The Impact of Focused Ultrasound Thalamotomy of the Anterior Nucleus for Focal-Onset Epilepsy on Anxiety

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the feasibility, safety, and effects on anxiety of high intensity focused ultrasound ablation (FUSA) in patients suffering from treatment-refractory focal epilepsy and anxiety. FUSA is a non-invasive neurosurgical procedure that uses ultrasound waves, sent directly through the scalp and skull, to precisely target small abnormal areas of the brain. For this study, the targeted area of the brain is the anterior nucleus of the thalamus. This brain region may cause seizures and may also be involved in anxiety. The study will test if FUSA is safe and tolerated, and if it reduces anxiety and brain response to threat in patients with anxiety receiving the procedure for partial-onset epilepsy that is resistant to medications.

Detailed Description
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This is an open-label, Phase 1 prospective intervention study. Ten (10) adults with refractory, partial-onset epilepsy with moderate-severe anxiety and able to provide informed consent will be enrolled. Patients, eligible for Magnetic Resonance Imaging-guided Focused Ultrasound Ablation (MRgFUSA) of the anterior nucleus of the thalamus (ATN) for treatment-refractory epilepsy and who present moderate-severe anxiety will be enrolled. In addition to the diagnosis of medically refractory epilepsy, patients will need to present moderate to severe anxiety (as measured by the Hamilton Anxiety Rating Scale, HAM-A; HAMA score > 17) and other protocol specific inclusion and exclusion criteria. Medication-refractory partial or focal-onset epilepsy is often associated with enhanced fear behaviors and clinical anxiety. Exaggerated amygdala reactivity to threat is a cardinal neural phenotype of fear and anxiety disorders. The study will determine if MRgFUSA-ATN is feasible and safe and its effects on anxiety, using neuroimaging and neurological, neurocognitive/neuropsychological, psychiatric assessments before, and 1 day, 1 week, 1 month, 3 months, 6 months and 12 months post MRgFUSA. Feasibility is defined as the ability to create the desired lesion within the anterior nucleus of the thalamus and perform fMRI to measure threat reactivity. Safety will be measured by recording and analyzing any adverse effects that may occur from before surgery through 12 months following the surgery. These will include any new onset of neurological deficits, or performance deterioration on neuropsychological testing. Effects on anxiety will be measured using amygdala reactivity to threat by fMRI and patient- and clinician-reported measures of anxiety symptoms before and after MRgFUSA-ATN up to 12 months.

Official Title
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Magnetic Resonance-guided Focused Ultrasound Ablation of the Anterior Thalamus as a Novel Treatment Paradigm for Anxiety

Conditions
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Anxiety, Medication-refractory Focal-onset Epilepsy

Intervention / Treatment
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* Device: Magnetic Resonance Imaging-guided Focused Ultrasound Ablation (MRgFUSA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disabling, medically refractory epilepsy (≥2 anti-epileptic drug failures). Focal onset seizures with secondary generalization; with or without primary generalized seizures. Previous seizure work-up within 12 months of enrollment date to include: A. Home EEG or EMU video EEG or intracranial EEG. B. High definition MRI imaging/PET imaging. C. Baseline neuropsychological assessment, which includes the Wechsler Advanced Clinical Solutions - Test of Premorbid Functioning (TOPF). ≥ 3 seizures/month on average within 3 months of enrollment. Stable medication (including anti-epileptic and psychotropic/psychoactive medications) dosage for 3 months before enrollment. Moderate-severe anxiety as measured by the Hamilton Anxiety Rating Scale (HAM-A) score > 17. Anterior Nucleus (AN) identifiable on MRI (structural T1 and T2 images). Willing to maintain seizure diary (3 months before & 3 months after). Involved care provider. Written informed consent to participate. Ability to comply with all testing, follow-ups, and study appointments and protocols. Exclusion Criteria: Low seizure frequency (<3 seizures/month). Generalized epilepsy (Lennox Gastaut, drop attacks). Post infectious epilepsy (post herpetic). Unable or unwilling to maintain anti-epilepsy drug dosage for 3 months post treatment. Active (current in past 12 months), uncontrolled DSM-5 psychiatric disorder, except for anxiety disorders. Recent (past 12 months) history of drugs or alcohol abuse as evidenced by diagnosis of Substance Use Disorder. Active suicidal ideation current and past 30 days. Clinically significant neurological disorder, except for epilepsy. Presence of any neurodegenerative disease suspected on neurological examination. These include but are not limited to: Multisystem atrophy; Progressive supranuclear palsy; Dementia with Lewy bodies; Alzheimer's disease; Parkinson's disease. Cerebrovascular disease (multiple CVA or CVA within six months). Significant structural brain abnormalities. Surgical lesion identifiable on imaging. Symptoms and signs of increased intracranial pressure. Patients with any types of brain tumors, including metastases. Previous vagal nerve stimulator. Previous corpus callosotomy. Patients who have had deep brain stimulation. Prior stereotactic ablation. Positive urine drug screen at study entry or any follow-up testing session. For cannabis, exclusion includes positive drug screen with self-report of cannabis use in the past 48 hours. Known allergic reaction and/or hypersensitivity to IV dye and/or IV contrasting agent(s). Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc. History of claustrophobia. Unstable cardiac status including: Unstable angina pectoris on medication; documented myocardial infarction within last 40 days to protocol entry; Congestive heart failure; Severe hypertension (diastolic BP> 100 on medication). Patients receiving dialysis; Patients with risk factors for intraoperative or postoperative bleeding: Platelet count less than 100,000 per cubic millimeter; PT> 14PTT > 40; INR > 1.43. History of abnormal bleeding and/or coagulopathy. Receiving anticoagulant (e.g., Warfarin) or antiplatelet (e.g., aspirin) therapy within one week of focused ultrasound procedure or drugs known to increase risk of hemorrhage (e.g., Avastin) within one month of scheduled focused ultrasound procedure. History of intracranial hemorrhage. Active or suspected, acute or chronic uncontrolled infection or known life-threatening systemic disease; History of immunocompromised status, including patients who are HIV positive. Subjects with remarkable atrophy and poor healing capacity of the scalp. Evidence for calcifications that might interfere with treatment safety (per CT). Skull Density Ratio (SDR) <0.4. Pregnancy or lactation or planning to become pregnant during the time-period of the study. Any illness that in the investigators' opinion preclude participation in this study. Individuals who are not able or willing to tolerate the required prolonged stationary supine position during treatment (can be up to 4 hrs of total table time); IQ score of <70 on the Wechsler Advanced Clinical Solutions - Test of Premorbid Functioning (TOPF), measured as part of screening neuropsychological assessment. Presence of significant cognitive impairment as determined with a score ≤24 on the Mini Mental Status Examination (MMSE). Patients unable to communicate with the investigator and staff. Legal incapacity or limited legal capacity.

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: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Single arm, open-label, prospective intervention study of MRgFUSA for adults with refractory, partial-onset epilepsy with moderate-severe anxiety
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Unilateral Magnetic Resonance Imaging-guided Focused Ultrasound Ablation (MRgFUSA) of the anterior nucleus of the thalamus (ATN) | Device: Magnetic Resonance Imaging-guided Focused Ultrasound Ablation (MRgFUSA)<br>* Unilateral Magnetic Resonance Imaging-guided Focused Ultrasound Ablation (MRgFUSA) of the anterior nucleus of the thalamus (ATN)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Safety will be determined by an evaluation of the incidence and severity of MRgFUSA-ATN and other research procedures related adverse events from the 1st study visit through the 12-month post-treatment time point. Post-procedural imaging will be evaluated for evidence of swelling, hemorrhage, and the evolution of the ATN lesion. Emergence of complications will be monitored by neurological examination at day 1, day 7, month 1, month 3, month 6 and month 12 post-procedure. A comprehensive battery of neuropsychological assessments will be conducted by board-certified neuropsychologists at study screening, 3-month and 12-month postoperative time points. All events that are not procedure related will also be captured and recorded. | 12 months | 
| Target | Feasibility will be determined by ability to create the desired lesion within the anterior nucleus of the thalamus as assessed by neuroimaging | 1 month | 
| Change in Anxiety symptoms | Change in anxiety symptoms will be measured using clinician-administered HAM-A scale before the procedure and at various time points after the procedure. HAM-A is the scale of reference used in clinical trials to rate the severity of symptoms of anxiety in patients. It will be collected before and after the procedure at day 1, 7, months 1, 3, 6 and 12 to determine any effect and its change overtime. | 12 months | 
| Effect on Threat Reactivity | Change in Threat reactivity measured by fMRI task just before and after MRgFUSA | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seizure frequency | Change in seizure frequency between before the procedure and after will be assessed by online or hard copy seizure diary | 12 months | 
| Ability to perform the threat reactivity fMRI task just before and after MRgFUSA | Ability to perform the fMRI task before and after MRgFUSA will be assessed by recording any delay or inability to perform the assessment | 4 years | 
| Change in self-reported anxiety symptoms | Change in Self-report symptoms of anxiety using the Beck Anxiety Inventory from before the procedure up to 12 months post-procedure. | 12 months | 
| Change in self-reported anxiety symptoms | Change in Self-report symptoms on the Anxiety, Depression, Stress scale from before the procedure up to 12 months post-procedure | 12 months | 
| Change in quality of life | Change in quality of life between before and after the procedure will be measured using the Quality of Life in Epilepsy Inventory before and up to 12 months after the procedure | 12 months | 
| Rate of Patient Accrual | Feasibility will be assessed by measuring the rate of patient accrual over the 4 years of the study | 4 years |