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Modern treatment of Parkinson’s disease (PD) has come a long way from those suggested by James Parkinson in the early 19th century. Parkinson advocated blood-letting and use of vesicatories to induce blistering of the skin and production of purulent discharge, aiming to divert blood and inflammatory pressure away from the brain.
Levodopa was first used to treat PD in 1961 and is now the gold standard in the treatment of the disease. Other modern therapies include dopamine agonists (DAs), monoamine oxidase B (MAO-B) inhibitors and catechol-O-methyl transferase (COMT) inhibitors. This review will focus, however, on more advanced therapies for PD patients with levodopa-resistant symptoms or those with significant side-effects from these therapies. Three treatments will be discussed: Deep brain stimulation (DBS), duodopa therapy and apomorphine. In general, the first step in considering a patient for any advanced PD therapy is referral to a specialist neurologist or geriatrician with a special interest in PD.
Deep brain stimulation
DBS is now an established treatment for PD. While traditionally reserved for patients whose symptoms were not adequately controlled with medications, there is a move towards introducing the therapy earlier in the disease. In fact, younger patients are often more suitable for DBS as they have fewer risk factors for surgery.
Patients in whom medical treatment is still effective for motor symptoms are better candidates for DBS. Intact cognitive function is also essential. A Mini-Mental State Examination (MMSE) score of less than 24 is considered an absolute contraindication to DBS in most centres. Caution is required in patients with significant depression, as there is an increased risk of suicide. It is important to counsel patients prior to surgery to ensure that they have realistic expectations of the outcomes. In particular, the non-motor symptoms of PD (including psychological or cognitive symptoms and autonomic dysfunction) may often be more disabling than motor symptoms for patients with PD, yet may not respond to DBS despite excellent motor improvements.
Setting up treatment
Arranging DBS for patients can be a long process, so it is important to select those most likely to benefit. Unfortunately, the surgery is currently not available in Ireland so patients must be referred to a specialist centre in the UK. There, they will undergo extensive review by a multidisciplinary team, which includes neurology, neurosurgery, neuropsychology and psychiatry. After surgery, it is important to taper oral medication slowly to reduce the risk of mood disorders and apathy. Subthalamic nucleus (STN) DBS allows reduction of medication by about 50 per cent, thus reducing the risk of dyskinetic side-effects.
The EARLYSTIM study was a two-year randomised-controlled trial, where 251 PD patients with early motor complications were randomised to receive either DBS plus medical therapy or medical therapy alone. The mean age of subjects was 52 years and the mean duration of disease was 7.5 years, which was a younger population with shorter disease duration than previous studies. The primary outcome was quality-of-life, measured using the Parkinson’s Disease Questionnaire (PDQ-39). This improved from baseline to 24 months by 26 per cent in the DBS group, but worsened in the medical therapy group by 1 per cent (p = 0.002). DBS was also superior to medical therapy in improvement of motor disability, activities of daily living (p <0.001), levodopa-induced motor complications (p <0.001) and time with good mobility and no dyskinesia (p <0.01).
The NSTAPS study randomised 128 subjects to receive either STN or globus pallidus (GPi) bilateral DBS. Primary outcomes were disability (ADLS) and number of patients with a negative composite score of cognitive, mood and behavioural effects. No statistically significant difference was found between the two groups in terms of these outcomes. However, there were significantly better improvements in off-phase motor symptoms among the STN group (p = 0.03), mean change in ADLS scores and levodopa equivalent drug reduction (p = 0.01). This study suggests that the STN may be a preferred target for DBS in advanced PD.
Another useful option for patients with significant motor fluctuations is duodopa, which contains carbidopa/levodopa in a stable methylcellulose gel. This is given as an infusion through a percutaneous endoscopic jejunostomy (PEJ) tube. The infusion is started during waking hours but, occasionally, can be extended overnight if the patient suffers from significant night-time symptoms. The patient carries a pump that also allows them to deliver a bolus if necessary. The overall effect of this is more stable levels of levodopa in the body and thus fewer motor fluctuations.
Importantly, duodopa can be offered to a wider range of candidates than DBS. It is particularly useful in those in whom DBS is contraindicated due to age, cognitive/psychiatric problems or medical comorbidities that could complicate surgery. As with DBS, the main inclusion criterion is confirmed response to levodopa.
Setting up treatment
When considering this therapy, the first step is to get an early review by the gastrointestinal team. It is also important to inform patients of the risks, including PEJ site infection, tube occlusion and displacement. There have also been reports of peripheral neuropathy, thought to be related to reduced levels of vitamin B12, so patients may benefit from replacement therapy.
Initiating duodopa therapy involves a three- to five-day ward admission, depending on whether a trial of duodopa via a nasogastric tube is preferred prior to PEJ insertion. Duodopa is then titrated to achieve optimum response. It is essential that these patients have easy access to neurology, gastroenterology and radiology services in case of complications. They should also be provided with prescriptions for emergency carbidopa-levodopa, to be taken in the event of tube occlusion.
In the absence of any head-to-head randomised trials comparing DBS to duodopa therapy, a recently published five-year retrospective trial looked at efficacy and safety of STN-DBS, duodopa and oral medical therapy (OMT). In this study, there were 20 patients in each group, all with similar baseline characteristics. STN-DBS and duodopa showed a similar deterioration in activities of daily living, but both had significantly less deterioration than OMT (p = 0.005). Off-time also improved with both STN DBS and duodopa, whereas it worsened with OMT (p < 0.001). Moreover, whereas dyskinesia duration and severity both increased with OMT, they were reduced in the STN DBS and duodopa groups. Despite being limited by open label design and lack of randomisation, the results of this study suggest both DBS STN and duodopa may lead to sustained improvement in off periods compared to OMT and that STN DBS may possibly be superior to duodopa in targeting dyskinesia.
Apomorphine is a highly potent dopamine agonist, which can be delivered as intermittent subcutaneous injections or as a continuous subcutaneous infusion using a small pump carried by the patient. Both forms of the treatment are used in patients with poor control of motor symptoms or significant adverse effects with oral medications.
Indications for intermittent apomorphine injection include anticipated rescue during motor and non-motor off periods, impaired absorption of levodopa or gastric emptying problems, delayed on effect after oral medications and relief of early morning motor symptoms including akinesia and dystonia. Apomorphine is highly effective in patients with these problems due to its very short time to onset of four to 12 minutes.
Patients who may benefit from continuous apomorphine infusion include those with off periods that are not adequately controlled by oral treatment; those with significant drug-drug interactions between oral medications; and those who are requiring frequent rescue doses or are experiencing dyskinesia associated with intermittent injections. A major advantage of apomorphine is that it can be used in patients in whom DBS and duodopa are contraindicated and is sometimes used to provide symptomatic relief while those treatments are being set up. Apomorphine can also be used temporarily when oral intake is limited, for example, perioperatively.
Setting up treatment
Patients must undergo a pre-treatment workup, including an ECG to exclude prolonged QT interval and tachy- and brady-arrhythmias. Pre-existing haemolytic anaemia must also be excluded.
Domperidone must be commenced at a dose of 10mg TDS one day prior to treatment with apomorphine and continued for three-to-seven days in total, as apomorphine is a potent emetic. Infusion therapy requires a short ward admission, where apomorphine is titrated up slowly to achieve an optimum dose where motor symptoms and dyskinesias are adequately controlled and adverse effects are minimal. The pump is active during waking hours. Oral dopamine agonists are discontinued gradually during the titration phase, followed by MAO-B and COMT inhibitors. Levodopa can also be reduced, or even stopped completely, in order to relieve dyskinesia.
There have been many randomised controlled trials on the efficacy and safety of intermittent apomorphine injections. The largest of these involved 62 patients and found that apomorphine reduced UPDRS scores by 24.2 points compared with a 7.4 point reduction in a placebo group (p < 0.0001). The evidence for continuous infusion is more limited. A 2014 review by Wenzel et al summarises the results of a small number of randomised controlled trials as well as data from open label and observational studies. The available evidence suggests that the treatment is effective in controlling motor fluctuations and reducing off-time.
DBS, duodopa and apomorphine are all effective treatment options for PD patients with inadequate control using oral medication or those who have significant motor complications from treatment. However, it is important to consider the patient’s individual symptoms, comorbidities and treatment goals when selecting an appropriate treatment. Whichever treatment is offered, it is essential to involve the patient and/or primary carer in the decision and to ensure realistic expectations.