Does Memantine Improve Verbal Memory Task Performance in Subjects With Partial Epilepsy and Memory Dysfunction?

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.