MR Guided Focused Ultrasound Treatment for Essen7al Tremor

Transcription

1 MR Guided Focused Ultrasound Treatment for Essen7al Tremor Paul S. Fishman MD, PhD Professor of Neurology University of Maryland School of Medicine Chief of Neurology VA Maryland Health Care System

2 Brain Surgery for Movement Disorders 1960s: Cryo-Thalamotomy for ET and PD, Pallidotomy for PD. Effec7ve, but unexpected complica7ons on speech and swallowing, and replaced by DBS

3 Seventy Years of Brain Therapeu7c Ultrasound 1940 s Lynne and Putnam Neuromodula7on in cats 1950 s Frey brotherscoagula7on lesions deep in primate brain 1960 s Early treatment of brain tumors Meyer, Lindstrom Early studies needed to remove the skull

4 Sonic Energy and Tissue Sonic Energy Can: Penetrate, Reflect (ScaZer) or be Absorbed (related to 7ssue density) Sonic Energy can be focused Absorbed sonic energy is converted to thermal energy-heat Moderate temperature rise reversible (40-50) change in func7on. Higher temperature (55-60 degrees) irreversible 7ssue coagula7on

5 Applica7on of Therapeu7c Ultrasound to the CNS Accuracy of targe7ng is enhanced by using a focusable array of aligned sonic emizers (1000) where the point of intersec7on receives mes the sonic energy. (same principle as Gamma Knife)

6 MRI can measure local brain temperature a^er each sonic treatment in real 7me sonica7on Controlled crea7on of a temporary and then permanent lesion monitoring of both brain temperature and pa7ent response for both symptom relief and side effects

7 First FUS Thalamotomy Trial for ET 15 Patients (Elias 2013 NEJM) Underwent Unilateral FUS for Severe, Disabling, Medically Refractory Tremor of the Dominant Hand

8 Adverse Effects in FUS/ET Trial (N=15)

9 ET/FUS Pivotal Trial (Elias 2016, NEJM) Mul7-center, sham controlled, double blind with primary outcome by videotape with raters unaware of side or 7ming

10 ET/FUS Pivotal Trial: Pa7ent Selec7on Medically refractory or intolerant to at least two medica7ons including propranolol or primidone Tremor ra7ng of >/= 2/4 in dominant hand Disabling tremor on at least 1 of 8 ADL items (such as wri7ng, drinking) MRI able (not claustrophobic, no pacemaker) Able to lay flat for up to 4 hours No bleeding disorders, severe depression, demen7a Skull Density Ra7o of greater than 0.45 (excluded 11%) on special CT scan

11 ET/FUS Pivotal Trial: Tremor Severity in Treated Hand

12 ET/FUS Pivotal Trial: Improvement in Disability

13 Improvement for U of Maryland Patients *Clinical Rating Scale for Tremor

14 ET/FUS Trial: Side Effects a^er Treatment

15 ET/FUS Pivotal Trial: Side Effects During Treatment (N=50)

16 MRI Loca7on of Peak Brain Temperature Predicts Lesion Loca7on with Reduc7on Of Tremor Thermal lesion will shrink with 7me 1 WK 1 MO

17 DBS and FUS: Similari7es and Differences DBS Standard Care (150K pa7ents) Head Frame Pa7ent coopera7on needed with pain Surgical placement of system (two stages) with known risks of bleeding (1%), infec7on (1-2%) Adjustable device to maximize long-term benefit, but requiring programming, bazery replacement with chance of breakage malfunc7on (2%) Treats both sides FUS FDA approved (7/16) for ET (700 brain pa7ents) Head Frame Pa7ent coopera7on needed with discomfort Non- Incisional local brain destruc7on with frequent (10-15%) mild deficits, but without bleeding of infec7on One 7me treatment no device, no bazery, but no opportunity (currently) for retreatment if loss of benefit or worsening symptoms Only treats one side (currently)

18 Long-Term Efficacy DBS Majority of pa7ents con7nue to worsen, but are significantly bezer when the s7mulator is on a^er at least 5 years Majority of pa7ents worsen in spite of programing (3 visits per year with travel) Lesioning/FUS Significant worsening over years a^er lesioning, but with significant improvement with re-lesioning Mild worsening in the first year a^er FUS No experience with re-lesioning with FUS Conclusion: Current superiority of DBS over FUS

19 Could MRgFUS Be Less Injurious to the Brain than Op7mal DBS? HIFU makes a brain lesion while DBS does not require an inten6onal brain injury All of the HIFU lesion is at/ near the target (5mm diam. = 50mm 3), while DBS makes 1.5 passes with a 2x50mm rigid probe = 250mm 3 of poten7ally compromised nontarget brain 7ssue. Increasing reports of worsening gait and cogni7on in PD pa7ents years a^er DBS. Is this a pass effect on damaged sub-cor7cal fibers? 3

20 Current Status of CNS MRgFUS IndicaHons IndicaHon Stage/Status ET Unilateral treatment FDA approved July 2016 (U of MD) PD Phase I trial ongoing for pallidotomy wearing off/dyskinesia (U of MD). Phase I thalamotomy for tremor-dominant PD completed (UVA) Brain tumor BBB disruphon Phase I study now recrui7ng in Toronto Depression/OCD Phase I- cingulotomy, ALIC Pain Open-label - thalamotomy for neuropathic pain published/expanding Epilepsy Preclinical models inves7ga7ng the feasibility of amygdalohippocampectomy, Enrolling for focal subcor7cal epilepsy (UVA/Miami) AD Preclinical models in transgenic mice showing BBB disrup7on, and plaque reduc7on. Phase I approved in Toronto

21 FUS CNS Research: Highly Inter-Disciplinary Radiology/MRI/FUS: Frenkel, Gullapalli, Ghandi, Melham, Xu Medical Physics: Dayan (Insightec) Neurosurgery: Eisenberg, Woodworth, Simard Pharmacology: Shen, Yarowsky Neurology: Fishman, VonCoelln University of Maryland/Bal7more VA is one of only two US sites with both small animal and clinical MRIgFUS systems with funding by the FUS Founda7on, VA, MJ Fox Founda7on, Insightec