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Parkinson disease (PD) is the most common primary or idiopathic form of Parkinsonism and comprises the majority of cases encountered in clinic. It is the second most common neurodegenerative disorder after Alzheimer disease, with a prevalence of 1–2% in adults over age 65 [1]. PD is heterogeneous in terms of its presentation and clinical course, but overall the natural history is characterized by gradual decline and growing disability. Despite great advances in medical and surgical treatments which restore motor function, PD remains an unremittingly progressive disorder without a cure or proven neuro-protective therapies.

The motor symptoms of PD begin insidiously and commonly go unrecognized by the patient for months to years. Symptoms typically present asymmetrically and eventually affect the other side of the body. Hand tremor is present in 50–70% of patients at presentation and is often what prompts a patient to seek medical attention. The tremor is classically present during rest at a frequency of 4–6 Hz, may re-emerge when the arm is held outstretched, and subsides with active movement of the limb. The tremor may involve the lips, chin and tongue to varying degrees. Sometimes the initial manifestation of PD is a shuffling gait, pain or stiffness (particularly at the shoulder), or slowing of movements known as bradykinesia. Patients with bradykinesia also have a loss of automatic movements. In the extremities, bradykinesia is manifested by decrementing amplitude and velocity when performing repetitive movements. Axial symptoms include hypomimia (masked facies), reduced blinking, dysarthria, hypophonia, dysphagia, difficulty rising from a chair, slowness and shuffling of gait, and reduced arm swing during ambulation. Pain or stiffness may be caused by rigidity, which refers to increased resistance to passive movement of the limb across a joint. In PD, the rigidity is described as “lead pipe” due to the constant nature (not velocity dependent) of the resistance throughout the movement and “cogwheeling” due to the presence of superimposed tremor. Rigidity may be present axially as well, manifesting as stiffness of the neck and a flexed posture.

Balance problems typically begin later in the disease course and result from the loss of postural reflexes. In advanced disease, more disabling gait abnormalities emerge, such as freezing and festination. Gait freezing refers to the patient’s inability to lift his or her feet off the floor and tends to be most prominent during gait initiation and passage through tight spaces, such as doorways and turning. Gait festination describes the tendency of patients with stooped posture to walk faster and faster to keep up with their center of gravity. These gait disturbances, combined with postural instability, result in falls and loss of independent ambulation.

Table 1. Hoehn and Yahr (HY) stages of Parkinson disease

HY stage	clinical features	Functional impact
I	Unilateral involvement	Minimal
II	Bilateral or midline involvement No impairment of balance	MildStill able to do all activities of daily living
III	Emergence of postural instability	Mild to moderateStill physically independent
IV	Fully developed, incapacitating disease Still able to walk unassisted	Severe disabilityNo longer independent
V	Bed or wheelchair bound without assistance	Complete physical dependence

A number of subgroups within PD have been identified in an attempt to understand variations in presentation and predict prognosis. Two distinct clinical phenotypes have been described: tremor-dominant, which tends to have a more favorable prognosis due to slower progression and less disability, and postural instability and gait difficulty, which is characterized by more severe bradykinesia, faster deterioration, and higher likelihood of cognitive impairment. Age of disease onset has also been consistently identified as a predictor of progression, as those with younger onset symptoms tend to have slower disease progression compared to older onset patients. These subgroups have been shown to demonstrate different pathologic patterns in clinicopathological studies, suggesting that PD may represent a constellation of distinct pathologic entities.

The true natural progression of PD remains incompletely characterized. The introduction of levodopa in the late 1960s dramatically altered the clinical course of PD, and its routine use essentially abolished the study of long-term untreated PD. Pre-levodopa studies were few and limited by lax inclusion criteria, lack of systematic methodology, and bias towards more severe disease. Conclusions that may be drawn cautiously from these studies include a greatly variable rate of disease progression among individuals and a high level of disability overall. Hoehn and Yahr [2] reported in their landmark 1967 study that over one-quarter of patients were dead or severely disabled within 5 years of disease duration, and by 14 years this proportion had increased to over 80%. In the modern era, data are available regarding the short-term progression of early, untreated PD from a number of observational and placebo-controlled studies. The rate of motor worsening relative to baseline is reported to be about 30–40% annually [3], suggesting an aggressive decline in accordance with the pre-levodopa studies. With the use of levodopa and other effective symptomatic therapies, the progression of disability has become markedly slower. Most of the newer studies report intervals of several years between successive stages on the Hoehn and Yahr [2] scale, a widely used grading system based on the level of disability (Table 1). Latency to stage IV (severe disability) has been found mostly in the range of 7–14 years, but has been reported to take as long as 26 years [3]. The natural evolution of motor symptoms most likely occurs in a nonlinear fashion, with evidence suggesting more rapid decline in the first several years [2, 4]. In treated PD, however, clinical progression usually occurs in 3 distinct phases: significant improvement (treatment effect) in the first 2–3 years after diagnosis, a return to baseline followed by relative stability for several years, and then progressive deterioration until death.

Nearly all epidemiological studies in PD report a higher mortality over age-matched controls. In the original study by Hoehn and Yahr [2], the overall mortality was increased 2.9-fold. In a recent meta-analysis of 88 studies, mortality ratios ranged between 0.9 and 3.8 overall but in inception cohorts, which had less between-study heterogeneity, the pooled mortality ratio was approximately 1.5 [5]. Survival estimates vary widely, with median survival ranging 6–22 years from disease onset [5]. It remains unclear whether levodopa has any significant effect on mortality, despite its clear benefit in reducing disability. While older studies report decreased mortality on levodopa compared to pre-treatment era data, more recent epidemiologic studies have not shown convincing evidence that levodopa prolongs life to any significant degree [5]. Older age at onset and the presence of dementia are the most consistent predictors of mortality. The most common causes of death reported in PD include pneumonia, cardiovascular events, stroke, and cancer.

An important contribution to morbidity in PD comes from the nonmotor symptoms, which are often present for years prior to onset of motor symptoms. The most common nonmotor features include gastrointestinal dysfunction (constipation), urinary disturbances (frequency, urgency), orthostatic hypotension, cognitive changes (bradyphrenia, executive dysfunction, dementia), neuropsychiatric disorders (depression, anxiety), sleep disturbances (REM sleep behavior disorder), and olfactory deficits. The burden of nonmotor symptoms increases with the progression of disease, and evidence from a number of studies suggests that nonmotor symptoms become more disabling than motor symptoms in advanced PD. Dementia occurs in 24–31% of patients with PD overall and the prevalence increases with age [6]. The Sydney Multicenter Study, a longitudinal study of 136 patients, reported that non-levodopa responsive problems dominated at 15 years [7], and dementia was present in 83% of survivors at 20 years [8].

The defining pathogenic mechanism of PD is the degeneration of dopamine-producing neurons in the substantia nigra pars compacta, with a majority of neurons lost by the onset of motor symptoms. Lewy bodies (eosinophilic cytoplasmic inclusions of alpha-synuclein) are a key histologic feature of PD, found typically (but not universally) in the substantia nigra pars compacta and locus ceruleus, and are also present in a widespread distribution involving extranigral pathways in the brain as well as the peripheral and autonomic nervous systems. Their exact role in the pathogenesis remains unclear. The worsening of motor symptoms reflects the progressive loss of striatal dopamine, thus making dopamine replacement strategies the cornerstone of therapy. In early PD, symptomatic treatments usually provide effective control of motor symptoms. There are a number of medication options to choose from, including levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, anticholinergics, and amantadine. Levodopa, a dopamine precursor, is the most potent and often best tolerated therapy, and remains the mainstay of treatment as the disease advances. However, with long-term levodopa treatment in the setting of continued loss of neurons needed to convert levodopa to dopamine, patients begin to experience instability of therapeutic response, leading to the development of motor complications. After several years of levodopa therapy, the majority of patients begin to experience motor fluctuations and dyskinesias. Motor fluctuations include wearing off between doses and unpredictable shifts between on and off states. Dyskinesias are involuntary choreiform movements and when severe may be uncomfortable or disabling. The development of motor complications is generally believed to depend on the duration of levodopa exposure, as a number of studies comparing initial treatments in PD have shown that starting with levodopa results in more rapid development of motor complications than starting with a dopamine agonist. Additionally, younger age at onset is also a risk factor for the development of motor complications. Because these complications present challenges to the long-term management of PD, many practitioners choose to start with a “levodopa-sparing” strategy in younger patients.

When patients develop motor fluctuations, strategies to adjust the levodopa include increasing the dosing frequency, lowering or raising the dose, and adding other agents such as COMT inhibitors. Some patients at this stage benefit from continuous intestinal infusion of levodopa. In addition to the growing complexity of motor symptoms, advancing disease is also accompanied by an increasing burden of nonmotor symptoms such as orthostasis, mood disorders, and dementia, which not only are unresponsive to levodopa but may be exacerbated by dopaminergic therapies.

The first consideration of surgical therapy usually occurs in the moderate-to-severe stages of PD, when patients have developed some type of motor complication. Historically, ablative or lesioning procedures were used, producing effective but irreversible symptom control. Since the 1990s, deep brain stimulation (DBS) has grown in popularity and has largely replaced lesioning approaches. The ventral intermediate nucleus of the thalamus can be chosen for the treatment of tremor but lacks efficacy for other motor symptoms of PD. The subthalamic nucleus and globus pallidus internus are currently the standard targets in PD, with evidence showing comparable outcomes in efficacy as well as complications. DBS may provide effective control of many motor symptoms (in particular tremor, bradykinesia, and rigidity) as well as smooth out motor fluctuations and reduce dyskinesias. Many patients are able to reduce medications following surgery. Gait disturbance that responds to medications will usually improve with surgery as well, but axial symptoms such as speech disturbance and postural instability will not usually benefit from surgery. Most current approaches consider an optimal therapeutic window for surgery as beginning when medications diminish in efficacy or motor complications develop, and ending before symptoms become refractory to medications or severe nonmotor complications such as dementia arise. However, there has been an increasing interest in performing DBS earlier in the disease course and studies investigating this approach are underway.

Fig. 1. Disease evolution in Parkinson disease: the preclinical phase encompasses pre-symptomatic and pre-motor stages and may last for many years; the clinical phase can be subdivided into stages of mild, advancing, severe, and end-stage disease. Progression of disability is inevitable.

To summarize, the contemporary natural history of PD can be divided clinically into several stages (Fig. 1): the preclinical period, early/mild disease, moderate/advancing disease, severe disease, and end-stage disease.