Nervenheilkunde 2017; 36(08): 647-654
DOI: 10.1055/s-0038-1627509
Schattauer GmbH

Update zur intensivierten Therapie des fortgeschrittenen idiopathischen Parkinson-Syndroms

Update on the intensified therapies for the advanced stages of idiopathic Parkinson’s disease
P. Kolber*
1   Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxem-bourg; Centre Hospitalier de Luxembourg (CHL), Luxembourg
C. Stallinger*
1   Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxem-bourg; Centre Hospitalier de Luxembourg (CHL), Luxembourg
R. Krüger
1   Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxem-bourg; Centre Hospitalier de Luxembourg (CHL), Luxembourg
› Author Affiliations
Further Information

Publication History

eingegangen am: 16 December 2016

angenommen am: 29 May 2017

Publication Date:
20 January 2018 (online)


Das idiopathische Parkinson-Syndrom ist eine heterogene neurodegenerative Erkrankung. Während konservative pharmakologische Therapien in den anfänglichen Phasen der Krankheit gut wirken, können in fortgeschrittenen Stadien mit motorischen Komplikationen invasive Methoden wie die tiefe Hirnstimulation sowie die pumpengestützte Dauerinfusion von L-Dopa bzw. Apomorphin notwendig sein. Durch die in den letzten Jahrzehnten gewonnene Studienevidenz und klinische Erfahrung ist bei indikationsgerech tem Einsatz dieser Therapien auch bei einer fortgeschrittenen Parkinson-Krankheit ein er heblicher Gewinn an Lebensqualität für den Patienten möglich. Der Prozess zur Auswahl der individuell am besten geeigneten Therapie bleibt für den Patienten und den Neurologen komplex und schließt das Erkennen und Besprechen der Indikation auch außerhalb spezialisierter Zentren als notwendig ein. Hierzu bedarf es eines Überblicks über die einzelnen Therapieoptionen und ihrer Besonderheiten, der in den folgenden Abschnitten dargestellt wird.


Idiopathic Parkinson’s disease is a heterogeneous neurodegenerative disorder. While conservative therapies are very effective in the early stages of the disease, advanced stages of with motor complications demand more invasive methods like deep brain stimulation or pump-based infusion of L-DOPA and apomorphine. In the last decades, clinical experience and evidence on these therapies were established that considerably improve the patient’s quality of life even in advanced Parkinson’s disease. The choice for the right therapy remains complex for both the patient and the neurologist. However, the early identification and discussion of the indications with the patients and their caregivers are possible and needed outside of special izedcentres. Here we provide an up-to-date overview of the different therapy options and their individual characteristics.

* Beide Autoren haben zu gleichen Teilen beige tragen.

  • Literatur

  • 1 Trenkwalder C, Chaudhuri KR, García PJRuiz, LeWitt P, Katzenschlager R, Sixel-Döring F. et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson’s disease – Clinical practice recommendations. Parkinsonism Relat Disord 2015; 21 (09) 1023-30.
  • 2 Schuepbach WMM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L. et al. Neurostimulation for Parkinson’s disease with early motor complication. N Engl J Med 2013; 368 (07) 610-22.
  • 3 Shoulson I, Glaubiger GA, Chase TN. On-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975; 25 (12) 1144-8.
  • 4 Antonini A, Chaudhuri KR, Martinez-Martin P, Odin P. Oral and infusion levodopa-based strategies for managing motor complications in patients with parkinsons disease. CNS Drugs 2010; 02: 119-29.
  • 5 Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol 2006; 05 (08) 677-87.
  • 6 Krüger R, Hilker R, Winkler C, Lorrain M, Hahne M, Redecker C. et al. Advanced stages of PD: interventional therapies and related patientcentered care. Journal of Neural Transmission 2016; 123: 31-43.
  • 7 Ceballos-Baumann AO. Eskalationstherapien bei Morbus Parkinson. Nervenheilkunde 2016; 35 (04) 222-9.
  • 8 Volkmann J, Albanese A, Antonini A, Chaudhuri KR, Clarke CE, De Bie RMA. et al. Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: An evidence-based review. Journal of Neurology 2013; 260: 2701-14.
  • 9 Odin P. et al. Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson’s disease: Consensus from an international survey and discussion program. Park Relat Disord 2015; 21 (10) 1133-44.
  • 10 Boyle A, Ondo W. Role of apomorphine in the treatment of Parkinson’s Disease. CNS Drugs 2015; 29 (02) 83-9.
  • 11 Stibe CMH, Kempster PA, Lees AJ, Stern GM. Subcutaneous Apomorphine in Parkinsonian on-off oscillations. Lancet 1988; 331 (8582): 403-6.
  • 12 Hilker R, Antonini A, Odin P. What is the best treatment for fluctuating Parkinson’s disease: Continuous drug delivery or deep brain stimulation of the subthalamic nucleus?. J Neural Transm 2011; 118 (06) 907-14.
  • 13 Gancher S, Nutt J. Tolerance to apomorphine develops and reverses rapidly. Movement Disorders 2010; 26: 803-4.
  • 14 Merims D, Galili-Mosberg R, Melamed E. Apomor phine: An underutilized therapy for Parkinson’s dis ease. Mov Disord 2000; 15 (05) 789-94.
  • 15 De Gaspari D. Clinical and neuropsychological follow up at 12 months in patients with complicated Parkinson’s disease treated with subcutaneous apomorphine infusion or deep brain stimulation of the subthalamic nucleus. J Neurol Neurosurg Psychiatry 2006; 77 (04) 450-3.
  • 16 Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffmann M, Swinn L. et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: A prospective study using single-dose challenges. Mov Disord 2005; 20 (02) 151-7.
  • 17 Maass A, Reichmann H. Sleep and non-motor symptoms in Parkinson’s disease. J Neural Transm 2013; 120 (04) 565-9.
  • 18 Gasser T, Schwarz J, Arnold G, Trenkwalder C, Oertel WH. Apomorphine test for dopaminergic re sponsiveness in patients with previously untreated Parkinson’s disease. Arch Neurol 1992; 49 (11) 1131-4.
  • 19 Antonini A, Tolosa E. Apomorphine and levodopa infusion therapies for advanced Parkinson’s disease: selection criteria and patient management. Expert Rev Neurother 2009; 09 (06) 859-67.
  • 20 Gancher ST, Bennett W, English J. Studies of renal function in animals chronically treated with apomorphine. Res Commun Chem Pathol Pharmacol 1989; 66 (01) 163-6.
  • 21 Antonini A. Apomorphine and Levodopa Infusion Therapies for Advanced Parkinson’s Disease. J Mov Disord 2009; 02 (01) 4-9.
  • 22 LeWitt PA, Ondo WG, Van Lunen B, Bottini PB. Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating “off “ episodes in advanced Parkinson disease. Clin Neuropharmacol 2009; 32 (02) 89-93.
  • 23 Rambour M, Moreau C, Salleron J, Devos D, Kreisler A, Mutez E. et al. Le traitement par apomorphine en perfusion continue sous-cutanée dans la maladie de Parkinson: analyse rétrospective d’une série de 81 patients. Rev Neurol (Paris) 2014; 170 (03) 205-15.
  • 24 Tyne HL, Parsons J, Sinnott A, Fox SH, Fletcher NA, Steiger MJ. A 10 year retrospective audit of longterm apomorphine use in Parkinson’s disease. J Neuro 2004; 251 (11) 1370-4.
  • 25 Fietzek UM, Kavaldjieva G, Messner M, Ceballos-Baumann A. Die kontinuierliche subkutane Apomorphingabe: Ergebnisse einer katamnestischen Be fragung. Nervenheilkunde 2015; 34 (03) 180-6.
  • 26 Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson’s disease: Long-term fol low-up study of 64 patients. Mov Disord 2002; 17 (06) 1235-41.
  • 27 Borgemeester RWK, Lees AJ, van Laar T. Parkinson’s disease, visual hallucinations and apomorphine: A review of the available evidence. Parkinsonism Relat Disord 2016; 27: 35-40.
  • 28 García PJRuiz, Sesar AIgnacio, Ares BPensado, Castro AGarcía, Alonso FFrech, Alvarez MLópez. et al. Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations: a multicenter study. Mov Disord 2008; 23 (08) 1130-6.
  • 29 Licher MT. Ratgeber Hautpflege. Wedemark: Lichter MT; 2014
  • 30 Lewitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Movement Disorders 2015; 30: 64-72.
  • 31 Hughes AJ, 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. BMJ Group 1999; 55 (03) 181-4.
  • 32 Hauser RA, Olanow CW, Dzyngel B, Bilbault T, Shill H, Isaacson S. et al. Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson’s disease. Mov Disord. 2016 Jul 19; E-pub.
  • 33 Dewey RB, Maraganore DM, Ahlskog JE, Matsumo-to JY. A double-blind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov Disord 1998; 13 (05) 782-7.
  • 34 Nyholm D, Nilsson ARemahl, Dizdar N, Constantinescu R, Holmberg B, Jansson R. et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005; 64 (02) 216-23.
  • 35 Olanow CW, Kieburtz K, Odin P, Espay AJ, Stan DGdaert, Fernandez HH. et al. Continuous in trajejunal infusion of levodopa-carbidopa intesti nal gel for patients with advanced Parkinson’s dis ease: A randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014; 13 (02) 141-9.
  • 36 Wirdefeldt K, Odin P, Nyholm D. Levodopa-Car bidopa intestinal gel in patients with Parkinson’s disease: A systematic review. CNS Drugs 2016; 30 (05) 381-404.
  • 37 Bredberg E, Nilsson D, Johansson K, Aquilonius SM, Johnels B, Nyström C. et al. Intraduodenal in fusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson’s disease. Eur J Clin Pharmacol 1993; 45 (02) 117-22.
  • 38 Pulikkalpura H, Kurup R, Mathew PJ, Baby S. Le vodopa in Mucuna pruriens and its degradation. Sci Rep 2015; 05: 11078.
  • 39 Honig H, Antonini A, Martinez-Martin P, Forgacs I, Faye GC, Fox T. et al. Intrajejunal levodopa infu sion in Parkinson’s disease: A pilot multicenter study of effects on nonmotor symptoms and quality of life. Mov Disord 2009; 24 (10) 1468-74.
  • 40 Fernandez HH. et al. Levodopa-carbidopa intestinal gel in advanced Parkinson’s disease: final 12-month, open-label results. Mov Disord 2015; 30 (04) 500-9.
  • 41 Antonini A, Fung VSC, Boyd JT, Slevin JT, Hall C, Chatamra K. et al. Effect of levodopa-carbidopa in testinal gelon dyskinesia in advanced Parkinson’s disease patients. Mov Disord 2016; 31 (04) 530-7.
  • 42 Annic A, Devos D, Seguy D, Dujardin K, Destée A, Defebvre L. Intérêts de la stimulation dopaminergique continue par Duodopa® dans la maladie de Parkinson évoluée: efficacité et tolérance. Rev Neurol (Paris) 2009; 165 (8–9): 718-27.
  • 43 Devos D, Agid Y, Al Khedr A, Annic A, Azulay JP, Bakchine S. et al. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson’s disease. Mov Disord 2009; 24 (07) 993-1000.
  • 44 Löser C, Aschl G, Hébuterne X, Mathus-Vliegen EMH, Muscaritoli M, Niv Y. et al. ESPEN guidelines on artificial enteral nutrition – Percutaneous endoscopic gastrostomy (PEG). Clin Nutr 2005; 24 (05) 848-61.
  • 45 Lew MF, Slevin JT, Krüger R, Martinez JCCastrillo, Chatamra K, Dubow JS. et al. Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials. Park Relat Disord 2015; 21 (07) 742-8.
  • 46 Nyholm D. Duodopa treatment for advanced Parkinson’s disease: A review of efficacy and safety. Park Relat Disord 2012; 18 (08) 916-29.
  • 47 Deleu D, Hanssens Y. Long-term 24-hour duo denal infusion of levodopa: Outcome and dose requirements. Neurology 2006; 66 (10) 1611.
  • 48 Ricciardi L, Bove F, Espay KJ, Lena F, Modugno N, Poon YY. et al. 24-Hour infusion of levodopa/carbidopa intestinal gel for nocturnal akinesia in advanced Parkinson’s disease. Mov Disord 2016; 31 (04) 597-8.
  • 49 Mancini F, Comi C, Oggioni GD, Pacchetti C, Ca-andrella D, Coletti MMoja. et al. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens. Park Relat Disord 2014; 20 (01) 27-31.
  • 50 Lang AE, Rodriguez RL, Boyd JT, Chouinard S, Zadikoff C, Espay AJ. et al. Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials. Mov Disord 2016; 31 (04) 538-46.
  • 51 Hariz MI, Blomstedt P, Zrinzo L. Deep brain stimulation between 1947 and 1987: the untold story. Neurosurg Focus 2010; 29 (02) E1.
  • 52 Hess NCL, Carlson DJ, Inder JD, Jesulola E, Mcfarlane JR, Smart NA. Clinically meaningful blood pressure reductions with low intensity isometric handgrip exercise. A randomized trial. Physiol Res 2016; 65 (03) 461-8.
  • 53 Cotzias G, Van Woert M, Schiffer L. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967; 276 (c): 374-379.
  • 54 Duker AP, Espay AJ. Surgical treatment of parkinson disease. past, present, and future. Neurologic Clinics 2013; 31: 799-808.
  • 55 Breit S, Schulz JB, Benabid AL. Deep brain stimulation. Cell Tissue Res 2004; 318 (01) 275-88.
  • 56 Siegfried J, Lippitz B. Bilateral chronicelectros timulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkin sonian symptoms. Neurosurgery 1994; 35: 1126-9.
  • 57 Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Perret JE. et al. Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995; 345 (8942): 91-5.
  • 58 Deuschl G, Paschen S, Witt K. Clinical outcome of deep brain stimulation for Parkinson’s disease. Handb Clin Neurol 2013; 116: 107-28.
  • 59 Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P. et al. Pallidal versus subthalamic deepbrain stimulation for Parkinson’s disease. N Engl J Med 2010; 362 (22) 2077-91.
  • 60 Deuschl G, Agid Y. Subthalamic neurostimulation for Parkinson’s disease with early fluctuations: Balancing the risks and benefits. Lancet Neurol 2013; 12 (10) 1025-34.
  • 61 Herzog J, Weiss PH, Assmus A, Wefer B, Seif C, Braun PM. et al. Improved sensory gating of urinary bladder afferents in Parkinson’s disease following subthalamic stimulation. Brain 2008; 131 (01) 132-45.
  • 62 Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. The benefit of subthalamic deep brain stimulation for pain in parkinson disease: A 2-year follow-up study. Neurosurgery 2012; 70 (01) 18-23.
  • 63 Dafsari HS, Reddy P, Herchenbach C, Wawro S, Petry-Schmelzer JN, Visser-Vandewalle V. et al. Beneficial effects of bilateral subthalamic stimulation on non-motor symptoms in Parkinson’s dis ease. Brain Stimul 2016; 09 (01) 78-85.
  • 64 Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ. et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease. JAMA 2009; 301 (01) 63-73.
  • 65 Russmann H, Ghika J, Villemure JG, Robert B, Bogousslavsky J, Burkhard PR. et al. Subthalamic nucleus deep brain stimulation in Parkinson disease patients over age 70 years. Neurology 2004; 63 (10) 1952-4.
  • 66 Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL. et al. Management of referred deep brain stimulation failures. Arch Neurol 2005; 62 (08) 1250-5.
  • 67 Okun MS, Gallo B V, Mandybur G, Jagid J, Foote KD, Revilla FJ. et al. Subthalamic deep brain stimulation with a constant-current device in Parkin-son’s disease: An open-label randomised controlled trial. Lancet Neurol 2012; 11 (02) 140-9.
  • 68 Charles D, Konrad PE, Neimat JS, Molinari AL, Tramontana MG, Finder SG. et al. Subthalamic nucleus deep brain stimulation in early stage Parkinson’s disease. Park Relat Disord 2014; 20 (07) 731-7.
  • 69 Krack P, Batir A, Van BN, Chabardes S, Fraix V, Ardouin C. et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. Massac husetts Medical Society 2003; 349 (20) 1925-34.
  • 70 Pollak P, Krack P, Fraix V, Mendes A, Moro E, Chabardes S. et al. Intraoperative micro-nd macrostimulation of the subthalamic nucleus in Parkinson’s disease. Mov Disord. 2002 17. (Suppl. 3).
  • 71 Tommasi G, Krack P, Fraix V, Le Bas J-F, Chabardès S, Benabid A-L. et al. Pyramidal tract side effects induced by deep brain stimulation of the subthalamic nucleus. J Neurol Neurosurg Psychiatry 2008; 79 (07) 813-9.
  • 72 Contarino MF, Bour LJ, Verhagen R, Lourens MAJ, De Bie RMA, Van Den Munckhof P. et al. Direc tional steering: A novel approach to deep brain stimulation. Neurology 2014; 83 (13) 1163-9.
  • 73 Bartels AL, Balash Y, Gurevich T, Schaafsma JD, Hausdorff JM, Giladi N. Relationship between freezing of gait (FOG) and other features of Parkinson’s: FOG is not correlated with bradykinesia. J Clin Neurosci 2003; 10 (05) 584-8.
  • 74 Weiss D. et al. Nigral stimulation for resistant axial motor impairment in Parkinson’s disease? A randomized controlled trial. Brain 2013; 136 (07) 2098-108.
  • 75 Golestanirad L, Elahi B, Graham SJ, Das S, Wald LL. Efficacy and safety of pedunculopontine nuclei (PPN) deep brain stimulation in the treatment of gait disorders: A meta-analysis of clinical studies. Can J Neurol Sci 2016; 43 (01) 120-6.
  • 76 Bronte-Stewart H, Barberini C, Koop MM, Hill BC, Henderson JM, Wingeier B. The STN betaband profile in Parkinson’s disease is stationary and shows prolonged attenuation after deep brain stimulation. Exp Neurol 2009; 215 (01) 20-8.
  • 77 Morrell M. Brain stimulation for epilepsy: can scheduled or responsive neurostimulation stop seizures?. Curr Opin Neurol 2006; 19 (02) 164-8.
  • 78 Berg D. et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord 2014; 29 (04) 454-62.
  • 79 Weiss D, Herrmann S, Wang L, Schulte C, Brock-ann K, Plewnia C. et al. Alpha-synuclein gene variants may predict neurostimulation outcome. Mov Disord 2016; 31 (04) 601-3.
  • 80 Masellis M, Collinson S, Freeman N, Tampakeras M, Levy J, Tchelet A. et al. Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson ‘ s disease: a pharmacogenetic study. Brain 2016; 139 (07) 1-13.
  • 81 Schüpbach M, Lohmann E, Anheim M, Lesage S, Czernecki V, Yaici S. et al. Subthalamic nucleus stimulation is efficacious in patients with Parkinsonism and LRRK2 mutations. Mov Disord 2007; 22 (01) 119-21.
  • 82 Moro E, Volkmann J, König IR, Winkler S, Hiller A, Hassin-Baer S. et al. Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism. Neurology 2008; 70 (14) 1186-91.
  • 83 Lerche S, Liepelt-Scarfone I, Alves G, Barone P, Behnke S, Ben-Shlomo Y. et al. Methods in Neuro epidemiology Characterization of European Longitudinal Cohort Studies in Parkinson’s Disease-Report of the JPND Working Group Bio-C PD. Neuroepidemiology 2015; 45 (04) 282-97.
  • 84 Schork NJ. Personalized medicine: Time for one person trials. Nature 2015; 520 (7549): 609-11.
  • 85 Deuschl G, Oertel W, Reichmann H. Leitlinien für Diagnostik und Therapie in der Neurologie Idiopathisches: Idiopathisches Parkinson-Syndrom. 2016