Device-assisted therapies for Parkinson disease

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Parkinson disease is a progressive degenerative neurological disorder, for which there are no disease modifying treatments, and so, management is focused on symptom relief. As Parkinson disease progresses and symptoms become more severe, devices that assist with medication delivery or directly treat symptoms are options for some patients.

I'm Dr Laura Beaton, your GP host for this episode, and my guests are the authors of a really great article in Australian Prescriber. The article summarises device-assisted therapies for advanced Parkinson disease. Nadia Mouchaileh is a senior pharmacist at Austin Health, an adjunct lecturer at Monash University, and Dr Jill Cameron is a neurologist and the head of the Movement Disorders Clinic at Austin Health. Thank you so much for the article and for joining me today.

NM: Thank you so much for having us.

JC: Thanks very much.

So let's start off by talking about the oral and transdermal therapies, which are the classic therapies for Parkinson disease, and why for some people with Parkinson's, these don't actually adequately control their symptoms.

NM: In the early stages of disease, most patients do respond well to the oral or transdermal treatments that we have available, and these aim to either boost dopamine levels in the brain or help the brain use the dopamine more effectively.

So the first go-to first-line treatment that most of us are familiar with is levodopa. Now first in those early stages of disease, levodopa works really well. Its absorption and response is fairly predictable, but what we see over time is that patients start experiencing motor fluctuation, and that's where the effect of levodopa becomes less predictable and we start to see patients shift between what we term "on periods" where the motor symptoms are well controlled and "off periods" where the medication wears off and the motor symptoms return. And so we start to see these really problematic shifts between on and off periods, and the patients can experience wearing off effects, where, say, a dose that used to last 5 or 6 hours might only last 3 or 4 hours.

Then there's the issue of dyskinesia, which are basically involuntary jerky movements, almost like fidgeting or restlessness, and these usually happen at peak levodopa levels, which suggests there's too much dopamine in the system at that moment. And these tend to occur more in the advanced or moderate stages of disease.

And we do have strategies to try and manage these complications. For example, we might shorten the time between levodopa doses, giving more frequent administrations. That helps to minimise those wearing off effects. The other option is to add in additional medications, like dopamine agonists. Rotigatine is available as a transdermal patch and helps to avoid absorption or swallowing issues. COMPT inhibitors such as entacopone or opicapone and MAO-B inhibitors such as residuline or cephinomide can be used as add-ons to levodopa. And we also have amantadine, which is sometimes used specifically to treat dyskinesias. So for many patients, tweaking or optimising these oral or transdermal therapies help, but for some patients symptoms can remain quite debilitating and unpredictable. And so that's when we start to look at more specialised drug-assisted therapies to help smooth those symptoms.

Thanks, Nadia, for that great summary. And I will point our listeners to your article because in the appendix there's a very helpful summary of all of the oral and transdermal treatments for Parkinson disease.

And Jill, I wonder if we can think about what are the clinical scenarios where people in the community, GPs like myself, should really be thinking this person should be referred to a specialised centre for movement disorders for consideration of some advanced therapies?

JC: Yeah, absolutely. I think this is a really important question. And in answering it, it's important to consider when do we as movement disorder specialists think about initiating some of these device-assisted therapies? And I think as Nadia said, it's really when those oral and transdermal options that we have earlier on in the course of the disease are not adequately managing patient symptoms. And really importantly, I think it's about when those symptoms are having an impact on patient's quality of life. Parkinson disease is a really variable complex condition. No 2 people with Parkinson disease will be the same, and it's really important to take that into consideration when we're thinking about when is the right time to start thinking about device-assisted therapy.

There are a couple of other clinical criteria out there that in some situations people use. There's the so-called 5-2-1 rule. So when patients are on 5 doses of levodopa, experiencing at least 2 hours of problematic off-state and 1 hour of problematic dyskinesia, that's one of the established criteria in the literature and that we use in clinical practise to define the moderately advanced Parkinson disease, and it's in these patients on the whole that we're really considering using the device-assisted therapies.

I think the other thing to mention is that these are complex therapies. They're not decisions that can be made within one clinic appointment. And so I think it's really important if we start those conversations early, then we can take time to make the right decision for the right patient. So that's really when we would be keen to see these patients. Early referral I think is really helpful so that we can take the time to get to know the patient, get to know their disease, and make the right decisions in terms of which of these device-assisted therapies is most appropriate for them.

Thanks, Jill, and that's really helpful. I know everybody's experience is different, but what proportion of patients end up actually needing device-assisted therapies?

JC: The short answer is there isn't great epidemiological data on this. It's a very individual patient-specific journey and there can be lots of variability, but we clearly see a huge proportion in our subspecialty service. I think the key point is that it really should be considered in all patients who have moderately advanced Parkinson disease where their quality of life is being impacted by particularly the motor fluctuations that can be better managed with these device-assisted therapies.

The focus of your article really is on the device-assisted therapies and advanced Parkinson's, and you've got a great summary table. Maybe we could talk through it from least invasive to most, because I imagine that's maybe how you present them to patients. But I thought we could start off with the infusion options, and these are in medication delivery systems, either subcutaneous or intestinal.

NM: Yeah. Thanks, Laura. We can start off with apomorphine. So apomorphine, it's a dopamine agonist. It works by stimulating dopamine receptors in the brain to help manage those motor symptoms. It can be delivered in 2 ways, through a continuous subcutaneous infusion via small portable pump or through intermittent bolus doses.

And so when it's delivered through this continuous infusion, it really does help to smooth out those on and off swings that we see in advanced stages of disease. The infusion is given subcutaneously, or under the skin, typically in the abdomen or thigh, and because it's administered subcut, it helps to bypass those issues like delayed gastric emptying, which can affect absorption of oral meds.

The pump itself is typically worn in a pocket or a belt, which makes it relatively easy for patients to manage throughout their day. It's usually set up in the morning upon waking, and it can be done by the patient or the carer, and it's left running continuously during the waking hours. So, typically it's on for 12 to 16 hours per day. Most patients will stop the pump overnight, although in some cases it might be continued for full 24 hours, but this is rarer.

Typically, apomorphine infusion is started in a hospital or an outpatient specialist clinic, and that's where the treating team can assess the patient's response to apomorphine and titrate the dose. The usual dose range that we see is between 2 to 7 mg per hour, and most pumps will be programmed to include bolus function as well, so that allows patients to administer additional rescue doses during off periods. The pump rates and the bolus doses are set up by the clinic, so the patients or carers can't adjust these themselves once they're home and managing the infusion themselves.

The second device-assisted therapy in Australia is the levodopa intestinal gel infusions. Now these ones are a bit more invasive compared to apomorphine infusions, and that's because they require a surgical insertion of a PEJ tube, which is a tube that gives us direct access to the small intestine, and this would require an inpatient hospital admission, so the patient is admitted into hospital for the surgery. They might stay for a few extra days after to monitor their response to allow for dose titration. Again, because the gel is delivered directly into the intestine, it bypasses the stomach, and so it can be a useful option for patients in advanced disease who have those severe motor fluctuations.

Like the apomorphine infusions, the intestinal infusions run continuously during waking hours and are stopped overnight. And that's to help reduce the risk of tolerance developing. The pump is typically programmed to deliver a morning bolus dose. That's to give a quick effect. And then it's followed by a continuous infusion, which can range from 20 to 200 mg of levodopa per hour. And again, extra bolus doses can be administered as required during those off periods. And also those pumps are pre-programmed as well, so the patients can't be adjusting the doses once they're home.

Currently, the only intestinal gel product available in Australia is Duodopa, which are levodopa and carbidopa gel cassettes, but we do have a new intestinal gel called Lecigon, which is levodopa and carbidopa formulation plus added entacapone, and it's been recently approved by the TGA and is currently moving through that PBS approval process.

Another new product that has also recently been TGA approved is subcutaneous levodopa infusion, which is foslevodopa and foscarbidopa, and these are both pro drugs to levodopa and carbidopa. And this is a continuous infusion also delivered via portable pump, but the advantage of the subcutaneous levodopa infusion over the intestinal levodopa infusion is that it's less invasive to initiate. It won't require surgery or hospital admission like with the intestinal gels, and that's also moving through the PBS approval process.

Great. Well, we can watch this space. Do people normally progress from a subcutaneous option like apomorphine before something like an intestinal gel, or is it so patient specific that one may not be suitable at all for subcut apomorphine and actually would go straight to the intestinal gel?

JC: From a clinical perspective, typically what we see, although of course there's a bit of variability patient to patient, is that there'll be various reasons why either from a medical point of view or from a patient perspective, one of these therapies is more appropriate than others, so it's not typically a transition through the various therapies. There's a couple of situations where that's not quite the case.

And I think particularly with the subcutaneous apomorphine, just another point to make is that it is available as an intermittent pen injection, so an intermittent subcutaneous injection device that we use as sort of an on-demand rescue therapy. So patients will be on their usual oral medications. But particularly when they're troubled by, for example, end-of-dose wearing off or those problematic off periods, the intermittent apomorphine injections gives a rescue therapy that can be given at the time and is quite quickly effective. So patients may in some situations start on an intermittent apomorphine injection regime and then transition onto a continuous apomorphine infusion if they're needing to use the injections more frequently through the course of the day. And in that situation, a pump is a good idea to transition on to get even better control of symptoms.

So to answer your initial questions, typically it's one device-assisted therapy that is most appropriate for the patient, and so that tends to be the typical patient journey, with a little bit of variation, particularly for deep brain stimulation as well.

I guess when it comes to side effects or disadvantages or things that GPs might be looking out for, is this mostly related to the actual device itself and how it is situated in the body?

NM: I think GPs can play a really important role in monitoring complications and side effects of these therapies, especially once the patients or carers are managing the devices themselves at home.

And so for apomorphine infusions, the most common issue that arises, especially during that initiation, is nausea, and that's typically managed with an anti-emetic like domperidone, which is a dopamine antagonist. It doesn't cross the blood-brain barrier, so it's quite safe to use in Parkinson disease. It is usually started as a pre-treatment 1 or 2 days before the apomorphine is commenced, and then it's gradually withdrawn as the nausea improves. So GPs can help [with] monitoring this, and assist with the titration of those anti-emetics.

Injection site reactions, they can also occur, and they include things like redness, irritation, infections at the infusion site. Some of these can just be managed with basic skincare or rotating the injection site. Dizziness and orthostatic hypertension can also occur, especially during dose titrations, so encouraging adequate hydration and reviewing medications that can contribute to hypotension can be helpful. QTc prolongation is a rare but important consideration, especially in patients with cardiac risk factors or with patients who are taking other QTc prolonging medications.

With intestinal gel infusions, the main risks are related to the surgical procedure and the device itself, so GPs should look out for surgical site complications such as pain, infection, or bleeding at the PEJ site, especially in that early period after surgery. Tube-related issues or device malfunctions such as dislodgement, blockage, or kinking in the line, they can lead to a sudden interruption of therapy and sudden worsening of symptoms, and so that would require urgent attention or input from the specialist.

Thanks for that. I did want to make sure we covered off both of those devices before we moved to the most invasive, deep brain stimulation. And so this works very, very differently. Jill, would you mind explaining to us how deep brain stimulation works in Parkinson's?

JC: Yeah, absolutely. Deep brain stimulation has been really a game changer, I think, in terms of what advanced therapies we're able to offer our patients. In the clinic, it's not uncommon for me to see patients who have had deep brain stimulation and really describe it as a life-changing procedure. It is of course, however, very complex and our most invasive treatment option that we have.

Essentially deep brain stimulation is now a very well-established invasive neurosurgical procedure to treat Parkinson disease, where essentially electrodes are implanted into targeted brain regions to deliver high-frequency electrical stimulation to these regions. And we know now that this results in really effective treatment of a number of symptoms of Parkinson disease.

Interestingly, exactly how deep brain stimulation works and how it provides this benefit in Parkinson disease remains a bit of a mystery. It's certainly a question that is the focus of a lot of preclinical and clinical research at the moment, but certainly the clinical benefits in terms of improvement in motor symptoms and improvement in quality of life is really quite significant.

Thank you also for correcting my misguided understanding that people might step through the different devices, but it sounds like that isn't the case, and maybe somebody's first choice, if they're appropriate, might be deep brain stimulation.

JC: I don't want to say that no one steps through the various device-assisted therapies, but particularly things like deep brain stimulation that we know the risks associated with it are higher, for example, as people get older and there are various different situations where deep brain stimulation can become not a feasible or medically appropriate option.

And it makes sense to me that some of the things GPs might be looking out for is related to the actual surgery, but then once everything's stable and they're in the community, there are some other symptoms we might want to be looking out for. What are the symptoms you might want to know about for someone who's got a deep brain stimulation, to say, ‘Look, is this right?’

JC: The risks of deep brain stimulation we think about broadly in 3 categories. There are the surgical risks obviously at the time of the operation, and they're really important for the patients to know about in terms of potential risks, but obviously that's mainly monitored for in their intraoperative period and their postoperative recovery in hospital.

In the community, I think the main risks that particularly GPs are well-placed to keep an eye out for and that we want to hear about is device-related problems, particularly if their implantable programmer or anywhere near their leads is looking like there's signs of skin breakdown or any signs of infection. The risk of infection and then the risk of infection tracking into the central nervous system is quite high and certainly managed best sooner rather than later.

The other main category of potential complications really relates to the stimulation-related risks, so that's why these patients are coming back to our outpatient clinic quite frequently, particularly in the early post-operative period, because of needing to adjust the programme settings to get that optimal benefit of symptomatic response, but to minimise the risk of stimulation-related side effects. So again, that tends to happen early on. But if anything is occurring in terms of new neurological symptoms or new psychiatric symptoms as concerns, sometimes these can be related to the stimulation settings, and we certainly want to know about it sooner rather than later so we can try to adjust things and improve these side effects.

And with these very specialised devices, as a GP, if I'm concerned, who are we contacting for urgent or semi-urgent assistance? Is it always going through your multidisciplinary clinic? I mean, this is a big clinic with lots of different specialists. Thinking about that pathway, how do we get help and from whom?

JC: I think the first thing to say is that for urgent medical issues, if there's any concerns, then referral to the emergency department of any particularly tertiary hospital, but really any emergency department for further investigation and assessment. If there's urgent concern, it's absolutely appropriate.

For those more semi-urgent kind of assistance, there's a couple of different pathways. And again, this is going to be a little bit different in every service, but I think contacting the patient's treating movement disorders team, be it the treating neurologist or neurology team or nursing team. Usually these patients are very well known to the multidisciplinary services. Patients will have our team's contact details and we're easily contactable to try and help troubleshoot and bring patients in as required.

The other thing to note is that a lot of pharmaceutical companies [that supply Parkinson disease infusion systems] provide a support service that is really helpful and beneficial to the patients, but also in conjunction with the treating team, provides another contact for GPs, for patients, and for anyone who may have concerns.

I was interested to read in your article about how this might work when you have patients who are regional or remote, and what kind of ways things can be provided to our regional and rural patients. Do you mind talking a little bit to the models of care that you see work really well?

JC: There's no doubt subspecialty services are unfortunately still largely metropolitan based, and so I think there is a bit of a divide between ease of access and ease of follow-up for regional and remote patients. Certainly we have now many regional and remote patients who, yes, may have needed to come to a tertiary centre for initiation and for initial assessments early on, but then were able to manage things through both a combination of telehealth and community support nurses more regionally.

I know around Australia there's a bit more funding and support to set up outreach programmes, where the specialists or the subspecialty movement disorder teams are actually going out to the bigger regional centres, and then allowing for some of those assessments, education sessions and those sorts of things to happen. There's definitely still room to improve how well we service our regional and remote patients, but I think it's gradually heading in the right direction.

Thank you so much, Jill and Nadia, for your time today and for the article. Like me, I imagine our listeners are reflecting on which of their patients with Parkinson's would really benefit from device-assisted therapies, and I hope that our discussion today has helped us all feel a bit more confident when we next see somebody who is using a device to help manage their Parkinson's. The article is a great reference to come back to and is available for free on the Australian Prescriber website.

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The views of the hosts and the guests on this podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Jill Cameron received support from Abbvie to attend a conference in 2023, previously received honoraria from Abbvie, CSL Seqirus, and Stada for involvement in educational seminars and presentations, and has been on advisory boards for AbbVie and Stada.