidine-carbamazepine interaction in a coronary stent patient.Can. J. Cardiol.13, 853–854(1997).
- Donahue S , FlockhartDA, AbernethyDR: Ticlopidine inhibits phenytoin clearance.Clin. Pharmacol. Ther.66, 563–568(1999).