Approach to the Patient with Parkinson Disease

Amy A. Pruitt

Parkinson disease (PD) is the second most common neurodegenerative disease in older Americans, affecting more than 1 million people in North America. It is characterized by tremor at rest, rigidity, and bradykinesia. A wealth of evidence-based therapies has widened therapeutic options for patients with PD; nonetheless, the approach to treatment must be individualized, targeting the symptoms that are of greatest personal concern. Considerations regarding when to start dopaminergic medication and whether to use putative neuroprotective agents or dopamine agonists require significant patient-physician engagement, which can be facilitated by neurologic consultation. While patients responding well to one or two drugs can be readily managed in the primary care setting, those with more advanced disease requiring complicated anti-Parkinson treatment fare better when managed by the neurologist.

The primary care physician remains in the best position to suspect the diagnosis, institute therapy, and monitor the often substantial side effects associated with antiparkinsonian agents and their interactions with other concurrent medications. In addition, treatment of the many nonmotor complications of PD including dementia, depression, autonomic dysfunction, and sleep disturbances often falls in the realm of the primary care physician.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6 and 7)

Pathophysiology

PD is a neurodegenerative condition. Its most characteristic pathologic feature is a loss of dopamine-containing neurons; the nuclei of these neurons reside in the pars compacta of the substantia nigra, and the axons terminate in the caudate nucleus and putamen (the striatum). Other pigmented and nonpigmented nuclei in the brainstem and elsewhere are also affected. Associated with neuronal loss is the development of concentric hyaline inclusions in the cytoplasm of affected neurons, called Lewy bodies. An emerging hypothesis suggests that neurodegeneration, spread of pathology, and symptoms are mediated via misfolded proteins, including alpha-synuclein, which generate interneuron fibrils producing Lewy body inclusions and accounting for the spread of pathology and progression of clinical symptoms.

Symptoms are believed to be related to the imbalance between dopaminergic and cholinergic influences on striatal tissue created by the loss of dopamine-containing neurons. Proper striatal function depends on this balance. Loss of sympathetic innervation can occur in the nigrostriatal system in the brain and in the sympathetic nervous system of the heart, eventually leading to neurocirculatory failure.

Both genetic and environmental factors have been implicated in the development of PD. Their relative contributions differ for early-onset and late-onset disease.

Genetic Contributions

Gene mutations appear to be most important in hereditary forms of the disease, which typically have onset before the age of 50 years. Several gene mutations have been identified as contributory, including mutations of the parkin gene on chromosome 6 and the a-synuclein gene on chromosome 4. The products of these genes are likely to be important in pathogenesis, with α-synuclein being a major component of presynaptic terminals and Lewy bodies and the product of the parkin gene being involved in protein degradation and clearance.

In persons with the more common idiopathic form of PD, gene mutations probably do not play as large a role, but some evidence suggests a susceptibility function for mutations of the tau gene, which codes for the tau protein, a component of microtubules.

Environmental Contributions

In sporadic idiopathic PD with onset older than the age of 50 years, environmental factors are believed to be possibly important. The substantia nigra of patients with PD seems particularly vulnerable to oxidative insults. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an analogue of meperidine injected by intravenous drug abusers) and the pesticide rotenone (used in animal models of the disease) both inhibit mitochondrial complex I, impairing mitochondrial function and leading to findings nearly identical to those of idiopathic disease.

The demonstration that mitochondrial toxins can produce parkinsonism has stimulated an ongoing search for causative environmental precipitants. It is suspected that long-term,
low-level exposures may be important and predate the onset of symptoms by years. Of note, being from a rural area using well water is a risk factor for parkinsonism, as is not smoking. Separately, high caffeine intake is associated with a decreased risk of PD, suggesting a role for the adenosine receptor, which it antagonizes. An important modifiable environmental feature is exercise, which can slow the rate of symptomatic decline.

Clinical Presentation

PD is an affliction of middle to late adult life, although 30% of patients report recognizable symptoms before the age of 50 years. In another 40%, the disease develops between the ages of 50 and 60 years, and the remainder is older than 60 years old at the time of diagnosis. The classic syndrome of parkinsonism includes tremor at rest, rigidity, bradykinesia, masked face, stooped posture, and a shuffling gait. Although tremor is the most obvious initial finding, it is absent in 20% of patients. PD may begin insidiously with vague, aching pain in the limbs, neck, or back and with decreased axial dexterity before tremor is noted. Dysarthria may be an early feature; dysphagia usually occurs later. The onset of PD, whether primarily with tremor, rigidity, or bradykinesia, is usually asymmetric (see Fig. 174-1).

Subtler symptoms may also be noted, sometimes early. Orthostatic hypotension suggests cardiac sympathetic denervation, which can be found in many patients and may cause neurocirculatory failure. Micrographia (decrease in the caliber of handwriting), decrease in volume of the voice, and anosmia are other subtle but characteristic manifestations. Depression may be a feature of early disease. The estimated frequency of dementia (which usually develops late) varies widely, but cognitive impairment, including hallucinations and psychosis, develops in at least 15% to 20% of patients (some of whom are likely to have Lewy body disease; see Chapter 169). However, dementia and psychosis are not inevitable, and remediable causes of changes in mental status always need to be sought.

Figure 174-1 Approach to management of Parkinson disease.(Adapted from Suchowersky O, Reich S, Perlmutter J, et al. Practice parameter: diagnosis and prognosis of new-onset Parkinson disease (an evidence-based review). Neurology 2006;66:968, with permission. Copyright © 2006, AAN Enterprises, Inc.)

Clinical Course

Before the introduction of levodopa, PD had a fairly predictable course. At 5 years after onset, 60% of patients were severely disabled, and at 10 years, nearly 80% were. The rate of progression varied widely. Death rarely was a direct consequence of parkinsonism; rather, it was a consequence of immobility (aspiration pneumonia, urinary tract infections) or of trauma. Patients with PD comprise several different subgroups manifesting specific clinical patterns. It is believed that patients who present primarily with tremor have a slower course than do those for whom bradykinesia is the primary symptom. Patients who present with significant instability of posture and gait are largely an older group who are more likely to have cognitive impairment and a more rapid progression of disease.

The advent of dopaminergic agents has changed the natural history of the disease significantly. The initial benefit of levodopa therapy is one of the diagnostic criteria for the disease. Although patients with idiopathic PD usually respond to levodopa, the initial benefits of therapy decline for as many as one half of all treated patients after two or more years. Nonmotor symptoms contribute significantly to decline in quality of life. Predictive factors for more rapid progression and shorter survival time are older age at onset, presentation with rigidity and bradykinesia, and imperfect dopamine responsiveness

DIAGNOSIS (1,7; TABLE 174-1)

The classic presentation of PD usually poses few diagnostic problems. However, atypical presentations may be more problematic, such as isolated tremor confined to half the body (hemiparkinsonism) in a younger patient. Symptomatic parkinsonism can be seen in several other disorders, such as progressive supranuclear palsy and multisystem atrophy, or as a side effect of numerous medications (Table 174-1). Other neurodegenerative conditions having extrapyramidal features can resemble PD. Alzheimer disease may have slowed gait and stooped posture, posing a frequently encountered diagnostic dilemma in primary care practice. Small-vessel vascular disease may produce a parkinsonian-like state. The list of causes of parkinsonism includes toxins, central nervous system infections, structural lesions of the brain, and drugs. Dopamine antagonists including neuroleptic agents and atypical neuroleptics, antiemetic drugs, valproate, and lithium all have been reported to cause parkinsonism (Table 174-1).

The clinical diagnosis of PD is based on a careful examination in which the clinician looks for physical signs other than those associated with the basal ganglia, elicits a careful drug and family history, and considers neuroimaging (usually magnetic resonance imaging [MRI]) to exclude significant small-vessel vascular disease.

Reference to inclusionary and exclusionary criteria (Table 174-2) should help the primary physician in making an accurate clinical diagnosis. Among the inclusion criteria is a sustained responsiveness to levodopa therapy, with improvement lasting for 1 year or more—many parkinsonian syndromes due to other causes may show only a transient response to dopaminergic agents. There are no confirmatory laboratory tests or imaging studies, but ligands that bind the dopamine transporter and are visible on single-photon emission computed tomography can be helpful in the investigational setting.

PRINCIPLES OF MANAGEMENT (1, 2, 3, 4, 5 and 6,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22)

PD cannot be cured, but advances in treatment have improved prospects for patients.

Goals and Overall Strategy

The goals of therapy are (a) to delay disease progression, (b) to relieve symptoms, and (c) to preserve functional capacity. Restoring the striatal balance between dopaminergic and cholinergic activity is at the core of efforts to achieve symptomatic relief. Inhibiting oxidative injury appears to be helpful in retarding disease progression. The patient may be able to tolerate many of the early signs of parkinsonism, which are sufficient to prompt medical consultation but, aside from provoking psychological discomfort, are not disabling. The goal of therapy is to maintain the patient at maximum function with minimal medication.

TABLE 174-1 Differential Diagnosis of Parkinsonism

Idiopathic Parkinsonism (Parkinson Disease)
	Infectious and postinfectious
		Postencephalitic parkinsonism (von Economo disease)
		Other viral encephalitides
	Toxins
		Manganese
		Carbon monoxide
		Carbon disulfide
		Cyanide
		Methanol
		MPTP^a
	Drugs
		Neuroleptics
		Reserpine
		Metoclopramide
		Lithium
		Amiodarone
		α-Methyldopa
		Valproate
Neurodegenerative Disorders
	Multiple system atrophies
		Striatonigral degeneration
		Olivopontocerebellar atrophy
		Shy-Drager syndrome
	Tauopathies
		Progressive supranuclear palsy
	Corticobasal degeneration
	Frontotemporal dementia
Primary Dementing and Other Degenerative Disorders
	Alzheimer disease
	Lewy-body disease
Other Central Nervous System Disorders
	Multiple cerebral infarctions (lacunar state, Binswanger disease)
	Hydrocephalus (normal pressure or high pressure)
	Posttraumatic encephalopathy (pugilistic parkinsonism)
Genetic Disorders with Some Parkinsonian Features
	Wilson disease
	X-linked dystonia-parkinsonism
	Fragile X premutation associated ataxia-tremor-parkinsonism syndrome
	Huntington disease
	Prion disease
Metabolic Conditions
	Hypoparathyroidism with basal ganglia calcifications
	Chronic hepatocerebral degeneration (non-Wilsonian hepatolenticular degeneration)
	Idiopathic calcification of basal ganglia
This list is not meant to be all-inclusive. Rather, it highlights the more common disorders that may have parkinsonism as a prominent feature. ^a^a1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a meperidine analogue used by intravenous drug abusers. Adapted from Koller WC. How accurately can Parkinson’s disease be diagnosed? Neurology 1992;42(Suppl 1):6, with permission.