Professional Reference articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
This article is focused on the management of Parkinson's disease (PD). See the separate article on Parkinsonism and Parkinson's Disease for further discussion of PD.
Treatment, as always, should be tailored to the needs of the individual. Patients should be helped to make informed decisions about their care, and try to involve the carers as much as the patient will allow.
Aims are to communicate information about the disease, help the patient accept the diagnosis, reduce distress and minimise symptoms and, ultimately, improve prognosis.
The National Institute for Health and Clinical Excellence (NICE) recommends using the UK Parkinson's Disease Society (PDS) Brain Bank Criteria for diagnosis.
- Arrange nursing assessment.
- Consider carer support - health and social care assessment.
- Driving - patient should inform DVLA and insurers.
Aims to establish a care package and lines of communication, build support for the patient and look out for any complications.
- Ensure regular access to specialist care - for clinical monitoring and medication adjustments.
- The diagnosis should be regularly reviewed, particularly if atypical symptoms or signs develop.
- NICE suggests specialist review every 6-12 months.
- Assess disability and cognition regularly, both by the patient self-reporting (eg, time how long it takes the patient to walk 20 yards; whether the patient can dress alone; whether he or she can turn over in bed) and by objectively rating motor symptoms (as in the Unified Parkinson's Disease Rating Scale).
- Don't focus solely on motor symptoms - consider other common problems such as sleep disturbance, depression, dementia and psychosis.
- Multidisciplinary management is essential. Ideally, all patients should have access to:
- Nurses with a special interest in PD who can monitor the clinical condition and adjust medication, as well as providing ongoing support for both patient and family and a reliable source of information about all aspects of care.
- Physiotherapy - to help improve gait, balance and flexibility, improve aerobic activity and movement initiation, increase independence and provide advice re fall prevention and other safety information.
Avoid Zimmer frames (flow of movement is interrupted) unless fitted with wheels and a handbrake.
- Occupational therapy - give advice and help on maintaining all aspects relating to activities of daily living, both at work and at home, with the aim of maintaining work and family relationships, encouraging self-care where appropriate, assessing any safety issues, making cognitive assessments and arranging any appropriate interventions.
- Speech and language therapy - improving loudness and intelligibility of speech where possible, ensuring methods of communication are available as the disease progresses and to help with swallowing (reducing risk of aspiration).
- Consider referral to other services as needed: chiropody/podiatry, continence advisor, psychologist or counsellor, dietician, social services.
- If patients are hospitalised, every effort should be made to continue the patient's normal routine (especially timing of drug therapy), or catastrophic deterioration of PD may occur.
Ongoing patient and carer support, diagnosis and treatment of complications, juggling medications. Aim to optimise quality of life, whilst providing information and support.
- Good communication between primary and secondary care is essential. Specialist services are likely to be very involved adjusting extremely complex drug regimens.
- Ensure follow-up plans are clear.
- Consider apomorphine - in patients with severe motor complication resistant to oral medications.
- Consider Duodopa® pump treatment in patients with severe motor complication resistant to oral medications. Duodopa® is a formulation of levodopa and carbidopa which is infused into the intestine via a percutaneous endoscopic gastrostomy (PEG) tube. This may provide smoother plasma levodopa levels than oral levodopa, leading to fewer motor fluctuations.
- Consider surgery:
- Bilateral subthalamic nucleus (STN) stimulation in suitable patients who are refractory to medical treatment. Globus pallidus interna (GPi) is also suggested as an alternative by NICE, although this is rarely performed in the UK.
- Thalamic stimulation is an alternative for patients with severe tremor who are unsuitable for STN stimulation.
To allow patients to die with dignity in a supportive environment for both patients, family and other carers.
- Palliative care requirements - these should be considered and discussed with patients and relatives during all phases of the disease so patients' feelings are known.
- Referrals may be needed to social services to increase the care package.
- Decide with the patient and family whether referral for a hospice, nursing home or for home palliative care is appropriate.
- Treat any symptoms (eg, pain, anxiety) appropriately and consider withdrawal or reduction of dopaminergic drugs.
There is no universal first-choice drug - this depends on the patient's age, clinical symptoms, lifestyle and personal preferences.
Early untreated Parkinson's disease:
- The choice of drug depends on the impact of improving motor disability (better with levodopa) compared with the risk of motor complications (more common in younger patients) and neuropsychiatric complications (more common in older and cognitively impaired patients; greater with agonists). Options include the following:
- Monoamine-oxidase-B inhibitors (MAO-BIs) - selegiline, rasagiline.
- Oral or transdermal dopamine agonist. Pramipexole, ropinirole and rotigotine are effective. Initial treatment with an agonist is recommended in younger patients.
- Levodopa is the most effective symptomatic drug. The use of controlled-release formulations or adding entacapone is not effective in the delay of motor complications.
- Amantadine or an anticholinergic.
- Ergot derivatives are not recommended as first-line medication because of the risk of fibrotic reactions.
Adjustment of initial therapy in patients without motor complications:
- Patients not on dopaminergic therapy:
- if a patient has started on an MAO-BI, anticholinergic, amantadine or a combination of these, a stage will come when adding levodopa or a dopamine agonist will be required.
- Patients on dopaminergic therapy:
- If on dopamine agonist therapy: increase the dose, switch between agonists, or add levodopa.
- If on levodopa: increase the dose, add an agonist, or add a catechol-O-methyltransferase (COMT) inhibitor.
- Patients with disabling tremor
- If significant tremor persists: the options are anticholinergics, clozapine, beta-blockers (propanolol) or deep brain stimulation.
Initial drug treatments
- Levodopa is the most effective drug in the treatment of PD. Virtually all patients respond to it and treatment is associated with reduced morbidity.
- It is given with a peripheral dopa-decarboxylase inhibitor, which prevents peripheral conversion to dopamine. Sinemet® and Madopar® are the main preparations.
- Use the lowest effective dose that maintains good function:eg, Sinemet® 62.5 mg tds (at mealtimes) increased to 125 mg after two weeks.
- It is usually well tolerated and adverse effects (nausea and dizziness) are quite rare and mild.
- There is no evidence that using modified-release levodopa initially delays onset of motor complications.
- Clinicians should be aware that prolonged levodopa use may be associated with weight loss.
- Dopamine agonists:
- They are effective in treating motor features of PD and can be used in early disease. In the long term they are associated with fewer dyskinesia and motor fluctuations compared with levodopa and may therefore be more appropriate for use in younger patients.
- Acute adverse effects are similar to levodopa but more common and severe and are associated with increased treatment withdrawal and poorer motor scores. These occur at the start of treatment and abate over several days to weeks.
- They are less effective than levodopa, and levodopa is eventually required.
- Prolonged monotherapy (longer than one year) is not always successful because of side-effects.
- In people with response fluctuations to levodopa, adjuvant dopamine agonists reduce 'off' time, improve motor impairment and activities of daily living and reduce levodopa dose but increase dopaminergic adverse effects and dyskinesias.
- Non-ergot-derived agonists are preferred (pramipexole and ropinirole); the ergot-derived drugs (bromocriptine, cabergoline, lisuride and pergolide) need renal function, ESR and CXR before treatment, and repeated annually (see individual drug monographs).Apomorphine is not used first-line and is considered in the section 'Adjuvant therapy for more advanced Parkinson's disease', below.
- Monoamine-oxidase-B inhibitors (MAO-BIs):
- Early treatment with selegiline alone can delay the need for levodopa therapy.
- One study suggested that addition of selegiline to a levodopa/decarboxylase inhibitor combination was more effective when introduced at 5 years than 10 years from the onset of the disease.
- An orally disintegrating formulation increases bioavailability and can be administered at lower doses than conventional selegiline, with similar clinical effect. It also leads to less variable blood concentrations and produces significantly fewer methamfetamine metabolites. It may be especially useful for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.
- Rasagiline is a new MAO-BI. Studies suggest it has a protective effect against neurodegeneration and may exert more disease-modifying effects.
Long-term levodopa treatment is associated with adverse motor effects that limit its use. These are motor fluctuations (on-off phenomena, wearing off, dose failures and freezing) and dyskinesias (peak-dose dyskinesias, diphasic dyskinesia and dystonia). They are best managed by a specialist.
- 'Wearing off' phenomenon - several strategies are available:
- Add in or adjust dose of dopamine agonist.
- Smaller, more frequent doses of levodopa.
- Prolonged-release levodopa preparations (ideally taken at bedtime). Taking both sorts early in the morning may be effective in 'jump starting' the system.
- Severe fluctuations may be helped by a liquid carbidopa.
- Adding selegiline or a dopamine agonist may help.
- Dietary adjustments: take levodopa 30 minutes before food.
- COMT inhibitors (eg, entacapone) can be used to prolong the action of levodopa and increase the 'on time', reduce the levodopa dose and modestly improve motor impairment and disability.
- 'On-off' fluctuations (patients may switch from severe dyskinesia to immobility in a few minutes):
- Combine levodopa with a dopamine agonist. Cabergoline can be used to reduce the levodopa dose and modestly improve motor impairment and disability.
- Fewer doses of levodopa with intermittent injections or subcutaneous infusion of apomorphine.
- Liquid forms of levodopa (enable more close titration of the dose).
- Diet: small snacks and one large evening meal.
- Dyskinesias (may occur either at the beginning or end of a dose, or sometimes at its peak):
- At peak dose (usually choreic):
- Reduce each dose of levodopa but make it more frequent so that the total daily dose remains the same.
- Add a long-acting dopamine agonist.
- Frequent dyskinesias may respond to slow-release or liquid levodopa.
- Surgery may be indicated.
- At the beginning or end of a dose:
- Try soluble levodopa before meals.
- Add a COMT inhibitor.
- At peak dose (usually choreic):
Depression and anxiety
Depression and anxiety are common in patients with PD. It is very important to detect and differentiate from dementia and to treat. Either tricyclics or selective serotonin reuptake inhibitors (SSRIs) can be used.
- Use tricyclic antidepressants if the sleep pattern is disturbed. Nortriptyline has the lowest anticholinergic effects and so may have the fewest side-effects.
- SSRIs can be helpful if apathy is a predominant feature (but should not be used with selegiline).
- Psychotherapy and support groups are helpful (both for the patient and carers).
- Cholinesterase inhibitors have been shown to be effective in patients with PD and dementia, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales.
- Dopamine agonists have been linked to the development of compulsive or disinhibited behaviours, including pathological gambling, hypersexuality, and compulsive eating and shopping, which can have a major impact on the lives of those affected. In rare cases, this may also be observed in some patients on levodopa.
- Patients and their families/carers should be made aware of this potential side-effect and significant behavioural changes should be monitored.
- A patient's drug regime should be reviewed by a PD specialist if compulsive behaviour is observed.
Hallucinations and psychosis
- May be related to dopaminergic therapy, PD dementia or due to a confusional state (eg, infection, malnutrition, dehydration or sudden withdrawal of a dopaminergic drug). Consider gradual withdrawal of PD drugs - which may have triggered the psychosis.
- Confusion and hallucinations imply a bad prognosis with high mortality within 1-2 years. Management is very difficult and admission to a nursing home is often required.
- Always consider other causes; it is not always due to PD or drugs.
- Mild symptoms may not need any treatment but atypical antipsychotics should be used rather than typical ones.
- Clozapine (selective D4 antagonist) may be used on occasions (only by specialists). It reduces hallucinations without aggravating the motor disability of PD.
Acute akinesia (Parkinson's crisis)
- A rare but life-threatening complication of Parkinson's disease, with a sudden worsening of motor symptoms and severe akinesia.
- Triggers include infections, surgery, gastrointestinal disease and changes in medication.
- Acute akinesia is difficult to treat and often needs hospital admission.
Adjuvant therapy for more advanced Parkinson's disease
- First-choice adjuvant drugs in later PD are dopamine agonists, MAO-BIs, or COMT inhibitors.
- COMT inhibitors:
- Reversibly inhibit the peripheral breakdown of levodopa by the COMT enzyme, increasing the amount available for conversion to dopamine in the brain and reducing fluctuations in plasma levels.
- Produce clinical benefits in people with levodopa motor fluctuations and in those with stable responses to levodopa.
- Entacapone should ideally be offered as a combination drug (levodopa carbidopa entacapone) because of poor patient compliance. One study found that early addition of entacapone to combined therapy produced more benefit than if it were introduced at a later stage (after five years). Tolcapone should only be used if entacapone fails (needs 2-weekly LFTs for the first year).
- Antimuscarinic drugs (orphenadrine, procyclidine and trihexyphenidyl) - evidence for efficacy is poor:
- May be effective in improving motor function but neuropsychiatric and cognitive adverse events occur frequently and are a more common reason for withdrawal than lack of efficacy.
- May have beneficial effects on tremor in some people. They are useful in reducing sialorrhoea.
- Adverse effects include confusion, hallucinations and memory impairment (particularly common in the elderly but may also occur in younger individuals).
- Reduce the symptoms of drug-induced Parkinsonism. They have no beneficial effect on tardive dyskinesia, however, and may make it worse.
- Amantadine can be used as monotherapy in early PD (for tremor or bradykinesia) but has a weak and short-lived benefit - and evidence for efficacy is poor.It can be used as an adjuvant in later PD for reducing dyskinesia but other drugs are usually considered better.
- Apomorphine is given subcutaneously. It can be used as a rescue agent in advanced disease to provide rapid but short-lived benefit for sudden, severe 'off' episodes - use intermittent injections to reduce 'off time' and continuous infusion to reduce 'off time' and dyskinesias.
- Modified-release levodopa can also help with symptom control in later stages.
- A whole host of drugs is currently being explored for the treatment of cognitive decline in PD, of which entacapone and amantadine are but two examples.
The surgical treatment of PD was developed in the mid-twentieth century before the advent of effective medical therapy. It still has a place in treatment and recently enjoyed a resurgence, as various procedures are required to deliver advances in scientific therapy:
- Pallidotomy: indicated for unilateral dyskinesia, severe 'on-off' fluctuations and drug failure. One systematic review found that unilateral pallidotomy improved motor examination and activities of daily living compared with medical treatment but there is a high incidence of adverse effects. Procedure is only performed on one side, as bilateral pallidotomy may cause speech and memory disorders.
- Thalamic surgery: an effective method of controlling tremor but it has no effect on bradykinesia. There are no randomised trials comparing this with medical treatment.
- Subthalamic surgery: can improve tremor, bradykinesia and rigidity but may provoke dyskinesias and hemiballismus.
- Deep brain stimulation:
- Electrodes are placed in the basal ganglia and attached to an internal stimulator, which is placed subcutaneously below the clavicle.
- May be used to provide unilateral or bilateral stimulation.
- The subthalamus is the preferred target for stimulation. It may reverse akinesia, rigidity and tremor.
- Complications include intracerebral haemorrhage and confusion.
- NICE has recommended that patients receiving this treatment should be carefully counselled about the risks and benefits and that it should only be considered after drug treatment has failed.
- Recent scientific advances - eg, gene therapy, nanotechnology and neural transplantation - require surgical techniques for their application and hold much promise.
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