Stimulation of the Thalamus for Arousal Restoral in Temporal Lobe Epilepsy

NCT04897776 | Completed DMC FDA Device

• 2 other identifiers: 20000302891UG3NS112826-01
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 3

Brief Summary

The goal is to provide a novel therapeutic option for temporal lobe epilepsy patients when focal impaired awareness seizures cannot be stopped by medications, surgical or laser ablation, or by neurostimulation. The goal is restore consciousness when seizures cannot be stopped. If successful, addition of bilateral thalamic stimulation to existing responsive neurostimulation to rescue consciousness would greatly alter clinical practice and patient outcomes. Importantly, previous approaches aim to stop seizures, whereas this study aims to use thalamic stimulation to improve a major negative consequence when seizures cannot be stopped. The potential impact extends beyond temporal lobe epilepsy to other seizure types, and may also extend more broadly to inform treatment of other brain disorders associated with impaired consciousness and cognition.

Conditions

Epilepsy, Temporal Lobe

Keywords

Thalamic Stimulation; Hippocampal Stimulation; Awareness; Ictal Awareness; Post-ictal Awareness; Consciousness; Temporal Lobe Epilepsy; Epilepsy; Quality of Life; Cognition; Neurostimulation; Deep Brain Stimulation; Responsive Neurostimulation; Intralaminar Thalamus; Thalamic Central Lateral Nucleus; Device; Behavioral Assessment

Outcome Measures

Primary Outcomes (1)

• Change in Conscious Awareness

  Evaluate levels of conscious awareness during and following seizures, based on a behavioral responsiveness scale. Behavioral responsiveness is delivered on a tablet device automatically when a seizure is identified by the neurostimulator device. Automatic Responsiveness Testing in Epilepsy has a score range of 0 to 18, where 0 is not consciousness and/or unable to interact appropriately to commands and 18 is conscious, aware, and able to interact appropriately to commands. This is measured at scheduled in weekly intervals prior to implant and continuously over the 45 months of participation that occur post-implant.

  Up to 45 months

Secondary Outcomes (2)

• Change in Seizure Severity

  Up to 45 months

• Change in Quality of Life

  Up to 45 months

Other Outcomes (1)

• Change in Seizure Frequency

  Up to 45 months

Study Arms (2)

Therapeutic Thalamic Stimulation

EXPERIMENTAL

Four months post implant, the neurostimulator device will provide patients with hippocampal stimulation for all seizures. For seizures longer than five seconds, thalamic stimulation will be administered at a therapeutic level established based on the physician's evaluation and patient specific parameters established at a previous visit. This will occur in half of the seizures the patient experiences and will be randomly assigned during this phase of the study. If no benefit is experienced during this phase of the study, patients may participate in an optional randomized CL stimulation phase for an additional four months.

Device: Central Thalamic Stimulation; Device: Hippocampal Stimulation

Non-Therapeutic Thalamic Stimulation

SHAM COMPARATOR

Four months post implant, the neurostimulator device will provide patients with hippocampal stimulation for all seizures. For seizures longer than five seconds, thalamic stimulation will be administered at below therapeutic threshold to control for implant and placebo effects. This will occur in half of the seizures the patient experiences and will be randomly assigned during this phase of the study. If no benefit is experienced during this phase of the study, patients may participate in an optional randomized CL stimulation phase for an additional four months.

Device: Hippocampal Stimulation

Interventions

Central Thalamic Stimulation DEVICE

Stimulation of the bilateral thalamic CL is a promising approach in human patients to improve conscious arousal. To restore conscious arousal by stimulation of the thalamic intralaminar CL it is necessary to provide bilateral stimulation, placing one lead in each thalamus. Bilateral thalamic CL stimulation was shown previously to improve human conscious arousal and is based on existing research in patients with disorders of consciousness.

Therapeutic Thalamic Stimulation

Hippocampal Stimulation DEVICE

The hippocampus has been a target for brain stimulation for seizure reduction in epilepsy. While the efficacy of HC stimulation varies considerably among different studies, the surgical procedure and therapeutic electrical stimulation are well tolerated by patients, with few peri-operative complications being reported, and histopathologic analysis not revealing a difference between stimulated and non-stimulated hippocampal tissue (Han et al. 2014)

Non-Therapeutic Thalamic Stimulation; Therapeutic Thalamic Stimulation

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients will have evidence of mesial temporal seizures based on either
• Intracranial EEG monitoring with mesial temporal lobe onset
• or scalp EEG evidence of temporal lobe seizures and other evidence of mesial temporal lobe epilepsy.
• Subject's seizure focus, based upon clinical history, semiology, electroencephalographic (EEG) findings, and/or neuroimaging, shall demonstrate bilateral or unilateral mesial temporal lobe epilepsy, and subject shall not be good candidate for surgical resection.
• Focal epilepsy with disabling seizure counts mean of ≥ 2 per month. Disabling seizures are those with significant negative impact on the patient's life, involving impaired conscious awareness. Seizures counts will be based on patient's self-report. Note that patient's typically have more disabling seizures than they are able to self-report, and may also have additional non-disabling seizures in addition to the disabling seizures required for enrolment.
• i. Mean seizure count ≥ 2 per month is established initially for the preceding 6 months at time of Enrollment, using seizures reported by the patient and/or caregiver. Seizures during EMU admissions are not included.
• Drug resistance to at least two antiseizure medications (ASM) with adequate dose and duration.
• Subject is willing to remain on stable ASM from the Baseline phase through the end of the Randomized CL Stimulation phase. Stable is defined as same medications, but dose adjustments are allowed within accepted therapeutic ranges. Also, short-term benzodiazepines allowed for acute seizure worsening as in prior studies.
• Apart from epilepsy, subject must be medically and neurologically stable and must have no other medical condition in the opinion of the treating physician that would preclude the patient from participation. This could include conditions like severe ischemic cardiac disease, progressive dementia or other disorders that could affect surgical eligibility or compliance.
• The local treating epilepsy center has recommended the patient for brain stimulation therapy on clinical grounds and without reference to this protocol.
• Age 18 to 75 years, inclusive, at time of consent.
• Ability and willingness to provide informed consent and participate in the study protocol.
• Subject can interpret and to respond, in accordance with the study protocol, to the advisory indicators provided by the device. This includes the ability to recharge the device.
• Subject has seizures that are distinct, stereotypical events that can be reliably counted by the patient or caregiver.
• Subject can reasonably be expected to maintain a seizure diary alone or with the assistance of a competent individual.

You may not qualify if:

• Subject has a contraindication to magnetic resonance imaging.
• Subject has a significant substance abuse history (alcohol, prescription, or illicit medications) within the preceding two years with evidence of impact on daily function.
• Subject participated in another drug or device trial within the preceding 30 days.
• Demonstrates that they fulfill criteria on any of the three subscale of the SCID-5-PD for borderline, antisocial, or narcissistic personality disorders and these criteria are then corroborated by psychiatric interview, and that this would significantly affect participation in the study.
• Suicide attempt in the past year.
• Arrest for assault or possession of drugs or weapons with intent to sell/distribute in the past year.
• Subject is implanted with pacemaker, implantable cardiac defibrillator, cardiac management product, or a medical device that interferes with the RC+S device. This includes, but is not limited to, direct brain neurostimulators, spinal cord stimulators, vagus nerve stimulators (VNS), and cochlear implants. Patients with a vagus nerve stimulator implanted but turned off through the duration of the study may be enrolled, provided their clinical status has been stable for at least one month with VNS turned off. Alternatively, patients with a VNS may have the previously disabled VNS removed at time of surgery to implant the Medtronic RC+S.
• Subject has confirmed active diagnosis of psychogenic or non-epileptic seizures.
• Subject has confirmed diagnosis of primary generalized seizures.
• Subject has experienced unprovoked status epilepticus in the preceding year.
• Subject has had therapeutic surgery to treat epilepsy that may interfere with electrode placement.
• Subject has progressive neurological disorder or medical condition that would prevent the participant to fully participate in the clinical trial.
• Subject has severe chronic pulmonary disease or cardiac disease, local, systemic acute or chronic infectious illness.
• Subject is on anticoagulants and is unable to discontinue them peri-surgically, as required by the neurosurgeon or Investigator.
• Subject has significant platelet dysfunction from medical conditions or medications (including, particularly, aspirin or sodium valproate). If platelet dysfunction is suspected, subject can be enrolled only if a hematologist, the Investigator, and the neurosurgeon judge it to be advisable.

Sponsors & Collaborators

• Yale University: lead
• Mayo Clinic: collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Dartmouth-Hitchcock Medical Center: collaborator

Study Sites (3)

Yale New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (5)

• Han CL, Hu W, Stead M, Zhang T, Zhang JG, Worrell GA, Meng FG. Electrical stimulation of hippocampus for the treatment of refractory temporal lobe epilepsy. Brain Res Bull. 2014 Oct;109:13-21. doi: 10.1016/j.brainresbull.2014.08.007. Epub 2014 Sep 6.

  PMID: 25200252 BACKGROUND

• Geller EB, Skarpaas TL, Gross RE, Goodman RR, Barkley GL, Bazil CW, Berg MJ, Bergey GK, Cash SS, Cole AJ, Duckrow RB, Edwards JC, Eisenschenk S, Fessler J, Fountain NB, Goldman AM, Gwinn RP, Heck C, Herekar A, Hirsch LJ, Jobst BC, King-Stephens D, Labar DR, Leiphart JW, Marsh WR, Meador KJ, Mizrahi EM, Murro AM, Nair DR, Noe KH, Park YD, Rutecki PA, Salanova V, Sheth RD, Shields DC, Skidmore C, Smith MC, Spencer DC, Srinivasan S, Tatum W, Van Ness PC, Vossler DG, Wharen RE Jr, Worrell GA, Yoshor D, Zimmerman RS, Cicora K, Sun FT, Morrell MJ. Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia. 2017 Jun;58(6):994-1004. doi: 10.1111/epi.13740. Epub 2017 Apr 11.

  PMID: 28398014 BACKGROUND

• Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, Labar D, Sperling MR, Sharan A, Sandok E, Handforth A, Stern JM, Chung S, Henderson JM, French J, Baltuch G, Rosenfeld WE, Garcia P, Barbaro NM, Fountain NB, Elias WJ, Goodman RR, Pollard JR, Troster AI, Irwin CP, Lambrecht K, Graves N, Fisher R; SANTE Study Group. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015 Mar 10;84(10):1017-25. doi: 10.1212/WNL.0000000000001334. Epub 2015 Feb 6.

  PMID: 25663221 BACKGROUND

• Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber M, Fritz B, Eisenberg B, Biondi T, O'Connor J, Kobylarz EJ, Farris S, Machado A, McCagg C, Plum F, Fins JJ, Rezai AR. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature. 2007 Aug 2;448(7153):600-3. doi: 10.1038/nature06041.

  PMID: 17671503 BACKGROUND

• Kremen V, Brinkmann BH, Kim I, Guragain H, Nasseri M, Magee AL, Pal Attia T, Nejedly P, Sladky V, Nelson N, Chang SY, Herron JA, Adamski T, Baldassano S, Cimbalnik J, Vasoli V, Fehrmann E, Chouinard T, Patterson EE, Litt B, Stead M, Van Gompel J, Sturges BK, Jo HJ, Crowe CM, Denison T, Worrell GA. Integrating Brain Implants With Local and Distributed Computing Devices: A Next Generation Epilepsy Management System. IEEE J Transl Eng Health Med. 2018 Sep 26;6:2500112. doi: 10.1109/JTEHM.2018.2869398. eCollection 2018.

  PMID: 30310759 BACKGROUND

Related Links

• Mayo Clinic Appointment Request
• Yale University Appointment Request
• Dartmouth-Hitchcock Medical Center Appointment Request

MeSH Terms

Conditions

Epilepsy, Temporal Lobe; Epilepsy

Condition Hierarchy (Ancestors)

Epilepsies, Partial; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes

Study Officials

• Hal Blumenfeld, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

• Barbara Jobst, MD, PhD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

• Gregory Worrell, MD, PhD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neuroscience and of Neurosurgery

Model Details: After controlling for implant effects and hippocampal stimulation, there will be a period of blinding for thalamic stimulation. Physician and patient will not know which seizures during this period receive stimulation or sham stimulation. The primary outcome measure will be comparing behavioral awareness scores during this period, sham stimulation compared to therapeutic stimulation.

Study Record Dates

• First Submitted: May 11, 2021
• First Posted: May 24, 2021
• Study Start: October 31, 2021
• Primary Completion: June 16, 2025
• Study Completion: July 15, 2025
• Last Updated: December 26, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)