Parkinson Disease: REFERENCES: EVIDENCE-BASED MEDICINE: RELEVANT GUIDELINES:

Key words: Parkinson disease, neurodegenerative diseases, essential tremor, parkinsonism

Parkinson disease (PD) is the second most common neurodegenerative disease among elderly persons (after Alzheimer disease), and the incidence is expected to double in the next 15 to 20 years.¹ About a million Americans have PD, which means that it is about 3 times as common as multiple sclerosis and half as common as epilepsy.² Most studies indicate that men are more often affected than women, although the reason is unknown. Coffee drinkers and smokers appear to be at reduced risk.²

Age is the only established risk factor for PD; the average age at diagnosis is 55 to 60 years. PD is diagnosed in fewer than 5% of patients before the age of 40 years.³

Because the manifestations of PD are protean and complex, the diagnosis can be difficult and treatment challenging. However, an awareness of the key clinical features and familiarity with 2 or 3 of the dopaminergic medications can facilitate management. In this article, we address the diagnostic principles of PD and offer an initial approach to the patient. In a second article (page 1333), we review therapeutic options.

DIAGNOSIS

The diagnosis is established clinically and relies on a thorough history taking and physical examination. The lack of a reliable, affordable, and widely accessible test for PD, coupled with the variable clinical presentation, sometimes creates uncertainty about the diagnosis, even among the most experienced clinicians.

Brain MRI cannot detect the pathologic changes associated with PD. Generally, an MRI scan is ordered only to rule out another condition, such as normal pressure hydrocephalus (NPH), that sometimes mimics PD and can be detected by imaging. In some centers, functional imaging such as beta-CIT single photon emission CT (SPECT) or fluorodopa positron emission tomography (PET) may provide information about dopamine metabolism in the brain, but these scans are not infallible and their accuracy depends on the experience of those performing and interpreting them. SPECT and PET scans are not considered standard for the diagnosis of PD; they are seldom covered by insurance plans and represent a substantial expense.

History. Unilateral tremor, usually in a hand, often more prominent at rest, coupled with a change in handwriting (smaller size and a decline in legibility) in a person aged 55 years or older strongly suggests PD. The handwriting changes are often present even when the tremor does not affect the patient's dominant hand.

Slowness of movement. Many patients (or their spouses) observe movement that is slow (bradykinesia); decreased (hypokinesia); or difficult to initiate (akinesia.)

Speech. Many patients (or their spouses), when questioned, report that their voice has lowered (hypophonia) and that they are frequently asked to repeat themselves. Speech may become hoarse and monotonous.

Gait and balance. Gait is often affected fairly early, although the changes may be subtle. When asked specifically about walking, patients may observe that they drag a foot or shuffle. Although impaired balance is regarded as a central feature of PD, it is rarely evident early. Unsteadiness or falling in a patient with suspected PD suggests progressive supranuclear palsy.

Functional status. Inquire about activities of daily living as well as occupational and social functioning. Patients may report increasing difficulties. Some may be aware of slowness or awkwardness in certain activities, such as getting out of bed in the morning or fastening buttons. A spouse or other family member may have noticed a change in facial expressiveness, the so-called masked facies of PD. A full picture of daily functional status, in conjunction with the physical examination, helps in the selection or modification of the treatment plan.

Physical examination. Have the patient sit with his or her hands supported by the armrests of the chair or in the lap. Engaging the patient in conversation allows for better assessment; moreover, with diversion, a subtle or significant tremor may emerge that might otherwise be missed. Conversation also allows for assessment of facial expressiveness (including diminished blinking) and speech.

When patients are seated and asked to shrug their shoulders, the affected sidewill often show a slight lag. We check the tone in patients' arms and legs by asking them to relax, go limp, and not help us in moving their limbs. Subtle rigidity can be elicited by asking the patient to simultaneously move the contralateral arm while the practitioner moves his other arm or a leg.

We check for speed and excursion of index finger tapping, hand opening and closing, and alternating hand movements. Alternatively, patients can be asked to rapidly tap the palm and then back of their hand on their knee. Patients with PD demonstrate slowing and awkwardness in these movements.

We ask patients to stand up from a seated position with their arms folded on their chest and observe whether they are able to do so or whether they need to push against the armrests to rise. Persons with PD may require more than 1 attempt to rise, or will need to assist themselves with that push. We then stand behind them and pull them backward with a forceful tug on the shoulders to check their balance. We warn them beforehand, and demonstrate that they should take a step backward to steady themselves if they need to. Position larger patients with a wall behind them.When pulled, a patient with early PD may need to take a few steps backward, beyond the normal 1 or 2. Frank falling, with the need to be caught by the examiner, is not typical of early PD and may suggest an alternative diagnosis.

Finally, we watch our patients walk 30 feet in the corridor, looking for postural changes (such as leaning forward or asymmetric shoulder height), and for arm swing. Commonly, the arm on the affected side will swing less than the unaffected arm, or it may be held flexed at the elbow.

Patients with an appropriate history and clinical findings of unilateral resting tremor, limb rigidity, and asymmetric slowness of movement meet the criteria for PD.

COMMON MIMICS

Essential tremor (ET), a condition sometimes confused with early PD, is about 10 times more prevalent than PD. Distinguishing characteristics are listed in Table 1.

Other disorders that may mimic PD include NPH and other neurodegenerative diseases. These include progressive supranuclear palsy, multiple systems atrophy, corticobasal degeneration, and diffuse Lewy body disease. It can be challenging--and sometimes impossible--to distinguish among these diagnoses with certainty. However, a definitive diagnosis may have important ramifications for treatment; for example, NPH sometimes responds to neurosurgical intervention, whereas the other conditions most often do not. Furthermore, other neurodegenerative diseases usually respond poorly to medications used to treat PD. Features that suggest neurodegenerative diseases other than PD include:

•Absence of tremor.

•Symmetric findings at the time of presentation.

•Early, prominent gait disorder, falls, or cognitive impairment.

•No improved mobility with levodopa treatment.

Drug-induced parkinsonism. Dopamine antagonists (including metoclopramide or prochlorperazine) may produce symptoms and signs identi-cal to those of PD. Other classes of agents that may induce parkinsonism include older and newer antipsychotic agents, antiemetic drugs and, rarely, calcium channel blockers.Discontinuation of the offending medication reverses the symptoms, athough this process may take a number of months or up to a year or more.

AN APPROACH TO THE PATIENT

After concluding the history taking and physical examination, we discuss our observations with the patient, including findings that are obvious to him and those, like tone changes or asymmetric arm swing, that may not be.

Patients often suspect the diagnosis, so it does not come as a complete shock, but confirmation of the suspicion is at least unsettling and sometimes devastating. Support and education are crucial at this point (Table 2). Stress that PD, like most disorders, covers a broad spectrum of symptom severity. Although PD is a progressive disorder, a course of relentless decline is not inevitable. Many patients have long periods of clinical stability with little perceptible change. Emphasize that although the cause of PD remains unknown and a cure is not yet available, many of its symptoms are treatable.

It is important to stress to patients that PD symptoms do not worsen abruptly. Sudden changes may occur with a medication mishap--for example, the addition of a dopamine antagonist to the medication regimen--or because of a concurrent acute condition, such as a urinary tract infection, pneumonia, or prolonged constipation.

Finally, although the genetics of PD is an increasingly fruitful area of research, PD does not typically run in families in any identifiable Mendelian pattern. The risk of PD in the children of patients with the disease, although higher than that of a person without an affected first-degree relative, is still very low.

THE SPECTRUM OF SYMPTOMS

PD does not manifest solely as a neurologic disorder that produces tremor and impairment of mobility. The initial appearance of pathology in the brain may be outside areas that affect motor function and instead affect olfactory pathways and brain stem structures involved in sleep regulation. The clinical consequences include impaired sense of smell and rapid eye movement (REM) sleep behavior disorder that may appear years before the more typical motor symptoms.⁴

The microscopic pathology of PD is found also in the autonomic nervous system.⁵ This may explain symptoms of autonomic dysfunction, such as constipation, urinary urgency and frequency, abnormal sweating, erec-tile dysfunction, and blood pressure regulation problems. Constipation is thought to be a possible early symptom that precedes motor dysfunction.⁶

Most PD patients have both motor and nonmotor symptoms. Sleep disturbances and bladder and bowel difficulties are particularly common and troublesome. Patients report a variety of sleep problems.⁷ Some fall asleep but awaken prematurely and have difficulty in getting back to sleep. Restless legs syndrome is common. Patients may be somnolent and doze irresistibly during the day and also fall asleep at meals or during conversation or sedentary activities. Their dreams are frequently intense, realistic, and unpleasant and may be associated with REM sleep behavior disturbance. Patients may fling their limbs and grab or strike their bed partner as they wrestle with imaginary characters or animals. Some yell loudly while dreaming.

Patients often report visual problems despite normal findings on ophthalmologic evaluation. Occasionally, patients have impaired eye movements that result in frank diplopia. The complaint of reduced acuity may be attributable to retinal changes that are detectable only with specialized testing, such as electroretinography for color contrast sensitivity.⁸ Some patients report dry eyes or increased tearing; these can contribute to altered acuity.

Patients sometimes complain of shortness of breath despite normal pulmonary and cardiac assessments. This may be a result of restriction of chest wall expansion when medication has worn off and symptoms are returning, irregular breathing as a medication side effect, or alterations of brain stem respiratory centers.⁹

Fatigue, depression, and anxiety are also commonly reported. Suicide, although uncommon, is not unknown among PD patients. Mood may sometimes correspond to medication: a decline in mood and an increase in anxiety may coincide with the time when the last dose of medication wears off.¹⁰ Fatigue, the most troubling symptom for some patients, is poorly understood as a manifestation of PD and usually difficult to treat.

Many patients with a new diagnosis of PD fear cognitive loss, dementia, and dependence. Cognitive impairment in many patients takes the form of slowing of memory and difficulty with visual spatial tasks and executive function (multitasking, creating a plan, and bringing it to completion). Reports of the incidence of dementia in PD vary, but frank dementia, such as Alzheimer disease, is uncommon.¹¹

Of all the PD symptoms, those that affect motor function have been investigated most thoroughly. Many reports demonstrate that these symptoms respond to treatment, but not all of them respond equally, and some do not respond at all. Stiffness and slowness often improve with dopaminergic medication, for example, where- as tremor may improve less reliably. Thus, a more realistic treatment goal than tremor eradication is improved overall mobility.

Some of the most troubling motor symptoms that may occur later in the course, such as impairment of balance and freezing of gait, change very little or not at all with medication, regardless of the agent or regimen. *

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