This activity is supported by an educational grant from GlaxoSmithKline.

Target Audience:
This program is intended for family practitioners and gerontologists.

Credits:
1 AMA PRA Category 1 Credit™

Learning Objectives:
Upon completion of this educational activity, participants should be able to:
• Characterize the unique aspects of seizure presentations in the older adult, and differentiate the presentation of seizures from other conditions.
• List the aspects of seizure diagnosis and treatment that patients should be aware of in order to make informed decisions about therapeutic choices.
• Discuss ways in which physicians can assist older patients diagnosed with epilepsy to maintain independence.
• Address the stigma of epilepsy, quality-of-life issues, depression, social issues, driving, and resources available in the community.
• Discuss adverse effects and drug interactions when treating epilepsy in older adults.
• Utilize the knowledge gained to enhance physicians’ provision of care to patients.
• Describe the epidemiology, clinical course,work-up, and age-related pharmacokinetic challenges in older adults with epilepsy.
• Review advantages and disadvantages of antiepileptic drugs (AEDs) in older adults, and summarize the results of safety/efficacy class I studies involving use of AEDs to treat seizures in older adults.

Release Date:
June 15, 2007

Expiration Date:
June 14, 2008

Method of Participation:
Read the journal article, complete the post-activity test and evaluation form, and return both to:
North American Center for CME
83 General Warren Blvd., #100
Malvern, PA 19355
Fax: (610) 560-0501

Successful Completion:
Successful completion entails participants obtaining a score of at least 70% on the post-test.A certificate of completion will be mailed to the address listed on your post-test/evaluation form within 6 weeks of receipt of the documents.

Accreditation:
MD/DO:This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the North American Center for Continuing Medical Education and The Epilepsy Foundation. The North American Center for Continuing Medical Education is accredited by the ACCME to provide continuing medical education for physicians and takes responsibility for the content, quality and scientific integrity of this CME activity. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s) ™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.

Faculty Disclosures:
All those with control over the content of continuing education programs sponsored by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants.

Dr. Sirven has disclosed that he has received research support from NeuroPace, Inc. and UCB Pharma.

Dr. McAuley has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of his article.

Dr. Uthman has disclosed that he has received grant/research support is a consultant and member of the speakers’ bureau for Cyberonics, Inc., Pfizer Inc, Abbott Laboratories, OrthoMcNeil, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, and UCB. He is a scientific advisor for the Epilepsy Foundation. He is an employee/officer or member of the board of the Epilepsy Foundation, University of Florida College of Medicine, and
Department of Veterans Affairs.

Dr. Bishop has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of his article.

Commercial Supporter:
This activity is supported by an educational grant from GlaxoSmithKline.

Conflict of Interest Resolution/Content Validation:
In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the NACCME Advisory Board in May 2007 for clinical content validity, to ensure that the activity’s materials are fair, balanced and free of bias toward the commercial supporter(s) of the activity, and that activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community.

Sponsor:
This activity is sponsored by the North American Center for Continuing Medical Education.

Geriatric Epilepsy: Challenge of Diagnosis
Joseph I. Sirven, MD

Epilepsy affects 1.5 to 3 million people in the United States annually.1-4 Epilepsy is often mistakenly perceived as a disorder of childhood, but in reality, seizures are most prevalent in individuals over the age of 60.5-11 The prevalence of epilepsy in patients age 65 years or older is twice that in young adults and continues to increase with age.1-11 One of the problems associated with epilepsy in older adults is that it is often misdiagnosed. This misdiagnosis often leads to inappropriate treatment, which may contribute to the morbidity of the condition. The goals of seizure treatment in older adults are the same as younger adults, which is to preserve quality of life, minimizing injury and adverse effects related to seizures themselves. Older adults often have unique challenges associated with seizure management. There is a higher incidence of adverse effects from medications, drug interactions, and altered pharmacokinetics, as well as a narrowed therapeutic window for various antiseizure drugs, a particular area of concern.12-18 Unfortunately, there is also a dearth of evidence-based data regarding the use of antiepileptic drugs in this population. Because of this lack of information, management of the older patient with epilepsy often is based on information extrapolated from younger individuals without considerations for unique problems and issues associated with a geriatric population.

Seizures occur frequently in older adults because they are often secondary to conditions more common in patients over the age of 60.These conditions include cerebrovascular disease, cerebral hemorrhage, brain neoplasms, and neurodegenerative diseases such as Alzheimer’s disease.4,9,11-20 Seizures are often divided into two distinct categories based on the International League Against Epilepsy classification: partial or generalized.21 Partial seizures suggest an underlying lesion from which the electrical abnormality arises, whereas generalized seizures imply bilateral hemisphere involvement at the onset of the event. Seizures of partial onset are much more common in older adults and are most prevalent.21

An obstacle to the treatment of epilepsy in older adults is misdiagnosis. In a Veterans Administration study of newonset epilepsy in elderly patients, seizure disorders were not seriously considered as a diagnosis at first evaluation in 25% of the cases.22 Another study of protracted, nonconvulsive status epilepticus in older adults found that there was a significant delay in diagnosis because the presentation often mimicked that of delirium.23 Moreover, patients were assumed to have a condition associated with either metabolic derangement or a neurodegenerative condition.This often led to a serious delay in diagnosis.23

Seizures are commonly misdiagnosed as a myriad of conditions including syncope, blackout, altered mental status, or dementia.11,22-24 While it is relatively easy to recognize a generalized tonic-clonic seizure, older adults are much more likely to experience partial seizures with clinical manifestations unique from those seen in younger patients. One suggested reason is that the foci of abnormality for seizures in older adults often involves the frontal and parietal lobes as opposed to the more commonly ascribed area in younger adults, which is the temporal lobe.9,20,22 Because patients with epilepsy arising from the temporal lobe often have experiences such as déjà vu and other psychic symptoms associated with temporal lobe epilepsy, it is often assumed that all patients with epilepsy present in the same manner. However, because older adults have epilepsy emanating from a different lobe, seizures may present with nondescript symptoms such as dizziness, posturing, paresthesias, and other symptoms related to frontal and parietal lobe function.9,20,22 Further confusion arises because of the increased presence of multiple comorbidities, polypharmacy, and, in some instances, difficulty obtaining a history due to underlying cognitive impairment.2,7,9 The postictal period, which is the time period occurring immediately after a seizure, can last for days in older adults, mimicking a delirium or cerebrovascular event, and further contributing to the difficulty in diagnosis.

Correctly diagnosing epilepsy requires a detailed and accurate history. Patients are often unaware of what has occurred. Therefore, obtaining an eyewitness account is invaluable. Syncope, transient ischemic attacks, transient global amnesia, and vertigo are common conditions at this age that can present similarly to seizures. Carefully detailed questions about the spells in question and epilepsy risk factors, including minor or major head trauma and concomitant medications, must be asked.

Seizures can be distinguished from its mimickers based on a number of clinical, historical, and electroencephalogram (EEG) findings. Seizures often have a warning, termed an aura, that can precede their onset. Although not always present, when it does occur, it is suggestive of partial seizures. The average duration of a seizure is approximately 1-2 minutes, and they are not precipitated by changes in posture.1-5 Incontinence, although often associated with seizures, does not necessarily have to occur. There are increases in heart rate associated with seizures. The postictal period can be associated with confusion and/or lethargy.25,26 The EEG during a seizure is the gold standard for diagnosis and will show an evolving epileptiform discharge during the event.

In contrast, syncopal spells are much briefer in duration. These events last from seconds to a maximum of 1 minute. Sometimes, there is a preceding feeling of faintness or “lightheadedness.” Changes in posture are often associated with the onset of these events. During syncope, the patient may lose tone. Rarely, tonic-clonic movements are seen. When brief clonic jerks occur, the distinction between syncope and seizure is difficult. Incontinence can also occur with syncope and contribute to misdiagnosis. Heart rate may be decreased or irregular. After syncopal events, most patients are alert and are not confused or sleeping.The EEG during syncope shows diffuse slowing, in contrast to the diagnostic findings of the EEG during a seizure. For a more detailed discussion regarding differentiating a seizure from its mimickers, the reader is referred to the suggested reading list and resources at the end of this section.

References
1. Annegers JF, Hauser WA, Lee JR, et al. Incidence of acute symptomatic seizures in Rochester, Minnesota 1935-1984. Epilepsia 1995;36:327-333.
2. Hauser WA,Rich SS, Lee JR, et al. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998;338:429-434.
3. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1993;34:453-468.
4. Hauser WA. Epidemiology of seizures and epilepsy in the elderly. In: Rowan AJ, Ramsay RE, eds. Seizures and Epilepsy. Boston, MA: Butterworth-Heinemann; 1997:7-18.
5. Hauser WA. Seizure disorders: The changes with age. Epilepsia 1992; 33(Suppl 4): S6-S14.
6. Hopkins A, Garman A, Clarke C.The first seizure in adult life.Value of clinical features,
electroencephalography, and computerized tomographic scanning in prediction of seizure recurrence. Lancet 1988;1:721-726.
7. Loiseau J, Loiseau P, Duche B, et. al. A survey of epileptic disorders in southwest France: Seizures in elderly patients. Ann Neurol 1990;27:233-237.
8. Luhdorf K, Jensen LK, Plesner AM. Epilepsy in the elderly: Incidence, social function, and disability. Epilepsia 1986;27:135-141.
9. Rowan AJ. Seizure Presentation in the Elderly. In: Rowan AJ, Ramsay RE, eds. Seizures and Epilepsy in the Elderly. Boston, MA: Butterworth-Heinemann; 1997:239-307.
10. Sanders JWA, Hart YM, Johnson AL, et al. Natural general practice study of epilepsy: Newly diagnosed epileptic seizures in general population. Lancet 1990;336:1267-1270.
11. Tallis R, Hall G, Craig I, Dean A. How common are epileptic seizures in old age? Age Ageing 1991;20:442-448.
12. Cloyd JC, Lackner TE, Leppik IE. Antiepileptics in the elderly. Pharmacoepidemiology and pharmacokinetics. Arch Fam Med 1994;3:589-598. 13. Ettinger AB, Shinnar S. New-onset seizures in an elderly hospitalized population. Neurology 1993;43(3 Pt 1):489-492.
14. Garrard J, Cloyd J, Gross C, et al. Factors associated with antiepileptic drug use among elderly nursing home residents. J Gerontol A Biol Sci Med Sci 2000;55:M384-M392.
15. Gurwitz JH, Field TS,Avorn J, et al. Incidence and preventability of adverse drug events in nursing homes. Am J Med 2000;109:87-94.
16. Lackner TE, Cloyd JC, Thomas LW, Leppik IE. Antiepileptic drug use in nursing home residents: Effect of age, gender, and comedication on patterns of use. Epilepsia 1998;39:1083-1087.
17. Ramsay RE, Rowan AJ, Pryor FM. Special considerations in treating the elderly patient with epilepsy. Neurology 2004; 62(5 Suppl 2):S24-S29.
18. Tallis R. Treatment of epilepsy in the elderly patient. In: Shorvon S, Dreifuss D, Fish D,Thomas D, eds. The Treatment of Epilepsy. London: Blackwell Science Ltd.; 1996:227-237.
19. Giroud M, Gras P, Fayolle H, et al. Early seizures after acute stroke:A study of 1640 cases. Epilepsia 1994;35(5):959-964.
20. Loiseau P. Pathologic processes in the elderly and their association with seizures. In: Rowan AJ, Ramsey RE, eds. Seizures and Epilepsy in the Elderly. Boston, MA: Butterworth-Heinemann; 1997:63-68.
21. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47:1094-1120.
22. Rowan AJ, Ramsay RE, Collins JF, et al;VA Cooperative Study 428 Group. New onset geriatric epilepsy. A randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868-1873.
23. Sheth RD, Drazkowski JF, Sirven JI, et al. Protracted ictal confusion in elderly patients. Arch Neurol 2006;63(4):529-532.
24. Tinuper P. The altered presentation of seizures in the elderly. In: Rowan AJ, Ramsey RE, eds. Seizures and Epilepsy in the Elderly. Boston, MA: Butterworth-Heinemann; 1997:123-130.
25. Silverman AJ, Busse EW, Barnes RH. Studies in the process of aging: Electroencephalographic findings in 400 elderly subjects. Electroencephalogr Clin Neurophysiol 1955;7:67-77.
26. Roubicek J. The electroencephalogram in the middle aged and the elderly. J Am Geriatr Soc 1977;25:145-152.

Resources
American Epilepsy Society: www.aesnet.org

Epilepsy Foundation: www.epilepsyfoundation.org

Suggested Reading
Rowan AJ, Ramsay RE, eds. Seizures and Epilepsy in the Elderly. Boston, MA: Butterworth-Heinemann; 1997

Primary Care Physicians and Epilepsy
James W. McAuley, RPh, PhD

Epilepsy affects 1-2% of the U.S. population. It has been reported that a majority (> 80%) of patients with epilepsy are seen by primary care physicians.1 There has been and continues to be tremendous growth in the knowledge on both the disease and its treatment, thus necessitating continued education for all involved with the care of patients with epilepsy. For the epilepsy specialist, most of the issues relating to diagnosis and treatment are well known because of the large number of patients seen routinely. This is not the case in a vast majority of primary care practices, given the low incidence of epilepsy. The comfort level in diagnosing and managing patients with epilepsy may be lower than in more frequently seen conditions in a primary care physician’s practice.2 In an attempt to aid this need, an algorithm for diagnosing3 and treating4 adults with epilepsy in a primary care setting was developed as a tool for busy physicians.

Although no published studies specifically examine the primary care physician’s role as related to elderly patients with epilepsy, a small number of published works address the issue of general practitioners (GPs) and epilepsy care. In their 1998 publication, Chappell and Smithson5 describe how they queried patients on their views about care received from GPs. Responses from the 178 patients indicated that GP care is reactive, rather than proactive. And though patients are satisfied overall with their GP services, they would value more information and time for discussion. In an attempt to better understand the educational needs of GPs in relation to the care of the patient with epilepsy, these same authors surveyed GPs on what they want to learn and how.6 Based on responses from 124 GPs, they desire education on drug therapy, lifestyle advice, nondrug therapies, and diagnostic issues.

Moore and colleagues7 reported findings on their investigation into primary care physicians’ behavior with respect to referral patterns, antiepileptic drug initiation, and level of comfort in managing patients with seizures. In a cross-sectional, descriptive study, primary care physicians who interacted regularly with patients with epilepsy were asked to respond to a survey. Five-hundred and four physicians throughout the state of Ohio responded.While a majority (n = 382) referred more than half of these patients to neurologists, a minority of physicians (n = 122) referred less than half of their patients. Drug initiation, for the most part, was not done by the primary care physician. Overall, most patients were referred, but a minority of physicians felt comfortable in managing these patients without referral to a neurologist.

In a more recent paper, non-neurologists (family practice physicians and internal medicine practitioners) have more restrictive beliefs as compared to neurologists when it comes to driving issues for patients with epilepsy.8 And to no one’s surprise, this was identified as an important topic for quality of life in older patients with epilepsy.9

References
1. Smith MC, Buelow JM. Epilepsy. Dis Mon 1996;42:729-827.
2. Matchar DB, Rosenberg JH, Carter S. Commentary: A new era in epilepsy care.
Guidelines address first steps in diagnosis and treatment. Postgrad Med 2005;118:18-21.
3. Trost LF 3rd,Wender RC, Suter CC, et al; National Epilepsy Management Panel. Management of epilepsy in adults. Diagnosis guidelines. Postgrad Med 2005;118:22-26.
4. Trost LF 3rd,Wender RC, Suter CC, et al; National Epilepsy Management Panel. Management of epilepsy in adults. Treatment guidelines. Postgrad Med 2005;118:29-33.
5. Chappell B, Smithson WH. Patient views on primary care services for epilepsy and areas where additional professional knowledge would be welcome. Seizure 1998;7:447-457.
6. Chappell B, Smithson H. Meeting the educational needs of general practitioners for epilepsy. Seizure 1999;8:157-162.
7. Moore JL, McAuley JW, Mott D, et al. Referral characteristics of primary care physicians for seizure patients. Epilepsia 2000;41:744-748.
8. Vogtle LK, Martin R, Russell Foushee H, Edward Faught R. A comparison of physicians' attitudes and beliefs regarding driving for persons with epilepsy. Epilepsy Behav 2007;10:55-62. Epub 2006 Oct 18.
9. Martin R,Vogtle L, Gilliam F, Faught E.What are the concerns of older adults living with epilepsy? Epilepsy Behav 2005;7:297-300.

Pharmacotherapy: Agents, Efficacy, Clinical Trials, and Which Drug to Choose Basim M. Uthman, MD

“For the first time in the history of humanity, the number of people on the planet aged 60 or over will soon surpass those under 5.”1

Age-related comorbid illnesses and pharmacokinetic changes like slower drug metabolism and reduced renal clearance imply special considerations in treating epilepsy in the elderly.2,3 Serum creatinine levels may no longer correlate with renal function since creatinine production decreases at nearly the same rate as renal clearance of creatinine.4 Dose adjustments are necessary in older patients, as they may respond to smaller doses and experience side effects at lower doses.2

Comorbid illnesses indicate more concomitant medications and chances for drug interactions (as discussed by Dr. McAuley). Drug interactions can be related to hepatic enzyme induction of other drugs, autoinduction, hepatic enzyme inhibition, absorption, and protein receptor displacement. Elderly patients may have decreased serum proteins and higher drug-free fraction that could lead to toxicity, even at “therapeutic” serum levels.5 Most established antiepileptic drugs (AEDs) are highly protein-bound: phenytoin is 90%; valproate is 90% and 75% (at higher and lower concentrations, respectively); and carbamazepine is 75%. Of the new AEDs, tiagabine is 96% protein-bound.

A study of the most commonly used AEDs in a large nursing home population (n = 21,551) found that 12% (2582) of the residents were on AEDs for treatment of seizure and other disorders. Of these, 52% were on phenytoin and 38% were on carbamazepine, phenobarbital, or valproate.6 Of the co-medications taken by nursing home residents in another study, those having potential interactions with AEDs included antidepressants (18.9%), antipsychotics (12.7%), benzodiazepines (22.4%), thyroid supplements (14.0%), antacids (8.0%), calcium channel blockers (6.9%), warfarin (5.9%), and cimetidine (2.5%).7 The combination of warfarin and either carbamazepine or phenytoin (both are hepatic enzyme inducers) is most challenging, due to the complexity of the pharmacokinetics of these drugs and the potential for injury and toxicity when one is added or withdrawn.
Most established AEDs (carbamazepine, phenobarbital, phenytoin, primidone, and valproate, but not ethosuximide) are FDA-approved for the treatment of partial seizures with or without secondary generalization in monotherapy and combination therapy. The efficacy of all newer AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide) as add-on therapies in the same condition has been proven in prospective, randomized, controlled trials in adult patients of all ages with epilepsy. Oxcarbazepine and topiramate have been approved as initial monotherapy and lamotrigine as conversion to monotherapy in the treatment of seizures of partial onset with and without secondary generalization (according to the Physicians’ Desk Reference). Although felbamate has been approved for add-on and monotherapy treatments, its use is limited due to serious adverse effects on the liver and hematopoietic system.

There is no clear superiority of one AED over the other where efficacy in treating seizures is concerned. Other factors important in the choice of a particular AED include cost, adverse event profile, potential for drug interactions, ease of use and titration, need for monitoring serum AED levels, availability of parenteral formulations, history of previous allergic reactions, and comorbid conditions. Most side effects are undesirable, but some may be beneficial for some patients. Some side effects are considered desirable by some patients but not by others. Effects on mood and weight (increase or decrease) are examples of side effects that can be both desirable and undesirable.

There is no one drug that fits all needs, and weighing all these factors together usually determines the most suitable choice AED for a particular patient. Knowledge of salient features and adverse events of available AEDs prepares the health provider to help patients make an informed decision regarding the addition of an AED to their usually long list of medications.

Although there are numerous AED monotherapy trials in adults of all ages,8,9 there have been, thus far, only three prospective, randomized, controlled clinical AED monotherapy trials performed specifically in the elderly population. Two have been published and the third recently completed. Other reports of unblinded or uncontrolled studies are included in the following summary to shed some light on clinical experience with new AEDs in the elderly.

Lamotrigine vs Carbamazepine in the Elderly10
This was a prospective multicenter, double-blind, randomized, monotherapy trial comparing lamotrigine and carbamazepine in 150 elderly patients (mean age = 77) with newly diagnosed epilepsy.The primary endpoints were the patient’s continuation of treatment and remaining seizure-free during the last 16 weeks of treatment. Although this study did not prove that lamotrigine was more efficacious than carbamazepine, it showed that: (1) more patients continued on treatment with lamotrigine than carbamazepine for the duration of the study; (2) a carbamazepine-treated patient was more than twice as likely to discontinue medication as one taking lamotrigine (2.4 hazard ratio for withdrawal); and (3) lamotrigine is an acceptable choice as initial treatment for
elderly patients with newly diagnosed epilepsy.
VA Cooperative Study #428: Carbamazepine vs Gabapentin vs Lamotrigine in the Treatment of New-Onset Geriatric Epilepsy11
This multicenter, double-blind, randomized, longitudinal study of 593 elderly subjects with new-onset seizures is the largest of its kind. The objective of the study was to determine whether one or both of two new AEDs, gabapentin and lamotrigine, have significantly fewer side effects while providing equal, or better, seizure control than carbamazepine—a traditional choice for treatment of partialonset seizures. At the end of one year, 47.8% of the patients had completed the study. Early terminations were due to a variety of reasons: side effects (19.4%); voluntary withdrawal, often due to transportation problems (10.0%); death from a variety of causes (7.2%); uncontrolled seizures (3.3%); lost to follow-up (2.3%); noncompliance (1.7%); and other (3.9%). The carbamazepine group had significantly fewer completers (36.6%) than either the gabapentin (49.2%) or lamotrigine (57.9%) groups.There was no significant difference in completion between the gabapentin or lamotriginetreated groups. The study showed that: (1) 12-month retention was higher for both the gabapentin and lamotrigine groups than for the carbamazepine group; (2) adverse effects over 12 months were greatest for carbamazepine and least for gabapentin; and (3) there was little difference among the three groups with respect to seizure control.

Topiramate Monotherapy in New-Onset Seizures in the Elderly12
In a 24-week, double-blind, randomized, multicenter study, patients age 60 years or older with a confirmed diagnosis of partial-onset epilepsy were randomized to either topiramate 50 mg daily (n = 38) or topiramate 200 mg daily (n = 39) as add-on or monotherapy. The final analysis has not been published, but interim data presentations suggested effectiveness starting at lower doses of topiramate.

Other AED Monotherapy Reports in the Elderly
Four investigations, while relevant to AED use in the elderly, were not prospective, double-blind, placebo-controlled studies. The reader is referred to references 13-16 for a more detailed discussion of these observational studies.

Summary
Epilepsy in the elderly is more prevalent than commonly believed.With a few exceptions, selection of AED therapy for older patients has been extrapolated from the results of trials in young adults. Although open-label, uncontrolled trials do not prove efficacy, they help the clinician learn about the tolerability of AEDs and practical suggestions for their use. Double-blind, prospective comparative AED trials in the elderly patient with epilepsy have demonstrated that the newer AEDs gabapentin or lamotrigine are better tolerated than the standard AED carbamazepine, and there is less likelihood of an older patient to stop taking gabapentin or lamotrigine due to intolerable adverse effects or lack of efficacy.

A study comparing the effectiveness of levetiracetam to carbamazepine in older patients with epilepsy is currently underway. A prospective study comparing the effectiveness of all available AEDs in older patients (or any age group for that matter) is time and labor-intensive, as well as statistically prohibitive. Each patient should be treated individually. Affordability of an AED is a must since there is no sense in prescribing an AED that the patient does not have access to.

The first given responsibility of health providers is to do no harm. In patients with liver disease, AEDs that are metabolized in the liver may be avoided or their doses adjusted at the least. Patients with renal disease may need significantly smaller doses to maintain therapeutic effect. AEDs associated with renal stones may not be choice drugs for patients with personal or family history of renal stones. AEDs that may accelerate osteoporosis should especially be avoided in frail older patients. Patients taking sodium-losing drugs may have clinically significant hyponatremia should AEDs associated with hyponatremia be added. AEDs associated with tremor may significantly impair the quality of life of patients with preexisting tremor.

Patients with known allergies to certain drugs should not be exposed to AEDs known to have cross-reactivity with those drugs. AEDs associated with agitation and irritability should be used carefully in patients with prior history of hostility or impulse dyscontrol. To minimize pharmacokinetic drug interactions, patients may benefit better from AEDs that are not metabolized in the liver or highly protein-bound. AEDs associated with weight gain or weight loss should be regarded with caution in obese and slim patients, respectively. On the other hand, patients with epilepsy and problems related to headache, insomnia, mania, depression, overweight, underweight, or neuropathic pain may welcome an AED with antimigraine, hypnotic, antimanic, antidepressant, weight loss, weight gain, or analgesic properties, respectively.

Finally, as older patients may be more sensitive to AEDs where intolerable adverse effects may occur at lower doses and efficacy at lower serum levels compared to younger adults, it behooves health providers to start AED doses low and titrate slow. ¦

References
1. The Week; April 16, 2004.
2. Sabers A, Gram L. Newer anticonvulsants: Comparative review of drug interactions
and adverse effects. Drugs 2000;60:23-33.
3. Rowe JW, Andres R,Tobin JD, et al. The effect of age on creatinine clearance in men: A cross-sectional and longitudinal study. J Gerontol 1976;31:155-163.
4. Lindeman RD,Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33:278-285.
5. Scheuer ML. Drug treatment in the elderly. In: Engel J Jr, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia, PA: Lippincott Raven; 1977:1211-1219.
6. Garrard J, Cloyd J, Gross C, et al. Factors associated with antiepileptic drug use among elderly nursing home residents. J Gerontol A Biol Sci Med Sci 2000;55:M384-M392.
7. Lackner TE, Cloyd JC, Thomas LW, Leppik IE. Antiepileptic drug use in nursing home residents: Effects of age, gender, and comedication on patterns of use. Epilepsia 1998;39:1083-1087.
8. Kwan P, Brodie MJ. Clinical trials of antiepileptic medications in newly diagnosed
patients with epilepsy. Neurology 2003;60(11 Suppl 4):S2-S12.
9. Beydoun A, Kutluay E. Conversion to monotherapy: Clinical trials in patients with
refractory partial seizures. Neurology 2003; 60 (11 Suppl 4):S13-S25.
10. Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotraine Elderly Study Group. Epilepsy Res 1999;37:81-87.
11. Rowan AJ, Ramsay RE, Collins JF, et al; The VA Cooperative Study 428 Group. New onset geriatric epilepsy: A randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868-1873.
12. Morgenroth L, Pryor FM, Ramsay RE, Hulihan J. Topiramate monotherapy: Interim blinded data from a study in elderly patients. Presented at:The American Epilepsy Society Annual Meeting; December 5-10, 2003; Boston, MA.
13. Kutluay E, McCague K, D’Souza J, Beydoun A. Safety and tolerability of oxcarbazepine in elderly patients with epilepsy. Epilepsy Behav 2003;4:175-180.
14. Werz MA, Lang P, Rienzo T. Levetiracetam therapy for epilepsy: Use and tolerability in the elderly. Presented at:The American Epilepsy Society Annual Meeting; December 5-10, 2003; Boston, MA.
15. Ferrendelli JA, French J, Leppik I, et al. Use of levetiracetam in a population of patients aged 65 years and older: A subset analysis of the KEEPER trial. Epilepsy Behav 2003;4:702-709.
16. Ramsay RE. Zonisamide: Efficacy and safety stratified by patient age: Charting a course in neurology. Presented at:The American Epilepsy Society Annual Meeting; December 5-10, 2003; Boston, MA.

Adverse Effects and Drug Interactions Relating to Epilepsy Treatment in Older
Adults
James W. McAuley, RPh, PhD

Adverse Effects
Amain factor in antiepileptic drug (AED) selection is tolerability. In general, elderly patients not only show response at lower doses and concentrations, but also toxicity when compared to younger patients. One reason for the latter is because as patients age, there is generally a decline in organ function that is responsible for clearing drugs from the body (kidneys and liver). The pharmacokinetics of most AEDs have been studied in the elderly, showing a decrease in clearance as compared to younger patients.1 The Table describes selected AED properties as they relate to adverse effects and drug interactions
in elderly patients with epilepsy.

One way to gather clinically relevant data on adverse events seen with AEDs is to examine results from head-tohead studies.While rare in patients with epilepsy, even fewer studies exist that focus solely on elderly patients.Two studies in particular are important when discussing elderly persons with epilepsy. Brodie and colleagues2 published the first direct comparison trial in elderly patients with epilepsy.This trial was discussed in Dr. Uthmans’s article.

In a more recently published, randomized, parallel study, gabapentin (1500 mg/day), lamotrigine (150 mg/day), and carbamazepine (600 mg/day) were compared for efficacy and tolerability in 593 patients over age 55 (mean age, 72 yr).3 Although the efficacy was similar in all three groups, study termination for adverse events was statistically different. Lamotrigine had the lowest termination rate for adverse events (12.1%), followed by gabapentin (21.6%) and carbamazepine (31%) (P = 0.001). Additionally, the authors described systemic and neurologic toxicities that were reported at least once by patients during the 12-month study. Specific systemic toxicities reported by > 10%, followed by AED with highest rate in parentheses, included gastrointestinal problems (lamotrigine), weight gain (gabapentin), weight loss (lamotrigine), water retention (gabapentin), and hyponatremia (carbamazepine). Neurologic toxicities reported by > 10% of patients included nystagmus (gabapentin), dysarthria (gabapentin), gait problems (gabapentin and carbamazepine), tremor (lamotrigine), sedation (carbamazepine), change in mood (carbamazepine), cognitive disturbances (carbamazepine), dizziness (carbamazepine), and headaches (lamotrigine). The authors concluded that “lamotrigine and gabapentin should be considered as initial therapy for older patients with newly-diagnosed seizures.”3

Though not a report on an individual clinical study, Giorgi and colleagues4 published the pooled data from 13 lamotrigine clinical trials in respect to this AEDs’ tolerability in elderly patients with epilepsy. This data from the manufacturer’s global epilepsy database on clinical trials included 208 elderly (> 65 years old) patients with epilepsy. Not surprising, because 102 of the 146 lamotrigine patients (72%) were from the Brodie trial mentioned above,2 this analysis revealed the overall incidence of drug-related adverse events was the lowest for lamotrigine (49%) when compared to carbamazepine (72%) and phenytoin (89%). The authors concluded that lamotrigine “was well tolerated in elderly patients with epilepsy.”4

Though evaluating the impact of AEDs on cognition is an important issue for all patients with epilepsy, it is perhaps an even greater issue in elderly patients. Three recent studies provide more information and show the need for enhanced concern in this patient population. Martin and colleagues5 evaluated cognitive functioning via a number of standardized measures in 25 older adults with epilepsy (> 60 years) and compared them to healthy older adults (n = 27).The patients with epilepsy faired worse than their healthy counterparts, especially if they were receiving AED polytherapy. Piazzini et al6 found very similar results in 40 patients over age 60 as compared to 40 controls. In 2007, Bambara and colleagues7 reported that 20 older adults (> 60 years) with epilepsy
demonstrated deficits in their ability to provide informed consent for medical treatment.These authors expressed concern over their patients’ medical decision-making abilities.

As individuals age, bone health becomes a major concern. Although this is an expressed concern for women,8 as the effect of the loss of estrogen at menopause puts them at an increased risk of bone disease, it is a problem for all patients with epilepsy treated with certain AEDs. Some AEDs have a negative impact on bone.9 Duration of therapy and the number of AEDs are thought to be the strongest predictors of severity of bone abnormalities. Carbamazepine, phenobarbital, and phenytoin are the AEDs most frequently associated with a negative impact on bone. Men and women on long-term therapy with enzyme-inducing AEDs should be counseled on bone health. Less is currently known about the impact of the second-generation AEDs on bone metabolism in patients with epilepsy.

As evidenced from the Veterans Affairs (VA) Cooperative study mentioned above,3 central nervous system (CNS) toxicities such as dizziness, unsteady gait, and ataxia are common adverse effects of AEDs. This brings up the concern for falls in the elderly and all of the morbidity and mortality associated with them, especially if patients have had an AED-induced negative effect on their bones. In an effort to prospectively compare the impact of three AEDs on balance, Fife et al10 have reported their findings on patients with epilepsy over age 50. Three groups of 10 patients each on monotherapy with carbamazepine, gabapentin, or lamotrigine underwent extensive testing in this cross-sectional study. Findings showed that older patients with epilepsy on lamotrigine monotherapy exhibited better scores on select measures of balance as compared to carbamazepine. Though not statistically significant, perhaps due to a small sample size, gabapentin showed a trend to better balance scores than carbamazepine.

In addition to gathering data from clinical trials, it is imperative to talk with patients about their concerns. A recent study describes that adverse effects are very much on the minds of older patients with epilepsy.11 Martin and colleagues11 polled 33 community-dwelling adults with epilepsy about their concerns. In response to being asked to simply list their concerns on a piece of paper, the two most frequent concerns they identified were driving/transportation and medication side effects (64% apiece).When compared to younger patients in earlier studies, medication side effects appear to be more of a concern for older patients.

Drug Interactions
The number of concomitant medications taken by older patients with epilepsy is a concern for not only adverse effects, but also for drug interactions. In the recent study by Rowan and colleagues,3 their patients were on an average of seven concomitant medications.This is not uncommon, and thus it is important to be knowledgeable on drug interactions within and between AED therapies.

Pharmacokinetic drug interactions can occur in the absorption, distribution, metabolism, and/or the elimination of AEDs.The best characterized of these are metabolic drug interactions involving the liver’s cytochrome P450 (CYP450) system. The main drug metabolizing isozyme is 3A4 (CYP4503A4). Drugs, both AEDs and non-AEDs, which are substrates for this pathway, have the potential for drug-drug interactions.

According to the literature, the most commonly used AEDs in older patients with epilepsy are the older or “firstgeneration” AEDs.12 Of the first-generation AEDs, phenytoin, phenobarbital, and carbamazepine are inducers of the CYP450 system.Valproic acid is not an enzyme inducer, it is an enzyme inhibitor. Of the new or “second-generation” AEDs, felbamate, oxcarbazepine, and topiramate are weak
inducers of CYP4503A4.The inducing properties of topiramate and oxcarbazepine appear to be dose-dependent.13,14 Gabapentin, levetiracetam, lamotrigine, pregabalin, tiagabine, and zonisamide are not enzyme inducers, and thus have a low potential for causing metabolic drug interactions (Table).

As women with epilepsy get older, the issue of menopause becomes an important issue for discussion. Postmenopausal women use hormone replacement therapy. AEDs can interact with oral contraceptives.15 It is possible that AEDs, which induce CYP4503A4 metabolism, could affect the metabolism of the steroid hormones in hormone replacement regimens. Currently, there is little known about drug-drug interactions between AEDs and hormone replacement therapy.

More recent attention has also turned to the concern of complementary/alternative medicine (CAM) use in patients with epilepsy.16 In a cross-sectional study asking patients about their use of CAM, nearly one-third of the respondents were older than age 60. This study and others raises questions about CAM-induced changes in seizure activity, adverse effects, and the potential for drug interactions.17

Drug interactions can occur as a result of a pharmacodynamic or a pharmacokinetic interaction.18 More published literature clearly exists on the latter than the former. It is important to realize that, in general, older persons are more sensitive to medication effects.

References
1. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin Pharmacokinet 2006;45:351-363.
2. Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res 1999;37:81-87.
3. Rowan AJ, Ramsay RE, Collins JF, et al;VA Cooperative Study 428 Group. New onset geriatric epilepsy: A randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868-1873.
4. Giorgi L, Gomez G, O'Neill F, et al. The tolerability of lamotrigine in elderly patients with epilepsy. Drugs Aging 2001;18:621-630.
5. Martin RC, Griffith HR, Faught E, et al. Cognitive functioning in community dwelling older adults with chronic partial epilepsy. Epilepsia 2005;46:298-303.
6. Piazzini A, Canevini MP,Turner K, et al. Elderly people and epilepsy: Cognitive function. Epilepsia 2006;47 Suppl 5:82-84.
7. Bambara JK, Griffith HR, Martin RC, et al. Medical decision-making abilities in older adults with chronic partial epilepsy. Epilepsy Behav 2007;10:63-68.
8. Vazquez B, Gibson P, Kustra R. Epilepsy and women’s health issues: Unmet needs. Survey results from women with epilepsy. Epilepsy Behav 2007;10:163-169.
9. Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: Epidemiology, mechanisms and therapeutic implications. CNS Drugs 2001;15:633-642.
10. Fife TD, Blum D, Fisher RS. Measuring the effects of antiepileptic medications on balance in older people. Epilepsy Res 2006;70:103-109.
11. Martin R,Vogtle L, Gilliam F, Faught E.What are the concerns of older adults living with epilepsy? Epilepsy Behav 2005;7:297-300.
12. Pugh MJ, Foreman PJ, Berlowitz DR. Prescribing antiepileptics for the elderly: Differences between guideline recommendations and clinical practice. Drugs Aging 2006;23:861-875.
13. Doose DR, Wang SS, Padmanabhan M, et al. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia 2003;44:540-549.
14. Patsalos PN, Zakrzewska JM, Elyas AA. Dose dependent enzyme induction by oxcarbazepine? Eur J Clin Pharmacol 1990;39:187-188.
15. McAuley JW, Anderson GD.Treatment of epilepsy in women of reproductive age: Pharmacokinetic considerations. Clin Pharmacokinet 2002;41:559-579.
16. Sirven JI, Drazkowski JF, Zimmerman RS, et al. Complementary/alternative medicine for epilepsy in Arizona. Neurology 2003;61:576-577.
17. Spinella M. Herbal medicines and epilepsy: The potential for benefit and adverse effects. Epilepsy Behav 2001;2:524-532.
18. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61:246-255.

How to Help Older Patients with Epilepsy Stay Independent
Malachy Bishop, PhD, CRC

Among older adults, the ability to stay independent depends on the maintenance of a complex and often fragile system of characteristics and abilities.1 Elements of this system include physical and mental health; social support; financial status; access to transportation, health services, and social services; and the ability to maintain personal routines.1 A disruption in any of these sometimes delicately balanced components can threaten independence. Independence is frequently interpreted to mean the ability to live independently in the community rather than in a residential care facility. In a broader sense, however, it also implies maintaining the ability to make decisions about and retain control over one’s life. Epilepsy has significant implications for both perspectives. The increased prevalence of specific physical, social, and economic problems among older persons with epilepsy, such as reduced mobility due to injury, reduced access to transportation, and social isolation, presents a number of threats to independence. This situation is complicated by the fact that epilepsy often is not the older patient’s only chronic condition2,3; the existence of a comorbid condition puts patients at greater risk for functional decline and loss of independence.3,4

An important concern among older patients is injury from falls, which increases the risk of permanent nursing home placement tenfold.3 Thirty percent of community-living adults over age 65 and 50% of those over age 80 fall each year, with 10% of falls resulting in serious injuries.3 Many older adults who incur fall-related hip fractures do not recover their pre-fracture level of function in ambulation or activities of daily living.5 The risk for falls and skeletal fracture is significantly higher in patients with epilepsy than in the general population.6,7 Although it is commonly assumed that most fractures occur as the result of a seizure, data suggest that less than half are directly related to seizures.7 Other contributing risk factors for falls include older age, female gender, polypharmacy, side effects of antiepilepsy medications (including dizziness or ataxia), and coexisting neurological conditions and deficits.6,7 The high prevalence of osteoporosis among older patients with epilepsy who are using epilepsy medications increases the risk of injury.2,8-10 The risk for falling in elderly women is increased more than twofold for women using epilepsy medications, primarily phenytoin, phenobarbital, or carbamazepine.7

The fear of falling has also been recognized as an important consequence of having experienced a fall. Between 30% and 73% of older persons who have fallen acknowledge a persistent fear of falling.11-14 This fear frequently leads patients to voluntarily restrict their activities, limiting their independence and ability to engage in routines and participate in their community.

Interventions that have been shown or suggested to reduce the risk of falling include treating the underlying medical condition, increasing physical activity, and promoting self-management and medication adherence.3,15 People over age 60 have the lowest rates of physical activity among adults, and rates are especially high for persons age 75 or older.3 Available evidence also suggests that people with epilepsy are only half as active as age- and gender-matched controls, and have generally lower levels of physical fitness.16 Regular comprehensive functional assessments and evaluation for the use of assistive devices are also recommended.

Assistive and rehabilitation technology in the living space can help older individuals with epilepsy maintain their independence and maximize their safety. Such interventions range in sophistication from grab bars or safety rails to monitoring and tracking systems designed to locate an individual who may have wandered away from home during a seizure.17

Showers have proven to be safer than baths in terms of the risk of drowning.18 However, several studies19,20 investigating injuries as a consequence of seizures in individuals with epilepsy have found that a subset of these individuals are at increased risk for burns received while showering. Spitz and colleagues20 reported that showering was the second most common activity associated with a burn. Cooking on a stove is the primary cause of burn injuries. Most shower-related burns are avoidable, as modern water heaters have thermostats that can be set to limit the maximum temperature of the water.20 Another precaution that individuals with epilepsy may consider is installing an anti-scald safety device.21 These devices limit the flow of water to a mere trickle when the temperature reaches a predetermined temperature (eg, 120 degrees F). Other common recommendations for the shower area include grab bars, bathtub rails, shower seats, and the removal of existing glass shower doors.22

References
1. Kelshiker A, Rehman K. Maintaining independence in the over-85s. Update 2006;73(1):83-86.
2. Rowan AJ; Epilepsy Foundation of America. Epilepsy in older adults: Common morbidities influence development, treatment strategies, and expected outcomes. Geriatrics 2005;60(12):30-34.
3. U.S. Department of Health and Human Services. Administration on Aging: Fact Sheet: Evidenced-Based Disease Prevention Program. Available at:
http://www.aoa.gov/press/fact/pdf/fs_EvidencedBased.pdf. Accessed April 9, 2007.
4. Bromfield EB. Epilepsy and the elderly. In: Schachter SC, Schomer DL, eds. The Comprehensive Evaluation and Treatment of Epilepsy.A Practical Guide. San Diego,CA:
Academic Press; 1997:233-254.
5. Magaziner J, Simonsick EM, Kashner TM, et al. Predictors of functional recovery one year following hospital discharge for hip fracture: A prospective study. J Gerontol 1990;45:M101-M107.
6. Mattson RH, Gidal BE. Fractures, epilepsy, and antiepileptic drugs. Epilepsy Behav 2004;5 Suppl 2:S36-S40.
7. Fife TD, Blum D, Fisher RS. Measuring the effects of antiepileptic medications on balance in older people. Epilepsy Res 2006;70:103-109. Epub 2006 May 3.
8. Greenspan SL, Myers ER, Maitland LA, et al.Trochanteric bone mineral density is associated with type of hip fracture in the elderly. J Bone Miner Res 1994;9(12):1889-1894.
9. Cohen A, Lancman M, Mogul H, et al. Strategies to protect bone mass in the older patient with epilepsy. Geriatrics 1997;52(July):70, 75-78, 81.
10. Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms, and therapeutic implications. CNS Drugs 2001;15;633–642.
11. Tinetti ME, Baker DI, McAvay G.A multifactorial intervention to reduce the risk of falling among elderly people living in the community. N Engl J Med 1994;331:821-827.
12. Vellas BJ,Wayne SJ, Romero LJ, et al. Fear of falling and restriction of mobility in elderly fallers. Age Ageing 1997;26:189-193.
13. Tinetti ME,Williams CS. Falls, injuries due to falls, and the risk of admission to a
nursing home. N Engl J Med 1997;337:1279-1284.
14. Sirven JI. Management of epilepsy in older adults. Clinical Geriatrics 2000;8(1): 93.
15. RAND Report: Evidence report and evidence-based recommendations: Falls prevention interventions in the Medicare population. Contract number 500-98-0281.
RAND Corporation Southern California Evidence-Based Practice Center, 2003.
16. Nakken KO, Bjorholt PG, Johannessen SI, et al. Effect of physical training on aerobic
capacity, seizure occurrence, and serum level of antiepileptic drugs in adults with epilepsy. Epilepsia 1990;31:88-94.
17. Schuch JZ. Living safely with seizures: Assistive technology, rehabilitation technology, and resources. Clin Nurs Pract Epilepsy 1998;5(1):13.
18. Ryan CA, Dowling G. Drowning deaths in people with epilepsy. CMAJ 1993;148:781-784.
19. Buck D, Baker GA, Jacoby A, et al. Patients’ experiences of injury as a result of epilepsy. Epilepsia 1997;38(4):439-444.
20. Spitz MC,Towbin JA, Shantz D, Adler LE. Risk factors for burns as a consequence of seizures in persons with epilepsy. Epilepsia 1994;35:764-767.
21. Spitz MC. Injuries and death as a consequence of seizures in people with epilepsy. Epilepsia 1998;39:904-907.
22. Vogtle LK. Assistive technology applications for older persons with epilepsy. Technology Special Interest Section Quarterly 2003; 13(1): 1-3.