High-Intensity Focused Ultrasonic Ablation of the Centromedian Thalamic Nucleus for Treatment of Medically Refractory Generalized Epilepsy in Patients Ages 18 Years to 89 Years

High-Intensity Focused Ultrasonic Ablation of the Centromedian Thalamic Nucleus for Treatment of Medically Refractory Generalized Epilepsy

The purpose of this study is to find out if magnetic resonance (MRI)-guided high-intensity focused ultrasound (HIFU) is safe and effective for treating medically refractory generalized epilepsy. HIFU is a procedure that delivers ultrasonic waves to brain regions with great precision to remove tissue that may cause problems. HIFU is approved by the Federal Drug Administration (FDA) for treating patients with essential tremor.

This study aims to find out if HIFU can safely reduce seizure burden in patients with medically refractory generalized epilepsy (MRGE) using metrics commonly used in other treatments for epilepsy, and by the change in frequency of convulsive (generalized tonic-clonic) seizures before and after the intervention.

The primary purpose of this study is to evaluate the safety of thalamotomy targeting the centromedian thalamic nucleus (CMN) using magnetic resonance-guided high-intensity focused ultrasound (HIFU), an incisionless, ablative procedure that selectively delivers ultrasonic waves to brain regions with submillimeter precision, which is already FDA-approved for thalamotomy in essential tremor and in practice at many institutions, including that of the investigators. The proposed study aims to determine if ablation of CMN using HIFU can safely reduce generalized seizure burden in patients with medically refractory generalized epilepsy (MRGE) using success metrics commonly used in interventions for epilepsy and by the change in frequency of convulsive (generalized tonic-clonic) seizures before and after the intervention.

Current literature suggests that thalamotomy with HIFU for essential tremor produces minimal and generally transient side effects, while targeted lesioning of CMN with other modalities such as radiofrequency ablation (RFA) produces similarly transient side effects in patients with MRGE. No mortality associated with treatment was reported in any study. Furthermore, the benefits for this patient population from RFA or from deep brain stimulation (DBS) of CMN ranged from 50-98% reduction in generalized seizures as long as 36 months post-operatively. Thus, we hypothesize that HIFU ablation of CMN will safely produce a similar durable reduction in generalized seizure burden for patients with MRGE.

In the proposed study, patients will be evaluated for three months pre-intervention and followed for one year after Intervention 1. The same schedule will be followed by subjects who proceed to receive Intervention 2.

Seizure freedom will be defined according to the International League Against Epilepsy (ILAE) outcome classification scale. The ILAE outcome scale includes six classes of outcome: Class 1 = seizure free; Class 2 = auras only; Class 3 = one to three seizure days/year and auras; Class 4 = four seizure days/year to 50% reduction in baseline and auras; Class 5 = <50% reduction in baseline number of seizure days to 100% increase in baseline number of seizure days and auras; Class 6 = >100% increase in baseline number of seizure days and auras. Only patients classified as ILAE Class 1 or Class 2 will be considered seizure-free.

This is a proof-of-concept interventional study whose primary aims are as follows:

Primary Aim 1: To characterize the safety of bilateral CMN ablation using HIFU in terms of both somatic and neuropsychological adverse events.

Primary Aim 2: To determine the efficacy of bilateral CMN ablation using HIFU in reducing generalized seizure burden and effect on interictal Electroencephalogram (EEG) anomalies.

Inclusion Criteria:

1. Ages 18 years to 89 years.
2. Adult males or females, non-pregnant, on reliable contraceptive regimen as appropriate.
3. Patient and legal representative as appropriate capable of signing written informed consent, completing electronic seizure diary, participating in questionnaires.
4. EEG features of generalized epilepsy performed within two years of enrollment with EEG anomalies not explained by contributory medical history; CT and/or MRI within the last ten years demonstrating no anatomic etiology of epilepsy.
5. MRGE, defined as persistent generalized tonic-clonic seizures, with or without concomitant absence, myoclonic, or focal seizures, despite compliance with at least two anti-seizure medications at therapeutic doses, with at least two generalized tonic-clonic seizures per month in the three months prior to HIFU procedure; must be willing to continue medication regimen during the duration of participation in the study.
6. Patient has not already undergone surgical implantation of RNS, VNS, DBS, or any other device used for management of MRGE that is not compatible with 3 Tesla MRI.

Exclusion Criteria:

1. 1. Pregnancy.

2. Unable or unwilling to comply with inclusion criteria as described.

3. Prior disqualifying medical or surgical history:

   1. Patients with advanced kidney disease or on dialysis
   2. Patients with unstable cardiac status:

   I. Unstable angina pectoris on medication II. Subjects with documented myocardial infarction within six months of protocol entry III. Significant congestive heart failure defined with ejection fraction < 40 IV. Subjects with unstable ventricular arrhythmias V. Subjects with atrial arrhythmias that are not rate-controlled c. Patients with severe hypertension (diastolic BP>100 on medication) d. Patients exhibiting any behavior consistent with ethanol or substance abuse e. Patients with history of abnormal bleeding, hemorrhage, and/or coagulopathy f. Patients receiving anticoagulant or drugs known to increase risk of hemorrhage within one month of focused ultrasound procedure g. Patients with cerebrovascular disease h. Patients with brain tumors i. Patients who are not able or unwilling to tolerate the required prolonged stationary position during treatment. The average treatment time (the time from the first scan to allocate transducer position and ending with the last energy delivery) is 1:56 ± 0.41 hrs (Min: 0.48 hrs, Max: 5:54 hrs) j. Patients with unstable psychiatric disease, uncontrolled depressive symptoms, psychosis, delusions, hallucinations, or suicidal ideation

4. Patients who are not candidates for HIFU.

   a. Patients who have an Overall Skull Density Ratio of 0.40 (±0.05) or less as calculated from the screening CT

5. Patients with standard contraindications for MRI such as non-MRI compatible implanted devices including cardiac pacemakers, size limitations, etc.

6. Inability to tolerate MRI without premedication, sedation, or anesthesia.

7. Known intolerance or allergies to MRI contrast agent (e.g. Gadolinium or Magnevist)

8. History of craniotomy or other prior cranial procedure that would render phase correction with CT inaccurate.

9. Subjects with risk factors for intraoperative or postoperative bleeding:

   1. Platelet count less than 100,00 per cubic millimeter
   2. INR coagulation studies exceeding local institution laboratory standards
   3. Documented coagulopathy

10. Subject with life-threatening systemic disease that include and not limited to the following: HIV, liver failure, blood dyscrasias, etc.