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
Parkinson’s disease (PD) is a common neurodegenerative disorder diagnosed by the presence of bradykinesia and at least 1 of the symptoms of rigidity, resting tremor, or postural instability. It is increasingly recognized that nonmotor symptoms are common and can adversely affect quality of life, yet they often are not diagnosed and consequently are often untreated. Nonmotor symptoms include neuropsychiatric issues such as anxiety, depression, hallucinations, impulse control disorders, and cognitive impairment, as well as autonomic dysfunction, which may present as gastrointestinal, urinary, and sexual disturbances. Nonmotor symptoms also include excessive sweating, orthostatic hypotension, and sleep disturbances. Management of PD requires recognition of both motor and nonmotor symptoms as well as an understanding of the relationship between these symptoms and how they can be affected by treatments for PD. Therapy should be individualized for each patient, as treatments for the motor symptoms of PD can improve some nonmotor symptoms while they can worsen others. In many cases, symptom-specific treatments are necessary to control nonmotor symptoms of PD.
Am J Manag Care. 2011;17:S308-S314
Parkinson’s disease is the second most common neurodegenerative disorder, after Alzheimer’s disease.4 The prevalence of PD is estimated to be 329 per 100,000 people, with an annual incidence ranging from 16 to 19 per 100,000 people.1 The prevalence of PD increases with age, affecting about 1% to 2% of adults 60 years and older, and greater than 4% of adults 80 years and older.5 As the elderly population grows, the incidence is expected to double by 2030 from the current estimates of 1 million patients in the United States and 5 million worldwide.1,4 The annual economic impact of PD in the United States has been estimated at $10.8 billion, of which 58% is direct medical costs.4 The annual direct medical cost per patient with PD is estimated to be between $10,000 and $12,500, more than double that of patients without the disease. Prescription drugs and long-term care account for approximately 14% to 22% and 41% of these costs, respectively. In addition, annual indirect costs, including lost productivity for patients and caregivers, are estimated at $9000 per patient.4
Although motor symptoms are diagnostic for PD, nonmotor symptoms are also prevalent and are often important determinants of quality of life (QOL) in PD.5 Motor and nonmotor symptoms commonly associated with PD are summarized in the Table. The rising incidence of PD resultant from an aging US population will lead to clinicians increasingly encountering PD in their clinical practice. The high costs associated with PD, the expected rise in frequency, and the increasingly recognized importance of associated nonmotor symptoms highlight the necessity for increased understanding of all aspects of the disease and treatment options. As such, this article will provide an overview of the nonmotor symptoms of PD and their treatment options.
Motor symptoms are the hallmark of PD and there are multiple treatment options available. It is important to adequately treat motor symptoms, as many nonmotor symptoms are increased during “off ” periods when PD medications are not controlling symptoms.6 In other cases, PD medications can exacerbate some nonmotor symptoms, particularly neuropsychiatric and cognitive symptoms. Early treatment options include monoamine oxidase type B (MAO-B) inhibitors (rasagiline and selegiline), dopamine agonists (pramipexole and ropinirole), and the mainstay of PD treatment, carbidopa/ levodopa. Less commonly, amantadine is used for mild symptoms; anticholinergics, particularly benztropine and trihexyphenidyl, have limited use due to a poor side effect profile.7 Levodopa is generally used earlier in older patients, as dopamine agonists result in more neuropsychiatric and cognitive side effects, while dopamine agonists are often used in younger patients in an attempt to delay levodopa-induced side effects.7 As symptoms progress, nearly all patients with PD will require levodopa therapy. However, motor complications such as dyskinesia (characterized by abnormal involuntary movements) and motor fluctuations (characterized by wearing-off, on-off, or unpredictable-off effects) are common side effects of levodopa.8 These motor complications occur in up to 90% of patients with PD within 5 to 10 years after the initiation of levodopa.9 Motor fluctuations may be managed by altering the frequency or dosage of levodopa, adding a catechol-O-methyltransferase (COMT) inhibitor (eg, entacapone, tolcapone) to decrease metabolism of levodopa and extend the levodopa effect, adding an MAO-B inhibitor (selegiline, rasagiline), or using a dopamine agonist (pramipexole, ropinirole).10 Other than altering the frequency or dosage of levodopa and other PD medications, amantadine is currently the only pharmacological treatment option that has been shown to reduce dyskinesia.11 In a recent review, complications of levodopa therapy and gait disturbances were the most important motor symptoms affecting QOL in patients with PD.5
Nonmotor symptoms are often not recognized and therefore remain untreated in many patients with PD. In 1 report, patients with PD reported an average of 11 nonmotor symptoms; however, on average, only 5 nonmotor symptoms were recorded in their medical charts.12 A partial list of nonmotor symptoms related to PD is provided in the Table. The American Academy of Neurology has recommended that in addition to the regular assessment of PD motor symptoms, nonmotor symptoms should also be regularly assessed. Specifically, it was recommended that neuropsychiatric and cognitive assessments be performed annually, and that patients also be asked about autonomic and sleep disturbances annually.13 Formal assessment of the nonmotor dimensions of PD can be accomplished clinically with a 30-item scale called the Nonmotor Symptoms Scale (NMSS). The NMSS has 9 dimensions, including cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal tract abnormalities, urinary tract abnormalities, sexual dysfunction, and miscellaneous symptoms.14 The NMSS is a validated tool for rating frequency and severity of nonmotor symptoms in PD.14,15 The Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) has also been validated in PD and includes an assessment of nonmotor symptoms of PD.16 Although nonmotor symptoms of PD may be categorized in many ways, for purposes of this review, nonmotor symptoms will be categorized as follows: neuropsychiatric, cognitive, autonomic, and sleep dysfunction.
Since PD frequently occurs in an older population, the question of whether nonmotor symptoms of PD differ from normal aging has been raised. A recent case-control study addressed this issue by studying 174 patients with PD and 128 age-matched controls.17 In that study, the frequency of nonmotor symptoms and the NMSS scores were significantly greater among patients with PD in all domains, including cardiovascular disease, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal tract abnormalities, urinary tract abnormalities, urinary dysfunction, sexual dysfunction, and miscellaneous symptoms. Additionally, the group of patients with PD demonstrated no effect of age and minimal effect of sex on nonmotor symptoms, while in controls, symptoms increased with age, and sex failed to demonstrate an effect. These results suggest that nonmotor symptoms of PD are disease-specific and not purely a result of normal aging.1,7,17 In addition, nonmotor symptoms significantly impact QOL.5,12
Depression can occur in up to 80% of patients with PD and, according to a recent systematic review, is the most consistently identified determinant of adverse health-related quality of life (HRQOL) in patients with PD.5,18 The review of included studies determined that depression was a significant predictor of QOL.5 Depression is often untreated, as symptoms can be mistaken for symptoms of PD such as loss of appetite, lack of motivation, slowed movement, slowed thinking or confusion, and sleep disturbances.9 It is important to also interview the family/caregiver, as patients often do not recognize that they are depressed. Counseling or other forms of psychotherapy can be helpful but it is generally believed that depression is both psychological and organic in PD; therefore, treatment with medication is often required.9 Depression can be worsened during “off” time, so it is important to make sure that PD symptoms are well controlled. Early randomized studies of antidepressants for the treatment of depression in PD included the tricyclic antidepressants (TCAs) amitriptyline and nortriptyline, and the selective serotonin reuptake inhibitors (SSRIs) citalopram and fluvoxamine. A Cochrane review summarized these randomized studies, and found insufficient data to determine efficacy and safety of these antidepressants.19 Adverse effects were minimal in the trials; however, visual hallucinations and confusion were noted.19 These are currently the most common treatments for depression in PD; however, in some cases other antidepressants such as bupropion, mirtazapine, and venlafaxine (recently evaluated in the Study of Antidepressants in Parkinson’s Disease [SAD-PD] trial,20 sponsored by the National Institute of Neurological Disorders and Stroke) can be beneficial. Finally, studies have shown that the dopamine agonist pramipexole may also improve depression in some patients.21
In a systematic review of HRQOL in PD, anxiety and fatigue predicted adverse QOL in 83% and 80% of studies, respectively.5 Anxiety often occurs in combination with depression and can manifest as excessive nervousness or worrying, generalized anxiety disorder, panic attacks, or obsessive compulsive disorder. Anxiety can be increased during “off” periods. In 1 study, 66% of patients with PD experienced anxiety and 88% of the time the anxiety occurred during a medication “off” period.6 Optimizing dopaminergic therapy to limit “off” time may be beneficial, but the use of benzodiazepines in low doses or SSRIs may also be helpful.10 Benzodiazepines may cause fatigue or drowsiness, especially in higher doses.