Parkinson’s disease (PD) is the second most common neurodegenerative condition after Alzheimer’s dementia.1 It is a progressive and terminal condition. In 2018, in Wales and England, 2% (11,700)2 of all deaths were recorded as PD being an “underlying cause or as a contributory factor” on the death certificate.3
PD is characterised by psychiatric, neurologic, and autonomic features, together with profound emotional effects from the impact of diagnosis, changing social roles and the resulting strain on carers.4
A division into motor and non-motor symptoms is used to categorise the symptoms. ‘Motor’ describes tremor, bradykinesia and rigidity.5 ‘Non-motor’ describes autonomic features, bowel disturbance, pain, disturbance to sleep, depression, apathy, hallucinations and psychosis and can predate the onset of motor symptoms.5
It is known that the pathology causing the typical symptoms and signs of rigidity and bradykinesia are largely explained by loss of dopamine producing neurons in the substantia nigra of the brainstem. During the later stages of the disease, further loss of dopamine neurons leads to lessening of the effect of dopaminergic medication partly explaining the more frequent motor fluctuations including severe motor ‘off’ periods.6
The natural course of PD can be traced through stages from pre-diagnosis through a complex stage, when medication related side-effects become more problematic, to the last stages or dying phase. The Parkinson’s UK website describes these stages, under the section “What are the stages of Parkinson’s?”:
- Early or diagnosis stage. The time when someone is first experiencing symptoms, being diagnosed and then coming to terms with this.
- Maintenance stage. When symptoms are controlled, perhaps by medication.
- Advanced stage. Often called the 'complex phase'.
- Palliative stage. Providing relief from the symptoms, stress and pain of the condition.7
What symptoms can be expected in advanced PD?
Published studies have looked into patients’ and caregivers’ reported symptoms in advanced PD and at the end of life, as well as reported causes of death.4,8-13 In a UK longitudinal study, of 50 patients with late stage disease, the following symptoms were reported in more 50% of patients; examples of which with their reported frequency are the following:
- Pain – 86%
- Fatigue - 84%
- Difficulty communicating – 58%
- Insomnia – 58%
- Shortness of breath – 54%
- Problems in swallowing – 40%14
In an analysis of 339 death certificates and medical notes in the UK, pneumonia was found to be a “terminal event in 45%”.13
Caregiver distress with choking and the risk of “choking to death” is also mentioned in a separate study in to experiences regarding all stages of PD.4
In a survey of symptoms and their association with quality of life, in those patients with advanced disease, uncontrolled pain, anxiety and hallucinations were significantly associated with poor quality of life.9
Seizures are also noted in a description of the last phase of Parkinsonian syndromes,15 and in retrospective studies of PD patients’ overall.16,17
These above symptoms often occur on the background of weight loss, pain, and cognitive impairment. It is important therefore to note which medications given at the end of life may exacerbate these symptoms, and which should be considered in anticipation of them.
How to manage symptoms at the end of life?
At the end of life, good practice is to plan for any potential symptoms that may arise. The most common symptoms anticipated are pain, dyspnoea, nausea and vomiting, agitation, anxiety, delirium and noisy respiratory secretions.18 For patients with PD particular considerations should be given to the more commonly used medicines, specifically anticholinergics and antidopaminergics. These are usually prescribed for treatment of respiratory secretions and nausea and vomiting. Alternatives are available for respiratory secretions, and include glycopyrronium, in preference to hyoscine hydrobromide. Although this is an anticholinergic, only a small proportion crosses the blood brain barrier.
For nausea and vomiting, ondansetron,19 cyclizine, domperidone (no parenteral dose available) have all been suggested in PD.20 However, ondansetron has been shown to be inferior to domperidone in the pre-treatment of apomorphine.21 Cyclizine has anticholinergic properties and may exacerbate confusion, especially when comorbid psychosis or cognitive impairment are present. Levomepromazine, although it has antidopaminergic effects, has been shown to be effective for nausea with rotigotine in a case report.22
Agitation, dyspnoea and pain can all be managed with the same anticipatory medications as recommended.20 Specifically relating to PD, several case reports have supported the intraoperative use of midazolam, during sedation, for tremor and dyskinesias,23,24 as well as for agitation at the end of life.20
What are the considerations for pain management in the last days of life in PD?
It is important to consider that pain can be a risk factor for, and associated with, many other symptoms which might be the presenting features in a patient with complex or advanced PD. These include a new or worsened confusion, hallucinations, agitation and symptoms of depression or apathy.
As well as being an underlying cause of another symptom, pain can also be the symptom of other features of PD, such as rigidity, dyskinesia, but also non-motor features, for example, depression and fatigue.
Identifying whether pain is at the root of the presenting complaint and what might be causing the pain is therefore the most important part of the initial history from the patient and the carer. Then using the clinical examination to confirm findings from the history and identify any features not already elicited such as abnormal posturing, or dystonia.
A recent review into the pathophysiology and treatment of pain in PD suggests simple analgesia with paracetamol and non-steroidal anti-inflammatory drugs but advises caution with opiate analgesia as constipation is a recognised problem in PD patients.25 The review mentions, however, the lack of evidence for many widely used analgesics specifically in PD.26
Which medications can make confusion and hallucinations worse?
As PD progresses, non-motor symptoms including psychosis and hallucinations become more prominent both for the patient and caregivers.9 Dopaminergic medication can exacerbate these symptoms and this can be reduced through a “last in, first out approach.” 27,28 Medications that have an anticholinergic effect also may cause or worsen acute confusion and the anticholinergic burden in the patient’s medication history should be considered.29
Can a patient’s ability to make decisions in the last days of life be impaired and how is this managed?
In a North American study of 47 carers of idiopathic PD patients in the last months of life most described the goal of care as comfort, and almost half “of the patients were described as unable to make any decisions in the last month of life.” 10
When presenting, the patient may already be unable to communicate their symptoms and care preferences due to cognitive impairment and confusion. Also, there might be a physical difficulty in communication from severe rigidity. Care should be taken in considering the presence and consequent treatment of an intercurrent illness, and whether dopaminergic medication is exacerbating confusion due to hallucinations and/or psychosis.27
Continued attempts at verbal and non-verbal communication should be made throughout given the often fluctuating symptoms associated with PD and possible improvement in the intercurrent illness. In the absence of a next of kin or other person who is able to inform the clinical team, decisions should be made on a best interest basis as recommended in end of life care guidance.30
What are the risks of not receiving any dopaminergic medication?
There is the possibility of neuroleptic malignant-like syndrome (Parkinsonism-hyperpyrexia syndrome, PHS), a life-threatening and distressing condition resulting in rigidity and fever, from withdrawal of therapy.31 This can also occur with sudden cessation of Deep Brain Stimulation (DBS).32,33,34 To reduce the risk of this, dopaminergic therapy at the end of life should be continued.27 It should also be noted that in a patient dying of another condition, whose PD is still responsive to dopaminergic medication, the cessation of this also risks aspiration pneumonia.35 Transdermal rotigotine can be used in patients in whom a NG tube may cause excessive distress or is not possible. The dose should be calculated with an accepted converter.36
What to do with deep brain stimulation at the end of life?
Deep brain stimulation (DBS) uses an Implantable Pulse Generator, usually placed in the infraclavicular area, connected to leads within the brain. There is a remote programmer, and also a charging unit in the case of a rechargeable device, which are given to the patient and their carer. It improves dyskinesias and also has a levodopa sparing effect.37
Deactivation of DBS may lead to increased symptom burden as mentioned in the section above and so awareness of features of PHS should be considered if there is failure at the end of life. Supportive treatment should be given if possible,38 and anticipation of symptoms of distress from rigidity and fever.
After death, deactivation of the device with the patient’s handheld programmer is required before removing the pulse generator and battery in the case of a cremation.
What are the important points regarding apomorphine at the end of life?
Apomorphine is a dopamine agonist, which is given as a subcutaneous infusion either continuously or intermittently and also as single subcutaneous injections. An overview of studies into apomorphine use shows improvement in motor off periods and in dyskinesias.39
Apomorphine has side-effects similar to other dopaminergic medication but also notably nausea and vomiting. Ondansetron is not recommended for nausea in patients using apomorphine due to adverse effects.21
Subcutaneous apomorphine has been used at the end of life in a patient with advanced PD although with the recommendation that this is by a healthcare professional experienced in its use.40
What are the important points regarding Duodopa at the end of life?
Duodopa is a continuous infusion of dopaminergic medication (carbidopa-levodopa) administered as a gel into the gut, pumped via a percutaneously inserted gastrostomy tube (PEG). There is a requirement for care of the stoma and PEG tube together with functioning of the pump by the patient or carer.41 It reduces the time in motor off periods in advanced PD and quality of life.42 There is evidence of effective treatment up until death from within a case series.43
When encountering a patient at the end of their life who has a diagnosis of PD, knowledge of the differing symptoms and their sensitivity to medications must be considered. A holistic approach is essential in order to ensure appropriate care which aims to provide comfort and minimise distress to the patient and carer.
Dr Robin Davie is a ST6 in Geriatric Medicine, Wales
For more news and articles on Parkinson's disease go to our neurology section
- Grant I, Kavanagh J. Estimating prevalence of neurological disorders in Scotland from the Scottish Burden of Disease study. Scottish Burden of Diseases Study Team, ScotPHO collaboration, Public Health and Intelligence National Services Scotland, April 2018
- Office for National Statistics website, search result: “Deaths from Parkinson’s Disease, England and Wales, 2001 to 2018”, 2018 data males and females used from spreadsheet obtained. Last accessed 10th May 2020
- Office for National Statistics website “Deaths registered in England and Wales: 2018”. Last accessed 10th May 2020
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- Hawkes CH. The prodromal phase of sporadic Parkinson's disease: does it exist and if so how long is it? Mov Disord. 2008;23(13):1799‐ doi:10.1002/mds.22242
- Fabbrini G, Mouradian MM, Juncos JL, Schlegel J, Mohr E, Chase Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, part I. Ann Neurol 1988;24:366-371
- Parkinson’s UK, 2020, ‘What are the stages of Parkinson’s?’ in the section ‘Advanced Parkinson’s’ [Last Accessed 26/5/2020]
- Fasano A, Fung VSC, Lopiano L, et al. Characterizing advanced Parkinson's disease: OBSERVE-PD observational study results of 2615 patients. BMC Neurol. 2019;19(1):50. Published 2019 Apr 2. doi:10.1186/s12883-019-1276-8
- Tarolli CG, Zimmerman GA, Auinger P, et al. Symptom burden among individuals with Parkinson disease: A national survey. Neurol Clin Pract. 2020;10(1):65‐ doi:10.1212/CPJ.0000000000000746
- Goy ER, Carter JH, Ganzini L. Parkinson disease at the end of life: caregiver perspectives. Neurology.2007;69(6):611‐doi:10.1212/01.wnl.0000266665.82754.61
- Goy ER, Carter J, Ganzini L. Neurologic disease at the end of life: caregiver descriptions of Parkinson disease and amyotrophic lateral sclerosis. J Palliat Med. 2008;11(4):548‐ doi:10.1089/jpm.2007.0258
- Goy ER, Carter JH, Ganzini L. Needs and experiences of caregivers for family members dying with Parkinson disease. J Palliat Care. 2008;24(2):69‐
- Pennington S, Snell K, Lee M, Walker R. The cause of death in idiopathic Parkinson's disease. Parkinsonism Relat Disord. 2010;16(7):434‐ doi:10.1016/j.parkreldis.2010.04.010
- Higginson IJ, Gao W, Saleem TZ, et al. Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors. PLoS One. 2012;7(11):e46327. doi:10.1371/journal.pone.0046327
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- Chp 14, Prescribing in Palliative Care; in PCF 6 Palliative Care Formulary, 6th Ed, Ed. Twycross R et al. Printed in UK.
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