Low Frequency Electrical Stimulation of the Fornix in Intractable Mesial Temporal Lobe Epilepsy (MTLE)

Study Overview
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Brief Summary
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The primary aim of the current proposal is to evaluate safety and tolerability, in terms of neuropsychological effects of low frequency electrical stimulation of the fornix (LFSF) in participants with medically-intractable Mesial Temporal Lobe Epilepsy. Secondary aims include evaluation of psychiatric changes, seizure frequency, and quality of life during LFSF.

Detailed Description
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Low frequency stimulation is an attractive, uninvestigated method for treatment of intractable epilepsy. Preliminary animal and human data suggest safety and remarkable efficacy of Low frequency stimulation (LFS) in epilepsy. In addition, the duty cycle of LFS is very low, implying less electric current injection, with less charge density on the target tissue and electrodes, and longer battery life. The current project is a classic translational, single-blinded, randomized research project, demonstrating a clear path from the laboratory to bedside. If successful, this new therapy will be of great value to patients with medically and surgically intractable Mesial Temporal Lobe Epilepsy (MTLE). The study is expected to last approximately 5 years, from enrollment of the first patient to completion of the final subject, taking into consideration attrition and otherwise-eligible subjects who will not elect to participate. Once the study is completed, and enrolled participants have completed all required elements of the protocol, a final report will be submitted to the FDA. Participants may also discontinue their participation in the study, if they wish, at any time.

Official Title
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Low Frequency Electrical Stimulation of the Fornix in Intractable Mesial Temporal Lobe Epilepsy (MTLE)

Conditions
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Mesial Temporal Lobe Epilepsy

Intervention / Treatment
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* Device: Medtronic Deep Brain Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are between the ages of 18 -65 years of age Participants must have had a non-invasive video-EEG monitoring revealing seizure semiology and ictal EEG consistent with unilateral or bilateral MTLE Participants must have tried and failed two trials of antiepileptic drugs (AEDs) Participants may have lesional or non lesional hippocampi, as evidenced by brain MRI acquired within the previous two years Participants are prescribed and taking 1-4 AEDs at the time of study entry Study participants will have intractable (MTLE) with a seizure frequency of at least 1/month averaged over the preceding 6 months prior to enrollment, including maximum seizure-freedom periods of no more than 60 days. Participants must have a platelet count greater than 125,000 per cubic millimeter and prothrombin time (PT) and activated partial thromboplastin time (aPTT) within normal limits at the visit prior to surgery Exclusion Criteria: Progressive neurological or medical diseases, such as brain tumors or neurodegenerative disease or cancer Non-compliance with antiepileptic medications as demonstrated by the medical record Any conditions interfering with electrode implantation Any non-epileptic seizures Inability or unwillingness to complete neuropsychological tests or complete seizure diaries Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements Pregnant, or planning to become pregnant* Participation in another research trial where the participant was treated with another investigational drug or device within 30 days prior to enrollment of study Intelligence Quotient showing a general ability Quotient of less than 70. The score excludes the contribution of working memory and processing speed (which are areas of cognitive functioning that are vulnerable to numerous influences including seizures and fatigue and effects of AEDs) Inability or unwillingness of individual to give written informed consent Participants who have changes to their antiepileptic medications during the baseline phase (as they will need to repeat the baseline phase) Subjects with history of status epilepticus within the preceding year History of psychiatric illness necessitating hospitalizations Subjects who have any of the following implanted devices: aneurysm clips, cardiac pacemaker or defibrillator, cochlear implant, spinal cord, DBS, or vagal nerve stimulator Co-morbid conditions that would interfere with study stimulation activities or response to treatment, which may include: Neoplasm with life expectancy < 5 years Severe chronic pulmonary disease Local, systemic acute or chronic infectious illness Life threatening cardiac arrhythmias Severe collagen vascular disorder Kidney failure or other major organ system failures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stimulation group 2 Hz<br>Patient will be randomized to a stimulation group of 2 Hz using Medtronic deep brain stimulation device | Device: Medtronic Deep Brain Stimulation<br> <br> |
| Experimental: Stimulation group 5 Hz<br>Patient will be randomized to a stimulation group of 5 Hz using Medtronic deep brain stimulation device | Device: Medtronic Deep Brain Stimulation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Low Frequency Stimulation of the Fornix With Regards to Memory Function | The primary outcome is safety and tolerability of LFSF in participants with intractable MTLE with regards to memory function. The number of participants listed are those who had a significant changes in RAVLT score. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psychiatric Health (Effects of LFS on Psychiatric Symptoms Using Standardized Measures That Are Known to be Sensitive to Changes to Surgical Treatment of TLE) | Since LFSF is expected to activate limbic structures, we will assess the effects of LFS on psychiatric symptoms using standardized measures that are known to be sensitive to changes to surgical treatment of TLE. The number of participation listed are those who had a significant change in anxiety, depression, or suicidality based on a qualitative overview of the psychiatric assessments performed preoperatively and postoperatively. | 1 year | 
| To Assess if Electrode Implantation in the Fornix is Feasible as is Done in Patients With Parkinson's Disease. | The DBS leads are routinely implanted for patients with Parkinson's disease. Thus, we planned to implant Model 3389 DBS leads using the same technique of stereotactic implantation. A secondary aim of this trial is to standardize the implantation, the evoked potential and electric current determination procedures in preparation for a large-scale phase III trial. The number of participants with the outcome measure are those in whom bilateral hippocampal CCEPs were consistently present. | 1 year | 
| Effect on Seizure Frequency | Seizure reduction: Subjects underwent implantation of pulse generators and long-term low-frequency stimulation with mean monthly seizures during blinded phase | 1 year |