Redefining Treatment Success in Patients With Parkinson’s Disease
INTRODUCTION
Parkinson’s disease (PD) is a chronic, progressive, neurologic disorder characterized pathologically by the degeneration of dopaminergic neurons in the substantia nigra and the subsequent depletion of striatal dopamine.1,2 The disease is named for the English physician James Parkinson who first described it in An Essay on the Shaking Palsy in 1817.3 Hallmark clinical motor features of PD include tremor at rest, bradykinesia, rigidity, freezing, flexed posture, and postural instability (Table 1).1,2,4-6 Rest tremor is a common early symptom that occurs in approximately 70% of patients with PD and typically diminishes with action and during sleep.2,6 Bradykinesia, one of the most disabling manifestations of PD, is characterized by slowness of movement that causes prolonged reaction times and difficulty executing simultaneous tasks.4 Muscular rigidity is resistance to movement when a joint is passively flexed and extended and is frequently associated with pain (eg, frozen shoulder).2,5 Postural instability (ie, loss of balance when standing) often occurs in later stages of PD as the result of loss of postural reflexes and, along with freezing of gait, is the most frequent cause of falls and hip fractures in patients with PD.2,7 As no definitive diagnostic test exists for PD, the presence of 2 clinical features, with at least 1 being tremor at rest or bradykinesia, is needed to confirm a diagnosis of PD.1,2 However, the clinical course of PD is not limited to motor symptoms, as patients can exhibit a variety of nonmotor features that substantially lessen their health-related quality of life (HRQOL), including depression, anxiety, dementia, sleep abnormalities, constipation, orthostatic hypotension, anosmia, fatigue, and weight loss (Table 1).1,2,8
Table 1. Clinical Motor and Nonmotor Features of PD
| Motor Features | Nonmotor features |
|---|---|
| Resting tremor 1,2,6 • 70% of patients • Often manifests as supination-pronation tremor in hands (ie, “pill-rolling”) • Can also involve lips, chin, jaw, and legs Bradykinesia1,2,4,9 • 80% to 90% of patients • Slowness of movement • Most disabling symptom of PD Rigidity1,2,9 • >90% of patients • Resistance to passive movement of flexor and extensor muscles • Characterized as “cogwheel” (resistance fluctuates in intensity usually due to superimposed tremor) or “lead pipe” (continuous resistance) Postural instability2 • Usually last symptom to occur • Indicative of progression to advanced stages of disease • Frequent cause of falls and injuries | Psychiatric disorders8 • Depression in up to 40% of patients • Anxiety in ~30% of patients Cognitive disorders1,8 • Mild cognitive impairment (bradyphenia) • Dementia in 15% to 40% of patients Sleep abnormalities2,8,9 • Insomnia • Affects >70% of patients • Daytime somnolence • REM sleep behavior disorder Autonomic dysfunction1,2,8,9 • Dysphagia and choking • Hypersalivation • Impaired gastrointestinal motility • Constipation • Orthostatic hypotension Sensory2 • Olfactory dysfunction (ie, anosmia) • Pain Miscellaneous1,8 • Fatigue • Weight loss |
PD, Parkinson’s disease; REM, rapid eye movement.
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease, and with the aging of the population, the global burden of PD continues to increase.1 Estimating the prevalence of PD is challenging due to varied health-service access for diagnosis and because other forms of parkinsonism (eg, drug-induced parkinsonism, vascular parkinsonism, multiple-systems atrophy) are frequently misdiagnosed as PD.2 One systematic review estimated that the prevalence of PD in 2005 was 4.1 million worldwide and 340,000 in the United States for individuals older than 50 years (Figure 1).10 Current estimates of the direct and indirect costs associated with PD exceed $20 billion annually in the United States.11 Due mainly to the aging population, the number of PD cases is predicted to reach 8.7 million worldwide and 610,000 in the United States by the year 2030.10 However, because the clinical presentation of PD varies among patients and can be easily misdiagnosed in the initial stages, it is not uncommon for PD symptoms to go unrecognized for years by patients and their physicians.9,10 Thus, identifying patients with PD and providing affordable, effective treatment continues to be a substantial worldwide public health challenge.
Figure 1. Age-specific prevalence estimates of PD worldwide. The number of individuals >50 years of age with PD was estimated to be 4.1 million in 2005 and projected to double to 8.7 million in 2030. PD, Parkinson’s disease.10
The primary goal of therapy for PD is control of neurologic symptoms.11 Dopamine replacement therapy with levodopa remains the most effective choice for managing symptoms of PD but is associated with motor complications that often overshadow the clinical benefits of therapy.11,12 It is unclear whether levodopa modifies disease progression.13,14 Pharmacologic therapy with dopamine agonists (eg, ropinirole, pramipexole, rotigotine) and monoamine oxidase-B (MAO-B) inhibitors (eg, rasagiline, selegiline) has demonstrated efficacy in improving disease symptoms and delaying the need for levodopa therapy.11,12,15,16 While the majority of clinical studies have assessed motor endpoints, additional measures to define treatment success should be considered, with the goals being to slow progression of physical disability and improve patient quality of life. As disease symptoms are highly variable, optimal management of PD should involve individualized therapy customized to the specific needs of the patient.12,13
Patients with PD experience substantial disability, poor HRQOL, and higher risk of early death compared with the general population.8,9,17 In clinical studies, HRQOL has been shown to be affected by nonmotor symptoms as much as or more than by motor symptoms.17,18 A survey of 99 patients with PD employed validated questionnaires to evaluate the presence of nonmotor symptoms and reported that 88% of patients had 1 or more nonmotor symptoms, with 34% having 4 or more nonmotor symptoms during the course of their disease.19 Increased comorbidity of nonmotor symptoms was associated with worsened severity of PD. Additionally, a large patient survey demonstrated a greater impact of psychiatric symptoms on HRQOL in the early-to-middle stages of PD compared with later stages of the disease.20 Thus, early diagnosis of PD is crucial for long-term treatment success, as diagnosis in the initial stages of PD provides the opportunity to treat the early, subtle nonmotor symptoms and administer disease-modifying therapies that may potentially slow the rate of disease progression.21 The objective of this chapter is to give healthcare providers the information needed to develop and implement an appropriate individualized treatment strategy for patients with PD.
