Focused ultrasound therapy: Back to the future

• DOI: 10.1016/j.parkreldis.2024.106023
• Publication Date: 2024-02-02T00:59:13Z
• Authors: Leo Verhagen Metman; Mariana H.G. Monje; José A. Obeso; Raúl Martínez-Fer...

•MRgFUS is an FDA approved, incisionless, therapy for the treatment of ET and PD.•RCTs MRgFUS targeting VIM, GPi STN demonstrate benefit.•Case series PTT also suggest significant benefit.•Low-intensity can transiently open BBB.•Future technical developments studies will further define role MRgFUS. The surgical movement disorders, primarily tremor, started with radiofrequency lesioning globus pallidus thalamus in 1950s [[1]Hassler R. Riechert T. Symptomatology & surgery extrapyramidal disorders.Med. Klin. 1958; 53: 817-824http://www.ncbi.nlm.nih.gov/pubmed/13551836PubMed Google Scholar]. While this became a state-of-the-art over following decades, bilateral lesions were associated side effects such as gait, balance, speech disturbances [[2]Krayenbühl H. Wyss O.A.M. Yasargil M.G. Bilateral thalamotomy pallidotomy parkinsonism.J. Neurosurg. 1961; 18: 429-444https://doi.org/10.3171/jns.1961.18.4.0429Crossref PubMed Scopus (61) In 70's, radiosurgery gamma knife showed promise because procedure was incisionless. However, it used ionizing radiation, target could not be confirmed real-time, effect delayed by around six months. Consequently, never mainstream [[3]Walter B.L. Vitek J.L. Surgical Parkinson's disease.Lancet Neurol. 2004; 3: 719-728https://doi.org/10.1016/S1474-4422(04)00934-2Abstract Full Text PDF (138) Then, 1997, approved deep brain stimulation (DBS) tremor which gold standard treatment, no lesion made, reversible adjustable, allowed intraoperative confirmation target, and, done bilaterally 2016, we went 'back to future' when Magnetic Resonance-guided Focused Ultrasound (MRgFUS) ablation novel, tool make disorders (Fig. 1). Since its appearance early 2000s, technology has progressively gained traction disorder community incisionless therapy. consists helmet-shaped phased array transducer 1024 elements, controlled individually refocus ultrasound beams common focal point. Guided real-time magnetic resonance imaging, pass through intact skull focus precisely onto selected targets, major advantage avoiding penetration tissue between target. When focused at high frequency (MRgHiFU) (650 kHz) continuous-wave mode, cumulative thermal dose point (target) great enough produce coagulative necrosis. During MRgHiFU procedures, verified real time MR-thermography map, clinical feedback, structural MRI. addition, initial delivery low-energy sonication allows 'test lesion' only after exam shows benefit without effects, energy (temperature) increased becomes permanent, immediate results evident [[4]Krishna V. Sammartino F. Rezai A. A review current therapies, challenges, future directions transcranial technology: advances diagnosis treatment.JAMA 2017; : 1-9https://doi.org/10.1001/jamaneurol.2017.3129Crossref (171) Scholar] 2). Conceptually, any that been treated or DBS from lesioning. there ample evidence (ventral intermediate nucleus, VIM) [[5]Elias W.J. Lipsman N. Ondo W.G. Ghanouni P. Kim Y.G. Lee W. Schwartz M. Hynynen K. Lozano A.M. Shah B.B. Huss D. Dallapiazza R.F. Gwinn Witt J. Ro S. Eisenberg H.M. Fishman P.S. Gandhi Halpern C.H. Chuang Butts Pauly Tierney T.S. Hayes M.T. Cosgrove G.R. Yamaguchi Abe Taira Chang J.W. randomized trial essential tremor.N. Engl. Med. 2016; 375: 730-739https://doi.org/10.1056/NEJMoa1600159Crossref (687) Scholar,[6]Bond A.E. D.S. Warren Harrison M.B. Sperling S.A. Wang X.-Q. Elias Safety efficacy patients medication-refractory, tremor-dominant Parkinson disease.JAMA 74: 1412https://doi.org/10.1001/jamaneurol.2017.3098Crossref (210) Scholar], pars interna (GPi) [[7]Krishna Kaplitt Baltuch G. W.-C. Martinez Fernandez del Alamo Eleopra Guridi Khemani McDannold Fasano Constantinescu Schlesinger I. Dalvi Trial disease.N. 2023; 388: 683-693https://doi.org/10.1056/NEJMoa2202721Crossref (19) subthalamic nucleus (STN) [[8]Martínez-Fernández Máñez-Miró J.U. Rodríguez-Rojas Álamo Hernández-Fernández Pineda-Pardo J.A. Monje M.H.G. Fernández-Rodríguez B. Mata-Marín Guida Alonso-Frech Obeso Gasca-Salas C. Vela-Desojo L. Randomized subthalamotomy 2020; 383: 2501-2513https://doi.org/10.1056/NEJMoa2016311Crossref (99) other structures pallido-thalamic tract (PTT) [[9]Gallay M.N. Moser Rossi Magara Strasser Bühler Kowalski Pourtehrani Dragalina Federau Jeanmonod pallidothalamic tractotomy chronic therapy-resistant disease 51 consecutive patients: single center experience.Front. Surg. 6https://doi.org/10.3389/fsurg.2019.00076Crossref (34) cerebello-thalamic (CTT) [[10]Gallay accuracy MR-guided functional neurosurgery: single-center experience 253 targets 180 treatments.J. 2018; https://doi.org/10.3171/2017.12.jns172054Crossref considered but require assessment. If, on hand, low (MRgLiFU) (220 pulsed manner, low, due physical, non-thermal, interactions. This "per se" induce neuromodulation intravenous administration bubble-rich contrast agent. convergence bubbles circulation being leveraged preclinical attempts BBB, temporarily 'loosening' tight junctions endothelial cells normally restrict drugs endovascular space into surrounding tissue. Here aim summarize data regarding a) indications Essential (ET) (PD); b) investigational PD; 3) investigations MRgLiFU. first two open-label unilateral FUS-VIM medically refractory published 2013 [[11]Elias Voss Loomba Khaled Zadicario E. Frysinger R.C. Wylie Monteith S.J. Druzgal Wintermark pilot study 2013; 369: 640-648https://doi.org/10.1056/nejmoa1300962Crossref (0) Scholar,[12]Lipsman M.L. Huang Y. Sankar Chapman tremor: proof-of-concept study.Lancet https://doi.org/10.1016/S1474-4422(13)70048-6Abstract (438) suggested might effective treat improvements both disability quality life. Soon after, colleagues pivotal follow-up analyses 3 [[13]Halpern Santini Aldrich Jung N.Y. Rosenberg Three-year prospective tremor.Neurology. 2019; 93https://doi.org/10.1212/WNL.0000000000008561Crossref (62) 5 years [[14]Cosgrove V.E. imaging–guided 5-year results.J. 2022; 1-6https://doi.org/10.3171/2022.6.JNS212483Crossref (8) Using Clinical Rating Scale Tremor (CRST), they found contralateral postural maintained > 70 % improvement years. combined scores postural, kinetic rest well writing, drawing spirals pouring cup (CRST + B) affected hand improved 55 one year, 40 score (CRST-C) decreased 67 45 As far are concerned, reported analysis adverse events (AEs) including above [[15]Fishman Krishna Yamada Igase Kashima Neurological event profile tremor.Mov. Disord. 33: 843-847https://doi.org/10.1002/mds.27401Crossref (79) They documented 443 AEs 186 grouped them three categories: 1. Frame related, pin site numbness, infection, pain; 2. Sonication headache, scalp burn, lightheadedness, nausea, vomiting; 3. Thalamotomy divided four subgroups: A) Sensory disturbances, paresthesia, dysesthesias, dysgeusia; Speech swallowing dysarthria, dysphagia; C) Balance gait ataxia; D) Weakness limb coordination. Most mild (79 %) moderate (20 %). Of 1 (n = 5) rated severe, sonication-related transient, lasting less than days post-procedure. changes most neurological (45 all AEs), none severe 91 (84 92) mild. Severe rare (3 balance deficits) December 2022. (NCT04112381) still published, previous smaller [16Iorio‐Morin Yamamoto Sarica Zemmar Levesque Brisebois Germann Loh Boutet G.J.B. Azevedo Adam Patel U. Lenis Kalia S.K. Hodaie (BEST‐FUS Phase 2 trial).Mov. 2021; 36: 2653-2662https://doi.org/10.1002/mds.28716Crossref (45) Scholar, 17Martínez-Fernández Mahendran Imbach L.L. Büchele Rodriguez-Rojas Werner Matarazzo Gonzalez-Quarante L.H. Deuschl Stieglitz Baumann C.R. staged resonance-guided case study.J. Psychiatry. 92: 927-931https://doi.org/10.1136/jnnp-2020-325278Crossref (26) 18Fukutome Hirabayashi Osakada Kuga Ohnishi imaging-guided tremor.Stereotact. Funct. 100: 44-52https://doi.org/10.1159/000518662Crossref (14) support relative safety FUS-VIM. BEST-FUS trial, 10 received second, contralateral, 9 months [[16]Iorio‐Morin primary outcome life response question; 'given what you know now, would second again', outcomes met. Improvement severity expected, more importantly, benign. After had some difficulties resolved within number missteps during 6 m tandem walking slightly up initially returned baseline There person dysarthria persisted 3-month On Spanish-Swiss study, where secondary outcome, underwent least [[17]Martínez-Fernández Six experienced instability weeks, permanent. concerned 71 total CRST (67 B, 81 C). 66 head voice respectively PD, thalamic VIM (TDPD), advanced disease. These nuclei have ablative procedures PD motor complications (MRCs), respectively, decades. explored, PTT. summary main trials each Table European Union, additional application.Table 1Main disease.ReferenceStudy designTargetNumber patientsFollow-upAdverse last (12 months)Primary outcomeBond et al., 2017 [[6]Bond Scholar]Prospective, randomized, sham-controlled, double blind trialThalamic Vim27 TDPD patients. 20 receiving 7 sham procedure3 blinded (1ary outcome), 12 labelHemiparesis n (10 Paresthesia (25 %)Ataxia (5 %)Vocal change %)62 median reduction subscores (parts on-medication active-treatment arm vs 22 sham-procedure armMartínez-Fernández 2020 double-blind trialSTN40 asymmetrical 27 13 procedure4 labelLevodopa-induced dyskinesia (7 %)Clumsy %)Dysarthria (4 %)Balance %)−53 mean MDS-UPDRS III off-medication 4.2 arm.-Between-group difference 8.1 points.Krishna 2023 trialGPi94 69 25 labelDysarthria (2 %)15 Serious 10)−69 responders rate* 32 arm.Mean MDS---UPDRS 6.0 points.-Mean IV 5.1 pointsGallay Scholar]Open-label seriesPTT47 (15 treatment)12 %)−51 off-medication.-Mean 84 rigidity, 73 bradykinesia hemibody.−100 levodopa-induced dyskinesiasAE: events; CRST: Tremor; GPi: interna; MDS-UPDRS: Movement Disorders Society-Unified Disease Scale; PD: disease; PTT: tract. STN: nucleus; TDPD: dominant VIM: ventral nucleus. Open table new tab AE: earliest placebo. Primary groups. ON-medication 62 year. quite persistent months: finger paresthesia (1), orofacial (4), ataxia hemiparesis (2), (1). authors commented encouraging, dealing learning curve, likely improve "as monitoring improves" (Table 26 TDPD, Israel long term results, relief few [[19]Sinai Nassar Sprecher Zaaroor disease: long-term Parkinsons Dis. 12: 199-206https://doi.org/10.3233/JPD-212810Crossref (23) Median hemi-CRST hemi-UPDRS month (N 26) 60 92 %, 53 61 7). permanent transient unsteadiness, ataxia, weakness, taste changes, then resolved. complete, 8 partial return. Similar Japan [[20]Yamamoto Ito Fukutake Odo Kamei YamaguchiI 1-year study.Neurol. Med.-Chir. (oa.2020-0370)https://doi.org/10.2176/nmc.oa.2020-0370Crossref (17) recently (2021) GPi, indicated MRCs. An label 20) FUS-GPi OFF-medication MDS-UPDRS-III 43 Unified Dyskinesia (UDysRS). No AE occurred frequent complication [[21]Eisenberg C.E. feasibility.J. 135: 792-798https://doi.org/10.3171/2020.6.JNS192773Crossref (28) subsequent double-blind, (3:1 ratio), sham-controlled enrolled 94 MRCs positive response, defined (improvement) points either part state OR UDysRS state, clinically meaningful worsening scale, percentage twice group (69 compared (33 active 65) 29 met criterion only, 28 criteria, 31 neither criterion. 22), these numbers 0 68 respectively. For side, 21 MDS-UPDRS-IV 48 %. Corresponding 39 who months, 30 continued included 1), visual disturbance 1) facial weakness At patient remained Anecdotally, successful presenting disabling dyskinesias [[22]Stieglitz Oertel M.F. Parkinson‐related dyskinesia—a report.Mov. Clin. Pract. 9: 647-651https://doi.org/10.1002/mdc3.13462Crossref (2) Contrary classically therapeutic neurosurgical [[23]Máñez-Miró Del Martínez-Fernández Present management systematic review.Expert Rev. 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