Does Memantine Improve Verbal Memory Task Performance in Subjects With Partial Epilepsy and Memory Dysfunction?
Condition: Epilepsy
MeSH terms: Epilepsy
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Memantine; Sugar Pill; Memantine
Intervention type(s): Drug; Other; Drug
Intervention description(s): All subjects in the treatment group will be placed on memantine. The dosage of memantine will begin at 5mg once per day (qday), and increase by 5mg every week. The titration will continue over a period of 3 weeks until a goal of 10mg bid is reached. The dosing will increase slowly, to minimize the risk of side effects. The subject will then remain on memantine at 10mg bid for 10 weeks, until the conclusion of the first phase of the study. At the conclusion of the first 13 weeks, subjects will discontinue the treatment (memantine or placebo) and enter the open label phase.; In the control arm of the study, subjects will take one placebo sugar pill per day for one week, then increase to one tablet twice per day for the following 12 weeks. At the end of this phase of the study, subjects will enter the open-label phase (unblinded treatment with memantine).; Open label: When the blinded phase is complete (Weeks 1-13), all subjects will receive open-label treatment with memantine (Weeks 14-26). The dosage of memantine will begin at 5mg once per day (qday), and increase by 5mg every week. The titration will continue over a period of 3 weeks until a goal of 10mg bid is reached. The dosing will increase slowly, to minimize the risk of side effects. The subject will then remain on memantine at 10mg bid for 10 weeks, until the conclusion of the study. At the conclusion of the study, subjects will discontinue the treatment.
Other intervention name(s): Namenda; Placebo; Namenda
Intervention MeSH terms: Memantine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: epilepsy; memory; memantine; localization related epilepsy; focal epilepsy