Clinical rationale for the optimal therapeutic window for deep brain stimulation in Parkinsonʼs disease

Abstract

Background. Parkinsonʼs disease remains one of the most rapidly progressive neurodegenerative disorders, leading to early disability and a substantial decline in patient quality of life. Although pharmacotherapy provides high efficacy in the initial stages, long-term levodopa therapy inevitably results in motor fluctuations and dyskinesias. Deep brain stimulation (DBS) is a proven gold-standard intervention for restoring motor control; however, determining the precise «therapeutic window» for surgical intervention remains a critical challenge in modern neurology. Timely candidate selection is frequently delayed by reliance on rigid disease duration metrics rather than comprehensive clinical predictors, a lack of standardized multidisciplinary evaluation algorithms, and the underestimation of non-motor symptoms, ultimately leading to late neurosurgical referrals and the loss of optimal rehabilitation potential. Purpose – to provide a clinical justification for the optimal therapeutic window for deep brain stimulation (DBS) in patients with Parkinsonʼs disease. Materials and Methods. A prospective comparative cohort study was conducted involving 112 patients with clinically confirmed Parkinsonʼs disease. The optimized medical therapy group included 63 patients, while 49 patients underwent bilateral subthalamic nucleus deep brain stimulation (STN-DBS). All candidates for surgery underwent a comprehensive multidisciplinary evaluation including the Movement Disorder Society–Unified Parkinsonʼs Disease Rating Scale (MDS-UPDRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Beck Depression Inventory (BDI), Beck Anxiety Scale (BAS), Parkinsonʼs Disease Questionnaire-39 (PDQ-39), a standardized levodopa challenge test, and calculation of the levodopa equivalent daily dose (LEDD). Independent predictors of DBS effectiveness were assessed using a multivariable Cox proportional hazards regression model. Results. The most informative clinical markers indicating the approach of the optimal therapeutic window were the earlier onset of motor fluctuations (53.7±8.0 vs. 60.5±6.1 years; p<0.001), earlier development of levodopa-induced dyskinesias (55.0±8.3 vs. 61.7±6.3 years; p<0.001), and the need to increase the LEDD to 1185.8±303.9 mg (p=0.005). Twelve months after STN-DBS, the MDS-UPDRS Part III OFF score improved by 59.6%, daily OFF time decreased by 69.9%, levodopa requirements were reduced by 34.0%, and the proportion of functionally independent patients increased from 36.7% to 73.5% (all p<0.001). DBS was associated with a significantly lower risk of long-term functional deterioration (HR=0.48; 95% CI 0.29–0.81; p=0.005), whereas improvement of more than 50% during the levodopa challenge test was the strongest positive predictor of a favorable surgical outcome (HR=0.39; 95% CI 0.22–0.68; p=0.001). The principal reasons for missing the therapeutic window included delayed referral, underestimation of non-motor manifestations, excessive reliance on disease duration as a referral criterion, and financial barriers related to patients having to purchase DBS systems themselves. Conclusions. The optimal therapeutic window for DBS is determined by a combination of clinical characteristics rather than chronological age or disease duration alone. Early recognition of motor complications in patients with preserved levodopa responsiveness, comprehensive assessment of non-motor symptoms, and multidisciplinary decision-making enable timely identification of suitable candidates for functional neurosurgery. The implementation of a standardized referral algorithm together with a national registry of patients with extrapyramidal disorders represents a promising strategy for optimizing DBS outcomes in Ukraine.