Are there Predictors for the Effects of Subthalamic Versus Thalamic Lesions for the Treatment of Parkinsonian Tremor?

Abstract

We thank Dr. Aubignat for his inquiry regarding the potential use of the preoperative levodopa test as a predictor of the response of tremor to focused ultrasound (FUS) ablation of the subthalamic nucleus (STN-FUS) versus thalamotomy (ventral intermediate nucleus [VIM]-FUS).¹

The two patient groups (STN-FUS and VIM-FUS) did not differ significantly in their levodopa response for the tremor score (30.6 ± 4.3 vs. 21.5 ± 5.3, P = 0.255), for the lateralized motor score, or the International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score. There was no correlation between levodopa response and tremor outcome of STN-FUS or VIM-FUS treatment. For our patients with levodopa-responsive tremor, the key factor in the outcome of FUS treatment was the choice of the target (STN-FUS or VIM-FUS) and we could not identify a further predictor to guide the decision for lesioning the thalamic VIM versus the STN.

While Dr. Aubignat's proposal is appealing, related questions have been elucidated previously with a negative result. The most extensive data concern the effects of deep brain stimulation (DBS) on the various Parkinsonian symptoms including Parkinsonian tremor. It was an early conclusion from the Grenoble studies^{2, 3} that the response of akinesia and rigidity to STN-DBS is to some degree predictable by the preoperative levodopa test but only poorly for the long-term tremor outcome, partly because all tremors are improved with STN-/VIM-/globus pallidus interna (GPi)-DBS. This has led to the early recommendation that the result of the levodopa test for tremor should not be a criterium for the target selection of DBS⁴ because it is improved with stimulation of all the three targets. This is confirmed by a recent analysis of a large, multicenter population of patients with STN stimulation reporting that the prediction of DBS outcome, both in terms of tremor subscores and the total motor score, is clinically unsatisfactory provided levodopa-sensitive patients are tested.⁵

The question of the better effect of STN versus VIM stimulation to treat tremor in Parkinson's disease (PD) has never been addressed in a prospective randomized trial. How can we then assume that one target is better as regards Parkinsonian tremor than another?

Recent studies^{6, 7} have shown that an acute levodopa test with a standard dosage provides a spectrum of responses which can be separated into sensitive, intermediate, and insensitive responses. This is an important confirmation that the response of tremor to levodopa can deviate from the response of other motor features.

There is increasing knowledge about the mechanisms of tremor in PD and its phenomenological variability. The most convincing data are related to the existence of different tremor loops with two main circuits,⁸ the basal ganglia and the cerebello-thalamic loop (switch and dimmer) being involved with different pathophysiological roles. However, such a division is not entirely realistic functionally as tremor activity essentially consists of the coincidental recruitment and coupling of neuronal activity at 4–6 Hz in various nuclei and circuits. It is noteworthy that subthalamotomy may have a wider impact and greater effect towards restoring the functionality of the parkinsonian brain than the more limited effect of thalamotomy. Certainly, a prospective randomized study is the way to resolve this issue. Until then, care should be taken with unproven predictors.

(1) Research Project: A. Conception, B. Organization, C. Execution; D. Data Integrity and Analysis; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

S.P.: 1D, 3A, 3B.

E.N.-V.: 3A, 3B.

J.A.P.-P: 3B.

M.d.A.: 3B.

R.R.-R.: 3B.

A.-K.H.: 3B.

J.H.: 3B.

G.D.: 3A, 3B.

J.A.O.: 3A, 3B.

R.M.-F.: 1D, 3A, 3B.

S.P. reports speaker honoraria from Insightec, AbbVie, Medtronic GmbH, and Boston Scientific outside the submitted work and grant/research funding from Deutsche Forschungsgemeinschaft (DFG), Parkinson Fonds Deuschland gGmbH, and UCB Pharma GmbH. E.N.-V. has received financial support from Zambon, Bial, Esteve, and Insightec to attend scientific meetings and received grants from Sociedad Española de Neurología and Asociación Madrileña de Neurología. J.H. has served as a consultant for Stryker Neurovascular and Balt. He has received reimbursement of travel expenses to attend scientific meetings by Rapid Medical outside the submitted work. J.A.P.-P. has received speaker honoraria from Insightec, Palex, and Zambon outside the submitted work. M.d.A. has received speaker honoraria from Insightec, Palex, and Boston Scientific and reimbursement of travel expenses to attend scientific conferences from Boston Scientific and Medtronic outside the submitted work. R.R.-R. has received speaker honoraria from Zambon and Insightec outside the submitted work. A.-K.H. has received lecture fees from Boston Scientific and Insightec outside the submitted work. G.D. has served as a consultant for Boston Scientific, Insightec, and Functional Neuromodulation. He has received royalties from Thieme Publishers, funding from the German Research Council (SFB 1261, T1), and private foundations. J.A.O. has received honoraria for lecturing and reimbursement of travel expenses to attend scientific meetings by Insightec outside the submitted work. R.M.-F. reports speaker honoraria from Insightec, Palex, Esteve, Zambon, and Bial outside the submitted work and grant/research funding from Instituto de Salud Carlos III, Madrid, Spain for health research projects (PI21 Proyectos de investigacion en salud, AES 2021).

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.