The Management of Epilepsy in Older Adults, Part 2

In the May 2015 issue of Annals of Long-Term Care, “Ask the Expert” featured the first installment of an interview with Dr. Robert T. Wechsler, MD, PhD, FAAN, a Board-certified epileptologist and neurologist in private practice in Boise, Idaho. Dr. Wechsler serves as Medical Director of the Idaho Comprehensive Epilepsy Center and Board President of the Epilepsy Foundation of Idaho, is an active member of the Epilepsy Studies Consortium, and has been involved as a clinical investigator in a large number of epilepsy clinical trials. He is also co-Editor of the medications section of epilepsy.com. Dr. Wechsler has provided consulting services and has done promotional work for a variety of pharmaceutical companies.

In Part 1 of this series, Dr. Wechsler shared his perspective on the treatment of epileptic seizures in older adults, touching upon the importance of accurately diagnosing the type of epilepsy before determining a treatment approach and of considering the nonpharmacological aspects of controlling seizures. In Part 2, Dr. Wechsler discusses the benefits and limitations of pharmacological and surgical approaches for the treatment of epilepsy, with special consideration of epilepsy in older adults.

ALTC: To control seizures, how do prescribers choose which drug to start in older adults with epilepsy?
When a clinician needs to initiate or change treatment in a patient with epilepsy, the starting point needs to be an understanding of the epilepsy type (eg, focal, primary generalized, and syndromic). A careful history or chart review remains the most useful tool in making this distinction. Details of the seizure—onset, aura, physical manifestation, evolution, duration, and recovery—all can aid in making a correct diagnosis. Diagnostic testing can help to confirm an epilepsy diagnosis but almost never can be used to exclude it. People with epilepsy often will have normal or non-specific findings on imaging studies (ideally MRI) and on EEG. In the evaluation of epilepsy, these tests can have high specificity but have low sensitivity. When the diagnosis is in doubt, one tends to favor the broad-spectrum anti-seizure medications (eg, valproate, lamotrigine, levetiracetam, topiramate, and zonisamide). Benzodiazepines also can cover a broad range of seizure types but are generally not used for long-term treatment, particularly in older adults, and are most often used for rescue in seizure emergencies. Lamotrigine can exacerbate myoclonus in some cases, but not all. Anti-seizure medications that can potentially exacerbate absence seizures and myoclonic seizures (eg, phenytoin, carbamazepine, oxcarbazepine, gabapentin, pregabalin, and tiagabine) and should be avoided in the treatment of primary generalized epilepsies and in cases where the epilepsy type is not known (unless other options have been exhausted). Some of the newest medications approved for focal seizures are of uncertain utility in other seizure types, but several are being investigated.

Once the epilepsy type has been defined, then the next most important considerations in choosing an anti-seizure medication are tolerability, co-morbidities, and drug interactions. These factors are particularly important in older adults. The anti-seizure medications are sometimes divided into first and second generations. Although there have been relatively few head to head trials, and although no single anti-seizure medication has ever proven to be consistently superior to any other, it is generally accepted that the first generation anti-seizure medications (eg, phenobarbital, phenytoin, primidone, carbamazepine, and valproate) tend to be more prone to concerns about tolerability and long-term health consequences. For example, several of these agents can predispose to osteoporosis as well as to dizziness and disturbance of balance, a particularly troubling combination in older adults. Many of these agents also are hepatic enzyme inducers that can affect the metabolism of many other medications. Phenytoin also has non-linear pharmacokinetics and levels can fluctuate and can be inaccurate, particularly in older adults. One of the best studies to compare older to newer agents actually was done in an older VA population and reported that lamotrigine and gabapentin were superior to carbamazepine, but it was not clear whether this was due to better adherence resulting from better tolerability with the newer agents.¹ Several of the newer agents undergo relatively little hepatic metabolism and do not bind significantly to serum protein, making them less prone to drug-drug interactions (eg, levetiracetam, lacosamide, gabapentin, and pregabalin). These may be preferable in older adults taking multiple other medications for other conditions.

Of course all anti-seizure medications can have rare but potentially serious side effects of which the prescriber must be aware. For example, phenytoin can prolong the QT interval on ECG whereas carbamazepine, lamotrigine, pregabalin, and lacosamide can prolong the PR interval. All of these agents should be used with caution in patients with known cardiac conduction abnormalities particularly when such medications are used in combination with each other or in combination with other concurrent medications that have similar side effects. Rashes have been reported with most anti-seizure medications, although incidence is higher with some and rare with others. More rare but serious systemic reactions also have been seen with several anti-seizure medications. These medications should be used with caution in patients who have had previous similar reactions with other agents. Nephrolithiasis has been associated with topiramate and zonisamide in some patients and should be avoided in patients prone to this. A comprehensive listing of anti-seizure medication side effects is beyond the scope of this review. The reader is directed to the medications portion of epilepsy.com or to individual package inserts for more detailed explanations of side effects.

Co-morbidities also are an important consideration, particularly in patients on polypharmacy, where using a single agent for multiple conditions can reduce the total medication burden. For example, patients with epilepsy and comorbid migraine might benefit from topiramate, valproate, or zonisamide; whereas patients with epilepsy and comorbid mood disorders may benefit from valproate, carbamazepine, or lamotrigine but might see a worsening of mood with levetiracetam or perampanel. Patients with epilepsy and comorbid neuropathy might benefit from gabapentin or pregabalin.  As with all medications, the prescriber should know the indications, common uses, common side effects, and rare side effects of the anti-seizure medications they prescribe.

What are the different types of epilepsy surgery?
For the roughly 30% of epilepsy patients who cannot achieve complete seizure freedom with medication, we often rely on combination therapy to minimize seizure activity.  When seizures continue despite these approaches and are disruptive to quality of life, then surgical interventions may be warranted and can be very successful.² Focal cortical resections can be done to remove identified seizure foci in the brain. This type of surgery hinges on identifying the seizure focus through converging lines of evidence from neuroimaging (usually MRI), interictal EEG, ictal EEG recordings of the seizures with concurrent video in an epilepsy monitoring unit, the physical movements during the seizures themselves, and a variety of neurocognitive tests. Age is not an absolute contraindication to this type of surgery and it is sometimes done in older adults with drug-resistant epilepsy. The surgical selection criteria for older adults are the same as for younger adults and for children and are primarily driven by the severity of the epilepsy and the lack of response to anti-seizure medicines.

For those in whom medications have failed and resective surgery is not an option, there are implantable neurostimulators approved for epilepsy. The vagus nerve stimulator (VNS) is most often used and is the least invasive option. The device is implanted below the clavicle, usually on the left side of the chest. The stimulating electrode is placed around the vagus nerve. The device delivers a programable stimulus at a set interval and has been shown to be beneficial in reducing seizure frequency. There have been no head-to-head comparisons of VNS and add-on medications. However, the device has been shown to work in some patients, is generally accepted as being equally useful to medications, and is not associated with the common medication side effects. Some patients can experience cough, voice change, or throat discomfort with VNS but these often can be managed with programming adjustments. The responsive neurostimulator (RNS) also has been approved for epilepsy. This device is implanted on the skull and the stimulating electrodes are placed on the brain surface, overlying the non-resectable seizure focus. The device is then programmed to recognize seizure discharges and delivers a stimulus in response to these detections. At this time, it is only available in highly specialized epilepsy centers. The deep brain stimulator (DBS) that is sometimes used to treat Parkinson’s disease also has been studied for the treatment of epilepsy using a different anatomical target in the brain. It is approved in Europe but is not yet available in the United States.

As you say on your website, “Even the best medical management fails to achieve seizure control in up to a third of people with epilepsy. In these cases, care can often be improved through consultation with an epilepsy specialist and/or evaluation in an Epilepsy Monitoring Unit [EMU].” Can you briefly speak to the services that your clinic provides when medical management has failed?
The most important services that an epilepsy center can provide are to clarify the epilepsy diagnosis and to optimize treatment. Our goal is always “no seizures and no side effects”, recognizing that this goal may be more difficult to achieve in the patients requiring our services. The first visit to an epilepsy center will focus on a very detailed review of the patient’s history and seizure descriptions. Corroborative testing may be ordered, including MRI and EEG. Even if these tests have already been done in the recent past, they may need to be repeated using special techniques.  All of this information is used to clarify the epilepsy diagnosis so that treatment can be optimized. This may require changing one or several medications, which is usually done gradually over a period of weeks or months. Sometimes all that is needed is to eliminate medications that are causing intolerable side effects, perhaps replacing them with alternate agents.

In cases in which optimized medical treatment still does not yield acceptable seizure control, an admission to the inpatient epilepsy monitoring unit may be warranted. These admissions fall into two major categories: pre-surgical admissions and diagnostic admissions. Pre-surgical admissions can lead to the surgical interventions previously discussed. Diagnostic admissions, on the other hand, are meant to clarify the diagnosis—focal epilepsy, generalized epilepsy, a variety of behavioral events, and conversion disorder manifesting with psychogenic non-epileptic seizures all can look and sound very similar to each other but can usually be distinguished from each other on the basis of video EEG done in an EMU. The time the patient spends in the EMU also enables the assessment of other needs the patient may have, such as for social services or mental health services.

What are the current limitations and challenges of treating epilepsy in older adults (eg, lack of clinical trials, adverse effects)?
Epilepsy is a very common disorder and is at least as common in older adults as it is in younger ones. Indeed, older adults are a growing segment of the epilepsy population. It is important to keep in mind that epilepsy is very treatable and that at least two-thirds of patients can achieve complete seizure control, often with few or no side effects. Treatment success hinges on making a correct diagnosis of the epilepsy type and choosing appropriate anti-seizure medications, keeping tolerability, comorbidities, and quality of life in mind. The treatment of epilepsy in older adults is really not very different from the treatment of epilepsy in younger adults. In fact, epilepsy with onset later in life may be more responsive to anti-seizure medications. However, older adults are more prone to side effects and to drug-drug interactions. Dosing may need to be lower and dosing titration may need to be slower in older adults. Much of what we know about the treatment of epilepsy in older adults is based on clinical experience and smaller studies because older adults generally make up a small proportion of clinical trial participants.

References:
1.    Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology. 2005;64(11):1868-1873.

2.    Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Eng J Med. 2001;345:311–318.