Clinical trial NCT04897776: Stimulation of the Thalamus for Arousal Restoral in Temporal Lobe Epilepsy
Official title: Thalamic Stimulation to Prevent Impaired Consciousness in Epilepsy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
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
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: Dartmouth-Hitchcock Medical Center
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2021-05-24
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: Impaired consciousness during seizures has a major negative impact on quality of life for people with epilepsy. Consequences include risk of motor vehicle accidents, drowning, poor work and school performance, and social stigmatization. Impaired ictal/postictal arousal may also compromise breathing leading to sudden unexpected death in epilepsy. Although the primary goal of epilepsy care is to stop seizures, restoring conscious awareness in patients whose seizures cannot be stopped (by medications, surgery or deep brain stimulation) could significantly improve outcome. Disorders of consciousness other than epilepsy have long been known to arise from dysfunction of subcortical-cortical arousal circuits. Deep brain stimulation (DBS) of the thalamic intralaminar central lateral nuclei (CL) is a promising approach to restore conscious arousal currently being trialed for chronic disorders of consciousness. Recent neuroimaging and EEG studies have shown that transient impaired consciousness in temporal lobe epilepsy (TLE) seizures also depends on subcortical-cortical arousal including thalamic CL. Translational studies from this research group further demonstrate depressed CL function in limbic seizures, and most importantly that thalamic CL stimulation has the potential to restore physiological and behavioral arousal in the ictal and postictal periods. DBS treatment of epilepsy has advanced rapidly with FDA approval of responsive neurostimulation (RNS, NeuroPace) and thalamic anterior nucleus stimulation (Medtronic). Investigational devices such as the Medtronic Summit RC+S provide a unique opportunity for responsive stimulation of up to four separate brain regions, enabling conventional sites such as hippocampus (HC) to be combined with innovative targets such as thalamic CL. Meanwhile, collaborators Mayo Clinic have developed the Epilepsy Personal Assistant Device (EPAD), a custom application running on a hand-held device with bi-directional communication with the RC+S. The EPAD will enable cloud-based data storage, seizure diaries, and automatic behavioral tests. Therefore, the goal is to develop and pilot test the feasibility and safety of bilateral thalamic CL stimulation using RC+S to restore conscious arousal in TLE seizures which are not stopped by conventional responsive neurostimulation, offering hope to greatly improve quality of life in these patients.

Eligibility criteria: Inclusion Criteria:

1. All patients will have evidence of mesial temporal seizures based on either

   1. Intracranial EEG monitoring with mesial temporal lobe onset
   2. or scalp EEG evidence of temporal lobe seizures and other evidence of mesial temporal lobe epilepsy.
2. 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.
3. 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.
4. Drug resistance to at least two antiseizure medications (ASM) with adequate dose and duration.
5. 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.
6. 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.
7. The local treating epilepsy center has recommended the patient for brain stimulation therapy on clinical grounds and without reference to this protocol.
8. Age 18 to 75 years, inclusive, at time of consent.
9. Ability and willingness to provide informed consent and participate in the study protocol.
10. 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.
11. Subject has seizures that are distinct, stereotypical events that can be reliably counted by the patient or caregiver.
12. Subject can reasonably be expected to maintain a seizure diary alone or with the assistance of a competent individual.
13. Subject can complete regular office visits and telephone appointments in accordance with the study protocol requirements.
14. A female subject must have a negative pregnancy test and if sexually active, must be using a reliable form of birth control for the duration of the trial, be surgically sterile, or be at least two years post-menopausal.
15. Subject has been informed of his or her eligibility for resective surgery as a potential alternative to the study, if such surgery is a reasonable option.
16. Subject speaks and reads English.
17. Subject's anatomy will permit implantation of the Medtronic Investigational Summit RC+S generator within 20 mm of the skin surface.
18. Subject is capable of completing the proposed neuropsychology evaluation and will score no lower than 2 standard deviations below average on the Wechsler Adult Intelligence Scale.

Exclusion Criteria:

1. Subject has a contraindication to magnetic resonance imaging.
2. Subject has a significant substance abuse history (alcohol, prescription, or illicit medications) within the preceding two years with evidence of impact on daily function.
3. Subject participated in another drug or device trial within the preceding 30 days.
4. 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.
5. Suicide attempt in the past year.
6. Arrest for assault or possession of drugs or weapons with intent to sell/distribute in the past year.
7. 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.
8. Subject has confirmed active diagnosis of psychogenic or non-epileptic seizures.
9. Subject has confirmed diagnosis of primary generalized seizures.
10. Subject has experienced unprovoked status epilepticus in the preceding year.
11. Subject has had therapeutic surgery to treat epilepsy that may interfere with electrode placement.
12. Subject has progressive neurological disorder or medical condition that would prevent the participant to fully participate in the clinical trial.
13. Subject has severe chronic pulmonary disease or cardiac disease, local, systemic acute or chronic infectious illness.
14. Subject is on anticoagulants and is unable to discontinue them peri-surgically, as required by the neurosurgeon or Investigator.
15. 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.
16. Subject is ineligible for cranial surgery.
17. Subject scores equal to or below a full-scale intelligence quotient (FSIQ) of 70, as measured by the Wechsler Adult Intelligence Scale.
18. Pregnancy.
19. Any condition or finding that in the judgement of the site PI significantly increases risk or significantly reduces the likelihood of benefit from participation in the study.

Primary outcomes:
measure: Change in Conscious Awareness
timeFrame: Up to 45 months
Secondary outcomes:
measure: Change in Seizure Severity
timeFrame: Up to 45 months
measure: Change in Quality of Life
timeFrame: Up to 45 months
Other outcomes:
measure: Change in Seizure Frequency
timeFrame: Up to 45 months
Locations:
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
Study officials:
affiliation: Yale University
name: Hal Blumenfeld, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dartmouth-Hitchcock Medical Center
name: Barbara Jobst, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Gregory Worrell, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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