Subthalamotomy by ExAblate Transcranial System to Treat Motor Features of Parkinson's Disease

This ExAblate Transcranial system was built atop the ExAblate Body system technology, which has received EMA and CE approvals for the treatment of uterine fibroids and bone metastasis palliation, and is currently being evaluated under various EMA Investigational Device Exemptions "IDE". It should be noted that the ExAblate Transcranial/Neuro has received CE approval (Dec-2012).

There are many potential advantages for applying ExAblate Transcranial subthalamotomy for the treatment of idiopathic PD:

- The procedure is transcranial, requiring no incision, no burr hole, and no electrode. The risk of hemorrhagic complication should be reduced, and this procedure should eliminate the risk of infectious complications.

- Unlike stereotactic radiosurgery, ExAblate Transcranial system does not use ionizing radiation and does not carry a risk of radiation-induced tumorigenesis. The effects are immediate and not latent as with radiosurgery.

- Unlike radiofrequency ablation, ExAblate Transcranial system thermal lesioning can be performed without open surgery.

- The ExAblate treatment can be monitored in real-time with MRI and MR-thermal feedback which permits immediate confirmation of the targeting process. Additionally, the treatment can be monitored with clinical testing.

- Unlike DBS treatment, there is no implanted hardware, no concern of interference with external sources of electromagnetic noise, no need for extensive follow-up for programming, and no need for periodic battery replacement.

ExAblate Transcranial treatments may represent a simpler treatment algorithm for a patient suffering from a complicated disease process like PD. Hours of clinic time will be saved from DBS device management and replacement and health care costs may be greatly reduced.

- Rational for ExAblate Transcranial System subthalamotomy for the Treatment of PD Conceptually, lesioning the subthalamus seems logical since preclinical studies have confirmed the role of the subthalamic nucleus in the development of parkinsonism and by the fact that the experimental Parkinsonian state by MPTP can be relieved by exocytotic or thermolytic lesions of the STN. Furthermore, clinical studies of deep brain stimulation targeting the subthalamic nucleus have proven that this nucleus is the most effective for the treatment of advanced Parkinson's disease.

From a clinical perspective, unilateral subthalamotomy for medication-refractory Parkinson's disease certainly has proven beneficial in the alleviation of contralateral off-medication motor symptoms in several series. The largest and best reported experience comes from the CIREN (La Habana, Cuba) where this project was initiated and directed by Prof. Jose Obeso over a 10 years period leading to a large accumulated experience. This was described for 89 patients followed for up to 36 months. In these reports, significant improvements were noted on UPDRS ratings with bradykinesia, rigidity and tremor. Improvements remained at two years and were most pronounced for tremor. With regards to the "on" state, contralateral dyskinesia was reduced during the two-year study and the mean dose of Levodopa was decreased by 34-47% while the total on time without dyskinesia increased fourfold. In the study significant reductions in part three of the off-medication UPDRS were noted at 12 (50%), 24 (30%), and 36 months (18%) following unilateral subthalamotomy. In the "on" state, contralateral dyskinesia improved throughout the 3-year study period although ipsilateral dyskinesia progressively worsened during this time. In a limited number of patients bilateral staged ( N-7) and simultaneous ( N-11) subthalamotomy was carried out without major adverse effects and highly significant motor improvement. Cognitive changes were specifically ascertained prospectively without evidence of deterioration. More recently, the impact of unilateral subthalamotomy on inhibitory mechanisms was also reported from the same study group. Unexpectedly, speed of stopping an initiated action was improved after STN lesion.

Subthalamotomy has never been widely accepted because of concerns for hemiballismus primarily due to observations in humans with stroke in the region of the subthalamus (Purdon Martin 1927) and by the confirmation in the 1940's by Whittier and Mettler who were able to experimentally reproduce this by subthalamic lesions in primates. Arguments against such dogma were amply discussed years ago leading to the understanding that the parkinsonian state modifies the threshold to hemiballism after STN lesion.

The ExAblate modality permits a very precise focused lesion to be created without disruption of other motor pathways or nuclei. In order to test the feasibility of using the ExAblate Neuro system for the ablation of the subthalamic nucleus two patients (University of Virginia) were active-sham treated using a sublethal dose of energy (50-54⁰C). The subjects were observed for 30 days without developing any adverse effects like worsening involuntary movements. Since there were no adverse effects of worsening involuntary movements, the actual second stage treatment was then performed. Again, no adverse effects of worsening involuntary movements were observed. The safety profile remains favorable.

Interestingly, the rationale for choosing target temperatures of 50-54⁰C as a ' subtherapeutic/test' lesion was based on the experience acquired during the feasibility study for Essential Tremor under IDE # G10016969 and preclinical lesioning in a swine model. In 15 patients with ET, the typical onset of neurologic phenomena (ie sensory symptoms) or tremor suppression is observed when the peak voxel temperatures on MR thermography reached the low 50's ⁰C. It was observed that the tremor effect first occurs during the titrated lesioning process with transient suppression of postural and rest tremor. Later at higher temperatures of 55-65⁰C, the tremor effect becomes more lasting. Also T2 signal change on MRI is not typically visible acutely in human thalamus until peak voxel temperatures approach this 55-65⁰C range. These higher temperatures resulted in thalamotomy volumes comparable to traditional radiofrequency lesions where the diameter became maximal at 1 week (mean=171 mm3) and measured 6.8mm in diameter. Soon by one and three months, HIFU thalamotomy volumes subsided to 55 and 14 mm3, respectively.

Thus, small lesions with reversible clinical effects would occurre by confining the first, subtherapeutic/test lesion to 50-54⁰C. The therapeutic treatment goal must be to perform the final, peak voxel temperatures of 55-65⁰C which will result in a substantial target ablation which is analogous to the volume achieved with contemporary RF lesioning.

The rationale for unilateral subthalamotomy for advanced PD is summarized as follows:

1. A well-placed stereotactic lesion is similarly efficacious to DBS.

2. Stereotactic radiofrequency subthalamotomy has been shown to ameliorate the motor features of PD .

3. The risk for involuntary movements like hemichorea-ballism following subthalamotomy in humans is about 15% but only in the 9% of patients a second procedure (pallidotomy) was needed to treat the dyskinesias.

4. Studies of DBS in PD have consistently shown equivalent results between the stereotactic targets: STN and GPi.

5. The subthalamus is amenable to an image-guided ablation because it is small and easily visualized with contemporary MRI.

6. DBS, while effective for advanced PD, has complexities for patients, their caregivers, and their doctors and potentially carries a higher risk than ExAblate mediated lesion.

Summary Based on published animal and human studies, ExAblate Transcranial subthalamotomy can be as safe and as effective as any of the surgical treatments within the currently accepted standard of care including RF lesioning and DBS. A unilateral lesion of the subthalamic nucleus has shown reduction of contralateral motor symptoms in PD. Using ExAblate Transcranial MRgHIFU to create the subthalamotomy has several potential advantages over current therapies including the fact that transcranial lesioning can be performed in a precise manner with simultaneous as well as continuous clinical and radiographic monitoring. If the potential of ExAblate Transcranial subthalamotomy can be realized, it could supplant radiofrequency and radiosurgery techniques and provide a viable alternative procedure for subjects considering DBS.

This study will include ten Parkinson's disease patients who will be treated with unilateral subthalamotomy performed by MRIgHIFU and followed in an open-label fashion for up to 6 months to demonstrate safety and sustained benefit.