A Second Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Essential Tremor
A Second Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Essential Tremor
This study will be a single-centre, prospective, single-arm, open-label, 12-week pilot trial
 assessing the safety and preliminary efficacy of a second MR-guided focused ultrasound
 (MRgFUS) thalamotomy on the naïve brain hemisphere after 48 weeks or more of the first MRgFUS
 thalamotomy in patients with medication-refractory ET.

 This study will be conducted at the Focused Ultrasound Centre of Excellence at Sunnybrook
 Health Sciences Centre/University of Toronto.
Patients who are medication-refractory for ET often require a surgical option to relieve
 symptoms of ET and improve quality of life. To-date, unilateral MRgFUS has been beneficial in
 providing patients with some of relief from tremor. However, tasks that require two hands
 remain a challenge for many patients. Historical risks of bilateral treatment have been an
 impediment to complete tremor relief. The introduction of MRI and current stereotactic
 methodologies has significantly reduced the probability of non-target tissue injury. In this
 study, a second MRgFUS thalamotomy will be performed in a cohort of patients who have already
 successfully undergone unilateral MRgFUS treatment. Tremor severity, speech, balance, gait,
 and cognition will be assessed during baseline and follow up visits.
Inclusion Criteria:

 1. Individuals aged 22 years or older;

 2. Subjects who are able and willing to give consent and able to attend all study visits
 and MRgFUS procedure, understanding the associated risks, benefits, and alternative
 treatments;

 3. Diagnosis of ET as confirmed from clinical history and examination by a neurologist or
 neurosurgeon and unilateral MRgFUS thalamotomy at least 48 weeks prior;

 4. On a stable dose of medication for tremor for at least 4 weeks;

 5. Medication-refractory criterion: tremor refractory to adequate trials of at least two
 medications, one of which should be a first line therapy of either propranolol or
 primidone. An adequate medication trial is defined as a therapeutic dose of each
 medication or the development of side effects as the medication dose is titrated;

 6. Moderate-severe tremor severity criteria in the untreated hand: Despite medical
 treatment, untreated hand score of ≥2 points in the postural or intention component of
 the item 5 or 6 in the Part A of CRST, AND untreated hand score of ≥2 points in any
 one of the items 12-15 of the Part B of CRST;

 7. Disability criterion: ≥2 points in any one of the Part C items 17-23 as measured by
 the CRST;

 8. Able to communicate sensations during the MRgFUS treatment and to press the device
 STOP button.

 Exclusion Criteria:

 1. Patients with standard contraindications for MR imaging such as non-MRI compatible
 implanted metallic devices including cardiac pacemakers, size limitations, etc;

 2. Women who are pregnant;

 3. Gait subscore ≥2 points in the SARA scale;

 4. Speech subscore ≥2 points in the SARA scale;

 5. Patients with advanced kidney disease (with estimated glomerular filtration rate <30
 mL/min/1.73m2) or on dialysis;

 6. Patients with unstable cardiac status or severe hypertension including:

 1. Documented myocardial infarction within six months of enrollment

 2. Unstable angina on medication

 3. Unstable or worsening congestive heart failure

 4. Left ventricular ejection fraction below the lower limit of normal

 5. History of a hemodynamically unstable cardiac arrhythmia

 6. Cardiac pacemaker

 7. Severe hypertension (diastolic BP > 100 on medication);

 7. Patients exhibiting any behaviour(s) or clinical assessment consistent with ethanol or
 substance abuse;

 8. Patients with history of abnormal bleeding, hemorrhage, and/or coagulopathy defined as
 abnormal coagulation profile (platelet < 100,00/μl), PT (>14 sec) or PTT (>36 sec),
 and INR > 1.3;

 9. Receiving anticoagulant (e.g. warfarin) or antiplatelet (e.g. aspirin) therapy within
 one week of focused ultrasound procedure or drugs known to increase risk or hemorrhage
 (e.g. Avastin) within one month of focused ultrasound procedure;

 10. Ischemic or hemorrhagic stroke within 6 months;

 11. Patients with brain tumors;

 12. Individuals who are not able or unwilling to tolerate the required prolonged
 stationary position during treatment (approximately 2-3 hours);

 13. Patients who are currently participating in another clinical investigation with an
 active treatment arm;

 14. Patients who have had deep brain stimulation (DBS) or a prior stereotactic ablation of
 the basal ganglia with GKRS or radiofrequency;

 15. Patients who have been administered botulinum toxins into the arm for 5 months prior
 to baseline.

 16. Evidence of clinically important movement disorder, such as chorea, dystonia, or
 parkinsonism. Anyone with the presence of parkinsonian features including
 bradykinesia, rigidity, or postural instability will be excluded. Subjects who exhibit
 only mild resting tremor but no other symptoms or signs of Parkinson's disease may be
 included.

 17. Symptoms and signs of increased intracranial pressure (e.g. headache, nausea,
 vomiting, lethargy, and papilledema);

 18. Untreated, uncontrolled sleep apnea;

 19. Presence of any other neurodegenerative disease like multisystem atrophy, progressive
 supranuclear palsy, dementia with Lewy bodies, and Alzheimer's disease;

 20. Mild cognitive impairment with impairment in the domain of language as determined by
 screening neuropsychological battery and judged by study neuropsychologist;

 21. A known diagnosis of dementia of any cause;

 22. Uncontrolled major psychiatric disorder or suicidal ideation. Patients with
 psychiatric disorders identified on initial screening can be treated for these
 conditions before MRgFUS treatment and enrolled if deemed psychiatrically stable for
 at least three months before study entry. Any presence of psychosis will be excluded;

 23. Any illness that in the investigator's opinion preclude participation in this study;

 24. Patients with a history of seizures within the past year.

 25. Inability to generate a thermal thalamic lesion during the first MRgFUS procedure;

 26. Poor tolerance to the first MRgFUS procedure;

 27. Severe adverse event or moderate-severe adverse event related to the MRgFUS procedure
 or thalamotomy, such as clinically significant and permanent speech, language,
 sensory, motor or gait dysfunction.