#68772: Parkinson Disease

The first line of investigation began in the early 1960s, with an unexpected finding that linked cigarette smoking with protection against PD. This association between smoking and neuroprotection from PD has been replicated in numerous epidemiologic, pre-clinical, and case-control studies. These studies also identified coffee drinking (and caffeine) as a factor that reduced risk of developing PD [13].

In these studies, risk of developing PD is shown as odds ratio (OR), where the odds of developing PD in cigarette or coffee users was compared to non-user reference groups. An OR of 1.00 signifies no difference from the reference group, while a number greater than 1 means increased odds of developing PD and a number less than 1 indicates decreased odds of PD.

In one study, smoking, other lifestyle behaviors, family history of PD, and their interaction were examined for possible association with risk of PD diagnosis by comparing 1,808 patients in Denmark with PD diagnosis with 1,876 matched population controls [14]. Strong inverse associations were found between cigarette smoking and risk of PD, even in smokers who quit 10 years before PD diagnosis. Compared with never-smokers without PD family history, the OR was 2.81 in never smokers with family history, versus 1.60 in smokers with family history. Duration had the greatest effect in modulating the smoking-PD relationship. Current smokers who smoked 40 years or more had ORs as low as 0.30. Unlike the correlation between longer smoking and lower PD odds, smoking more than 10 cigarettes per day did not further reduce odds.

Moderate coffee intake (3.1 to 5 cups per day) (vs. no coffee intake) showed an OR of 0.45. Moderate alcohol intake (3.1 to 7 units per week) (vs. no alcohol use) was associated with an OR of 0.60; higher daily alcohol did not further reduce the odds of developing PD. Stronger negative OR for PD was found in smokers with medium-high coffee or moderate alcohol intake than with each alone. Coffee intake association with lower PD odds was found in men and women; only men showed lower risk estimates with caffeine and alcohol, largely attributed to beer consumption [14].

These findings were consistent with numerous prior studies, including publications from the prospective NIH-AARP Diet and Health Study [7,15]. In this study, 306,895 participants (58.8% male, 50 to 71 years of age) were evaluated in 1995–1996 and again in 2000–2006 for development of PD.

One NIH-AARP study examined caffeine intake, risk of PD, and whether smoking affected this relationship [15]. Higher caffeine uses in 1995–1996 were associated with lower risk of PD diagnosis in 2000–2006 for men (OR=0.75) and women (OR=0.60). The linear trend for lower odds with higher caffeine was significant for both sexes [15].

The authors also performed a meta-analysis, which confirmed the inverse association between caffeine intake and risk for PD in men and women. Together with the study findings, this data led the researchers to conclude that gender differences do not influence caffeine risk reduction of PD. Smoking and caffeine may act independently to reduce PD risk [15].

Another NIH-AARP study examined cigarette smoking and risk of PD by comparing those who developed PD to those who did not. Odds for developing PD were 0.78 in past smokers and 0.56 in current smokers, with 0.47 in men and 0.74 in women. For few current smokers at baseline who developed PD, other comparisons were not relevant [16]. The greatest reductions in odds for PD were found with current smoking and higher daily amount/duration of past smoking [16].

In the NIH-AARP study, amount and type of alcohol use was studied for risk of PD. Compared to non-drinkers, the odds ratio for developing PD was 0.73 with 1 to 1.99 drinks of beer per day, 1.22 with liquor, and 0.74 with wine. Beer and liquor consumption showed opposite effects [17].

Higher circulating levels of uric acid have also been associated with decreased incidence of PD and with slower rate of decline in patients with PD. This suggests a link to the neuroprotective effects of caffeine and the purinergic system [7,18].

A second line of investigation began when the first environmental risk factor was identified. In the early 1980s, a parkinsonism syndrome developed in persons who used a tainted street drug. An illicit lab produced a meperidine (Demerol) analog that contained 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxic impurity. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B. MPP+ is a neurotoxin that, following dopamine neuron uptake via the dopamine transporter, destroys striatal dopamine neurons by inhibiting mitochondrial complex I activity. Ten persons who ingested this batch developed a severe, irreversible parkinsonism syndrome [19,20]. Extensive evaluation of these patients at onset and over time led to many breakthroughs in the understanding of PD and related conditions. Also identified were several persons with MPP+ exposure who developed mild-to-moderate, but not severe, parkinsonism. For the first time, an environmental factor was linked to PD pathogenesis, initiating environmental risk factor research. The variable consequences from exposure also helped prompt research into protective factors [19,21,22,23].

The origin of motor dysregulation in PD is neuronal degeneration in the substantia nigra pars compacta and loss of dopaminergic regulation of the striatum. The striatum is an entry point for cortical projections into the basal ganglia. The basal ganglia-thalamocortical motor circuit modulates the cortical output required for normal movement. Cortical signaling enters the striatum and is processed through the basal motor circuit; motor circuit output is relayed through the internal globus pallidus and the substantia nigra pars reticulata. The basal ganglia circuit involves two dopaminergic pathways:

In PD, striatal dopamine depletion deactivates the excitatory D1 direct pathway and hyperactivates the inhibitory D2 indirect pathway. Alterations in these two pathways inhibit voluntary movement [7,8,12].

There is a consistent line of evidence linking PD to a neurodegenerative process involving oxidative stress, mitochondrial dysfunction, and neuroinflammation. Environmental and genetic factors induce mitochondrial dysfunction, resulting in abnormal accumulation of miscoded proteins (mostly alpha-synuclein) and generation of oxidative stress in enteric, peripheral, and central nervous systems. In turn, oxidative stress, excitotoxicity, and mitochondrial dysfunction promote the destruction of dopamine neurons and dopaminergic function in midbrain systems [12,38,39,40].

REM sleep behavior disorder is characterized by dream enactment behavior during sleep, including yelling, laughing, or crying; complex voluntary movements; falling out of bed; and even violent behaviors with injury. REM sleep behavior disorder is an extremely powerful predictor, or prodromal marker, of developing synuclein-mediated neurodegenerative diseases, which eventually occurs in at least 80% and most frequently involves PD [53,54].

A 16-year follow-up study of men diagnosed with REM sleep behavior disorder found that 80.8% eventually developed parkinsonism/dementia and were diagnosed with PD (62%); dementia with Lewy bodies (14%); multisystem atrophy (9.5%); clinically diagnosed, autopsy-confirmed Alzheimer disease plus Lewy body pathology (9.5%); or profound unspecified dementia (5%) [55]. Of those who progressed to parkinsonism, the mean age of REM sleep behavior disorder onset was 57.7 years; the mean age of parkinsonism/dementia onset was 71.9 years. Overall, the mean interval from REM sleep behavior disorder onset to parkinsonism/dementia onset was 14.2 years (range: 5 to 29 years). In these patients, lower brainstem involvement, particularly the pons, appeared long before the onset of motor features [55].

The first published methodology with high accuracy in predicting PD development used data from patients with REM sleep behavior disorder. These patients were regularly evaluated throughout the 10-year period following their initial REM sleep behavior disorder diagnosis. Using this data, prodromal markers of PD were analyzed for predictive validity. Factors that highly predicted PD when combined were (in descending order of strength) subtle motor dysfunction, nonuse of antidepressants, abnormal color vision, olfactory loss, and advanced age. Factors found non-predictive when aggregated were mild cognitive impairment, depression, "Parkinson personality," treatment with clonazepam or melatonin (for REM sleep behavior disorder), autonomic markers, and male sex [53].

Studies of olfaction in PD have shown abnormalities in up to 100% of patients, making olfactory dysfunction the most robust predictor of developing PD. As noted, many patients complain of declining sense of smell long before parkinsonism onset. As it is not disabling and relatively nonspecific, anosmia has mostly failed to gain traction as a predictive and clinical feature of PD [56].

Constipation is a notoriously bothersome and common symptom in PD that results from peripheral autonomic involvement in the early pathogenic process [56]. Compared with middle-aged men who reported more than two bowel movements per day, men who reported fewer than one bowel movement per day were prospectively identified as more than four times more likely to develop PD. This suggests lower bowel involvement is an early sign that, in some patients, predated PD by 15 years or more [57].

Excessive daytime sleepiness has also been identified as a midlife risk factor for PD, suggesting early brainstem involvement and subsequent sleep disturbances as a pre-diagnostic feature [58].

In PD, the cardinal motor features of bradykinesia, resting tremor, rigidity, and postural/gait impairment reflect parkinsonism [62]. A mnemonic for the core motor features is TRAP [7]:

It is important to note that postural instability, while a cardinal motor feature, is seldom a problem early in the course of PD and may not be evident at diagnosis, as it usually appears later in the disease course [60].

Bradykinesia

Bradykinesia, as typically defined, combines the definitions of bradykinesia (slowness) and hypokinesia (decreased movement amplitude) [60]. Bradykinesia is reduced speed in initiating and executing movement, and altered fine motor control and dexterity. It is not just slowness in movements, but slowness in initiating voluntary movement, with progressive fatiguing during repetitive movements that presents in reduced speed and amplitude during finger or foot tapping. Slowness of movements, progressive reduction in speed and amplitude of repeated movements, delay in initiating movements, and freezing gait eventually occur in 80% to 90% of patients with PD [63].

Bradykinesia is the defining feature of parkinsonism and the essential clinical sign because the slowed, disordered motor movements directly correlate with functional abnormality in basal ganglia-cortical neuronal circuits, where aberrant dopamine-mediated firing patterns within indirect and direct pathways inhibit activity in cortical motor system neurons [4,7]. The slowed, small-amplitude movements in bradykinesia interfere with limb control, dexterity in tying shoes or buttoning shirts, and swallowing (dysphagia). It may also present as decreased facial expression and eye blinking (hypomimia), weak voice (hypophonia), and progressively smaller handwriting (micrographia) [4,62,64].

Rigidity

Rigidity is increased muscle tone in flexor and extensor muscle groups at rest and resistance to passive stretch movement in flexor and extensor muscles with the limb relaxed. Rigidity is present in 80% to 90% of patients with PD, usually unilaterally at the onset of motor symptoms. It often, but not always, co-occurs with tremor. Rigidity results from altered firing rates in the basal ganglia, a fundamental feature of parkinsonism. The resultant motor system output reflects inappropriate activation of agonist and antagonist muscles that present in bradykinesia and rigidity [7]. In early-stage disease, rigidity may manifest as pain, such as frozen shoulder or low back pain, obscuring the diagnosis of a CNS disorder [4].

Rest Tremor

Rest tremor, an initial symptom in 70% to 90% of patients, refers to a 4–6 Hz tremor in the fully resting limb, suppressed during movement initiation. Rest tremor is a rhythmic, oscillatory involuntary movement and one of the most characteristic signs in clinical medicine. The most distinguishing rest tremor is the "pill-rolling" type, with rubbing movements of thumb and index fingers against each other. Rest tremor is thought to initiate with nigrostriatal degeneration and subthalamic nucleus or globus pallidus disinhibition, or disrupted thalamo-cortical-cerebellar circuits leading to abnormal thalamic pacemaker cell function [4,7].

Tremor in parkinsonism is distinct from other forms of tremor by its asymmetry, speed, dominance at rest, reduction or cessation during action, re-emergence when maintaining a posture, and increased amplitude during tasks requiring mental concentration [4].

Postural instability is defined as difficulty adjusting to postural change, and together with gait impairment and postural abnormalities, it comprises the axial motor signs of PD [65]. Postural instability and other axial signs do not usually present in early PD, reflecting pathophysiology beyond dopamine motor neuron loss [7]. As such, the inclusion of axial signals in the cardinal motor features required for the parkinsonism diagnosis in PD has been challenged [60].

Postural and gait impairment result from loss of postural reflexes, which leads patients to adopt a stooped posture. The loss of postural reflexes is also a major contributor to falls [66]. In PD, the gait is slow, with short shuffling steps on a narrow base that appears as if the patient is chasing his or her own center of gravity. Patients show decreased arm swing; turning around is slow, with multiple small steps, and freezing gait can occur, especially in crowded or narrow places. Festination, a very fast succession of steps with the patient only able to stop when meeting an obstacle, may also be present. Walking and turning becomes difficult or impossible in patients with PD when additional cognitive load, such as dual tasking, is imposed [67,68].

Brainstem pathology is now recognized as a major contributor to the clinical features in PD. Postural control problems with imbalance, falls, and freezing gait tend to occur later in PD and reflect cholinergic neuron degeneration and dysfunction outside of the basal ganglia [7]. Persons with parkinsonism or other extrapyramidal neurodegenerative disorders frequently develop problems with balance and may experience frequent falls. The vestibular system controls balance and is synaptically linked to the extrapyramidal system, possibly contributing to posture and balance dysfunction [62].

The frequency and diversity of non-motor symptoms in PD is substantial, and includes autonomic, neuropsychiatric, olfactory, sensory, and sleep disorders that occur in 80% to 90% of patients (Table 4). Non-motor symptoms can manifest before, during, or after motor symptoms and may result in greater impairment of quality of life. The prevalence of cognitive, autonomic, and mood disorders is very high; progression can result in patients requiring care in a supervised environment [7].

A 2010 survey found that up to 62% of patients with PD do not volunteer symptoms such as apathy, pain, sexual dysfunction, bowel incontinence, constipation, or sleep disorders either through embarrassment or unawareness of symptom relevance to PD. Clinicians may not understand that these symptoms require assessment. Their under-reporting has important therapeutic and societal implications, as most are treatable. Left unaddressed, non-motor symptoms detrimentally affect patient quality of life, frequently lead to hospitalization and institutionalization, and quadruple the cost of PD care [69].

To assess bradykinesia, ask the patient to perform repetitive movements as quickly and widely as possible, such as opening and closing the hand, tapping thumb and index fingers, or tapping the foot on the ground. Progressive slowness and/or loss of amplitude should emerge and may bring movement to full arrest (freezing). To globally assess bradykinesia, observe spontaneous movements while the patient is sitting, standing up from a chair, or walking [62,64]. To avoid misdiagnosis, distinguish clinical bradykinesia from simple slowness in patients with decreased muscle power, spasticity, or reduced motivation in depression or in normal elderly populations that reflect non-specific slowness [62,64].

Rigidity refers to "leadpipe" resistance, whereby velocity-independent resistance to passive movement is not influenced by inability to relax (i.e., distinct from spasticity). This resistance is felt throughout the full range of movement, and unlike spasticity, it does not increase with higher mobilization speed. When resting tremor co-occurs with rigidity, "cog-wheel rigidity" can be felt during passive limb mobilization, especially in the wrist. When assessing rigidity, interruption of passive movement by a "cog-wheel" movement reflects the underlying 4–6 Hz tremor oscillation. In contrast, pyramidal tone (spasticity) is dependent on the velocity of passive movement, described as ''clasp knife'' in quality because of the higher resistance during early acceleration of the passive movement followed by giving way, such as is seen when opening lock-blade knives [62]. Rigidity is assessed by passive movement of a joint and reinforced by asking the patient to move the opposite limb in a circular motion or open/close a fist.

Resting tremor is often observed in patients with PD, and postural tremor and re-emergent resting tremor may be seen with arms outstretched. Resting tremor is best observed in the hands during patient focus on a mental task (e.g., eyes-closed countdown from 100) that facilitates muscle relaxation; in the legs with the patient seated on the edge of an exam table, with legs hanging and feet unsupported; and in the jaw when the patient is engaging another part of the body in activity [4,62].

Gait may be stooped or shuffling, with reduced arm swing. Patients often turn en bloc, requiring numerous steps to complete a 180° turn. The pull test (briskly pulling the patient backwards while standing) may be used to assess postural reflexes. Loss of postural reflexes generally occurs in later-stage disease.

Clues from the medical history and atypical exam findings should prompt a careful work-up to rule out or confirm an alternate diagnosis. The most common syndromes mimicking PD are essential tremor, vascular parkinsonism, Lewy body dementia, progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and drug-induced parkinsonism (Table 8). Neurologic consultation and neuroimaging studies are often needed to adequately assess many of these possibilities [1,2,63,79,80].

Determining the presence of parkinsonism is the first step in considering therapeutic options for PD and distinguishing PD from other central nervous system pathologic states. Although exclusion of alternative diagnoses may not expand options for disease-modifying or curative therapies, arriving at a definitive diagnosis is important for purposes of patient and family education, prognosis, reassurance, and options for therapy. A definitive diagnosis gives a name to the condition. This is very important for the patient experience and helps in coming to terms with a chronic disease. An "atypical parkinsonism" or "parkinsonian syndrome" diagnosis leaves patients and family with vague uncertainty and fails to provide a clear basis for management decisions and prognosis. A hierarchical list of diagnostic possibilities should be discussed if definitive diagnosis is elusive. Diagnostic criteria for progressive supranuclear palsy, cortico-basal degeneration, and multisystem atrophy allow for possible and probable diagnostic categories, according to diagnostic certainty [4].

Exogenous dopamine administration is ineffective for treatment of PD, because circulating dopamine does not cross the blood-brain barrier so as to reverse brain dopamine depletion. Levodopa is a dopamine prodrug able to cross the blood-brain barrier where it is converted to dopamine by aromatic amino acid decarboxylase (AAAD). The regular administration of oral levodopa leads to repletion of dopamine in the substantia nigra pars compacta, and to storage in presynaptic dopamine neurons for subsequent use. The majority of patients treated with levodopa realize significant and prolonged improvement in motor function, though there are side effects and, in time, many patients experience fluctuations in beneficial effects of the drug. Levodopa was introduced for use in PD in the late 1960s, and remains the criterion-standard treatment [7].

The bioavailability of orally administered levodopa is reduced by extensive metabolism to dopamine in the gut. Only 30% of an oral dose reaches systemic circulation for distribution to the brain. For this reason, Levodopa used to treat PD is always combined with carbidopa, a peripherally acting AAAD inhibitor. Carbidopa inhibits peripheral conversion of levodopa to dopamine, which triples levodopa bioavailability and lowers the dosage requirements. Carbidopa 75–100 mg/day is the dose needed to inhibit peripheral conversion of levodopa to dopamine. Carbidopa also helps to diminish acute peripheral dopamine side effects, such as nausea, vomiting, and hypotension, and improves tolerability [88].

The risk for side effects and toxicity, including troublesome dyskinesia, is high in patients on chronic levodopa therapy. For this reason, careful dose titration and tight adherence to the effective dose is important for PD symptom management. No evidence has been found that using an extended-release levodopa/carbidopa formulation, or adding a catechol-O-methyltransferase (COMT) inhibitor, delays or prevents the development of motor fluctuations [89].

Because levodopa is absorbed in the proximal small intestine, food may delay absorption. Levodopa also competes with dietary proteins for transport into the brain. High-protein meals should be kept separate from levodopa dosing, and daily dietary protein intake should be reduced to approximately 0.8 g/kg (of body weight). Levodopa is metabolized in the gastrointestinal tract, kidneys, and liver, with 70% excreted in the urine. Levodopa half-life is roughly one hour. Dosing should be reduced 10% to 30% when other dopaminergic agents are added to carbidopa/levodopa. Available formulations in the United States are [88]:

Potential adverse events associated with levodopa/carbidopa can be generally categorized as CNS, gastrointestinal, or other. Adverse effects involving the CNS include confusion, sedation, vivid dreams, dizziness, hallucinations, psychosis, and depression. Gastrointestinal effects may include nausea, vomiting, and changes in bowel habits. Orthostasis, leg edema, dyskinesia, dystonia, hemolytic anemia, and leukopenia may also occur. All patients taking levodopa should be monitored for changes in blood pressure, pulse, mental status, and clinical response.

With prolonged therapy and disease progression, the duration of benefit from each levodopa dose often becomes increasingly shorter. "End of dose deterioration," "wearing-off," "off periods," or simply "off" refers to the waning or absent effects of levodopa within four hours of the last dose. As "off" periods increase, "on" periods (levodopa-related motor symptom control) decrease [4].

Caregivers monitoring the course of a stable patient on chronic levodopa therapy for PD often face two potential therapeutic challenges. First is the development of dyskinesia, indicative of drug intolerance or excessive dosage. The second is fluctuation in motor symptoms, perhaps indicative of inadequate dosage, failing compliance, or waning therapeutic effectiveness. The frequency, or risk, of dyskinesia and motor fluctuations during chronic levodopa therapy for PD is difficult to predict. One literature review of publications spanning 1966 through 2000 showed that among patients receiving levodopa therapy, the median frequency of dyskinesia was 39%, and after a satisfactory first year of therapy, the frequency of motor fluctuations gradually increased to 40% of patients by four to six years of treatment [151].

Dopamine D2/3 receptor agonists bind post-synaptic striatal dopamine receptors to increase dopaminergic neurotransmission and reduce parkinsonism symptoms. Ropinirole (oral), pramipexole (oral), and rotigotine (transdermal) are the most widely used agents. In advanced disease, subcutaneous apomorphine is continuously delivered via external pump or is used for rapid rescue therapy (via injection). The ergot derivative dopamine agonists cabergoline, pergolide, and bromocriptine are not recommended as first-line dopamine agonist therapy, and bromocriptine is associated with the development of fibrotic tissue. Ergot derivatives require specialized side effect monitoring, but they remain options for patients lacking benefit or tolerability with other dopamine agonists [74,90].

Dopamine agonists are the second most potent drug class (after levodopa) for motor symptom control in PD and are effective at all stages of the condition. Initial dopaminergic therapy using dopamine agonists (versus levodopa) is associated with reduced/delayed treatment-related complications, such as levodopa-induced dyskinesia and motor fluctuations [7,91].

However, poor tolerability can limit the use of dopamine agonists. While dopamine agonists are less likely to lead to motor fluctuations in early disease than levodopa, they are less effective for motor symptoms and carry greater risk of side effects such hallucinations, psychosis, hypotension, peripheral edema, excessive daytime somnolence, and impulse control disorders. In patients older than 70 years of age, dopamine agonists should be used with caution or avoided entirely [89]. All patients taking ropinirole, pramipexole, or rotigotine should be monitored for changes in blood pressure, daytime alertness, weight, and heart rate [88].

Ropinirole

Ropinirole undergoes hepatic metabolism, with a half-life of about six hours. It is associated with various adverse effects in various systems, including the gastrointestinal system (e.g., nausea, vomiting, dyspepsia, abdominal pain, constipation) and the CNS (e.g., dizziness, somnolence, headache, syncope, confusion, hallucinations, impulse control disorders, sleep attacks). Other potential adverse effects include fatigue, asthenia, dependent/leg edema, viral infection, pain, increased sweating, orthostatic symptoms, pharyngitis, abnormal vision, and urinary tract infection [88].

Pramipexole

Pramipexole is administered orally for PD and is available in immediate- and extended-release formulations. The half-life in healthy adults is about 8 hours, but this is extended to 12 hours in elderly patients. It is excreted in the urine primarily as unchanged drug, and dose adjustment is required in renal impairment. Overnight switch from immediate- to extended-release is successful in 80% of patients [88]. Potential adverse effects include nausea, abdominal pain/discomfort, constipation, dizziness, somnolence, headache, hallucinations, impulse control disorders, dyskinesia, orthostatic hypotension, xerostomia, peripheral edema, and muscle spasms [88].

Rotigotine

Rotigotine is available as a transdermal patch for the treatment of PD. It undergoes extensive metabolism via conjugation and N-dealkylation. The initial half-life is three hours, with the terminal half-life five to seven hours after patch removal. Potential adverse effects have included nausea, vomiting, somnolence, dizziness, application-site reactions, dyskinesia, anorexia, hyperhidrosis, visual disturbance, and peripheral edema, and all patients should be monitored for skin reactions. Patients with sulfa allergy should not be prescribed rotigotine, and patches contain aluminum and should be removed prior to MRI [88].

Apomorphine

Apomorphine for PD is given as a subcutaneous injection into the abdominal wall, upper arm, or upper leg; the injection site should be rotated. It is indicated for hypomobility and "off" episodes associated with PD.

Apomorphine undergoes extensive first-pass metabolism, with a terminal half-life of about 40 minutes. Nausea, vomiting, drowsiness, somnolence, dizziness, orthostatic hypotension, hallucinations, confusion, dyskinesia, rhinorrhea, and edema/swelling of extremities may occur. It is important to avoid use of apomorphine with serotonin blockers, as co-ingestion may cause profound hypotension. All patients taking this agent should be monitored for orthostatic hypotension and drowsiness [88].

Bromocriptine Mesylate

Bromocriptine mesylate is taken orally and is metabolized by the liver. The half-life is approximately 5 to 15 hours. Potential adverse effects include nausea, vomiting, abdominal discomfort, abnormal involuntary movements, ataxia, hallucinations, confusion, "on-off" phenomenon, dizziness, syncope, drowsiness, insomnia, depression, visual disturbance, hypotension, shortness of breath, constipation, vertigo, and asthenia. Long-term treatment with this drug is associated with pleural thickening (fibrosis). As such, patients' pulmonary function should be monitored during treatment [88].

Monoamine Oxidase B Inhibitors

MAO-B is an enzyme that inactivates dopamine by breaking it down into metabolic byproducts. MAO-B inhibitors block the breakdown of dopamine, slowing the loss of dopamine and several of the effects of PD. MAO-B inhibitors are generally considered for initial treatment of early PD as monotherapy and as adjunctive therapy to augment the effects of levodopa in later PD. The preferred agents are selegiline and rasagiline, both of which have shown symptomatic benefit and multiple neuroprotective effects in pre-clinical research [7,89,92].

Selegiline

In the treatment of PD, selegiline may be used as monotherapy or combined with levodopa. This agent blocks the breakdown of dopamine via MAO-B inhibition. It is metabolized via CYP450 enzymes to amphetamines, with a half-life of 10 hours. In high doses, it may precipitate a hypertensive crisis. Other potential adverse effects include nausea, weight loss, dyspepsia, hypotension, decreased heart rate, headache, hallucinations, vivid dreams, dizziness, insomnia, flu-like symptoms, dyskinesias, dystonia, rash, and photosensitivity [93]. All patients undergoing treatment with selegiline should be monitored for rash, drug interactions, and changes in blood pressure, cardiac status, and mental status (i.e., increased anxiety) [93].

In addition to a capsule/tablet, selegiline is available as an orally disintegrating tablet. Pharmacology, potential adverse effects, and monitoring are similar, but metabolism of the disintegrating tablet bypasses the liver to reduce formations of amphetamine metabolites, which reduces the risk of insomnia side effects [93].

Rasagiline

Oral rasagiline may be used in monotherapy or combination therapy for patients with PD. This agent inhibits the breakdown of dopamine via MAO-B inhibition and is metabolized via CYP1A2. The half-life is three hours. The potential adverse effects and patient monitoring requirements are the same as with selegiline [93].

Catechol-O-Methyltransferase Inhibitors

COMT is an enzyme that converts levodopa in peripheral circulation to 3-O-methyl-DOPA (3-OMD). This metabolite cannot be converted to dopamine and accumulates in plasma during levodopa therapy. Inhibition of COMT increases the bioavailability of levodopa, allowing a larger amount of the drug to reach the brain and consequently raise dopamine levels. COMT inhibitors are always taken in combination with levodopa because they lack intrinsic dopaminergic activity. They are used in PD to potentiate levodopa effects when "wearing off" or other motor complications appear during carbidopa/levodopa therapy [93].

Entacapone

As a COMT inhibitor, entacapone inhibits the peripheral metabolism of levodopa. It is metabolized to active isomer and undergoes glucuronidation to inactive metabolites, with a half-life of two hours. Potential adverse effects include exacerbation of levodopa adverse effects, brown/orange urine, and diarrhea. All patients should be monitored for changes in blood pressure and mental status. A fixed-dose combination of entacapone with carbidopa/levodopa is available and reduces the number of tablets needed for treatment, which may improve adherence [93].

Tolcapone

Tolcapone inhibits peripheral and central metabolism of levodopa. It has a half-life of about three hours and is metabolized via glucuronidation and CYP2A6 and CYP3A4 enzymes. The adverse effects are the same as those described for entacapone, plus transient elevations in liver enzymes and fulminant liver failure. In addition to the monitoring recommended for entacapone, these patients should be regularly tested for liver enzymes and function [93].

Opicapone

Opicapone is a novel, once-daily, third-generation COMT inhibitor. Research has compared opicapone with entacapone and placebo as a levodopa adjunct. In a study involving 590 patients with PD-associated motor fluctuations, the mean reduced times in "off" state were 56 minutes for placebo, 96.3 minutes for entacapone, and 116.8 minutes for opicapone after 14 to 15 weeks. Opicapone 50 mg was statistically superior to placebo and non-inferior to entacapone, but lower-dose opicapone did not differ from placebo [94].

The most common adverse events with opicapone are dyskinesia, insomnia, and constipation. Serious adverse events were reported in six patients with placebo, eight with entacapone, and four with opicapone 50 mg. In addition to "off" time efficacy, an advantage of opicapone is the once daily dosing [94].

Anticholinergic agents used in PD treatment include benztropine (Cogentin) and trihexyphenidyl. Anticholinergics may be helpful as a symptomatic treatment in younger patients with early PD and severe tremor or dystonia, but they should not be drugs of first choice due to their narrow range of efficacy. Adverse effects from nonselective cholinergic receptor blockade are a major drawback and include CNS-related side effects of cognitive impairment, exacerbation of dementia, delirium, sedation, and hallucinations. Other side effects include constipation, xerostomia, blurred vision, and urinary retention; higher doses may cause or worsen orthostatic hypotension and palpitations. Elderly patients are especially prone to these side effects plus confusion and memory difficulties, and anticholinergic agents are not recommended in this population [89].

Amantadine is an N-methyl-d-aspartate (NMDA) antagonist with modest benefit in early PD and efficacy in suppressing levodopa-induced dyskinesia in later/advanced PD. The mechanism of action is thought to involve augmentation of pre-synaptic dopamine release and NMDA glutamatergic antagonism. Common side effects include pedal edema and livedo reticularis (violet, lace-like coloration) [7].

Amantadine is the only agent demonstrated to suppress levodopa-induced dyskinesia without worsening parkinsonism, and the American Academy of Family Physicians recommends that amantadine should be considered for treatment of dyskinesias in patients with advanced PD [2]. However, use in frail elderly patients with advanced PD may result in confusion, hallucinations, and/or worsening motor symptoms [95].

The acetylcholinesterase inhibitor rivastigmine is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild-to-moderate PD dementia. Other approved drugs for dementia, including donepezil, galantamine, and memantine, have been evaluated for the treatment of PD dementia, but their efficacy has not been clearly shown [95].

Rivastigmine has shown significant improvement in PD dementia that was maintained through 48- and 76-week follow-up in different trials. In long-term trials comparing rivastigmine capsules (12 mg/day) versus transdermal patch (9.5 mg/24 hours), the rates of adverse effects from worsening PD were 36.1% with the capsule (tremor in 24.5%) versus 31.9% with the patch (tremor in 9.7%). Both formulations showed a 2.1-point worsening on the UPDRS-III motor scale [96,97].

Istradefylline

In 2019, the FDA approved istradefylline as an add-on treatment to levodopa/carbidopa in adult patients with PD experiencing "off" episodes [155]. This agent is an adenosine receptor antagonist with evidence of significantly decreasing daily "off" time compared with patients receiving a placebo. Potential side effects include dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia [155].

Adenosine A2A Receptor Antagonists

A2A receptors are co-localized on dopamine D2 receptors and may be over-activated in PD. Thus, A2A receptor antagonism may reduce PD motor symptoms [98]. Istradefylline was the first A2A antagonist evaluated in PD, but it received a "not approvable" letter from the FDA due to lack of clinical benefit and association with dyskinesias. A subsequent review concluded istradefylline 50 mg had clinical potential as a levodopa adjunct in PD, with support from a clinical trial showing significant reduction in "off" time and good tolerance [95,99].

Riluzole

There has been interest in glutamate receptor antagonists for the treatment of PD based on the finding that PD is linked to glutamate overactivation in basal ganglia circuits, resulting in oxidative stress and cell death. Riluzole, an NMDA receptor antagonist approved for the treatment of amyotrophic lateral sclerosis, was studied in PD, but it lacked significant effects on survival or disease progression [93].

Safinamide

Safinamide is an alpha-aminoamide developed as adjunct therapy to dopamine agonist or levodopa therapy in patients with PD. This drug shows dopaminergic and non-dopaminergic activity, including MAO-B inhibition, sodium channel antagonism, and inhibition of glutamate release. Clinical trials have shown significantly improved motor symptoms versus placebo. In a six-month double blind, placebo-controlled study of patients with mid-to-late stage PD with motor fluctuations, the addition of safinamide 50–100 mg/day was shown to significantly improve "on time" without increasing dyskinesia and to improve motor function, activities of daily living, quality of life measures, and depressive symptoms [152]. Clinical benefit was sustained over an additional 18-month period of continued treatment and observation.

In 2017, the FDA approved safinamide as "add-on" treatment for patients with PD who are taking levodopa/carbidopa and experiencing "off" periods [8].

Cannabidiol

Cannabidiol, the primary non-psychoactive constituent in Cannabis, has been evaluated for treatment efficacy in several non-motor PD conditions. In patients with PD-associated psychoses of at least three months' duration, oral cannabidiol treatment ≤400 mg/day for four weeks significantly reduced psychotic symptoms. No cognitive or motor side effects were found in study participants [101].

A small case series of patients with PD and REM sleep behavior disorder examined treatment response to oral cannabidiol 75 mg/day or 300 mg/day for six weeks. In this sample, symptoms of REM sleep behavior disorder included swearing, laughing, yelling, pushing, kicking, or punching during REM sleep, occurring two to seven times per week. After six weeks of cannabidiol, REM sleep behavior disorder symptom frequency was no times per week in 75% and one time per week in 25% of patients. All patients reported elimination of nightmares. Shortly after cannabidiol cessation, symptom frequency returned to baseline level in all patients. No side effects were observed [102].

Inosine

The antioxidant urate precursor inosine has been associated with lower risk of PD and slower PD progression and was suggested as neuroprotective in laboratory assays. The effects of inosine on PD are currently in phase III clinical trial evaluation in the Safety of Urate Elevation in Parkinson Disease (SURE-PD) study [83].

In addition to investigational new drugs, several FDA-approved medications have been studied for their off-label use in the treatment of PD. Calcium-channel blockers are one such group. In one study, the calcium-channel blocker isradipine was found to reduce risk of PD in patients 65 years of age or older [103]. Isradipine, a calcium-channel blocker in use as hypertension therapy, may be neuroprotective in PD. The drug is currently in phase III trials (known as STEADY-PD) to determine its utility in treating early PD [83].

Evidence for the role of neuroinflammation in the pathogenesis of PD have prompted trials of several anti-inflammatory agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be protective against PD, but the overall evidence of neuroprotective effect with aspirin or NSAIDs in PD is inconsistent [93].

The stimulant methylphenidate has been found in limited studies to improve gait hypokinesia and freezing in patients with PD receiving deep brain stimulation of the subthalamic nucleus [104].

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes. In a 12-month trial of 45 patients with moderate PD, subcutaneous exenatide showed clinically relevant improvements in PD across motor and cognitive measures versus untreated controls [105,106].

Zonisamide is an anticonvulsant with neurotransmitter effects, including stimulation of dopamine synthesis, and is approved in Japan for the treatment of PD. Use as an adjunct to levodopa found improvements in "off" time [107].

Beta-blockers are considered a therapeutic option for PD tremor, although some patients may not benefit from or tolerate these agents [108].

The initial choice of drug depends on the likelihood of improving motor function (better with levodopa) compared with the risk of motor complications (more common in younger patients, delayed by agonists) and the presence of neuropsychiatric complications (more common in older and cognitively impaired patients, greater with agonists). Levodopa is the mainstay of initial treatment and the most effective drug for improving motor function. One should avoid controlled-release formulations or adding entacapone, as this is not effective for delaying the onset of motor complications. Other treatments include MAO-B inhibitors (e.g., selegiline, rasagiline) or oral or transdermal dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). Initial treatment with an agonist can be recommended in younger patients. Ergot derivatives (e.g., bromocriptine, cabergoline) are not recommended due to the increased risk of fibrotic development [74]. Amantadine and anticholinergic agents are also options. Rehabilitation in early-stage disease has seldom been evaluated, and therefore a recommendation for or against its use cannot be made [74].

Dose adjustments with dopamine agonists and levodopa preparations are made in response to clinical effect, emerging symptoms, and/or side effects. Risks of psychiatric side effects and dyskinesias are greater at higher doses, and treatment with the lowest dose possible to achieve benefit is favored; this better maintains patient function and quality of life. Patients older than 50 years of age who receive levodopa doses greater than 600 mg/day are more likely to develop dyskinesia [4].

Patients who initiate treatment with an MAO-B inhibitor, anticholinergic agent, amantadine, or their combination will, at some point, require levodopa or a dopamine agonist added. When patients on dopaminergic therapy require treatment intensification, the options are to increase the dose, switch to another agonist, or add levodopa. Patients who are initiated on levodopa may be better managed by an increase in the dose, the addition of an agonist, or the addition of a COMT inhibitor [74]. If significant tremor persists in patients with disabling tremor, add or initiate with [74]:

While early PD can be effectively managed with levodopa for many years, disease progression invariably leads to peak-dose dyskinesias, including tics, tremors, and other involuntary movements [8]. In addition to levodopa, dyskinesias can also develop with dopamine agonists or MAO-B inhibitors. Men and younger patients have higher risk of dyskinesias. Mild dyskinesias do not require specific treatment, but more severe cases may respond to a reduction in levodopa dose or addition of an NMDA antagonist or dopamine receptor agonist [4].

Motor complications become the dominate clinical issue when patients develop end-of-dose deterioration (symptom relapse) or peak-dose dyskinesias. Several potential mechanisms contribute to the development of motor complications. Low plasma levels of dopaminergic drugs lead to "off" periods, while high levels increase peak-dose dyskinesia; the levodopa therapeutic window is narrowed. Motor complications accrue in an estimated 10% of patients with PD per year, with an estimated 50% prevalence with five years of levodopa treatment. Other motor signs and symptoms can emerge, including axial motor symptoms of gait and postural abnormalities, that increase the risks of falling, dysphagia, dysarthria, and cognitive problems [8].

The common, debilitating axial motor symptoms/signs of late-stage PD are gait impairment, postural instability, and other postural abnormalities. Unlike the cardinal motor symptoms of PD (rest tremor, bradykinesia, and rigidity), axial motor symptoms do not respond well to dopaminergic therapy and physiotherapy. This is likely because motor control of axial and cardinal functions is mediated by different anatomical-functional pathways [65].

Freezing gait often appears later in the disease course and can lead to significant declines in quality of life. Walking requires shifting from one leg to the other, and patients with freezing gait experience a sense of falling every time they lift a foot up off the floor. Every step forward resembles a controlled fall. Research has shown that auditory stimuli (e.g., sound of a metronome) or visual cues (e.g., a flash of light or lines on the floor indicating stride length) can reduce episodes of freezing, but how these cues work is unknown [8].

When motor complications emerge, manipulation of levodopa dose or frequency is often the first strategy, but the initial improvement is eventually precluded by the emergence of dyskinesias.

Levodopa Wearing Off

Studies comparing immediate- and modified-release levodopa found roughly 25% less levodopa absorbed with the modified-release formulation, and this should be considered when switching between preparations. Erratic levodopa absorption in later PD and significant reduction in doses per day with modified-release levodopa can result in delayed or no "on" responses. Modified-release levodopa has greatest benefit in reducing overnight wearing-off [4].

The next strategy is adding adjunctive therapies to levodopa to control fluctuating motor response. Wearing-off symptoms can be reduced by adding MAO-B inhibitors, COMT inhibitors, or dopamine agonists. The MAO-B inhibitor rasagiline reduces "off" time by around 1.5 waking hours per day; the same results were found with the COMT inhibitor entacapone [4]. The COMT inhibitors entacapone and tolcapone can improve CNS delivery of levodopa by inhibiting its peripheral degradation to 3-OMD. Entacapone is most widely used due to rare hepatic failure associated with tolcapone, although the latter agent may be more effective [7,74]. COMT inhibitors can increase ''on'' time, but these drugs lack intrinsic antiparkinsonism efficacy as monotherapy [4].

The dopamine agonists pramipexole and ropinirole reduce "off" time by around 15% but can cause problematic side effects, including drowsiness, sudden onset of sleep, and impulse control disorders, in 15% or more of patients. Patients should be screened for pre-existing drowsiness and tendencies toward compulsive disorders (e.g., gambling) before prescribing a dopamine agent. Patients should be monitored for the development of impulse control disorders throughout the course of treatment. Apomorphine can be administered by continuous infusion or intermittently to treat sudden "off" periods unresponsive to other medications [4].

Severe Motor Fluctuations

Deep brain stimulation is effective against motor fluctuations and dyskinesia [74]. However, because the risk for adverse events is elevated, this modality is only recommended in patients younger than 70 years of age without major psychiatric or cognitive problems. Other options include subcutaneous apomorphine administered via penject or pump or intrajejunal levodopa/carbidopa enteric gel administered through percutaneous gastrostomy [74].

Unpredictable "On-Off"

Deep brain stimulation of the subthalamic nucleus is effective to manage unpredictable "on-off" symptoms [74]. In treatment studies for wearing-off, patients with unpredictable "on-off" have been excluded or were uncommon. Thus, there is insufficient evidence to conclude if the results are valid for unpredictable "on-off." The strategies described for dyskinesia and wearing-off should be considered. For delayed "on," dispersible levodopa and subcutaneous apomorphine injections have some value [74]. Reducing or redistributing dietary proteins may be helpful, but a more practical approach is to take levodopa on an empty stomach one hour before, or at least one hour after, each meal.

Freezing

Management options for "off" freezing are the same as for wearing-off. However, freezing during "on" often does not respond to dopaminergic strategies. Visual or auditory cues are empirically useful for facilitating the start of motor acts [74].

Dyskinesias

The first step in managing dyskinesias is to reduce the levodopa dose. This elevates the risk of increasing "off," but it can be compensated for by increasing the number of doses or adding a dopamine agonist. MAO-B or COMT inhibitors should also be reduced or discontinued at the risk of worsening wearing-off [74].

Amantadine (an NMDA antagonist) is the sole effective agent in suppressing levodopa-induced dyskinesia without worsening parkinsonism and should be initiated at 200–400 mg/day [74,95]. In younger patients, an anticholinergic agent may be prescribed [74].

Deep brain stimulation of the subthalamic nucleus also reduces dyskinesia symptoms and dopaminergic dosing. Stimulation of the globus pallidus pars interna may reduce severe dyskinesia.

Clozapine or quetiapine may be added. Clozapine is associated with potential serious adverse events (e.g., agranulocytosis, myocarditis) and requires monitoring. Intrajejunal levodopa infusion is another option. Continuous subcutaneous infusion of apomorphine allows reduction of levodopa [74].

Biphasic Dyskinesia

Biphasic dyskinesias can be very difficult to treat, and well-designed treatment studies are sparse. Deep brain stimulation of the subthalamic nucleus appears effective [74]. The strategies described for managing peak-dose dyskinesias may also be considered.

Another option is increasing the size and frequency of levodopa dosing, at the risk of increasing peak-dose dyskinesia. However, larger and less frequent doses may give more predictable responses. Apomorphine and intrajejunal levodopa infusion may be tried [74].

Off-Period and Early-Morning Dystonias

The strategies for wearing-off can be applied to patients with off-period dystonias. Additional levodopa or dopamine agonist doses at night may be effective if the symptoms are worst in the morning. Deep brain stimulation is recommended, and botulinum toxin injection may be employed [74].

With apomorphine, the rapid onset of action makes it an effective intervention for "off" periods with use as a rescue injection. Apomorphine is also available as a continuous infusion treatment, suggested by clinical trials as effective in treating motor symptoms and some non-motor advanced PD symptoms [95].

With FDA approval in 2015, intestinal gel is the most recent formulation of levodopa/carbidopa to improve its blood concentration consistency and stability. In advanced PD, delayed and unpredictable spontaneous gastric emptying interferes with the passage of oral medication from the stomach to the small intestines for absorption and circulation to the brain. Levodopa/carbidopa intestinal gel (Duodopa) was developed to bypass this problem by delivering the drug directly to the proximal jejunum via a percutaneous endoscopic gastrojejunostomy tube connected to a portable infusion pump [113].

Compared to conventional immediate-release levodopa, levodopa/carbidopa intestinal gel has been found superior in improving motor fluctuations and quality-of-life scores. For example, 71 patients with advanced PD were randomized to levodopa/carbidopa intestinal gel plus oral placebo or oral levodopa/carbidopa plus placebo intestinal gel. After 12 weeks, the levodopa/carbidopa intestinal gel group showed a significant reduction in "off" time (-4.04 hours/day), versus the active oral/placebo gel group (+2.14 hours/day). This extent of improvement was also observed in "on" time without troublesome dyskinesia, and in "on" time without dyskinesia. Most side effects involved complications related to the percutaneous gastrojejunostomy therapy pump [114].

According to the European Federation of Neurological Societies, deep brain stimulation of the subthalamic nucleus is effective against motor fluctuations and dyskinesia in later-stage PD, but because of the risk for adverse events, the procedure is only recommended for patients younger than 70 years of age without major psychiatric problems or cognitive decline.

(https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch15 Last Accessed: April 19, 2022)

Level of Evidence: A (At least one convincing randomized, controlled clinical trial or at least two consistent, convincing prospective matched-group cohort studies)

Surgical approaches are considered in patients with advanced PD when optimized medical treatment fails to control motor symptoms. Surgical interventions used in the past include ablative lesions in the nuclei of the basal ganglia or thalamotomy for tremor, and pallidotomy for levodopa-induced dyskinesias; however, approaches such as these incurred a high risk of permanent side effects. Although pallidotomy or thalamotomy remain options in carefully selected patients, deep brain stimulation is now the surgical treatment of choice for patients with advanced PD and symptoms refractory to medical management [2,159]. This approach requires a small craniotomy for placement of electrodes connected to a pulse generator that is implanted in the chest wall. By modifying the frequency and amplitude of electrical stimuli, it is possible to improve motor symptoms and minimize side effects of brain stimulation over time. Unlike fixed ablative surgery, deep brain stimulation can be modified in response to changing symptoms as the disease progresses; adverse effects are usually reversible. The procedure can be performed in one or both hemispheres, depending on whether symptoms are unilateral or bilateral [89]. Although deep brain stimulation is able to reduce symptoms of motor fluctuations, dyskinesia, and tremor, other refractory PD symptoms (e.g., cognitive impairment, gait instability, mood disorders, speech impairment, autonomic dysfunction) are unlikely to improve and may worsen as a result of this mode of therapy. Guidelines recommend that deep brain stimulation only be performed in experienced centers [2].

For treatment of PD, deep brain stimulation targets the subthalamic nucleus of the internal capsule or the globus pallidus. Clinical trials of deep brain stimulation have reported a 40% to 60% reduction in the severity of motor symptoms and up to 50% reduction in medication use [159]. Short- and long-term studies have been conducted to assess the effectiveness of subthalamic nucleus stimulation for levodopa-refractory signs and symptoms. The overall improvement in activities of daily living and motor UPDRS scores averaged 50% compared to pre-surgery. Severity of levodopa-induced dyskinesias have been reduced by an average 69%. Surgical implantation of electrodes deep in the brain has a 1% to 6% risk of postoperative intracranial hemorrhage, infection, or stroke. Late-onset adverse events include migration or misplacement of the leads (5.1%), lead fractures (5%), and skin erosion (1.3%) [115,159].

Factors contributing to deep brain stimulation outcome include clinical indications, patient selection, implantation accuracy, stimulation programming, and medication management. The symptoms and signs most frequently considered as possible late complications of deep brain stimulation include eyelid opening apraxia (1.8% to 30%), dysarthria/hypophonia (4% to 17%), gait disturbances (14%), postural instability (12.5%), weight gain (8.4%), and verbal fluency decline (14%) [89,116]. As of 2016, more than 100,000 patients had undergone deep brain stimulation surgery for the treatment of PD and other movement disorders [117].

Timing

While deep brain stimulation was formerly offered only in late-phase disease (mean: 13 to 14 years post-diagnosis), several considerations have now moved the timing of surgery earlier [117]. Deep brain stimulation produces improvement in symptoms responsive to dopaminergic drugs, but in late-stage disease, symptom responsiveness to brain stimulation is less predictable and often unsatisfactory. Performing deep brain stimulation at advanced stages of illness can alleviate some motor dysfunction features but does not much benefit ongoing sense of well-being or functional status in relation to family, occupation, and social roles. In addition, older patients are more likely to develop surgical complications and/or worsening of axial motor functions.

The value of earlier deep brain stimulation surgery for PD was studied by comparing best medical treatment with deep brain stimulation of the subthalamic nucleus in 251 patients with early-stage motor fluctuation (mean: seven years post-diagnosis). Early and sustained improvement was found in quality of life for patients who received deep brain stimulation. Deep brain stimulation of the subthalamic nucleus has been proposed in patients less than four years after diagnosis without motor fluctuation, but this approach is less compelling, as it exposes patients to potentially dangerous side effects without improving motor function or quality of life. The long-term impact is also unclear [117].

Targeting

Several trials comparing subthalamic nucleus and globus pallidus pars intera stimulation have helped define relative advantages between these two targets. While motor benefits are comparable, other parameters show advantages with subthalamic nucleus for more severe on-off symptoms and cost-efficacy, and advantages with globus pallidus pars intera for dyskinesia suppression, long-term stability of effects, and cognitive symptoms [117].

Experimental and clinical observations suggest contribution from the pedunculopontine nucleus to the pathophysiology of gait and stability impairment. However, pedunculopontine nucleus stimulation remains investigational, with several unresolved issues [117].

Long-Term Impact

Early open-label studies reporting long-term (more than 10 years) outcomes in subthalamic nucleus stimulation consistently found durable benefits in motor fluctuation, dyskinesias, and the cardinal symptoms of PD (tremor, rigidity, and to a lesser extent, bradykinesia). A survival advantage was suggested when comparing eligible patients who chose deep brain stimulation versus those who continued medical treatment. However, subthalamic nucleus stimulation does not halt disease progression, and "long-term deep brain stimulation syndrome" with axial motor problems can emerge from long-term therapy. Reappraisal of current targets and investigation of new ones is ongoing [117].

Radiofrequency ablation and focused ultrasound are alternative modalities that can target the subthalamic nucleus and produce fixed brain lesions. The success rate of radiofrequency ablation of subthalamic nuclei for relief of parkinsonism is comparable to that of deep brain stimulation. Unfortunately, the benefit often dissipates after three years due to worsening PD or return of abnormal activity. Like deep brain stimulation, radiofrequency ablation requires craniotomy; it also has some risk of hemorrhage and stroke. Potentially irreversible adverse events include dyskinesia or hemiballismus, gait impairment, dysarthria, and loss of verbal fluency [159].

Ablation of certain deep brain centers can also be performed using focused ultrasound (FUS). Ablation with FUS has the advantage of producing lesions without the need for craniotomy; however, this modality has not yet proven to be safer than ablation methods that require craniotomy. Disadvantages of FUS for treatment of PD include persistent adverse effects (dysarthria, weakness, gait unsteadiness) and lack of the ability to modulate treatment over time [159].

Psychosis in Parkinson Disease

Psychosis in PD is common and multifactorial in etiology. Up to 60% of patients with PD develop psychosis. Following its onset, PD psychosis remains a persistent, lifelong problem for most patients [118]. Pharmacologic management is challenging, in part because dopaminergic agents required for motor control can exacerbate psychotic symptoms, and antipsychotic agents can exacerbate motor symptoms [119]. The onset of psychosis in PD predicts a poor prognosis, including increased likelihood of nursing home placement and early mortality [120].

The early clinical manifestations of PD-associated psychosis differ from other psychotic disorders in that hallucinations are common and patients initially remain lucid and connected with reality. Visual hallucinations are the most prevalent form. Functional MRI performed on patients with PD who are experiencing visual hallucinations show several abnormalities: altered cortical visual processing; decreased occipital response and increased caudate and frontal cortical activation to visual stimuli; overactive visual association cortex; and decreased primary visual cortex activity [119].

Auditory, tactile, olfactory, and gustatory hallucinations do occur, though less commonly and usually in combination with visual hallucinations. Confusion states, delusions, paranoia, agitation, and delirium may also develop.

The stage of PD at which psychotic features emerge has some diagnostic import. In newly suspected or recently diagnosed (within three months) cases of PD, the appearance of psychotic symptoms suggests early-onset dementia with Lewy bodies, but could also indicate an alternative neuropsychiatric diagnosis, such as Alzheimer disease with extrapyramidal symptoms or underlying functional (psychiatric) psychosis. Differences in the initial presentation of PD-associated psychosis do not substantively change the management approach (with some caveats) [119].

Risk factors for PD-associated psychosis include cognitive impairment, dementia, advanced age, sleep disturbances, and disease duration/severity [121]. Psychosis is unrelated to total dose or duration of dopaminergic medication, and no differences have been found in the incidence rate among patients receiving levodopa versus those on dopamine agonists or anticholinergic drugs [122].

The association between sleep disturbance and PD psychosis is sufficiently robust to suggest REM sleep behavior disorder manifests from an evolving synucleinopathy in patients with PD-associated psychosis or dementia. Both factors may develop from a single epiphenomenon, such as neurodegeneration. Evidence also suggests contribution to PD psychosis from non-dopaminergic neurotransmitters, including serotoninergic or cholinergic systems [119].

Visual hallucinations require medication adjustment and possibly specific therapies if they are troublesome, threatening, or associated with behavioral change [4]. Triggering factors, such as infection, metabolic disorders, fluid/electrolyte imbalance, and sleep disorder, should be controlled. In addition, steps should be taken to reduce polypharmacy. Tricyclic antidepressants and anxiolytics/sedatives should be reduced or stopped. Antiparkinsonism drugs should also be reassessed. Anticholinergics and amantadine should be halted, while dopamine agonists and MAO-B and COMT inhibitors should be reduced or halted. The levodopa dose may be reduced [74,123].

Unfortunately, most commonly used antipsychotic drugs have side effects that exacerbate PD. Consequently, atypical antipsychotics are often key in the management of PD-associated psychosis. Almost all antipsychotic drugs can exacerbate PD. Clozapine is the only antipsychotic with high-level evidence of efficacy; in some patients, it also improves motor function [124]. Clozapine is widely recommended as the first-line choice, but it is associated with potentially fatal agranulocytosis, which develops in 1% of patients and makes routine blood neutrophil counts mandatory. Less serious side effects include sedation, tachycardia, orthostatic hypotension, and sialorrhea. Low-dose clozapine (less than 50 mg) also has efficacy, with less frequent and more tolerable side effects and rare agranulocytosis [125,126].

The AAN states quetiapine can be considered in the treatment of PD-associated psychosis [76]. However, some studies have found quetiapine no better than placebo in antipsychotic effect in this group of patients [127,128]. Despite clozapine superiority, quetiapine is the most frequently used antipsychotic for PD-associated psychosis in the United States, due to better safety and despite inconsistent antipsychotic benefit [75,119].

First-generation antipsychotics (e.g., haloperidol) should not be used. This drug class is a common cause of drug-induced parkinsonism, shows little to no psychotic symptom relief, and can worsen motor symptoms [119]. Other atypical antipsychotic agents (e.g., olanzapine, risperidone) can worsen parkinsonism and should not be used [75]. The FDA requires all atypical antipsychotics to carry black box warnings for increased risk of death in elderly patients with dementia [119].

Adding a cholinesterase inhibitor (e.g., rivastigmine, donepezil) is an option [74]. In patients requiring sedation for severe agitation, non-neuroleptics such as lorazepam should be considered over standard agents like haloperidol [75,76].

Pimavanserin is an investigational drug with a novel mechanism of antipsychotic action as a selective serotonin 5-HT2A receptor inverse agonist. The activity of this drug does not block dopamine receptors and does not adversely affect PD. In clinical trials for the treatment of PD-associated psychosis, pimavanserin has shown efficacy and tolerability, including significant improvements in positive symptoms of psychoses, caregiver burden, and overall clinical improvement without worsening of motor function. No safety signals have emerged [95,129].

Dementia

Dementia is the progressive decline in cognitive function (i.e., thinking, planning, organizing, problem solving) beyond what might be expected from normal aging. The dementia of PD takes two forms: an early, more rapidly progressive dementia characterized pathologically by an abundance of Lewy bodies within the brain (i.e., dementia with Lewy bodies), and a later onset, less rapid form characterized by neurodegenerative change and fewer Lewy bodies (i.e., PD dementia) [8]. The cognitive signs of dementia with Lewy bodies begin within one year of motor symptom onset, while the cognitive problems associated with PD dementia begin one or more years after motor symptom onset.

Dementia affects a substantial portion of people with PD and has virtually no effective treatment [8]. Cognitive impairment, autonomic dysfunction, and falls are all features of PD dementia that substantially affect function and quality of life and incompletely respond to medication manipulation [4].

In patients with typical PD dementia, there is an initial rapid loss of midbrain dopamine neurons followed by slow progression of Lewy body infiltration into the brain over decades. Dementia manifests later when Lewy bodies invade the neocortex. Patients diagnosed with PD after 70 years of age develop dementia earlier in the disease, show more alpha-synuclein-containing Lewy bodies throughout the brain, and often have additional age-related plaque pathology. In contrast, dementia with Lewy bodies occurs with PD diagnosed at a younger age, is more rapidly progressive, and shows substantial amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that age at symptom onset and the extent and type of age-related, Alzheimer-type pathology influence pathologic progression in PD [8].

Management involves discontinuation of potential aggravators, including anticholinergics, amantadine, tricyclic antidepressants, tolterodine, oxybutynin, and benzodiazepines [74,123]. A cholinesterase inhibitor, such as rivastigmine, donepezil, or galantamine, should be initiated. With idiosyncratic clinical response or side effects, an alternate agent may be tried. If cholinesterase inhibitors lack tolerability or efficacy, memantine should be added or substituted.

Depression

As many as 90% of patients with PD experience depression, which can appear in early and advanced disease. This neuropsychiatric problem has a major impact on both patients' and caregivers' quality of life. With many overlapping features between depression and PD before and during dopaminergic treatment (e.g., loss of facial expression, hypophonic speech, slowed movement, reduced appetite, sleep disorders), depression in PD often goes on unrecognized [89,130].

Tricyclic antidepressants may be the best choice for depression treatment in PD, followed by selective serotonin or norepinephrine reuptake inhibitors (SSRIs/SNRIs) or dopaminergic agonist therapy. Cognitive-behavioral therapy also appears promising. Most PD experts use an SSRI, SNRI, or tricyclic antidepressant and follow the patient closely for four to six weeks, adjusting as needed [95,131].

The potential of antidepressants to worsen PD motor symptoms has been debated, but studies show no significant increase in risk of motor deterioration. A review of tricyclic antidepressant and SSRI/SNRI treatment of depression in PD concluded possible efficacy in reducing levodopa-induced dyskinesia [132]. There is a minor risk of impairing levodopa motor control, but this finding is inconsistent. The effect is usually minor when it happens and can be resolved by increasing levodopa dose [132]. Nortriptyline has no effect on dyskinesia or motor symptoms.

Tricyclic antidepressants and SSRIs/SNRIs are probably effective for depression [132]. The strongest evidence is for nortriptyline and paroxetine. SSRIs may not be the preferred drug class when rapid effect is needed, and quicker onset of therapeutic benefit is achieved with noradrenergic antidepressants. Tricyclic antidepressants and SSRIs/SNRIs are also beneficial in treating anxiety in patients with PD.

In other drug classes, the dopamine agonist pramipexole (up to 1 mg three times per day) significantly improved depression compared to placebo, an effect unrelated to motor improvement [95,131]. Depression symptoms confined to "off" time may respond well to any treatment that reduces motor fluctuations and improves "on" time. Electroconvulsive therapy remains a potentially lifesaving treatment in major depression and has been used successfully in PD, but sufficient trials in PD depression do not exist [95,131].

Apathy

Apathy in non-demented and non-depressed patients with PD is not associated with dopamine transporter activity in the striatal sub-regions. It is more likely the result of extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits [133].

No established treatment for apathy is available. Levodopa, selegiline, and antidepressants have been suggested as useful. In a small clinical trial, rivastigmine 9.5 mg/day transdermal significantly improved apathy symptoms beyond placebo response. There was also improvement in activities of daily living and caregiver burden, but not quality of life. Methylphenidate is probably effective in treating apathy and fatigue in later PD [132]. There is a lack of literature on the subject, many experts use a dopamine agonist for severe apathy, but with caution for impulsive behaviors [95,134].

Impulse Control Disorders

Impulse control disorders and aberrant behaviors can develop during dopamine agonist treatment in PD and worsen patient and caregiver quality of life. Often, patients lack insight into the negative consequences of their behavior. Risk factors include male sex, younger age at onset, personality traits of high impulsivity and novelty seeking, and personal or family history of addictive disorders. In predisposed patients, overstimulation of mesocorticolimbic dopamine receptors by dopamine agonists leads to impulse control disorders and compulsive medication use. Impulse control disorders are more likely in early PD with normal-range medication dosing, while compulsive medication use is more commonly associated with fluctuations in advanced disease. Affected patients often lack noteworthy psychiatric histories and cognitive impairment, making identification difficult. Management requires reducing dopaminergic therapy, and psychosocial support is often necessary. SSRIs may help, while atypical antipsychotics have limited benefit. Prevention is based on the identification of at-risk individuals and active monitoring [135].

In a study of 203 patients with PD, the most common impulse control disorders were compulsive eating (14%), hypersexuality (10%), compulsive shopping (6%), and pathologic gambling (3%). Age younger than 68 years and exposure to dopamine agonists or MAO-B inhibitors were identified as risk factors for developing disorders of impulse control. Affected patients on dopamine agonists received a daily dose 60% higher than those without the disorders. Impulse control disorder symptoms showed a nonlinear dose-response relationship with dopamine agonists [136].

Constipation

In patients with PD, constipation may develop due to impaired gastrointestinal motility and medication side effects. Treatment is often behavioral, with a focus on increasing fluid ingestion, fiber intake, and physical activity. If additional treatment is necessary, polyethylene glycol solution, fiber supplements (e.g., psyllium, methylcellulose), and/or osmotic laxatives are recommended. Short-term irritant laxatives may help in selected patients [74,123].

Dysphagia

Management of dysphagia requires optimization of motor control approaches. Speech therapy is indicated for assessment, swallowing advice, and further investigations, if needed. Videofluoroscopy may be conducted in selected cases to exclude silent aspiration. In severe cases, enteral feeding options (e.g., short-term nasogastric tube, percutaneous endoscopic gastrostomy) may be considered [74,123].

Orthostatic Hypotension

Orthostatic hypotension is a symptomatic drop of 20 mm Hg systolic or 10 mm Hg diastolic blood pressure when rising to standing from sitting or lying down. Orthostatic hypotension is associated with lightheadedness, syncope, or nonspecific complaints including fatigue, unsteadiness, headache, neck tightness, or cognitive slowing. Because supine hypertension often accompanies orthostatic hypotension, the first step of treatment should be non-pharmacologic to avoid worsening supine hypertension. Patients should avoid, reduce, or eliminate large meals, alcohol, warm environments, volume depletion, diuretics, antihypertensive drugs, tricyclic antidepressants, nitrates, dopaminergic drugs (if possible), and alpha-blockers used for benign prostatic hypertrophy. Increasing salt intake may also help. Tilting the head of bed at night (30° to 40°) is recommended, as is exercise, as tolerated. Waist-high elastic stockings, abdominal compression bands, and counter-maneuvers (e.g., leg crossing, toe raising, thigh contraction) are effective prevention measures.

Midodrine has the greatest level of evidence in terms of pharmacotherapy. Fludrocortisone is also possibly effective, but it is important to monitor for side effects [74,95,123].

Urinary Dysfunction

Urinary incontinence in patients with PD is thought to result from hyper-reflexia caused by basal ganglia dysfunction. When symptoms appear suddenly, it is important to rule out urinary tract infection. If incontinence occurs mainly at night, fluid intake should be reduced after 6 p.m. and the head of the bed should be tilted up for sleep.

Night-time dopaminergic therapy should be optimized, and if necessary, an anticholinergic drug may be added. Guidelines recommend trospium chloride (10–20 mg two to three times per day) or tolterodine (2 mg twice per day) [74,123]. However, trospium is less able to penetrate the blood-brain barrier, and cognition may worsen. Botulinum toxin type A injected in the detrusor muscle is also an option [74,123].

Sexual Dysfunction

Sexual dysfunction is common in men and women with PD and is a complex problem from diverse etiologies, including motor dysfunction, medication side effects, mood disorders, and autonomic dysfunction manifesting in erectile dysfunction, reduced genital sensitivity and lubrication, and difficulty reaching orgasm [123].

Erectile dysfunction is widespread in PD and affects at least 50% to 75% of men with PD. Good evidence supports the use of sildenafil citrate, and similar drug class members, such as tadalafil and vardenafil, are also likely to be effective [89].

Excessive Sleepiness

Excessive daytime somnolence and sudden sleep onset can originate from the disease process, medications, or other sleep disorders. Excessive daytime somnolence can result from dopaminergic medications—more commonly dopamine agonists than levodopa. Patients with these symptoms should be assessed for nocturnal sleep disturbances. Nocturnal sleep may be improved by reducing akinesia, tremor, and urinary frequency.

Sedative drugs should be reduced or discontinued. All dopaminergic drugs may induce daytime somnolence, so the dose of the current dopamine agonist may be reduced or the patient may switch to another dopamine agonist. Modafinil and/or other wake-promoting agents (e.g., methylphenidate) should be added [74,123]. Patients with excessive daytime somnolence should be advised to stop driving.

Restless Legs Syndrome

Restless legs syndrome (RLS) is a movement disorder of the limbs whereby patients have a bothersome, irresistible urge to move the legs. RLS often interferes with sleep, leading to chronic sleep deprivation and stress. The prevalence of RLS was 12% in one study of patients with PD [137]. Drugs considered the most efficacious for RLS include levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin; second-line options include rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine [138].

Insomnia

Insomnia in PD may be the result of mood disturbances, persistent tremor, night-time re-emergence of PD symptoms, nocturia, and reversal of sleep patterns [123]. Levodopa/carbidopa may contribute to insomnia while improving sleep-related motor symptoms. Melatonin may be effective in improving patients' perception of sleep quality [123].

REM Sleep Behavior Disorder

As discussed, REM sleep behavior disorder is a type of parasomnia characterized by the behavioral enactment of dreams during REM sleep. REM sleep behavior disorder is one of the most robust predictors of PD development and is very prevalent throughout the motor symptom phase of disease progression. Standard treatment is clonazepam or melatonin [54].

Among non-motor symptoms, 60% to 83% of patients with PD report pain of heterogeneous presentation and disabling effect on quality of life. Pain has received minimal attention in PD due to its association with the reappearance of motor symptoms and dystonic muscle contraction with dissipation of levodopa dose response. Pain also occurs as skeletal-muscle or neuropathic (peripheral or central) pain. Evidence suggests patients with PD have abnormal nociceptive processing in pain-free states, independent of parkinsonism motor symptom presence, that is unaffected by levodopa stimulation. Few therapeutic strategies for pain management in PD have been developed [139,140].

A concern in using opioids to treat pain in patients with PD is potential exacerbation of constipation, a common, burdensome symptom of autonomic dysfunction. To possibly mitigate this issue, an oral formulation combining prolonged-release oxycodone with naloxone has been evaluated. In an eight-week trial, patients with PD-associated chronic pain received low-dose oxycodone/naloxone (5 mg/2.5 mg) twice daily. Of the 87.5% who completed the trial, significant pain reduction was achieved, no adjustment of dopaminergic therapy was required, no significant changes were observed in bowel function and constipation symptoms, no changes were observed in sleep symptoms, and improvements were recorded in clinician impression of therapeutic effect [141].

During end-stage PD, the focus of care is on palliation of symptoms and comfort. Patients with end-stage PD often exhibit cognitive impairment and progress to the point of requiring assistance with most activities. The best approach for patients with PD at the end of life is multidisciplinary palliative care with adequate physical, psychologic, and spiritual support. In earlier stages, the goal is to maintain patient independence for as long as possible; however, in end-stage PD, the focus is mainly on comfort and supportive care [149].

Non-motor symptoms such as depression, psychosis, urologic dysfunction, pain, and respiratory depression, become more common in end-stage PD. Over time, these symptoms may become the most prominent medical problem, leading to increasing decline in quality of life [149]. The first step in managing these symptoms may be reduction or discontinuing triggering pharmacotherapeutic agents, such as anticholinergics, MAO-B inhibitors, and opioids.

In the last days, the goals of the healthcare team are to ensure a peaceful death for the patient and to support the family during the dying process and throughout grief and mourning. The focus for the patient is management of symptoms and emotional and spiritual ease, and the focus for the family is education to prepare them for the dying process.

When capable of doing so, persons with PD should be encouraged to maintain a regular program of stretching and other physical exercise. In a randomized, controlled trial, tai chi training was seen to be more effective than resistance training or stretching in reducing balance impairments and falls in patients with mild-to-moderate PD [153]. The American Parkinson Disease Association has developed a free, web-based training program designed to teach fitness professionals how to best meet the unique needs of persons with PD [154]. Cognitive training is likely helpful for other patients. Patient and family member education is a key component of PD management, as is the use of support groups [93].

Many patients with PD require hospital admission for problems unrelated to motor pathology. Their medical care is typically received on non-neurology wards from staff unfamiliar with PD management, increasing the risk of inappropriate medications that exacerbate PD. Among inpatients with PD, 43.8% received inappropriate anti-dopaminergic medication at some point, primarily haloperidol and metoclopramide. The highest prevalence occurred in patients with PD on chronic antipsychotics [75].

Nausea and vomiting, common adverse effects of levodopa and dopamine agonists, may require antiemetic use. The centrally acting dopamine antagonists metoclopramide and prochlorperazine should not be used; the peripheral dopamine antagonist domperidone is the antiemetic of choice. The serotonin receptor antagonist ondansetron is another option [74,75].

Healthcare professional education is suggested to improve the care of inpatients with PD. Pharmacists can play a key role in identifying inappropriate medications and in educating non-PD specialist professionals [75].

With disease progression, patients with PD become more reliant on medication to maintain their ability to function. In addition to regular monitoring for drug-specific side effects, clinicians should be careful not to abruptly withdraw dopaminergic medication [89]. Patients and family should be educated on the importance of medication compliance and regular dosing so as to avoid rapid changes in efficacy. Special attention is required during periods of intercurrent illness, such as gastroenteritis or abdominal surgery, which may result in interruption of dosage or poor intestinal absorption. These measures help to avoid the potential development of acute akinesia or neuroleptic malignant syndrome. "Drug holidays" are not recommended due to the risk of developing neuroleptic malignant syndrome.

Considering the risks of sudden changes in dopaminergic medication, patients with PD admitted to hospitals or care facilities should receive their medication at the appropriate times or be allowed self-medication. Medication adjustment should be reserved for specialists in PD management [89].

In managing newly diagnosed patients, healthcare professionals should exhibit great sensitivity and understanding in describing disease symptoms and progression. As it progresses, PD complicates every aspect of daily living. Formerly routine tasks demand full attention and often cause frustration and anxiety. Over time, PD reduces work capacity, erodes earning potential, and may compromise social and family relationships. Disease progression leads to increased dependency and fosters feelings of being a burden to others. Increasing difficulties with writing and speaking, coupled with the loss of independence, often lead to social withdrawal, isolation, depression, frustration, and anger. Access to primary care, speech therapists, exercise programs, and emotional support is critical to managing the disease and living with dignity, and people living with PD require understanding and support as they struggle to maintain independence and adapt to living with a chronic condition [89].

Good communication is the foundation of care between patients with PD, their caregivers, and health professionals. Healthcare professionals' commitment to clear, compassionate communication can make a meaningful difference to their patients. When patients with PD understand healthcare professionals' recommendations, they can know what to expect and are better prepared to navigate the system, ask the right questions, and make the best personal choices [89].

Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. According to the U.S. Census Bureau, more than 31 million Americans speak a language other than English in the home, with approximately 9.4 million of them (11.7% of the population) speaking English less than "very well" [144]. It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" [145]. In addition, patients should also be asked what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English [145]. Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [146,147].

"Ad hoc" interpreters (untrained staff members, family members, friends) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, the reliability and specificity of information obtained through ad hoc interpreters is less than with professional interpreters [148]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [70]. A systematic review of the literature has shown that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters [147].

Care decisions should be based upon best available evidence and provided by applicable professional standards. Issues to consider when communicating with people with PD and their caregivers include [89]:

Traditionally, management of PD has focused on drug treatment and interdisciplinary care for a long-term, slowly progressive disorder. Palliative care specialists have not routinely been involved. Due to the long duration of the disease and the difficulty in predicting the time of death, patients with PD are frequently refused access to hospice and palliative care services [89].