Spinal Cord Stimulation for Freezing of Gait in Parkinson's Disease

Freezing of gait (FOG) is a severely disabling gait disorder in Parkinson's disease (PD). FOG leads to falls, anxiety and loss of independence and heavily affects quality of life (QoL). The incidence of FOG increases from 38% in the first 5 years following diagnosis to 65-80% in advanced stages. FOG is a therapeutic challenge, as it often responds poorly to (dopaminergic) pharmacotherapy or deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal pallidum. Likewise, rehabilitation strategies such as gait training achieve small and short term effects at best. The therapeutic response of FOG is far more complex and variable than that of other PD motor symptoms. This reflects the current shortfall in knowledge about FOG pathophysiology, which has drastically impeded adequate therapy development. Furthermore, objective and reliable FOG assessments are challenging and therefore still rarely implemented in clinical trials, limiting the interpretation of the findings. However, recent insight into the underlying mechanisms has resulted in a growing body of literature suggesting a therapeutic promise of spinal cord stimulation (SCS) for FOG.

Spinal cord stimulation is an invasive technique in which specific neuronal circuits are stimulated electrically through spinal epidural electrodes. The stimulation settings can be adjusted to achieve a therapeutic effect, often by eliciting paraesthesia. SCS has been applied mostly in patients with refractory neuropathic pain. Serendipitously, PD patients who underwent SCS to treat comorbid neuropathic pain also noticed a beneficial effect on FOG. This finding led to SCS being further investigated as a therapy for FOG, but despite the encouraging results in animal studies, studies in humans are limited to case reports and series with inconsistent results. Randomised, double-blinded, high-quality trials in large cohorts are much needed for translation to clinical use. Correct blinding in SCS studies was historically impeded by stimulation-induced paraesthesia. However, recent innovations in SCS devices now enable paraesthesia-free stimulation and spinal cord electrophysiology recordings, creating new opportunities for research and trial design.

In addition to the small sample sizes and lack of randomisation and blinding, currently published reports on SCS for FOG lack clear clinical phenotyping of freezing and many also fail to use objective, reliable FOG assessments. Moreover, much remains unknown about the effect of SCS on spinal cord and STN electrophysiology and about optimal stimulation paradigms.

This sham-controlled randomized double-blinded cross-over study aims to define the outcome, safety, optimal stimulation paradigm and underlying mechanism of SCS for FOG in PD patients. Twenty-nine patients will receive a 3-week SCS trial with an implanted lead connected to an external stimulator, during which two SCS paradigms (one with and one without paraesthesia) and a sham paradigm will be compared:

1. Tonic SCS (paraesthesia-eliciting) 2. DTM SCS (paraesthesia-free) 3. Sham SCS (stimulation off)

The three SCS paradigms will be evaluated for 5 days each in a randomised order, split by a 2-day wash-out. SCS outcome on FOG will be evaluated through a wearable accelerometer, questionnaires and a FOG-provoking protocol at home. During this FOG-provoking protocol, participants have to perform 4 different tasks:

1. Timed Up and Go test; 2. One minute of 360° turns in place, alternating the direction after each turn; 3. Bathroom task, where patients have to walk 2m, enter the toilet through the doorway, turn around there and return to the starting position; 4. Clearing the table, where patients need to set and clear the table with 2 plastic plates and cups. Starting and ending point is at 2m away from the table. During the task, they are also required to move the chairs in place.

The first two tasks will be executed twice, once while dual-tasking (serial-3 subtractions) and once without. Patients are allowed to use a walking aid if necessary to complete the protocol. Each FOG-protocol is conducted both in off-meds (≥ 12h withdrawal) and on-meds (±1h after intake) conditions. The entire protocol is videorecorded and annotated afterwards to determine percentage time frozen (%TF) and characterisation of FOG. During the FOG-protocol, the participant will wear 5 intertial measurement units to quantify gait parameters. In patients with DBS including BrainSense technology, we will explore the effect of SCS on pathological beta oscillations in the STN.

Upon completion of the core trial, participants who exhibit a clinically relevant improvement in freezing or gait will receive a permanent implanted neurostimulator and continue into the long-term open-label phase. In participants who do not perceive a clinically relevant FOG improvement from SCS during the core trial, the trial electrode is removed. Six months following either implantation of the permanent neurostimulator or removal of the trial electrode, long-term therapeutic efficacy and safety of SCS for FOG will be assessed and compared between patients who received permanent SCS and those who did not. In addition, electrophysiological recordings of the dorsal spinal cord will be conducted at the end of the external trial stimulation and at the 6-month follow-up. These electrophysiological signal characteristics will be compared to two control groups of patients who received an Inceptiv SCS system outside research settings for approved indications (one group without PD, one group with PD but without FOG).

To conclude, this study will provide new insights into the pathophysiology of FOG, pave the way for SCS implementation in clinical practice and enhance future patient selection.

• Safety [Срок оценки: 6 months]
• FOG-provoking protocol [Срок оценки: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.]
• FOG-provoking protocol [Срок оценки: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.]
• Changes in home-based gait function [Срок оценки: Core-trial: 3 weeks]
• Patient Global Impression of Improvement (PGI-I) [Срок оценки: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.]
• Changes in daily patient-reported FOG severity, falls and near-falls [Срок оценки: Core-trial: 3 weeks]
• Change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III and part IV.6 [Срок оценки: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.]
• Change in Numeric (Pain) Rating Scale (NRS) [Срок оценки: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.]
• Change in Medication Quantification Scale (MQS) [Срок оценки: Core trial: day 7, 14 and 21 post-surgery. Long-term: at 6 months follow-up.]
• Patient satisfaction [Срок оценки: Core-trial: 3 weeks]
• Change in New Freezing of Gait Questionnaire (NFOG-Q) [Срок оценки: 6 months]
• Change in Characterizing Freezing of Gait questionnaire (C-FOG) [Срок оценки: 6 months]