The potential of focused ultrasound in Neurosurgery.

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Né le 31 décembre 1491 Saint-Malo, duché de Bretagne Décédé le 1er septembre 1557 (à 65 ans) Saint-Malo, Royaume de France Occupation navigateur et explorateur français Connu pour être le premier Européen à voyager à l'intérieur des terres en Amérique du Nord. Réclamé ce qui est maintenant connu sous le nom de Canada pour le Royaume de France Jacques Cartier

Transcript of The potential of focused ultrasound in Neurosurgery.

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Né le 31 décembre 1491

Saint-Malo, duché de Bretagne

Décédé le 1er septembre 1557 (à 65 ans)

Saint-Malo, Royaume de France

Occupation navigateur et explorateur français

Connu pour être le premier Européen à voyager à l'intérieur des terres en Amérique du Nord. Réclamé ce qui est maintenant connu sous le nom de Canada pour le Royaume de France.

Jacques Cartier

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The potential of focused ultrasound in Neurosurgery

Thérapie ultrasonore pour les troubles cérébraux

1. Lésions 2. Stimulation 3. Ouverture BBB

Andres M Lozano MD PhD

Professor and Chairman of Neurosurgery

University of Toronto

Congres Annuel de la Societe Francaise de Neurochirurgie

St-Malo, France

Octobre 14, 2020

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Pénétration trans-cranienne

Guide par imagerie

1950’s to 2010’s

1. Ultrason concentré pour faire des lésions dans le cerveau

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MR guided Focused Ultrasound in Neurosurgery

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Magnetic Resonance Guided Focused Ultrasound

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Fig. 3 Evolution of magneticresonance-guided focusedultrasound thalamotomy lesionover time. On the day 1 scan, thecenter of the lesion in the rightventro-intermediate (Vim)nucleus of the thalamus is marked with a red asterisk. The lesion in the same location is shown at 1 week, and 1 and 3 months following treatment. Over time, edema surrounding the ablation site subsides leaving a wellcircumscribed lesion within the Vim thalamus by 3 months

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PRE TREATMENT TREMOR EVALUATION

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N=16 Bilateral Thalamotomies

N=27 UnilateralThalamotomies

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N=12 Bilateral ViM DBS

N=16 Unilateral ViM DBS

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Staged bilateral FUS thalamotomy in ET patients with arrow side 1, * side 2 with a 6m to 12 m interval between sides.

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Major Treatment Options for Parkinson’s and other Movement Disorders

When medications fail as first line therapy, surgical options may be considered. There are 3 major surgical options for the treatment of PD and other movement disorders.

Surgery Radiofrequency lesioning (RF) Deep Brain Stimulation (DBS) Radiosurgery MR-Guided Focused Ultrasound (MRgFUS)

RF pallidotomy or thalamotomy involves inserting a probe into the brain and heating the tip of it, so that the neurons in that region are destroyed.

DBS involves the implantation of electrodes into the brain. Electrodes are then connected to a battery placed under the collar bone (a device similar to a pacemaker), which provides constant electrical stimulation to disrupt activity in this brain region.

A non-invasive procedure uses radiation to generate a permanent brain lesion.

MR-guided focused ultrasound uses ultrasound waves to generate a permanent lesion in a specific brain region.

Benefits Highly effective at controlling dyskinesias, and off-period dystonia . Tremor, rigidity and slowness can also improve.

Highly effective at controlling dyskinesias, and off-period dystonia. Tremor, rigidity and slowness can also improve.

Non-invasive Non-invasive (i.e. no incision or hole in the skull)

Large local and global experience Large local and global experience Radiation No radiation- sound

Pallidotomy has a prolonged effect on dyskinesia with reported benefit of up to 13.5 years. Thalamotomy is effective for tremor control.

Reversible (i.e. no lesion is generated and the hardware can be removed)

Delayed clinical effects Real-time MRI image guidance immediate effects

Thalamotomy effective for tremor Stimulation levels can be externally programmed and adjusted to minimize side-effects

Risks Stroke (e.g. bleeding in the brain) Stroke (e.g. bleeding in the brain) No risk of stroke Little risk of Stroke

Infection Infection

Neurologic injury (e.g. temporary or permanent numbness, weakness, tingling, unsteadiness, speech difficulty)

Neurologic injury with surgery or stimulation induced side effects(e.g. temporary or permanent numbness, weakness, tingling, unsteadiness, speech difficulty)

Neurologic injury possible Neurologic injury (e.g. temporary or permanent numbness, weakness, tingling, unsteadiness, speech difficulty)

Frame, Burr hole Hardware malfunction Frame Discomfort from positioning (lying 3-4 hours in MRI during treatment). Frame, hair shave.

Attributes Requires an operation with passage of a needle electrode through the brain tissue (skin incision, drilling)

Requires an operation, skin incision, drilling the skull, inserting electrodes in the brain and general anesthesia

Approved for tremor, other indications experimental treatment.

Irreversible (permanent lesion generated) Irreversible (permanent lesion generated)

Usually only one side can be treated Can treat both sides of the brain Bilateral? Usually Only one side can be treated

Follow up visits required to maintain and adjust the implanted system

Low maintenance Low maintenance

Periodic need to replace the battery (i.e. approximately every 3-5 years)

Long term effectiveness for tremorPallidotomy safety?

Long-term effectiveness for tremorSafe for thalamotomy and pallidotomy

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Indication Stage Status

ET Phase II, III 2 phase I studies completed. Randomized, double-blind, sham-controlled study currently being conducted [39, 46]

PD Phase I Phase I trial now recruiting for MRgFUS pallidotomy for levodopa-induced dyskinesias of PD and thalamotomy for tremor-dominant PD

Brain Tumor Ablation Phase I Phase I study now recruiting patients

Brain tumor—BBB disruption Phase I Phase I study now recruiting patients

Depression/Anxiety Phase I Phase I trial now in development for MRgFUS cingulotomy in patientswith treatment-refractory OCD and major depression

Pain Syndrome Phase I Models in cadaveric models completed and have shown feasibility of trigeminal nerve root entry zone lesions [56]. Phase I study under development

Open-label studies of centromedian thalamotomy for neuropathic painpublished and continue to recruit [35, 52]

Epilepsy Preclinical Models investigating the feasibility of MRgFUS-mediatedamygdalohippocampectomy now in process

AD Preclinical Models in transgenic mice have shown that MRgFUS BBB disruptionresults in influx of anti-Aβ antibodies and subsequent reduction ofplaque burden [22, 91]

Thrombolysis/intracerebral hemorrhage

Preclinical Swine and human cadaveric models demonstrated feasibility of ICH liquefaction. Rabbit carotid occlusion model demonstrated feasibility of this model for vascular recanalization [61, 75–77]

CSF diversion Preclinical Preclinical study performed, providing proof-of-principle of MRgFUSthird ventriculostomy [92]

Table 1 Current magnetic resonance-guided focused ultrasound (MRgFUS) indications under investigation and their status

ET=essential tremor; PD=Parkinson’s disease; BBB=blood–brain barrier; AD=Alzheimer’s disease; CSF=cerebrospinal

fluid; OCD=obsessive–compulsive disorder; Aβ=amyloid beta; ICH=intracerebral hemorrhage

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VIM

PTT

STN

GPi

FUS lesion Targets in use for PD

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Pallidotomy

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Results: The Unified Parkinson’s Disease Rating Scale (UPDRS) off-medication postoperative score was compared to the baseline on-medication score and revealed percentage reductions of the mean of 84% for tremor, 70% for rigidity, and 73% for distal hypobradykinesia, all values given for the treated side. Axial items (for voice, trunk and gait) were not significantly improved. PTT achieved 100% suppression of on-medication dyskinesias as well as reduction in pain (p < 0.001), dystonia (p < 0.001) and REM sleep disorders (p < 0.01). Reduction of the mean L-Dopa intake was 55%. Patients reported an88%meantremorreliefand82%meanglobalsymptomreliefontheoperatedsideand 69% mean global symptom improvement for the whole body. There was no significant change of cognitive functions. The small group of bilateral PTTs at 1 year follow-up shows similar results as compared to unilateral PTTs but does not allow to draw firm conclusions at this point.

36 Unilateral, 15 bilateralUPDRS part III 55% reduction

Pallidothalamic Tractotomy

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Subthalamotomy

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MRgFUS Bilateral Thalamotomy for pain

from Daniel Jeanmonod

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Beistesteiner and

Lozano 2020

2. Focused Ultrasound for Brain Stimulation

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Ultrasons et stimulation cerebraledéveloppements possibles

• Cartographie du cerveau- repérage des fonctions -moteur, sensoriel, la parole, etc

• Livraison d’ultrasons à des cibles profondes pour prédire l’effet des interventions chirurgicales - DBS

• Possibilité de stimulation chronique répétitive pour produire des effets thérapeutiques par exemple l’inhibition des noyaux profonds comme cela se produit avec DBS

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Perturbation de BBB à l’aide de microbulles

qui s’accompagnent d’une contraction et

d’une expansion avec ultrasons

3. FUS for BBB Opening

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Chimiotherapie

Thérapie génique

Facteurs neurotrophiques

Correction génétique

Oligonucléotides antisens Compensation des protéines pathologiques

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Cellules

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Beisteiner et al., 2019

Delivery of FUS

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Conclusions

• DBS est bon, mais ... • Retour aux lésions ? Un pas en arriere?• Tendance vers des thérapies mini-invasives- MRgFUS• Contrairement à Gamma Knife, les effets de la lésion FUS sont immédiats• Cirurgie ambulatoire • patients et médecins qui fuient la chirurgie accepte MRgFUS• L’innocuité et l’efficacité de la chirurgie bilatérale est en cours d’évaluation• Rapprochement / Brouillage des frontières entre la neurologie, la radiologie et la

neurochirurgie-• Première indication tremblement, plusieurs nouvelles indications en cours de

développement • FUS peut contribuer non seulement en faisant des lésions mini-invasives, mais possiblement

aussi en neuromodulation et l’ouverture BBB.

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Colleagues • Neurology/Psychiatry

David Tang Way, Richard Wennberg, Anthony Lang

Alfonso Fasano, Renato Munoz, Elena Moro, Blake Woodside

Helen Mayberg, Sid Kennedy, Peter Giacobbe, Kostas Lyketsos

• Psychology/imaging

Mary Pat McAndrews, Gwenn Smith, Mallar Chakravorty, Alex Boutet

• Neurosurgery

Michael Schwartz, Clement Hamani, Hiroki Toda,

Adrian Laxton, Nir Lipsman, Tejas Sankar,

Soha Alomar, Ido Strauss, Vibhor Krishna, Moji Hodaie

Suneil Kalia, Elise Gondard, Irene Harmsen, Gavin Elias, Anton Fomento

• Corporate: GE, Insightec, Boston Scientific, Functional Neuroneuromodulation

Fellows- 70 talented fellows, PhD students from throughout the world.

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Funding