Motor features and response to oral levodopa in patients with Parkinson’s disease under continuous dopaminergic infusion or deep brain stimulation

Background: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson’s disease (PD), although it remains unsettled how they compare to each other. Methods: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS‐III, hand taps, the AIMS dyskinesia score and patients’ diaries. Outcome measures were time to best motor ‘on’ after start of morning treatment, daytime variability of motor condition, motor scores. Results: The time to ‘on’ was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable ‘off’ episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS‐III and taps) and the most frequent off‐states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to ‘on’ and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS‐III or taps. Conclusions: STN DBS provided adequate trade‐off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to ‘on’ and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.     

Continuous dopaminergic stimulation—From theory to clinical practice

Patients with advanced Parkinson's disease (PD) experience worsening motor fluctuations and dyskinesia. Management options include deep brain stimulation of the subthalamic nucleus (STN-DBS), subcutaneous apomorphine (in combination with oral levodopa) or continuous duodenal levodopa administration. We have used all three therapies at our clinic in Milan and report our experience. Apomorphine infusion reduced daily off time but did not improve dyskinesia; long-term treatment was associated with impulse control disorders. STN-DBS provided motor benefit, but was associated with behavioural changes including attempted suicide. Duodenal levodopa produced significant clinical benefit without behavioural changes and allowed patients to discontinue all other PD medications. Duodenal levodopa should be considered in PD patients with advanced disease.     

Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review

Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.     

Dojelitowa postać lewodopy w leczeniu zaawansowanej choroby Parkinsona

Medical treatment of advanced Parkinson disease complicated with fluctuations and dyskinesias remains difficult or in some patients totally ineffective. Recently, new methods were introduced to manage those problems: deep brain stimulation, subcutaneous apomorphine infusion and the Duodopa system for intrajejunal continuous delivery of gel containing levodopa/carbidopa (through percutaneous gastrostomy). This last method was proven to be very effective in reducing the fluctuations of levodopa plasma levels and furthermore in reducing the off periods and dyskinesias. The Duodopa system is used in patients with contraindications to deep brain stimulation or apomorphine infusions. According to recently published studies, it may also be more effective in reducing motor complications than other methods. The authors present the current knowledge on the Duodopa system, its effectiveness (also in relationship to other methods, specially deep brain stimulation and apomorphine) and possible complications (mostly due to gastric tube failures) along with the indications and contraindications.     

Motor response following repeated apomorphine administration is reduced in Parkinson's disease

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.     

Apomorphine in treatment of Parkinson's disease with fluctuations

Apomorphine is a non-specific dopamine agonist, most similar to it, with a strong action on D2, D3, D4 receptors and weaker action on D1 and D5 receptors. It has been known since 100 years, and in Parkinson's disease it was used first in 1970 by Schwab and Cotzias. Apomorphine is used in Parkinson's disease with high-grade fluctuations of symptoms which cannot be controlled by oral drugs, especially in off" periods resistant to levodopa. After subcutaneous administration it changes the "off" to "on" period within 5-10 minutes. Unfortunately, its effect is short-lasting and wears off after 40-90 minutes. Apomorphine is administered in repeated single subcutaneous injections or in continuous subcutaneous infusion, if more than 7-9 single injections are required daily. Before beginning of treatment the optimal dose of apomorphine should be determined. For counteracting its emetic action domperidon (Motilium) is given additionally 20 mg t.d.s. Apomorphine produces no tolerance and is not losing its effectiveness with continued treatment. The most frequent adverse effects during long-term treatment are local cutaneous reactions, increased intensity of dyskinesia during the "on" period, visual hallucinations whose illusory character is clear to the patient, psychoses, orthostatic hypotension. The authors treated 8 patients with marked fluctuations in Parkinson's disease treated with levodopa. In 7 cases the effects was good--6 of them received 2-3 mg s.c. 3-4 times in 24 hours for 7-12 days. One patient has been treated 9 months with good result. In one case the intensity of dyskinesia made impossible treatment continuation.     

Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson's disease: long-term results

Fluctuations in motor disability and dyskinesias are the major problem in the long-term treatment of Parkinson's disease (PD). Many authors and ourselves have shown that by giving patients a continuous infusion of levodopa it is possible to control motor fluctuations. Levodopa can be administered continuously only be intravenous, intragastric or intrajejunal delivery. Continuous dopaminergic stimulation an be achieved more easily by infusing dopamine agonists subcutaneously. Apomorphine is a potent water-soluble dopamine receptor agonist that has been shown to successfully control motor fluctuation when subcutaneously infused in complicated parkinsonian patients. We report the clinical data of 30 PD patients having at least five years of treatment with subcutaneous continuous apomorphine infusion.     

Ciągła stymulacja dopaminergiczna – doświadczenia kliniczne

Both disease progression and pulsatile stimulation of dopaminergic receptors are responsible for development of fluctuations and dyskinesia in about 50% of patients with Parkinson disease (PD) after 4-6 years of therapy with levodopa. In order to prevent motor complications, the ideal therapy should secure continuous dopaminergic stimulation (CDS). The concept of CDS is supported by the results of both experimental and clinical studies. Several treatment options are available to achieve CDS. Dopamine agonists have a longer half-life than levodopa and the development of dyskinesia is delayed when they are used as monotherapy in early PD. Continuous delivery of agonists can be improved with prolonged-release oral preparations, a transdermal delivery system or continuous subcutaneous infusion. Continuous enteral infusion of levodopa is another way to achieve CDS and it is very effective in reducing motor complications in advanced PD.     

Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.     

Continuous dopaminergic delivery in Parkinson’s disease

Motor fluctuations and dyskinesias occur in the majority of patients with Parkinson’s disease (PD) and are likely to result from changes in dopamine production, storage and release, occurring as consequences of the nigrostriatal degenerative process. All studies comparing levodopa versus dopamine agonist early therapy indicate that initiation with agonists is associated with a reduced risk of motor complications —in particular, dyskinesias— possibly because agonists’ longer half-lives provide continuous dopaminergic delivery. In advanced PD patients, switching from a pulsatile to continuous dopaminergic delivery may widen patients’ therapeutic window. Currently, this can be accomplished only with subcutaneous apomorphine or duodenal levodopa infusions. Apomorphine is a highly soluble agonist whose effect is similar to dopamine. Conversely, replacing whole oral therapy with levodopa infusion bypasses gastric emptying and avoids peaks and troughs in plasma by releasing levodopa in the duodenum/jejunum.

     

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: comparison of pre- and postoperative neuropsychological evaluation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of advanced Parkinson's disease (PD). The aim of this study was to assess the effect of the bilateral surgical procedure and STN DBS on the neuropsychological functions. Twenty Parkinson's disease patients underwent a neuropsychological assessment before and 6 months after surgery in four different conditions: medication on (with levodopa) and medication off (without levodopa) during the preoperative period, medication on/stimulation on (levodopa plus stimulators switched on) and medication off/stimulation on (stimulators switched on without levodopa) during the postoperative period. We did not find any significant difference in the four conditions for all the neuropsychological tests, confirming the lack of an overall cognitive decline after surgery. From a neuropsychological point of view, these results seem to indicate that bilateral STN DBS is a safe treatment for advanced PD.     

Bilateral subthalamic nucleus stimulation in the treatment of advanced Parkinson's disease. Five years' personal experience

Background and purposeThe objective of the study was to assess bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with advanced Parkinson disease (PD).Material and methodsThe study population included 5 patients with bilateral STN DBS who completed a 5-year postoperative follow-up period. In all patients electrodes (Model 3387 or 3389) were stereotactically bilaterally inserted into the STN using a Leksell stereotactic G frame. The clinical rating tests included Unified Parkinson's Disease Rating Scale (UPDRS) and two motor-timed tests derived from CAPIT (rapid movements between two points and stand-walk-sit test). All patients were assessed in off and on condition before implantation and 1, 3 and 5 years in medication on and off condition and stimulation on condition and stimulation off condition. To compare preoperative to postoperative UPDRS scores, only mean values and standard deviations are presented because of the small study population.ResultsThe stimulation effect was noted in the off state, resulting in a 59% improvement in motor scores of UPDRS at 5-year follow-up, when compared to preoperative scores. In the on state the stimulation improved motor scores by 17%. At 5-year follow-up, reduction of daily levodopa dose was 50%.ConclusionsBilateral STN DBS is an effective and safe treatment for patients with advanced PD. Bilateral STN DBS contributes to improvement of parkinsonian symptoms in the off state and levodopa-induced dyskinesia. This can be correlated with a 50% reduction of daily levodopa dose 5 years postoperatively.     

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.     

The effect of deep brain stimulation on the frontal N30 component of somatosensory evoked potentials in advanced Parkinson's disease patients.

OBJECTIVES: In the present study we investigated whether in advanced Parkinson's disease (PD) patients the frontal component of short somatosensory evoked potentials (SEPs) to median nerve stimulation may be modified by basal ganglia deep brain stimulation (DBS). METHODS: We recorded the SEPs in 6 PD patients undergoing bilateral functional neurosurgery in the internal globus pallidus (GPi) (4 patients) and in the nucleus subthalamicus (STN) (two patients) during ineffective and effective bilateral BDS. Pre-operatively, the SEPs were also recorded in off therapy and during apomorphine infusion. RESULTS: From the evaluation of the latency and the amplitude characteristics of the major parietal (N20 and P25) and frontal (N30) components, we observed that whereas the parietal waves did not vary in any condition, the N30 potential showed a remarkable amplitude increase during apomorphine as well as during effective bilateral GPi or STN DBS. Furthermore, after the stimulators were turned off we noticed that the N30 amplitude potential progressively faded almost in parallel with the attenuation of DBS clinical effects. CONCLUSIONS: Our results lead to the conclusion that the bilateral DBS of both GPi and STN is really effective in producing a selective increase of frontal N30 amplitude probably improving the supplementary motor area functional activity, but these results do not clarify whether this amelioration is due to a central or a 'long loop' mechanism.     

Enfermedad de Parkinson avanzada. Características clínicas y tratamiento. Parte II

Introduction

Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa.

Objective

To define the indications and results for the 3 available therapies for advanced PD.

Development

Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease.

Conclusions

Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique.     

Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study.

OBJECTIVE: We investigated the effect of bilateral subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on intracortical inhibition (ICI) in patients with advanced Parkinson's disease (PD). METHODS: The activity of intracortical inhibitory circuits was studied in 4 PD patients implanted with stimulating electrodes both in STN and GPi by means of paired-pulse transcranial magnetic stimulation, delivered in a conditioning-test design at short (1-6 ms) interstimulus intervals (ISI). The effect of apomorphine on the same PD patients was also investigated. RESULTS: We observed that implanted PD patients showed a significant increase in ICI during either bilateral STN or GPi DBS at 3 ms ISI, and during bilateral STN DBS at 2 ms ISI in comparison to their off DBS condition. The same statistical improvement was observed during apomorphine infusion at 3 and 2 ms ISI. In each condition, the electrophysiological changes were associated with a significant clinical improvement as measured by the Unified Parkinson's Disease Rating Scale motor examination. CONCLUSIONS: These results are consistent with the hypothesis that basal ganglia DBS can mimic the effects of pharmacological dopaminergic therapy on PD patients cortical activity. We propose that in PD patients, the basal ganglia DBS-induced improvement of ICI may be related to a recovery in modulation of thalamo-cortical motor pathway.     

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine

OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.     

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.     

Parkinson's disease advanced therapies - A systematic review: More unanswered questions than guidance

In advanced Parkinson's disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). We reappraised the evidence guiding the decision of appropriate device-aided therapies in advanced PD, and systematically reviewed the literature (including ongoing clinical trials) comparing CSAI, LCIG, DBS in terms of efficacy and cost-effectiveness, with particular consideration to possible conflicts of interests. Of 14,980 documents screened, sixteen were included (4 and 13 studies examining efficacy and cost-effectiveness, respectively). LCIG and DBS showed higher efficacy compared to best medical therapy (BMT). DBS was more expensive than BMT and LCIG. Lifetime costs of CSAI were lower of those of DBS, and DBS lifetime costs were lower than those of LCIG. The majority of studies (11 out of 16) showed direct or indirect sponsorship from pharmaceutical or device companies. Only one ongoing clinical trial comparing LCIG with DBS was found. Device-aided therapies address unmet needs in advanced PD. LCIG and DBS are superior to BMT in head-to-head studies; however, initial and lifetime costs should be considered when choosing those therapies. Guidelines to assist clinicians and patients to choose device-aided therapies, free from conflict of interests, are required.