A Systematic Review of the Literature
Evidence Report/Technology Assessment: Number 57
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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
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Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report
Parkinson's Disease (PD) is a chronic,
progressive, neurodegenerative disorder with an
estimated prevalence of 31 to 328 per 100,000
people worldwide. It is estimated that more than 1
percent of the population over age 65 are afflicted
with PD; incidence and prevalence increase with
PD is caused by idiopathic degeneration of
dopamine-producing cells in the substantia nigra,
located in the midbrain. Three "cardinal signs" of
PD are resting tremor, cogwheel rigidity, and
bradykinesia. Postural instability, typically a late
finding in PD, is the fourth cardinal sign.
Additional common findings are asymmetrical
onset of symptoms and symptomatic response to
L-dopa (levodopa). Diagnosis of PD is
problematic because of the lack of a reference
standard test. The diagnosis is generally made
clinically, although up to 25 percent of patients
with clinical diagnoses of PD have received
different pathological diagnoses at autopsy.
L-dopa is the mainstay of pharmacological
treatment for PD; however, its use is limited by
the development of motor fluctuations and drug-induced
dyskinesias. Dopamine agonists (DAs) are
also used, either alone or in combination with L-dopa.
DAs act directly on dopamine receptors,
mimicking endogenous dopamine. Monoamine
oxidase B (MAO-B) inhibitors act by inhibiting
dopamine catabolism, increasing dopamine levels
in the basal ganglia. Catechol O-methyl transferase
(COMT) inhibitors act by inhibiting catabolism
of dopamine, thereby extending L-dopa's
peripheral half-life. Despite the large selection of
medications available to treat PD, all PD patients
ultimately require L-dopa.
In patients with early PD, the goal of treatment
is to alleviate symptoms and maintain
independent function. In advanced PD, the focus
is aimed toward maximizing "on" time (time when
medication is effective), minimizing "off" time
(time when medication is not effective), and
treating medication-related complications, such as
dyskinesias, motor fluctuations, and psychiatric
Surgical treatment for PD is generally
considered for patients who respond to
medications but have intolerable side effects.
Surgical options include ablative procedures
(pallidotomy or thalamotomy), deep brain
stimulation (DBS), and tissue transplantation.
There are numerous unanswered questions
regarding the diagnosis and management of PD.
MetaWorks investigators developed an evidence
base through a systematic review of the English-language
literature from 1990 to 2000 pertinent
to patients with PD. This synthesis of the best
available and most recent evidence is intended to
serve as an information resource for
decisionmakers and developers of practice
guidelines and recommendations. It also should
serve to highlight gaps in the literature and areas
that require future research.
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Reporting the Evidence
This report presents the results of a systematic
review of published studies of adult patients with
PD. The following key questions guided this
- What are the results of neuroimaging studies or other
diagnostic tests in determining the diagnosis of PD?
- What are the results of L-dopa challenge in PD? What are
the accuracy, sensitivity, and specificity of this test for
- What is the efficacy of medication used to treat early PD? What is the efficacy of initial treatment with L-dopa vs. a
- What is the evidence for neuroprotection with selegiline,
Vitamin E, or Vitamin C?
- What is the efficacy of medication used to treat late PD?
What is the efficacy of medication used to treat patients
who have an insufficient response to L-dopa? What are the
outcomes of treatment of medication-induced side effects?
- What are the outcomes of treatment for patients who
experience motor fluctuations and/or dyskinesias while
- What serious adverse events are associated with
medications used to treat PD?
- What are the outcomes of treatment of PD patients with
psychotic symptoms or nonpsychotic behavioral and
- When is surgery performed on PD patients? What types
of surgeries are performed and what are their outcomes?
- What are the outcomes of rehabilitation in PD?
- What are the results of recent review articles regarding
genetic testing in PD?
- What is the evidence that PD patients are treated
differently or have different outcomes based on the
following: age, presentation of symptoms, cognitive status,
duration of illness, comorbidities, gender, race, ethnicity, or
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MetaWorks investigators applied methods derived from the
evolving science of systematic review research. The review
followed a work plan that had been developed a priori and
shared with the Task Order Officer at the Agency for
Healthcare Research and Quality (AHRQ), the project's
nominator (American Academy of Neurology), and a
multidisciplinary Technical Expert Panel.
The work plan outlined the methods to be used for the
literature search, study eligibility criteria, data elements for
extraction, and methodological strategies employed both to
minimize bias and to maximize precision during the process of
data collection and synthesis.
The published literature from January 1, 1990, to December
31, 2000, was searched using MEDLINE®, Current Contents®, and
Cochrane Library databases. The electronic searches were
supplemented by a manual search of the reference lists of all
accepted articles, recent review articles, and relevant Internet
Two levels of screening were applied. Level I screening
involved rejection of abstracts on the basis of predefined
exclusion criteria, such as animal studies, case reports, or
ineligible languages. Level II screening involved assessment for
fit with inclusion criteria. To be eligible, a study had to be
published in English. Only randomized controlled trials (RCTs)
were accepted for pharmacological treatment. For other areas,
due to rarity of RCTs, other study designs were accepted,
including nonrandomized controlled trials (NRCTs),
uncontrolled case series (UCSs), and observational studies.
Each study was required to include a minimum of 10 patients.
Relevant data from all accepted studies were entered onto
data extraction forms designed specifically for this project. All
data elements were extracted by one investigator and reviewed
by a second investigator. One hundred percent agreement
between the two reviewers was required prior to entry of data
elements into the database. At least one physician reviewed all
data elements extracted from every study.
All accepted studies were evaluated for quality by using the
previously published methods of Level of Evidence and the
Jadad Quality Score Assessment.
The information captured from each study included date of
publication, location and type of study, primary objective of
study, description of interventions (e.g., medications or
surgery), PD scale measurements at baseline and after
treatment, and adverse events. Summary statistics were
calculated and meta-analyses were performed, comparing
standardized mean changes in PD severity rating scales.
A group of 19 peer reviewers was assembled to review and
provide suggestions for the draft final report describing this
project. Their comments, in addition to those of the Technical
Expert Panel, were incorporated into the final report.
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The studies covered by the review of the literature on
diagnosis of PD and review findings are:
- Fifty-nine studies, 141 treatment arms, 3,369 patients.
- Study designs: 46 cross-sectional studies, 5 UCSs, 2
NRCTs, 6 others.
- Five studies of apomorphine challenges: insufficient
evidence to support role in diagnosing PD.
- Six autopsy studies: evidence to support role in confirming
clinical diagnosis of PD.
- Ten studies of clinical or laboratory evaluation:
inconclusive evidence to determine role in diagnosing PD.
- Two studies of color vision testing: inconclusive evidence to
determine role in diagnosing PD.
- Three studies of magnetic resonance imaging (MRI):
insufficient evidence to determine role in diagnosing PD.
- Seven studies of olfactory function: evidence to support
ability to distinguish parkinsonism from healthy controls
but not to distinguish PD from atypical parkinsonism.
- Three studies of PD test battery (includes tests of motor
function, olfaction, and depression): preliminary evidence
suggesting usefulness in diagnosing PD, but long-term
confirmatory studies are needed.
- Eight studies of positron emission tomography (PET)
scans: insufficient evidence to determine role in diagnosing
- Thirteen studies of single photon emission computed
tomography (SPECT) scans: insufficient evidence to
support role in diagnosing PD.
- Two studies of other scans (nuclear magnetic resonance
(NMR), ultrasound): insufficient evidence to support role
in diagnosing PD.
The review of pharmacological treatment included:
- Forty-nine studies (all RCTs), 111 treatment arms, 9,968
- Thirty-two studies regarding patients with early PD
(disease duration 5 years or less), 17 with advanced PD.
While most studies reported Unified Parkinson Disease
Rating Scale (UPDRS) scores or other common PD rating
scales, comparison of different treatments across studies
presented numerous methodologic obstacles. It was not always
possible to discern the number of patients who received L-dopa
or the doses they received because many studies simply reported
that L-dopa was given to patients as needed. Studies were not
consistent in reporting the same PD rating scales or in
reporting both baseline and endpoint scores, with standard
deviations, for all parameters. Studies did not consistently
report whether the PD scale scores were measured when
patients were in the "off" or "on" state. Given these limitations,
however, the following associations were noted:
- Meta-analysis suggests that in early PD, treatment with
DAs plus L-dopa may control PD symptoms better than
treatment with L-dopa alone, but this was not a consistent
- In studies in which patients were randomized to L-dopa vs.
L-dopa plus DAs, the combination of L-dopa plus DAs
resulted in better UPDRS scores than L-dopa alone. This
was true in both short- and long-term (over 1 year) studies.
- In studies where patients were randomized to L-dopa vs.
DAs, where additional L-dopa was discretionary, L-dopa
alone resulted in better UPDRS scores than DAs (with or
without additional L-dopa).
- There was no evidence that different DAs varied in
- Meta-analysis did not suggest that treatment with selegiline
plus L-dopa controlled PD symptoms better than
treatment with L-dopa alone.
- Meta-analysis showed that in patients with advanced
disease, treatment with COMT inhibitors combined with
L-dopa provided significantly greater PD symptom control
than L-dopa alone and was associated with lower L-dopa
doses. However, long-term (over 7 months) results are
lacking, and hepatotoxicity is a rare but potentially lethal
side effect that has been associated with tolcapone.
- These meta-analysis results should be viewed with caution,
as they are based on the small number of RCTs that met
the inclusion criteria for this systematic review. Due to the
small number of studies within each meta-analysis, these
findings are sensitive to possible publication bias in the
The review of surgical treatment included:
- Forty-two studies, 52 treatment arms, 1,380 patients.
- Study designs: 35 UCSs, 4 RCTs, 2 NRCTs, 1 other.
- Pallidotomy: 20 treatment groups, 764 patients.
- Thalamotomy: 5 treatment groups, 134 patients.
- DBS: 16 treatment groups, 288 patients.
- Globus pallidus (GPi): 4 treatment groups, 22
- Subthalamic nucleus (STN): 8 treatment groups,
- Thalamus: 4 treatment groups, 131 patients.
- Tissue transplants: 9 treatment groups, 165 patients.
- Adrenal medulla: 3 treatment groups, 91 patients.
- Human fetal tissue: 5 treatment groups, 62 patients.
- Porcine fetal tissue: 1 treatment group, 12 patients.
- No surgery: 2 treatment groups, 29 patients.
The findings were:
- The overall quality of the surgery literature was lower than
the quality of the pharmacology literature, as very few
RCTs were done to evaluate the efficacy and safety of
surgical procedures. It must be recognized, however, that it
is very difficult to perform RCTs of surgical procedures,
and other study designs may have to suffice.
- For all surgical procedures, "off " scores improved to a
greater degree than "on" scores.
- On average, endpoint PD scale scores for pallidotomy and
DBS treatment were significantly better than baseline
- DBS of the STN and GPi both improved PD scores, but
only STN DBS was associated with decreased L-dopa
- There were insufficient studies of thalamotomy to draw
any conclusions regarding efficacy or safety.
- An insufficient number of studies have been done to make
more than tentative conclusions about the effectiveness of
fetal brain transplantation. A recent RCT comparing tissue
transplant to sham surgery raised important questions
regarding the long-term efficacy and safety of the
- Due to the small number of studies within each meta-analysis,
these findings are sensitive to possible publication
bias in the literature.
Treatment of Psychiatric Disorders
The review of treatment of psychiatric disorders covered:
- Ten studies, 12 treatment arms, 392 patients.
- Study designs: 6 UCSs, 2 RCTs, 2 others.
The findings were:
- Evidence from 6 studies (314 patients) supports the
efficacy of clozapine in improving symptoms of psychosis
in PD patients.
- There was insufficient evidence regarding treatment of
depression in PD patients.
Ancillary Treatment of PD
The review of ancillary treatment covered:
- Twenty studies, 37 treatment arms, 1,049 patients.
- Study designs: 13 RCTs, 3 UCSs, 2 NRCTs, 2 cross-sectional
- Physical therapy: 7 studies.
- Speech, swallowing, or voice therapy: 5 studies.
- Multidisciplinary rehabilitation programs: 4 studies.
- Other: 4 studies.
It was found that:
- Short-term efficacy was demonstrated in all of the above
ancillary treatments, but long-term trials are needed.
- Intensive speech treatment has been shown to improve
vocal intensity up to 12 months after treatment; however
these long-term results are from only one study of 22
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Standardization of reporting results is essential. Investigators
should consistently report baseline, endpoint, and change in
UPDRS scores, along with standard deviations. The number of
patients who receive L-dopa should be clearly stated, as well as
the L-dopa doses. Patients with comorbidities should be
included in clinical trials. As nearly all of the studies in the
database excluded patients with serious illnesses, the
generalizability of study results is limited. In particular, studies
should include more elderly patients, patients with young age
of disease onset, and members of different racial and ethnic
groups. RCTs should be performed to evaluate surgical
procedures. Further studies of physical therapy, occupational
therapy, speech therapy, and other nonpharmacologic and
nonsurgical treatment modalities should be of longer duration
and should measure standardized, clinically meaningful
Given the large volume of studies that are published
regarding PD, semiannual updates are recommended to keep
this database current.
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Availability of Full Report
The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the MetaWorks, Inc., Evidence-based Practice Center (EPC) in Medford, MA, under Contract No. 290-97-0016. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 57, Diagnosis and Treatment of Parkinson's Disease: A Systematic Review of the Literature.
The Evidence Report is also online on the National Library of Medicine Bookshelf or can be downloaded as a PDF File (6 MB) [PDF Help].
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AHRQ Publication Number 03-E039
Current as of June 2003