Dr Katherine Grosset (left), Dr Graeme Macphee, and Dr Donald Grosset review the SIGN guideline on the diagnosis and pharmacological management of Parkinson’s disease
- Patients with suspected PD should be referred untreated to a specialist
- PD can be confused with other degenerative and non-degenerative disorders
- Early PD can be treated with:
- levodopa (in combination with a dopa decarboxylase inhibitor)
- non-ergot oral/transdermal dopamine agonist
- monoamine oxidase B inhibitor
- Patients with advanced PD who are receiving levodopa should be monitored for dopamine dysregulation syndrome
- Addition of a second drug in later disease is dependent on individual patient characteristics
- Depression, psychosis, and dementia can all develop in patients with PD
- GPs are often the first contact for patients with PD who are having difficulties (motor or non-motor)
Parkinson’s disease (PD) is the second most common degenerative neurological condition after Alzheimer’s disease, with a prevalence of between 120 and 230 per 100,000 people.1,2 However, recent research has shown that diagnosis of this condition is not straightforward, and there is diagnostic error in 4%–14% of cases.2 Moreover, there is now a complicated array of treatments for PD: decisions about treatment initiation, drug choice, and dosage titration are all important issues that need to be tailored to the individual patient.
The SIGN guideline on Diagnosis and pharmacological management of Parkinson’s disease examines the evidence around the diagnostic process and makes recommendations designed to improve accuracy of diagnosis.1 Pharmacological management in early disease, initiating adjunctive therapy, and the management of motor complications are all considered. There is also advice on diagnosing depression and on pharmacological treatment of mental health disorders in people with PD. Additionally, there is a narrative section that covers issues of concern to patients with PD. This includes topics such as communication, attitudes to drug therapy, information needs, family/carer needs, non-motor symptoms, and multidisciplinary team working.1
The SIGN guideline does not cover other important aspects of managing patients with PD, such as multidisciplinary team input from physiotherapy, occupational therapy, speech and language therapy, and other allied healthcare professionals (e.g. pharmacists, dieticians), and the organisation of local services.1
From a primary care point of view, GPs need to be aware of diagnostic error in some cases of PD, as an accurate diagnosis is essential for an optimal management plan. A GP with an average list size of 1500 patients will see one new case of PD every 3.3 years, and will accumulate limited experience in managing the detailed aspects of PD.1 Motor complications from medication ‘wearing off’, involuntary movements (dyskinesia), or fluctuations from immobility (‘off’ periods) to good function (‘on’ periods), which occur later on in the disease pathway, are challenging to manage, even for a specialist in PD.1 Moreover, the GP will often be the first point of contact for many patients when they begin to experience new problems. Non-motor features intrinsic to all stages of PD, such as depression, anxiety, constipation, and sleep disorder, are often under recognised by both GPs and specialists.
General practitioners have a wealth of experience in diagnosing, treating, and monitoring such co-morbidities, and collaborative care with specialist services will optimise patient management.
Diagnosis of PD
The main differential diagnoses of patients presenting with possible parkinsonism are shown in Table 1. The key recommendations in relation to diagnosis of PD are:1
- clinicians should be aware of the poor specificity of a clinical diagnosis of PD in the early stages of the disease, and should consider this uncertainty when giving information to the patient, and planning management
- patients with suspected PD should be referred untreated to a hospital clinician with sufficient expertise in movement disorders to make a diagnosis.
Accurate diagnosis of PD is not always easy. Five studies, involving 507 patients, have assessed the accuracy of an expert diagnosis (usually by a neurologist) against post-mortem diagnosis.1 These showed a good sensitivity (above 0.90), but a poor specificity (range 0.42 to 0.77).1 Two studies assessed the accuracy of diagnosis made by a GP or hospital non-movement disorder specialist versus a hospital movement-disorder specialist.1 General practitioners made more diagnostic errors overall and were more likely to confuse PD with a non-degenerative condition, such as essential or dystonic tremor. Hospital non-specialists were more likely to make errors between PD and other degenerative parkinsonian conditions (see Table 1). In practical terms, diagnostic uncertainty often results in clinicians using terms, such as possible or probable PD.1
Treatment for PD can mask core clinical signs of the disease so it is desirable that patients are referred untreated.1 There is no clear evidence that early treatment influences disease progression so there is nothing to be lost by delaying therapy. Where patients have significant functional disability as a result of parkinsonism, an urgent referral is warranted and they should be seen within 2 weeks.3
|Table 1: Common mimics of Parkinson’s disease1|
|Degenerative disorders||Non-degenerative disorders|
|Multiple system atrophy||Essential tremor|
|Progressive supranuclear palsy||Dystonic tremor|
|Corticobasal degeneration||Cerebrovascular disease|
|Dementia with lewy bodies||Drug-induced parkinsonism|
|Scottish Intercollegiate Guidelines Network. Diagnosis and pharmacological management of Parkinson’s disease. A national clinical guideline. SIGN 113. Edinburgh: SIGN, 2010. Reproduced with kind permission of the Scottish Intercollegiate Guidelines Network|
Assessment of PD
The SIGN guideline examined the evidence for the use of various diagnostic tools and concluded that formal research criteria such as the UK Brain Bank Criteria4 for diagnosis should not be used in isolation in routine practice.1 Functional imaging (using a radio-isotope measuring basal ganglia dopamine activity) assists the differentiation of degenerative parkinsonian from non-degenerative causes.1 Structural imaging (brain magnetic resonance or computed tomography) can helpfully assist the definition of cerebrovascular disease, brain atrophy, and in rare cases may identify a structural lesion.1
Subcortical cerebrovascular disease is common in elderly people and may mimic PD or contribute to disability, particularly with gait disorders in patients with PD. The need for investigations is assessed on an individual patient basis by the specialist clinic. The following diagnostic tools are not recommended in the diagnosis of PD:1
- transcranial ultrasound
- acute levodopa challenge tests
- olfactory testing (loss of sense of smell can be an early and even pre-motor feature of Parkinson’s disease).
Diagnosing co-morbid depression
Clinically significant depression is present in around 35% of patients with PD.1 However, this diagnosis is difficult to make in these patients because of the overlap of cognitive and somatic symptoms of PD. There is a risk of overdiagnosis (e.g. the appearance of depression through reduced facial expression is actually a physical marker of the condition). On the other hand, underdiagnosis of depression often results from the incorrect assumption that the patient’s lack of motivation or apathy is caused by the physical limitations of PD.
Self-rating scales were assessed by the Guideline Development Group (GDG)with the following conclusion: the Hospital Anxiety and Depression Scale (HADS) or the Hamilton Depression Rating Scale (Ham-D) may be used to screen for depression in patients with PD. General practitioners are already familiar with using these scales as they are part of the quality and outcomes framework (QOF) for new diagnoses of depression and for diagnoses in people with other chronic diseases.5 The expert opinion of the GDG for PD recommends that these self-rating scales should not be used in isolation; a structured interview with supplementary information from relatives or carers remains the gold standard in assessing and diagnosing depression.
Genetic Parkinson’s disease
Approximately 20% of patients with PD have a family history of the disease in a first-degree relative and around 2%–3% of all PD cases result from a genetic mutation.1 The commonest is a leucine-rich repeat kinase 2 mutation (LRRK2) and this is present in 5%–8% of people with PD with a first-degree relative with the condition. The patient with LRRK2-positive gene testing shows a clinically similar appearance to that of classical PD.1
Autosomal recessive parkin mutations are associated with young onset PD, occurring in nearly 50% of cases where there is a positive family history. Affected siblings usually develop symptoms before the age of 46 years. There is no evidence for a different therapeutic approach in an individual with genetic parkinsonism.1
The SIGN guideline concluded that genetic testing is not recommended in routine clinical practice, but counselling and testing can be considered in a specialist movement disorder clinic for patients who request it, particularly in those with young onset PD.1
Pharmacological management of motor complications
The timing of when to initiate treatment is dependent on individual circumstances, such as the degree of disability and employment status. Treatments offer symptomatic control, and there is no clear evidence that any of the currently available therapies are neuroprotective.1 There is grade A evidence that levodopa (always in combination with a dopa decarboxylase inhibitor), a non-ergot oral/transdermal dopamine agonist, or a monoamine oxidase B (MAO-B) inhibitor may be considered for patients with PD who have motor symptoms.1
If a dopamine agonist is being initiated, patients should be warned of the potential adverse effects of this drug type, including impulse control disorders (pathological gambling, hypersexuality, compulsive shopping, and binge eating) and excessive daytime somnolence, which has implications for people who drive and operate machinery.1 In patients who are prescribed levodopa, the lowest effective dose should be used to minimise adverse effects.1
In later disease, when prescribed medication doses are higher, there should be surveillance for dopamine dysregulation syndrome. This emerges when patients self escalate their dose far in excess of what is required for motor control. Such patients have behavioural disturbance and disabling involuntary movements (severe dyskinesia).1
Anticholinergics should be avoided at every stage of PD because of the potential for adverse cognitive effects. Amantadine has limited efficacy and is therefore not recommended,1 although in clinical practice it is often tried as an antidyskinetic agent in later disease.
Later disease—when to add in therapy
The addition of a second agent after the patient is showing an impaired response to initial monotherapy is again subject to individual patient characteristics and depends on a number of features. Motor and non-motor symptoms, the risk of adverse effects, and the presence of co-morbidities all influence the choice of additional antiparkinsonian medication. The decision to use an additional agent and the choice of agent should be based on an informed discussion with the patient/carer, and should also involve the PD nurse specialist (PDNS).1
Managing motor complications
A systematic review reports that 40% of people with PD treated with levodopa for 4–6 years experience motor complications (ranging from end-of-dose wearing off to dyskinesia and random fluctuations).1 For a patient with more advanced PD, the second agent added can be from one of several drug classes and will obviously depend on what has initially been used as monotherapy. There is evidence of benefit for addition of each of the following:1
- levodopa to dopamine agonist
- a MAO-B inhibitor to any other type of drug
- a non-ergot dopamine agonist to levodopa.
Catechol-o-methyl transferase (COMT) inhibitors, principally entacapone, can reduce ‘off’ time.1 When oral and transdermal antiparkinsonian agents have inadequate efficacy in advanced stages of PD, apomorphine can be given by intermittent subcutaneous injection, or alternatively by semi-continuous (daytime) subcutaneous infusion with a miniature pump. The use of apomorphine requires specialised support from a unit with appropriate expertise and resources.1
There is insufficient evidence to support the use of amantadine or the more recently available intraduodenal levodopa (which is administered via a percutaneous endoscopic gastrostomy tube with the drug being delivered in the jejunum). In addition, intraduodenal levodopa is not approved by the Scottish Medicines Consortium (SMC)6 and was not covered by the NICE guideline on Parkinson’s disease because it was not licensed at the time of publication.
It is recommended that patients with complex motor fluctuations who have explored all other treatment options, are assessed regularly by a movement disorder specialist. Reduction or withdrawal of some drugs becomes appropriate in later PD when side-effects outweigh the benefits, and decisions of this type are made by the patient and carer in combination with the specialist team.1
Pharmacological management of mental health disorders
The evidence for treating depression in Parkinson’s disease is limited. The SIGN guideline concluded that it is not possible to recommend a specific pharmacological treatment for depression in patients with PD.1 In clinical practice, selective serotonin reuptake inhibitors (SSRIs) are the most commonly used drug type. However, in patients taking a MAO-B inhibitor (such as selegiline) there is a potential interaction that can lead to serotonin syndrome.7 Accordingly there is often a requirement for the MAO-B inhibitor to be discontinued, or for the antidepressant not to be initiated if treatment with the MAO-B inhibitor is required.
Psychosis is one of the key neuropsychiatric features of PD and can vary from ‘benign’ visual hallucinations (where the patient retains insight and does not find them bothersome) to frank delusions and paranoia. Other treatable causes of psychotic symptoms should be excluded in the first instance. Drug treatments for PD (particularly non-levodopa treatments) can exacerbate these symptoms and where possible should be reduced gradually.1 However, this may be at the expense of worsening motor symptoms, and a satisfactory balance between good motor control and clear mental state may be difficult to attain.
The best evidence for efficacy of treating psychosis in PD is for low-dose clozapine, but this is associated with agranulocytosis and regular monitoring is required (grade A evidence); low-dose quetiapine can be considered as an alternative (grade B evidence).1 In clinical practice, patients with significant neuropsychiatric complications often require specialist mental health assessment. The GDG recognised the need for better coordination of mental health and Parkinson’s services for patients with PD.1
Cognitive impairment usually precedes dementia, which is present in between 24% and 31% of patients with late PD. Drugs with potential adverse effects on cognitive function (such as tricyclic antidepressants) should be gradually withdrawn followed by the gradual and sequential withdrawal of ‘non-essential’ drugs, such as anticholinergic agents, amantadine, selegiline, and dopamine agonists.1
The SIGN guideline recommends that other causes of cognitive impairment should be considered before adding a specific drug treatment for dementia.1 Although there was evidence for limited benefit of rivastigmine in treating mild to moderate dementia in PD, this agent is not recommended by the SMC because of a non-submission by the manufacturer.8
Best practice is to refer patients with suspected parkinsonism to a specialist movement disorder clinic. Patients should be referred untreated. The availability of specialist movement disorder clinics varies across the country and GPs should be aware of their local services. In situations where patients decline referral, GPs may need to take on their management. The provision of PDNSs is also very variable, but in some localities these nurses will take referrals from GPs or directly from the patient.
General practitioners need to be aware of diagnostic uncertainty and to keep the diagnosis under review. They are often the first port of call when a patient runs into problems and these may be of a motor or non-motor nature. Therefore, GPs need strategies for dealing with these issues when they have relatively little experience in this area.
General practitioners should be aware of the local availability of multidisciplinary services, such as physiotherapy, speech and language therapy, occupational therapy, dietary and nutrition services, social work, and mental health services, and should involve these services when it becomes appropriate.
- A patient with suspected PD should always be referred to a clinician with special experience in movement disorders for specialist opinion
- Commissioners should ensure a specialist movement disorder service is available locally
- PD nurses specialists can be useful in monitoring treatment and response and can be commissioned as a community service to avoid paying full tariff charges
- Commissioners should ensure that there is adequate provision of therapy services to support cases in the community through discussion with local movement disorder specialists
- A local care pathway could define referral options and the responsibilities of specialist, community, and primary care services:
- this could include a local formulary for pharmacological therapies to ensure cost efficiency
- Tariff charges for outpatients:a
- general medicine £222 (new), £104 (follow up)
- geriatric medicine £257 (new), £123 (follow up)
- Scottish Intercollegiate Guidelines Network. Diagnosis and pharmacological management of Parkinson’s disease. SIGN 113. Edinburgh: SIGN, 2010. Available at: www.sign.ac.uk/guidelines/fulltext/113/index.html
- Newman J, Breen K, Patterson J et al. Accuracy of Parkinson’s disease diagnosis in 610 general practice patients in the West of Scotland. Mov Disord 2009; 24 (16): 2379–2385.
- National Institute for Health and Care Excellence. Parkinson’s disease: Diagnosis and management in primary and secondary care. Clinical Guideline 35. London: NICE, 2006. Available at: www.nice.org.uk/guidance/CG35
- Hughes A, Daniel S, Kilford L, Lees A. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55 (3): 181–184.
- British Medical Association, NHS Employers. Quality and outcomes framework guidance for GMS contract 2009/10. London: BMA, NHS Employers, 2009. Available at: www.nhsemployers.org/PayAndContracts/GeneralMedicalServicescontract/qof/Pages/QualityOutcomesFramework.aspx
- Scottish Medicines Consortium. Co-careldopa intestinal gel, 20mg/5mg levodopa/cabidopa per ml for continuous intestinal infusion (Duodopa). www.scottishmedicines.org.uk/smc/5017.html (accessed 23 March 2010).
- British National Formulary. BNF 59. March 2010. London: BMJ Publishing, RPS Publishing, 2010.
- Scottish Medicines Consortium. Rivastigmine. www.scottishmedicines.org.uk/smc/5005.html (accessed 23 March 2010).G