Selecting Patients for Continuous Dopaminergic Stimulation Therapy

Rationale for Continuous Dopaminergic Stimulation Treatment

Rationale for Continuous Dopaminergic Stimulation Treatment
The link between long-term levodopa treatment for Parkinson’s disease (PD) and the development of motor fluctuations and dyskinesia is well established.¹ As the therapeutic window narrows in advanced disease, the patient has more ‘off’ time and more dyskinesia with levodopa treatment. This relationship between motor complications and levodopa is dose-dependent – studies have demonstrated a clear increase in dyskinesia at higher levodopa doses.^2,3 However, a prerequisite for the development of motor complications and dyskinesias in PD is pulsatile dopaminergic stimulation. It is suggested that pulsatile stimulation of the PD-related dopamine-denervated striatum enhances the likelihood of a cascade of events, downstream to dopamine receptors, including D1 receptor-dependent induction of immediate early genes, increased DNA binding, phosphorylation of dopamine- and cyclic adenosine monophosphate (cAMP)-regulated neuronal phosphoprotein (DARPP-32) and loss of depotentiation of long-term induction. These events result in an irreversible enhanced sensitivity to dopamine D1 receptor stimulation with induction of extracellular signal-regulated kinases in the direct striato-nigral pathway.⁴ This is not unique to oral levodopa treatment but has been demonstrated also with other dopaminergic drugs, as shown in a study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys that received daily apomorphine injections or an apomorphine implant. All animals receiving injections developed dyskinesia by a mean of 8.3 days, no animals with continuous delivery of apomorphine developed dyskinesia (see Figure 1).⁵ Providing more continuous dopaminergic stimulation (CDS) with treatment is, therefore, an important goal to prevent and reduce motor complications.

Options for Continuous Dopaminergic Stimulation
Dopamine agonists are longer-acting than levodopa and are therefore often used as initial treatment for PD to reduce the risk of developing dyskinesia, dystonia and motor fluctuations.⁶ However, the clinical effects are inferior to those with levodopa and most patients subsequently require levodopa or other treatments to achieve optimum control of their disease. Adding catechol-O-methyl transferase (COMT) inhibitors to levodopa treatment in early-PD patients, in order to provide more continuous delivery of levodopa to the brain, also appears to be of limited efficacy in preventing and/or reducing motor fluctuations and dyskinesia;⁷ as does the addition of monoamine oxidase (MAO)-B inhibitors. To achieve more powerful CDS, there are three options widely available for the treatment of PD: levodopa/carbidopa intraduodenal gel infusion (Duodopa®), subcutaneous apomorphine infusion (APO) and deep brain stimulation (DBS), which is not strictly CDS treatment but has similar effects. These therapies are well established and there is a growing number of studies that provide high-quality evidence (i.e. from open-label, non-randomised studies through to randomised controlled trials),⁸ but there have been no direct comparisons of the three CDS options. We must therefore rely on indirect comparisons and clinical experience to judge the appropriateness of each CDS therapy for individual patients.

Method of Administration
APO is the least invasive procedure and DBS is the most invasive. This could affect patient perceptions and preferences and for elderly patients (>65 years), DBS is not recommended. APO and Duodopa are both infusion therapies provided by pumps, but the subcutaneous infusion of APO is less invasive than the intraduodenal infusion of Duodopa (which requires surgical implantation). However, Duodopa use is more likely to be provided as monotherapy, which again mayinfluence patient preference for simpler drug regimens.

Motor Fluctuations
When assessing publications investigating the efficacy of APO, a mean reduction in ‘off’ time of approximately 60 % (range 40–85 %) has been observed after 3–44 months of treatment.^9–17 However, additional levodopa administration is often required to achieve these response rates. Furthermore, patients sustain APO treatment for a limited period of time.¹⁸ Greater reductions in ‘off’ time of 70–90 % have been observed with Duodopa treatment, but this is based on fewer patients and fewer studies.^19–22 These reductions with Duodopa appear to be similar to effects on motor status achieved after DBS.²³

Dyskinesia
The tendency to react with dyskinesias is reduced by approximately 40 % after six months of APO treatment.²⁴ DBS produces around 80 % reduction of dyskinesias.²³ Small-scale studies with Duodopa suggest that dyskinesia intensity may be reduced by 75–90 %¹⁹ (includes unpublished data from the Bremerhaven clinic) – larger-scale studies would be useful to better assess these effects.

Non-motor Symptoms
It is increasingly obvious that in addition to motor symptoms in PD, non-motor symptoms have a detrimental effect on patient quality of life (QoL). As of yet, the effects of the three CDS treatments on non-motor symptoms cannot be fully understood. From the data that are available, Duodopa has a statistically significant benefit in six of the nine domains of the non-motor symptoms scale (NMSS) including gastrointestinal, urinary, cardiovascular, sleep/fatigue, memory/attention and other miscellaneous non-motor symptoms (see Figure 2).²⁵ The other three domains also showed a trend towards improvement. In preliminary reports, DBS reduced sleep, urinary and miscellaneous symptoms²⁶ and APO improved depression (in the ‘off’ phase), anhedonia, nocturia and pain after one month (see Figure 2).²⁷ Because there is a wide range of non-motor symptoms that affect a large proportion of patients with PD, and because different CDS treatments may improve different non-motor symptoms, the effects of CDS treatments on these symptoms may, in future, be a crucial factor in the choice of treatment.

Health-related Quality of Life
Because non-motor symptoms may have such an important impact upon QoL, the benefits of CDS treatments described above may have a positive effect on QoL. Using the Parkinson’s disease questionnaire (PDQ)-8 as a measure, there was a significant improvement in health-related quality of life (HRQoL) with Duodopa among 22 patients with PD and 77 % of patients had improved HRQoL.²⁵ In a second report, nearly 90 % of patients receiving Duodopa had a great or moderate improvement in QoL as measured on a five-point rating scale from ‘great improvement’ to ‘worsening’.²⁸ Similarly using PDQ-8, APO resulted in a significant improvement in HRQoL,²⁷ and there is good evidence that DBS also significantly improved HRQoL.²⁹

Side Effects and Complications
The most frequently observed complications with Duodopa are technical issues with the percutaneous endoscopic gastrostomy (PEG) tubing such as leaking, occlusion and dislocation.³⁰ The pharmacological adverse events are the same as those expected with oral levodopa and include, among others, cobalamine-deficiencyinduced polyneuropathy.³¹ New types of tubing are being developed by the manufacturer, with promising results and these technical problems are usually reduced with increasing experience. The most common adverse events with APO are skin reactions – noduli at the point of infusion is a very common side effect – but complications such as hypotension, eosinophilia and nausea are also relatively common (>5 % in one patient series).³² Among the most common complications of DBS are behavioural and cognitive changes, with more than 40 % of patients experiencing cognitive problems in one study – depression and mania also occur relatively frequently with DBS.^33,34

Patient Selection
The indications for using any CDS treatment are similar and include: severe disease, pronounced motor fluctuations, dyskinesias, nocturnal akinesia and severe tremor that does not respond to medication. A simple algorithm has been proposed (see Figure 3)³⁵ and factors that play an important part in the decision-making process are age of patient and severity of dyskinesia. Such an algorithm may be useful for choosing the most appropriate CDS therapy for an individual patient and in the following case studies, we present some examples of the issues that can contribute to clinical decisions and discuss alternative scenarios for each case. At the fourth International Forum on Advanced Parkinson’s Disease, interactive electronic voting was used to gauge the opinions of the whole audience. Where interesting issues were raised through this voting, these are included in the report of the case studies below.

Case 1 – A Patient with Early Onset Disease
Patient History
A 27-year-old man was diagnosed with PD in 1998 – three years after the onset of slowly progressive tremor and slowness of the right hand and leg. Therapy was initiated with a dopamine agonist, but none of the dopamine agonists that were available in 1998 (pergolide, ropinirole and pramipexole) were well tolerated. Owing to persistent dopamine agonist-induced nausea and vomiting (domperidone was not effective at reducing this), this treatment was withdrawn and levodopa/carbidopa 100 mg three times daily (tid) was given. Initial symptomatic improvement was observed.

Subsequent Treatment
Approximately four years after starting levodopa therapy, motor fluctuations and mild dyskinesia developed (in 2002). This was managed initially by adding low-dose dopamine agonist (cabergoline, which at that point in time was tolerated), amantadine and a COMT inhibitor.

In 2006 (approximately three to four years later), the patient was receiving levodopa/carbidopa 100 mg six times daily (every three hours), the COMT inhibitor tolcapone tid and the dopamine agonist cabergoline 4 mg daily.

The patient had three hours of ‘off’ time per day, with some peak-dose dyskinesia and non-motor symptoms that included sleep fragmentation, ‘off-time’ anxiety and bladder urgency. It was decided at this time that a change in therapy was needed to improve symptoms.

Five possible options were considered at the meeting:

• CDS with either APO or Duodopa;
• DBS;
• an increased dose of dopamine agonists;
• a levodopa controlled-release formulation; or
• doing nothing.

The group opinion was split between the three CDS options (approximately 64 % voted for the first two options), with others suggesting that dopamine agonists or levodopa controlled-release could be tried before ‘progressing’ to these more invasive and expensive treatments. In the real-life case, the patient was switched to APO initially at 1 mg/h and titrated to 1.5 mg/h, because the managing team did not want to increase the medications being administered or increase the frequency of oral levodopa doses.

Outcomes on Continuous Dopaminergic Stimulation Therapy
While receiving APO, the patient had some reductions in ‘off’ time but developed nausea and compliance was poor. APO was therefore withdrawn and the patient was administered the following treatment regimen:

• levodopa/carbidopa 600 mg/day in eight administrations;
• tolcapone tid (300 mg/day);
• cabergoline 2 mg in the evening; and
• pramipexole 0.7 mg/day.

However, the patient still had severe dyskinesia for three hours/day, frequent ‘off’ periods totalling 5.5 hours in the daytime and a unified Parkinson’s disease rating scale (UPDRS) III (‘off’) score of 40 and UPDRS III (‘on’) score of 15. The audience was polled again at this point and group opinion was split (approximately 1:1) between DBS and Duodopa as the next best option for treatment.

DBS would be an excellent option for this patient, but he was reluctant to receive this (as he felt he was still young and would leave this as a ‘last resort’ as he had had a previous bad experience with surgery) and he was administered Duodopa. The patient was started on an infusion rate of 2.1 ml/h for 15–16 hours with a morning bolus of 3 ml and up to three extra bolus doses of 2.2 ml (total levodopa dose of 700 mg/day). The outcome was UPDRS III (‘off’) score of 27 and UPDRS III (‘on’) score of 15; ‘off’ time was 45 minutes/day and ‘on’ time with dyskinesia was 60 minutes/day. More than two years after starting Duodopa therapy, the patient continues on a stable dose (infusion rate of 2.1 ml/h for 12–16 hours with a morning bolus of 2.7 ml, and one extra bolus dose of 2.2 ml [total levodopa dose of 500–700 mg/day]) and has a UPDRS III (‘off’) score of 37 and a UPDRS III (‘on’) score of 22; ‘off’ time was 60 minutes/day and ‘on’ time with dyskinesia was unchanged at 60 minutes/day.

Case 2 – A Patient with Motor Complications and ‘Off’ Time Depression
Patient History
A 58-year-old man who had PD from the age of 44 years, developed motor fluctuations and dyskinesia at the age of 54 years. Non-motor symptoms included depressive thoughts and sleep fragmentation. His treatment regimen consisted of:

• levodopa/carbidopa 150 mg every three hours (seven doses/day);
• entacapone 200 mg seven times/day;
• pramipexole 0.7 mg tid;
• selegiline 5 mg once daily; and
• amantadine 100 mg tid.

Despite this polypharmacy, the patient had two hours ‘on’ time with dyskinesia and four hours ‘off’ time/day.

Continuous Dopaminergic Stimulation Treatment and Outcome
Increasing the dose of levodopa or dopamine agonists would have added to the high level of oral medication that this patient was already receiving, so consensus was reached to treat this patient with CDS treatments. In this patient, APO 6 mg/h for 16 hours was initiated and supplemented with levodopa 100 mg six times/day and amantadine 100 mg tid. After six months, ‘off’ time was decreased to 1.5 h/day and ‘on’ time with dyskinesia was decreased to 1.5 h/day. After two years (and an increased infusion rate of 7 mg/h), ‘off’-time was 2 h/day and ‘on’ time with dyskinesia was decreased to 2.5 h/day. Because at that time motor complications were worsening, the other options considered were:

• switching to oral dopamine agonists;
• increasing levodopa dose;
• Duodopa;
• DBS; or
• increasing the APO infusion rate.

In this patient, DBS of the subthalamic nucleus (STN-DBS) was chosen because the patient had already been treated with APO and did not want another infusional therapy. The resulting outcome was very positive; ‘off’ time was approximately 90 minutes/day and the patient had no more dyskinesia.

Case 3 – A Patient with Impulse Control Disorder
Patient History
A 58-year-old man had PD since the age of 45 years (otherwise healthy). He had motor fluctuations and dyskinesia since the age of 52 years, which included ‘on/off’ fluctuations, severe ‘off’ phases with freezing and ‘on’ phases with pronounced dyskinesias. He had depressive symptoms, but no dementia. His treatment consisted of:

• pramipexole 1.4 mg/day;
• levodopa 525 mg/day;
• entacapone 1,400 mg/day;
• amantadine 200 mg/day; and
• quetiapine 50 mg/day.

Unfortunately, the patient developed dopamine dysregulation syndrome (DDS), consuming up to 3 g levodopa daily and neglecting the advice to restrict medication. He not only gradually suffered more and more from punding, but also from impulse control disorder (ICD), including hypersexuality and gambling. On top of this, he developed psychotic symptoms, which included hallucinations and confusion. Eventually he lost his family and home, went into a nursing home and needed a legal guardian to control his finances.

Continuous Dopaminergic Stimulation Treatment and Outcome
The patient was initially switched to a supervised regimen of levodopa 800 mg/day monotherapy. Psychotic symptoms improved, but did not disappear. DDS and ICD did not change, however, and motor fluctuations and dyskinesia worsened. The next step was to add quetiapine 200 mg/day, but again DDS and ICD did not change. Similarly, clozapine 50 mg/day did not improve DDS and ICD. At this stage, CDS treatment was considered. The group consensus (70 %) was that Duodopa was the best treatment option for this patient, which confirmed the actual strategy as the patient was treated with Duodopa 5.2 ml/h daytime and 3.6 ml/h night-time, with a maximum of five boluses of 2 ml and the quetiapine dose was reduced to 75 mg/day. The outcome was:

• DDS resolved almost completely;
• ICD resolved completely;
• psychotic symptoms and confusion decreased further;
• cognitive function returned to normal;
• motor fluctuations improved; but
• there were problems with the PEG/J tube on two occasions.

The positive outcome was encouraging, as there is a potential risk that patients with DDS may intentionally stop Duodopa therapy in order to enjoy the oral levodopa-related ‘kick’ again.

Case 4 – A Patient Seeking to Maintain an Active Lifestyle
Patient History
A male farmer who enjoyed many sports including windsurfing was diagnosed with PD at the age of 38 years in 1998. He was initiated on ‘levodopa-free’ therapy that consisted of cabergoline (titrated up to 12 mg/day), amantadine (up to 400 mg/day) and selegiline (10 mg/day). The patient responded well to this treatment and continued with his active life for approximately five years.

Treatment Intensification
In 2003, levodopa therapy was deemed necessary and small doses were added to the patient’s existing treatment regimen. After one year, levodopa was being administered at doses of 500 mg/day and by 2005, the patient had ‘on-off’ fluctuations with moderate dyskinesia and severe ‘off’ periods. Following a freezing episode while windsurfing, which resulted in the patient being stranded at sea and requiring air-rescue, further therapy was discussed.

Continuous Dopaminergic Stimulation Treatment and Outcome
APO, Duodopa and DBS were all considered for this patient. APO treatment was chosen as it was reversible (unlike DBS) and was less invasive and the patient felt there was, therefore, less stigma than Duodopa treatment. After three months of APO treatment, ‘off’ time was dramatically reduced to less than 30 minutes/day and this could be managed with bolus doses. The patient was now on a monotherapy with APO at a dose of 5.5 mg/h for 16 h/day. He was taking a long-acting levodopa preparation in the evening to cover the night. The patient had no skin reactions or other adverse events resulting from APO treatment and although he has stopped windsurfing, he continues an active lifestyle that includes sailing.

Conclusions
The case studies presented here illustrate some examples of the issues that can influence CDS treatment choice. Decision trees have been developed and some general contraindications can be identified from the literature (see Figure 3). Pronounced dementia and a lack of support/compliance are contraindications for APO and Duodopa. Additionally, a tendency to have hallucinations restricts the use of APO and contraindications for abdominal surgery rule out Duodopa use. DBS is contraindicated when the patient is unsuitable for brain surgery, when dementia, depression or anxiety are present and, most importantly, in patients aged >70 years – this last contraindication rules out a large number of patients for DBS.

More good-quality evidence of the main CDS therapies is needed, before consensus on more detailed treatment algorithms can be achieved. In particular, trials directly comparing CDS treatments would be most worthwhile. However, using the general principles outlined above and using clinical experience such as that presented in the cases here, will help with selection of the most appropriate CDS therapy for individuals with advanced PD.