Parkinson Disease: An Update

JOHN D. GAZEWOOD, MD, MSPH, University of Virginia Health System, Charlottesville, Virginia
D. ROXANNE RICHARDS, MD, MedStar Physician Partners at St. Clement’s, Leonardtown, Maryland
KARL CLEBAK, MD, Lake Monticello Primary Care, Palmyra, Virginia

Parkinson disease is a progressive neurologic disorder afflicting approximately 1 percent of Americans older than
60 years. The cardinal features of Parkinson disease are bradykinesia, rigidity, tremor, and postural instability. There
are a number of neurologic conditions that mimic the disease, making it difficult to diagnose in its early stages. Phy-
sicians who rarely diagnose Parkinson disease should refer patients suspected of having it to physicians with more
experience in making the diagnosis, and should periodically reevaluate the accuracy of the diagnosis. Treatment is
effective in reducing motor impairment and disability, and should be started when a patient begins to experience
functional impairment. The combination of carbidopa and levodopa is the most effective treatment, but dopamine
agonists and monoamine oxidase-B inhibitors are also effective, and are less likely to cause dyskinesias. For patients
taking carbidopa/levodopa who have motor complications, adjunctive therapy with a dopamine agonist, a mono-
amine oxidase-B inhibitor, or a catechol O-methyltransferase inhibitor will improve motor symptoms and functional
status, but with an increase in dyskinesias. Deep brain stimulation is effective in patients who have poorly controlled
symptoms despite optimal medical therapy. Occupational, physical, and speech therapy improve patient function.
Fatigue, sleep disturbances, dementia, and depression are common in patients with Parkinson disease. Although
these conditions are associated with significantly lower quality of life, they may improve with treatment. (Am Fam
Physician. 2013;87(4):267-273. Copyright © 2013 American Academy of Family Physicians.)

P
Patient information:
▲

arkinson disease is a progres- parkinsonism, progressive supranuclear

A handout on Parkinson
sive neurodegenerative disorder palsy, and drug-induced parkinsonism.5,6
disease, written by the
authors of this article, is that is pathologically defined by Table 1 describes common disorders to con-
available at http://www. degeneration of the dopaminergic sider in the differential diagnosis.1,4,7-9
aafp.org/afp/2013/0215/ neurons in the substantia nigra and develop- Features that increase the likelihood of
p267-s1.html. Access to
the handout is free and
ment of Lewy bodies in the residual dopami- Parkinson disease include those associated
unrestricted. nergic neurons.1 Pathologic changes may be with bradykinesia, such as micrographia, a
detected up to 20 years before the onset of shuffling walk, and difficulties performing
motor symptoms, and are accompanied by a motor tasks such as turning in bed, rising
clinical prodrome of nonspecific symptoms from a chair, or opening jars.10 Features that
such as hyposmia, constipation, and fatigue.2 make Parkinson disease less likely include
The disease affects approximately 1 percent falls in the early stages of the disease, poor
of persons older than 60 years, and up to response to levodopa, symmetry at onset,
4 percent of those older than 80 years.3 rapid progression, lack of tremor, and
dysautonomia.9
Diagnosis The diagnosis of Parkinson disease is
The diagnosis of Parkinson disease is clini- difficult and diagnostic error is common,
cal, and relies on the presence of the cardi- particularly in the early stages.5,6 A physi-
nal features of bradykinesia, rigidity, tremor, cian who rarely diagnoses Parkinson disease
and postural instability, coupled with grad- should consider referring a patient suspected
ual symptom progression and a sustained of having it to a physician who has more
response to therapy with levodopa.4 How- experience with the disease to confirm the
ever, some of these features are shared by diagnosis.4,11 No clinical decision rules are
other neurologic conditions. Conditions of proven usefulness in diagnosing early
commonly misdiagnosed as Parkinson disease,4 although the Parkinson’s UK Brain
disease include nonparkinsonian tremors Bank criteria improve diagnostic accuracy in
such as essential tremor, and diseases with patients with advanced disease.11 Given the
parkinsonian features such as vascular inherent uncertainty of diagnosis in early
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Parkinson Disease

Table 1. Characteristics of Conditions Commonly Misdiagnosed as Parkinson Disease

Condition Clinical features

Essential tremor Symmetric postural tremor; worsens with movement; affects distal extremities, head, and voice; family
history common; improves with alcohol, beta blockers7
Vascular parkinsonism Clinical features similar to Parkinson disease; may have focal neurologic findings; stepwise progression with
poor response to carbidopa/levodopa; presence of basal ganglia and/or thalamic infarcts on computed
tomography or magnetic resonance imaging4,8
Drug-induced Clinical features similar to Parkinson disease; drug history and drug withdrawal evaluation can confirm
parkinsonism diagnosis; antiemetics and psychotropic drugs most common causative agents1
Dementia with Lewy Onset of motor symptoms accompanied by dementia and visual hallucinations; patients have marked
bodies fluctuations in attention and cognition; poor response to carbidopa/levodopa8
Atypical parkinsonism Clinical features similar to Parkinson disease, but with other signs early in the disease process: prominent
(includes progressive gait and speech impairment, prominent postural instability, and axial rigidity greater than extremity
supranuclear palsy and rigidity; absence of resting tremor and prominent autonomic dysfunction; poor response to carbidopa/
multisystem atrophy) levodopa1,9

NOTE: Conditions are listed in descending order of prevalence among patients with suspected Parkinson disease.
Information from references 1, 4, and 7 through 9.

disease and the increasing diagnostic accuracy with Physicians’ Health Study, which enrolled 22,071 male
disease progression, physicians caring for patients with physicians between 40 and 83 years of age, the adjusted
Parkinson disease should periodically reevaluate the relative risk of mortality for the 560 men who developed
diagnosis.4 the disease during 23 years of follow-up was 2.3.13 The
relative risk of mortality was 1.8 in a longitudinal Dutch
ROLE OF IMAGING IN DIAGNOSIS cohort of 6,969 men and women.14 In a community-
Imaging plays a limited role in diagnosis and should based cohort in Norway, men with Parkinson disease at
not be used routinely.4,11 Imaging may help when the age 70 had a median life expectancy of eight years, and
clinical presentation makes it difficult to differentiate women with Parkinson disease at age 70 had a median
Parkinson disease from another disorder with similar life expectancy of 11 years.12
characteristics. For example, limited-quality studies
indicate that magnetic resonance imaging may help Treatment of Motor Symptoms
differentiate the disease from progressive supranuclear EARLY MEDICAL THERAPY
palsy.4 Better data support using single-photon emission The American Academy of Neurology recommends ini-
computed tomography to distinguish the disease from tiating treatment once patients develop functional dis-
essential tremor.4,11 Table 2 summarizes current recom- ability.15 Levodopa, nonergot dopamine agonists, and
mendations for imaging in the diagnosis of Parkinson monoamine oxidase-B inhibitors can be used for initial
disease.4,9,11 therapy 4,11,15 (Table 3). Levodopa is administered with
carbidopa, which inhibits the peripheral metabolism of
Prognosis levodopa, thereby allowing therapeutic concentrations
Patients with Parkinson disease experience progressive of levodopa to enter the brain without disabling adverse
decline in motor and cognitive function and increased effects. The combination of carbidopa and levodopa
mortality. Risk factors for more rapid decline in motor (Sinemet) is the most effective agent available for the
function include older age at diagnosis, and promi- treatment of motor symptoms. However, its early use is
nent bradykinesia and rigidity at diagnosis. Prominent associated with earlier development of dyskinesias (abnor-
tremor at diagnosis may predict a slower rate of dis- mal involuntary movements). Dopamine agonists such as
ease progression.9 The incidence of dementia increases pramipexole (Mirapex) and ropinirole (Requip) directly
with patient age and duration of Parkinson disease, stimulate dopamine receptors. They are less effective than
with 60 percent of patients who have the disease devel- levodopa in treating motor symptoms of Parkinson dis-
oping dementia within 12 years of diagnosis.12 In the ease, but have a lower incidence of dyskinesias. Compared

268  American Family Physician www.aafp.org/afp Volume 87, Number 4 ◆ February 15, 2013
 Parkinson Disease
Table 2. Recommendations for Imaging in the Diagnosis of Parkinson Disease

National Institute for Health and Scottish Intercollegiate

Imaging modality American Academy of Neurology 9 Clinical Excellence 11 Guidelines Network 4

Fludeoxyglucose positron Evidence insufficient to make Use only in research settings Not recommended
emission tomography recommendation

Magnetic resonance Possibly useful to distinguish Not recommended for diagnosis Not recommended for routine
imaging Parkinson disease from of Parkinson disease diagnosis of idiopathic
multisystem atrophy Consider for diagnosis of Parkinson disease
parkinsonian syndromes

Single-photon emission Possibly useful to distinguish Distinguish Parkinson disease from Distinguish Parkinson disease
computed tomography Parkinson disease from essential essential tremor from nondegenerative
tremor parkinsonism or other
tremor disorders

Ultrasonography Evidence insufficient to make No recommendation Not recommended

recommendation

Information from references 4, 9, and 11.

Table 3. Drugs Used to Treat Motor Symptoms in Patients with Parkinson Disease

Drug/drug class Examples Advantages Disadvantages

Carbidopa/levodopa Immediate- and Most effective, improves disability, Motor complications: dyskinesias, dystonia,
(Sinemet) sustained-release prolongs capacity to perform confusion, psychosis, sedation
carbidopa/levodopa instrumental activities of daily living

Dopamine agonists Nonergot: pramipexole Can be used as monotherapy in early All: dopaminergic adverse effects (nausea,
(Mirapex), ropinirole disease or added to levodopa for vomiting, orthostatic hypotension),
(Requip) treatment of motor complications neuropsychiatric adverse effects
Ergot: bromocriptine Less risk of developing motor (hallucinations, psychosis, impulse control
(Parlodel), pergolide complications in early disease disorder), excessive daytime sleepiness
Ergot: pulmonary fibrosis, cardiac valve
fibrosis, erythromelalgia

Monoamine oxidase-B Selegiline (Eldepryl), Can be used as monotherapy in Amphetamine and methamphetamine
inhibitors rasagiline (Azilect) early disease or to treat motor metabolites may cause adverse effects,
complications in late disease risk of serotonin syndrome
Once-daily dosing, well tolerated

Catechol Entacapone (Comtan), Used to treat motor complications; Dopaminergic adverse effects,
O-methyltransferase tolcapone (Tasmar) no titration, decreased off time,* discoloration of urine, tolcapone
inhibitors mild improvement in activities of associated with explosive diarrhea and
daily living and quality-of-life scores fatal liver toxicity

Injectable dopamine Apomorphine (Apokyn) Reduces off time in late disease Requires initiation in hospital, regular
agonist subcutaneous injections

N-methyl- d -aspartate Amantadine Treatment of dyskinesias in late Cognitive adverse effects, livedo reticularis,
receptor inhibitor disease edema, development of tolerance,
potential for withdrawal

Anticholinergics Benztropine, Useful for the treatment of tremor Use limited by anticholinergic adverse
trihexyphenidyl in patients younger than 60 years effects
without cognitive impairment

NOTE: Medications are listed in approximate descending order of preference for use. Pergolide is not available in the United States.
*—”Off time” is a complication of Parkinson disease in which the medications used to control the disease become less effective over time, resulting
in a gradual or abrupt recurrence of symptoms.

February 15, 2013 ◆ Volume 87, Number 4 www.aafp.org/afp American Family Physician 269
Parkinson Disease

with carbidopa/levodopa, dopamine agonists cause more reasons previously noted.4,11,21 Apomorphine (Apokyn)
sleepiness, edema, nausea, and hallucinations, and have is a nonergot dopamine agonist injected subcutaneously
higher dropout rates in clinical trials.16 that decreases off time. It has significant adverse effects,
Ergot-derived dopamine agonists such as cabergoline, and treatment should be started in an experienced cen-
bromocriptine (Parlodel), lisuride, and pergolide should ter.4,11 Monoamine oxidase-B inhibitors also decrease off
not be used as first-line treatments because of the risk time in patients. Catechol O-methyltransferase inhibi-
of serosal fibrosis and cardiac valvulopathies. (NOTE: tors decrease levodopa metabolism, allowing for more
Lisuride and pergolide are not available in the United levodopa to enter the brain. They also modestly decrease
States.) If ergot-derived dopamine agonists are used, off time.4,11,21,22 The catechol O-methyltransferase
baseline and annual echocardio­graphy, chest radiogra- inhibitor tolcapone (Tasmar) is associated with fatal
phy, and testing of erythrocyte sedimentation rate and hepatotoxicity and should be avoided.4,11 These treat-
renal function should be performed.4,11 Monoamine ments all increase dyskinesias and other adverse effects,
oxidase-B inhibitors are less effective than either carbi- including hallucinations, nausea, vomiting, constipa-
dopa/levodopa or dopamine agonists in treating motor tion, hypotension, insomnia, and somnolence.4,11,21,23
symptoms of Parkinson disease, cause less dyskinesia A Cochrane review that indirectly compared these
than carbidopa/levodopa, and generate fewer adverse drugs concluded that dopamine agonists were most
effects than dopamine agonists.4,11,15,17 Administering effective at reducing off time.23 Only amantadine has
carbidopa/levodopa in combination with a dopamine been shown to reduce dyskinesias. This effect is modest
agonist in early disease does not delay the development and may last less than eight months.4,11,21
of dyskinesias.18
SURGERY
The choice of initial therapy should be guided by the
patient’s preferences after a discussion of the risks and Most patients will develop disabling symptoms despite
benefits of each class of medications, taking into account optimal medical therapy, and are candidates for deep
the degree of the patient’s functional disability. Although brain stimulation, which targets either the subthalamic
up to 40 percent of patients who have Parkinson disease nucleus or the globus pallidus interna.24 Factors that pre-
use an alternative therapy,19 no good evidence shows that dict a good response to surgery for advanced Parkinson
any herbal medica- disease include good response to levodopa, few comor-
tion or supplement bidities, absence of cognitive impairment, and absence of
Sixty percent of patients
is effective for treat- (or well-controlled) depression.24 Risks of surgery include
with Parkinson disease
ment of the disease, intracranial hemorrhage; stroke; infection; lead migra-
develop dementia within
and there is no con- tion, misplacement, or fracture; and death.24
12 years of diagnosis.
vincing evidence that A recent randomized multicenter trial compared
any such treatment is best medical therapy to deep brain stimulation over
neuroprotective.20 In particular, vitamin E should not be six months. Patients receiving deep brain stimulation
used for neuroprotection because there is good evidence had significant gains in on time, and improvements in
indicating that it does not slow disease progression.4,20 motor function and quality of life. However, adverse
effects were more frequent in the surgical group; these
LATE MEDICAL THERAPY included surgical site infection, falls, and depression.25
As Parkinson disease progresses, initial therapy Deep brain stimulation does not slow disease progres-
becomes less effective and additional motor complica- sion, and patients eventually develop treatment-resistant
tions develop, including dyskinesias and motor fluc- symptoms such as gait freezing.24-26
tuations. The patient’s “on time,” when medication is
PHYSICAL, OCCUPATIONAL, AND SPEECH THERAPY
effectively controlling the disease’s symptoms, becomes
shorter, and “off time” occurs when disease symptoms Physical therapy improves balance, muscle strength,
recur gradually or abruptly. These complications impair and walking speed in patients with Parkinson dis-
function and quality of life.21 ease.11,20 No evidence shows that one type of physical
Several medications are used as adjunctive therapy therapy is better than another.11 Although there is less
with levodopa to help reduce motor fluctuations. Dopa- evidence that occupational therapy is beneficial,11,20 it
mine agonists decrease off time in patients and improve may help patients maintain family, social, and work
function. The nonergot dopamine agonists pramipexole roles and improve safety and motor function, and
and ropinirole are preferred to the ergot agonists, for should be offered to those having difficulty performing

270  American Family Physician www.aafp.org/afp Volume 87, Number 4 ◆ February 15, 2013
 Parkinson Disease

tasks of daily living.11 Many patients who have the constipation, is present in most patients late in the dis-
disease develop dysarthria, with low speech volume, ease. No treatments have demonstrated effectiveness in
decreased pitch, and pronunciation difficulties. Speech treating either orthostatic hypotension or urinary incon-
therapy, particularly therapy aimed at improving the tinence in Par-
volume of speech, is effective.11,20 kinson disease.4,28
Parkinson disease affects
Sildenafil (Viagra)
Management of Nonmotor Symptoms approximately 1 percent of
may improve erec-
persons older than 60 years,
Even early in the course of Parkinson disease, nonmo- tile dysfunction in
and up to 4 percent of those
tor symptoms such as fatigue are common. Later in the patients with the
older than 80 years.
course, nonmotor symptoms significantly lower patients’ disease, and one
28

quality of life. Recognizing and treating these symptoms randomized trial

improve the quality of life for patients who have Parkin- showed that polyethylene glycol (Miralax) improved
son disease, as well as for their caregivers. stool frequency and consistency.28 Drooling can be
treated with either onabotulinumtoxinA (Botox)28 or
FATIGUE AND SLEEP DISTURBANCE glycopyrrolate.32
Fatigue is present in one-third of patients with Parkin-
PSYCHIATRIC DISORDERS
son disease at diagnosis, and is associated with sever-
ity of illness. It is less common in patients treated with Depression and psychosis occur in up to 50 percent of
carbidopa/levodopa.27 Methylphenidate (Ritalin) may patients who have Parkinson disease.33 Mild depres-
improve fatigue in patients with the disease.28 Exces- sion can be difficult to diagnose, because some of the
sive daytime sleepiness occurs in more than one-half of motor symptoms of Parkinson disease and depres-
patients who have Parkinson disease, and is caused by sion overlap.4 Physicians should have a high index of
both the disease itself and the adverse effects of medi- suspicion for de­pression, and consider screening with
cations, such as dopamine agonists.29 Physicians should the Beck De­pression Inventory.34 Amitriptyline, desip-
educate patients about good sleep hygiene.11 Melatonin is ramine (Norpramin), and nortriptyline (Pamelor)
not effective for improving sleep.4 Three small random- improve depression in patients with Parkinson dis-
ized trials show that modafinil (Provigil) improves sub- ease.4,34,35 However, tricyclic antidepressants can cause
jective measures of sleepiness without changing objective anticholinergic adverse effects and should not be used
measures of sleep.28 It should not be used to prevent sleep in patients with cognitive impairment. When choosing
attacks that may interfere with potentially hazardous an antidepressant, physicians should take into consid-
activities.4 Physicians should advise patients with sleep eration comorbid conditions and the potential for drug
attacks to refrain from hazardous activities, such as driv- interactions.4,11,34
ing or operating machinery.11 Psychosis, manifested by visual or auditory hallucina-
In one study, rapid eye movement sleep behavior dis- tions and delusions, is treated most effectively with clo-
order was found in 46 percent of patients with Parkin- zapine (Clozaril). It requires weekly monitoring because
son disease.30 This disorder is characterized by dramatic of the risk of agranulocytosis.4,11,34 If regular monitoring
and potentially violent behaviors that occur during sleep, is not possible, quetiapine (Seroquel) is modestly effec-
such as yelling, kicking, or jumping, and diagnosis is con- tive.4,11,34 Olanzapine (Zyprexa) worsens motor symp-
firmed by video polysomnography in a sleep laboratory.31 toms and is not effective for psychosis in patients with
Limited data suggest that rapid eye movement sleep Parkinson disease.4,11,34 Typical antipsychotics (e.g.,
behavior disorder may respond to low-dose clonazepam haloperidol) should be avoided because they will worsen
(Klonopin).31 Other movement disorders affecting sleep, motor symptoms.4
such as restless legs syndrome and periodic limb move-
DEMENTIA
ment disorder, occur in almost 20 percent of patients with
Parkinson disease. One small study showed that taking Dementia becomes more prevalent as Parkinson dis-
carbidopa/levodopa at bedtime decreased the number of ease progresses. In two studies of patients with Parkin-
movements in patients with restless legs syndrome.28 son disease, 44 percent of whom met the Diagnostic and
Statistical Manual of Mental Disorders, 4th ed., criteria
DISORDERS OF AUTONOMIC FUNCTION for dementia, the Mini-Mental State Examination had a
Autonomic dysfunction, evidenced by orthostatic hypo- sensitivity of 98 percent and a specificity of 77 percent,
tension, erectile dysfunction, urinary incontinence, and and the longer Cambridge Cognitive Examination had a

February 15, 2013 ◆ Volume 87, Number 4 www.aafp.org/afp American Family Physician 271
Parkinson Disease

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Physicians who have limited experience caring for patients with Parkinson disease should consider C 4, 11
referring a patient with suspected disease to a physician who has expertise in movement disorders to
confirm the diagnosis.
Carbidopa/levodopa (Sinemet), nonergot dopamine agonists, or monoamine oxidase-B inhibitors should be A 4, 11, 15
used for initial treatment of Parkinson disease.
Nonergot dopamine agonists, catechol O-methyltransferase inhibitors, or monoamine oxidase-B inhibitors A 4, 11, 21, 23
should be added to levodopa to treat motor complications in advanced Parkinson disease.
Amantadine should be considered for treatment of dyskinesias in patients with advanced Parkinson disease. B 4, 11, 21
Deep brain stimulation should be offered to patients with functional impairment despite optimal medical B 25, 26
treatment, but it should be performed in experienced centers, and it carries a risk of serious adverse effects.
Physical therapy should be offered to patients with Parkinson disease to improve gait, and speech therapy B 11, 20
should be offered to improve speech volume.
Occupational therapy may help patients with Parkinson disease to maintain family, social, and work roles; C 11
continue activities of daily living; and improve safety and motor function.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
org/afpsort.xml.

sensitivity of 95 percent and a specificity of 98 percent.34 written, she was a PGY-3 resident in the Department of Family Medicine
Clinicians should evaluate patients for other causes of at the University of Virginia School of Medicine.
dementia, and consider discontinuing anticholinergic KARL CLEBAK, MD, is a staff physician at Lake Monticello Primary Care in
or dopaminergic medications that may contribute to Palmyra, Va. At the time this article was written, he was a chief resident
in the Department of Family Medicine at the University of Virginia School
cognitive impairment.4,11 In controlled trials, rivastig- of Medicine.
mine (Exelon) therapy has led to small but clinically
significant improvements in cognitive, clinical, and Address correspondence to John D. Gazewood, MD, MSPH, CAQGM,
University of Virginia Health System, P.O. Box 800729, Charlottesville,
activities of daily living scales, but has caused increased VA 22911 (e-mail: [email protected]). Reprints are not available from
tremor and vomiting.4,11,34 Donepezil (Aricept) also the authors.
improves cognitive function. Although dropout rates Author disclosure: No relevant financial affiliations to disclose.
in placebo-controlled trials with donepezil are lower
than those with rivastigmine, no studies have directly
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