Managing advanced Parkinson’s disease: A guide to device-aided therapy options
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Managing advanced Parkinson’s disease: A guide to device-aided therapy options

 

Regina Katzenschlager MD


Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, Vienna, Austria

 

In Parkinson’s patients whose motor complications can no longer be adequately controlled by oral medication, device-aided treatments may be used.  These interventions cannot halt the progression of the underlying neuropathological process but they can lead to considerable clinical improvements [1].

 

Surgical procedures, in particular deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi), have been shown to greatly reduce motor fluctuations and dyskinesia in randomised controlled studies [1], including in a recent study that used sham stimulation [2], and to improve quality of life [3].  DBS significantly reduces daily OFF time [1].  Dyskinesias can also be reduced significantly, either due to a direct antidyskinetic effect (GPi) or indirectly through the reduction in dopaminergic medication (STN) [1].  Adverse effects include dysarthria, balance problems, intracerebral haemorrhage, and device-related complications including inflammation [4].  Cognitive impairment has been found to be a risk factor for cognitive worsening following surgery [5].  Recent developments include electrodes with a directional shape of the current field [6]. 

 

Continuous dopaminergic drug delivery using externally worn pump systems aims at approaching the physiological state with more constant striatal dopamine levels. This can be achieved by administering levodopa directly to the site of its absorption in the small intestines or by administering the highly potent dopamine agonist apomorphine into the subcutaneous tissue. Both pump therapies can be used either during the waking day or around the clock.

 

The dopamine agonist apomorphine is as efficacious as levodopa [7].  When administered via a subcutaneous infusion, it offers continuous drug delivery. The efficacy and tolerability of apomorphine infusion have been observed in numerous open-label studies [8-10].  The TOLEDO study was the first prospective, randomized, placebo-controlled trial of apomorphine infusion [11].  This 12-week double-blind study confirmed that, in patients with persistent motor fluctuations despite optimised oral therapy, apomorphine infusion leads to a marked and significant improvement in OFF time, associated with a clinically meaningful improvement in ON time without troublesome dyskinesias.  The 52-week open-label follow-up data showed sustained clinical benefits and tolerability, with a significant reduction in oral treatment [12].  Adverse effects include skin changes, nausea, somnolence, haemolytic anaemia and neuropsychiatric changes [10,12].

 

Levodopa can also be administered in a continuous manner, using a pump connected to a PEG-J tube which delivers levodopa/carbidopa into the proximal small intestine, bypassing gastric emptying. This has been shown to lead to stable plasma concentrations of levodopa and to a stable rise in striatal dopamine [13].  A double-dummy design study showed significantly greater OFF time reduction and a concomitant increase in ON time without troublesome dyskinesia over 12 weeks [14], and data from several large observational studies and registries have provided information on safety and tolerability as well as efficacy over the longer term.  Adverse effects include device complications, inflammation – including, rarely, peritonitis –, polyneuropathy, and neuropsychiatric changes [14-17].

 

Both infusions may be considered for a larger proportion of patients with motor complications than DBS because there is no age cut-off and eligibility criteria overall are less strict.  Once motor complications become difficult to manage, either due to dyskinesia or due to absorption problems, device-aided treatments should be considered. 


References

1.    Fox SH, Katzenschlager R, Lim SY et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease. Mov Disord 2018;33:1248-66


2.    Vitek JL, Jain R, Chen L et al. Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study. Lancet Neurol 2020;19:491-501. Erratum in: Lancet Neurol 2020;19(9):e8 PMID: 32822637


3.    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;355:896-908


4.    Kleiner-Fisman G, Herzog J, Fisman DN et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord 2006;21(Suppl 14):S290-304


5.    Daniels C, Krack P, Volkmann J. Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's disease. Mov Disord 2010;25:1583-9


6.    Krauss JK, Lipsman N, Aziz T et al. Technology of deep brain stimulation: current status and future directions. Nat Rev Neurol 2021;17(2):75-87


7.    Kempster PA, Frankel JP, Stern GM, Lees AJ. Comparison of motor response to apomorphine and levodopa in Parkinson's disease. J Neurol Neurosurg Psychiatry 1990;53:1004-7


8.    Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1988;1:403-6


9.    Jenner P, Katzenschlager R. Apomorphine - pharmacological properties and clinical trials in Parkinson's disease. Parkinsonism Relat Disord 2016;33(Suppl 1):S13-21


10.    Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs 2019;33(9):905-18


11.    Katzenschlager R, Poewe W, Rascol O et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2018;17:749-59


12.    Katzenschlager R, Poewe W, Rascol O et al. Long-term safety and efficacy of apomorphine infusion in Parkinson’s disease patients with persistent motor fluctuations: results of the open-label phase of the TOLEDO study. Parkinsonism Relat Disord 2021;83:79-85


13.    Politis M, Sauerbier A, Loane C et al. Sustained striatal dopamine levels following intestinal levodopa infusions in Parkinson's disease patients. Mov Disord 2017;32(2):235-40


14.    Olanow CW, Kieburtz K, Odin P et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13(2):141-9. Erratum in: Lancet Neurol 2014;13(3):240


15.    Antonini A, Poewe W, Chaudhuri KR et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry. Parkinsonism Relat Disord 2017;45:13-20


16.    Fernandez HH, Boyd JT, Fung VSC et al. Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson's disease. Mov Disord 2018;33(6):928-36.


17.    Poewe W, Bergmann L, Kukreja P et al. Levodopa-Carbidopa Intestinal Gel Monotherapy: GLORIA Registry Demographics, Efficacy, and Safety. J Parkinsons Dis 2019;9:531-41.

 

 

UK-APO-2100029
February 2021