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REVIEW ARTICLE

Diagnosis and Medical

ÿ
CONTINUUM AUDIO
INTERVIEW AVAILABLE
Management of
ON-LINE

Parkinson's disease

By Avner Thaler, MD, PhD; Roy N. Alcalay, MD, MS

ABSTRACT
PURPOSE OF REVIEW: Parkinson disease (PD) is a common neurodegenerative CITE AS:

movement disorder, the prevalence of which is rising as the world population CONTINUUM (MINNEAP MINN)
2022;28(5, MOVEMENT DISORDERS):
ages. It may present with motor and nonmotor symptoms, and symptomatic 1281–1300.
treatment significantly improves quality of life. This article provides an overview of
the workup and differential diagnosis for PD and reviews genetic and environmental Address correspondence to Dr
risk factors and current treatments. Roy N. Alcalay MD, MS, 6
Weizman St, Tel Aviv 6423906,
Israel, [email protected]

RELATIONSHIP DISCLOSURE:
RECENT FINDINGS: Novel treatments for the motor (eg, fluctuations and off times)
Dr Thaler has received personal
and nonmotor (eg, hallucinations and orthostatic hypotension) complications of compensation in the range of
PD have been approved in recent years. In addition, with recent advances in our $500 to $4999 for serving as a
consultant for AbbVie Inc. The
understanding of the genetics of PD, significant research is focusing on identifying institution of Dr Thaler has
at-risk populations and introducing genetically targeted interventions (precision received research support from
medicine). Biogen and The Michael J. Fox
Foundation. Dr Alcalay has
received personal
SUMMARY: PD is a heterogeneous neurodegenerative movement disorder. compensation in the range of
$500 to $4999 for serving as a
Affected individuals may receive substantial symptomatic relief from
consultant for AVROBIO, Inc;
nonpharmacologic, pharmacologic, and surgical interventions. Although no intervention Caraway Therapeutics, Inc;
to modify the progression of PD is currently available, precision medicine and GlaxoSmithKline plc; Janssen
Global Services, LLC; Merck &
modulation of the immune system are a major focus of ongoing research. Co, Inc; Ono Pharmaceutical Co,
Ltd; and Takeda Pharmaceutical
Company. Dr Alcalay has
received personal
compensation in the range of
$10,000 to $49,999 for serving as
a consultant for Sanofi. The
institution of Dr Alcalay has
INTRODUCTION received research support from
Biogen, the Department of
Defense, The Michael J. Fox
disorder,1 afflicting more than 6.1 million people across the world as of Foundation, the National
2016,2 with effective symptomatic treatment available for decades.3 Institutes of Health, and the
Parkinson's Foundation.
The natural history of PD is heterogeneous and includes a wide range
Parkinson disease
of motor(PD)
andisnonmotor
the second most common
symptoms. neurodegenerative
The traditional definition of PD is UNLABELED USE
OF PRODUCTS/INVESTIGATIONAL
based on cardinal motor symptoms, including bradykinesia, resting tremor, rigidity,
USE DISCLOSURE:
and gait impairment4 ; However, more recent diagnostic criteria have been developed Drs Thaler and Alcalay report no
that integrate nonmotor symptoms, including autonomic, affective, cognitive, and disclosures.

sleep impairments (refer to the section on clinical diagnosis later in this article).
Because of the heterogeneity in symptoms and rate of progression, clinical management © 2022 American Academy
should be tailored individually. of Neurology.

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

RISK FACTORS
Age is the single most important risk factor for PD.5 Juvenile PD, defined as onset
younger than 21 years of age, is exceedingly rare, and only 5% to 10% of patients
are diagnosed before the age of 50.6 Mean age at onset is approximately 60 but
varies across studies, and women are less often affected than men.5 To date,
most studies have been performed on patients of European decent, thus less is
known about PD prevalence and clinical presentation in underrepresented
populations. Specifically, it remains unknown whether people of African descent have
a lower prevalence and incidence of PD or if prevalence/incidence
discrepancies are a result of disparities in health care access.7

TABLE 2-1 Major Genetic Causes and Risk Factors for Parkinson Disease

Gene(s) Mode of inheritance Population Phenotype

SNCA (additional Autosomal dominant point Mostly European; A53T mutation Early-onset Parkinson disease (PD)
gene symbols: mutations, duplications, and more common in Greece with more rapid progression than in
PARK1, PARK4) triplications with incomplete idiopathic PD; good levodopa
penetrance response but early fluctuations11;
psychiatric features in gene
duplication cases; dementia may be
present early

PRKN (Parkin) Autosomal recessive; role of Worldwide; mutations relatively Early-onset PD with slow rate of
(previous gene heterozygous mutations is common when PD onset is in progression; atypical features may be
symbol: PARK2) controversial third or fourth decade of life present (dystonia, prominent freezing
of gait)12; less cognitive impairment
than in idiopathic PD

PINK1 (previous Autosomal recessive; role of Rare; worldwide Early-onset PD with slow rate of
gene symbol: heterozygous mutations is progression; good levodopa
PARK6) controversial response13; some atypical features
such as dystonia

PARK7 (previous Autosomal recessive; role of Rare; Dutch, Italian Case reports only; early-onset PD with
gene symbol: DJ1) heterozygous mutations is good levodopa response but with motor
unknown fluctuations14

LRRK2 (previous Autosomal dominant with Present worldwide; varies by Similar motor phenotype with slower rate
gene symbol: incomplete penetrance mutation: G2019S (North African of progression than idiopathic
PARK8) Berber and Ashkenazi Jews), PD15; fewer nonmotor
R1441G/C/H (Spanish Basque), manifestations, including cognitive
G2385R (Chinese, Japanese, changes, than in idiopathic PD
Korean), I2020T (Japanese)

VPS35 (PARK17) Autosomal dominant European, Japanese Case reports only; similar to
idiopathic PD16

G.B.A. Autosomal dominant, with Worldwide; highest risk in Similar motor phenotype as in
markedly reduced Ashkenazi Jewish populations idiopathic PD but with more rapid motor
penetrance (may be and cognitive progression17; more
considered a risk factor) severe nonmotor features than in idiopathic
PD, particularly cognitive
impairment; earlier onset and more
severe motor and nonmotor
features in homozygotes/ compound
heterozygotes

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KEY POINTS
PD is a genetically complex disorder that can result from genetic alterations,
environmental exposures, and the interaction among these factors.
• Older age and male sex are
Of all environmental risks, exposure to pesticides has been most consistently associated with PD the most established risk
risk; consumption of dairy products, rural living, and traumatic brain injury have also been factors for Parkinson
associated with increased risk.8 In contrast, consumption of coffee, smoking, physical activity, and use disease (PD). The most
established environmental risk
of nonsteroidal anti-inflammatory drugs are associated with lower risk for PD.8 Several toxins can
factor for PD is pesticide
produce a clinical syndrome resembling PD, including 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine
exposure.
(MPTP), which causes irreversible damage to dopaminergic neurons in the substantia nigra.9
• The seven genes clearly
associated with PD risk are
SNCA, LRRK2, and VPS35
(dominant); PRKN, PINK1,
Genetic Risk Factors
and DJ-1 (recessive); and
Significant headway has been made in the understanding of PD genetics within the past 2 decades. GBA (risk factor).
Genetic risk factors can be crudely organized by the level of risk they convey. Rare pathogenic variants
• The definitive diagnosis of PD
in SNCA, LRRK2, and VPS35 cause dominantly inherited PD, with varying levels of penetrance.
is based on pathology.
Homozygous and compound heterozygous mutations in PRKN, PINK1, and PARK7 (previously known The two key required criteria are
as DJ-1) can cause recessively inherited PD. Glucocerebrosidase (GBA) pathogenic variants are atrophy of dopaminergic cells in
relatively common but convey a lower risk for PD. the substantia nigra and
accumulation of ÿ-
synuclein.
Combined, pathogenic variants in these seven genes are present in about 10% to 15% of all people with
PD.10 TABLE 2-1 summarizes clinical and phenotypic data on these seven genes.11-17 Currently,
clinical genetic testing is rarely offered in the workup of PD,18 but with the rapid evolution of genetic
research, clinical genetic testing is on the rise.10 Various commercial laboratories offer different PD
panels that look for mutations among the 5 to 62 genes associated with an increased risk of PD.19
Most of these panels include the seven genes mentioned above. In addition to Mendelian inheritance,
many single-nucleotide polymorphisms (SNPs) are associated with a mildly increased risk of PD;
Combined, these may have a significant role in the development of PD. Recent
research studies have analyzed the risk of these SNPs when combined to generate a polygenic risk
score, with a high polygenic risk score suggesting a high risk of PD diagnosis.20 Currently, polygenic risk
scores are not commercially available for PD.

DIAGNOSIS OF PARKINSON DISEASE

The gold standard diagnosis of PD is by pathology, which is not, of course, practiced in the clinical
setting. This section describes the pathological and clinical diagnosis of PD.

Pathology: the Gold Standard Diagnosis The definitive

diagnosis of PD is based on pathology, which is obtained by postmortem analysis. The two key
criteria for the diagnosis are atrophy of dopaminergic cells in the substantia nigra, not otherwise
explained, and accumulation of ÿ-synuclein in Lewy bodies and neurites in the brain.21 Indeed,
many of the motor symptoms that define PD are a result of cell loss in the substantia nigra dopaminergic
neurons. This results in an imbalance between the direct and indirect pathways of the basal
ganglia, leading to bradykinesia.22 When PD symptoms appear, up to 60% of the dopaminergic neurons
have already been lost.23 This loss is greatest in the ventrolateral tier of the substantia nigra and
in the caudal putamen.24 The primary cause of this slowly progressive cellular atrophy is unknown.
Several mechanisms have been involved in PD

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

pathophysiology, including mitochondrial, proteasomal, and lysosomal

dysfunction; protein aggregation; oxidative stress; and neuroinflammation.25 In
many autopsies of people with PD, and especially in those who died at advanced
age, mixed pathology (of Alzheimer-like and vascular changes) may be found.
Identifying mixed pathology highlights the role of additional pathologic
processes (in addition to ÿ-synuclein deposition) in the development of PD
symptoms (eg, cognitive impairment) and may reduce enthusiasm in identifying
ÿ-synuclein as a potential target for future PD therapies.26 .27

Clinical Diagnosis
Historically, the clinical criteria for the diagnosis of PD were developed in
comparison to the gold standard pathologic diagnosis (ie, criteria that will
accurately predict the pathologic diagnosis based on motor symptoms).4 In 2015,
the International Parkinson and Movement Disorder Society (MDS) updated
its criteria for PD diagnosis (MDS-PD)28 to improve diagnostic accuracy relative
to the previously used Queen Square Brain Bank criteria.29 In the MDS-PD
criteria, the motor syndrome remains the core feature of the disease, but
nonmotor features are also included.
The diagnosis of PD is based on major motor manifestations: bradykinesia in
combination with either resting tremor or rigidity or both. The assessment of
these symptoms should be performed according to the revised MDS-Unified
Parkinson's Disease Rating Scale (UPDRS) to encourage interterrater
reliability among examiners.30 Bradykinesia is defined as slowness in
movement and reduction in amplitude or speed of continuous movements. It
should be assessed in each limb separately. Rigidity is defined as increased
resistance to passive movement, with cogwheel phenomena usually present on
examination. Resting tremor is a 4-Hz to 6-Hz tremor in a fully resting limb.
Postural instability, which is a feature of parkinsonism, is not a part of the MDS-
PD criteria as it usually appears at later stages of PD.
Supportive criteria for the diagnosis of PD include beneficial response to
dopaminergic therapy (ie, to levodopa or dopamine agonists), levodopa-induced
dyskinesia, hyposmia, and cardiac sympathetic denervation as demonstrated on
metaiodobenzylguanidine (MIBG) scintigraphy. Observations that make the
diagnosis of PD less likely include supranuclear gaze palsy (suggesting a

TABLE 2-2 Hoehn and Yahr Scale for Severity of Parkinson's Disease

Stage Clinical symptoms

1 Unilateral involvement only

2 Bilateral involvement without impairment of balance

3 Mild to moderate bilateral disease, some postural instability, physically independent

4 Severe disability, still able to walk or stand unassisted

5 Uses wheelchair or bedridden unless assisted

to
Data from Hoehn MM, Yahr MD, Neurology.34

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KEY POINTS
diagnosis of progressive supranuclear palsy [PSP]), cerebellar symptoms (indicating a diagnosis
of multiple system atrophy [MSA] or PSP), parkinsonism restricted to the lower limbs for more than 3 years
• The clinical diagnosis of PD
(suggestive of vascular parkinsonism), a diagnosis of probable frontotemporal dementia, recent was historically based on motor
treatment with a dopamine receptor blocker or dopamine depletor, absence of response to high- symptoms. More recently,
dose levodopa (>600 mg/d), cortical sensory loss, and normal presynaptic dopaminergic imaging.28 nonmotor symptoms
were added to the criteria to
improve accuracy.

In addition, several red flags were proposed to indicate the possibility of an alternative diagnosis:
• Postural instability, which is a
feature of parkinsonism, is not a
u Rapid progression requiring use of wheelchair within 5 years of diagnosis (often seen in part of the International
MSA and PSP) Parkinson and Movement
Disorders Society criteria
u No motor progression for 5 years (suggesting essential tremor)
for PD diagnosis as it
u Early bulbar dysfunction (dysphonia, dysarthria, or dysphagia, suggesting MSA) usually appears at later
stages of PD.
u Inspiratory respiratory dysfunction (stridor, suggesting MSA)

u Severe autonomic failure within 5 years of diagnosis (orthostatic hypotension or urinary

incontinence, suggesting MSA or dementia with Lewy bodies [DLB]) • Clinical red flags raise
suspicion to an alternative
u Recurrent falls (>1 per year) within 3 years of diagnosis (suggesting PSP)
diagnosis, most often
u Disproportionate anterocollis within 10 years of diagnosis (suggesting MSA) multiple system atrophy,
progressive supranuclear
u Absence of nonmotor symptoms (suggesting either dystonic or essential tremor)
palsy, or dementia with
u Unexplained pyramidal signs (seen in PSP and MSA) Lewy bodies.

u Bilateral symmetric disease from onset (seen in PSP and MSA)

• The Hoehn and Yahr scale
is often used to capture the
Diagnostic errors, which depend on the clinical presentation,31 are common in early stages of PD and severity and progression of
improve with longer follow-up as the development of additional symptoms and the time course of motor symptoms of PD.
Movement Disorders
symptom progression are considered. Up to 15% of patients with an initial clinical diagnosis of PD
Society Unified Parkinson's
are found to be misdiagnosed based on postmortem pathology.32 When the primary presentation is tremor, Disease Rating Scale is used to
essential tremor and other causes of tremor may lead to a diagnostic error. When the primary quantify disease severity.
symptoms are bradykinesia, rigidity, and gait impairment, the differential diagnosis of PD includes vascular
parkinsonism, MSA, PSP, and corticobasal degeneration.

Progression of Motor Symptoms The motor

symptoms of PD tend to progress over time. After the initiation of dopaminergic treatment, motor
fluctuations may appear, in which the effect of the dopaminergic therapy does not last until the next dose
is administered, and an on-off phenomenon develops, in which patients may feel that their symptoms
are well controlled in the on state and less controlled in the off state.

Further, dyskinesia may appear at the peak of the dopaminergic effect or before or after doses. Freezing of
gait is a common PD symptom that may appear later in the disease course; it is defined as a brief episodic
absence or reduction of forward progression of the feet despite the intention to walk.33 Freezing episodes
can be triggered by motor, cognitive, or affective causes.

The severity of the motor symptoms of PD can be described using the five-point Hoehn and
Yahr scale (TABLE 2-2) 34; However, the rate of motor progression of PD is very heterogeneous and
nonlinear. A 2020 study that assessed patients with PD without access to treatment identified that
40% of participants reached Hoehn and Yahr stage 3 after 7 years of disease.35

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

TABLE 2-3 Nonmotor Symptoms of Parkinson's Disease

Treatment proven in Parkinson's Treatment for condition in

Symptom Stage of occurrence disease generalb

depression Prodromal or after diagnosis Selective serotonin reuptake inhibitors Tetracyclic antidepressants,
(SSRIs), serotonin trazodone, mirtazapine,
norepinephrine reuptake bupropion, monoamine oxidase
inhibitors (SNRIs), pramipexole, B (MAO-B) inhibitors
nortriptyline, desipramine

Anxiety Prodromal or after diagnosis SSRIs Benzodiazepines

Apathy Any stage Piribedil (still investigational),

rivastigmine

Hallucinations and late stage Pimavanserin, clozapine, First- and second-generation

psychosis quetiapine antipsychotics

Impulse control Late stage or as a result of Cessation of dopamine agonist

disorders dopamine agonist use use

Moderate to severe Mild cognitive impairment can Cholinesterase inhibitors N-methyl-D-aspartate (NMDA)
cognitive impairment and appear as early as at time of antagonist
dementia diagnosis or the prodromal stage;
dementia appears in late stage

Orthostatic Prodromal or after diagnosis Droxidopa, midodrine, Pyridostigmine, atomoxetine,

hypotension fludrocortisone pseudoephedrine

Urinary dysfunction Any stage; early urinary Solifenacin Antimuscarinics, ÿ-adrenergic

and incontinence symptoms may be receptor agonists
concerning for multiple
system atrophy

Erectile dysfunction Prodromal or after diagnosis Sildenafil Tadalafil, vardenafil, avanafil

Constipation Prodromal or after diagnosis Hydration, probiotics, fiber, lubiprostone, Lactulose, linaclotide
macrogol

Excessive sweating late stage Anticholinergics

Rapid eye movement Prodromal or after diagnosis Melatonin, clonazepam

(REM) sleep behavior
disorder

Sleep fragmentation Prodromal, after diagnosis, or late Rotigotine, eszopiclone,

and insomnia stage melatonin

Excessive daytime Prodromal, after diagnosis, or late Modafinil

sleepiness stage

Pain Prodromal or after diagnosis MAO-B inhibitors, oxycodone/ naloxone Nonsteroidal anti-inflammatory
prolonged release drugs, acetaminophen, opioids,
cannabis

Fatigue Prodromal, after diagnosis, or late Rasagiline

stage

Olfactory dysfunction Prodromal or after diagnosis

to
Data from Seppi K, et al, Mov Disord.36
b
Blank entries indicate a lack of data.

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Nonmotor Symptoms KEY POINTS

The nonmotor features of the disease significantly affect patients' well-being

• The diagnosis of PD is
(TABLE 2-3).36 Dementia often occurs as PD progresses, and up to half primarily clinical. Ancillary
of people with PD will report substantial cognitive impairment within 10 years diagnostic tests can be
of diagnosis,37 resulting from neuronal loss and both dopaminergic and useful when the clinical

cholinergic impairment.38 The cognitive domains involved include frontal/ diagnosis remains unclear.

executive, memory, visuospatial, and, less commonly, language. Patients should • MRI or other structural
be screened yearly for cognitive decline.39 It should be noted that the MDS-PD Imaging may detect causes of
criteria do not consider dementia as an exclusion criterion for PD, regardless secondary parkinsonism, such
of when it develops in relation to motor symptoms.28 Further, the new MDS-PD as hydrocephalus or stroke.

criteria recommend that for patients with a diagnosis of DLB made according to
consensus criteria, the diagnosis can optionally be qualified as PD (DLB • Dopamine transporter
subtype). For more information, refer to the article “Diagnosis and Treatment of single-photon emission
Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia computed tomography may be
helpful in detecting
With Lewy Bodies” by Daniel Weintraub, MD, and David Irwin, MD,40 in this issue
of Continuum . dopamine deficiency but is
less useful in tracking the
Autonomic dysfunction is also common in PD, in both early and late stages of progression of intermediate or
the disease.41 It is associated with both motor symptom severity and cognitive advanced stages of PD or in
deterioration42 and is caused by accumulation of ÿ-synuclein within the central distinguishing PD from other
neurodegenerative
and peripheral nervous systems.43 However, severe autonomic involvement is parkinsonian syndromes.
suggestive of MSA. For more information on MSA, refer to the article “Multiple
System Atrophy” by Daniel O. Claassen, MD, MS, FAAN,44 in this issue of
Continuum.

ANCILLARY DIAGNOSTIC METHODS

PD is primarily a clinical diagnosis. However, ancillary diagnostic tests can
sometimes assist the diagnosis in cases in which the clinical diagnosis is not clear.

Structural Imaging
Structural MRI is usually normal in patients with PD; However, it can be useful in
detecting causes of secondary parkinsonism, such as infarcts, iron deposition,
normal pressure hydrocephalus, or space-occupying lesions such as neoplasms.45
New protocols, including neuromelanin imaging and high-resolution structural
scans of the substantia nigra , may hold promise for future structural assistance
in diagnosis.46

Radiotracer Imaging
Radionuclide tracers can assess presynaptic and postsynaptic striatal
dopaminergic functions using positron emission tomography (PET) or
single-photon emission computed tomography (SPECT) imaging. Dopamine
transporter SPECT detects loss of striatal dopaminergic terminals and can
assist in the identification of nigrostriatal degeneration and distinguish these
cases from non-neurodegenerative cases (eg, essential tremor, psychogenic
or vascular causes) (CASE 2-1 ) . Dopamine transporter SPECT may also
be useful in evaluating patients with parkinsonism who are treated with dopamine
blockers.47 However, dopamine transporter SPECT cannot distinguish between
the different neurodegenerative parkinsonian syndromes.48 A rapid decline
in nigrostriatal terminals up to 4 years from diagnosis of PD has been reported,
with a floor effect for change in striatal binding afterwards. Thus, dopamine
transporter SPECT is a good tool for the detection of neurodegeneration but

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

less so for the assessment of progression of disease in intermediate or advanced

stages.49

ÿ-Synuclein Tissue Markers ÿ-

Synuclein deposition is the pathological hallmark of PD; However, no ÿ-
synuclein radiotracer is commercially available. Conversion assays that
amplify ÿ-synuclein using either real-time quaking-induced conversion (RT-QuIC)
assay or protein misfolding cyclic amplification, currently termed synuclein

CASE 2-1 A 65-year-old woman with a long history of tremor presented with worsening
symptoms. She had been diagnosed with essential tremor 27 years earlier
because of bilateral hand tremor affecting her handwriting and her
ability to eat certain foods like soup. Propranolol provided mild symptomatic
effect, and she could not tolerate pidone.
More recently, her handwriting, which was always tremulous, became small,
and her gait became slower and more effortful. She was concerned
she may have developed Parkinson's disease (PD) since her father died of
PD.
Neurological examination was significant for bilateral action and
postural tremor in her hands. She also had a resting tremor in her right arm and
reduced arm swing while walking. Rapid alternating movements, including
finger taps and opening and closing her fists, were mildly slower on the right
than on the left.
The patient's diagnosis of essential tremor was confirmed, based on her long-
standing action tremor, but given her new symptoms, PD was suspected as
well. MRI of the brain was within normal limits. Dopamine transporter single-
photon emission computed tomography (SPECT) demonstrated reduced
radiotracer uptake in the left and right striata, with more extensive involvement
in the putamen relative to caudate.
Deficits were more pronounced on the left caudate and putamen
compared with the right.
Given the mild PD symptoms, she chose to defer pharmacologic
treatment and was referred to physical therapy for gait training and an exercise
program. Twelve months later, rasagiline 1 mg was started with mild improvement
of motor symptoms.

COMMENT When the neurological examination cannot conclusively distinguish between

essential tremor and PD, dopamine transporter SPECT imaging can be
helpful in establishing a diagnosis. Dopamine transporter SPECT, however, would
not help distinguish between PD and other syndromes of dopamine deficiency,
such as multiple system atrophy. Physical activity should be encouraged for
patients with PD. Nonpharmacologic treatment, such as physical therapy and
occupational therapy, can be extremely helpful in alleviating symptoms of
stiffness and may improve gait. No evidence supports postponing
symptomatic therapy when symptoms are disruptive.

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seeding assays, have emerged as promising ÿ-synuclein biomarkers with KEY POINTS

excellent sensitivity and specificity for distinguishing PD from controls using

• Exercise and physical
either CSF or tissue as substrates.50 These tests are often performed for activity should be
research purposes, but they are now emerging for clinical use. It is anticipated recommended for all
that when they are more widely clinically available these assays will be very useful patients with PD.
in clinically complicated cases (eg, when normal pressure hydrocephalus
• No evidence exists that
is suspected or if PD is suspected in patients taking dopamine blockers).
early pharmacologic (eg,
levodopa) treatment of
Parkinson disease has
SUBTYPING PARKINSON DISEASE disease-modifying
properties. However,
The heterogeneity of disease progression makes counseling patients on PD neither evidence exists for the
prognosis and designing clinical trials challenging. Genetic profiles may benefit of delaying
explain some of the heterogeneity (TABLE 2-1), but most patients are not carriers of pharmacologic treatment.
mutations in mendelian genes. Another useful classification of patients is based
on the predominant motor symptoms. Patients may be divided into three
groups: those with tremor-dominant features, those with postural instability-
gait difficulty, and an intermediate group. The differential diagnosis for tremor-
dominant PD includes essential tremor and dystonic tremor. In tremor cases in
which the diagnosis is not clear, dopamine transporter SPECT may be useful.
Patients with PD with the tremor-dominant subtype tend to have slower
progression and less cognitive involvement compared to those with postural
instability-gait difficulty.51 When the primary symptoms are postural instability
and gait difficulty, dopamine transporter SPECT may not be as useful, because
the differential diagnosis includes other causes of parkinsonism, such as
PSP or MSA, in which the scan would demonstrate reduced uptake similar to
that seen in patients with PD.52

MANAGEMENT OF PARKINSON DISEASE SYMPTOMS

Nonpharmacologic interventions for treating the motor symptoms of PD may include
physical therapy, occupational therapy, speech-language therapy, and exercise,
with mounting evidence of efficacy for each.53 Assessment and treatment of
motor and nonmotor symptoms by a multidisciplinary team is advised.54 All
newly diagnosed patients should be screened for depression and treated as
needed.36 An exercise program and in-person and online support groups may
be extremely helpful. Tai chi has been shown to be effective for balance issues in
PD.55
Many factors should be considered when choosing the timing and type of
treatment in PD, including age, comorbidities, symptom severity, potential
adverse effect profile, cost, and patient preferences. Given that no interventions to
slow the rate of progression are available and that all currently available
treatments are considered symptomatic,56 no evidence exists for the added value of
early pharmacologic treatment. However, neither does evidence exist for the benefit
of delaying pharmacologic treatment.3

Levodopa
Levodopa is a precursor of dopamine; when supplemented with a peripheral
decarboxylase inhibitor, sufficient levels of dopa enter the striatum and improve
motor function. It does not correct the underlying neurodegenerative disruption.
Levodopa remains the mainstay of pharmacologic treatment in PD, even 50 years
after its discovery.

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

Dopaminergic pharmacotherapy should be initiated at the lowest dose

that provides symptomatic relief when motor symptoms cause impairment in
daily function. After a period of good motor response (the “honeymoon”),
levodopa-related complications may occur, mainly dyskinesias and motor
fluctuations (on-off periods), which are a major source of disability for
many patients. Dyskinesias appear in up to 40% of patients treated with
levodopa after 4 years, with higher risks among young patients treated with
higher doses of levodopa,57 and can be separated into peak dose
(when plasma levels of the drug are at their maximum) and diphasic
dyskinesia (which occurs at lower drug levels). Chronic constipation and
simultaneous intake of proteinaceous meals might increase off symptoms
because of poor medication absorption.58 Additional strategies to
overcome off symptoms, including adjustment of dose timing and introduction of
additional drugs (eg, dopamine agonists, catechol-O-methyltransferase
[COMT] inhibitors) which might improve on time but potentially with
more
dyskinesias.58 Previous notions that early initiation of levodopa
treatment might be deleterious have been disproven59 and delaying levodopa
treatment was not shown to reduce motor complications and dyskinesia.60
Thus, it is not the duration of levodopa therapy that is associated with the
drug-related motor complications but rather the disease progression
itself.60 In addition, levodopa does not seem to have a negative impact on
the progression of the neurodegenerative process on the basis of PD35; however,
it does not seem to have a positive disease-modifying effect either.59 Certain
motor features of PD (eg, bradykinesia and rigidity) respond better than others
(eg, postural instability, freezing of gait, and dysarthria) to dopaminergic
treatment; however, they all
may respond to some extent.35 Comparing levodopa to dopamine agonists
and monoamine oxidase type B (MAO-B) inhibitors has indicated that although
all three therapies are efficacious, levodopa treatment is best
tolerated and maximizes improvement in mobility scores.61

Dopamine Agonists
Dopamine agonists are synthetic compounds that act as agonists to the
dopaminergic D2 receptors within the central nervous system, thus mimicking
the function of dopamine. First-generation compounds, which were ergoline
derived (pergolide, bromocriptine, cabergoline, lisuride), may cause cardiac
valvular disease and are rarely used. The FDA currently approves
dopamine agonists as tablets (pramipexole, ropinirole), patch (rotigotine),
sublingual film (apomorphine), and subcutaneous injections (apomorphine).
The side effect profile of dopamine agonists includes nausea, leg
edema, orthostatic hypotension, sleep attacks, and impulse control disorders58
such as gambling, hoarding, excessive shopping, binge eating, and hypersexuality.
Impulse control disorders may have devastating psychological, social,
legal, and economic consequences. When impulse control orders occur, a
reduction in the dosage of dopamine agonist therapy is warranted; However, this
might be complicated by the development of a dopamine agonist
withdrawal syndrome, which is characterized by agitation, anxiety,
depression, fatigue, and autonomic symptoms including orthostatic
hypotension and irritability, despite compensatory increases in levodopa dosage.62

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Amantadine KEY POINTS

Amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist,63 was approved

• Comparing levodopa to
for the treatment of PD in 1973, and its extended-release form was approved for the dopamine agonists and
treatment of levodopa-induced dyskinesia. It has a mild antiparkinsonian effect monamine oxidase type B
and may be efficacious in treating resting tremor; it can be administered orally or inhibitors has indicated that

intravenously (in some countries). Side effects include confusion, hallucinations, ankle Although all three therapies are
efficacious, levodopa
edema, constipation, and livedo reticularis.64 treatment is best tolerated and
maximizes improvement in
Monoamine Oxidase Type B Inhibitors MAO- mobility scores.
B inhibitors (rasagiline and selegiline) improve motor symptoms in early PD to a lesser
• When impulse control
extent than dopamine agonists and levodopa.61 A potential interaction may
disorder occurs, reduction in
occur with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants the dosage of dopamine
that might cause serotonin syndrome; however, this is extremely rare.65 Although agonist therapy is
the ADAGIO (Attenuation of Disease progression with Azilect GIven Once-daily) study warranted; However, this
might be complicated by the
demonstrated a benefit of early-start treatment with rasagiline and a potential for
development of a dopamine
disease modification, a follow-up study failed to substantiate these findings.66 The agonist withdrawal
MAO-B inhibitor safinamide has been FDA approved as an add-on treatment for syndrome.
patients who are currently taking carbidopa/levodopa and experiencing off episodes.
• When motor symptoms
advance, a key
consideration is to reduce the
Anticholinergics motor off time and
Anticholinergics are effective in relieving some motor symptoms of PD, fluctuations. Continuous
especially tremor.67 However, cognitive changes while taking the medications are levodopa administration or
deep brain stimulation
common, and they should therefore only be considered in younger patients and with should be considered.
extreme caution. In one study, exposure to anticholinergic drugs was associated with
increased risk of dementia.68 Additional side effects include dry mouth, constipation,
and urinary retention, making this class of drugs less favorable for use among
patients with PD.

TREATMENTS FOR ADVANCED STAGES OF PARKINSON DISEASE

Levodopa is also used to treat advanced PD. In these cases, a shorter time
interval between doses, treatment of constipation, and taking the medication on an
empty stomach are recommended to improve absorption. Extended release
levodopa formulations are another method for the treatment of fluctuations.

COMT inhibitors, such as entacapone and opicapone, are useful in the

treatment of motor complications.69 They enhance levodopa's duration of action and
reduce motor fluctuations. MAO-B inhibitors (such as safinamide and other medications)
and zonisamide have been found useful in treating motor fluctuations70;
However, zonisamide is not FDA approved for this purpose.
Istradefylline, a selective adenosine A2A receptor antagonist, has been approved as an
add-on to carbidopa/levodopa for the treatment of off periods in patients with PD.71
Another
phenomenon that may happen in advanced PD is a sudden off state, for which rescue
drugs are indicated. Apomorphine delivered by subcutaneous injection or inhaled
levodopa is indicated for treatment of sudden off time.
A sublingual form of apomorphine was also recently FDA-approved to reduce off
time.72 Debilitating fluctuations are a reason to introduce device-aided therapies,
such as deep brain stimulation, subcutaneous apomorphine and levodopa-
carbidopa intestinal gel, discussed in the coming sections.

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

CASE 2-2 A 68-year-old man presented for a follow-up visit for Parkinson's disease (PD). He was diagnosed 9
years earlier when he developed resting tremor in his right hand and stiffness. Since his diagnosis, he
has been treated with monamine oxidase type B (MAO-B) inhibitors and levodopa in escalating
doses. Four years after diagnosis, I developed fluctuations, with each levodopa dose lasting 4
hours. At the time, entacapone (a catechol-O-methyltransferase [COMT] inhibitor) was added, and the
levodopa dose was increased to be taken every 4 hours while awake.

When the duration of the on time further decreased to 3 hours, the levodopa formulation was
changed to an extended-release capsule; However, dyskinesia developed. Furthermore, he
developed spells in which he would abruptly reach an off state. These spells made him hesitate to
leave home on his own.

The patient presented for a follow-up visit to check his options for further therapies. The dosage
of levodopa was reduced and amantadine extended-release capsule was added to address the
dyskinesia, and inhaled levodopa was prescribed for off spells. A discussion about deep brain
stimulation was initiated, and the patient was interested in pursuing it. In preparation for the procedure,
he had an MRI, which was within normal limits, and neuropsychological testing, which identified deficits
that were diagnosed as mild cognitive impairment with executive dysfunction. He chose to pursue
genetic testing, which revealed a heterozygous mutation in the glucocerebrosidase (GBA) gene.
Because of the cognitive changes, which can represent higher risk for worse outcome for
deep brain stimulation, he decided to pursue levodopa-carbidopa intestinal gel treatment. He
underwent percutaneous endoscopic gastrojejunostomy for the administration of levodopa-carbidopa
intestinal gel successfully, and his fluctuations significantly improved.

COMMENT In recent years, the treatment of fluctuations and sudden spells of the off state, which are complications
of moderate and advanced PD, has improved significantly. Treatment options include
pharmacologic and surgical interventions. Combined, these interventions improve the quality of
life of patients struggling with the motor complications of PD and levodopa treatment.

Cognitive changes are common as PD advances and can be subtle, mild, or severe, causing PD
dementia. Roughly 10% to 15% of people with PD carry a pathogenic variant in one of seven genes
linked to PD risk. Carriers of pathogenic variants in glucocerebrosidase are at risk for faster motor
and cognitive progression. Clinical trials targeting the biological pathway of the gene are ongoing.
Deep brain stimulation surgery may aggravate cognitive changes. Alternative interventions, such as
levodopa-carbidopa intestinal gel, may be indicated, as in this patient.

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Deep Brain Stimulation/Focused Ultrasound Neurosurgical KEYPOINT

intervention targeting the basal ganglia with high-frequency stimulation (deep brain stimulation)
• Careful adjustment of the
or with lesioning (focused ultrasound) are currently approved for the treatment of motor dopaminergic treatment is a
complications in PD as they have been proven to improve the motor signs and quality of life of logical first step in the
patients with PD.73 Magnetic resonance-guided focused ultrasound targets basal ganglia treatment of nonmotor
structures without craniotomy and electrode placement. For more information on deep brain symptoms in PD.

stimulation and focused ultrasound, refer to the article “Surgical Therapies for Parkinson
Disease” by Ashley E. Rawls, MD, MS,74 in this issue of Continuum.

Apomorphine As
mentioned above, apomorphine is a short-acting dopamine agonist. It can be delivered
subcutaneously either intermittently via injection or continuously via pump (in some
countries but not the United States).75 It may provide rapid relief from PD symptoms, but intermittent
injections have a short half-life.76

Levodopa-Carbidopa Intestinal Gel The use of

levodopa-carbidopa intestinal gel via pump aims to reach a steady plasma concentration of
levodopa by bypassing the stomach to continuously improve motor performance.77 It is used
for 16 hours daily, with evidence of improved quality of life and improvement in both motor
symptoms and nonmotor symptoms such as sleep.78 Peripheral neuropathy due to
vitamin B complex deficiency may become an issue with chronic treatment.79

CHOOSING AMONG THE DIFFERENT ADVANCED-STAGE THERAPIES

Currently, no randomized controlled trials have compared the efficacy of the different advanced
treatments. However, deep brain stimulation seems to have the most positive effect but with the
highest potential for adverse effects.80 CASE 2-2 illustrates the complexity of decision making
in advanced PD.

TREATMENT OF NONMOTOR SYMPTOMS

The medications for PD discussed above focus on the motor symptoms of the disease; However,
the nonmotor symptoms are often more debilitating and require specific attention. Some of
the nonmotor symptoms, such as depression, anxiety, and pain, can fluctuate similarly to the motor
symptoms between the on and off states; Hence, dopaminergic treatment might be considered as
treatment.
However, the same treatment might worsen other nonmotor symptoms, such as hallucinations,
orthostatic hypotension, and psychosis. Careful adjustment of the dopaminergic treatment is a
logical first step in the treatment of nonmotor symptoms in PD. Randomized controlled trials
for nonmotor symptoms in PD are lacking, although these symptoms significantly affect the quality
of life of patients with PD.

Depression
SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs), specifically venlafaxine and
paroxetine, have been found effective for the treatment of depression in PD.81 However,
another study did not replicate these findings for SSRIs.82 The updated MDS task force report on
nonmotor treatment in PD lists

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

other SSRIs and SNRIs as possibly useful for the treatment of depression in PD.36
Pramipexole, a dopamine agonist, has been found to be efficacious for the
treatment of depression in PD.83 Furthermore, the tricyclic antidepressants
nortriptyline and desipramine are labeled likely efficacious. A 2021 meta-analysis
found electroconvulsive therapy useful for the treatment of refractory
depression in PD; However, the number of participants was relatively small.84

Hallucinations and Psychosis

Given that most antipsychotic drugs block dopamine receptors, the treatment of
hallucinations in PD can be challenging. Both PD itself and its treatment increase the
risk for hallucinations. The only FDA-approved drug for the treatment of hallucinations
and psychosis in PD is pimavanserin, a selective serotonin 5-hydroxytryptamine,
serotonin receptor 2A (5-HT2A) inverse agonist.85 Although concerns about
the safety of pimavanserin have been raised, a recent study of Medicare beneficiaries
demonstrated lower mortality among pimavanserin users than those
treated with atypical antipsychotic medications.86 Of the antipsychotic drugs used for
schizophrenia, the two that are not primarily dopamine blockers are quetiapine and
clozapine.87 Clinical trials have shown clozapine to be effective in treating PD-
related psychosis,88 but the need for monitoring agranulocytosis hinders its use.
Quetiapine, which is widely used in the treatment of PD-related psychosis, has not
been demonstrated to be superior to placebo in clinical trials.89 Other antipsychotic
agents block dopamine and should be avoided, if possible, in people with PD.

Urinary Incontinence
Urinary incontinence in PD can have several causes, including motor, sensory, and
autonomic function impairments.90 Thus, the nature and cause of the urinary
symptoms should be ascertained before treatment initiation. Many different
compounds are used for the treatment of urinary incontinence, several of which have
prominent anticholinergic properties that have the potential of affecting both motor
and cognitive functions in PD.91 Solifenacin is used to treat overactive bladder and
neurogenic detrusor overactivity. It has been assessed for PD with partial symptomatic
improvement; However, it, too, carries peripheral antimuscarinic side effects.92
Mirabegron, a selective ÿ3 agonist, has also been shown to effectively treat
overactive bladder in patients with PD.

Orthostatic Hypotension
Orthostatic hypotension is diagnosed by a drop of 20 mm Hg in systolic or 10
mm Hg in diastolic blood pressure with standing. It is common in patients with PD,
may be asymptomatic, and can cause falls.93 Nonpharmacologic interventions
such as increased fluid intake, slow transitions from recumbency to standing, and
specific leg-strengthening exercises might be effective in treating this condition.

Droxidopa (a norepinephrine prodrug) and midodrine (an ÿ1 receptor

agonist) are considered efficacious for the short-term treatment of orthostatic
hypotension in PD94 and should be taken 20 minutes before upright activity.
They should be avoided before supine activity. Fludrocortisone, which is taken daily,
is approved for the treatment of orthostatic hypotension and is labeled possibly
useful in the updated MDS task force report on the treatment of nonmotor
symptoms.36

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Cognitive Decline KEY POINTS

A meta-analysis of cholinesterase inhibitors demonstrated improvement in

• Hallucinations in PD may
cognitive functions in patients with PD and dementia95; however, this has not been significantly impair quality of life
demonstrated for cognitive impairment without dementia in PD.36 For more and limit the use of
information, refer to the article “Diagnosis and Treatment of Cognitive and dopaminergic intervention.
Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Careful management of
hallucinations is indicated.
Bodies” by Daniel Weintraub, MD, and David Irwin, MD,40 in this issue of
Continuum.
• Although the link
between rapid eye
Constipation movement (REM) sleep
behavior disorder and PD is
Constipation is prevalent in PD both before and after diagnosis. Many treatments
well established, evidence on
are available for constipation, including adequate hydration, physical activity, and effective management of REM
associated medications.96 Lubiprostone, probiotics, and fibers are considered sleep behavior disorder is
useful in the treatment of constipation in PD.97,98 insufficient.

Rapid Eye Movement Sleep Behavior Disorder

When patients have rapid eye movement (REM) sleep behavior disorder (RBD),
it is important to maintain a safe sleep environment, including the removal of
sharp objects near the bed and the addition of bedrails, if indicated. Potential
aggravators of RBD should be addressed, including the use of SSRIs, SNRIs, or
tricyclic antidepressants.99 Treatment options for RBD include clonazepam or
melatonin, although no firm evidence supports their use.

Impulse Control Disorders

Patients with a premorbid history of behavioral addictions or drug abuse and
younger patients are at increased risk for impulse control disorders. A slow
decrease of dopamine agonists until discontinuation of use is the mainstay of
treatment.100

Apathy
Although apathy has a significant negative effect on both patients and
caregivers, no official guidelines for the treatment of this condition are
currently available. Some studies detected improvement in apathy scores when
treating depression and cognitive impairment with rivastigmine and rotigotine.101

Anxiety
Anxiety in PD is often treated with SSRIs and, to a much lesser extent,
benzodiazepines because of their adverse effect profile, which includes cognitive
impairment and falls.102 Anxiety and depression are often treated simultaneously
with a single agent in PD.102

Pain
Several mechanisms are involved in pain in PD, including musculoskeletal,
dystonic, radicular, and central mechanisms. The first step in treating pain is to
assess which mechanism is involved.103 One study identified safinamide, a novel
MAO-B inhibitor, as efficacious in treating pain in patients with motor
fluctuations.104 Cannabis has also been evaluated for pain relief in PD with
positive effects.105

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DIAGNOSIS AND MANAGEMENT OF PARKINSON DISEASE

CONCLUSION

PD is a common neurodegenerative disease with numerous symptomatic treatments for both the motor and
nonmotor symptoms but no disease modifying treatments. Nonmotor symptoms have a large impact on
quality of life and require clinical attention similar to the motor symptoms of the disease.

The discovery of genetic causes of PD has opened the way for targeted trials; The results of these trials, together
with ÿ-synuclein–reducing treatments, are anticipated to change the way we treat the disease.

ACKNOWLEDGMENT

The authors would like to thank Adina Wise, MD, for her careful English editing.

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