Approach

It is important to use a tailored and personalised approach to treating patients with PD, taking into account sex, gender, and cultural context. In particular, when treating women with PD, management needs to be customised to take into consideration various stages of the patient's life, including child-bearing years, menopause, and post-menopausal stages.[98]

Treatment is symptomatic as no curative or disease-modifying agents are available.

Pharmacological treatment is designed to supplement depleted dopamine stores in the substantia nigra, thus minimising or eliminating symptoms and improving quality of life.[99] Initiation of treatment is based on severity of symptoms. Patients with mild disease may elect to postpone treatment until disability occurs.[99]

Response to pharmacological therapy manifesting as an improvement or resolution of symptoms is, by convention, referred to as 'on-time'. Conversely, 'off-time' refers to time spent with maximal symptoms.

All patients with PD should be offered physical and occupational therapy, including gait and balance training, stretching, and strength exercises.

Symptomatic parkinsonism (symptoms requiring treatment)

Early in the disease, dopaminergic supplementation is often sufficient to markedly reduce, and even eliminate, symptoms. As the disease progresses, complications develop. Adjunctive medication regimens are moderately effective in managing these complications. However, in most patients, medications will become less effective and complications will make treatment challenging.

Given the constellation and diverse list of symptoms associated with PD, optimal treatment strategies involve a multidisciplinary team approach aimed at improving quality of life.[17][100] Digital technology, including access to telehealth visits, is increasingly being used to support people with PD by improving communication with care teams (especially for patients with long travel distances to specialist centres) and supporting self-care.[17][101]

Physical and non-pharmacological therapies

Exercise should always be encouraged; it has been shown to improve functional performance on motor tasks at any stage of disease.[102][103] [ Cochrane Clinical Answers logo ]

Physiotherapy, occupational therapy, and speech therapy are important in the evaluation and management of specific symptoms, and in maintaining function.[100][104][105][106][107]

Progressive resistance exercise, aerobic exercise, and balance training have been shown to reduce motor symptoms and improve functional status.[102][108][109][110] Activities such as Tai Chi, dance, and music therapy have also been shown to be safe and beneficial for patients with PD, and may improve quality of life and reduce falls.[111][112][113][114][115] Water-based therapy has shown benefits in improving balance, mobility, and quality of life in people with PD, and may be preferred to land-based therapy by patients with fear of falling.[109][116][117]

Gait-specific training, rather than generic exercise programmes, should be employed if improved gait performance is the specific outcome of interest.[109][118] Specific physiotherapy programmes aimed at improving freezing of gait in PD, such as Lee Silverman Voice Treatment-BIG therapy (LSVT-BIG), have been shown to be effective in reducing motor impairments.[119][120]

External cueing (external temporal or spatial stimuli, including rhythmic auditory cues, visual cues, verbal cues, or attentional cues) during physiotherapy reduces motor disease severity and improves gait outcomes.[109][121]

Community-based exercise programmes, which may include a home exercise component, are recommended. These reduce motor disease severity and improve non-motor symptoms, functional outcomes, and quality of life.[109]

Virtual reality interventions may be effective for improving balance, motor function, gait, quality of life, and ability to perform activities of daily living in patients with PD, although the evidence is mostly of low quality.[122][123][124]

Management of non-motor symptoms

Clinicians should screen for non-motor symptoms, as they cause significant psychological and physical disability.[68][70]

Non-motor symptoms are numerous, and treatment is specific to each symptom.[15][68][100][125]​ Depression, anxiety, fatigue, cognitive impairment, autonomic dysfunction (e.g., orthostatic hypotension, constipation, incontinence, dysphagia), and/or sleep disorders can develop at any time during the disease course, and are often present before diagnosis or evolution of the widely recognised motor symptoms.[15] Depression and anxiety are under-recognised and probably under-treated; depression may affect up to 25% to 35% of patients with PD, and anxiety may affect 6% to 55%.[125][126][127]​ Cognitive behavioural therapy is reported to be effective for treating depression and anxiety in patients with PD.[128][129] See Complications.​

Individually tailored and standard cognitive training may improve memory, executive function, and attention in people with PD.[130] Similarly, cognitive rehabilitation has been reported to lead to improvements in one or more cognitive domains.[125][131] There is some evidence for beneficial effects of exercise on cognition.[132]

Vitamins and dietary supplements

Despite pre-clinical data indicating that nutritional antioxidants may be neuroprotective in PD, there is no compelling clinical evidence that any vitamins, food additives, or supplements can improve motor function or delay disease progression.[112][133][134][135][136]

Mild parkinsonism

When symptoms begin to interfere with the patient's quality of life or activities of daily living, treatment is initiated with a dopaminergic agent. An attempt is made to improve symptoms without causing unwanted adverse effects. Adverse effects are typically dose-dependent and differ slightly between agents. However, overall, these medications are well tolerated and safe.[137]

Options for initial therapy for motor symptoms include levodopa, a dopamine agonist, or a monoamine oxidase-B (MAO-B) inhibitor. There is no evidence of disease modification by any of these agents as initial therapy.[99][100][137]

Levodopa

Levodopa, in the form of carbidopa/levodopa, is the preferred initial dopaminergic therapy to improve motor symptoms for patients with early PD.[99] Studies demonstrate that levodopa provides greater benefit for motor symptoms than dopamine agonists or MAO-B inhibitors, and a lower risk of discontinuation due to adverse effects than MAO-B inhibitors.[99][Evidence C]

There is no evidence to support superiority of one formulation of levodopa over another in patients with early PD; however, guidelines recommend immediate-release in preference to controlled-release levodopa, due to higher bioavailability and more predictable symptom relief.[99]

Although treatment with levodopa provides superior motor benefits, it is associated with a higher risk of dyskinesia compared with dopamine agonists. Risk factors for levodopa-induced dyskinesia include younger age at disease onset, lower body weight, female sex, and greater disease severity. Levodopa should be prescribed at the lowest effective dose to minimise the risk of dyskinesia and other adverse effects, and patients should be monitored for response to treatment and adverse effects.[99]

Levodopa is combined with carbidopa to reduce nausea and vomiting. If nausea and vomiting occur, they can be treated with additional doses of carbidopa. Ondansetron and domperidone may also be considered for treating nausea. Metoclopramide and prochlorperazine should not be used, as they can cause or exacerbate parkinsonism.[138]

Dopamine agonists

A dopamine agonist (e.g., pramipexole, ropinirole, rotigotine) may be considered as initial dopaminergic therapy to improve motor symptoms instead of levodopa in younger patients (<60 years) with early PD who are at higher risk for developing dyskinesia.[99][137][139][140][141] Dopamine agonists are not suitable for patients with early PD who have a higher risk of medication-related adverse effects, including patients aged >60 years, or with a history of impulse control disorders, pre-existing cognitive impairment, excessive daytime sleepiness, or hallucinations.[99]

There is no strong evidence supporting any particular drug, mode of administration, or drug formulation when using dopamine agonists to treat early PD. Patient preference should be taken into account. Patients should be regularly monitored for adverse effects such as lower extremity swelling, excessive daytime sleepiness, hallucinations, and worsening of postural hypotension and impulse control disorders. Dopamine agonists should be tapered and discontinued if adverse effects become disabling.[99]

MAO-B inhibitors

A trial of an MAO-B inhibitor (e.g., selegiline, rasagiline, safinamide) is reasonable if levodopa is not suitable. MAO-B inhibitors may confer modest symptomatic benefit and are well tolerated, but additional therapy is required earlier with MAO-B inhibitors than with levodopa or dopamine agonists.[99][137][141][142] Early treatment with rasagiline does not confer long-term benefits.[143] Selegiline is only approved for adjunctive use, but may be substituted for rasagiline if rasagiline is not available.

Other treatments for mild parkinsonism

Anticholinergic agents (e.g., trihexyphenidyl) may be considered for treatment of PD with tremor-predominant symptomatology. Possible adverse effects, including worsening of cognitive decline and constipation, should be carefully monitored.

Amantadine is often considered for treatment of levodopa-induced dyskinesia and resistant tremor. However, amantadine use is often limited in older patients due to concerns about potentiating cognitive impairment, and it is not suitable for patients with hallucinations.[137]

Moderate parkinsonism

The moderate stage of parkinsonism is arbitrarily defined by increased severity in symptoms, as well as evolution of complications of disease treatment.

Management is similar to that of mild parkinsonism.[99] Symptoms may become more severe, and higher doses of medication are needed. Using carbidopa/levodopa plus a dopamine agonist or an MAO-B inhibitor is more common.

Wearing off (motor fluctuations)

Of the complications of disease, wearing off with motor fluctuations is the most common. This is defined as fluctuations in the response and duration of response to medications. Patients begin to experience an 'up and down' of symptoms based on the timing of their medications.

Treatment strategy is aimed at minimising off-time by prolonging the duration of response to dopaminergic supplementation.

Specific measures include the following:

  • Taking carbidopa/levodopa more frequently may improve symptoms in patients who experience wearing off (motor fluctuations).

  • The addition of a catechol-O-methyltransferase (COMT) inhibitor (e.g., entacapone, opicapone, tolcapone) may extend carbidopa/levodopa therapeutic benefit.[144][145][146][147][148] Due to the risk of serious hepatotoxicity, tolcapone is not a first-line adjunct therapy to carbidopa/levodopa.

  • An MAO-B inhibitor (e.g., selegiline, rasagiline, safinamide) or a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine) can be added to carbidopa/levodopa to reduce off-time, with or without reducing the requisite levodopa dose.[144][149][150][151][152]

  • The pharmacokinetics of currently available extended-release formulations are often unpredictable. An extended-release capsule formulation of carbidopa/levodopa that combines immediate- and sustained-release pellets has been shown to reduce daily off-time compared with immediate-release formulations and the combination of carbidopa/levodopa and entacapone.[153][154][155]

  • Istradefylline is an adenosine A2A receptor antagonist that may be considered as an add-on therapy to carbidopa/levodopa.[156] It can reduce off-time, improve motor function, and reduce tremor during off-time in patients with PD. Possible adverse effects, including emergence or worsening of dyskinesia, should be carefully monitored.[156][157][158][159] Istradefylline is approved for use in PD in the US and some other countries; however, the European Medicines Agency refused a marketing authorisation for istradefylline as it concluded that the benefits of treatment did not outweigh the risks.

Refractory tremor

If patients have tremor that shows insufficient response to dopaminergic agents:[137][160]

  • Adding amantadine or an anticholinergic agent (e.g., trihexyphenidyl) may be considered. However, anticholinergic agents can cause or worsen cognitive impairment and constipation; patients should be educated about and monitored for these potential adverse effects. Anticholinergics should be used with caution in patients with any cognitive impairment or severe constipation.

  • Medications used to treat essential tremor, such as propranolol and primidone, are second-line options.

  • Deep brain stimulation may be considered in some patients with tremor that is refractory to medication.

Dyskinesias

A common complication of moderate disease. If mild and not bothersome, dyskinesias can be observed. However, dyskinesias often lead to discomfort and, in some cases, undesired weight loss and balance dysfunction due to excessive body sway.

Excessive movements reflect overstimulation of dopamine receptors. Therefore, consider:[137][161]

  • A dose reduction and an increase in frequency of carbidopa/levodopa treatment; and decreasing the dose of other dopaminergic medications, if this can be done without loss of therapeutic efficacy.

  • Use of amantadine, if the preceding measures cannot be achieved. An extended-release amantadine formulation has been approved by the US Food and Drug Administration (FDA) for the treatment of dyskinesias in people with PD receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

  • Deep brain stimulation, in severe cases of resistant dyskinesia.

Advanced parkinsonism

This stage of disease is often complicated by changes in response to carbidopa/levodopa and sudden and unpredictable off-periods. Progression of the disease often leads to motor and non-motor fluctuations, dyskinesia, freezing of gait, and worsening of gastrointestinal symptoms such as dysphagia, gastric emptying delay, and constipation. Commonly patients have cognitive impairment and may have hallucinations.

Patients with severe refractory fluctuations who experience delayed onset of on-time after taking each dose of levodopa, and sudden off-times, and who require very frequent dosing of levodopa, may be ideal candidates for carbidopa/levodopa enteral suspension (also known as levodopa/carbidopa intestinal gel, or LCIG). This provides a continuous intrajejunal infusion of carbidopa/levodopa enteral suspension that reduces plasma concentration variability, and is an effective therapy for reducing motor fluctuations and improving quality of life.[162][163]

For patients with sudden and unpredictable off-time symptoms, apomorphine (a non-selective dopamine agonist available as subcutaneous injection or sublingual formulation) can be considered.[164][165][166] Apomorphine is often helpful for patients who have dysphagia in the off-state, or first thing in the morning, when symptoms are severe. Dissolvable carbidopa/levodopa and/or levodopa inhalation powder may also be considered if dysphagia is problematic.[167] These are considered rescue treatment approaches.

Deep brain stimulation

Deep brain stimulation (DBS) is effective for refractory complications such as tremor, motor fluctuations, and dyskinesias, in patients with moderate to severe PD.[137][163][168][169]

The two primary targets for DBS are the globus pallidus interna (GPi) and the subthalamic nucleus (STN).[161][170][171][172] Guidelines provide advice on target selection when using DBS to improve motor symptoms or levodopa-induced dyskinesias under various circumstances.[163][168]

In general, the goal of DBS is to provide a constant 'best medicine' state; no additional improvement beyond what is achieved with dopaminergic agents is expected, but drug-refractory tremor often responds to DBS.[160]

The DBS device is typically left on, but patients can turn it off when desired.

Supportive and palliative treatment

Although dopaminergic agents continue to provide benefit in alleviating some motor symptoms, other motor features of advanced PD, including postural instability, do not respond to medication. In addition, the non-motor features of the disease, including cognitive impairment and orthostatic hypotension among others, may have a greater effect on quality of life in patients with advanced PD, and are typically more challenging to treat pharmacologically. Treatment becomes supportive and ultimately palliative. Early discussion of goals of care and advance care planning (before the onset of cognitive impairment) with the patient and their family is recommended.[17][100][173]

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