Review Article

Diagnosing Parkinson
Address correspondence to
Dr Christopher W. Hess,
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University of Florida Health

Center for Movement

Disease Disorders and

Neurorestoration, 3450 Hull
Rd, Gainesville, FL 32607,
Christopher.Hess@neurology.
Christopher W. Hess, MD; Michael S. Okun, MD, FAAN ufl.edu.
Relationship Disclosure:
Dr Hess has received personal
ABSTRACT compensation as a speaker
for the Davis Phinney
Purpose of Review: While establishing the diagnosis of Parkinson disease (PD) can Foundation and the National
be straightforward, it can be challenging in some patients, even for the experienced Parkinson Foundation, has
neurologist. The misdiagnosis rate ranges from 10% to 20% or greater depending received grant support from
the University of Florida,
on clinician experience. and has participated in CME
Recent Findings: Despite promise in the search for a biomarker that can establish and educational activities
the presence of PD and act as a marker of its progression, the diagnosis of PD continues on movement disorders
sponsored by Allergan, Ipsen,
to be based on clinical examination. Core criteria, exclusion criteria, and suppor- Mertz Pharma, PeerView
tive criteria have been developed to aid the clinician in establishing the diagnosis. Press, and QuantiaMD.
Nonmotor symptoms of PD are usually present at the time of diagnosis, may precede Dr Okun serves as a consultant
for the National Parkinson
motor symptoms, and should be specifically sought during evaluation. Ancillary testing Foundation and has received
can be appropriate, but its indications and utility must be clearly understood. research grants from the
Summary: The diagnosis of PD requires the recognition of the core features of PD Bachmann-Strauss Dystonia &
Parkinson Foundation Inc,
and the differentiation of its clinical presentation from other entities with similar and the Michael J. Fox Foundation,
potentially overlapping symptoms. A careful history and examination guided by the National Institutes of
clinical diagnostic criteria will usually establish the diagnosis of PD or uncover red Health, the National Parkinson
Foundation, the Parkinson
flags for the possibilities of other diagnoses. Appropriate selection and interpretation Alliance, Smallwood Foundation,
of ancillary testing is critical to avoid misdiagnosis and unnecessary tests. the Tourette Association of
America, Tyler’s Hope, and the
University of Florida Foundation.
Continuum (Minneap Minn) 2016;22(4):1047–1063. Dr Okun has participated as a
site principal investigator and
coinvestigator for several trials
sponsored by the National
INTRODUCTION diagnostic pitfalls. This article focuses Institutes of Health and other
on establishing the clinical diagnosis of foundations and industries, but
Parkinson disease (PD) is the second has not received compensation.
most common neurodegenerative dis- PD and discusses the evolving defini- Dr Okun has received royalties
order after Alzheimer disease. Typically, tion of PD. The article also addresses from Amazon.com Inc,
Books4Patients LLC, Cambridge
PD develops in the fifth and sixth de- when PD occurs (premotor and motor), University Press, Demos,
cades. The disease affects 1% of persons the potential for biomarkers, genetic Manson Publishing Ltd,
Smashwords, and Taylor &
over the age of 60, and up to 60,000 testing, and the role of neuroimaging in Francis Group. Dr Okun serves
new cases are diagnosed each year in the diagnosis. as associate editor for the New
England Journal of Medicine
the United States.1,2 While establishing Journal Watch Neurology, and
the diagnosis of PD in many patients is MOTOR SYMPTOMS has lectured in CME activities for
Henry Stewart Conferences &
relatively straightforward, in some pa- Parkinsonism refers to the constellation Events, PeerView Press, Prime
tients it can be quite challenging, even of bradykinesia, rigidity, resting tremor, Education Inc, QuantiaMD,
for the experienced neurologist. The and postural and gait impairments. and Vanderbilt University.
Unlabeled Use of
rate of misdiagnosis of PD likely ranges While parkinsonism can have a variety Products/Investigational
from 10% to 20% or more, depending of etiologies (Table 1-1), the most com- Use Disclosure:
Drs Hess and Okun report
on the degree of specialization of the mon cause of parkinsonism is idio- no disclosures.
diagnosing physician.3,4 Being able to pathic PD. The motor symptoms are * 2016 American Academy
identify the core features of the disease secondary to the progressive loss of do- of Neurology.
as well as to evaluate the more nu- paminergic neurons in the pars compacta
anced characteristics that typify PD and of the substantia nigra.5 These neurons
its mimics can be helpful in avoiding project to the striatum (caudate and

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 Diagnosing Parkinson Disease
KEY POINTS
h Parkinsonism is a clinical
syndrome that can have a
variety of possible causes,
only one of which is
Parkinson disease.
h There are no clinically
available biomarkers to
indicate the presence of
Parkinson disease or track
disease progression.
h The diagnosis of
Parkinson disease
during the patient’s
lifetime is based on the
clinical examination.
h Core criteria, exclusion
criteria, and supportive
criteria have been
established that can
assist in the diagnosis
of Parkinson disease.
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TABLE 1-1 Classification of Parkinsonism
b Idiopathic parkinsonism (Parkinson disease, including sporadic and
genetic cases)
b Atypical parkinsonian syndromes (eg, multiple system atrophy, progressive
supranuclear palsy, corticobasal syndrome)
b Heredodegenerative parkinsonism (usually other additional neurologic
symptoms are present) (eg, PLA2G6-associated neurodegeneration,
aceruloplasminemia, X-linked dystonia-parkinsonism, spinocerebellar ataxias)
b Secondary parkinsonism (drug-induced, vascular, structural, infectious,
immunologic, toxic, traumatic, metabolic)
putamen) and modulate corticostriatal American Academy of Neurology (AAN),
transmission. PD must be distin- the most common clinical criteria used
guished from many other forms of to establish the diagnosis of idiopathic
parkinsonism.6 Additional or atypical PD is the UK Parkinson’s Disease Society
neurologic symptoms as well as key Brain Bank (UKPDSBB) clinical diag-
aspects of the reported history can nostic criteria (Table 1-2).8 These cri-
help point to the correct diagnosis. teria provide essential clinical findings
Despite a concerted and continued as well as supportive and exclusion-
effort to develop a biomarker that can ary criteria for diagnosing PD.
accurately confirm or refute the pres-
ence of PD and monitor disease pro- Bradykinesia
gression, none has been found. Thus, The first and most important step in
the diagnosis of PD during the patient’s diagnosing PD is to establish the pres-
lifetime is based on a careful clinical ence of bradykinesia, or slowness of
examination. Practically speaking, this movement. While akinesia (the failure
is the most important criterion as few or delay in execution of a purposeful
patients diagnosed with PD undergo movement) and hypokinesia (a de-
postmortem neuropathologic evalua- crease in movement size) are distinct
tion.7 Recently, the use of clinical criteria entities from the motor control stand-
as the practical gold standard for the point, for the purposes of the clinical
diagnosis of PD has been questioned, examination they are often included
and the manner in which PD is best under the umbrella term of bradykinesia,
defined continues to be a current topic especially when describing the de-
of interest, as the clinical diagnosis of crease and slowing of movements as
PD does not always match the patho- well as the loss or decrease of automatic
logic diagnosis (especially in genetic movements that occur in PD.9 With
forms of PD, in which the presence of continued movement, true bradykinesia
pathologic gene mutations is compli- typically gets worse (movements be-
cated by incomplete penetrance).7 come progressively smaller or decre-
These detailed discussions and debates mental), a feature that is required for
are outside the scope of this review, the UKPDSBB criteria and more recent
and this article focuses on diagnosing European guidelines.8,10 Common early
PD for the practicing clinician. manifestations of bradykinesia in PD
Although no clinical diagnostic include decreased facial expression
criteria are formally endorsed by the (hypomimia), soft speech (hypophonia),
August 2016
TABLE 1-2 UK Parkinson’s Disease Society Brain Bank Clinical
Diagnostic Criteriaa

b Step 1: Establish the presence of bradykinesia (slowness of initiation of

voluntary movement with reduced speed and amplitude of movements and/or
the loss or decrease of automatic movements) plus at least one of the following:
Rigidity
4Y6 Hz resting tremor
Postural instability (not otherwise explained by primary visual, vestibular,
cerebellar, or proprioceptive dysfunction)
b Step 2: Evaluate for exclusionary criteria for the diagnosis of Parkinson disease
The absence of a history of:
Repeated strokes with a stepwise progression of parkinsonism
Repeated head injury
Definite encephalitis
Neuroleptic treatment at onset of symptoms
More than one affected relative (although this exclusion criterion is
no longer commonly used)
Any period of sustained remission
Oculogyric crises
Early severe autonomic involvement
Early severe dementia with disturbances of memory, language, and praxis
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure
OR a finding of:
Strictly unilateral features after 3 years
Negative response to large doses of levodopa (if malabsorption is excluded)
Supranuclear gaze palsy
Cerebellar signs
Babinski sign
Cerebral tumor or communicating hydrocephalus on neuroimaging
b Step 3: Establish the presence of three or more of the supportive criteria
for the diagnosis of Parkinson disease
Unilateral onset
Resting tremor present
Progressive disorder
Persistent asymmetry with symptoms worse on the side of onset
Clear and definite response (70Y100% improvement on Unified
Parkinson’s Disease Rating Scale) to levodopa
Severe levodopa-induced chorea
Levodopa response for 5 years or more
Clinical course of 10 years or more
a
Modified with permission from Hughes AJ, et al, J Neurol Neurosurg Psychiatry.8 B 1992
British Medical Journal Publishing Group. jnnp.bmj.com/content/55/3/181.short.

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 Diagnosing Parkinson Disease
KEY POINTS
h Rigidity giving rise
to decreased range of
motion and shoulder
pain (often misdiagnosed
as orthopedic or
arthritic) and difficulty
turning over in bed at
night are common
presenting symptoms of
Parkinson disease.
h Parkinson tremor can
fluctuate significantly in
amplitude with mental
activity or voluntary
movements of other
limbs, and, thus, it is
not unusual to be
initially described as
intermittent. It often has
a reemergent quality
such that it can reappear
with postural sustention
after a variable delay, and
patients may report
noticing it for the first
time with sustained
postures, such as holding
a telephone or newspaper.
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and small handwriting (micrographia).
The latter can be tested by asking pa-
tients to write the same sentence at
least three times sequentially, observing
the possibility of a progressive decrease
in sentence length and the size of the
characters. Although bradykinesia is
required to make the diagnosis of PD,
it can sometimes be difficult to elicit in
strongly tremor-predominant patients
with PD, especially early in the PD course.
In addition to bradykinesia, at least one
additional cardinal symptom of rigidity,
resting tremor, or postural instability
must be present as a second step to
make the clinical diagnosis of PD.8
Rigidity
Rigidity refers to the resistance of mus-
cles to passive movement around a
joint. While rigidity is a clinical sign
detected by the examiner, it is experi-
enced and often described by patients
as stiffness.9 When absent or mild on
examination, rigidity can be augmented
by asking the patient to perform volun-
tary movements of the contralateral
limb. In evaluating rigidity, it is impor-
tant to distinguish true parkinsonian
rigidity from both paratonia (involuntary
variable and proportional resistance in
response to passive movement [also
known as gegenhalten]) and the cog-
wheel phenomenon that can be ob-
served with essential and other types of
tremor without any underlying in-
creased tone (Froment sign, which is
the increase in resistance to passive
movement about a joint with voluntary
action in another part of the body).11
Similarly, reduced arm swing on one
side can be misleading without the
appropriate clinical context, as some
degree of arm swing asymmetry can be
observed in healthy adults.12 Rigidity
giving rise to decreased range of motion
and shoulder pain (often misdiagnosed
as orthopedic or arthritic) and difficulty
turning over in bed at night are common
presenting symptoms of PD. Prominent
axial rigidity early in the course of symp-
toms is not typical and is commonly
observed in progressive supranuclear
palsy (PSP).
Resting Tremor
The classic parkinsonian resting tremor
is present in approximately 70% of
patients with PD.13 It is typically 4 Hz
to 6 Hz and starts unilaterally and distally
and, over time, progresses more proxi-
mally and often to the contralateral side.
The resting tremor can variably involve
oscillations around the wrist and finger
joints, although a pronation/supination
axis at the wrist and a pill-rolling qual-
ity to finger tremor are classic in PD.14
Parkinson tremor can fluctuate signifi-
cantly in amplitude with mental activity
or voluntary movements of other limbs,
and, thus, it is not unusual to be initially
described as intermittent.14 It often has
a reemergent quality such that it can
reappear with postural sustention after
a variable delay, and patients may
report noticing it for the first time with
sustained postures, such as holding a
telephone or newspaper (Case 1-1).15
This manifestation can sometimes lead
to confusion as it can be reported as an
action tremor. Some patients also re-
port a sensation of ‘‘inner tremor’’ that
does not involve oscillations around a
joint.16 A jerky quality to tremor can
sometimes be observed in younger
patients, but in older patients this can
signal the presence of multiple system
atrophy (MSA). Although more charac-
teristic of essential tremor, kinetic
tremor (occurring during active move-
ment) is not unusual in PD, and
amelioration of tremor with alcohol
(due to its relaxing effects) can also be
reported in PD, emphasizing the im-
portance of the clinical examination.17
Parkinsonian tremor does not uniformly
respond to levodopa, so occasionally
patients, in whom the other cardinal
August 2016
 KEY POINTS

Case 1-1 h The lack of resting

tremor does not
A 68-year-old right-handed man was referred for a neurologic evaluation of
exclude the diagnosis
tremor. The patient had first noted tremor of the right hand when driving
of Parkinson disease.
and holding a newspaper approximately 2 years previously. Initially, tremor
seemed to be intermittent, but it gradually progressed to be present h The cardinal symptoms
continuously throughout the day. Two glasses of wine in the evening could of Parkinson disease are
reduce but not stop his tremor, and he had not noticed any tremor in his bradykinesia, rigidity,
nondominant hand. He also had chronic right shoulder pain of 6-months resting tremor, and
duration for which his primary care doctor ordered a shoulder x-ray, which was postural instability.
read as normal. Despite these symptoms, he did not feel that he was h Actual falls occurring
functionally impaired in any way. Upon further questioning, he reported mild early in the disease
difficulty getting up from the low sofa in his basement, and he had both course and especially
chronic constipation and erectile dysfunction for at least 5 years. He denied in the first year of
noticing any change in his sense of smell, but his wife stated that he often presenting symptoms
commented that her cooking was less flavorful. His wife had begun to sleep should elicit suspicion
in the guest room due to the patient hitting her in his sleep. of the possibility of
His neurologic examination was remarkable for a ‘‘poker face’’ and soft an atypical form
voice, a delay in right shoulder shrug, and mild cogwheel rigidity in the right of parkinsonism.
arm that was only noticeable with voluntary movement of the opposite
hand. He had a low-amplitude, low-frequency right hand resting tremor
that reappeared with sustained posture after a short pause. His finger
movements were slightly smaller and slower on the right side, and rapid
sequential movements became progressively smaller with repetition. His
posture was slightly stooped, and he walked with decreased right arm swing
and a more pronounced pronation/supination tremor in the right wrist. He
turned easily and had normal postural stability.
Comment. This patient’s presentation is typical for tremor-predominant
idiopathic Parkinson disease. It illustrates the occurrence of the cardinal
motor symptoms of parkinsonism with multiple supportive criteria that were
preceded by nonmotor symptoms commonly reported in Parkinson disease.

symptoms of the disease are mild first year of presenting symptoms

and not noticeable, can report a lack
of benefit from levodopa despite an
observable improvement with levo-
dopa administration.
Postural Instability
Impairment in the ability to recover
one’s balance is often very subtle in
patients first presenting with PD and
sometimes does not develop until well
into the disease course. When present
in early PD, patients will often report
tripping or requiring increased con-
centration to avoid tripping on uneven
surfaces, yet will have a normal re-
sponse to pull testing in the clinic.
Actual falls occurring early in the
disease course and especially in the
should elicit suspicion of the possi-
bility of an atypical form of parkin-
sonism. Postural instability is also not
specific to parkinsonism and is com-
monly observed in the elderly, often
making it the least helpful criterion
in the initial diagnosis of PD, but it is
helpful in suggesting to the clinician
the possibility of other diagnoses or
comorbid diagnoses.18
Other Motor Abnormalities
Outside of the diagnostic criteria, other
motor features can be seen both at the
time of diagnosis and as the disease
progresses. Impaired finger dexterity,
difficulty multitasking, and increased
concentration required for both motor

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 Diagnosing Parkinson Disease
KEY POINT
h Nonmotor symptoms
such as hyposmia,
erectile dysfunction,
constipation, and rapid
eye movement sleep
behavior disorder can
precede the onset of
motor symptoms of
Parkinson disease
by years.
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and cognitive task completion are
common early reported symptoms, while
a progressively flexed posture, freezing
phenomenon, gait initiation difficul-
ties, postural deformities, and swal-
lowing difficulties tend to appear later
in the disease.
Exclusionary and Supportive
Criteria for Diagnosing
Parkinson Disease
The exclusionary criteria for PD listed
in Table 1-2 need to be practically
considered on an individual basis, as
some criteria reflect confounders in
attributing symptoms to PD while
others suggest the presence of other
diseases. For example, a history of
multiple concussions that preceded
the onset of parkinsonism is a poten-
tial confounder in diagnosing PD, but
it does not exclude the diagnosis of
PD or specifically suggest an alterna-
tive diagnosis. However, cerebellar
signs or a supranuclear gaze palsy de-
veloping simultaneously with progres-
sive parkinsonism would strongly
suggest an alternative diagnosis of an
atypical parkinsonism such as MSA or
PSP, respectively.
Supportive criteria (of which three
or more are required) are all charac-
teristics that commonly are observed
in PD. Patients with PD usually pres-
ent with a clear asymmetry of symp-
tom onset and respond well to trials of
levodopa when appropriate, but this
is not always the case. Resting tremor
is absent in 30% of patients with PD,
and patients without resting tremor
can experience a longer delay in
diagnosis due to physician familiarity
with the association between resting
tremor and PD.19 Patients with path-
ologically confirmed PD can go many
years from the onset of resting tremor
before developing other symptoms and
might never develop unequivocal
bradykinesia.20
Since the initial publication of the
UKPDSBB criteria, the inclusion of a
strong family history (more than one
affected relative) has been challenged
as an exclusionary criterion and is
often overlooked in the appropriate
clinical context. Other features (such
as hyposmia, rapid eye movement [REM]
sleep behavior disorder, and constipa-
tion) that are known to be strongly
associated with the diagnosis of PD
have been proposed as additional
formal supportive criteria, especially as
they often precede the motor symp-
toms of the disease.8,21Y23 Although
early severe dementia is an exclusion
criterion in the UKPDSBB criteria, more
than 15% of patients with PD can have
at least mild cognitive impairment at
the time of diagnosis.24 However the
presence of visual hallucinations at the
time of presentation and especially in
untreated patients is suggestive of
dementia with Lewy bodies, which
some argue should be considered a
subtype of PD.7
NONMOTOR SYMPTOMS
The function of the basal ganglia was
traditionally thought to be limited to
the modulation and processing of in-
formation related to motor control,
with projections solely to motor corti-
ces.25 However, it is now accepted
that the basal gangliaYthalamocortical
circuits consist of multiple subcircuit
loops projecting cortically to diverse
targets.26,27 These circuits are largely
parallel, somatotopically arranged, and
functionally specific, and are organized
into motor, oculomotor, associative,
and limbic circuits. They are involved
in a variety of activities including emo-
tion, reward behavior and habit forma-
tion, time estimation, attention, working
memory, and learning.28 Thus, it would
be expected that the basal ganglia
dysfunction that occurs in PD would
produce a more complicated clinical
August 2016
picture than isolated motor dysfunc-
tion. Similarly, basal ganglia pathology TABLE 1-3 Continued
is now recognized to be only one aspect
of the neuropathologic changes that b Gastrointestinal Dysfunction
occur in PD, which include changes Constipation (39%)
to multiple neurotransmitter systems
Early satiety (23%)
throughout the brain, further suggesting
that the clinical course of PD should Loss of appetite
include nonmotor as well as motor b Sexual Dysfunction
symptoms.29,30 The most common non- Erectile dysfunction (28%)
motor symptoms that occur in PD are
listed in Table 1-3.31 Reduced libido (42%)
Approximately 90% of patients with b Sleep Disturbances
PD will develop at least one nonmotor Excessive daytime sleepiness
symptom, and nonmotor symptoms can (28%)
be the presenting feature in PD.23,32
Insomnia (36%)
Later in the disease, the disability from
Rapid eye movement (REM)
nonmotor symptoms often overshadows
sleep behavior disorder (28%)
that from motor symptoms, and uncon-
trolled nonmotor symptoms can be a Sleep fragmentation

deciding factor in the timing of place- Vivid dreams (24%)

ment in a long-term care facility.33,34 For b Somatosensory Dysfunction
Restless legs syndrome (17%)

TABLE 1-3 Common Nonmotor Unexplained pain (20%)

Symptoms of
b Special Sensory
Parkinson Disease at the
Time of Diagnosisa,b Impaired olfaction (46%)
Impaired taste (14%)
b Affective Disorders
b Urinary Dysfunction
Anhedonia (32%)
Frequency (28%)
Anxiety (30%)
Incontinence (10%)
Apathy (31%)
Urgency (34%)
Depression (43%)
Weak urinary stream (25%)
b Autonomic Dysfunction
b Visual Disturbances
Orthostatic hypotension (21%)
Impaired color discrimination
b Cognitive Dysfunction
Visuospatial abnormalities
Bradyphrenia
a
Modified with permission from Pont-
Inattention (28%) Sunyer C, et al, Mov Disord.31 B 2014
International Parkinson and Move-
Memory impairment (32%) ment Disorder Society. onlinelibrary.
wiley.com/doi/10.1002/mds.26077/
Word-finding difficulties abstract.
b
Reported prevalence of symptom
b Fatigue (36%) (%) within a year of diagnosis when
information is available.

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 Diagnosing Parkinson Disease
KEY POINTS
h Parkinson disease
results in a variety of
nonmotor symptoms
that can sometimes be
more disabling than the
motor symptoms, and
studies suggest that the
nonmotor symptoms
have a greater effect
on quality of life.
h At least two subtypes
(tremor-predominant
Parkinson disease and
postural instability and
gait difficulty Parkinson
disease) have been
identified, and both of
these entities manifest
different rates of
progression, disability,
nonmotor symptoms,
and complications
of therapy.
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more information, refer to the article
‘‘Treatment of Advanced Parkinson Dis-
ease and Related Disorders’’ by Janis M.
Miyasaki, MD, MEd, FRCPC, FAAN,35 in
this issue of Continuum. In the patient
presenting with PD, nonmotor symp-
toms often precede or present with
motor symptoms but are not commonly
reported unless uncovered by the clini-
cian during the encounter.36
PARKINSON DISEASE SUBTYPES
One of the most remarkable aspects of
PD is the degree of clinical heterogeneity
that exists across patients, to such a de-
gree that some have questioned whether
PD can be considered a unified disease.7
It has long been recognized that
considerable variability exists between
patients with PD in the expression of
clinical symptoms, the rate of disease
progression, and the response to
therapies.37 The approaches that have
been used to try to organize this het-
erogeneity into distinct and useful clin-
ical subtypes have largely been based
on specific clinical or demographic
features (empirical approach) or on
methods of statistical clustering (data-
driven approach) with a variety of
classifications proposed.38 The obser-
vation that a predominance of tremor
in PD portends a slower disease pro-
gression was one of the earliest indi-
cators of the existence of PD subtypes
and dates back more than 45 years.39 A
tremor-predominant phenotype has
been associated with a slower disease
progression and less cognitive impair-
ment, depression, and apathy when
defined empirically in data-driven stud-
ies and retrospective clinicopathologic
studies.40Y46
PREDIAGNOSTIC PARKINSON
DISEASE
In the field of PD research, it is be-
coming increasingly clear that what is
commonly referred to as early PD in
clinical trials (in which motor symptoms
are just beginning to manifest) is a point
in time that is actually relatively later
in the disease course. Therefore, it has
been recognized by many experts that a
potential window for disease-modifying
and neuroprotective treatments exists,
but that earlier diagnosis and a bio-
marker are necessary. Many current
neuroprotective and disease-modifying
strategies are being tested in patients
where presumably a large proportion
of neurodegeneration has already
occurred.47 A variety of terms have
been proposed, including prephys-
iologic, preclinical, prodromal, premotor,
and prediagnostic, to describe the
various stages that can be identified
prior to the diagnosis of PD.7,48 From
the practical and clinical standpoint, it
is most important to remember two
main points. First, the vast majority of
patients with PD already manifest one
or more nonmotor symptoms of the
disease at the time of diagnosis and
often years prior. 23 Evaluation of
nonmotor symptoms in PD is a critical
part of the history at the initial presen-
tation and should be uncovered, if
present, in all patients. Second, some
patients may have nonmotor symp-
toms and mild soft signs of parkinson-
ism, but not enough clinical findings to
confer the diagnosis of PD. In these
patients, monitoring symptom stability
and progression over time is impor-
tant, especially prior to labeling the
patient as having PD.
DIFFERENTIAL DIAGNOSIS
A myriad of diseases and syndromes can
be mistaken for PD, including other
forms of parkinsonism (Table 1-1)
as well as nonparkinsonian mimics.
Table 1-4 lists the commonly consid-
ered differential diagnoses in the ini-
tial presentation of PD. Atypical
parkinsonism can sometimes initially
August 2016

TABLE 1-4 Common Differential
Diagnoses of
Parkinson Disease
b Atypical parkinsonian
syndromes (multiple system
atrophy, progressive
supranuclear palsy,
corticobasal syndrome)
b Dementia with Lewy bodies
b Drug-induced parkinsonism
b Dystonic tremor
b Essential tremor
b Frontotemporal dementias
b Functional or psychogenic
parkinsonism
b Normal pressure
hydrocephalus
b Vascular parkinsonism
be mistaken for idiopathic PD. Falls
and significant autonomic dysfunction
early within the disease course, a poor
response to levodopa, symmetry of
symptoms at onset, and rapid symp-
tom progression are useful red flags
indicating the possibility of atypical
parkinsonism. The presence of other
signs and symptoms can be suggestive
of other diagnoses. Visual hallucina-
tions within the first year of motor
symptoms are suggestive of dementia
with Lewy bodies. Essential tremor is
usually 5 Hz or faster and is most
prominent with action, although es-
sential tremor that is long-standing
can sometimes occur at rest (usually
bilaterally), and its frequency can fall
into the parkinsonian range.11 Pa-
tients with dystonia can have mild
parkinsonism, and patients with PD
can occasionally present with dystonia
(typically lower limb dystonia in young-
onset patients), although dystonia is
not commonly observed early in PD.
Drug-induced parkinsonism can be very
Continuum (Minneap Minn) 2016;22(4):1047–1063
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
difficult to distinguish from PD; the h Atypical parkinsonism
most important factor in its consider-
can sometimes initially
ation is a careful and complete medica- be mistaken for
tion history (Case 1-2). In cases of idiopathic Parkinson
parkinsonism with a predominance of disease. Falls and
lower body symptoms and urinary and significant autonomic
cognitive difficulties, structural neuro- dysfunction early within
imaging can uncover the diagnosis of the disease course, a
poor response to
normal pressure hydrocephalus. For
more information on normal pressure levodopa, symmetry
of symptoms at onset,
hydrocephalus, refer to the article ‘‘Di-
and rapid symptom
agnosis and Treatment of Idiopathic
progression are useful
Normal Pressure Hydrocephalus’’ by red flags indicating the
Michael A. Williams, MD, FAAN, and possibility of atypical
Jan Malm, MD, PhD,49 in the 2016 parkinsonism.
Dementia issue of Continuum. Tradi-
h Drug-induced
tionally, vascular parkinsonism was parkinsonism can be
thought to produce a nontremulous very difficult to
lower body predominance of symptoms distinguish from Parkinson
with a poor levodopa response and a disease; the most
stepwise progression; however, signifi- important factor in its
cant overlap exists in the clinical find- consideration is a
ings of vascular and other forms of careful and complete
parkinsonism, and the entity remains medication history.
poorly defined. MRI can be helpful in
the diagnosis of vascular parkinsonism
depending on the location of white
matter changes.50 Functional or psy-
chogenic parkinsonism can usually be
diagnosed readily by the recognition of
unusual or inconsistent examination
findings.
LEVODOPA CHALLENGE AND
SMELL TESTING
In some cases, clinical response to an
adequate dose of levodopa can be help-
ful in establishing the PD diagnosis
(Case 1-3). However, a lack of re-
sponse to a levodopa challenge (even
at doses greater than 200 mg per dose)
does not strictly rule out PD, and
patients with atypical parkinsonism
can have a partial levodopa response
as discussed in the article ‘‘Diagnostic
Approach to Atypical Parkinsonian
Syndromes’’ by Nikolaus R. McFarland,
MD, PhD,51 in this issue of Continuum.
A levodopa challenge can be useful
www.ContinuumJournal.com 1055
 Diagnosing Parkinson Disease

KEY POINT
h Laboratory testing can
sometimes be useful in
ruling out metabolic
abnormalities that may
present as parkinsonism.
Case 1-2
A 56-year-old woman with a past medical history of hypertension,
hyperlipidemia, and refractory major depressive disorder presented for
a neurologic evaluation because of a 4-month history of difficulty walking.
She reported problems with handwriting due to tremor and micrographia
and difficulty getting in and out of her car. She denied any sleep
disturbances, constipation, changes in her sense of smell, or urinary dysfunction.
A CT scan of her brain ordered by her primary care doctor 1 year previously
after an episode of acute dizziness was remarkable only for mild chronic
microvascular ischemic changes. She had been tried on multiple antidepressants
but denied ever taking a neuroleptic, and none was uncovered following
inspection of her current medication bottles. Her neurologic examination
was remarkable for decreased facial expression and blink rate, bilateral
rigidity, and low-frequency resting and action tremors. Perioral tremor was
noted as well. Since she had used the same pharmacy for the last 5 years, the
pharmacy was called and a list of all recently prescribed medications was
reviewed. The list included an atypical neuroleptic that had been prescribed
for depression 2 weeks prior to the onset of her neurologic symptoms. This
medication had been discontinued the month prior to her presentation, and
her symptoms gradually improved over the next few weeks and resolved
completely within 2 months.
Comment. Although features such as a subacute onset and relative
symmetry of symptoms can suggest a secondary cause of parkinsonism
such as drug-induced parkinsonism, it may not be possible to distinguish
these entities on a clinical basis alone. An accurate history of current and
recently prescribed medications is critical in establishing the accurate
diagnosis when a patient presents with parkinsonism.

in the diagnosis of PD; however, the from PSP or corticobasal degeneration

absence of a response to levodopa does
not rule out PD and can result from
gastric emptying issues. Thus, in these
cases, clinicians will sometimes order a
gastric emptying study to uncover this
potential issue.
Olfactory impairment can be a
useful screening test for PD, and recent
European guidelines recommend its
use in the differentiation of PD from
atypical and secondary parkinsonism.10
A number of smell-identification tests
are commercially available, including
the University of Pennsylvania Smell
Identification Test, Brief Smell Iden-
tification Test, and Sniffin’ Sticks. A
caveat of such tests is their low speci-
ficity, as decreased sense of smell can
be seen in normal aging and other
neurodegenerative diseases. It may be
more helpful in differentiating PD
as less olfactory impairment occurs in
these diseases compared to MSA.52
LABORATORY TESTING
There are currently no available labo-
ratory tests that can establish the
diagnosis of PD, despite a number of
potential serum-based biomarkers un-
der evaluation.53 In patients with less
than a classical presentation or an ap-
propriate history, exclusion of thyroid
and parathyroid dysfunction (which can
result in parkinsonism) and basic labo-
ratory testing (including liver function
tests) can be useful in ruling out sec-
ondary causes of parkinsonism. In ad-
dition, any patient who is less than
50 years old and presenting with
parkinsonism should be screened for
Wilson disease with appropriate copper
studies including serum ceruloplasmin

1056 www.ContinuumJournal.com August 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINT
h Genetic testing in
Case 1-3 Parkinson disease
A 60-year-old right-handed woman presented for a second neurologic opinion is generally not
for the diagnosis of parkinsonism. She had developed masked face, stiffness, recommended except
and slowing in her activities of daily living 3 years earlier, and she had been for very specific
diagnosed with parkinsonism the following year. She had been started on patient populations.
carbidopa/levodopa 25 mg/100 mg 1 tablet 3 times a day, which she had
continued, but she had not noticed any benefit. Over the past year she had
developed freezing when going through doorways and when turning to get
into a chair. Over the past 6 months she had fallen backward multiple times,
and she reported a subjective difficulty with swallowing and bothersome
urinary urgency and frequency. She had been frustrated by her lack of
improvement and heard about ‘‘the brain scan that could diagnose Parkinson
disease’’ in her support group and requested it to be ordered. Neurologic
examination was remarkable for masked facies, hypophonia, moderately
asymmetric rigidity and bradykinesia, and diffusely increased reflexes without
tremor. She had a lack of postural response on pull testing, and mental
status examination was within normal limits.
Comment. This patient presented with a parkinsonian syndrome with the
most important differential diagnosis being Parkinson disease versus an
atypical parkinsonism such as multiple system atrophyYparkinsonism type.
Neuroimaging of the dopamine transporter will be abnormal in both diseases
and would not add any additional useful diagnostic or treatment information.
A further titration of her levodopa to at least 900 mg/d (up to 300 mg per dose
if she can tolerate it) to determine her responsiveness to an adequate dose of
carbidopa/levodopa would be far more helpful in clarifying her diagnosis.

levels, and 24-hour urine copper excre-
tion should be considered. For more
information, refer to the article ‘‘Wilson
Disease’’ by Ronald F. Pfeiffer, MD,
FAAN,54 in this issue of Continuum.
GENETIC TESTING
Most patients (approximately 90%)
diagnosed with PD do not have a family
history of the disease and are, there-
fore, considered to be sporadic cases.55
While monogenic forms of PD have
been identified and may provide insight
into the pathophysiology and genetic
heterogeneity of PD, they constitute a
very small portion of patients with PD.56
Recently, alleles that are more com-
mon in the general population and
that may increase the risk for PD have
been identified.57 No formal guidelines
exist regarding which patients with PD
should be considered for genetic test-
ing. A recent European guideline for
the diagnosis of PD recommends con-
sideration of specific gene testing in
patients without a family history of PD
but onset before the age of 40, patients
with a strong family history of either a
recessive pattern of inheritance (espe-
cially with onset before the age of 50)
or an autosomal dominant pattern of
inheritance, and patients who belong
to ethnic groups associated with foun-
der mutations.10 These recommenda-
tions are very similar to those put forth
by the Consortium on Risk for Early-
Onset Parkinson Disease (CORE PD) in
2010.58 In such patients, genetic test-
ing can be helpful in family and finan-
cial planning, aiding in prognosis, or in
patients with a strong personal desire
for testing.
Clinicians also need to be aware that
the first direct-to-consumer genetic
tests have been approved by the US
Food and Drug Administration (FDA)

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Diagnosing Parkinson Disease
KEY POINT
h While the research and may become available for PD.59
utility of dopamine These tests can potentially mislead
transporter single-photon asymptomatic patients into thinking
emission computed they are sure to develop the disease if
tomography is universally they are positive for an allele that
agreed upon, its use increases the risk of PD, or that they
in the clinical setting are no longer at increased risk when
for differential diagnosis a single gene or a limited number of
in the individual genes are tested. Any decision to pur-
remains controversial. sue clinical genetic testing should be
preceded by genetic counseling and
family discussions to ensure patients
are aware of the implications for them-
selves and their families.
NEUROIMAGING
The clinical utility of structural neuro-
imaging in the evaluation of PD has
traditionally been limited to ruling
out secondary causes of parkinsonism,
such as vascular parkinsonism or nor-
mal pressure hydrocephalus, as MRI
and CT are largely unremarkable in PD
beyond generalized cortical atrophy.
Most experts make a bedside decision
on the need for structural neuroimag-
ing on a case-by-case basis, and the most
recent AAN practice parameter on diag-
nosing PD did not render a recommen-
dation regarding the need for structural
imaging prior to making the diagnosis
of PD. However, structural imaging is
often recommended to rule out sec-
ondary causes of parkinsonism.60 Novel
techniques of diffusion, perfusion, and
functional MRI (fMRI) continue to be
developed and show promise as po-
tential biomarkers of PD.61,62
Metabolic imaging with fludeoxyglu-
cose positron emission tomography
(FDGYPET) measures regional differ-
ences in glucose metabolism, and these
studies have uncovered patterns of
activity that are characteristic for the
motor and cognitive symptoms of PD,
as well as patterns specific to atypical
forms of parkinsonism such as MSA or
PSP.17,63 Although approved in the
United States for neurodegenerative
1058 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
diseases, FDG-PET is currently lim-
ited to the differentiation of Alzheimer
disease and frontotemporal dementia.
FDG-PET may be especially useful in
the differentiation of atypical parkin-
sonism in the future as the research in
this area evolves.64
In 2011, ioflupane I-123 single-
photon emission computed tomogra-
phy (SPECT) was approved in the
United States as an adjunctive evalua-
tion tool for use in the diagnosis of
suspected parkinsonian syndromes.
This compound binds to the presyn-
aptic dopamine transporter (DAT) and
acts as a marker for dopamine levels in
the striatum. While the research utility
of DAT-SPECT is universally agreed
upon, its use in the clinical setting for
differential diagnosis in the individual
remains controversial.65
It is generally agreed on by experts
that DAT-SPECT does not currently
have a role in the differentiation of PD
from other neurodegenerative forms
of parkinsonism as DAT binding will
be reduced in all of these entities
(Case 1-3). Further, progression of
PD cannot yet be followed by DAT-
SPECT as it has not been shown to
define a clear and reliable relationship
between DAT binding and disease
severity.66 Therefore, DAT-SPECT is
currently limited to the differentiation
of a neurodegenerative parkinsonian
syndrome from entities such as essential
tremor, dystonia, or secondary causes
of parkinsonism. Yet even in these
populations, findings are not always
straightforward. DAT binding would be
expected to be normal in essential
tremor and thus useful for ruling out a
dopamine deficiency in the long-
standing patient with essential tremor
who has developed a superimposed
slowing of movement speed beyond
that which can be seen in essential
tremor.11 It should also be normal in
dystonia, which is believed to account
August 2016
for a significant proportion of patients
clinically diagnosed with PD who had TABLE 1-5 Relevant Drug Interactions With Dopamine
Transporter Single-Photon Emission Computed
DAT imaging scans without evidence Tomography (DAT-SPECT)a
of dopaminergic deficit (SWEDD).67
Yet even in such patients, false positives Effect on DAT-SPECT Time to Be Stopped Prior to
have been reported and some patients and Drug DAT-SPECT
with essential tremor may have mild Minor effectb
abnormalities with DAT imaging.68,69
Amantadine 6 days
Similarly, patients with parkinsonism
who have normal DAT-SPECT imaging Budipine 6 days
have been reported to both transition Citalopram 8 days
to abnormal scans on follow-up and Clomipramine 21 days
respond well to dopaminergic therapy.70
Duloxetine 3 days
Rarely, patients with vascular parkinson-
ism and drug-induced parkinsonism Ephedrine, epinephrine, 6Y10 hours
phenylephrine,
can also have abnormal DAT-SPECT
pseudoephedrine
imaging, and in these patient groups
its utility may be primarily focused on Escitalopram 8 days
those patients observed to have nor- Fluoxetine 45 days
mal DAT binding and a clinical presen- Fluvoxamine 5 days
tation of parkinsonism.66 However, DAT Imipramine 5 days
is usually negative in cases of drug-
Memantine 5 days
induced parkinsonism.
DAT-SPECT also has a number of Paroxetine 5 days
limitations that need to be considered, Sertraline 6 days
even when used judiciously. With the Venlafaxine 3 days
exception of a few studies that have Ziprasidone 2 days
included clinicopathologic correlation, c
Significant effect
most studies that have evaluated the ac-
curacy of DAT-SPECT in the diagnosis Amphetamine 7 days
of PD have used the clinical diagnosis Benztropine 5 days
of PD as the gold standard, which is Bupropion or 8 days
obviously problematic when one is amfebutamone
looking to the DAT-SPECT for support- Cocaine 2 days
ive data when the clinical diagnosis is
Dextroamphetamine 7 days
not clear.71 Additionally, interpretation
of the DAT-SPECT is currently qualita- Mazindol 3 days
tive, with a binary normal or abnormal Methylamphetamine 3 days
reading assigned based on visual in- Methylphenidate 2 days
spection. While objective quantitative
Modafinil 3 days
measures of DAT binding have been
developed, they are not currently clin- Phentermine 14 days
ically available.72 a
Modified with permission from Kägi G, et al. J Neurol Neurosurg Psychiatry.73
If DAT-SPECT imaging is pursued, it B 2010 BMJl Publishing Group Ltd. jnnp.bmj.com/content/81/1/5.abstract.
b
is important to note that a number of May have small effect on uptake (at most 15%). This is acceptable for routine
DAT-SPECT but not for research.
commonly prescribed medications can c
All of these drugs are likely to alter (usually decrease) radioligand uptake by at
interfere with DAT binding and pro- least 20% and often substantially more and, therefore, have to be stopped
prior to routine DAT-SPECT.
duce erroneous results (Table 1-5).73
Most of the drugs listed in this resource
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 Diagnosing Parkinson Disease
KEY POINT
h If dopamine transporter
single-photon emission
computed tomography
imaging is pursued, it is
important to note that a
number of commonly
prescribed medications
can interfere with
dopamine transporter
binding and produce
erroneous results.
1060 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
reduce DAT binding (potentially
resulting in a false-positive interpreta-
tion). The duration of discontinuation
recommended for some of these agents
is significant (such as for some of the
selective serotonin reuptake inhibitors
[SSRIs]), and the decision to stop medi-
cations needs to be considered on an
individual basis. In contrast, dopami-
nergic medications such as levodopa and
dopamine agonists are generally not held
prior to scanning, as their influence on
DAT binding is not thought to be a
significant confounder.73 Recommenda-
tions on which medications to hold
prior to DAT scanning and for how long
have yet to be agreed upon by experts.
CONCLUSION
Making an accurate diagnosis of PD in
the early stages of the disease can be
challenging. A careful history and
examination guided by clinical diag-
nostic criteria will usually establish PD
or alternatively uncover red flags sug-
gesting other diagnoses. The symptoms
of PD can be variable, and subtypes
exist that have differing clinical symp-
toms and rates of progression. Some
patients may not fulfill criteria for the
clinical diagnosis in the initial stages
of their disease. The key is to closely
follow patients, as disease progression
usually gives the answer. Over time,
patients initially suspected of having PD
will either have their diagnosis solidi-
fied by their clinical course and re-
sponse to medication or an alternative
diagnosis will emerge. Structural neu-
roimaging and laboratory testing can be
helpful in ruling out other diseases.
While imaging of the striatal DAT can
be useful in specific situations, clinical
evaluation by a movement disorders
specialist or neurologist experienced in
movement disorders is usually ade-
quate to the establish the diagnosis of
PD for most patients presenting with
parkinsonism. Since other PD syndromes
can emerge over time, it is important for
the clinician to continue to follow the
patient long-term, monitor the exami-
nation, and document the response to
dopaminergic therapy. In many cases,
the diagnosis may be revised based on
the emergence of a pattern of symp-
toms suggesting an atypical parkinso-
nian syndrome or other diagnosis.
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