Does Memantine Improve Verbal Memory Task Performance in Subjects With Partial Epilepsy and Memory Dysfunction?
Does Memantine Improve Verbal Memory Task Performance in Subjects With Partial Epilepsy and Memory Dysfunction?
Many patients with epilepsy have memory deficits in the setting of otherwise normal
 intelligence. Unfortunately, the treatment options for memory dysfunction in patients with
 epilepsy are limited. The investigators are conducting a study to evaluate the effects of
 memantine for the treatment of verbal memory dysfunction in subjects with
 localization-related seizures. The study involves randomization to memantine therapy or
 placebo, with cognitive testing and EEG pre- and post-treatment, as well as after an
 open-label memantine treatment phase.

 The primary aim of this study is to evaluate the efficacy of memantine for the treatment of
 verbal memory dysfunction in subjects with left temporal lobe epilepsy. The investigators
 expect that verbal memory task performance will improve in those taking memantine, but not in
 those taking a placebo.

 The investigators propose that the expected benefit of memantine is specific to verbal memory
 in subjects with left temporal lobe seizures, rather than representing an overall improvement
 in cognitive function. The investigators expect no improvement on other cognitive tasks in
 either the memantine or placebo groups.

 The investigators will evaluate whether subjects with left temporal lobe epilepsy and memory
 difficulties have self-reported improvement in memory while taking memantine. The
 investigators expect improvement of self-rated memory function on the Quality of Life in
 Epilepsy Patient Inventory (QOLIE-89) in the memantine group, but no change on this scale in
 the placebo group.
Patients with epilepsy frequently demonstrate subtle cognitive difficulties in the setting of
 otherwise normal intelligence. Those with left temporal lobe seizures often have particular
 deficits in verbal memory (Blum 2001). These memory difficulties may be the most distressing
 aspect of epilepsy for the patients.

 Unfortunately, treatment options for memory dysfunction are limited. Cognitive therapy, for
 example, may help patients to cope, but does not treat the memory loss or address the
 underlying pathologic process. Two studies examined the pharmacologic management of memory
 dysfunction in patients with epilepsy using donepezil (Aricept), but with inconsistent
 results and questionable benefit. A pilot study by Fisher et al. (2001) showed some promise
 for use of the drug. The study found improved immediate recall and consistent long-term
 retrieval scores on the Buschke Selective Reminding Test after three months of open-label
 treatment when compared to a pre-treatment baseline. A more recent randomized, double-blind,
 placebo-controlled cross-over trial of donepezil, however, showed no effect on memory as
 measured by delayed recall on the Hopkins Verbal Learning Test (Hamberger et al. 2007).

 Use of donepezil, an acetylcholinesterase inhibitor, may pose a risk of seizure exacerbation
 in this population. Fisher et al. (2001) reported a significant increase in the frequency of
 generalized tonic-clonic seizures during donepezil treatment. Cholinergic agents have been
 shown to cause seizures in animal models as well (Turski et al. 1989). Given isolated case
 reports of seizures associated with donepezil use, the manufacturer issued an advisory note
 warning of a possible relationship, although data have been insufficient to establish
 causality. While an increase in seizures was not noted in the Hamberger et al. (2007) study,
 seizure exacerbation remains a concern regarding the use of this drug in patients with
 epilepsy.

 The mechanism for the postulated effect of donepezil is unclear. Cholinergic transmission has
 not traditionally been viewed as a contributor to hippocampal pathology. It is believed that
 excitotoxicity, mediated by glutamate acting on NMDA receptors in the hippocampus, causes
 hippocampal sclerosis. This process leads to further seizures and memory dysfunction.
 Alteration of this excitotoxic pathway would be a novel, and potentially safer and more
 effective, approach to the treatment of memory loss.

 The possible effect of intervention at the level of excitotoxicity is supported by animal
 data. Such studies demonstrate that induced seizures in a rat model of epilepsy will lead to
 decrements in performance of a spatial memory task, the Morris water maze. This memory
 dysfunction, however, can be mitigated by NMDA antagonists, such as MK-801, administered
 prior to seizure induction. The underlying concept is that NMDA receptor antagonists would
 block the pathway of excitotoxicity that leads to hippocampal injury and memory loss (Kelsey
 et al. 2000).

 An NMDA antagonist, memantine (Namenda), is prescribed in humans for treatment of moderate to
 severe Alzheimer's disease (Tariot et al. 2004, Reisberg et al. 2003, 2006). Patients with
 Alzheimer's disease have attained significant cognitive improvements with use of the drug, as
 measured by the Severe Impairment Battery. The time-course of benefit is less clear, with
 some studies demonstrating sustained improvement (Tariot et al. 2004) and others showing more
 transient benefits over the first several weeks of treatment (Reisberg et al. 2003).

 It is unknown, however, if an NMDA antagonist such as memantine would be of benefit in humans
 with memory dysfunction and seizures. The proposed study tests the hypothesis that treatment
 with memantine would improve verbal memory test performance in patients with
 localization-related epilepsy. If beneficial, this would provide a much-needed treatment
 option.

 The study will examine the primary specific aim:

 Aim 1: Improvement in memory test performance. The primary aim of this study is to evaluate
 the efficacy of memantine for the treatment of verbal memory dysfunction in subjects with
 left temporal lobe epilepsy. We expect that verbal memory task performance, as measured by
 the Buschke Selective Reminding Test (SRT), will improve in those taking memantine, but not
 while taking a placebo. Such a finding would support the use of memantine for treatment of
 memory loss in this population, as well as more generally support the hypothesis that NMDA
 receptor hyperactivity is an appropriate target for intervention.

 The study will examine two secondary specific aims:

 Aim 2: Selectivity of response. We propose that the postulated benefit of memantine is
 specific to verbal memory in subjects with left temporal lobe seizures, and visuospatial
 memory in subjects with right temporal lobe seizures, rather than representing an overall
 improvement in cognitive function. We expect no improvement on other cognitive tasks in
 either the memantine or placebo groups, with measures including the Digit Span (for sustained
 attention, immediate span), Spatial Span (for visuospatial working memory and span), Block
 Design (for visuospatial construction), Verbal Fluency, Design Fluency, and Stroop Color Word
 Interference (for executive function) tests. This would lend support to the hypothesis that
 blockade of NMDA receptor hyperactivity in the hippocampus would lead to improved performance
 on cognitive tasks that depend specifically on the integrity of that hippocampus, as opposed
 to a general benefit in overall cognition.

 Aim 3: Improvement in self-reported memory function. We will evaluate whether subjects with
 localization-related epilepsy and memory difficulties have subjective improvement in memory
 with the administration of memantine. We expect improvement of self-rated memory function on
 the Quality of Life in Epilepsy Patient Inventory (QOLIE-89) with memantine, but no change on
 this scale with placebo. This measure serves to evaluate the hypothesis that memantine
 treatment leads to clinically meaningful improvement.
Inclusion Criteria:

 -  18-65 years of age

 -  Normal IQ as estimated by the Wechsler Test of Adult Reading (WTAR)

 -  Able to give consent

 -  Able to live independently and complete activities of daily living

 -  Stable frequency of seizures. There is no minimum/maximum criteria for the frequency
 of partial seizures. Those with infrequent secondary generalized seizures may
 participate, with infrequent seizures defined as two or fewer per year.

 -  The subject's treating physician does not believe a change in anticonvulsant regimen
 to be warranted. The anticonvulsant drugs must remain unchanged during the 26 week
 trial.

 -  Partial-onset seizures. Seizure type will be determined by clinical history, MRI,
 SPECT and/or PET imaging, and interictal and/or ictal EEG.

 -  Either symptomatic or idiopathic seizures.

 Exclusion Criteria:

 -  Non-epileptic seizures

 -  Prior surgical resection for treatment of seizures

 -  Progressive neurologic illness (i.e. tumor evident on MRI)

 -  Current alcohol or drug abuse, as this may affect memory by other mechanisms. This
 information may be obtained by self-report, from the referring physician or by medical
 record.

 -  Diagnosis of Alzheimer's disease, nutritional deficiency, infection or
 metabolic/electrolyte disorder causing memory loss.

 -  Non-native English speaking and/or multilingual.

 -  Seizure(s) must not have occurred within 3 days of testing.

 -  Subjects who are pregnant will not be eligible to take part in the study, as memantine
 is classified as a Pregnancy Category B drug and may pose risk to the fetus.

 -  Women who are breastfeeding may not participate in this study.

 -  Those with renal tubular acidosis or infections of the urinary tract will not be
 eligible for participation, as memantine is renally cleared and conditions that
 alkalinize the urine may reduce clearance of the drug.

 -  Subjects with severe renal impairment, defined as a creatinine clearance of ≤29
 mL/min, will be excluded as such patients may not tolerate the proposed dosing
 schedule.