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Parkinson disease

Article in Annals of Internal Medicine · November 2012

DOI: 10.7326/0003-4819-157-9-20121106-01005 · Source: PubMed

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 In theClinic
In the Clinic

Parkinson
Disease
Diagnosis page ITC5-2

Treatment page ITC5-7

Tool Kit page ITC5-14

Patient Information page ITC5-15

CME Questions page ITC5-16

Physician Writer The content of In the Clinic is drawn from the clinical information and education
Kelvin L. Chou, MD resources of the American College of Physicians (ACP), including PIER (Physicians’
Information and Education Resource) and MKSAP (Medical Knowledge and Self-
Section Editors Assessment Program). Annals of Internal Medicine editors develop In the Clinic
Deborah Cotton, MD, MPH from these primary sources in collaboration with the ACP’s Medical Education and
Darren Taichman, MD, PhD Publishing divisions and with the assistance of science writers and physician writ-
Sankey Williams, MD ers. Editorial consultants from PIER and MKSAP provide expert review of the con-
tent. Readers who are interested in these primary resources for more detail can
consult http://pier.acponline.org, http://www.acponline.org/products_services/
mksap/15/?pr31, and other resources referenced in each issue of In the Clinic.

CME Objective: To review current evidence for the diagnosis and treatment of
Parkinson disease.

The information contained herein should never be used as a substitute for clinical
judgment.

© 2012 American College of Physicians

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 arkinson disease is a progressive neurodegenerative disorder that af-

P fects approximately 1% of persons older than 65 years and 2.5% of

persons older than 80 years (1). More than 4 million individuals are
affected worldwide, and this number is expected to double by 2030 (2). The
disease is associated with increased morbidity and mortality and a high eco-
nomic burden. The direct cost of care for Parkinson disease in the United
States varies from $2000 to more than $15 000 a year for each patient (3).

The cause of Parkinson disease is unknown. When observers examine the part
1. Nussbaum RL, Ellis CE.
of the brain known as the substantia nigra pars compacta, they find reduced
Alzheimer’s disease numbers of neurons; gliosis; and Lewy bodies, which are round, eosinophilic,
and Parkinson’s dis-
ease. N Engl J Med.
intracytoplasmic inclusions containing α-synuclein. Similar changes can be
2003;348:1356-64. found in other brainstem nuclei, such as the locus ceruleus and the dorsal vagal
[PMID: 12672864]
2. Dorsey ER, Constanti- nucleus (4). Neurons in the substantia nigra pars compacta provide the largest
nescu R, Thompson
JP, Biglan KM, Hol-
input of dopamine to the striatum, and their loss leads to the motor features of
loway RG, Kieburtz K, Parkinson disease. The mechanism of neuronal death is unclear, and there is
et al. Projected num-
ber of people with
ongoing debate about whether Lewy bodies are part of the disease or a com-
Parkinson disease in pensatory mechanism that benefits the neuron.
the most populous
nations, 2005
through 2030. Neu- Parkinson disease has long been considered a motor system disorder, but it is now
rology. 2007;68:384-6.
[PMID: 17082464]
recognized that many nonmotor manifestations are part of the clinical picture.
3. Weintraub D, Comella These manifestations are diverse and include sensory, neuropsychiatric, and
CL, Horn S. Parkin-
son’s disease—-Part autonomic symptoms (5).
1: Pathophysiology,
symptoms, burden,
diagnosis, and assess- Diagnosis
ment. Am J Manag
Care. 2008;14:S40-8. What symptoms should prompt a typing or buttoning clothes. Other
[PMID: 18402507] clinician to consider a diagnosis of common symptoms of bradykinesia
4. Dickson DW, Braak H,
Duda JE, Duyckaerts Parkinson disease? include dragging the legs; shorter
C, Gasser T, Halliday
GM, et al. Neu-
A clinician should consider a diag- steps (shuffling); a feeling of unsteadi-
ropathological as- nosis of Parkinson disease when one ness; and difficulty turning over in
sessment of Parkin-
son’s disease: refining of the following clinical features is bed, standing up from a chair, or get-
the diagnostic crite- present: tremor at rest, bradykinesia, ting out of a car.
ria. Lancet Neurol.
2009;8:1150-7. or rigidity (6). Clinical features of
[PMID: 19909913] Parkinson disease are typically asym- Rigidity is increased resistance to
5. Langston JW. The
Parkinson’s complex: metric, starting on one side and passive joint movement. When
parkinsonism is just
spreading to the other after a few “cogwheel rigidity” occurs, there is
the tip of the iceberg.
Ann Neurol. years; the initially affected side con- a ratchet-like pattern of catch and
2006;59:591-6.
[PMID: 16566021] tinues to be more severely affected release as the examiner moves the
6. Lang AE, Lozano AM. throughout the course of the disease. patient’s limb through its range of
Parkinson’s disease.
First of two parts. N motion. Some patients may instead
Engl J Med. The rest tremor in Parkinson dis- have “lead-pipe rigidity,” which is a
1998;339:1044-53.
[PMID: 9761807] ease typically has a frequency of smooth resistance through the range
7. Ponsen MM, Stoffers
D, Booij J, van Eck-
3–7 Hz and is described as “pill- of motion. Rigidity can affect any
Smit BL, Wolters ECh, rolling.” The tremor often occurs in part of the body and may contribute
Berendse HW. Idio-
pathic hyposmia as a the hands when they are resting or to pain and stiffness.
preclinical sign of when the patient is walking, but
Parkinson’s disease.
Ann Neurol. parkinsonian tremor can also occur Onset of these symptoms can be
2004;56:173-81. in the legs, lips, jaw, and tongue. subtle. Because Parkinson disease
[PMID: 15293269]
8. Schenck CH, Bundlie commonly occurs in older persons,
SR, Mahowald MW. Bradykinesia is a generalized slowness family members and clinicians may
Delayed emergence
of a parkinsonian dis- of movement. Although some patients attribute early symptoms to some-
order in 38% of 29
older men initially di-
may have slowed movement, many thing else. For example, stiffness or
agnosed with idio- will describe bradykinesia as “weak- pain may be attributed to arthritis or
pathic rapid eye
movement sleep be- ness,” “incoordination,” or “tiredness.” aging. Astute clinicians will consider
haviour disorder. Bradykinesia interferes with a patient’s Parkinson disease as a possibility
Neurology.
1996;46:388-93. ability to do fine motor tasks, such as when these symptoms progress.
[PMID: 8614500]

© 2012 American College of Physicians ITC5-2 In the Clinic Annals of Internal Medicine 6 November 2012

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 What should clinicians ask
patients when evaluating them
for Parkinson disease?
Clinicians should ask patients about
tremor at rest, bradykinesia, and stiff-
ness, which is how most people expe-
rience rigidity. They also should ask
about the other common symptoms
of Parkinson disease, which include a
decreased volume of speech (hypo-
phonia), smaller handwriting (micro-
graphia), drooling or excess saliva in
the mouth, difficulty turning over in
bed, changes in posture (especially
stooping), changes in gait (such as
smaller steps or freezing in place),
constipation, anxiety, and depression.
In addition, clinicians should ask
about olfactory dysfunction and rapid
eye movement (REM) sleep behavior
disorder (which is characterized by
kicking, grabbing, yelling, falling, or
other dream-enactment behaviors
during REM sleep) because olfactory
dysfunction and REM sleep behavior
disorder often precede the onset of
motor manifestations (7, 8).
Finally, clinicians should ask about
exposure to drugs that can cause the
symptoms of Parkinson disease
(parkinsonism) but not the disease it-
self. Neuroleptics are the best-known
of these drugs, but atypical antipsy-
chotic agents also induce parkinsonism
(9). Notable exceptions include cloza-
pine and quetiapine (10). Antiemetic
agents, such as prochlorperazine or
metoclopramide, also cause parkinson-
ism and are often overlooked.
Clinicians should ask about a family
history of Parkinson disease because
an individual who has a first-degree
relative with Parkinson disease has a
2-fold higher risk for the disease than
someone without this history (11). Fi-
nally, clinicians should pay attention to
signs or symptoms that suggest a con-
dition other than Parkinson disease.
For example, postural instability does
not generally occur until later in the
disease course, and its presence early
on should prompt an evaluation for an
alternative diagnosis (12) (See the
6 November 2012 Annals of Internal Medicine
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Box: Features Suggesting a Diagnosis
Other Than Parkinson Disease ).
What should a clinician do during
the physical examination of a
patient with possible Parkinson
disease?
Clinicians should do a thorough neu-
rologic examination in patients with
suspected Parkinson disease, paying
special attention to decreased eye
blinking and diminished expression.
Tremor should be assessed when the
patient is sitting down with the hands
resting on the lap. Asking the patient
to do mental calculations or repetitive
movements of the contralateral limb
may accentuate a mild tremor or re-
veal a latent tremor. The tremor
should lessen with maintenance of
posture or during use of the involved
limb. To examine for bradykinesia, the
clinician should ask the patient to
move the limbs rapidly and repetitively
by, for example, tapping the index fin-
ger and thumb together, opening and
closing the hand, moving the hand
from pronation to supination, and al-
ternately tapping the heel and toe on
the ground. In mild Parkinson disease,
some slowing and decreased ampli-
tude will be seen after a few seconds,
but movements become less coordi-
nated as the disease progresses. Rigid-
ity should be tested by passively
manipulating the limbs. Asking the
patient to do repetitive maneuvers
with the contralateral limb may accen-
tuate rigidity. Also, clinicians should
ask the patient to stand up from a
chair without using the arms. When
the patient walks, it should be noted
how many steps are needed to turn
around and whether there is decreased
step length; decreased arm swing; or a
hand tremor, which may occur only
during walking. Clinicians should
assess postural stability with the “pull”
test, which involves standing behind
the patient who has been asked to
maintain an upright posture, and
firmly pulling backward on the shoul-
ders, being careful to prevent falling.
Patients with normal postural reflexes
should be able to recover upright pos-
ture with no more than 1 or 2 steps.
In the Clinic ITC5-3
Features Suggesting a Diagnosis
Other Than Parkinson Disease
History of encephalitis
History of repeated head injury
History of recurrent strokes with
stepwise progression of parkinsonism
History of oculogyric crisis (restlessness,
agitation, or malaise with a fixed
stare followed by sustained, usually
upward deviation of the eyes;
backward and lateral flexion of the
neck; and mouth and tongue
movements lasting minutes or hours
and concluding abruptly)
Current or recent (within 6–12 mo) use
of dopaminergic blockers or depletors
Structural abnormality with brain
imaging
Supranuclear gaze palsy (normal reflex
eye movements but an inability to
voluntarily look in a specific
direction)
Frequent falls at presentation or early
in the disease course
Dementia preceding or concurrent with
the onset of parkinsonism
Cerebellar signs
Autonomic nervous system dysfunction,
such as urinary incontinence, urine
retention requiring catheterization,
persistent erectile failure, or
orthostatic hypotension, early in the
disease course
Spasticity, hyperreflexia, or Babinski
responses
Inability to carry out learned motor
skills on command or in imitation
(apraxia)
Impaired sensation despite intact
primary sensory systems; for example,
impaired ability to identify objects in
hand with eyes closed but intact
perception of pinprick and touch
(corticosensory deficits)
Abrupt onset of symptoms or sustained
spontaneous remission of symptoms
Unilateral features after 3 y
Symmetrical motor signs
9. Rochon PA, Stukel TA,
Sykora K, Gill S,
Garfinkel S, Anderson
GM, et al. Atypical an-
tipsychotics and
parkinsonism. Arch
Intern Med.
2005;165:1882-8.
[PMID: 16157833]
© 2012 American College of Physicians
 How does the clinician establish a the cornea around the outer edge of
10. Miyasaki JM, Shan- diagnosis of Parkinson disease? the iris.
non K, Voon V, Rav-
ina B, Kleiner-Fisman Parkinson disease is a clinical diagno-
G, Anderson K, et al; sis. It depends on the history and What other conditions should be
Quality Standards
Subcommittee of physical examination because there are considered in the differential
the American Acad-
no readily available tests for diagnosis. diagnosis?
emy of Neurology.
Practice Parameter: It is generally accepted that bradyki- Tremor, bradykinesia, rigidity, and
evaluation and treat-
ment of depression, nesia plus tremor or rigidity should be postural instability are prominent in
psychosis, and de- present. Asymmetrical onset with per- many other disorders. The atypical
mentia in Parkinson
disease (an evi- sistent asymmetry as the disease pro- parkinsonian syndromes are neurode-
dence-based re-
gresses (the initially symptomatic side generative disorders that include
view): report of the
Quality Standards remains more severely affected) and multiple system atrophy, progressive
Subcommittee of
the American Acad- sustained clinical improvement with supranuclear palsy, corticobasal gan-
emy of Neurology.
levodopa or a dopamine agonist are glionic degeneration, and dementia
Neurology.
2006;66:996-1002. highly supportive of the diagnosis with Lewy bodies. They may be indis-
[PMID: 16606910]
11. Marder K, Tang MX, (13). Signs suggesting an alternative tinguishable from Parkinson disease
Mejia H, Alfaro B, condition should be ruled out (See the on clinical grounds, especially in the
Côté L, Louis E, et al.
Risk of Parkinson’s Box: Features Suggesting a Diagnosis early stages of disease. However, they
disease among first-
Other Than Parkinson Disease). typically respond poorly or not at all
degree relatives: A
community-based to levodopa, unlike Parkinson disease.
study. Neurology.
1996;47:155-60.
What tests should be considered Essential tremor may occasionally be
[PMID: 8710070] in the evaluation of possible confused with Parkinson disease, es-
12. Suchowersky O, Re-
ich S, Perlmutter J, Parkinson disease? pecially in patients who have a promi-
Zesiewicz T, Gron-
seth G, Weiner WJ;
Clinicians should do magnetic reso- nent tremor. Some gait disorders,
Quality Standards nance imaging (MRI) of the brain including normal pressure hydro-
Subcommittee of
the American Acad- (or computed tomography if MRI is cephalus, vascular parkinsonism, and
emy of Neurology. contraindicated) if the diagnosis is un- primary progressive freezing gait, can
Practice Parameter:
diagnosis and prog- certain because it may reveal abnor- be confused with Parkinson disease.
nosis of new onset Other neurodegenerative disorders,
Parkinson disease malities that suggest another cause of
(an evidence-based parkinsonism, such as severe vascular such as Alzheimer disease, may also
review): report of
the Quality Stan- changes, tumor, hydrocephalus, or oth- have prominent parkinsonian features.
dards Subcommittee
of the American
er changes of diagnostic significance. Finally, parkinsonism may be caused
Academy of Neurol- by medications, toxins, metabolic
ogy. Neurology.
2006;66:968-75.
Positron emission tomography (PET) problems, trauma, infection, ischemic
[PMID: 16606907] and single-photon emission computed insults, tumors, other mass lesions, or
13. Hughes AJ, Daniel
SE, Kilford L, Lees AJ. tomography (SPECT) can detect ab- genetic mutations (Table 1).
Accuracy of clinical normalities of the dopaminergic sys-
diagnosis of idio-
pathic Parkinson’s tem that may help diagnose early When should a specialist be
disease: a clinico-
Parkinson disease. However, PET is consulted for the diagnosis of
pathological study
of 100 cases. J Neu- typically available only in research Parkinson disease?
rol Neurosurg Psy-
chiatry. 1992;55:181- centers. Although the US Food and A neurologist should be consulted for
4. [PMID: 1564476] Drug Administration (FDA) recently any patient with early symptoms of
14. Benamer TS, Patter-
son J, Grosset DG, approved 123I-ioflupane dopamine Parkinson disease; this allows the pa-
Booij J, de Bruin K,
van Royen E, et al. transporter SPECT imaging to differ- tient and family to obtain a second
Accurate differentia- entiate parkinsonism from essential opinion and gives the patient a chance
tion of parkinsonism
and essential tremor tremor when it is difficult to distin- to learn more about the condition. A
using visual assess-
guish the conditions clinically (14), it neurologist may also be more likely to
ment of [123I]-FP-
CIT SPECT imaging: cannot differentiate Parkinson disease diagnose or rule out atypical parkin-
the [123I]-FP-CIT
study group. Mov from other parkinsonian syndromes. sonian syndromes, which would alter
Disord. 2000;15:503- the long-term prognosis if present.
10. [PMID: 10830416
15. Hughes AJ, Daniel For patients younger than 40 years There are no data suggesting that a
SE, Ben-Shlomo Y, with parkinsonism, Wilson disease neurologist specializing in Parkinson
Lees AJ. The accura-
cy of diagnosis of should be ruled out with serum cerulo- disease or movement disorders is more
parkinsonian syn-
dromes in a special-
plasmin measurement; 24-hour urinary cost-effective or more acceptable to
ist movement disor- copper test; and ophthalmologic refer- patients than a general neurologist;
der service. Brain.
2002;125:861-70. ral to look for Kayser–Fleischer rings, however, these specialists may diagnose
[PMID: 11912118] which are caused by copper deposits in Parkinson disease more accurately (15).

© 2012 American College of Physicians ITC5-4 In the Clinic Annals of Internal Medicine 6 November 2012

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 Table 1. Differential Diagnosis of Parkinson Disease
Condition
Parkinson disease with
known genetic cause
LRRK2-associated Parkinson
disease
Autosomal recessive juvenile
parkinsonism (due to a parkin
gene mutation)
Autosomal-dominant Parkinson
disease due to an α-synuclein
gene mutation
Other conditions
Multiple system atrophy
Progressive supranuclear palsy
Corticobasal degeneration
Dementia with Lewy bodies
Essential tremor
Vascular parkinsonism
6 November 2012 Annals of Internal Medicine
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Characteristics
Most common form of monogenic Parkinson disease. The
features of LRRK2-associated disease are generally indis-
tinguishable from those of idiopathic disease. Patients
respond well to levodopa.
This is currently considered as an autosomal recessive condition
due to a mutation in the parkin gene, and usually affects
persons aged <20 y. It is not associated (to date) with Lewy
bodies, which are the pathologic hallmark of Parkinson disease.
This condition is not fully understood, but parkin is suspected
to play a role in some cases of sporadic Parkinson disease.
α-synuclein is the first gene to be associated with autosomal-
dominant Parkinson disease. Two mutations were discovered:
1 in Greek and Italian families, and the other in a single
German family.
Characterized by autonomic failure with urinary incontinence
(or erectile dysfunction in men) or orthostatic hypotension
and parkinsonism or a cerebellar syndrome. Patients with
autonomic dysfunction and parkinsonism are labeled “MSA-P,”
whereas those with autonomic dysfunction and a cerebellar
syndrome are labeled “MSA-C.”
Patients often present with unexplained falls, typically backward.
They may have a “surprised” facial appearance and erect posture
and show minimal response to levodopa. Later in the disease
course, patients may show cognitive impairment, harsh dysar-
thric speech, dysphagia, and impaired vertical saccades before
developing a frank supranuclear gaze palsy. The disease course is
often rapid, leaving the patient cognitively impaired, wheelchair-
bound, and at risk for aspiration after several years of symptoms.
Presents with asymmetrical onset, typically with unilateral
impaired hand function due to rigidity, dystonia (abnormal
limb posturing), myoclonus (brief shock-like jerk movements),
and/or apraxia (inability to perform a previously learned task).
Loss of cortical sensory function and alien limb phenomenon
(wandering limb) may also occur. Cognitive impairment is
common, and these patients are poorly responsive to
dopaminergic treatment.
The central feature is progressive cognitive decline. Core features
include parkinsonism, fluctuations in cognition, and visual hal-
lucinations. Suggestive features include REM behavior disorder,
sensitivity to dopaminergic antagonists, and low dopamine trans-
porter uptake in the basal ganglia on SPECT and PET. Typically,
dementia precedes or accompanies the onset of parkinsonism.
Symmetrical action tremor typically of the hands and arms, but
also commonly involving the head and voice. Tremor is apparent
when the upper limbs are engaged in activities such as writing
or eating, but not at rest. Often, other family members may have
similar tremors, and the tremors may be responsive to alcohol.
Also known as lower-body parkinsonism with a wide-based
gait and often freezing of gait, but relatively few parkinsonian
features in the upper extremities. Seen in patients with stroke
risk factors, prior strokes, and white matter changes on MRI.
In the Clinic ITC5-5
Notes
This gene is estimated to cause as much as
50% of familial Parkinson disease in persons
of North African and Middle Eastern origin.
The G2019S mutation is the most common of
the LRRK2 mutations.
The parkin mutation is probably a rare cause
of parkinsonism that primarily affects young
persons; is seen worldwide. Parkin may
account for many young-onset (aged <40 y)
cases of parkinsonism.
This type of gene mutation is extremely rare;
other genetic causes are under study.
Multiple system atrophy is characterized by
early autonomic dysfunction, parkinsonism
with a poor response to dopaminergic
therapy (no response or short-lived response),
incoordination (ataxia) in a patient without a
family history of ataxia, or a combination of
these features. An MRI brain scan may show
characteristic findings (e.g., putaminal
“necrosis” or cerebellar atrophy).
Key early features are parkinsonism, falls, and
minimal response to dopaminergic therapy.
Supranuclear gaze palsy may develop later in
the disease course. Midbrain atrophy may be
seen on an MRI brain scan late in the course
of disease. Eye movement and cognitive stud-
ies may be useful for this diagnosis.
Cognitive impairment with asymmetrical limb
dysfunction along with minimal response to
dopaminergic therapy are clues to this
diagnosis. Absence of tremor is typical and
helps to distinguish it from Parkinson disease.
Parietal atrophy on MRI scan supports this
diagnosis. Treatment is supportive.
For a diagnosis of probable dementia with
Lewy bodies, the central feature plus 2 core
features (or, alternatively, the central feature
plus 1 core and 1 suggestive feature) are
needed.
This is the most common tremor condition.
Family history and alcohol responsiveness are
not necessary to diagnose essential tremor.
123
I-ioflupane dopamine transporter SPECT
imaging may be able to differentiate
parkinsonism from essential tremor.
Pathologic, clinical correlative studies are
limited.
© 2012 American College of Physicians
 Table 1. Differential Diagnosis of Parkinson Disease (Continued)
Condition
Normal pressure hydrocephalus
Medication-induced parkinsonism
Toxin- or metabolic-related
parkinsonism
Posttraumatic parkinsonism
Postencephalitic parkinsonism
Parkinsonism associated with
a tumor, subdural hematoma,
or infection
Wilson disease
Alzheimer dementia
Psychogenic parkinsonism
Dopa-responsive dystonia
CNS = central nervous system; CSF = cerebrospinal fluid; CT = computed tomography; LRRK2 = leucine-rich repeat kinase 2; MPTP = 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine; MRI = magnetic resonance imaging; MSA = multiple system atrophy; PET = positron emission tomography; REM = rapid eye
movement; SPECT = single-photon emission computed tomography.
© 2012 American College of Physicians
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Characteristics Notes
The triad of symptoms characteristic of normal pressure It may be difficult to differentiate normal-pressure
hydrocephalus begins with gait difficulties (a wide-based hydrocephalus from generalized cerebral
“magnetic gait”), followed by bladder and cognitive dysfunction. atrophy radiographically. Therefore ,the
MRI or CT brain imaging shows enlarged ventricles without history and examination combined with a “tap”
commensurate cerebral atrophy. Clinical improvement after removal test and/or CSF flow study may help.
of ≥30 mL of CSF may support the diagnosis, but the “tap test” is not It is important to consider the risks of
very reliable. MRI CSF flow studies are also supportive. Despite the placing a shunt (infection, shunt failure).
lack of a reliable diagnostic test, ventriculoperitoneal shunting may
provide a sustained benefit in some patients with presumed
normal pressure hydrocephalus.
Parkinsonism in the setting of exposure to dopamine-blocking Careful review of medications is necessary to
agents. Metoclopramide, prochlorperazine, tetrabenazine, make this diagnosis. Signs should resolve within
reserpine, and the antipsychotic agents with phenothiazine or months of stopping the offending agent but
butyrophenone structures are the common agents. may take as long as a year to resolve. Persistent
parkinsonian signs beyond 6–12 mo after
stopping an offending agent suggest an
alternative cause.
Exposure to manganese, carbon monoxide, carbon disulfide, History of exposure to selective toxins or
MPTP, and cyanide, as well as posthypoxic and parathyroid presence of a specific metabolic disorder
dysfunction, are all associated with a parkinsonian state. suggest this diagnosis.
Typically, affected patients have a history of coma followed by Recovery after a severe head injury that
recovery in which parkinsonism is seen. Less severe head injury resulted in coma may be accompanied by
might cause parkinsonism, but this remains poorly understood. the development of parkinsonian features.
This variant of parkinsonism is presumed to be caused by a virus. A recent history of a febrile illness with
Affected patients develop respiratory irregularities, oculogyric delirium before onset of parkinsonism
crises (marked by sustained eye deviation), and parkinsonism suggests postencephalitic parkinsonism.
after recovery from fever. At present, various viruses have
infrequently been associated with parkinsonian sequelae.
Various brain structural abnormalities may manifest with Brain imaging studies should be ordered for
parkinsonism, such as CNS infections seen in immunocompro- patients with significant medical conditions.
mised patients. Other more insidious infections, such as Occasionally, CSF analysis is appropriate to
Creutzfeldt–Jakob disease or HIV can manifest with eliminate a central infection agent or cancer.
parkinsonian features.
An autosomal recessive condition that usually presents with Patients aged <40–50 y with parkinsonism
hepatic or neurologic symptoms during adolescence or should have a work-up for Wilson disease.
young adulthood. Neurologic presentation often includes dys- This includes a slit lamp examination to rule
arthria, cognitive changes, and an assortment of movement out Kayser–Fleischer rings, and measurement
disorders (e.g., tremor and parkinsonism). of 24-h urine copper and serum ceroplas-
min levels; rarely, a liver biopsy is needed for
diagnosis.
Initially presents with cognitive changes. Parkinsonian Early cognitive changes herald a diagnosis of
features (bradykinesia, rigidity) are seen in later stages Alzheimer dementia or other dementing
because of pathologic involvement of the basal ganglia. conditions. In advanced parkinsonism, cogni-
Alzheimer pathology can coexist with changes of tive impairment may occur, of which there
Parkinson disease. are numerous potential causes, including
Alzheimer dementia.
This condition is uncommon and requires clinical expertise to Psychogenic parkinsonism is rare.
differentiate from other forms of parkinsonism. Caution should
be used in making this diagnosis.
Dopa-responsive dystonia is an autosomal-dominant This condition should be suspected in
transmitted condition associated with a mutation in children, adolescents, and young adults who
the gene for guanosine triphosphate cyclohydrolase I, present with foot dystonia, unusual cases of
which plays a role in the rate of dopamine production. cerebral palsy, or parkinsonism. A dramatic
Dopa-responsive dystonia may present with twisting of and sustained response to low-dose levo-
a foot (i.e., lower limb dystonia) or a parkinsonian-like dopa supports the diagnosis.
condition; however, unlike Parkinson disease, it responds
quite well to low doses of levodopa over a long period.
ITC5-6 In the Clinic Annals of Internal Medicine 6 November 2012
 Diagnosis... Clinicians should consider a diagnosis of Parkinson disease when a patient
has rest tremor, bradykinesia, or rigidity. They should conduct a thorough history and
neurologic examination and pay close attention to medications that may cause parkin-
sonism. The diagnosis should be based on clinical findings, although MRI may help rule
out secondary causes and 123I-ioflupane dopamine transporter SPECT imaging may help
differentiate parkinsonism from essential tremor. Alternative diagnoses should be consid-
ered and a neurologist should be consulted if atypical signs or symptoms are present or
the patient does not respond to typical doses of levodopa or a dopamine agonist.

CLINICAL BOTTOM LINE

Treatment
What is the role of exercise? medication as soon as possible; how-
Exercise has modest benefits in motor ever, no such medication has yet been
and functional outcomes. No specific identified (16).
form of exercise has been proven su-
perior, although researchers have In 1 double-blind trial, researchers randomly
assigned 1176 patients with untreated Parkin-
studied physical and occupational
son disease to an early-start group that re-
therapy, treadmill training, balance ceived rasagiline (1 or 2 mg/d) for 72 weeks or
training, and high-intensity resistance a delayed-start group that received placebo
training (16). Gains in motor function for 36 weeks followed by rasagiline (at a dose
may be lost if the activity is not con- of 1 or 2 mg/d) for the next 36 weeks. The re-
tinued on a regular basis. sults showed that early treatment with rasag-
iline at 1 mg/d, but not 2 mg/d, was consistent
Should patients alter their diets? with a disease-modifying effect when re-
Major alterations to the diet are usu- searchers used a 176-point scale to measure
ally unnecessary. However, it is im- the severity of Parkinson disease. Although the
portant that the diet include adequate authors suggested that a dose of 2 mg/d may 16. Suchowersky O,
fiber and hydration because constipa- have alleviated symptoms enough to mask Gronseth G, Perlmut-
ter J, Reich S, Ze-
tion is often an issue. The diet should any disease-modifying effect, many observers siewicz T, Weiner WJ.
also include enough calcium and vita- have concluded that rasagiline was not con- Practice Parameter:
neuroprotective
clusively proven to slow clinical progression of
min D to prevent osteoporosis be- strategies and alter-
Parkinson disease (17), and the FDA has not native therapies for
cause osteopenia is more common in approved the drug for this purpose. Parkinson disease
(an evidence-based
patients with Parkinson disease. In review): report of
addition, low-protein diets may help What drugs should be used for the Quality Stan-
dards Subcommittee
some patients who experience the initial treatment and how should of the American
Academy of Neurol-
“on–off ” phenomenon, which is an they be chosen? ogy. Neurology.
unpredictable shift from mobility For a patient with early, mild Parkin- 2006;66:976-82.
[PMID:16606908]
(“on”) to a sudden inability to move son disease whose symptoms cause 17. Olanow CW, Rascol
(“off ”) that may be worsened when O, Hauser R, Feigin
functional impairment, there are PD, Jankovic J, Lang
neutral amino acids associated with a several options (18) (Table 2). Most A, et al; ADAGIO
Study Investigators.
high-protein meal compete with levo- often, the clinician should decide A double-blind,
dopa for absorption from the gastro- between levodopa and a dopamine delayed-start trial of
rasagiline in Parkin-
intestinal track. agonist. However, there are also roles son’s disease. N Engl
J Med.
for anticholinergics and inhibitors of 2009;361:1268-78.
When should drug therapy be the B isoform of monoamine oxidase [PMID: 19776408]
18. Miyasaki JM, Martin
started? (MAO-B), which prevents dopamine W, Suchowersky O,
Drug therapy should begin when breakdown.
Weiner WJ, Lang AE.
Practice parameter:
symptoms interfere with what the pa- initiation of treat-
ment for Parkinson’s
tient wants to do. If a patient has a Levodopa is the most effective med- disease: an evi-
mild rest tremor that does not limit ication for managing motor symp- dence-based review:
report of the Quality
activities, it is not necessary to begin toms in Parkinson disease. However, Standards Subcom-
mittee of the Ameri-
treatment. If a medication existed that long-term use is associated with mo- can Academy of
could slow the progression of the dis- tor complications, such as dyskinesia Neurology. Neurolo-
gy. 2002;58:11-7.
ease, it would make sense to start that (involuntary choreiform movements [PMID: 11781398].

6 November 2012 Annals of Internal Medicine In the Clinic ITC5-7 © 2012 American College of Physicians

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 affecting any part of the body) and a 1 half-tablet 3 times daily for a week
“wearing-off ” effect (recurrence of before increasing gradually to 1 full
symptoms when plasma levodopa tablet 3 times daily. Controlled- or
19. Holloway RG, Shoul- levels decrease, which typically occurs sustained-release formulations of
son I, Fahn S,
Kieburtz K, Lang A, toward the end of the period between levodopa are less completely ab-
Marek K, et al;
Parkinson Study
doses). These motor complications sorbed and require doses as much as
Group. Pramipexole develop at a rate of 10% annually in 30% higher to achieve the same clin-
vs levodopa as initial
treatment for Parkin- patients older than 60 years, but they ical effect. If the patient takes levo-
son disease: a 4-year
randomized con-
develop more rapidly and are more dopa at doses greater than 1000
trolled trial. Arch severe in younger patients. Dopamine mg/d and there is no alleviation of
Neurol.
2004;61:1044-53. agonists, such as pramipexole and symptoms, an alternative diagnosis
[PMID: 15262734] ropinirole, may delay these motor should be considered.
20. Rascol O, Brooks DJ,
Korczyn AD, De complications when used instead of
Deyn PP, Clarke CE,
Lang AE. A five-year
levodopa as the initial treatment (19, In the United States, the dopamine
study of the inci- 20). Most clinicians initiate therapy agonists ropinirole, pramipexole, rotig-
dence of dyskinesia
in patients with early with a dopamine agonist in younger otine, bromocriptine, and apomorphine
Parkinson’s disease patients (aged <50 years) and levo- are approved for use in Parkinson dis-
who were treated
with ropinirole or dopa in older patients (aged >70 ease. However, only ropinirole,
levodopa. 056 Study
Group. N Engl J Med. years). Between these ages, there is pramipexole, and rotigotine, which are
2000;342:1484-91. no consensus on first-line therapy. All nonergot agonists, are typically used as
[PMID: 10816186]
21. Ives NJ, Stowe RL, patients, however, eventually require initial monotherapy. Pergolide, an er-
Marro J, Counsell C, got agonist, has been taken off the
Macleod A, Clarke
levodopa.
CE, et al. Mono- market because of concerns about car-
amine oxidase type A prospective, randomized, double-blind diac valve problems, and bromocrip-
B inhibitors in early
study compared ropinirole with levodopa as
Parkinson’s disease: tine, another ergot agonist, should not
meta-analysis of 17 initial treatment in 268 patients with early
randomised trials in-
Parkinson disease. Patients in the ropinirole
be used as initial therapy because of
volving 3525 pa-
tients. BMJ. group were less likely to have dyskinesia at 5 similar concerns. Apomorphine is an
2004;329:593.
years than those in the levodopa group injectable drug with a quick onset of
[PMID: 15310558]
22. Pahwa R, Factor SA, (hazard ratio [HR], 0.35 [95% CI, 0.23–0.56]; action and short duration of effect
Lyons KE, Ondo WG,
Gronseth G, Bronte- P < 0.001). This was true even in patients that clinicians usually use as rescue
Stewart H, et al; who started with ropinirole and were later therapy when patients have wearing-
Quality Standards
Subcommittee of supplemented with levodopa, demonstrat- off symptoms. Clinicians should ad-
the American Acad- ing that early Parkinson disease can be minister ropinirole and pramipexole
emy of Neurology.
Practice Parameter:
managed with a reduced risk for dyskinesia orally 3 times daily, starting at a low
treatment of Parkin- by initiating treatment with ropinirole alone
son disease with dose and titrating up over several
and supplementing with levodopa later on,
motor fluctuations
and dyskinesia (an if necessary (20). weeks. Ropinirole should be started at
evidence-based re- 0.25 mg 3 times daily and increased to
view): report of the
Quality Standards Another prospective, double-blind, random- 3 mg 3 times daily over 6 weeks.
Subcommittee of
the American Acad-
ized, controlled trial of initial treatment with Pramipexole should be started at
emy of Neurology. pramipexole versus levodopa in 301 patients 0.125 mg 3 times daily and increased
Neurology. with early Parkinson disease found that ini- to 0.5 mg 3 times daily over 3 weeks.
2006;66:983-95.
[PMID: 16606909] tial treatment with pramipexole reduced the Rotigotine is administered via trans-
23. Soykan I, Sarosiek I, risk for dyskinesia (24.5% vs. 54%; HR, 0.37
Shifflett J, Wooten dermal patch. It should be started at
GF, McCallum RW. [CI, 0.25–0.56]; P < 0.001) and wearing off
Effect of chronic oral (47% vs. 62.7%; HR, 0.68 [CI, 0.49–0.63]; 2 mg/24 h and increased weekly by
domperidone thera-
P = 0.02) compared with levodopa. Howev- 2 mg/24 h for a recommended dose
py on gastrointesti-
nal symptoms and er, levodopa caused less risk for freezing and of 4–6 mg/24 h.
gastric emptying in
patients with Parkin- better symptom control (19).
son’s disease. Mov The MAO-B inhibitors selegiline
Disord. 1997;12:952-
7. [PMID: 9399220]
In the United States, clinicians pre- and rasagiline are modestly effective
24. Frucht S, Rogers JD, scribe levodopa with carbidopa to for early Parkinson disease compared
Greene PE, Gordon
MF, Fahn S. Falling block levodopa’s peripheral conver- with placebo (21). Clinicians should
asleep at the wheel: sion to dopamine and to reduce prescribe selegiline at 5 mg twice dai-
motor vehicle
mishaps in persons nausea. Most clinicians prescribe an ly and rasagiline, 1–2 mg/d. Anti-
taking pramipexole
and ropinirole. Neu-
immediate-release formulation with cholinergics, such as trihexyphenidyl
rology. 25 mg of carbidopa and 100 mg of or benztropine, are useful for tremor,
1999;52:1908-10.
[PMID: 10371546] levodopa with meals, beginning with and possibly rigidity. They should be

© 2012 American College of Physicians ITC5-8 In the Clinic Annals of Internal Medicine 6 November 2012

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 Table 2. Drugs for Parkinson Disease
Agent Mechanism of Action Dosage Adverse Effects Notes
Dopamine Simulates the action Typical therapeutic doses: Nausea, lightheadedness, Pramipexole, ropinirole, and rotigotine are appropriate
agonists: of dopamine at pramipexole: 1.5-4.5 mg/d; hallucinations, sleepiness, for patients with early and advanced disease; prami-
pramipexole, postsynaptic ropinirole: 9-16 mg/d; sleep attacks, dyskinesia; prexole and ropinirole are available in generic form;
ropinirole, dopamine protein apomorphine: 2 mg may also cause edema, LA formulations of pramipexole and ropinirole are not
rotigotine, and receptor sites (e.g., subcutaneous injection constipation, headache, sleep available in generic form; ergot dopamine agonists
apomorphine D1, D2, and D3 to bridge “off periods”; disturbances, confusion, (pergolide, bromocriptine, cabergoline) have been
receptors) rotigotine: 2–8 mg/d orthostatic hypotension, associated with valvular disease and should not be
lower-extremity edema, and considered as first-line therapy; apomorphine is an
impulse control disorders injectable rapid-onset agonist that is mainly used as
“rescue” therapy for patients in severe off periods; it is
not available in generic form
Levodopa Direct precursor to Different doses and Nausea, lightheadedness, Most effective agent available for the treatment
dopamine; usually formulations are available; hallucinations, sleepiness, of Parkinson disease (the “gold standard”);
combined with doses combine ratios of sleep attacks, dyskinesia; appropriate for patients with early and advanced
carbidopa, which carbidopa and levodopa; may also cause edema, Parkinson disease
blocks aromatic regular formulation: constipation, headache, sleep
amino acid 10/100, 25/100, and disturbances, confusion,
decarboxylase, 25/250; continuous- and orthostatic hypotension;
peripherally release formulation: rarely, hypersexuality or
metabolizes 25:100 and 50:200; compulsive behaviors, such
levodopa; thus, carbidopa-levodopa as gambling, are seen
carbidopa lessens orally disintegrating
peripheral side effects tablets: 10/100,
and enhances 25/100, and 25/250
levodopa CNS
bioavailability
Anticholinergics: Blocks acetylcholine Doses vary Dry mouth, dry eyes, urine Use with caution in patients older than 65 y because
trihexyphenidyl, in the striatum retention, constipation, of adverse effects; anticholinergic properties may
benztropine confusion, lightheadedness alleviate bladder dysfunction, drooling, and tremor;
adverse effects, or lack of an effect, may limit use
Amantadine Stimulates dopamine 100 mg/d, up to Hallucinations, edema, livedo Use with caution in elderly patients
release, blocks 100 mg 3 times daily; reticularis; may cause
dopamine reuptake, higher doses can be “neuropathy”
blocks glutamate used with caution
receptors
COMT inhibitors: COMT inhibition Entacapone: 200 mg with May increase dyskinesia, Entacapone: changes urine color to orange; may cause
entacapone, increases CNS each dose of levodopa nausea, and other dopamin- diarrhea; improvement in motor fluctuations should
tolcapone levodopa (maximum of 8/d); tolcapone: ergic side effects; may cause be seen within a few days to a week of adding
bioavailability by 100-200 mg, 3 times daily; hypertension if administered entacapone; withdraw COMT inhibitors 24 h before
decreasing use only with levodopa with isoproterenol; elevated administering isoproterenol to avoid precipitating
peripheral levodopa LFT results, liver toxicity, severe hypertension; tolcapone: need to monitor liver
metabolism and death due to liver failure function every 2 wk for first 12 mo, then every 4 wk
have been reported with for 12-18 mo, then every 8 wk thereafter; probably a
tolcapone more potent agent than entacapone, but has risk for
liver problems that require blood testing; discontinue
tolcapone if liver abnormalities occur
MAO inhibitors: Irreversible MAO-B Selegiline: 5 mg each Nausea, insomnia, and Beware of interaction with SSRIs; could cause a rarely
selegiline, inhibitor morning and at noon; hallucinations reported “serotonergic crisis” (confusion,
rasagiline rasagiline: 1-2 mg once disorientation, fever, tremor, myoclonus, diarrhea,
per day flushing); avoid administering selegiline after noon
because of metabolism to amphetamine; whether
selegiline interacts with meperidine is uncertain;
therefore, if possible, patients are withheld from
selegiline when having elective surgeries
Carbidopa Peripherally blocks Minimum 75 mg/d; None This treatment is primarily administered only if the
enzyme aromatic typically administered at patient is receiving levodopa; carbidopa is combined
amino acid 25 mg, 3 times daily, with levodopa as carbidopa-levodopa; additional
decarboxylase that 30 min before routine carbidopa may be prescribed if the patient is having
breaks down levodopa medications adverse effects; if carbidopa is not beneficial, try other
and thereby increases antinausea medications but avoid metoclopramide
CNS levodopa because it can worsen parkinsonian symptoms
bioavailability

CNS = central nervous system; COMT = catechol-O-methyl transferase; HRT = hormone replacement therapy; LFT = liver function test; LA = long-acting; MAO
= monoamine oxidase; REM = rapid eye movement; SSRI = selective serotonin reuptake inhibitor.

6 November 2012 Annals of Internal Medicine In the Clinic ITC5-9 © 2012 American College of Physicians

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 used with caution in elderly patients
because of sedation and memory
impairment.
How should pharmacotherapy be
adjusted as motor symptoms
worsen?
Clinicians typically increase
dopaminergic medications over
time as the symptoms of tremor,
bradykinesia, and rigidity worsen.
At some point, however, most pa-
tients with Parkinson disease devel-
op dyskinesia and “wearing off,”
which can be difficult to manage.
If dyskinesia does not disturb the
patient, it does not need to be treated.
Patients receiving levodopa mono-
therapy who have dyskinesia that
needs treatment may benefit from
adding amantadine or a dopamine
agonist, with concomitant reduction
of levodopa. Patients receiving
carbidopa–levodopa who have dyski-
nesia that needs treatment may bene-
fit from a decreased dose at shorter
intervals.
If wearing off needs to be treated,
clinicians should start by adminis-
tering entacapone or rasagiline (22).
Entacapone is a catechol-O-methyl
transferase inhibitor that reduces the
metabolism of dopamine and pro-
longs the therapeutic effect of lev-
odopa. Tolcapone is another
catechol-O-methyl transferase in-
hibitor that may help with wearing
off, but its use is limited by hepato-
toxicity, which requires frequent
monitoring. Selegiline is an MAO-B
inhibitor similar to rasagiline that
also may be used to manage wearing
off. Other strategies include adding a
dopamine agonist, increasing the
levodopa dosage, and increasing the
frequency of levodopa administra-
tion. Apomorphine is often used as
a rescue therapy until the next
levodopa dose becomes effective be-
cause it works quickly but lasts only
about an hour. Patients who have
both dyskinesia and wearing-off
phenomena may be particularly dif-
ficult to treat and should be referred
© 2012 American College of Physicians
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to a neurologist who specializes in
movement disorders for drug man-
agement and consideration for
deep-brain stimulation.
How should adverse effects of
pharmacotherapy be managed?
Nausea is a common adverse effect of
carbidopa–levodopa combinations and
dopamine agonists. It is often mild,
and patients may develop tolerance
after a few days. Taking medication
with food may alleviate nausea and is
recommended at early stages. If
carbidopa–levodopa causes nausea,
administering additional carbidopa
may help. If nausea persists, there is
anecdotal evidence of the effectiveness
of the antiemetic domperidone (23),
which is not FDA-approved but is
available in Canada and the United
Kingdom. Such medications as meto-
clopramide and prochlorperazine
should not be prescribed to treat nau-
sea because they block dopamine
receptors and worsen parkinsonism.
Another common adverse effect is ex-
cessive sleepiness, which is most often
caused by dopamine agonists. Al-
though these drugs can cause a sud-
den, irresistible, overwhelming need
for sleep (24), this is uncommon. If
patients are sleepy, clinicians should
discontinue all medications that may
contribute to sleepiness, teach good
sleep hygiene, and evaluate patients for
underlying sleep disorders (see “How
should sleep problems be managed in
patients with Parkinson disease?”).
Peripheral edema is a recognized
complication of amantadine and a
class effect of the dopamine agonists.
It does not always need to be
treated, especially if it is mild. It dis-
appears when the offending medica-
tion is discontinued, but reducing
the dose will not help. There is no
evidence about the efficacy of diuret-
ics for this side effect.
Impulse control disorders, such as
pathologic gambling, excessive shop-
ping, overeating, hypersexuality, and
excessive use of dopaminergic medica-
tion, occur in as many as 14% of
ITC5-10 In the Clinic
treated patients (25). Clinicians should
ask all patients about these behaviors
because patients rarely volunteer in-
formation about them. If impulse
control disorders need to be treated,
clinicians should consider reducing or
discontinuing dopaminergic medica-
tions, especially dopamine agonists,
but recognize that worsening motor
symptoms may require returning to
the original dose schedule.
What are the nonmotor symptoms?
Nonmotor symptoms, which include
sleep disorders, neuropsychiatric com-
plications, gastrointestinal symptoms,
and symptoms of autonomic dysfunc-
tion, are increasingly accepted as part
of Parkinson disease. They can cause
more disability and diminish quality
of life more than motor symptoms, al-
though clinicians often do not recog-
nize them as part of the disease (26).
How should sleep problems be
managed?
Frequent awakening (sleep fragmenta-
tion) is a common symptom. There
are many possible causes of sleep frag-
mentation, including drug adverse ef-
fects; nocturia; anxiety and depression;
nocturnal rigidity, tremor, dystonia, or
cramps; or a concomitant sleep disor-
der, such as the restless leg syndrome,
obstructive sleep apnea, or REM sleep
behavior disorder. Clinicians should
educate all patients with sleep prob-
lems about proper sleep hygiene,
which includes a regular bedtime rou-
tine; refraining from daytime naps; and
avoiding stimulants, large meals, and
exercise shortly before bedtime. Drugs
that may inhibit sleep initiation should
be discontinued, if possible. Nocturia
can be prevented by decreasing fluid
intake after the evening meal or pre-
scribing an anticholinergic drug. Clini-
cians should consider prescribing an
extended-release carbidopa–levodopa
preparation to prevent tremor or diffi-
culty turning over in bed, which can
hinder sleep initiation or going back to
sleep after waking. Treating anxiety
and depression may improve sleep,
especially if the drug used for treat-
ment has sedating effects. The restless
Annals of Internal Medicine 6 November 2012
 leg syndrome responds to levodopa or not available, expert opinion suggests
dopamine agonists, whereas obstruc- using antidepressants and benzodi-
tive sleep apnea can be treated with azepines. If the anxiety seems to occur
mechanical devices that alter the posi- only with wearing off, adjusting
tion of oropharyngeal structures or Parkinson medications to prolong “on”
provide continuous positive airway times may be helpful.
pressure. REM sleep behavior disorder
is common, and patients who need Psychosis is the single greatest risk
treatment often have success with factor for nursing home placement
25. Weintraub D,
clonazepam. in patients with Parkinson disease Koester J, Potenza
MN, Siderowf AD,
and contributes to caregiver stress (30). Stacy M, Voon V, et
How should neuropsychiatric Although visual hallucinations can al. Impulse control
disorders in Parkin-
complications be managed? be benign with preserved insight, son disease: a cross-
sectional study of
Neuropsychiatric complications are they may progress over time and are 3090 patients. Arch
extremely common and should be the most common manifestations of Neurol. 2010;67:589-
95. [PMID: 20457959]
reviewed at every visit. Depression is psychosis in Parkinson disease. The 26. Zesiewicz TA, Sulli-
the most common complication but first step in managing Parkinson- van KL, Arnulf I,
Chaudhuri KR, Mor-
is often underrecognized because related psychosis is to treat reversible gan JC, Gronseth GS,
et al; Quality Stan-
many features of Parkinson disease causes, such as infection, metabolic dards Subcommittee
overlap with the somatic features of disturbances, and adverse effects of of the American
Academy of Neurol-
depression, including blunted facial medications. Reduction or elimina- ogy. Practice Param-
eter: treatment of
expression, psychomotor slowing, ap- tion of Parkinson medications is nonmotor symp-
petite changes, fatigue, and sleep dis- generally best made in consultation toms of Parkinson
disease: report of
turbances. Apathy, defined as a loss of with a neurologist. If psychosis per- the Quality Stan-
dards Subcommittee
motivation, interest, and effortful be- sists despite addressing these issues, of the American
havior, also frequently occurs with de- pharmacotherapy is warranted. Academy of Neurol-
ogy. Neurology.
pression but can occur independently Cholinesterase inhibitors may be 2010;74:924-31.
in Parkinson disease and should be beneficial in some patients with de- [PMID: 20231670]
27. Menza M, Dobkin
distinguished from depression. There mentia and are usually well-tolerated. RD, Marin H, Mark
MH, Gara M, Buyske
are no high-quality studies to guide If an antipsychotic is necessary, only S, et al. A controlled
treatment of depression. In small, clozapine or quetiapine should be trial of antidepres-
sants in patients
randomized, placebo-controlled trials, used (10). Although there are with Parkinson dis-
ease and depression.
the tricyclics nortriptyline (27) and stronger data for the efficacy of Neurology.
desipramine (28) have alleviated clozapine, it is rarely used because of 2009;72:886-92.
[PMID: 19092112]
depressive symptoms in Parkinson the concern for agranulocytosis and 28. Devos D, Dujardin K,
Poirot I, Moreau C,
disease compared with placebo, but the need for monitoring. Quetiapine Cottencin O, Thomas
selective serotonin reuptake inhibitors is typically tried first. P, et al. Comparison
of desipramine and
have not. Despite this, neurologists citalopram treat-
frequently use selective serotonin re- Cognitive impairment, especially ments for depres-
sion in Parkinson’s
uptake inhibitors to treat depression impairment of executive function, disease: a double-
in Parkinson disease (29), probably can be present in the early stages of blind, randomized,
placebo-controlled
because of their generally favorable Parkinson disease and even at the study. Mov Disord.
2008;23:850-7.
adverse effect profile. There are no time of diagnosis (31). Estimates of [PMID: 18311826]
known treatments for apathy. the prevalence of dementia vary 29. Chen P, Kales HC,
Weintraub D, Blow
from 25%–31% (32). If dementia is FC, Jiang L, Mellow
AM. Antidepressant
Anxiety can present as a feature of de- present, first consider and treat any treatment of veter-
pression, but it may also be a separate reversible causes of confusion, such ans with Parkinson’s
disease and depres-
complication. It can range from panic as infections, metabolic derange- sion: analysis of a na-
tional sample. J Geri-
disorder to generalized anxiety disor- ments, and medications. Afterwards, atr Psychiatry Neurol.
der but is also highly associated with try cholinesterase inhibitors, al- 2007;20:161-5.
[PMID: 17712099]
“on–off ” motor fluctuations in Parkin- though only rivastigmine is FDA- 30. Chou KL, Fernandez
son disease, with greater anxiety approved for the treatment of HH. Combating psy-
chosis in Parkinson’s
during “off ” periods and improvement dementia in Parkinson disease (33). disease patients: the
use of antipsychotic
during “on” periods. Although evi- There have been 2 randomized, drugs. Expert Opin
dence to support the use of specific double-blind, placebo-controlled Investig Drugs.
2006;15:339-49.
anxiety agents in Parkinson disease is trials of memantine for dementia in [PMID: 16548784]

6 November 2012 Annals of Internal Medicine In the Clinic ITC5-11 © 2012 American College of Physicians

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 Parkinson disease, but results were frequency, and nocturnal polyuria, are
mixed (34, 35). more common than voiding symp-
toms, such as straining and hesitancy
In a randomized, placebo-controlled trial of (38). Clinicians should rule out blad-
rivastigmine, 541 patients (not all of whom
31. Uc EY, McDermott der infection in any patient with uri-
MP, Marder KS, An- completed the study) with Parkinson disease
derson SW, Litvan I, and mild to moderate dementia had a base-
nary symptoms before initiating other
Como PG, et al;
line score of 24 on the Alzheimer’s Disease As- treatments. Treatment should be start-
Parkinson Study
Group DATATOP sessment Scale-Cognitive Subscale; this scale ed with nonpharmacologic interven-
Investigators. Inci-
dence of and risk ranges from 0 (no impairment) to 70 (severe tions, such as reducing evening fluid
factors for cognitive impairment). Patients in the rivastigmine intake to decrease nocturnal polyuria
impairment in an
early Parkinson dis- group had a mean improvement of 2.1 and timed voiding to minimize day-
ease clinical trial co- points, compared with a 0.7-point worsen-
hort. Neurology.
time urgency and urge incontinence.
2009;73:1469-77. ing among those in the placebo group Clinicians should consider using anti-
[PMID: 19884574] ( P < 0.001). In addition, patients in the ri-
32. Aarsland D, Zaccai J, cholinergic drugs, such as oxybutynin
Brayne C. A system- vastigmine group had clinically meaningful and tolterodine, for urine storage
atic review of preva- improvements in the Alzheimer’s Disease Co-
lence studies of de- symptoms but should recognize that
mentia in Parkinson’s operative Study-Clinician’s Global Impression
disease. Mov Disord. of Change and in all secondary outcomes
no randomized, controlled trials of
2005;20:1255-63.
[PMID: 16041803] compared with patients in the placebo these drugs have been done in Parkin-
33. Emre M, Aarsland D, group (33). son disease and they can contribute to
Albanese A, Byrne
EJ, Deuschl G, De cognitive impairment. Clinicians
Deyn PP, et al. Ri- How should gastrointestinal should also consider solifenacin and
vastigmine for de-
mentia associated symptoms be managed? darifenacin because they do not cross
with Parkinson’s dis-
ease. N Engl J Med.
Gastrointestinal symptoms include the blood–brain barrier (38). Other
2004;351:2509-18. dysphagia and constipation. Clinicians treatments that are supported by anec-
[PMID: 15590953]
34. Aarsland D, Ballard should refer patients with dysphagia dotal evidence include desmopressin
C, Walker Z, Bostrom to a speech pathologist and order a and cystoscopic injection of botulinum
F, Alves G, Kos-
sakowski K, et al. Me- modified barium swallow with video- toxin into the detrusor muscle of the
mantine in patients
with Parkinson’s dis- fluoroscopy to look for aspiration. bladder. Urodynamic studies and refer-
ease dementia or
dementia with Lewy
There are no drugs that can alleviate ral to a urologist should be considered.
bodies: a double- dysphagia in Parkinson disease; how-
blind, placebo-con-
ever, because some patients have im- Treatment of orthostatic hypotension
trolled, multicentre
trial. Lancet Neurol. proved swallowing in the “on” phase, includes increasing salt and fluid
2009;8:613-8.
[PMID: 19520613] adjusting Parkinson medications to intake as well as high-compression
35. Emre M, Tsolaki M,
improve “on” time may be helpful. stockings. If postprandial hypotension
Bonuccelli U, Destée
A, Tolosa E, Kutzel- Teaching safe swallowing techniques is an issue, small and frequent meals
nigg A, et al; 11018
Study Investigators. and changing diet may also be useful. may be helpful. Although there is evi-
Memantine for pa- dence for the use of fludrocortisone
tients with Parkin-
son’s disease de- Treatment of constipation involves and the selective α1-agonist mido-
mentia or dementia
with Lewy bodies: a
the use of dietary modification, bulk- drine for managing neurogenic ortho-
randomised, double- forming agents, stool softeners, and static hypotension, neither drug has
blind, placebo-con-
trolled trial. Lancet laxatives. Open-label studies of dom- been studied in Parkinson disease
Neurol. 2010;9:969- peridone (23) and tegaserod (36) (26). Furthermore, midodrine may
77. [PMID: 20729148]
36. Morgan JC, Sethi KD. suggest that they may be beneficial. exacerbate supine hypertension.
Tegaserod in consti-
pation associated
A randomized, controlled trial of Pyridostigmine does not exacerbate
with Parkinson dis- isosmotic macrogol electrolyte solu- supine hypertension, but it is less ef-
ease. Clin Neu-
ropharmacol. tion in 57 patients with Parkinson fective for orthostatic hypotension (39).
2007;30:52-4.
[PMID: 17272971]
disease showed improvement in the
37. Zangaglia R, Mar- frequency of bowel movements and When should patients be
tignoni E, Glorioso
M, Ossola M, Ri- stool consistency (36). hospitalized?
boldazzi G, Calan- Hospitalization should be consid-
drella D, et al. Macro-
gol for the How should symptoms of auto- ered when patients with Parkinson
treatment of consti- nomic dysfunction be managed? disease have symptoms that cannot
pation in Parkinson’s
disease. A random- The manifestations of autonomic dys- be managed effectively on an outpa-
ized placebo-con-
trolled study. Mov
function include urinary symptoms tient basis. Issues that may require
Disord. and orthostatic hypotension. Urine hospitalization include psychosis
2007;22:1239-44.
[PMID: 17566120] storage symptoms, such as urgency, (hallucinations, delirium), significant

© 2012 American College of Physicians ITC5-12 In the Clinic Annals of Internal Medicine 6 November 2012

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 mood disturbances (mania or de-
pression), profound fluctuations in
mobility, frequent or serious falls, or
infections (urinary tract infection or
aspiration pneumonia).
When should a specialist be
consulted?
Patients should consult a neurologist
at least annually. Patients who consult
a neurologist may have lower morbid-
ity and mortality than those who do
not (40).
Which surgical interventions are
effective, and which patients
should be considered for surgery?
Surgical interventions include lesion-
ing therapies (thalamotomy and palli-
dotomy) and deep-brain stimulation.
Although procedures that create brain
lesions are effective for treating the
symptoms of Parkinson disease, they
are irreversible and frequently cause
adverse effects, especially when lesions
are bilateral. As a result, current prac-
tice is to do deep-brain stimulation
when surgery is needed.
The FDA has approved unilateral or
bilateral deep-brain stimulation of the
subthalamic nucleus or the globus pal-
lidus interna for Parkinson disease
symptoms. Either target is effective
for alleviating tremor, bradykinesia,
and rigidity; increasing the amount of
“on” time; reducing wearing off; and
decreasing dyskinesia compared with
best medical management (41). The
FDA has also approved stimulation of
the ventralis intermedius nucleus of
the thalamus for disabling tremor in
Parkinson disease; however, thalamic
stimulation does not help other motor
symptoms.
In a randomized, controlled trial, 255 patients
with Parkinson disease received bilateral
stimulation in either the globus pallidus in-
terna or subthalamic nucleus or best med-
ical therapy. The primary outcome was time
spent in the “on” state (good motor function)
without troubling dyskinesia at 6 months.
Patients who received deep-brain stimula-
tion gained 4.6 hours per day of “on” time
without troubling dyskinesia, whereas those
managed with medication alone gained no
“on” time. Seventy-one percent of patients in
6 November 2012 Annals of Internal Medicine
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the deep-brain stimulation group and 32%
of patients in the best medical therapy group
had clinically meaningful improvement in
motor function. Parkinson disease quality-
of-life scores also improved significantly in
the deep-brain stimulation group compared
with the best medical therapy group (41).
The presence of dementia and un-
treated depression are contraindica-
tions to deep-brain stimulation. The
goal of this procedure is to improve
quality of life and the ability to
function. Deep-brain stimulation is
considered when patients have mod-
erate to advanced Parkinson disease
with significant motor fluctuations
and dyskinesia that are not ade-
quately managed with drugs. Deep-
brain stimulation may also be
considered in patients with severe,
isolated, disabling tremor that af-
fects daily living activities. Strict
criteria are in place for patients to
qualify for deep-brain stimulation
therapy, and only a small percentage
of patients with Parkinson disease 38. Blackett H, Walker R,
Wood B. Urinary dys-
are suitable candidates (22). Patients function in Parkin-
son’s disease: a re-
with atypical parkinsonian syndromes, view. Parkinsonism
such as progressive supranuclear pal- Relat Disord.
2009;15:81-7.
sy, multiple system atrophy, demen- [PMID: 18474447]
39. Singer W, Sandroni P,
tia with Lewy bodies, corticobasal Opfer-Gehrking TL,
degeneration, or vascular parkinson- Suarez GA, Klein CM,
Hines S, et al. Pyri-
ism, are not candidates for deep- dostigmine treat-
brain stimulation. ment trial in neuro-
genic orthostatic
hypotension. Arch
What is the prognosis of a patient Neurol. 2006;63:513-
8. [PMID: 16476804]
with Parkinson disease? 40. Willis AW, Schoot-
man M, Evanoff BA,
Parkinson disease is a progressive neu- Perlmutter JS,
rologic disorder. Some studies have Racette BA. Neurolo-
gist care in Parkin-
suggested that progression varies for son disease: a utiliza-
different types of the disease. For ex- tion, outcomes, and
survival study. Neu-
ample, the tremor-dominant type may rology. 2011;77:851-
7. [PMID: 21832214]
be associated with slower progression 41. Weaver FM, Follett K,
and less cognitive impairment than Stern M, Hur K, Har-
ris C, Marks WJ Jr, et
the akinetic-rigid type (42). Despite al; CSP 468 Study
Group. Bilateral deep
these suggestions, the clinical course brain stimulation vs
still varies greatly from one person to best medical thera-
py for patients with
another, and no symptoms or signs advanced Parkinson
will allow practitioner to accurately disease: a random-
ized controlled trial.
predict the future course for a given JAMA. 2009;301:63-
73. [PMID: 19126811]
individual. However, because the mo- 42. Rajput AH, Voll A,
tor symptoms in Parkinson disease Rajput ML, Robinson
CA, Rajput A. Course
respond well to dopaminergic medica- in Parkinson disease
subtypes: A 39-year
tions, many patients are able to live clinicopathologic
their lives with minimal functional study. Neurology.
2009;73:206-12.
impairment for a substantial period. [PMID: 19620608]
In the Clinic ITC5-13 © 2012 American College of Physicians
 Treatment... Clinicians should refer patients to a neurologist for comanagement
of their Parkinson disease. They should begin drug therapy when symptoms cause
functional impairment. Drug treatment should be started with levodopa,
dopamine agonists, or MAO-B inhibitors, depending on the severity of symptoms,
risk for motor complications, patient age, and drug adverse effects. The drug regi-
men should be adjusted and other agents should be added as the disease pro-
gresses. Clinicians should treat nonmotor symptoms, including sleep disorders,
neuropsychiatric complications, gastrointestinal symptoms, and autonomic
dysfunction, with appropriate drugs. Regular exercise to maintain physical func-
tioning should be encouraged. Deep-brain stimulation should be considered when
patients have substantial motor fluctuations, dyskinesia, or a disabling tremor
that is not adequately managed with drugs.

CLINICAL BOTTOM LINE

PIER Module
In the Clinic http://pier.acponline.org/physicians/diseases/d243/d243.html

In the Clinic
PIER module on Parkinson disease from the American College of

Tool Kit
Physicians.

Patient Information
http://pier.acponline.org/physicians/diseases/d243/d243-pi.html
Patient information materials that appear on the following page for
duplication and distribution to patients.
Parkinson www.nlm.nih.gov/medlineplus/parkinsonsdisease.html
www.nlm.nih.gov/medlineplus/tutorials/parkinsonsdisease/htm/index.htm
Disease www.nlm.nih.gov/medlineplus/spanish/tutorials/parkinsonsdiseasespanish/
htm/index.htm
Resources related to Parkinson disease from the National Institutes of
Health’s MedlinePlus, including an interactive tutorial in English and
Spanish.
www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease.htm
Information on Parkinson disease, including information on clinical trials
from the National Institute of Neurological Disorders and Stroke.
www.apdaparkinson.org/User1ND/Search.aspx
News and updates on Parkinson disease from the American Parkinson
Disease Association.

Clinical Guidelines
www.nice.org.uk/guidance/CG35
Guidelines on the diagnosis and management of Parkinson disease from
the U.K. National Institute for Health and Clinical Excellence in 2006.
www.aan.com/go/practice/guidelines
Guidelines on diagnosing and treating Parkinson disease from the
American Academy of Neurology in 2006. Guidelines on treatment of
nonmotor symptoms of Parkinson disease published in 2010.

Diagnostic Tests and Criteria

http://pier.acponline.org/physicians/diseases/d243/tables/d243-t2.html
List of exclusionary features for diagnosis of Parkinson disease from
PIER.
http://pier.acponline.org/physicians/diseases/d243/tables/d243-tlab.html
List of laboratory and other studies of Parkinson disease from PIER.

Quality-of-Care Guidelines
www.aan.com/globals/axon/assets/8002.pdf
Ten quality measures for Parkinson disease care, from the American
Academy of Neurology in 2010.

© 2012 American College of Physicians ITC5-14 In the Clinic Annals of Internal Medicine 6 November 2012

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 THINGS YOU SHOULD In the Clinic
Annals of Internal Medicine
KNOW ABOUT PARKINSON
DISEASE

What is Parkinson disease?

• Parkinson disease impairs muscle control, movement,
and balance.

• It occurs when nerve cells in the brain’s substantia

nigra area deteriorate and can’t produce dopamine.

• As a result, the brain loses the ability to communicate

normal muscle movement messages.

Can I prevent it?

• Doctors don’t know why Parkinson disease occurs or
what causes the neurons to deteriorate.

• Risk for the disease may be increased if a family

member has had it.
• It usually affects persons aged 50 years or older.
What are the signs and symptoms?
• Tremor in hands, arms, legs, jaw, and face.
• Rigidity of arms, legs, and trunk.
• Slowness of movement (called bradykinesia).
• Impaired balance and coordination.
• Diagnosis is based on medical history and a
neurologic examination.
• Your doctor may request brain scans or laboratory
tests to rule out other diseases.
• Ask your doctor to consult a specialist in movement
disorders.
How is it treated?
• Exercise can help maintain physical and mental
functioning.
• Medications can increase dopamine levels in your

• Emotional changes, urinary problems or
constipation, and sleep disruptions may also occur.
• Simple tasks, such as talking, walking, or eating,
may become difficult.
How is it diagnosed?
• There is no specific diagnostic test.
Patient Information
brain or improve its ability to respond to dopamine.
• Such medications can reduce tremor, stiffness, and
slowness and improve muscle control, balance, and
walking.
• Brain surgery may be recommended for severe
Parkinson disease.

For More Information

www.parkinson.org/parkinson-s-disease.aspx
Information on Parkinson disease and a patient hotline
(1-800-473-4636) from the National Parkinson Foundation.

www.michaeljfox.org/
Information on living with Parkinson disease and on Parkinson
disease research from the Michael J. Fox Foundation for
Parkinson’s Research.

www.nlm.nih.gov/medlineplus/ency/article/007341.htm
Information on brain positron emission tomography, an imaging
test that may be used in diagnosis and treatment.

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 CME Questions
1. A 46-year-old man is evaluated in the office
for a 6-month history of a resting right-arm
tremor. He says that his writing has gotten
smaller during this time and that he has had
difficulty buttoning his dress shirts. The
patient reports no prior medical problems
and is not aware of any neurologic problems
in his family. He takes no medications.
Results of a general medical examination
are normal. Neurologic examination shows a
paucity of facial expression (hypomimia).
Cranial nerve function is normal. Motor
examination shows normal strength but
mild right upper limb rigidity and a 5-Hz
resting tremor of the right upper limb. Deep
tendon reflexes are normal, as are results of
sensory examination. There is no truncal or
appendicular ataxia. Diminished arm swing
is noted bilaterally, but it is worse on the
right. A tremor in the right upper limb is
noted during ambulation. Upper limb
alternating motion rates are diminished but
worse on the right.
Which of the following is the best
treatment for this patient?
A. Amantadine
B. Pramipexole
C. Primidone
D. Propranolol
2. A 54-year-old man with a 1-year history of
Parkinson disease is brought to the office by
his wife, who is concerned about her
husband’s recent excessive gambling. She
says that in the past 6 months, he has been
spending increasing amounts of time at a
casino, where he rarely enjoyed going before
the diagnosis of Parkinson disease. His
behavior is otherwise unchanged. The patient
has been taking ropinirole since the diagnosis
and has had a marked diminution in tremor
as a result; he has had no difficulties with or
change in mood, cognition, or sleep.
General physical examination findings are
normal. Neurologic examination shows
normal speech, language, mood, and mental
status. There is mild left upper limb rigidity
and a minimal resting tremor, but no other
abnormalities are detected.
Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP, accessed at
http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/
to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.
© 2012 American College of Physicians
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View publication stats
Which of the following is the most likely
cause of this patient’s gambling problem?
A. Bipolar disorder
B. Frontotemporal dementia
C. Medication-related compulsive behavior
D. Parkinson-related dementia
3. A 53-year-old woman is evaluated in the
office for a 4-month history of tremor. The
tremor affects both upper extremities and is
present “most of the time.” She has a 15-
year history of type 2 diabetes mellitus; she
also has a history of hypertension,
gastroparesis, and chronic kidney disease.
Medications are insulin glargine, insulin
lispro, lisinopril, hydrochlorothiazide, and
metoclopramide.
On examination, she has diminished pedal
pulses. Speech, language, and mental status
are normal. Cranial nerve function is normal,
although a paucity of facial expression is
noted. Movements are slow, and there is
mild bilateral upper and lower extremity
rigidity. Deep tendon reflexes are normal, as
5. A 62-year-old woman is evaluated for a 1-
are results of manual muscle strength
testing. Sensory examination reveals distal
sensory loss. She had a mildly stooped
posture but no postural instability. A 4-Hz
resting tremor in both upper extremities is
noted, as is a prominent postural tremor.
Which of the following is the most likely
diagnosis?
A. Dementia with Lewy bodies
B. Drug-induced parkinsonism
C. Multiple system atrophy
D. Parkinson disease
4. A 68-year-old man is evaluated for fatigue.
He says that for the past 2 weeks, he has
been awakening at approximately 2 AM with
a left-sided tremor and left-sided stiffness.
Parkinson disease was diagnosed 3 years ago
after he noted a left-hand tremor and a
change in his handwriting; examination at
that time showed mild parkinsonian signs,
and he was started on carbidopa-levodopa.
He currently takes immediate-release
carbidopa-levodopa, which results in near-
resolution of his parkinsonian symptoms; he
notes, however, that the medication wears
off if too much time passes between doses.
ITC5-16 In the Clinic
During this recent period of early-morning
awakening, he has occasionally taken extra
carbidopa-levodopa, which has allowed him
to fall asleep again.
Results of a general medical examination
are normal. Neurologic examination reveals
slurred speech and a paucity of facial
expression. Deep tendon reflexes are normal,
as are results of manual muscle strength
testing and sensory examination. He has
mild upper extremity rigidity that is greatest
in the left arm and a very mild resting
tremor of the left upper limb. No
appendicular or truncal ataxia is noted.
Which of the following should be added
to this patient’s drug regimen to treat his
fatigue?
A. Clonazepam, before bedtime
B. Donepezil
C. Extended-release carbidopa-levodopa,
before bedtime
D. Fluoxetine
year history of tremor that affects both
upper extremities. She says that her
handwriting has become sloppier since she
first noticed the tremor and that she
occasionally spills her morning coffee
because of it. Although she feels otherwise
healthy, she is concerned that she may have
Parkinson disease. The patient has a history
of hyperlipidemia controlled by diet and
exercise but is otherwise healthy. Her
mother, who died at age 79 years, had a
similar tremor. Her only medication is a daily
multivitamin.
On examination, she has a mild tremor in
the upper extremities that is present with
the arms extended and during finger-to-
nose testing. No resting tremor is apparent.
Muscle tone and gait and limb coordination
are normal.
Administration of which of the following
drugs is the most appropriate treatment
of this patient?
A. Carbidopa-levodopa
B. Clonazepam
C. Propranolol
D. Ropinirole
Annals of Internal Medicine 6 November 2012