A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas

Study Overview
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Brief Summary
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This project is being done to induce remapping of functional cortex in patients with invasive gliomas to enable a greater extent of resection of invasive gliomas while minimizing the risk of a permanent neurological deficit. Adult diffuse gliomas, or the type of gliomas that are being targeted in this study, are not generally curable by surgery; however, life expectancy is generally believed to be increased by resecting more of the tumor. Because surgeons cannot resect all the tumor when it invades certain parts of the brain that are primarily responsible for language or movement, the investigators are attempting to see if they can electrically inactivate those parts of the brain with tumor in it so it can be resected in a subsequent surgery.

Detailed Description
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Specific Aim 1: To induce a remapping of primary motor function by pairing deficit-inducing cortical stimulation with targeted physiotherapy after an initial maximal safe, but subtotal, resection (i.e. standard of care). Introduction. The objective for this aim is to demonstrate the ability to induce glioma-involved hand M1 remapping with an ICS-TBT protocol using the RNS System (responsive neurostimulation device) to enable an extended EoR (extent of resection) upon a second surgery before the tumor has significantly grown. The working hypothesis is that the proposed protocol will mobilize motor function enough to allow extended resection during a second surgery without an associated permanent loss of function. My approach involves implanting the RNS System in 3 patients with M1-involved gliomas after they undergo a maximal safe, but subtotal, resection (i.e. current SoC (standard of care)). An outpatient ICS-TBT (inhibitory cortical stimulation-targeted behavioral therapy) protocol will then be initiated based on the previously demonstrated principles with our newly proposed techniques. The rationale for this aim is to provide initial evidence for the ability of this technique to safely induce plasticity in this anatomical location and patient population. The expected outcome will be a demonstration of the remapping of hand M1 function and a corresponding extended resection without permanent neurological deficit upon a second surgery. Preliminary Evidence. It is well established that the function inherent to certain critical cortical nodes, i.e. movement and speech generation, can remap to new areas after years of slow tumor invasion. Recently, however, such plasticity was accelerated by delivering deficit-inducing cortical stimulation (130 Hz) with implanted subdural grids. While this protocol generated remapping that enabled further resection in 5 patients, it also required an average inpatient stay of 33 days and unacceptable infectious morbidity, making it not a widely applicable protocol. The FDA-approved NeuroPace RNS device is fully implantable and can deliver similar stimulation in the outpatient. In fellowship, the investigator became well trained in the implantation of this device, and wrote a review of 57 consecutive cases at their institution without a single reported infection, lead migration, or hemorrhage. Similar technique will be applied to the proposed study. Research Design. This is a proof-of-concept study to be performed on 3 patients over approximately 3 years. Participants: Patients with radiographical evidence of lesions consistent with WHO grade II gliomas (i.e. non-enhancing lesions) involving hand M1 will be eligible for this study. WHO grade IV gliomas (glioblastomas) will not be considered due to their shorter life expectancy4, and WHO grade I gliomas will also not be included because they are more likely to receive a GTR (gross total resection). Patients with tumors invading or abutting primary motor cortices on structural and functional MRIs such that GTR is anticipated to be unlikely during initial resection as SoC will be targeted. Outside of active pregnancy, Neither sex nor gender will be considered inclusionary nor exclusionary as it is not expected to affect outcome and due to the small study N. Initial Surgery: Subjects will undergo an awake craniotomy for maximal safe tumor resection with DES (direct electrical simulation) motor mapping and continuous motor monitoring consistent with SoC and the anatomy of their lesion. Upon completion of the resection, a final DES map will be obtained, and an intraoperative MRI will be taken. If a GTR has been achieved, there is evidence of tumor widespread beyond the intraoperative functional map, or the final DES suggested new injury to motor pathways, the case will be concluded, consistent with SoC, and the patient will exit the study. Otherwise, if there is evidence of residual tumor which cannot be resected due to invasion of hand-M1 but which is small enough to be covered by two four-electrode strips, these strips will be placed on the functional cortex of interest and secured to the dura. The location of the leads will be registered into the navigation software (either Medtronic Stealth or Brainlab). The dura will then be closed as watertight as possible, and the RNS System will be incorporated into the craniotomy on closure. Prior to closure, four bone screws will be placed and registered to the intraoperative navigation system as internal fiducials to be retrieved for future procedures. Despite the newly proposed indication, the surgical technique used to implant the device is similar to those in combined subtotal resection epilepsy cases. Therefore, the device-related risk profile is expected to be similar. ICS-TBT Protocol: When the patient is clinically ready for discharge, prior to leaving the hospital and removing any intravenous lines, the patient will undergo another complete neurological examination and measurement of grip and pinch strength on a dynamometer. An extra-operative cortical stimulation map (ECSM) will be performed through the implanted electrodes using parameters similar to intraoperative mapping. After the ECSM is obtained, ICS will begin. Initial stimulation parameters will be chosen to closely approximate previously published parameters of 130 Hz and 1 ms pulse width, and they will be adjusted to clinical effect (i.e. a measurable decrease in strength on the Manual Motor Scale and/or dynamometer). The stimulation intensity at each electrode contact (or pair) will be increased by approximately 0.5 V increments every 3 minutes until the threshold for induction of weakness is discovered. Grip and pinch strength will be remeasured, and stimulation will be set at this threshold so that the patient might recover the corresponding disrupted function through daily intensive TBT practice. If this threshold is set without incident, ICS will remain on and the patient can be discharged after 1 hour of observation. Further sessions can be conducted on an outpatient basis. If stimulation induces a seizure, the stimulation will be paused and the patient will be treated as clinically necessary. If a seizure occurs that requires medical intervention, the stimulation will be paused and may be turned back on the following day with lower settings up to three more times. If it is determined that stimulation cannot be tolerated without seizure induction, no further ICS attempts will be made for that patient. Once a mild deficit is induced, a TBT regimen of movements focused on rehabilitating the affected area will be established. Supervised sessions will be conducted 5 days per week for 1 hour per session, and patients will be encouraged to continue unsupervised practice (self-applied training) at home. Such sessions will continue until an increase of 1.0 V from the previous session no longer induces any measurable deficit, at which point the patient will undergo another ECSM and may be considered a candidate for a second surgery. Previous patients received stimulation for an average of 16 days as inpatients; a similar timeline is anticipated here, with the possibility of extending up to 2 months if continued deficits are seen. If no improvements change is seen at 2 months, the patient will be offered a second surgery at that time to retest the DES map and explant the device. As the RNS System is designed to deliver stimulation in response to a detection algorithm (as opposed to continuous stimulation), the device will be set to its longest stimulation duration of 10-seconds and the lowest possible threshold for triggering. This will essentially trigger a responsive stimulation therapy constantly with a downtime of about 100-300ms between stimulations (i.e. 97-99% continuous stimulation). It is anticipated that this is to be essentially equivalent to 100% continuous stimulation. Battery life is expected to be sufficient for the proposed trial period, with the option of replacing the battery in case of longer-than-expected stimulation requirements with evidence of progress. Second Surgery: After opening the previous wound, the bone screw fiducials will be re-registered to the neuro-navigation system and lead locations will be reconfirmed. The RNS System will then be explanted. An intraoperative MRI with and without contrast will be obtained at this point to re-assess the tumor status (note that the RNS System precludes MRIs on magnets over 1.5T and with a head coil), and another intraoperative DES map will be obtained. Two attending neurosurgeons will discuss the results, and, if it agreed to be safe to proceed, an extended resection will be performed with continuous motor monitoring. Once the extended resection is completed based on functional constraints and tumor location, stable monitoring will be confirmed, and a final intraoperative MRI will be obtained. The wound will then be closed in the standard fashion, repairing the skull defect from the device with a titanium mesh plate. Standard post-craniotomy clinical care will be followed. Outcome Measures, Analyses, and Expected Outcome: Hand strength will be assessed by the Manual Motor Scale and dynamometer grip and pinch strength. Upper extremity function will be assessed with the Nine-Hole Peg Test (NHPT) and Duruoz Hand Index survey. Formal assessments will occur preoperatively, after the first surgery, before the second surgery, after the second surgery, and then weekly until the results return to within baseline (i.e. within the previously validated minimal clinically important difference [MCID]) or at 3 months. Extent of resection will be calculated as: (preoperative tumor volume - postoperative tumor volume)/preoperative tumor volume. Determination of volumes will be made by an attending radiologist without knowledge of clinical outcome. Manual segmentation will be performed to measure tumor volumes based on fluid-attenuated inversion recovery (FLAIR) axial slices. The expected outcome is that all assessments of hand strength and function in all three patients will return to within the MCID for their respective scales by 3-months postoperatively with a radiographically measurable increase in EoR from the first to second surgery, thereby demonstrating the first safe resections into previously unresectable hand M1 enabled by ICS delivered through a fully implanted device.

Official Title
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Inducing Functional Plasticity in Glioma-Involved Functional Cortex With Deficit-Inducing Cortical Stimulation and Targeted Behavioral Therapy to Increase Extent of Resection

Conditions
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Glioma, Glioma Intracranial, Gliomas Benign, Brain Tumor, Brain Cancer, Motor Cortex; Lesion

Intervention / Treatment
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* Device: RNS System Implantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years old Ability to understand a written informed consent document, and the willingness to sign it Radiographic evidence of likely low-grade glioma on MRI (i.e. non-enhancing) invading primary motor cortex in the non-dominant hemisphere. Karnofsky performance status (KPS) ≥ 75 Normal or near normal motor strength (i.e., at least 3/5 in relevant areas) Normal or near normal speech (Can consistently name at least 4/5 cards) No medical contraindication to surgery Free of other illness that may shorten life expectancy Exclusion Criteria: Presence of other malignancy not in remission Evidence of bi-hemispheric or widespread tumor involvement Likely candidate to receive GTR on initial resection Medically high-risk surgical candidate History of recent scalp or systemic infection Presence of other implants or foreign bodies in the head Inability to receive an MRI for any reason Inability to receive cortical stimulation for any reason Coagulation disorders and/or use of anti-thrombotic therapies Platelet count < 50 Diathermy procedures Electroconvulsive Therapy (ECT) Transcranial Magnetic Stimulation (TMS) Presence of implanted cardiac device (such as a pacemaker or defibrillator) Pregnant women

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: Device Feasibility
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RNS System Implantation<br>This is a device feasibility study, therefore participants will only be enrolled into the investigational arm and will receive the RNS System Implantation. | Device: RNS System Implantation<br>* Following resection consistent with SoC, if there is evidence of residual tumor which cannot be resected due to invasion of hand-M1 but which is small enough to be covered by two four-electrode strips, these strips will be placed on the functional cortex of interest and secured to the dura. The location of the leads will be registered into the navigation software (either Medtronic Stealth or Brainlab). The dura will then be closed as watertight as possible, and the RNS System will be incorporated into the craniotomy on closure Prior to closure, four bone screws will be placed and registered to the intraoperative navigation system as internal fiducials to be retrieved for future procedures.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of resection | Calculated as: (preoperative tumor volume - postoperative tumor volume)/preoperative tumor volume. Determination of volumes will be made by an attending radiologist without knowledge of clinical outcome. Manual segmentation will be performed to measure tumor volumes based on fluid-attenuated inversion recovery (FLAIR) axial slices. | Explantation surgery | 
| Hand strength - Manual Motor Scale | Quantitative assessment on a scale of 0 - 5 5 - normal strength 4 - give away weakness 3 - movement against gravity 2 - movement in anti-gravity position 1 - muscle twitch 0 - no movement | 3-months post-op | 
| Hand strength - Dynamometer grip and pinch strength | Scored using force production in kilograms (0-90) Standardized procedure for positioning Maximum grip and pinch strength is the mean of three trials | 3-months post-op | 
| Hand function - Nine-Hole Peg Test | Administered by asking the subject to take the pegs from a container, one by one, and place them into the holes on the board, as quickly as possible The pegs must then be removed from the holes, one by one, and replaced back into the container Scores are based on the time taken to complete the test activity, recorded in seconds | 3-months post-op | 
| Hand function - Duruoz Hand Index survey | 18 questions regarding ability to carry out manual tasks. Grouped in five domains: In the Kitchen (8), dressing (2), hygiene (2), in the office (2), and other (4) Subject instructed to answer each question in terms of the level of difficulty they experience completing various tasks without help from another person or assistive device Individual items are scored on a 6-point Likert scale where 0=without difficulty and 5=impossible. The 18 individual scores are summed to obtain a composite score The total score ranges from 0-90 with higher scores indicating poorer hand functioning | 3-months post-op | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Stimulation, NeuroPace, Cortex Stimulation, Neuroplasticity, Plasticity, Hand Motor Cortex, Primary Motor Cortex, M1, Motor Mapping, Resection, Surgery, Motor Rehabilitation, Prehabilitation