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 .
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 , including in a recent study that used sham stimulation , and to improve quality of life . DBS significantly reduces daily OFF time . Dyskinesias can also be reduced significantly, either due to a direct antidyskinetic effect (GPi) or indirectly through the reduction in dopaminergic medication (STN) . Adverse effects include dysarthria, balance problems, intracerebral haemorrhage, and device-related complications including inflammation . Cognitive impairment has been found to be a risk factor for cognitive worsening following surgery . Recent developments include electrodes with a directional shape of the current field .
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 . 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 . 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 . 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 . A double-dummy design study showed significantly greater OFF time reduction and a concomitant increase in ON time without troublesome dyskinesia over 12 weeks , 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.
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