Parkinson’s Disease and Its Management

Part 1: Disease Entity, Risk Factors, Pathophysiology,

Clinical Presentation, and Diagnosis
George DeMaagd, PharmD, BCPS; and Ashok Philip, PhD

INTRODUCTION approach to care that includes movement specialists, social

Parkinson’s disease (PD) was first described by Dr. James workers, pharmacists, and other health care practitioners.14,15
Parkinson in 1817 as a “shaking palsy.” It is a chronic, progres- Numerous risk factors and genetic mutations are associated
sive neurodegenerative disease characterized by both motor with PD. Risk factors for the disease include oxidative stress,
and nonmotor features. The disease has a significant clinical the formation of free radicals, and a number of environmental
impact on patients, families, and caregivers through its pro- toxins (Table 1).16,17 Limited data support genetic associations
gressive degenerative effects on mobility and muscle control. with PD, with some gene mutations identified (Table 2).18–20
The motor symptoms of PD are attributed to the loss of striatal Interestingly, an inverse relationship exists between ciga-
dopaminergic neurons, although the presence of nonmotor rette smoking, caffeine intake, and the risk of developing PD.
symptoms supports neuronal loss in nondopaminergic areas Inhibition of the enzyme monoamine oxidase (MAO) may
as well. The term parkinsonism is a symptom complex used explain the protective effects of tobacco smoking, whereas the
to describe the motor features of PD, which include resting benefits of caffeine may be related to its adenosine antagonist
tremor, bradykinesia, and muscular rigidity. PD is the most
common cause of parkinsonism, although a number of second- Table 1 Risk Factors Associated
ary causes also exist, including diseases that mimic PD and With Parkinson’s Disease16–20,22,23,29–38
drug-induced causes.1–3 • Elevated cholesterol
Research suggests that the pathophysiological changes • Environmental toxins
associated with PD may start before the onset of motor fea-
°° Carbon disulfide
tures and may include a number of nonmotor presentations,
°° Cyanide
such as sleep disorders, depression, and cognitive changes.
°° Herbicides
Evidence for this preclinical phase has driven the enthusiasm
°° Methanol and organic solvents
for research that focuses on protective or preventive therapies.4
°° Pesticides
PD is one of the most common neurodegenerative disorders. • Head trauma
The Parkinson’s Disease Foundation reports that approxi- • High caloric intake
mately 1 million Americans currently have the disease.5 The • Increased body mass index
incidence of PD in the U.S. is approximately 20 cases per • Inflammation associated with activation of microglia
100,000 people per year (60,000 per year), with the mean age • Methcathinone (manganese content)
of onset close to 60 years. The prevalence of PD is reported to • Methamphetamine/amphetamine abuse
be approximately 1% in people 60 years of age and older and • Mitochondrial dysfunction
increases to 1% to 3% in the 80-plus age group. However, an • Nitric oxide toxicity
important caveat associated with these numbers is that they • Oxidative stress
do not reflect undiagnosed cases.6,7
°° Formation of free radicals (e.g., hydrogen peroxide)
Although it is primarily a disease of the elderly, individuals
°° Potent neurotoxins (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahy-
have developed PD in their 30s and 40s.7 Gender differences dropyridine)
pertaining to the incidence of PD are reflected in a 3:2 ratio of • Post-infection states
males to females, with a delayed onset in females attributed • Signal-mediated apoptosis
to the neuroprotective effects of estrogen on the nigrostriatal
dopaminergic system.8,9
Table 2 Gene Mutations Associated
PD’s variable but pronounced progression has a significant
impact on patients, families, and society. Advanced and end-stage
With Parkinson’s Disease16–20,22,23,29–38
disease may lead to serious complications, including pneumonia, • Alpha-synuclein gene (SNCA)
which are often associated with death.10,11 Current treatment is • Eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1)
focused on symptomatic management.12,13 Evidence suggests • Glucocerebrosidase gene (GBA)
that PD patients may also benefit from a multidisciplinary • Leucine-rich repeat kinase 2 (LRRK2) gene loci
• PTEN-induced putative kinase 1 (PINK1) gene loci
Dr. DeMaagd is the Associate Dean of Academic Administration and • Superoxide dismutase 2 gene (SOD2)
a Professor of Pharmacy Practice at the Union University School of • Vacuolar protein sorting 35 homolog gene (VPS35)
Pharmacy in Jackson, Tennessee. Dr. Philip is an Associate Profes-
sor of Pharmaceutical Sciences at the Union University School of Disclosure: The authors report no commercial or financial interests
Pharmacy. in regard to this article.

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activity.21 The variable prevalence of PD throughout the world suggested that their formation may be secondary to refrac-
suggests that environmental and genetic factors along with tory proteolytic processes involving abnormal breakdown or
ethnic differences may all play a role in disease pathogen- overproduction influenced by genetic mutations.45–47 Gene
esis.22,23 Biomedical research in individuals with PD continues mutations involving the alpha-synuclein (αSyn) protein have
and may help to identify additional risk factors and to guide been found to aggregate and form insoluble fibrils associated
future prevention and treatment decisions.24–28 with LBs;53 αSyn proteins have been identified as a potential
target for future PD therapy.54
PATHOPHYSIOLOGY The formation of LBs involves excessive production of
PD is a disorder of the extrapyramidal system, which includes misfolded forms of ubiquitin proteins, which are involved in
motor structures of the basal ganglia, and is characterized by protein recycling. The accumulation of these proteins is sec-
the loss of dopaminergic function and consequent diminished ondary to malfunctioning of the ubiquitin proteasome system
motor function, leading to clinical features of the disease.4,30 (UPS).52,55 The formation of LBs appears to have a role in the
Research in the late 1950s identified striatal dopamine deple- neurodegeneration that is characteristic of PD, with various
tion as the major cause of the motor symptoms of PD, although lesion patterns seen at different stages of the disease. Lesion
the presence of nonmotor features supports the involvement patterns in the dorsal nucleus, medulla, and pons may support
of other neurotransmitters of the glutamatergic, cholinergic, early (premotor) olfactory and rapid eye movement (REM)
serotonergic, and adrenergic systems, in addition to the neuro- features of PD. Lesions in the nigrostriatal region during
modulators adenosine and enkephalins.39–44 Further evidence later stages of the disease contribute to the common motor
suggests that PD may originate in the dorsal motor nucleus features of PD.56,57 LBs are also associated with the dementia
of the vagal and glossopharyngeal nerves and in the anterior of PD, similar to their presence in patients with dementia with
olfactory nucleus, suggesting a disease pattern that begins in LBs (DLB). PD and DLB are differentiated by their clinical
the brain stem and ascends to higher cortical levels.45 The histo- presentations in that motor features are more prominent and
pathological features of PD include the loss of pigmented dopa- occur earlier in PD compared with DLB.47,52,55
minergic neurons and the presence of Lewy bodies (LBs).46,47 Although amyloid beta 1-42 is associated with Alzheimer’s
Progressive degeneration of dopaminergic neurons in the disease (AD) and its pathology, recent data suggest that cere-
substantia nigra pars compacta (SNpc), which project to the bral spinal fluid containing this biomarker may predict cogni-
striatum (the nigrostriatal pathway), results in the loss of dopa- tive decline in PD as well.58,59 These data are consistent with
minergic function in individuals with PD. Typically, patients previous research, which reported that the pathology of AD
experience the motor features of PD only after 50% to 80% of contributes to cognitive impairment in PD and may have rel-
dopaminergic neurons have been lost, suggesting the involve- evance in predicting the cognitive decline associated with PD.58
ment of a compensatory mechanism in the early stages of The involvement of inflammation in the pathogenesis of
the disease. Two types of dopamine receptors, D1 (excitatory PD is also being studied, especially the role of cytokines and
type) and D2 (inhibitory type), influence motor activity in the other mediators. Inflammatory responses secondary to the
extrapyramidal system. Components of this system include degeneration of dopaminergic neurons may play a role in PD
the basal ganglia, which involves the internal globus pallidal and contribute to its pathogenesis. In vitro data have supported
segment (GPi) of the ventral striatum, and the pars reticulata the activation of microglia and astrocytes secondary to injured
portion of the substantia nigra (SNpr). These components are dopaminergic neurons.60–64
part of larger circuits located in the thalamus and the cortex. In summary, PD is a complex neurodegenerative disease
The loss of dopamine in the striatum of PD patients results in involving an array of molecular pathways, all of which may
increased activity in the GPi/SNpr circuits and subsequent be implicated in the neuropathophysiology of the disease.60
gamma aminobutyric acid (GABA) dysfunction, leading to
inhibition of the thalamus. The end result is the decreased DIAGNOSIS
ability of the thalamus to activate the frontal cortex, resulting in The differential diagnosis of PD should include a comprehen-
the decreased motor activity characteristic of PD. Accordingly, sive history and physical examination. Difficult or questionable
restoring dopamine activity in the striatum through D2 and D1 cases should be referred to a movement-disorder specialist for
receptor activation with dopaminergic therapies mediates clini- further evaluation. There are no definitive tests to confirm the
cal improvement in the motor symptoms of PD.48 In addition, diagnosis of PD; therefore, a clinical diagnosis requires the
dopaminergic loss results not only in reduced activation of the clinician to review the patient’s history, to assess symptoms,
thalamus but also in increased cholinergic activity due to the and to rule out alternative diagnoses, such as multiple-system
loss of dopamine’s normal inhibitory influence.49,50 Research atrophy, DLB disease, and essential tremor (Table 3).65–70
continues to support evidence that PD involves a diffuse global The cardinal motor features of PD—described as the “clas-
network dysfunction at multiple levels in the nervous system.51 sical triad”—include a 4-Hz to 6-Hz resting tremor, “cogwheel”
The other major histopathological feature of PD is the pres- rigidity, and bradykinesia (Table 4). These cardinal features
ences of LBs, described as intracellular cytoplasmic aggregates are often reported as the first clinical findings of the disease. A
composed of proteins, lipids, and other materials. LBs have fourth feature, postural instability (Table 4), occurs in approxi-
also been identified as major hallmarks associated with chronic mately 50% of PD patients within five years of diagnosis.71–77
neurodegenerative diseases, including PD.45,52 In patients with Although PD is considered to be a disease of the elderly, some
PD, LBs are found in dopaminergic neurons in the substantia genetic variants are present in younger patients. Clinically,
nigra as round bodies with radiating fibrils.46,47 Research has younger individuals (under 60 years of age) may present with

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Table 3 Diseases and Conditions That May Require head involvement.71–77 DLB may present with features of PD,
although patients with DLB usually experience concurrent
Differentiation From Parkinson’s Disease65–79
cognitive changes and visual hallucinations.78 Many other
• Alzheimer’s disease conditions mimic PD and may require evaluations by experts
• Basal ganglia tumor in movement disorders to confirm the diagnosis. In addition,
• Benign essential tremor laboratory studies may be necessary to rule out nutritional
• Cerebrovascular disease deficiencies and other abnormalities, including thyroid disease,
• Corticobasal degeneration along with toxin screening when the patient’s history sug-
• Creutzfeldt–Jakob disease gests possible exposure. The measurement of plasma levels
• Dementia with Lewy bodies of copper and ceruloplasmin may also be warranted to rule
• Drug-induced parkinsonism out Wilson’s disease.71,72,75,79 Other diagnostic procedures
• Metabolic causes (e.g., hypoparathyroidism, thyroid dysfunction, include bedside dopaminergic challenge tests with levodopa
nutritional deficiencies) or apomorphine, although their use is not supported by some
• Multiple-system atrophy neurology experts.72–75 Additional diagnostic aids may include
• Normal-pressure hydrocephalus neuropsychiatric testing, sleep studies, and vision exams
• Olfactory dysfunction secondary to visual changes reported in some PD patients,
• Olivopontocerebellar atrophy such as abnormal color vision due to changes in intraretinal
• Post-traumatic brain injury Parkinson’s disease dopaminergic transmission.71,72
• Progressive supranuclear palsy Drug-induced parkinsonism (DIP) should be considered in the
• Shy–Drager syndrome differential diagnosis of PD because it is one of the few reversible
• Subdural hematoma causes of the disorder. Identifying DIP is important in order to
• Wilson’s disease avoid treating patients inappropriately and therefore necessitates
a complete medication evaluation in all patients suspected of
having PD. High-risk populations for DIP include elderly women,
Table 4 Motor Symptoms of Parkinson’s
patients with multiple comorbidities, and patients taking multiple
Disease71–78,90–101,120–128
medications at high doses for extended periods.80,81
Cardinal Motor Features (“Classical Triad”) The drugs most commonly associated with DIP include
• Bradykinesia those with dopamine receptor–blocking properties, such as
the antipsychotic agents haloperidol, thiothixene, and risperi-
°° Occurs in 80% to 90% of patients
done.82–85 If PD patients require antipsychotic agents, those
°° Slowness of movement
with a lower risk for DIP, such as quetiapine and clozapine, are
°° Decreased amplitude of movement
• Rigidity recommended.84,85 Antiemetics that contain a phenothiazine
core (e.g., prochlorperazine or promethazine) and the gastro-
°° Occurs in 80% to 90% of patients
intestinal prokinetic agent metoclopramide are also associated
°° Resistance to passive movement in both flexor and extensor
muscles with limb relaxed with DIP.80,81,86 Many other medications may also cause DIP,
including some antihypertensive agents, such as methyldopa
°° Often accompanied by “cogwheel” phenomenon
• Tremor at rest and calcium-channel blockers, along with antidepressants,
lithium, and anticonvulsant drugs.80,81,87
°° Common initial symptom (70% to 90% of patients)
The management of DIP involves identifying and discontinu-
°° Often resolves with action or during sleep
ing the contributing medication(s), which usually resolves the
°° Primarily distal, involving hands
symptoms, although in some cases these may linger for a few
°° May also involve jaw, tongue, lips, chin, or legs
months or up to a year or two.81,82
Other A challenge in diagnosing PD is that the disorder’s clinical
• Postural instability motor features may not present until approximately 50% to 80%
°° Predisposes patients to falls and injuries of dopaminergic neurons are lost. Unfortunately, at this point
°° Occurs in later stages of Parkinson’s disease significant disease progression may already exist.88–90 Adding
°° Results from loss of postural reflexes to this problem is the need to identify subtle motor features
• Dysarthria that can easily go unrecognized, such as the absence of arm
• Dystonia swing or jerking motions.91–93 Further complicating an early
diagnosis is the presence of nonmotor comorbidities, including
less rigidity and bradykinesia, and this may result in a delayed depression, anxiety, fatigue, constipation, anosmia, and sleep
or missed diagnosis.76,77 disorders (Table 5), which the clinician may not recognize
Identifying diseases that have presentations similar to those as being associated with PD.4,94–97 Early recognition of these
of PD is an important component of the diagnostic process. features and their possible association with PD may facilitate
Table 3 lists some of the diseases and conditions that should an earlier diagnosis.90–93 Since the onset of motor features
be a part of the differential diagnosis and that may require is the point at which PD is usually diagnosed and treatment
additional diagnostic tests to rule out their involvement. Benign is initiated, investigators continue to search for biomarkers
essential tremor, a common presentation, usually appears as an that may allow a more expeditious diagnosis.101–111 Once the
intention-type tremor (tremor with movement) and has greater diagnosis of PD has been confirmed, patients who receive

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Table 5 Nonmotor Symptoms of Parkinson’s Disease71–78,90–101,120–128 CLINICAL PRESENTATION

PD may begin insidiously, with early symptoms
Autonomic Dysfunctiona presenting in up to 90% of patients in a subtle
• Constipation (parasympathetic nervous system cholinergic) fashion, such as difficulty getting out of a chair.
• Orthostatic hypotension (sympathetic nervous system noradrenergic) Nonmotor symptoms may be misinterpreted as
• Sexual dysfunction (parasympathetic nervous system cholinergic) related to normal aging or other comorbidities,
• Sweating (sympathetic nervous system cholinergic) thereby delaying the diagnosis. The early disease
• Urinary retention (parasympathetic nervous system cholinergic) phase lasts approximately four to six years on
average and may include nonmotor features,
Neuropsychiatric Symptoms
as described previously.89–94 As the disease pro-
• Anxiety gresses, other clinical signs, including thermo-
• Cognitive impairment (mild) regulatory dysfunction, may occur. Although
• Dementia intolerance to cold is common, thermoregulatory
• Depression (e.g., dysphoria, suicidal ideation, apathy) abnormalities can also include profuse sweating.
• Impulse-control disorders (e.g., preoccupations, hypersexuality, compulsive Nociceptive (musculoskeletal) and neuropathic
shopping, binge eating)b pain may occur in some patients in early or later
• Panic disorder stages of the disease.79,90–93,118–121 Management of
• Psychosis (e.g., hallucinations, delusions) the nonmotor features of PD will be discussed in
Sensory Symptoms part 5 of this article.
As noted in the section on diagnosis, the
• Olfactory dysfunction (hyposmia) triad of clinical motor features in PD patients
• Paresthesias includes tremor, rigidity, and bradykinesia. Of
• Pain these three core features, tremor is most often
Sleep Disturbancec recognized by patients and caregivers, especially
• Daytime somnolence in individuals with the tremor-predominant PD
• Insomnia subtype.71–77,122–125 The motor presentations of
• Rapid eye movement disorder PD may correlate with the patient’s age at onset;
• Restless legs syndrome specifically, tremor at onset is twice as common in
• Sleep attacks patients older than 64 years compared with those
• Sleep apnea younger than 45 years of age. In addition, compli-
cations related to the duration of treatment—for
Other example, the association of dystonias and dyski-
• Fatigue nesias with the length of levodopa therapy—are
• Sialorrhea more common in patients diagnosed at younger
• Weight loss ages (45 to 55 years old).77
a Depends on components of nervous system that are affected. Tremor, which often presents as the initial
b Usually associated with use of dopamine agonists. symptom, occurs in approximately two-thirds
c Complex etiology; linked to neurodegenerative process, motor features, and drug therapy. of PD patients. It typically starts in a mild and
intermittent fashion, and is usually measured
appropriate treatment may have a life expectancy similar to at a level of 4 Hz to 6 Hz at rest. The usual course is an initial
that of unaffected individuals.70,77 unilateral tremor, which progresses to bilateral involvement
Olfactory screening may also be useful in diagnosing PD, over the duration of the disease.122–125 The tremor of PD is
although it should not be considered diagnostic by itself because usually described as a resting tremor of the hand (pill-rolling
of the multiple etiologies associated with olfactory abnormali- tremor), although it can be present in the lower limbs, toes,
ties.94–96 In the future, protein markers obtained from biopsy or and jaws. Stressful situations or asking the patient to perform a
other procedures, including spinal fluid, salivary gland, rectal, mental task may exacerbate and worsen a PD tremor, whereas
and colonic samples, may be used as well.104,105,109,111 In the movement or sleep diminishes the symptoms. Younger patients
diagnosis of PD, imaging techniques are primarily used to rule may have inconsistent presentations or tremor only during
out other neurological disorders; for example, magnetic reso- periods of fatigue.122,124 Although resting tremor is the most
nance imaging (MRI) may be used to identify normal-pressure common type of tremor in PD, some patients may present
hydrocephalus.112 Evaluating the anatomy of the substantia nigra with action tremor, e.g., tremor manifested during activity. The
(SN) with 7-T MRI may provide a future diagnostic option for diagnostic process is further complicated by the presence of
identifying patients with PD.113 Dopamine transporter scans mixed tremor, as well as by the fact that patients with benign
(DaT scans) may be used to differentiate LB-type dementias essential tremor (BET) may develop a resting tremor later
(PD and DLB) from non-LB dementias, such as Alzheimer’s in their disease. In imaging studies of PD patients, tremor
disease.114–116 Currently, the usefulness of genetic testing in was not necessarily associated with pathologic dopaminergic
diagnosing PD is debatable because of the lack of clarity on loss, and it was actually seen to decline in the later stages
which populations to test, the consequences of the test results, of the disease.68,124 Although tremor is common in PD, it is
and cost issues.23–26,117 considered to be the least disabling of the motor features

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compared with the other cardinal features—rigidity and influence the progression of PD. For example, patients who
bradykinesia.122,125 present with tremor as the initial clinical feature may experi-
Bradykinesia is a core clinical motor feature of PD and ence a slower disease course and experience a longer response
has been defined as a reduction in the speed, gait, and ampli- to drug therapy. Men who present with PD in their late 50s
tude of a repetitive action involving voluntary movements.126 or older, or patients who experience motor features and gait
Bradykinesia is the most common clinical feature observed problems along with postural instability early in the disease,
in patients with PD and is considered to be a key diagnostic may experience faster disease progression. Patients who experi-
criterion. The disorder usually appears later than tremor, ence a poor response to drug therapy and significant dementia
although in some cases it may be the initial symptom and often require early institutional placement.125,131 Mortality is
tremor may never develop (i.e., the akinetic–rigid subtype of often associated with complications related to immobility, such
PD).123,125 A common clinical presentation associated with this as pneumonia, pulmonary embolism, and falls.10,11,75
feature is difficulty getting started or initiating movements
and a slow, shuffling gait. Patients with bradykinesia may also GENERAL APPROACH TO MANAGEMENT
demonstrate hastening of their gait, in which their walking The primary goal in the management of PD is to treat the
speed increases with small, rapid steps in an effort to “catch symptomatic motor and nonmotor features of the disorder,
up” with their displaced center of gravity.123–126 Patients may also with the objective of improving the patient’s overall quality of
experience immobility associated with bradykinesia, typically life. Appropriate management requires an initial evaluation and
when confronted by the need to turn or enter through a narrow diagnosis by a multidisciplinary team consisting of neurologists,
door.121 Episodes of “freezing” are an extreme manifestation primary care practitioners, nurses, physical therapists, social
of PD and usually occur in advanced disease.125 workers, and pharmacists.14,132 It is also important that the patient
The third major cardinal feature of PD is rigidity, which and his or her family have input into management decisions.133–135
presents as increased muscle tone or amplified resistance to a Effective management should include a combination of non-
passive range of motion. The term commonly used to describe pharmacological and pharmacological strategies to maximize
this phenomenon in PD patients is “cogwheel rigidity.” 72,73,123 clinical outcomes. To date, therapies that slow the progres-
This is best described as tension in the muscle, which displays sion of PD or provide a neuroprotective effect have not been
small jerks or a ratchet-like quality when moved passively. identified.135,135 Current research has focused on identifying
Cogwheel rigidity requires an unambiguous diagnosis, since biomarkers that may be useful in the diagnosis of early disease
benign essential tremor may also present with a cogwheeling and on developing future disease-modifying interventions.136,137
phenomenon.71,74 The rigidity of PD can affect other body
parts besides the limbs, such as the face, which can display a SUMMARY
“masked” expression (hypomimia).73–75,125 PD is a chronic, progressive neurodegenerative disease
A fourth clinical feature that usually occurs later in the course characterized by both motor and nonmotor features.1–3 Striatal
of PD is postural instability. This symptom has a multifaceted dopamine depletion has been identified as the major cause of the
etiology related to other motor symptoms, such as rigidity disorder’s motor symptoms,39–44 which include resting tremor,
and neural degeneration in the hypothalamic brainstem or “cogwheel” rigidity, and bradykinesia.71–77 Nonmotor symptoms
peripheral nervous system. Postural instability can be seriously include sleep disorders, depression, and cognitive changes.4
disabling because of its association with the loss of balance The differential diagnosis of PD should include a compre-
and the risk of falls.94,120,127 hensive history and physical examination.65–70 Identifying
Other unique features of PD include difficulty with hand­writing diseases that have presentations similar to that of PD is an
(e.g., micrographia) and soft speech (hypophonia).73,74,119,123 important component of the diagnostic process.71–77 There
Various staging tools are used to assess the progression of are no definitive tests to confirm a diagnosis of PD.65–70 The
PD and to provide parameters for the use of different manage- UPDRS is the most commonly used scale for assessing the
ment strategies. The most commonly used scale for assessing clinical status of PD patients.129
the clinical status of patients with PD, including both motor The primary goal in the management of PD is to treat the
and nonmotor symptoms, is the Unified Parkinson’s Disease symptomatic motor and nonmotor features of the disorder,
Rating Scale (UPDRS). This four-part tool assesses motor with the objective of improving the patient’s overall quality of
features, psychological features, and activities of daily living life.14,132 Therapies that slow the progression of the disease or
in addition to complications related to therapy.129 Increases provide a neuroprotective effect have not been identified.134,135
of 2.5 and 4.3 points in the UPDRS motor and total scores, In the next issue of P&T, part 2 of this five-part article will
respectively, have been recognized as clinically relevant.129 discuss the pharmacological management of PD, with a focus
Another tool that is not commonly used in clinical practice on the use of dopaminergic agents.
is the staging scale developed by Hoehn and Yahr, which has
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