Focused Ultrasound Ablation Therapy of the Globus Pallidus for Parkinson’s

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“Resilience is not what happens to you. It’s how you react to, respond to, and recover from what happens to you.” Jeffrey Gitomer

Introduction: The clinical trial results were published in the New England Journal of Medicine by Krishna et al. (2023), dealing with ultrasound treatment of the globus pallidus internus for Parkinson’s. In this blog post, I will review the results of this study and give some insight into what FUSA is, or focused ultrasound ablation, and the future of FUSA in treating Parkinson’s. The citation for the paper is as follows: Krishna, V., Fishman, P.S., Eisenberg, H.M., Kaplitt, M., Baltuch, G., Chang, J.W., Chang, W.C., Martinez Fernandez, R., Del Alamo, M., Halpern, C.H. and Ghanouni, P., 2023. Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson’s Disease. New England Journal of Medicine, 388(8), pp.683-693.

“Man never made any material as resilient as the human spirit.” Bernard Williams

What is the Globus Pallidus? The globus pallidus is part of the basal ganglia. “The basal ganglia is situated at the base of the forebrain brain and consists of four subcortical nuclei: striatum (caudate nucleus, putamen, and nucleus accumbens); globus pallidus (internal and external segments); subthalamic nucleus; and substantia nigra (pars compacta and pars reticulata; they are considered components of the midbrain). The basal ganglia nuclei help regulate movement, which increases and decreases motor activity, respectively.” (click here to read the post on the basal ganglia).

The globus pallidus (external) is now considered a central hub for the basal ganglia in processing motor- and non-motor functions. It is almost like the globus pallidus is a conduit for connecting basal ganglia nuclei with other nuclei in the brain. Furthermore, abnormal globus pallidus activity has been measured in Parkinson’s. An excellent review of the globus pallidus can be found here: Dong, Jie, Sarah Hawes, Junbing Wu, Weidong Le, and Huaibin Cai. “Connectivity and functionality of the globus pallidus externa under normal conditions and Parkinson’s disease.” Frontiers in neural circuits 15 (2021): 645287.

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What is Focused Ultrasound Ablation (FUSA)? Remember when you were a kid and got your first magnifying glass? Did you go outside and direct the sun through the magnifying glass to create a focused beam of heat? That, in theory, is what one does with FUSA. Instead of the sun’s energy, one focuses rays of ultrasonic energy on a site (in this case, the globus pallidus in the brain) to generate heat. The rising temperature kills (or ablates) the tissue. The focusing of these highly-intense sound waves allows the surgeon to destroy tissue without the need for a craniotomy (surgical opening into the skull). Thus, FUSA allows ablative surgery using a very focused, directed, externally applied sonication energy to treat the brain.

In smaller clinical trials, FUSA of the thalamus was shown to reduce symptoms of tremor-dominant Parkinson’s and essential tremors, which were refractive to medical treatment. Furthermore, unilateral FUSA was used on the subthalamic nucleus for patients with markedly asymmetrical Parkinson’s. Additionally, targeting the globus pallidus internus by FUSA for treating the motor complications of Parkinson’s was found to help reduce both motor impairment and dyskinesia during the off-medication state.

The drawing below graphically summarizes the regions of the brain treated above by FUSA and gives one some orientation about ablating (or removing) specific brain regions in treating Parkinson’s.

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The Clinical Trial: The results were from a double-blind, randomized controlled trial of unilateral FUSA of the globus pallidus for motor complications in Parkinson’s. Krishan et al. (2023) enrolled 94 patients with motor fluctuations or dyskinesia. This was a multicenter study using a total of sixteen sites in North America, Asia, and Europe to enroll patients. Results from all sites were included in the publication.

Sixty-nine patients underwent ultrasound ablation (Active treatment group), and twenty-five patients were given the sham treatment (Control group). The part of the brain chosen to be treated was contralateral (relating to or denoting the side of the body opposite to that on which a particular structure or condition occurs.) to the patient’s dominant side (the side with more significant motor impairment). I will not further describe how they ablated the globus pallidus but say they reached the target temperature of 55^oC in 97% of actively treated patients. They typically made multiple lesions using MRI to guide the probe. They obtained an MRI of the brain in each patient to evaluate the location and size of the lesions created by FUSA.

The measured outcome was a response defined as an improvement (decrease) of at least three points in three months. The first primary outcome scale was motor impairment of the treated side during the off-medication state using the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS III). The second outcome was dyskinesia in the Unified Dyskinesia Rating Sale (UDysRS). These measurements were at baseline before treatment and at three months. Patients were assessed at one week, one month, and three months. After that, the blinded phase was done, and all patients were evaluated in the open-label format at six and twelve months.

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Results and Adverse Events from FUSA: From the original 94 patients (sixty-nine in the Active treatment group and twenty-five in the control group), sixty-five and twenty-two in the Active Treatment and Control groups, respectively, completed the study. At three months, 69% (45 patients) of the Active Treatment group had a response, compared to 32% (7 patients) of the Control group. Breaking down the results from the Active Treatment group, nineteen of sixty-five patients met the MDS-UPDRS III criterion only, with eight showed improvement in the UDysRS criterion, and eighteen patients met both requirements. Thirty of the thirty-nine patients who responded at three months continued to have a reaction when tested at twelve months. In the control group at three months, six of twenty-two patients met the MDS-UPDPRS III criterion, none met the UDysRS criterion only, one met both criteria, and fifteen patients were shown to have no change in response.

The MDS-UPDRS IV score, a composite analysis of motor complications of medical therapy, improved to 5.1 points in 3 months for the Active Treatment group, compared to 0.3 points improvement in the control group. The mean advance in the total MDS-UPDRS III score during off-medication was 6.0 points in the Active Treatment group and 1.5 points for the control group.

It should be noted that after three months, the control group was given the option to undergo FUSA again and then to be further assessed for twelve months. Fifty-five patients in the Active Treatment group were available at twelve months, with 37 of 53 (70%) having a response. Other scores were reported in the paper, with more details suggesting that FUSA improved MDS-UPDRS III and IV scores compared to the controls (please refer to the article to see all the additional detailed data sets).

There were several adverse reactions seen during the FUSA-directed globus pallidus trial. At three months, the most frequent adverse events (in two patients each) were dysarthria (a condition where you have difficulty speaking because the muscles you use for speech are weak), gait disturbance, and loss of taste. The gait disturbance and loss of taste resolved; however, the dysarthria persisted in one patient for one year. All pallidotomy adverse events were described as mild to moderate as defined by the FDA definition of severity.

A total of eleven patients in the Active treatment group and one patient in the Control group had adverse events rated as severe according to the FDA criteria; these included pulmonary embolism, cholecystitis, hernia, subdural hematoma, fall, stroke, deep vein thrombosis, metastatic endometrial cancer, myocardial infarction, laminectomy, leg fracture, diverticulitis, and interstitial pneumonia. The safety monitoring board determined the non-fatal pulmonary embolism, which happened within the first week of the study, was the only procedure-related adverse event.

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Remaining Issues: The FDA has approved unilateral treatment; however, most Parkinson’s patients have bilateral problems with motor symptoms. In contrast to deep-brain stimulation surgery (DBS), DBS offers an opportunity to treat the progressive worsening of motor symptoms. Interestingly, no immediate effect was observed from the FUSA procedure that was apparent to investigators and patients.

“Everyone experiences tough times, it is a measure of your determination and dedication how you deal with them and how you can come through them.” Lakshmi Mittalunilateral

Conclusions and a Personal Comment: This clinical trial confirms that FUSA of the globus pallidus effectively reduces motor complications of Parkinson’s. These results were gathered three months following the procedure. The data showed that ~1/3 of the FUSA-test group did not show improvement at three months, and about 1/3 of the patients showed improvement in both motor and dyskinesia scores. Interestingly, about 1/3 of the control patients had a response, revealing many placebo responses in this and other clinical trials for Parkinson’s. Further analyses of the various datasets suggest that younger patients had lower severity scores or more elevated dyskinesia scores, which implies they could improve substantially compared to older patients.

FUSA is non-reversible. Once the globus pallidus is heated to 65^oC, the tissue dies. The alternative for the advanced PwP is DBS. Neither procedure is perfect, but they are approved and appropriate for PwP with long-term issues from carbidopa/levodopa therapy. Compared to FUSA, DBS for treating Parkinson’s is considered reversible (brain tissue is not destroyed), and the stimulation is modified as the disorder progresses. While FUSA is safe and straightforward, testing for more extended periods is imperative.

I am not yet ready, or being forced, to consider surgery as my next treatment option. This FUSA clinical trial is more than a ‘baby step’ forward. Still, testing improvement for longer times and evaluating quality-of-life issues are essential. A step forward for FUSA, not a step backward; however, it is a few paces behind DBS. Finally, maybe within the next decade of FUSA clinical evaluation, this non-invasive method may be shown to be a worthy challenger to the invasive technique needed for DBS. Only time will tell.

“There is something in these moments of crisis that is really extraordinary about humanity and human beings’ resilience and the way in which everyone naturally comes together. I think you see the best in people in those moments for better or for worse and you find your best self.” Carla Gugino

Cover Photo Image by Maksim Kozlov from Pixabay