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Supplements The Case for Early Initiation of Monotherapies and Delayed Dopaminergic Therapy in Parkinson's Disea

The Impact and Management of Nonmotor Symptoms of Parkinson's Disease

Kelly E. Lyons, PhD and Rajesh Pahwa, MD
Hallucinations, which are most commonly visual, and psychosis occur in 25% to 30% of patients with PD, and may be related directly to the disease or to anti-PD medications. 11,22,23 It is important to initially assess the patient for other potential causes of hallucinations such as urinary tract or other infections and dehydration, as well as non-PD medications known to cause neuropsychiatric symptoms, such as psychotropics and anticholinergics. Anticholinergic agents, amantadine, dopamine agonists, and COMT inhibitors may worsen hallucinations, and if there are no obvious causes for the psychotic symptoms, these medications should be reduced or eliminated if possible.11,23 The atypical antipsychotics clozapine and quetiapine are preferred for use in PD due to their predominant affinity for D1, D4, and serotonergic receptors, with low affinity for D2 receptors.10,23 Despite promising results from open-label studies, a systemic review of randomized controlled trials involving quetiapine demonstrated disappointing results.24,25 In practice, however, clinicians still prefer quetiapine, since it does not appear to worsen motor function and has a favorable safety profile compared with clozapine, which is associated with agranulocytosis and requires monitoring.24,25 Other atypical antipsychotic agents as well as the typical antipsychotics such as haloperidol and similar medications should be avoided due to worsening of motor function.10 Finally, in some cases, cholinesterase inhibitors or antidepressants may be beneficial.

Impulse control disorders (ICDs) occur in up to 17% of patients with PD,26 especially in those taking dopamine agonists. ICDs include a group of disorders resulting from a failure to resist an urge, drive, or temptation to perform an act considered to be harmful to the patient or others. Hypersexuality, compulsive buying, binge eating, pathological gambling, and punding (a complex behavior involving repetitive meaningless activities) have all been reported.21 Pathological gambling, which occurs in up to 6% of patients with PD, is the most well-studied form of ICD.25 Indirect evidence suggests that pathological gambling is more common with dopamine agonists than with levodopa.27 Gambling, which usually occurs in patients who have not previously had a gambling problem, appears within a few months of initiating therapy, and may occur at any dose of dopamine agonists, but is more likely at higher doses.27 When ICDs are present, dose reduction or discontinuation of the dopamine agonist may be required; however, with a dose reduction or discontinuation of the dopamine agonist, a dose increase or initiation of levodopa or another PD medication may be necessary to treat motor symptoms.22,27 In 1 study, dopamine agonists were significantly reduced or discontinued in 15 patients with PD who experienced ICDs; an MAO-B inhibitor was added, and 84% of patients reported a reduction or complete resolution of the ICD.28 In some cases, a TCA or norepinephrine reuptake inhibitor (eg, mirtazapine, venlafaxine) may be required when mood changes occur.23

Cognitive Impairment

According to a systematic literature review published by the Movement Disorder Society, mild cognitive impairment is present in 19% to 38% of patients with PD who do not have dementia.29 It is estimated that dementia will eventually develop in 75% of patients within about 10 years. Cognitive deficits appear to be more prevalent in executive functions (eg, information processing speed, impaired planning, working memory) than in episodic memory storage and language. Visuospatial and attentional deficits have also been associated with PD.29 As in other forms of dementia, even mild cognitive defects in PD are associated with poor QOL.5 Furthermore, there is a strong relationship between PD-related cognitive impairment and neuropsychiatric issues such as depression, hallucinations, and psychosis.

Treatment of cognitive dysfunction generally begins with an evaluation to rule out other potential causes of cognitive impairment or confusion including depression, infection, dehydration, and sleep disturbances. All medications should be reviewed and non-PD medications known to cause cognitive disturbances should be reduced or eliminated if possible. PD medications may actually worsen cognitive function, so it is important to tailor therapy to achieve motor control while minimizing cognitive decline.10 Therefore, if no other potential causes of cognitive impairment are present, PD medications should be slowly reduced and eliminated in the following order: anticholinergics, amantadine, dopamine agonists, COMT inhibitors, and finally, MAO-B inhibitors. Cholinesterase inhibitors as well as memantine may provide improvement in cognitive function in patients with PD.

In a 2008 Cochrane review evaluating randomized, double- blind, placebo-controlled trials of cholinesterase inhibitors (ie, tacrine, donepezil, galantamine, rivastigmine) in PD dementia, 1 study of rivastigmine was identified for inclusion. The study included 541 patients, and the main outcome measure, the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog), improved by 2.5 points relative to placebo. Rivastigmine is the only cholinesterase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of cognitive dysfunction in PD. However, in the trial, rivastigmine was associated with a 3.25-fold increase in nausea, 2.8-fold increase in tremor, and 11.66-fold increase in vomiting.30 A smaller study evaluated donepezil and noted improvement in memory; however, 4 of the 7 patients treated with donepezil (57%) withdrew due to adverse effects.31 Adverse effects of cholinesterase inhibitors, such as diplopia, constipation, nausea, urinary frequency, increased tremor, gait impairment, and falls, appear to be due to peripheral cholinergic effects.31 In a meta-analysis of 54 randomized controlled trials of cholinesterase inhibitors and memantine, cholinesterase inhibitors were associated with a greater risk of syncope than placebo, but not falls, fracture, or accidental injury. In contrast, memantine was associated with fewer fractures, without effect on other events.32 A recent study of more than 13,000 participants documented that medications with definite or possible anticholinergic properties were associated with greater cognitive decline and mortality, after adjusting for sex, education level, social class, number of nonanticholinergic medications, number of comorbid conditions, and cognitive performance at baseline.33 These results suggest that cholinesterase inhibitors may be associated with improved cognition; however, anticholinergic medications are associated with cognition impairment and are rarely used in the treatment of PD.

Autonomic Dysfunction

Autonomic symptoms include gastrointestinal dysfunction such as drooling, dysphagia, nausea, constipation, urinary dysfunction, orthostatic hypotension, sexual dysfunction, and thermodysregulation.9 A recent cross-sectional study reported that drooling was among the most important determinants of HRQOL in patients with PD.34 Drooling, also known as sialorrhea, is a symptom of PD observed in a majority of patients and is a byproduct of dysphagia, rather than an overproduction of saliva.35 The forward head posture and open mouth often observed in more advanced PD also contribute to drooling. Speech and swallowing therapy can be beneficial in helping to improve posture and teach good swallowing techniques. Chewing gum or sucking on hard candy can increase swallowing and consequently reduce drooling. If drooling occurs primarily during the medication “off” state, increasing PD medications can be beneficial. Traditionally, anticholinergic agents or antihistamines have been used; however, their effectiveness is uncertain. A study of botulinum toxin B for sialorrhea demonstrated effectiveness in reducing drooling severity and frequency, without worsening dysphagia, although dry mouth and gait disturbances were noted.35 Dysphagia is linked to aspiration, malnutrition, weight loss, and dehydration, and thus may increase the risk of mortality.10

Other frequently experienced gastrointestinal complications include nausea and constipation.22 Nausea and vomiting may be related to dopaminergic therapy. If nausea results from impaired gastric motility, then levodopa absorption is likely to be impaired. Since levodopa is absorbed in the intestines, a prokinetic agent (eg, domperidone; although not currently available in the United States) or addition of carbidopa will improve nausea and levodopa absorption.8 Nausea may also be minimized by slow dose titration when initiating a new dopaminergic medication. In some cases, PD medications may need to be reduced, particularly dopamine agonists. It is important to note that dopamine antagonists such as metoclopramide and prochlorperazine should not be used, as they can worsen PD symptoms. Constipation, which is experienced by up to 60% of patients, may also result from impaired gastrointestinal motility or dehydration, and may be treated with standard therapies. The most common therapies include increased dietary fiber and fluid intake, increased exercise, and laxatives or stool softeners, if needed.10,22

Nocturia is often the initial urinary problem, and is a common complaint, occurring in over 60% of patients with PD. Patients should be advised to eliminate liquids in the evening. Urinary urgency, frequency, and incontinence become more common as the disease progresses. The most common reason for urinary frequency and urgency is detrusor overactivity.36 When urinary problems are reported, it is important to rule out urinary tract infections and prostate issues. If they occur primarily during the “off” state it may be beneficial to adjust PD medications to reduce “off” time. Anticholinergic agents (eg, tolterodine, trospium chloride, oxybutynin) may be beneficial.36

The most common cardiovascular feature of PD is orthostatic hypotension, a drop in systolic blood pressure of at least 20 mm Hg and diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing up. Orthostatic hypotension is most common in more advanced disease. Symptomatic orthostatic hypotension presents with dizziness, lightheadedness, cloudy thinking, generalized weakness, or syncope.37 Adequate hydration is mandatory; an intake of at least 2 liters of water and 8 grams of salt daily should be ensured.10 Waist-high support hose and elevation of the head of the bed can be helpful. If orthostasis becomes problematic, antihypertensive therapy and diuretics should be limited or eliminated if possible. The mineralocorticoid fludrocortisone or the alpha-adrenergic agent midodrine may be used if orthostatic hypertension is severe. If response to treatment is poor, a reduction in dopaminergic medications may be warranted.7,22 Amantadine should also be avoided to limit the risk of orthostatic hypotension.7 In addition, a recent study, which evaluated the effect of carbidopa/levodopa with or without entacapone, demonstrated an increased risk of myocardial infarction with entacapone, suggesting the potential for an increased risk of cardiovascular events in patients taking COMT inhibitors.38

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