Parkinson's disease treatment and management

Parkinson's disease is a progressive neurodegenerative condition resulting from the death of dopaminergic cells of the substantia nigra in the brain.

This article is focused on the management of Parkinson's disease. See the separate Parkinsonism and Parkinson's Disease article for further discussion of Parkinson's disease.

Parkinson's treatment and management^{1 2}

Parkinson's disease is an incurable progressive condition, and the aim of treatment is to control the symptoms and to improve the patient's quality of life.

Diagnosis

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 Care 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 - the patient should inform DVLA and insurers.³

Non-pharmacological management

Non-pharmacological management of motor and non-motor symptoms may involve:

• Parkinson's disease nurse specialists.

• Physiotherapists: if balance or motor function problems are present.

• Occupational therapists: if difficulties with daily activities.

• Speech and language therapists: if communication, swallowing or saliva problems.

• Dieticians: if nutritional advice and support is required.

Maintenance

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.

It is up to the clinician to evaluate which device is appropriate for the patient taking into account how easy they are to use or if one is more suitable than the other.

• The diagnosis should be regularly reviewed, particularly if atypical symptoms or signs develop. NICE suggests 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 Parkinson's disease 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 Parkinson's disease may occur.

Devices for remote monitoring of Parkinson's disease⁴

The National Institute for Health and Care Excellence (NICE) has approved the devices Kinesia 360, KinesiaU, PDMonitor, Personal KinetiGraph (PKG) and STAT‑ON to help monitor patients' symptoms. Patients' symptoms come and go or they just might not remember very well, so it is imperative to be able to assess the symptoms accurately and objectively to personalise treatment plans and make sure the medication is appropriate, titrated or augmented, or changed on time to improve quality of life.

Complex aims

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 complications 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.⁵

• 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.

Palliative aims

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.¹

• 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.

Drug treatments for Parkinson's disease¹

There is no universal first-choice drug. The choice depends on the patient's age, clinical symptoms and quality of life, lifestyle and personal preferences.

Initial drug treatments

• Levodopa should be offered to people in the early stages of Parkinson's disease whose motor symptoms impact on their quality of life.

• A choice of dopamine agonists, levodopa or monoamine oxidase-B inhibitors (MAO-BIs) should be considered for people in the early stages of Parkinson's disease whose motor symptoms do not impact on their quality of life.

• Levodopa is the most effective drug in the treatment of Parkinson's disease. 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.

  • 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.

To avoid the potential for acute akinesia (sudden deterioration in motor performance) or neuroleptic malignant syndrome, antiparkinsonian drug concentrations should not be allowed to fall suddenly due to poor absorption or abrupt withdrawal.

Dopamine agonists:

• They are effective in treating motor features of Parkinson's disease 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.⁶

• Non-ergot-derived agonists are preferred (pramipexole and ropinirole).

• Ergot-derived drugs (bromocriptine, cabergoline, lisuride and pergolide) should not be offered as first-line treatment for Parkinson's disease.

• An ergot-derived dopamine agonist should only be used as an adjunct to levodopa for people with Parkinson's disease who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy and whose symptoms are not adequately controlled with a non-ergot-derived dopamine agonist.

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.⁷

• 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 for patients who have swallowing difficulties.⁸

• Rasagiline is a monoamine oxidase-B inhibitor (MAO-BI): studies suggest it has a protective effect against neurodegeneration and may exert more disease-modifying effects.⁹

Drug management of non-motor symptoms

Daytime sleepiness and sudden onset of sleep
Drug treatment should be adjusted under specialist medical guidance. If reversible pharmacological and physical causes have been excluded, modafinil should be considered to treat excessive daytime sleepiness, and treatment should be reviewed at least every 12 months.

Patients with Parkinson's disease who have daytime sleepiness or sudden onset of sleep should be advised not to drive, to inform the DVLA about their symptoms, and to think about any occupational hazards.

Nocturnal akinesia
Levodopa or oral dopamine-receptor agonists should be considered as first-line options and rotigotine as second-line (if both levodopa or oral dopamine-receptor agonists are ineffective).

Postural hypotension
Review drug treatment to address any pharmacological cause. If drug therapy is required, midodrine hydrochloride should be considered as the first option and fludrocortisone acetate as an alternative.

Common management problems^{1 10}

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).

If a patient with Parkinson's disease develops dyskinesia or motor fluctuations, specialist advice should be sought before modifying antiparkinsonian drug therapy.

• Patients who develop dyskinesia or motor fluctuations despite optimal levodopa therapy should be offered a choice of non-ergotic dopamine-receptor agonists (pramipexole, ropinirole, rotigotine), monoamine oxidase-B inhibitors (rasagiline or selegiline hydrochloride) or catechol-O-methyltransferase (COMT) inhibitors (entacapone or tolcapone) as an adjunct to levodopa.

• An ergot-derived dopamine-receptor agonist (bromocriptine, cabergoline or pergolide) should only be considered as an adjunct to levodopa if symptoms are not adequately controlled with a non-ergot-derived dopamine-receptor agonist.

• If dyskinesia is not adequately managed by modifying existing therapy, amantadine hydrochloride should be considered.

'Wearing off' phenomenon

Several strategies are available:

• Add in or adjust the 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.

• Catechol-O-methyltransferase (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

In some cases, 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.¹¹

• 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

This 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 catechol-O-methyltransferase (COMT) inhibitor.

Patients at higher risk of falling must be referred for rehabilitation, including assessment for physiotherapy and occupational therapy, as early as possible, because anti-Parkinsonian drugs and surgery do not improve gait and posture in Parkinson's disease.¹²

Complications¹

Depression and anxiety

Depression and anxiety are common in patients with Parkinson's disease. 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 for carers).

Dementia

• Cholinesterase inhibitors have been shown to be effective in patients with Parkinson's disease and dementia, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales.¹³

Compulsive behaviours

• 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 Parkinson's disease specialist if compulsive behaviour is observed.

Daytime sleepiness

• People with Parkinson's disease who have daytime sleepiness and/or sudden onset of sleep should not drive and should consider any occupation hazards.

• Modafinil can be used to treat excessive daytime sleepiness, only if a detailed sleep history has excluded reversible pharmacological and physical causes.

Rapid eye movement sleep behaviour disorder

• Identify and manage restless legs syndrome and rapid eye movement sleep behaviour disorder (RBD) in people with Parkinson's disease and sleep disturbance.

• Consider clonazepam or melatonin to treat RBD if a medicines review has addressed any possible pharmacological causes.

Nocturnal akinesia

• Consider levodopa or oral dopamine agonists to treat nocturnal akinesia.

• Consider rotigotine if levodopa and/or oral dopamine agonists are not effective.

Orthostatic hypotension

• Review existing medicines to address possible pharmacological causes, including antihypertensives (including diuretics), dopaminergics, anticholinergics and antidepressants. Consider treatment with midodrine.

• If midodrine is contra-indicated, not tolerated or not effective, consider fludrocortisone.

Psychotic symptoms (hallucinations and delusions)

• Do not treat hallucinations and delusions if they are well tolerated.

• Reduce the dosage of any Parkinson's disease medicines that might have triggered hallucinations or delusions.

• Consider quetiapine to treat hallucinations and delusions. If standard treatment is not effective, offer clozapine. Lower doses of quetiapine and clozapine are needed than in other indications.

• Other antipsychotic medicines (eg, phenothiazines and butyrophenones) can worsen the motor features of Parkinson's disease.

Drooling of saliva

• Only consider pharmacological management if non-pharmacological management (eg, speech and language therapy) is not available or has not been effective.

• Consider glycopyrronium bromide. If treatment for drooling of saliva with glycopyrronium bromide is not effective, not tolerated or contra-indicated (eg, if cognitive impairment, hallucinations or delusions, or a history of adverse effects following anticholinergic treatment), consider referral to a specialist service for botulinum toxin.

• Only consider anticholinergic medicines other than glycopyrronium bromide to manage drooling of saliva in people with Parkinson's disease if their risk of cognitive adverse effects is thought to be minimal. Use topical preparations if possible (eg, atropine) to reduce the risk of adverse events.

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^{1 2}

• Patients with advanced Parkinson's disease can be offered apomorphine hydrochloride as intermittent injections or continuous subcutaneous infusions.

• Catechol-O-methyltransferase (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 two-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 should be considered if dyskinesia is not adequately managed by modifying existing therapy.¹

• 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.

• Levodopa-carbidopa intestinal gel is used for the treatment of advanced levodopa-responsive Parkinson's disease with severe motor fluctuations and hyperkinesia or dyskinesia. The gel is administered with a portable pump directly into the duodenum or upper jejunum.

Deep brain stimulation^{1 15}

Deep brain stimulation should only be considered for people with advanced Parkinson's disease whose symptoms are not adequately controlled by best medical therapy.

• 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.

• Well-established deep brain stimulation targets include the subthalamic nucleus, the globus pallidus pars interna and, to a lesser degree, the ventral intermediate nucleus of the thalamus. Studies of alternative targets are ongoing.¹⁶ The subthalamus is currently 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.