Abstract
BackgroundSevere gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages with important impact on quality of life. There is an unmet need for further symptomatic therapeutic strategies, particularly as gait disturbances generally respond unfavourably to dopaminergic medication and conventional deep brain stimulation of the subthalamic nucleus in advanced disease stages. Recent pathophysiological research pointed to nigro-pontine networks entrained to locomotor integration. Stimulation of the pedunculopontine nucleus is currently under investigation, however, hitherto remains controversial. The substantia nigra pars reticulata (SNr) - entrained into integrative locomotor networks - is pathologically overactive in PD. High-frequent stimulation of the substantia nigra pars reticulata preferentially modulated axial symptoms and therefore is suggested as a novel therapeutic candidate target for neuromodulation of refractory gait disturbances in PD.Methods12 patients with idiopathic Parkinson's disease and refractory gait disturbances under best individual subthalamic nucleus stimulation and dopaminergic medication will be enroled into this double-blind 2 × 2 cross-over clinical trial. The treatment consists of two different stimulation settings using (i) conventional stimulation of the subthalamic nucleus [STNmono] and (ii) combined stimulation of distant electrode contacts located in the subthalamic nucleus and caudal border zone of STN and substantia nigra pars reticulata [STN+SNr]. The primary outcome measure is the change of the cumulative 'axial score' (UPDRS II items '13-15' and UPRDS III items '27-31') at three weeks of constant stimulation in either condition. Secondary outcome measures include specific scores on freezing of gait, balance function, quality of life, non-motor symptoms, and neuropsychiatric symptoms. The aim of the present trial is to investigate the efficacy and safety of a three week constant combined stimulation on [STN+SNr] compared to [STNmono]. The results will clarify, whether stimulation on nigral contacts additional to subthalamic stimulation will improve therapeutic response of otherwise refractory gait disturbances in PD.Trial registrationThe trial was registered with the clinical trials register of http://www.clinicaltrials.gov (NCT01355835)
Highlights
Several approaches are under investigation in order to address the therapeutic need for gait disturbances refractory to dopaminergic treatment and subthalamic nucleus (STN)-deep brain stimulation (DBS)
Stimulation of the pedunculopontine area for refractory gait disturbances remains controversial at the moment [11,12,13], several experimental lines of evidence demonstrated the integrative role of reciprocal brainstem circuitries including substantia nigra pars reticulata (SNr) and the pedunculopontine area [14,15,16]
Activity of the SNr can be modulated after implantation for conventional STN-DBS, as the caudal electrode contacts are generally located in the caudal border zone of STN and SNr [17,18]
Summary
Severe gait disturbances in idiopathic Parkinson’s disease (PD) are observed in up to 80% of all patients in advanced disease stages with important impact on quality of life. Therapeutic deep brain stimulation of the subthalamic nucleus (STN-DBS) as an evidencebased therapy [6,7,8] generally ameliorates segmental symptoms and motor fluctuations, whereas axial symptoms and in particular gait disturbances may respond unfavourably and generally aggravate in parallel with the underlying neurodegeneration [9,3,10]. In this condition, increasing intensity of high-frequent STN-DBS at 130 Hz even worsens the condition [10]. Activity of the SNr can be modulated after implantation for conventional STN-DBS, as the caudal electrode contacts are generally located in the caudal border zone of STN and SNr [17,18]
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