Combined STN/SNr-DBS for the treatment of refractory gait disturbances in Parkinson's disease: study protocol for a randomized controlled trial

Trials

Rejko Krüger³  Sorin Breit³  Christian Plewnia²  Alireza Gharabaghi⁴  Melanie Fritz³  Christoph Meisner¹  Tobias Wächter³  Daniel Weiss³ 

[1] Department of Medical Biometry, University of Tübingen, Tübingen, Germany;Department of Psychiatry, University of Tübingen, Tübingen, Germany;Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany;Werner Reichardt Centre for Integrative Neuroscience and Department of Neurosurgery, University of Tübingen, Germany

关键词: subthalamic nucleus (STN);    substantia nigra pars reticulata (SNr);    stimulation;    Parkinson's disease;    interleaved pulses;    gait disturbance;    freezing of gait (FOG);    deep brain stimulation (DBS);    balance;   

Others  :  1095828
DOI  :  10.1186/1745-6215-12-222

 received in 2011-09-26, accepted in 2011-10-11,  发布年份 2011

【 摘 要 】

Background

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. 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.

Methods

12 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 registration

The trial was registered with the clinical trials register of http://www.clinicaltrials.gov webcite (NCT01355835)

【 授权许可】

   
2011 Weiss et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Giladi N: Medical treatment of freezing of gait. Mov Disord 2008, 23(Suppl 2):482-488.
• [2]Giladi N, Treves TA, Simon ES, Shabtai H, Orlov Y, Kandinov B, Paleacu D, Korczyn AD: Freezing of gait in patients with advanced Parkinson's disease. J Neural Transm 2001, 108:53-61.
• [3]Moore O, Peretz C, Giladi N: Freezing of gait affects quality of life of peoples with Parkinson's disease beyond its relationships with mobility and gait. Mov Disord 2007, 22:2192-2195.
• [4]Muslimovic D, Post B, Speelman JD, Schmand B, de Haan RJ: Determinants of disability and quality of life in mild to moderate Parkinson disease. Neurology 2008, 70:2241-2247.
• [5]Rahman S, Griffin HJ, Quinn NP, Jahanshahi M: Quality of life in Parkinson's disease: the relative importance of the symptoms. Mov Disord 2008, 23:1428-1434.
• [6]Deuschl G, Schade-Brittinger C, Krack P, et al.: A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006, 9:896-908.
• [7]Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE, Deuschl G: Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord 2006, 21(Suppl 14):290-304.
• [8]Weaver FM, Follet K, Stern M, et al.: Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama 2009, 1:63-73.
• [9]Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P: Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 2003, 349:1925-1934.
• [10]Moreau C, Defebvre L, Destee A, Bleuse S, Clement F, Blatt JL, Krystkowiak P, Devos D: STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2008, 71:80-84.
• [11]Ferraye MU, Debu B, Fraix V, Goetz L, Ardouin C, Yelnik J, Henry-Lagrange C, Seigneuret E, Piallat B, Krack P, Le Bas JF, Benabid AL, Chabardes S, Pollak P: Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease. Brain 2010, 133:205-214.
• [12]Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, Hutchison WD, Lozano AM: Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. Brain 2010, 133:215-224.
• [13]Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, Mazzone P: Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 2007, 130:1596-1607.
• [14]Aziz TZ, Davies L, Stein J, France S: The role of descending basal ganglia connections to the brain stem in parkinsonian akinesia. Br J Neurosurg 1998, 12:245-249.
• [15]Breit S, Lessmann L, Unterbrink D, Popa RC, Gasser T, Schulz JB: Lesion of the pedunculopontine nucleus reverses hyperactivity of the subthalamic nucleus and substantia nigra pars reticulata in a 6-hydroxydopamine rat model. Eur J Neurosci 2006, 24:2275-2282.
• [16]Jenkinson N, Nandi D, Miall RC, Stein JF, Aziz TZ: Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey. Neuroreport 2004, 15:2621-2624.
• [17]Chastan N, Westby GW, Yelnik J, Bardinet E, Do MC, Agid Y, Welter ML: Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease. Brain 2009, 132:172-184.
• [18]Weiss D, Breit S, Wächter T, Plewnia C, Gharabaghi A, Krüger R: Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease. J Neurol 2011, 258:1183-1185.
• [19]Herzog J, Pinsker M, Wasner M, Steigerwald F, Wailke S, Deuschl G, Volkmann J: Stimulation of subthalamic fibre tracts reduces dyskinesias in STN-DBS. Mov Disord 2007, 22:679-684.
• [20]Hughes A, Daniel SE, Kilford L, Lees AJ: Accuracy of clinical diagnosis of idiopathic Parkinson's disease. A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992, 55:181-184.
• [21]Fasano A, Herzog J, Seifert E, Stolze H, Falk D, Reese R, Volkmann J, Deuschl G: Modulation of gait coordination by subthalamic stimulation improves freezing of gait. Mov Disord 2011, 5:844-851.