INTRODUCTION
Seizing The Opportunity: Preserving Cognitive Function In Long-term Care Patients With Epilepsy
Including proceedings from a satellite symposium held in conjunction with the American Society of Consultant Pharmacists’ 37th Annual Meeting and Exhibition in Phoenix, Arizona
Activity Date: April 2007  — Activity Info: Volume 4, (3)
Goals & Objectives | Faculty | Introduction | Full Activity Content | CME Test & Evaluation (CME Expired)

 
Seizing The Opportunity: Preserving Cognitive Function In Long-term Care Patients With Epilepsy
William R. Garnett, PharmD, FCCP

Epilepsy, once considered primarily a disease of the young, is rapidly becoming an issue for the growing elderly population.1 Additionally, numerous antiepileptic drugs (AEDs) have become available and applications for them have been found for disorders other than epilepsy.2 It has been estimated that at least 10% of patients residing in long-term care facilities (LTCFs) are prescribed AEDs for epilepsy or psychosis. With the expansion of the arsenal of available AEDs, it has become possible to tailor therapy to the needs of the individual patient. This presents a challenge to consulting pharmacists at LTCFs because each AED has its own advantages and drawbacks.

Epilepsy is characterized by unprovoked seizures consisting of a hypersynchronous discharge of a population of neurons.3 Although many different factors interact to create this pathology in different individuals, there exist some commonalities. Excitatory and inhibitory neurons are organized in circuits. Each neuron activates through the opening of specific ion channels (ie, voltage-sensitive sodium and calcium channels) in response to changes in the membrane potential, allowing for the influx of positive ions into the cell and depolarization of the membrane potential. It is this wave of depolarization that constitutes the signal that travels down the axon and ultimately results in the release of a neurotransmitter at the next synapse in the circuit. Excitatory neurons release a neurotransmitter such as glutamate or serotonin, which promotes the activation of the next neuron in the circuit. Inhibitory neurons release a neurotransmitter such as g-aminobutyric acid (GABA), which promotes the inhibition of the next neuron. Physiologically, these changes in membrane potential are activated by ligand-gated ion channels that function as receptors and open (or close) in response to the presence of the appropriate neurotransmitter, which has been secreted into the synaptic space as part of the normal functioning of the circuit. Thus, at the cellular level, inappropriate activation can occur because of changes in the expression or activity of these neurotransmitter receptors.3 At the network level, a general loss of inhibitory neurons can confer a degree of hyperexcitability to this circuitry. Additionally, as voltage-sensitive ion channels respond to electrical signals, a wave of depolarization—if sufficiently large—can recruit additional neurons to the hypersynchronous pathological activation, ultimately creating seizure activity.

AEDs work by amplifying the inhibitory signals or inhibiting excitatory signals. Examples of AEDs that amplify inhibitory GABA signaling include gabapentin, phenobarbital, tiagabine, topiramate, and valproic acid. AEDs that block excitatory glutamate receptors include felbamate, lamotrigine, and topiramate. AEDs that block voltage-sensitive sodium currents (and thus the entire circuitry) include virtually all of the commonly used drugs except ethosuximide, tiagabine, and levetiracetam. Therefore, AEDs block seizure activity by several mechanisms. As might be expected, these drugs have general effects on cognition that are positive and negative. The therapeutic window in which these drugs act is often quite narrow and their rate of metabolism is sensitive to external factors. The diagnosis of disease for which these drug are used can be difficult in the absence of  sufficient information. Seizure presentation can be subtle and go unrecognized or be misdiagnosed. Cognitive deterioration may be a side effect of AED therapy or may be caused by other factors. These properties present a challenge to consulting pharmacists in their efforts to balance the therapeutic and adverse effects of these drugs, in addition to protecting the quality of life of their LTCF patients.

This issue of University of Tennessee Advanced Studies in Pharmacy highlights the proceedings of a satellite symposium held on November 17, 2006, in conjunction with the 37th American Society of Consultant Pharmacists’ Annual Meeting in Phoenix, Ariz. The goal of the symposium and this monograph is to inform consultant pharmacists about the most recent data on the use of AEDs to manage epilepsy and associated issues of cognitive function.

The first article, based on a presentation by James C. Cloyd III, PharmD, and myself, discusses the fundamentals of seizure activity in the elderly population. The presentation defined the concepts of seizure, epilepsy, and convulsion, and described the characteristic clinical presentation leading to the diagnosis of epilepsy. Seizure activity in the young and the elderly was compared, emphasizing the surprising bimodal epidemiology of this disease and the differences in the types of seizures commonly observed in these 2 populations. Elderly patients most commonly present with partial seizures and the varied presentation of these seizures was discussed. The complexities of management were discussed, including the necessity of accurate information gathering in generating the initial diagnosis, the changes in pharmacokinetics and pharmacodynamics caused by aging, the confusions of concurrent illnesses and medications, and the implications of the social stigma associated with epilepsy. The difficulties in diagnosis were underscored by the many different nonepileptic conditions that could be mistaken for seizure activity. Common laboratory tests were reviewed, along with the relative value of the data generated by these tests. The many possible causes for epilepsy were also covered, in addition to the tremendous contribution of vascular disease toward the development of epilepsy. The presentation concluded with an overview of the currently available AEDs, including their strengths and the adverse effects most commonly seen with each.

The second presentation by Dr Cloyd discussed the concept of altered pharmacokinetics in the elderly. Given the narrow therapeutic window in which these drugs act, increases or decreases in plasma concentrations can have a major effect on the well-being of the patient. Dr Cloyd provided examples of issues affecting absorption, plasma protein binding, and rates of metabolism. Strikingly, he demonstrated how seemingly minor factors can cause large changes in plasma phenytoin concentrations under conditions of constant dosing over a period of months. Given these complexities, it is unfortunate that few clinical trials of AEDs are performed in the elderly. Dr Cloyd presented one of the few trials, the VA Cooperative Study 428, which specifically focused on AED activity in this population. The effect of AED therapy on cognition can be significant and, given the probability of concomitant illness, this change in cognition can be difficult to observe. Dr Cloyd reviewed what is currently known of the cognitive effects of the first- and secondgeneration AEDs, highlighting relative effects and supplying practical advice about to how to optimize cognition in these patients. The presentation concluded with a discussion on pharmacoeconomics, in which the ability of an AED to markedly increase the metabolism of a cholesterol-lowering drug was demonstrated. Thus, finding the minimum effective dose not only decreases the possible adverse effects of AED therapy, but can also greatly reduce the indirect effects of metabolic induction on concomitant therapies.

The third presentation by D. Michael Collins, RPh, BS, focused on 4 case studies. Each case study illustrated an important subtlety in the management of LTCF patients and explained how the availability of numerous AEDs allows healthcare providers to tailor therapy to an individual patient’s needs.

Cases 1 and 2 portrayed patients who did not tolerate their AEDs. The usefulness of various laboratory and behavioral tests was discussed, in addition to the rationale behind the decision to switch patients from their current drugs to lamotrigine. The pharmacokinetic details of each transition were also covered.

Case 3 demonstrated the importance of establishing a minimum dose. The patient had a history of headaches and was treated with topiramate, an AED known for the treatment of migraine headaches and epilepsy. Mr Collins detailed the titration of the topiramate, the resultant loss of the patient’s quality of life because of cognitive impairment, and ultimately, how simply decreasing the dose solved the problem. He discussed many of the complex issues associated with controlling plasma concentrations in these patients.

The final case illustrated how a misdiagnosis can result in a significant decrease in a patient’s quality of life. The patient was suffering from a seizure disorder rather than intermittent oculogyric crisis and, through a neurology consult and an electroencephalogram, an AED was added that blocked this form of seizure. Interestingly, the patient could not tolerate being taken off of the first AED and, ultimately, the 2 drugs were given concurrently.

These clinical examples provided a practical counterpoint to the earlier, more theoretical discussions. Together, these presentations inspired a discussion of these topics, the highlights of which are presented after the third article.

AED therapy in the LTCF environment has expanded with the increasing elderly population. The primary application of AED therapy is to treat epilepsy; however, these drugs are increasingly being used to treat behavioral problems in addition to neuropathic pain. Epilepsy can be challenging to diagnose because seizures may present as subtle changes in behavior and numerous other illnesses share seizure symptomology. Plasma levels for certain AEDs can vary greatly in elderly patients because of altered pharmacokinetics, in addition to the high likelihood of concomitant illnesses and associated therapies.

AEDs can have marked cognitive effects in addition to their therapeutic function. In many instances, this leads to a decreased quality of life for the patient. Physicians are often reluctant to alter drugs and/or dosages on the basis of quality-of-life issues alone if the therapeutic target has been met.

Together, these issues present the consulting pharmacist with significant challenges. Newer AEDs have improved cognitive properties as compared with firstgeneration drugs. By carefully assessing the state of the patient and tailoring AED therapy to meet that patient’s needs, it is increasingly likely that the consulting pharmacist will have a positive impact on the quality of life for LTCF patients.

REFERENCES
1. Stephen LJ, Brodie MJ. Epilepsy in elderly people. Lancet. 2000;355:1441-1446.
2. Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic drugs and cognitive issues. Epilepsia. 2003;44(suppl 4):21-29.
3. Guberman A, Bruni J. Essentials of Clinical Epilepsy. 2nd ed. Boston: Butterworth Heinemann; 1999.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.

*Professor of Pharmacy and Neurology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia.
Address correspondence to: William R. Garnett, PharmD, FCCP, Professor of Pharmacy and Neurology, Virginia Commonwealth University, Medical College of Virginia, PO Box 980533, Richmond, VA 23298. E-mail: wrgarnet@vcu.edu.
     
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