Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease

Martínez‐Fernández, Raúl; Máñez-Miró, Jorge U; Rodríguez‐Rojas, Rafael; Álamo, Marta del; Shah, Binit; Hernández-Fernández, Frida; Pineda‐Pardo, José A.; Monje, Mariana H.G.; Fernández-Rodríguez, Beatriz; Sperling, Scott A.; Mata-Marín, David; Guida, Pasqualina; Alonso-Frech, Fernando; Obeso, Ignacio; Gasca-Salas, Carmen; Vela-Desojo, Lydia; Elias, W. Jeffrey; Obeso, José A.

doi:10.1056/nejmoa2016311

Cited by 157 publications

(169 citation statements)

References 24 publications

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“…Recently, the results of our randomized double-blind clinical trial in collaboration with Dr. J. Elias and colleagues from Virginia Medical Center (USA) studying unilateral subthalamotomy in 40 asymmetrical PD patients became available. 24 We found significant motor improvement in the treated body side (ie, contralateral to the lesion hemisphere) with a median reduction in the Movement Disorder Society -Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (for the treated hemibody) of 52.6% (Video 1). Side effects such as speech or gait disturbances after treatment were frequent but mostly mild and transient, and 5 patients developed contralateral motor weakness which recovered in all cases.…”

Section: Subthalamotomymentioning

confidence: 81%

“…One FUS unilateral subthalamotomy pilot study from our team 23 suggested that subthalamic ultrasound ablation was feasible and resulted in a positive effect on PD motor features. Recently, the results of our randomized double‐blind clinical trial in collaboration with Dr. J. Elias and colleagues from Virginia Medical Center (USA) studying unilateral subthalamotomy in 40 asymmetrical PD patients became available 24 . We found significant motor improvement in the treated body side (ie, contralateral to the lesion hemisphere) with a median reduction in the Movement Disorder Society ‐ Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) part III (for the treated hemibody) of 52.6% (Video 1).…”

Section: Parkinson's Diseasementioning

confidence: 99%

See 1 more Smart Citation

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience

Martínez‐Fernández

Matarazzo

Máñez-Miró³

et al. 2021

Movement Disord Clin Pract

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Section: Subthalamotomymentioning

confidence: 81%

Section: Parkinson's Diseasementioning

confidence: 99%

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience

Martínez‐Fernández

Matarazzo

Máñez-Miró³

et al. 2021

Movement Disord Clin Pract

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“…However, physicians should be cautious that the incidence of permanent complications of MRgFUS may be higher than DBS due to the nature of lesioning [ 66 ]. For example, a recent randomized trial of MRgFUS subthalamotomy reveals a complication rate as high as 25%, including gait and speech disturbance as well as new onset of dyskinesia [ 67 ]. The complications reported in the same study are consistent with conventional radiofrequency subthalamotomy, despite the fact that subthalamotomy is performed unilaterally [ 68 ], so clinicians should be aware that any form of subthalamotomy may result in similar problems.…”

Section: Advanced Treatmentsmentioning

confidence: 99%

“…Bond et al report the suppression of tremor following the application of unilateral MRgFUS thalamotomy in patients with PD [ 69 ]. Regarding other targets, MRgFUS subthalamotomy and pallidothalamic tractotomy for PD lead to the improvement of MDS UPDRS or UPDRS Part Three scores [ 67 , 70 ]. Based on these studies it is hoped that, in the not too distant future, this treatment will have an effect not only on tremor but also on other motor features.…”

Section: Advanced Treatmentsmentioning

confidence: 99%

Personalized Medicine in Parkinson’s Disease: New Options for Advanced Treatments

Mishima

Fujioka

Morishita

et al. 2021

JPM

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Parkinson’s disease (PD) presents varying motor and non-motor features in each patient owing to their different backgrounds, such as age, gender, genetics, and environmental factors. Furthermore, in the advanced stages, troublesome symptoms vary between patients due to motor and non-motor complications. The treatment of PD has made great progress over recent decades and has directly contributed to an improvement in patients’ quality of life, especially through the progression of advanced treatment. Deep brain stimulation, radiofrequency, MR–guided focused ultrasound, gamma knife, levodopa-carbidopa intestinal gel, and apomorphine are now used in the clinical setting for this disease. With multiple treatment options currently available for all stages of PD, we here discuss the most recent options for advanced treatment, including cell therapy in advanced PD, from the perspective of personalized medicine.

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“…While there are several stimuli-responsive delivery systems, thermosensitive nano-formulations are of particular interest 19 - 22 , as they can be combined with MR guided Focused Ultrasound (MRgFUS) technology. MRgFUS that is already used in the clinic for minimally invasive thermoablative interventions against neurological diseases 23 offers unique advantages for targeted drug release in brain tumors. Most notably it can target multiple small tissue volumes deep within the brain and through the skull via the use of multi-element phase arrays 24 .…”

Section: Introductionmentioning

confidence: 99%

Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors

et al. 2021

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Effective drug delivery in brain tumors remains a major challenge in oncology. Although local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in solid tumors and improve outcomes, their application in intracranial malignancies remains unexplored. We hypothesized that the combined abilities of closed-loop trans-skull Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) hyperthermia with those of thermosensitive drugs can alleviate challenges in drug delivery and improve survival in gliomas. Methods: To conduct our investigations, we first designed a closed loop MR-guided Focused Ultrasound (MRgFUS) system for localized trans-skull hyperthermia (ΔT < 0.5 °C) in rodents and established safety thresholds in healthy mice. To assess the abilities of the developed system and proposed therapeutic strategy for FUS-triggered chemotherapy release we employed thermosensitive liposomal Dox (TSL-Dox) and tested it in two different glioma tumor models (F98 in rats and GL261 in mice). To quantify Dox delivery and changes in the transvascular transport dynamics in the tumor microenvironment we combined fluorescent microscopy, dynamic contrast enhanced MRI (DCE-MRI), and physiologically based pharmacokinetic (PBPK) modeling. Lastly, to assess the therapeutic efficacy of the system and of the proposed therapeutic strategy we performed a survival study in the GL261 glioma bearing mice. Results: The developed closed-loop trans-skull MRgFUS-hyperthermia system that operated at 1.7 MHz, a frequency that maximized the brain (FUS-focus) to skull temperature ratio in mice, was able to attain and maintain the desired focal temperature within a narrow range. Histological evidence (H&E and Nissl) suggests that focal temperature at 41.5 ± 0.5 °C for 10 min is below the threshold for tissue damage. Quantitative analysis of doxorubicin delivery from TSLs with MRgFUS-hyperthermia demonstrated 3.5-fold improvement in cellular uptake in GL261 glioma mouse tumors (p < 0.001) and 5-fold increase in delivery in F98 glioma rat tumors (p < 0.05), as compared to controls (TSL-Dox-only). Moreover, PBPK modeling of drug transport that was calibrated using the experimental data indicated that thermal stress could lead to significant improvement in the transvascular transport (2.3-fold increase in the vessel diffusion coefficient; P < 0.001), in addition to promoting targeted Dox release. Prospective experimental investigations with DCE-MRI during FUS-hyperthermia, supported these findings and provided evidence that moderate thermal stress (≈41 °C for up to 10 min) can promote acute changes in the vascular transport dynamics in the brain tumor microenvironment (K trans value for control vs. FUS was 0.0097 and 0.0148 min -1 , respectively; p = 0.026). Crucially, survival analysis demonstrated significant improvement in the survival in the TSL-Dox-F...

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Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease

Cited by 157 publications

References 24 publications

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience

The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience

Personalized Medicine in Parkinson’s Disease: New Options for Advanced Treatments

Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors

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