Chapter  57:  Diagnosis and Treatment of Parkinson's Disease: A Systematic Review of the Literature

Overview

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 age.

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 problems.

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.

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 review.

1. What are the results of neuroimaging studies or other diagnostic tests in determining the diagnosis of PD?

2. What are the results of L-dopa challenge in PD? What are the accuracy, sensitivity, and specificity of this test for diagnosing PD?

3. What is the efficacy of medication used to treat early PD? What is the efficacy of initial treatment with L-dopa vs. a dopamine agonist?

4. What is the evidence for neuroprotection with selegiline, Vitamin E, or Vitamin C?

5. 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?

6. What are the outcomes of treatment for patients who experience motor fluctuations and/or dyskinesias while taking L-dopa?

7. What serious adverse events are associated with medications used to treat PD?

8. What are the outcomes of treatment of PD patients with psychotic symptoms or nonpsychotic behavioral and psychological dysfunction?

9. When is surgery performed on PD patients? What types of surgeries are performed and what are their outcomes?

10. What are the outcomes of rehabilitation in PD?

11. What are the results of recent review articles regarding genetic testing in PD?

12. 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 income level?

Methodology

Meta Works 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 was searched from January 1, 1990, to December 31, 2000, 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 sites.

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.

Findings

Future Research

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 outcomes.

Given the large volume of studies that are published regarding PD, semiannual updates are recommended to keep this database current.

Etiology

The clinical syndrome of PD results from idiopathic degeneration of the dopaminergic cells in the pars compacta of the substantia nigra.⁹ While the cause of the degeneration is not known, oxidative stress may play a role.^{10, 11} This leads to depletion of the neurotransmitter dopamine, which is produced by neurons in the substantia nigra and released in the caudate nucleus and putamen.

The pathogenesis of PD is believed to be multifactorial, caused by environmental factors acting on genetically susceptible individuals as they age.^{12, 13, 14} Many studies have examined the impact of environmental exposures on the risk of PD. No infectious etiologic agent has been identified.¹ Some studies have reported that exposures to herbicides, pesticides, welding, or well water may be associated with an increased risk of PD,^{15, 16} but a cause and effect relationship has not been established.

Studies examining diets in PD patients have generally been inconclusive.¹ Some studies have reported that caffeine, coffee, and smoking are associated with a decreased risk of PD.^{17 – 20} It has been hypothesized that antioxidants may be neuroprotective in PD, by preventing neuronal death caused by intracellular free radicals.¹⁰ Some researchers are investigating the role of coenzyme Q in the pathogenesis of PD.²¹ Some studies have reported that vitamin E²² or vitamin C²³ intake was significantly lower in PD patients than in controls, but other studies showed no association between PD and vitamins A, C, or E.²⁴ Dietary iron intake does not appear to be associated with PD status, while diets high in animal fats and carbohydrates have been associated with increased risk of PD.^{23, 24, 25}

Clinical Features

The clinical constellation of resting tremor (3–6 Hz), cogwheel rigidity, and bradykinesia are the hallmarks of parkinsonism.²⁶ A fourth “cardinal sign” is postural reflex compromise, or gait instability, which usually occurs later in the disease.^{26, 27} PD usually presents asymmetrically, although symptoms eventually become bilateral.²⁶ Although not specific for PD, response to levodopa (L-dopa) is another characteristic finding.²⁶

The clinical severity of PD varies, depending on the degree of neuronal loss. Pathologic studies suggest that patients may be symptom free until 60–80 percent of substantia nigral neurons have degenerated.⁹ Nonmotor symptoms of PD, such as depression, seborrheic dermatitis, olfactory dysfunction, and autonomic nervous system dysfunction (including constipation, urinary frequency, and orthostatic hypotension) may occur for years prior to the onset of overt motor symptomatology.²⁸

As their disease progresses, PD patients become increasingly unable to manage their activities of daily living (ADL) without assistance.²⁹ Falls are common, as a result of postural instability, dyskinesias, confusion, and dementia. Patients' nutritional status may be sub-optimal, due to difficulty with preparing, chewing, and swallowing foods. Dysphagia is a frequent complication in PD.³⁰ It is estimated that at least 75 percent of PD patients have speech disorders, which are collectively called hypokinetic or parkinsonian dysarthria, and consist of reduced loudness, monotone, imprecise articulation, and disordered rate.^{31, 32, 33} Sleep disturbances are also common in PD.³⁴

Psychiatric symptoms are important contributors to the morbidity and mortality of PD.⁶ Development of psychopathology in PD is related to multiple factors, including underlying PD disease processes, medication effects, and psychological reaction to illness.³⁵ Estimates of dementia prevalence in PD range from zero to 93 percent, based on numerous uncontrolled, cross-sectional studies.^{36, 37} The prevalence of cognitive decline is higher in patients with older age of PD onset.^{37, 38} It may be difficult to distinguish the dementia of Alzheimer's disease from that associated with PD. Published estimates of depression prevalence in PD range from 20 to 90 percent.³⁹ While the exact prevalence is not known, psychiatric disorders clearly have a major impact on PD patients.

Diagnosis

The abundance of guidelines for PD diagnosis is reflective of the difficulty in diagnosing this condition. One relatively straightforward list of research criteria for probable PD includes:⁴⁰

1. Evidence of disease progression.

2. Presence of at least two of the three cardinal features of parkinsonism (tremor, rigidity, bradykinesia)

3. Presence of at least two of the following:

   1. Marked response to L-dopa (functional improvement or dyskinesia)

   2. Asymmetry of signs

   3. Asymmetry at onset

4. Absence of clinical features of alternative diagnosis

5. Absence of etiology known to cause similar features

Other diagnostic guidelines incorporate requirements pertaining to disease duration, and more specifics regarding tremor and response to dopaminergic agonists.²⁷

The United Kingdom PD Society Brain Bank has similar, but more stringent, clinical diagnostic criteria, including a specific definition of bradykinesia, and numerous specific exclusion criteria ( Appendix A). ⁴¹

A more recent variation of clinical guidelines for PD diagnosis describes an adult-onset, slowly progressive motor disorder combining two or more of: rest tremor, bradykinesia, limb rigidity, and gait instability (late), with dramatic and sustained response to L-dopa. Accepted associated phenomena include depression (early or late), cognitive decline (late), and limited autonomic involvement, such as constipation. Some proposed diagnostic criteria for PD categorize patients as having definite, probable, or possible PD, based on the number of criteria they meet (Appendix A). ²⁶

The pathologic hallmark of PD is substantia nigra depigmentation and the presence of Lewy bodies, which are neuronal eosinophilic cytoplasmic inclusions. Lewy bodies are believed to be caused by altered neurofilament metabolism or transport. They are not specific for PD, and may be seen in small numbers in other neurodegenerative diseases.⁴¹

While autopsy provides the pathological gold standard, no clinical gold standard diagnostic test for PD has been identified. Comparisons of clinical and pathological diagnoses have shown that up to 25 percent of patients with clinical diagnoses of PD are found to have different pathological diagnoses at autopsy.^{42, 43, 44} Disease presentation may vary, leading to difficulties in making the diagnosis, particularly early in the disease. The marked clinical heterogeneity further complicates ability to accurately diagnose PD.

In the absence of a simple, inexpensive, reliable diagnostic test for PD, some clinicians use acute challenge tests with L-dopa or the dopamine agonist apomorphine to confirm the clinical suspicion of PD.⁴⁵ In a meta-analysis of 13 studies of acute apomorphine or L-dopa challenges compared with chronic L-dopa therapy in patients with PD, the authors concluded that the diagnostic accuracy of acute apomorphine and L-dopa challenges did not add additional useful diagnostic information compared with a therapeutic trial of chronic L-dopa.⁴⁵

Researchers have investigated the utility of measuring striatal dopamine levels, in the hopes of diagnosing PD in a preclinical stage, and following the progression of PD after diagnosis. [¹⁸F]-fluorodopa positron emission tomography (PET) scans detect changes in presynaptic striatal dopamine function, which is an indirect measure of the striatal storage of dopamine.⁴⁶ Single photon emission computed tomography (SPECT) scans use various cocaine analogues to provide a semi-quantitative measure of the concentration of the presynaptic dopamine transporter, which may be decreased in PD, and ¹²³I-iodobenzamide (IBZM) to evaluate the postsynaptic receptor density, which may be normal or increased in PD.⁴⁶ PET and SPECT scans are expensive and not always available. The appropriate role for these modalities in the diagnosis and management of PD patients is unclear.²⁶

Structural imaging modalities, such as computerized tomography (CT) and magnetic resonance imaging (MRI) have a limited role in diagnosing PD. Increased iron concentration in the substantia nigra causes decreased signal intensity on T₂ weighted images, but these changes are not sufficient to reliably distinguish PD patients from healthy controls.⁴⁷ These technologies are more useful for ruling out other conditions than for diagnosing PD.

Olfactory deficits occur early in PD,⁴⁸ and do not improve with L-dopa treatment.⁴⁹ The University of Pennsylvania Smell Identification Test (UPSIT) is a multiple choice “scratch and sniff” test that is used to evaluate olfactory function (See Appendix A). ⁴⁹ Olfaction is impaired in other neurodegenerative diseases, such as Huntington's Disease and Alzheimer's dementia (AD).⁴⁸ A meta-analysis of 43 studies of olfactory function in PD and AD showed uniform degrees of impairment, and no measure that could help to distinguish between the two entities.⁵⁰

Myriad other tests have been proposed to diagnose and evaluate patients with PD. Depletion of cerebrospinal fluid (CSF) homovanillic acid (HVA) levels indicate dopamine deficiency, but this test has not been shown to reliably discriminate healthy controls from PD patients.⁵¹ Studies of handwriting, tremor analysis, personality, reaction times, and movement velocities have shown differences between patients with PD and normal controls; however, the overlap between the two groups does not enable these tests to reliably diagnose PD in individual patients.

“Red flags” that suggest a diagnosis other than PD include early dementia or apraxia, early instability and falls, prominent autonomic impairment, oculomotor disturbances, and cerebellar signs. The most common atypical parkinsonian syndromes are progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). These conditions are frequently confused with PD, particularly early in their course. One goal of diagnostic testing for PD is to rule out atypical parkinsonian syndromes. Assessment of olfaction may be useful in this regard; olfactory function is normal in PSP, and impaired in MSA.⁴⁸

Patients with PSP generally present with postural instability, often coming to medical attention due to frequent falls. The hallmark of PSP is vertical gaze paralysis. Other symptoms include other visual disturbances, dysarthria, mental changes, speech difficulties, bradykinesia, nuchal dystonia, rigidity, and postural tremors, although resting tremors are uncommon. PSP is progressive, and usually leads to death within five to seven years after diagnosis.⁵²

MSA is a sporadic degeneration of the nervous system. In addition to parkinsonian symptoms, which are present in 90 percent of cases, patients present with cerebellar ataxia and autonomic dysfunction. MSA usually begins in the sixth decade, and is associated with a median survival of 9.3 years after diagnosis.⁵²

Assessment of PD Severity

Many clinical investigators use different scoring scales to assess the severity of PD symptoms, making it difficult to compare results across studies.⁵³ The most common scale used to assess PD severity is the Unified Parkinson Disease Rating Scale (UPDRS), which has superceded numerous other scales, including Hoehn & Yahr Disability Scale (H&Y), Schwab & England (S&E) Activities of Daily Living (ADL) scale, Webster scale, Columbia University Rating Scale (CURS), and Northwestern University Disability Scale (NUDS). Appendix A describes the major scales used to assess PD severity.

In the UPDRS, a rating tool that was developed in 1984, points are assigned for a comprehensive list of PD symptoms.^{53, 54, 55} Patients may receive a total of 199 points, with 0 representing no disability, and 199 representing total disability. The total score is composed of four major subscales:

1. Mentation, Behavior, and Mood (range 0–16),

2. ADL (range 0–104),

3. Motor Exam (range 0–56), and

4. Complications of therapy over the past week (range 0–23).

Each of these subscales is broken down into further subscales, which range from 0 (normal) to 4 (maximum severity). Each UPDRS score may be reported in the “off” and “on” state, which refer to presence or absence of L-dopa effectiveness. Practically-defined “off” scores are measured approximately 12 hours after the last dose of L-dopa, although in actual clinical practice, “off” scores often indicate periods when the patients feel their medication is not working. “On” scores are measured shortly after a dose, or when patients feel their medication is working. The UPDRS scales are validated tools that are useful in following the progression of disease and response to interventions.^{54, 55}

The H&Y scale divides patients into stages, based on their levels of clinical disability.⁵⁶ Stage 0 patients have no signs of disease. Stage I patients have unilateral involvement, with minimal or no functional impairment. Stage II patients have bilateral or midline involvement, without balance impairment. Stage III patients have impaired equilibrium, unsteadiness, and significant slowing of body movements. Stage IV patients have severe symptoms, are still able to walk and stand unassisted, but are extremely incapacitated and unable to live alone. Stage V patients are confined to bed or wheelchair, and require constant nursing care.

The S&E ADL scale has ratings from 0 to 100 percent, where 0 is bedridden with no swallowing, bladder, or bowel function, and 100 percent is completely independent.⁵⁷

Treatment

While there is no cure for PD, the goal of antiparkinsonian pharmacotherapy is to control signs and symptoms of PD while minimizing side effects for as long as possible. Current therapies are aimed toward compensating for decreased striatal dopamine levels, but have not been proven to slow or prevent progression of the disease.⁵⁸ Neuroprotective agents, defined as agents that protect vulnerable neurons and slow or stop disease progression, have not been demonstrated for PD.^{59, 60} Data are lacking in many areas of PD treatment, and there is currently wide variation in the management of PD.

Patients with early PD require different management strategies from patients with advanced PD. In early PD, the goal is to alleviate symptoms and keep patients functioning independently for as long as possible, using the least amount of medication necessary to achieve this goal. In advanced PD, much of the focus is toward treating medication-related complications, such as dyskinesias, motor fluctuations, and psychiatric problems.⁶¹

Objectives

There are numerous unanswered questions regarding the diagnosis and management of PD. This review of diagnosis and treatment of PD was nominated by the American Academy of Neurology (AAN), and a Task Order was commissioned by the Agency for Healthcare Research and Quality (AHRQ). The purpose of this report is to systematically review the published evidence regarding these issues, in order to answer specific questions posed by the AAN and the AHRQ. This evidence base should be useful to health care providers in developing evidence-based strategies to guide PD management. It will be useful to those planning new clinical trials and making regulatory decisions. Additionally, this evidence base may readily be updated as the literature evolves.

Original Key Questions

The following questions were formulated by AAN and AHRQ:

• 1. How accurate is the clinical diagnosis of PD? How accurate does the diagnosis need to be for proper clinical decisionmaking?

• 2. What diagnostic tests improve the accuracy of the clinical diagnosis of PD?

• 3. What is the role of neuroimaging in the diagnosis of PD? When neuroimaging is indicated, should CT or MRI scan be obtained? Are there data on the cost effectiveness of these diagnostic tests in PD? What is the current or projected role of fluorodopa PET scans in the diagnosis or management of PD? What is the current, or projected, role of SPECT scans using dopamine transporter ligands in the diagnosis or management of PD?

• 4. When, if ever, is genetic testing indicated in PD?

• 5. Should the ability of a patient to respond to levodopa be considered a diagnostic tool? From a diagnostic standpoint, what constitutes a levodopa challenge and a diagnostically positive response? How accurate is this maneuver (i.e., false positives and negatives) and how does it help the differential diagnosis? When is it indicated?

• 6. Based upon the patient's age and presentation of symptoms, what treatment should a PD patient receive upon initial diagnosis?

• 7. What is the evidence for neuroprotection with selegiline, Vitamin E, or Vitamin C? How long should neuroprotective therapy be given?

• 8. What is the role of pharmacotherapy in management of PD?

• 9. What is the role of Sinemet vs. dopamine agonists based on: age of presentation, cognitive status, symptom profile, duration of illness, and co-morbidities?

• 10a. What is the appropriate treatment of patients with advancing PD? In patients with moderate PD who are just beginning to experience motor fluctuations and/or dyskinesias, what is the evidence for advancing to the next drug (e.g. more levodopa, Sinemet CR, Mirapex, Requip, Permax, Parlodel, Tasmar, Comtan, Selegiline, Amantadine)?

• 10b. What is the optimal management of non-psychotic behavioral and psychologic dysfunction in PD? What is the appropriate management of psychotic symptoms? What is the differential diagnosis? How much simplification in antiparkinsonian pharmacotherapy is warranted before the addition of antipsychotics? Can conventional antipsychotics be justified in management of PD? Are atypical antipsychotics the drugs of choice in management of psychotic symptoms in PD? What are the differential effects of atypical antipsychotics in PD? Re: other uses of atypical antipsychotics in PD - are they justified?

• 11. What is the role of surgery in the management of PD? When should surgery be contemplated in a PD patient? What are the indications for one surgery vs. another? Are there minimal standards of pharmacotherapy that should be observed before contemplating surgery in PD? Re: surgical decisions in depressed or mildly demented patients - where to draw the line?

• 12. What is the role of rehabilitation in early and late stages of PD? Which patients are the most appropriate candidates for rehabilitation?

• 13. Does the evidence for Questions 1–12 vary depending on the patient's age, gender, race, or ethnicity, or income level?

After a preliminary review of the literature, the project team at MetaWorks and the co-investigator at Leonard Davis Institute (LDI) worked collaboratively to modify the original key questions, making them more amenable to answers by systematic literature review. The focus of the revised questions was unchanged. In general, where the original questions asked about what kinds of testing or treatment “should” be done, or “what is the role” of a particular test or treatment, the modified questions asked “what are the results,” or “what is the evidence.” The following revised questions were reviewed by the Technical Expert Panel (TEP) and the AAN representative, and were approved by the AHRQ Task Order Officer (TOO).

Revised Key Questions

1. What are the results of neuroimaging studies (CT, MRI, PET, SPECT) or other diagnostic tests in determining the diagnosis of PD?

2. What are the results of L-dopa challenge in PD? What is the accuracy, sensitivity and specificity of this test for diagnosing PD?

3. What is the efficacy of medication used to treat early PD? What is the efficacy of initial treatment with L-dopa vs. a dopamine agonist?

4. What is the evidence for neuroprotection with selegiline, Vitamin E, or Vitamin C?

5. 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?

6. What are the outcomes of treatment for patients who experience motor fluctuations and/or dyskinesias while taking L-dopa?

7. What serious adverse events are associated with medications used to treat PD?

8. What are the outcomes of treatment of PD patients with psychotic symptoms or non-psychotic behavioral and psychological dysfunction?

9. When is surgery performed on PD patients? What types of surgeries are performed and what are their outcomes?

10. What are the outcomes of rehabilitation in PD?

11. What are the results of recent review articles regarding genetic testing in PD?

12. 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, co-morbidities, gender, race, ethnicity, or income level?

Literature Search

The published literature was searched from January 1, 1990 to December 31, 2000, using Medline, Current Contents^®, and Cochrane Library databases. A manual search was performed of the bibliographies of all publications accepted for inclusion into the evidence base. In addition, the bibliographies of recent review articles were searched for potentially relevant citations. The retrieval cut-off date was February 1, 2001.

The Medline search included the following search strategies, with limits of publication dates 01/01/1990 to 12/31/2000, English language, Clinical Trial, and Human:

Diagnosis: (Parkinson disease OR parkinson syndrome OR parkinsonism) AND (diagnosis OR medical errors OR accuracy OR sensitivity OR specificity) OR (diagnosis AND antiparkinsonian agents).

Pharmacological Treatment: (Parkinson disease OR parkinson syndrome OR parkinsonism) AND (treatment OR levodopa OR carbidopa OR amantadine OR anticholinergic OR selegiline OR deprenyl OR dopamine agonist OR bromocriptine OR pergolide or lisuride OR cabergoline OR pramipexole OR ropinirole OR tolcapone OR entacapone). (Parkinson disease OR parkinson syndrome OR parkinsonism) AND (selegiline OR Vitamin E OR Vitamin C OR neuroprotective agents).

The search cut-off date for pharmacologic studies was initially 1985, for the purpose of including studies of anticholinergic agents. However, no acceptable studies of anticholinergic agents were published between 1985 and 1990; therefore the search cut-off date was changed back to 1990, in accordance with the search cut-off date established for the other questions.

Surgical Treatment: (Parkinson disease OR parkinson syndrome OR parkinsonism) AND (surgery OR pallidotomy OR brain tissue transplant OR deep brain stimulation)

Psychiatric Treatment: (Parkinson disease OR parkinson syndrome OR parkinsonism) AND (psychological OR psychotic OR mental disorder) AND (drug therapy OR drug interactions).

Ancillary Treatment: (Parkinson disease OR parkinson syndrome OR parkinsonism) AND rehabilitation.

Genetics: (Parkinson Disease OR parkinsonism OR Parkinson) AND genetics AND limit to review articles January 1, 1997-August 1, 2000.

The search of the Current Contents CD-ROM database employed the same strategies. The Cochrane Controlled Trials Register search strategy was “Parkinson's Disease.”

All citations and abstracts resulting from the above searches in Medline and Current Contents were downloaded and printed at MetaWorks.

To assist with the development of the evidence base, pertinent articles from the following Internet sites were reviewed:

American Parkinson Disease Association (http://apdaparkinson.com)

Medscape (http://www.medscape.com)

National Guidelines Clearinghouse (NGC; http://www.guideline.gov)

National Parkinson Foundation (http://www.parkinson.org)

Parkinson's Action Network (http://www.parkinsonsaction.org)

Parkinson's Disease Foundation (http://www.parkinsons-foundation.org)

United Parkinson Foundation (http://www.aoa.dhhs.gov/aoa/dir/221.html)

Clinical trials information (http://www.parkinson-study-group.org)

A list of potentially relevant studies was provided by the American Speech-Language-Hearing Association (ASHA). These citations were screened in the same manner as those identified by electronic searches.

Exclusion Criteria

During Level I screening, all abstracts were downloaded, reviewed and evaluated for the following exclusion criteria:

• Reviews, meta-analyses (except those regarding diagnosis and genetics)

• Letters, case reports, editorials, and commentaries.

• Abstracts and unpublished study reports.

• Pharmacokinetic and pharmacodynamic studies.

• Animal or in vitro studies.

• Studies written in languages other than English.

• Studies published prior to 1990.

• Studies with < 10 patients.

• Cross-over studies.

• Studies where results for PD population cannot be separated from results from other populations.

• Studies not pertaining to diagnosis or treatment of PD.

• Treatment studies with < 24 weeks of treatment and followup.

Cross-over studies were excluded for several reasons. It is frequently difficult to extract information from the mid-point of the trial, before the cross-over occurs. The patient response in the second phase of a study of cross-over design may be impacted by treatment administered during the first phase. When patients drop out in the first phase, the patients entering the second phase may be different from the baseline population, introducing selection bias. Additionally, the number of parallel design RCTs that met the inclusion criteria comprised a large enough evidence base to justify the exclusion of studies of cross-over design, with all of their attendant difficulties in data extraction and interpretation.

Given that PD is a chronic condition, and that patients stay on medications for years, the most clinically relevant data comes from long-term trials. For this reason, treatment trials had to be greater than or equal to 24 weeks duration for acceptance. Furthermore, the most useful data for analysis concerning pharmacological treatment of PD are in randomized controlled trials (RCTs); therefore, only RCTs were accepted for studies pertaining to pharmacological treatment. For trials pertaining to surgical treatment, 24 weeks of followup were required; however, study designs other than RCTs were accepted, due to the scarcity of RCTs evaluating surgical procedures for PD. For trials pertaining to diagnosis, study duration and design were not restricted.

Full articles were retrieved for all abstracts passing Level I screening. The articles then underwent Level II screening, which consisted of evaluating the articles for the following inclusion criteria (See Appendix E):

Inclusion Criteria

Diagnosis:

• The following study designs: observational [prospective, retrospective, and cross sectional (XS)], or interventional [RCTs, non-randomized controlled trials (nRCTs), uncontrolled case series (UCSs), XS].

• Adult patients with potential diagnosis of PD.

• Studies addressing any diagnostic test to establish or support a diagnosis of PD.

Pharmacological Treatment:

• RCTs only.

• ≥ 24 weeks treatment and followup duration.

• Studies reporting at least one objective clinical outcome measure (efficacy or safety) on at least one of the following drugs or category of drugs:

  • L-dopa/Carbidopa (Sinemet)

  • L-dopa/Benserazide (Madopar)

  • Amantadine (Symmetrel)

  • Dopamine agonists: Bromocriptine (Parlodel), Pergolide (Permax), Ropinirole (Requip), Pramipexole (Mirapex), Andropinole, Cabergoline (Dostinex), Apomorphine, Lisuride (Dopergin)

  • Monoamine oxidase B (MAO-B) inhibitors: Selegiline (Deprenyl), Rasagiline (TVP-1012), Lazabemide

  • Catechol-O-methyltransferase (COMT) inhibitors: Tolcapone (Tasmar), Entacapone (Comtan)

  • Anticholinergic agents: Trihexylphenidyl (Artane), Benztropine (Cogentin), Procyclidine

• Studies involving neuroprotection with selegiline, Vitamin E (tocopherol), or Vitamin C.

Surgical Treatment:

• The following study designs: interventional (RCTs, nRCTs, and UCSs).

• ≥ 24 weeks study and followup duration.

• Must report at least one objective clinical outcome measure.

• Studies addressing surgery in adult patients with PD including:

  • Ablative or destructive surgery (thalamotomy, pallidotomy),

  • Stimulation surgery or Deep Brain Stimulation (DBS),

  • Transplantation surgery.

Psychiatric Treatment:

• The following study designs: interventional (RCTs, nRCTs, and UCSs).

• ≥ 24 weeks study and followup duration.

• Studies addressing treatment of non-psychotic behavioral and psychological dysfunction in adult patients with PD.

• Studies addressing treatment of psychotic symptoms in adult patients with PD.

• Studies addressing use of antipsychotic medications in conjunction with antiparkinsonian agents.

• Studies addressing the use of atypical antipsychotic medications in management of adult patients with PD.

  • Clozapine (Clozaril)

  • Olanzapine (Zyprexa)

  • Quetiapine (Seroquel)

Ancillary treatment:

• The following study designs: interventional (RCTs, nRCTs, and UCSs).

• No minimum study duration.

• Studies reporting at least one of the following specific interventions:

  • Allied health interventions.

    • Occupational therapy (OT).

    • Physical therapy (PT).

    • Psychotherapy (counseling).

    • Speech therapy.

• Studies reporting at least one of the following specific outcomes:

  • Acute hospitalization.

  • Rehabilitation hospitalization.

  • Nursing home admission.

  • Work absenteeism.

  • Quality of Life (QoL).

  • Activities of Daily Life (ADL) assessment.

Genetics:

• Study design limited to recent review articles only.

• Adult patients undergoing genetic testing to support a diagnosis of PD.

General Considerations:

Studies pertaining to diagnosis were initially required to report sensitivity and specificity; however, as very few studies met this requirement, it was removed. Some of the peer reviewers commented that the inclusion criteria for surgical studies were less rigid than those for pharmacological studies. This disparity was due to the relative scarcity of RCTs pertaining to surgical treatment of PD.

For studies regarding ancillary treatment to be accepted, the initial requirement was that the study duration be at least 24 weeks. This resulted in acceptance of only six studies; therefore, this requirement was removed, and studies of < 24 weeks duration were also accepted.

Linked Studies

After the accepted studies were determined, linked studies were identified. These were studies in which the same patient population was reported in more than one publication. “Parent” studies were assigned, which contained primary data. “Child” studies contained supplemental information, such as followup data or additional analyses. Data elements were extracted from the parent studies, and supplemented by information presented in kin studies, when appropriate.

Rating the Evidence

All eligible studies were rated for both quality and level of evidence at the time of data extraction. Two established methods: 1) the Jadad method,¹¹² and 2) the Level of Evidence method¹¹³ were used (see Appendix B, Attachments B and C).

Data Extraction

Data Extraction Forms (DEFs) were designed in advance (see Appendix E), and pilot tested on a small sample of eligible studies. The pilot test allowed for necessary edits to the DEF to be made prior to implementation on all studies. Key data from each eligible study were extracted by a researcher recording data from original reports onto a DEF, and reviewed by a second researcher checking all DEF fields against the original report. Differences were resolved prior to data entry. In all cases, at least one physician reviewed each study. Dual review of all data served to reduce error and bias in the data extraction process. The data were then entered into MetaWorks' relational database of clinical studies, MetaHub™.

When trials consisting of several phases with different study designs were encountered, only data from the randomized phase was captured.

Key data elements sought for extraction from each study are listed in the Work Plan (Appendix B).

Database Development

Data were entered from the DEFs into a relational database of clinical trials. At the time each DEF was entered, 100 percent of the data entries were checked back against the original DEFs. In addition, a 20 percent random sample of data in the completed database was checked against the DEFs. Error rates in excess of 2 percent of QC-checked data would have triggered a 100 percent recheck of all data elements entered into the database.

Statistical Methods

The main goal of the statistical analysis was to estimate the difference in efficacy of various treatments for PD.

Meta-Analyses

Meta-analysis of efficacy outcomes of pharmacological studies was performed for all RCTs reporting outcome data on at least one of the PD rating scales mentioned above. Meta-analysis of the primary efficacy outcomes of the surgery studies was also performed for all studies reporting the necessary outcome data. The effect sizes calculated and meta-analyzed were standardized mean differences.¹¹⁶ Appendix F describes interpretation of the size of standardized mean differences.

Effect sizes for pharmacological studies. In the meta-analyses of pharmacological studies, the effect size represents the standardized difference between two groups on the change in patients' scores from the beginning of the treatment to the end of the treatment. Optimally, this effect size was calculated from baseline and outcome data for the two treatment groups, and (preferably) change-score standard deviations; however, in some cases calculations were possible from study p-values.

Unbiased change-score effect sizes were calculated using the standard formula:

where N is the total study sample size.¹¹⁶ The numerator represents the difference between the treatment and control groups on the amount of change each underwent from the beginning of the study. The denominator contains the pooled variance of the treatment and control change-scores. See Appendix F for a description of how this variance was estimated when the source studies reported baseline and outcome data but failed to report change-score standard deviations. The change-score effect sizes measured the standardized difference in change between a treatment and a control group, to see if one treatment led to more improvement (or less decline) in PD than the other. Effect sizes were scaled such that a positive effect size indicated that the treatment under investigation worked better than the control, where the control was always therapy with L-dopa alone.

Effect sizes for surgery studies. The meta-analysis of surgery data examined pre-post surgery standardized mean differences in PD scores:

These effect sizes simply compare pre-test to post-test scores to determine if there was any improvement at all due to the surgery. This means that the only comparisons between the efficacies of different types of treatment (e.g., pallidotomy versus DBS) that can be made are indirect comparisons.

Meta-analyses of pharmacological and surgery studies. Based upon available data, three sets of meta-analyses were conducted for the pharmacological studies: one that compared the efficacy of DAs (with L-dopa allowed) to L-dopa given alone, one that compared the efficacy of selegiline (with L-dopa allowed) to L-dopa given alone, and one that compared the efficacy of COMT inhibitors (with L-dopa allowed) to L-dopa given alone.

There were insufficient studies to allow a meta-analysis of any pharmacological treatment against placebo, with no L-dopa involved.

Based upon available data, three sets of meta-analyses were calculated for the surgery studies: one that investigated whether pallidotomy was associated with improved “off” or “on” scores, one that investigated whether DBS was associated with improved “off” or “on” scores, and one that investigated whether fetal brain cell transplants were associated with improved “off” or “on” scores. There were insufficient studies to perform a similar meta-analysis on thalamotomy treatment arms.

After effect sizes and their expected variances were calculated for a given set of studies, a fixed-effects meta-analysis was conducted within each set.¹¹⁶ The chi-square homogeneity statistic (Q_E) was calculated for each meta-analysis to determine whether there was any variation in the study effects that could not be explained due to sampling error. Given the low number of studies in each meta-analysis, there was very low power to detect effect heterogeneity. Thus, a more conservative random-effects model was utilized to calculate the final estimates and confidence intervals when the estimate of random-effects variation (defined as τ or Δ²) was greater than zero.¹¹⁷ The random-effects model accounts for treatment variation not explainable due to sampling error, and thus leads to wider confidence intervals for its parameters than the fixed-effects model. When data permitted, fixed-effects and/or random-effects meta-regressions (mixed-model meta-analyses that consider study characteristics as predictors of treatment effect) were examined as well.^{117, 118} Common study characteristics investigated were mean patient age, severity of disease at baseline, disease duration, and the time between initial treatment and post-test.

All meta-analyses and meta-regressions were performed using SPSS 10.1 and procedures written in SAS/IML 8.1.

Sensitivity Analysis. When the number of studies in the meta-analysis permitted, sensitivity analysis was performed to examine whether any design characteristics were associated with treatment effects. Characteristics (covariates) of interest included:

1. whether study data were intention-to-treat (ITT) or completers

2. adequacy of blinding, as reflected in Jadad score.¹¹²

The data were also inspected for “outliers” - study effects that were extreme enough, either in their value or in the value of their study characteristics, that they might by themselves “skew” the estimate of the mean effect, the estimate of effect size heterogeneity, or the relationship between a study characteristic and the study effects.

Role of Consultants

Eight people from both academic and community settings comprised the TEP (Appendix G). They all received copies of the Work Plan and its revision, causal pathways, topic refinement, study listings, and draft report. When TEP members provided feedback, MetaWorks investigators reviewed their comments, and applied them as deemed appropriate. Additionally, during the course of the project, monthly conference calls were instituted among MetaWorks, the topic nominator (AAN), the TOO, and the co-investigator from LDI. During these conference calls, project updates were provided and issues of concern were addressed.

Peer Review

A group of 19 peer reviewers (Appendix G) was assembled to review a draft version of this report. The panel was composed of neurologists, a neurosurgeon, an internist, two statisticians, a speech-language pathologist, and two PD patients. All reviewers were asked to complete peer review form relative to the content of the first draft of this report (Appendix G), and were also invited to provide additional written comments. Seven of the eight TEP members and 13 of the 19 peer reviewers provided feedback on the draft Evidence Report. All responses from the TEP and peer reviewers were reviewed and, where appropriate, incorporated into the final report.

Searches

Figure 2. Study Attrition

   Figure 2. Study Attrition

Figure 2

The screening strategies were reviewed a priori with the TEP, TOO, and AAN representative. A few studies did not meet inclusion criteria, but the consulting PD experts believed they should be mentioned in this review. These studies are discussed in Appendix J, but were not extracted, entered into the database, or included in the statistical analyses.

Studies

Diagnosis

There were 59 parent and six kin studies concerning diagnosis, consisting of 3,369 patients, 1,108 healthy controls, and 859 patients with other neurological diagnoses, such as secondary parkinsonism or essential tremor. The vast majority of studies were cross-sectional studies (k=46, n=2,055), six were retrospective observational studies (n=953), five were UCSs (n=278), and two were nRCTs (n=83). All were graded as level III evidence, and quality score could not be calculated because there were no RCTs.

An estimate of the diagnostic accuracy of any test should compare the test with a reference standard, which should be the best available method of assessing the presence or absence of the disease of interest.¹²⁰ The major difficulty in assessing diagnostic tests for PD is the lack of a validated reference standard for comparison.

Pharmacological Treatment of PD

The mean disease duration of all patients in pharmacological treatment groups that reported this parameter was 5.0 years (t=84, n=6,369, range 0.6 –13.6 years). Disease duration was distributed as follows: 23 treatment arms reported a mean disease duration of < 2 years, 26 reported 2–5 years, 14 reported 5–10 years, and 21 reported ≥ 10 years.

Seven studies reported “on” UPDRS scores only,^{66, 178 – 183} two reported both “off” and “on” scores,^{184, 185} one reported the average of “off” and “on” scores.¹⁸⁶ The remainder did not specify whether their UPDRS scores were “off” or “on.”

Studies were divided into early or advanced PD, based on the study authors' classification or disease characteristics reported in the studies. Thirty-two studies (t=74, n=7,405) that referred to patients as having “early” or “de novo” PD, or mean disease duration < 5 years were classified as early. Seventeen studies (t=37, n=2,563) that reported patients with “advanced” PD, mean disease duration > 5 years, or patients who suffered from fluctuations and dyskinesias due to long-term L-dopa treatment were classified as advanced. It must be recognized that this categorization has limitations. Disease duration is useful in classifying individual patients as having early vs. advanced disease, but mean disease duration of < 5 years does not mean that all patients have short disease duration. Studies that reported mean disease duration did not always report the range of disease duration in the individual patients.

Motor fluctuations are typically seen in patients with advanced PD; however some studies in which the patients were identified as having “early” PD reported motor fluctuations and “off” times. Given these limitations, three of the 32 studies that were classified as early,^{187, 188, 189} and five of the 17 studies that were classified as advanced^{185, 190, 192, 193, 194} may have actually contained mixed populations of patients with early and advanced disease.

In studies of patients with early PD, it was often difficult to ascertain whether or not patients had previously taken L-dopa. This is important to distinguish, because it may be assumed that patients who never received L-dopa have less severe PD symptoms than patients who had received L-dopa. In 12 studies, inclusion criteria required that patients had never received L-dopa prior to study entry.^{119, 180, 195 – 204} In 15 studies, some patients may have received L-dopa prior to study entrance, but it was not always possible to ascertain which patients had been on L-dopa.^{65, 66, 82, 178, 181, 188, 205 – 213} In five studies of patients with early PD,^{187, 189, 214, 215, 216} and all 17 studies of patients with advanced PD, all patients were on L-dopa prior to study enrollment.

L-dopa was combined with DAs in 33 treatment arms (n=2,935), with MAO-B inhibitors in seven treatment arms (n=700), and with COMT inhibitors in eight treatment arms (n=639). Seven treatment arms contained other combinations, including L-dopa/DA/MAO-B inhibitor (t=2, n=68), DA/MAO-B inhibitor (t=1, n=10), α-dihydroergocryptine (α-DHEC; t=1, n=62), α-DHEC and L-dopa (t=1, n=10), L-dopa/vitamin E (t=1, n=202), and L-dopa/vitamin E/MAO-B inhibitor (t=1, n=197). No studies of amantadine or anticholinergic medications met the criteria for inclusion into this systematic review.

Rejected pharmacological studies of interest that were not accepted for this review, but were deemed to be of interest by the TEP, are discussed in Appendix J. These studies were rejected mainly due to publication date prior to 1990, inadequate study duration, or cross-over design, and include studies of anticholinergic medications, pramipexole, pergolide, tolcapone, selegiline, and GM1 ganglioside.

Pharmacological Treatment of PD: Meta-analyses

Meta-analysis of DAs (plus L-dopa) vs. L-dopa alone. As shown in Evidence Table 6, seventeen studies provided sufficient data on one of the PD rating scales to calculate standardized mean differences between the pre-test/post-test change scores for a DA + L-dopa group and the pre-test/post-test change scores for an L-dopa group.^{65, 66, 178, 180, 182, 183, 185, 188, 190, 193, 195, 203, 208, 209, 212, 215, 216} Six studies investigated the effect of a DA+L-dopa versus L-dopa alone, but did not report enough data to allow the calculation of a pre-post effect size.^{184, 199, 204, 205, 214, 219}

Three of the studies in the meta-analysis examined patients naïve to L-dopa before the trial (all were studies of patients with early disease),^{180, 195, 203} seven of the studies examined patients with a mix of previous exposure to L-dopa (all early disease studies),^{65, 66, 178, 188, 208, 209, 212} and seven of the studies examined patients that were all previously exposed to L-dopa (all but two were studies of patients with advanced disease).^{182, 183, 185, 190, 193, 215, 216}

Twelve of the studies in the meta-analysis examined treatment arms of patients with mean disease duration ≤ five years (i.e., early disease),^{65, 66, 178, 180, 188, 195, 203, 208, 209, 212, 215, 216} and five studies examined treatment arms of patients with mean disease duration greater than five years (i.e., advanced disease).^{182, 183, 185, 190, 193} Six studies investigated bromocriptine,^{188, 195, 208, 209, 215, 216} while no other agonist was investigated more than three times.

In 11 of the studies in the meta-analyses, L-dopa was mandatory (i.e., patients were randomized to receive L-dopa or L-dopa plus a DA),^{178, 182, 183, 185, 188, 190, 193, 195, 209, 215, 216} and in five studies, the L-dopa was discretionary (i.e., patients were randomized to receive L-dopa or a DA, but L-dopa could be added at the practioner's discretion).^{65, 66, 180, 203, 208}

Figure 3. Dopamine Agonist + L-Dopa vs. L-Dopa

   Figure 3. Dopamine Agonist + L-Dopa vs. L-Dopa

A meta-analysis of differences between change in PD scores was performed. Figure 3 shows point estimates and 95 percent confidence interval error bars for the individual studies.

A fixed-effects meta-analysis showed that the change-score effect sizes (CHESs) were heterogeneous after sampling error was taken into account (Q_E = 87.95, p<0.001). A random-effects model led to slightly positive but only marginally statistically significant effect for treatment with a DA + L-dopa versus L-dopa alone ( = 0.16, SE( ) = 0.09), where represents the estimate of the mean effect size and SE ( ) represents its standard error. The 95 percent confidence intervals for this estimate are presented in Figure 3.

Given the presence of considerable heterogeneity, examination of study characteristics was warranted; however, multivariate analysis was made difficult by the presence of collinearity between the numerous predictors and the low number of studies. For instance, there was a strong relationship between stage of disease (early vs. advanced) and previous exposure to L-dopa. There was also a strong (yet unexplained) correlation between stage of disease and whether the DA investigated was bromocriptine; there were no studies in which bromocriptine was used and patients had a long disease duration. To simplify interpretation, univariate analyses for each study characteristic were conducted.

There were two study characteristics that were statistically significant: time of evaluation (p=0.009) and type of L-dopa delivery (p<0.001) (discretionary vs. mandatory). Studies with a duration of greater than one year had significantly lower effect sizes than studies with a duration of less than one year; studies with discretionary L-dopa delivery had significantly lower effect sizes than studies in which L-dopa delivery was mandatory in the dopamine agonist arm.

These findings suggest two different mechanisms at work. The first suggests that the effect of treatment with a DA+L-dopa, relative to L-dopa alone, may decline over time. The latter suggests that treatment which mandates L-dopa as an adjunct to a DA controls PD symptoms better than treatment which merely allows doctors to give L-dopa when they think it might be needed.

While the mechanisms are different, their individual impacts cannot be measured in this meta-analysis; these two variables were highly correlated (r=.60, p=.015), making it very difficult to separate their respective influences. Among the studies in which L-dopa delivery was mandatory, there was a mix of short- and long-term study durations; however, when L-dopa delivery was discretionary, the only studies present were long-term ones.

Meta-analyses within each level of each key study characteristic (e.g., a meta-analysis of studies with short disease duration, a meta-analysis of studies with long disease duration, a meta-analysis of studies with de novo patients, etc.) are presented in Figure 3. Studies in which the DA used was bromocriptine had a higher average effect size than those in which another DA was investigated. Studies of patients with advanced PD had a higher average effect size than those with patients with early PD, and studies with non-de novo patients had a higher average effect size than studies with de novo patients or patients with a mixed background. However, none of these differences were statistically significant.

Two groups of sensitivity analyses were conducted. In the first, three design characteristics (whether LOCF measurements were used, whether the study was blinded, and whether the study effect was known to be “on” or whether it was merely assumed to be “on”) were investigated univariately. None were close to being statistically significant (p>0.30 for each). In the second group of sensitivity analyses, re-analyses of the data were conducted to determine whether any particularly large or small effect sizes were having an unbalancing effect on the overall results. The first set of re-analyses deleted the largest effect size from one study,²¹⁵ and the second set deleted the smallest effect size from a different study.⁶⁵ All meta-regressions using the new subsets of studies found substantively what the initial meta-regressions found: a significant negative effect for treatment duration, suggesting that DAs work better in studies of short duration.

There were three studies in which head-to-head comparisons between bromocriptine and other DAs were performed. The comparator drugs were cabergoline,¹⁹¹ ropinirole,²⁰⁶ and pramipexole.¹⁸⁶ All studies used L-dopa as a supplementary treatment. Two studies were in patients with advanced disease^{186, 191} and one in patients with early disase.²⁰⁶ Effect size could only be calculated for two of the studies. The average effect size (positive indicating that bromocriptine performed better) was not significantly different from zero.

Conclusions of DA+L-dopa vs. L-dopa meta-analyses. There is no evidence that different DAs vary in treatment effects. 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 finding. However, given the wide heterogeneity in this small group of studies in type of treatment, focus of treatment, duration of treatment, and patient characteristics, it would be very difficult to detect such effects if they indeed existed.

Figure 4. Selegiline + L-Dopa vs. L-Dopa

   Figure 4. Selegiline + L-Dopa vs. L-Dopa

Meta-analysis of selegiline (plus L-dopa) vs. L-dopa alone. Evidence Table 7 shows the three studies that compared the effect of selegiline and L-dopa versus the effect of L-dopa alone in patients with early PD.^{181, 207, 208} All studies looked at patients with short disease duration. Figure 4 shows point estimates and 95 percent confidence interval error bars for the individual studies, as well as for the overall meta-analysis.

A fixed-effects meta-analysis showed that the CHESs were heterogeneous (Q_E = 11.79, p=0.003). A random-effects model led to a moderate sized estimate of mean effect that was statistically insignificant ( = 0.47, SE( ) = 0.25). Due to the small numbers of studies involved, reliable examination of the impact of study characteristics on treatment efficacy and sensitivity analysis were not possible.

Conclusions of Selegiline+L-dopa vs. L-dopa meta-analyses. While there is some evidence to suggest that selegiline + L-dopa may work better than L-dopa alone in controlling symptoms of PD, the difference between the two therapies in efficacy in controlling PD symptoms was statistically insignificant. However, the power to detect a difference between these two therapies was very small given the low number of studies involved and the wide variation between them.

Studies not included in selegiline meta-analysis. One study investigated the efficacy of the MAO-B inhibitor lazabemide relative to the efficacy of a placebo (as opposed to an L-dopa treatment).²¹¹ The average lazabemide effect was 0.302 (p<0.05), suggesting that lazabemide performed somewhat better than placebo. Two studies examined the effect of selegiline versus the efficacy of placebo.^{200, 202} In these placebo-controlled trials, the primary efficacy outcome was time until L-dopa treatment was required. In both cases, patients in the placebo arms needed L-dopa sooner than patients in the selegiline treatment arms.

In the DATATOP study, 800 patients with early PD were randomized to receive selegiline, vitamin E, the combination, or placebo.⁸² The primary endpoint was the time when L-dopa was required. Selegiline significantly delayed the L-dopa requirement, while vitamin E showed no evidence of benefit. This study could not be included in the meta-analysis because UPDRS scores at uniform time points prior to starting L-dopa were not available in the published literature.

Figure 5. COMT Inhibitor + L-Dopa vs. L-Dopa

   Figure 5. COMT Inhibitor + L-Dopa vs. L-Dopa

Meta-analysis of COMT-inhibitors (plus L-dopa) vs. L-dopa alone. Five studies compared the effect of COMT inhibitors with L-dopa versus the effect of L-dopa alone in patients with PD.^{86, 177, 179, 189, 220} Except for one study,¹⁸⁹ all were in the setting of advanced disease. As shown in Evidence Table 8, three of the studies provided a pair of effects (each for a different dose of tolcapone: 100mg and 200mg). The remaining two studies investigated entacapone as a treatment. A total of six of the eight study arms investigated patients with disease duration of > 10 years. Figure 5 shows point estimates and 95 percent confidence interval error bars for the individual studies, as well as for the overall meta-analysis.

The fixed-effects meta-analysis of CHESs were homogeneous (Q_E = 5.32, p=0.62). The estimate of the mean was 0.33 (SE( ) = 0.056), which was statistically significantly greater than zero (p<0.001). Error bars for each meta-analysis are presented in Figure 5.

There was little variance on most of the study characteristics, making the investigation of the impact of study duration, severity of disease, and baseline exposure of patients to L-dopa difficult. It is likely that this minimal variation in study characteristics contributed to the reason that the effect sizes were so homogenous. There was no statistically significant difference between the effect sizes of the three 100 mg tolcapone arms and the three 200 mg tolcapone arms (p>0.50), and no statistically significant difference between the effect sizes of the two arms in which average disease duration was less than five years and the six arms in which average disease duration was greater than ten years (p=0.25).

The significantly positive mean CHES for the COMT inhibitors remained significantly positive after the largest change-score effect was deleted (p<0.001).

Conclusions of COMT+L-dopa vs. L-dopa meta-analyses. Unlike the meta-analyses of the DAs and selegiline, the studies in the meta-analysis of treatment with COMT were very homogeneous with regard to disease duration, treatment duration, and baseline exposure of patients to L-dopa. It is likely that this led to the consistent moderately positive effect for COMT + L-dopa versus L-dopa. It can safely be concluded that in the short term (≤ seven months), patients with advanced PD who receive combination treatment with COMT and L-dopa can expect a reduction in PD symptoms substantively greater than similar patients who are treated with L-dopa alone. Most of the studies examined the COMT inhibitor tolcapone; however, there was no evidence that tolcapone treatment was better or worse than treatment with entcapone. Also, there was no evidence that treatment with 200mg of tolcapone alleviated symptoms more than treatment with 100mg of tolcapone.

Due to reports of hepatotoxicity associated with tolcapone, the three tolcapone studies were reviewed for mention of hepatotoxicity.^{86, 179, 189} Of the 451 patients taking tolcapone, 16 patients were reported to have transient elevations in LFTs (3.5 percent), leading to withdrawal of six patients from the three studies (1.3 percent). Of the 227 patients on the lower dose of tolcapone (100 mg per day), seven patients had reports of elevated LFTs (3.1 percent), and one patient withdrew from the study (0.4 percent). Of the 224 patients on the higher dose of tolcapone (200 mg per day), nine patients had reports of elevated LFTs (4.0 percent), and five patients withdrew from the studies (2.2 percent). All of the COMT studies had a duration of seven months or less; therefore, no conclusions may be made regarding long-term safety.

Surgical Treatment of PD

The vast majority of studies were UCSs (k=35, n=1,145), and the remainder were RCTs (k=4, t=8, n=105), nRCTs (k=2, t=7, n=117), and one case-control retrospective study (t=2, n=13). Thirty-eight of the studies were graded as level III evidence, and four were level II. Quality score could be calculated only for the four RCTs, and was a mean of 3, reflecting moderate quality.

Thirteen studies reported dyskinesia scores (t=16, n=426). This is an important outcome to assess in surgical patients, because patients commonly undergo surgery to reduce medication complications, such as dyskinesias. As dyskinesia is a medication side effect, dyskinesia scale results are reported in the “on” state. Pooling of these scales across studies is problematic, because studies reported different variations of the scales, the scales were not always defined, and standard deviations were generally not reported. Nearly all treatment arms showed improvement in mean dyskinesia scores, particularly contralateral scores, after surgery.

Scores that were reported less frequently include Beck Depression Inventory (BDI; t=4, n=62), postural instability and gait disturbances (PIGD; t=3, n=102), Perdue Pegboard Test (t=2, n=46), and Webster Score (t=1, n=12).

Two studies included concurrent control groups of patients who did not undergo surgery (n=29). ^{221, 222} In both of these control groups, baseline UPDRS scores were lower (better) than post-study scores, the opposite pattern from that seen in all surgical groups, suggesting that patients who did not undergo surgery deteriorated clinically.

Timing of post-surgical evaluation may affect results, and may give an indication of duration of postoperative benefit. Approximately half of the surgical treatment arms reported results at less than one year, and the other half reported results at greater than one year. No consistent pattern emerged in comparing earlier vs. later results.

“On-off” time was of interest, because surgical patients have advanced PD, where motor fluctuations are particularly problematic; however, it was only reported in ten studies, using inconsistent methods of measuring this phenomenon.

Surgical Treatment: Meta-analyses

Figure 6. Surgery: Pallidotomy

   Figure 6. Surgery: Pallidotomy

Figure 7. Surgery: Pallidotomy

   Figure 7. Surgery: Pallidotomy

Pallidotomy. Fifteen pallidotomy treatment arms provided sufficient pre-post data on any of the PD rating scales to calculate pre-post standardized mean differences for “off” scores, and 12 treatment arms provided sufficient pre-post data to calculate standardized mean differences for “on” scores (Evidence Table 12). Figures 6 and 7 show point estimates and 95 percent confidence interval error bars for the individual study effect sizes for “off” and “on” scores, respectively.

Meta-analyses - “Off” effects. A fixed-effects meta-analysis showed that the “off” effect sizes were heterogeneous (Q_E = 37.94, p<0.001). A random-effects model suggested that pallidotomy is effective in reducing “off” scores ( =0.77, SE( ) = 0.12). Given the heterogeneity of effects, examination of study characteristics was warranted. Univariate meta-regressions were conducted which investigated three study characteristics: time since surgery (≤ one year vs. > one year), average age of the participants, and average patient H&Y score at baseline. No predictors were statistically significant, although there was a marginally significant (p=0.095) effect for time since surgery; the estimated effect size of pallidotomy on PD scale scores was 0.87 in studies with a duration of one year or less, and 0.36 in studies with a duration greater than one year. This suggests that pallidotomy may be effective mainly for the first year, but the number of long-term studies is too limited to make more than a tentative conclusion. The 95 percent confidence intervals for estimates of the mean effect size are in Figure 6.

Meta-analyses - “On” effects. A fixed-effects meta-analysis showed that the “on” effect sizes seemed homogeneous (Q_E = 11.18, p=0.43). As mentioned previously, our rule was to use a random-effects model if the estimate of random-effects variation was greater than zero. In this case, the random-effect results are almost identical to those of the fixed-effects model. The random-effects model led to a small and statistically insignificant estimate of average effect for pallidotomy “on” scores ( =0.13, SE( ) = 0.08). Univariate meta-regressions were conducted for three study characteristics: time since surgery (≤ one year vs. > one year), average age of the participants, and average patient H&Y score at baseline. No study characteristics explained the significant amount of variation.

Sensitivity analyses were conducted to determine if any of the results seemed dependent on the inclusion of any one study. The only finding was that the effect of time since surgery was statistically significant if the largest effect size was deleted.²²⁹ The effect in this study is quite large (0.93), as opposed to the effects from the two other studies with surgery followups exceeding one year; the effect in one is 0.20,²²⁸ and the effect in the other is 0.10.²²³ The followup times in these three studies were 16, 24, and 48 months, respectively. It might be that the effect of pallidotomy on “off” scores does not decline until after at least a year and a half (or more) has passed. This result is suggestive at best, but may be worthy of future within-study investigation. The 95 percent confidence intervals for estimates of the mean effect size are in Figure 7.

Figure 8. Surgery: Deep Brain Stimulation

   Figure 8. Surgery: Deep Brain Stimulation

Figure 9. Surgery: Deep Brain Stimulation

   Figure 9. Surgery: Deep Brain Stimulation

Deep Brain Stimulation. Fourteen DBS treatment arms provided sufficient pre-post data on any of the PD rating scales to calculate pre-post standardized mean differences for “off” scores, and eight treatment arms provided sufficient pre-post data to calculate standardized mean differences for “on” scores (Evidence Table 13). Figures 8 and 9 show point estimates and 95 percent confidence interval error bars for the individual studies for “off” and “on” scores, respectively.

Meta-analyses - “Off” effects. Given that DBS takes place at three different sites (the GPi, the STN, and the thalamus), three separate meta-analyses were conducted. The “off” scores of the four studies of DBS of the GPi were very homogeneous (Q_E = 0.88, p>0.50). The fixed-effects estimated average effect of DBS-GPi on PD scale scores was significant and very large ( =1.31 (SE( ) = 0.33). The eight studies of DBS of the STN were quite heterogeneous (Q_E = 55.68, p<0.001). A random-effects model led to a large and statistically significant estimate of average effect ( =2.00, SE( ) = 0.47). Finally, the two studies of thalamic DBS seemed homogenous (Q_E = 0.27, p>0.50), but the fixed-effects estimated average effect was near zero ( = -0.08, SE( ) = 0.16). This latter result is not surprising, as DBS of the thalamus is generally done for different reasons than DBS of the other two sites, i.e., it is not done to control severe PD, but to control tremor.⁹⁷

Three study characteristics (time since implantation of the DBS device, average age of patients, and average H&Y score at baseline) were explored as possible explanations for the heterogeneity in the STN effect sizes. Three univariate meta-regressions were conducted to test whether any of these characteristics explained significant variation; however, no characteristics did (p>0.05). Sensitivity analyses were conducted to investigate whether any one study effect might be responsible for the excess variation; however, this was not the case.

Overall, meta-analyses of “off” effects showed that DBS led to significant improvement in “off” scores when performed on GPi or STN, and no significant change when performed on thalamic nuclei.

Meta-analyses - “On” effects. Two meta-analyses were conducted (there were no reports of “on” scores for thalamic DBS). The two studies of “on” effect sizes for DBS of the GPi were somewhat homogeneous (Q_E = 1.56, p=0.21). A random-effects model led to a mean effect size near zero ( = 0.01, SE( ) = 0.61). The eight studies of DBS of the STN were heterogeneous (Q_E = 14.96, p=0.01). A random-effects model led to a statistically significant estimate of average effect ( =0.79, SE( ) = 0.30).

Three study characteristics (time since implantation of the DBS device, average age of patients, and average H&Y score at baseline) were explored as possible explanations for the heterogeneity in the STN effect sizes. Three univariate meta-regressions were conducted to test whether any of these characteristics explained significant variation; however, no characteristics did (p>0.05). Sensitivity analyses were conducted to investigate whether any one study effect might be responsible for the excess variation. The analyses showed that the “on” effect from one study (2.47) was causing most of the heterogeneity;²⁴⁵ a re-analysis without this effect size resulted in a meta-analysis showing little heterogeneity (Q_E = 4.63, p=0.33). The mean effect size ( =0.49) was just short of being statistically significant (p=0.06).

This suggests the possibility that DBS does not significantly impact “on” scores; a finding which would not be surprising, given that surgery is only performed on patients who are responsive to medication.

Figure 10. Surgery: Fetal Cell Transplant

   Figure 10. Surgery: Fetal Cell Transplant

Figure 11. Surgery: Fetal Cell Transplant

   Figure 11. Surgery: Fetal Cell Transplant

Tissue Transplant. Four tissue transplant treatment arms provided sufficient pre-post data on any of the PD rating scales to calculate pre-post standardized mean differences for “off” scores, and five treatment arms provided sufficient pre-post data to calculate standardized mean differences for “on” scores (Evidence Table 14). Figures 10 and 11 show point estimates and 95 percent confidence interval error bars for the individual studies for “off” and “on” scores, respectively.

Meta-analyses - “Off” scores. Meta-analysis showed that the “off” score effect sizes may be homogeneous (Q_E = 3.18, p=0.36). However, given the low number of studies in these meta-analyses, the power to detect heterogeneity was very low. To be conservative, a random-effects model was employed. Random-effects modeling shows a positive and statistically significant benefit for tissue transplants ( =0.88, SE( ) = 0.21). The 95 percent confidence intervals for these estimates are presented in Figure 10.

Meta-analyses - “On” scores. A fixed-effects meta-analysis showed that the “on” score effect sizes were heterogeneous after sampling error was taken into account (Q_E = 9.36, p=0.05). A random-effects model suggested a positive and statistically significant effect for tissue transplants ( =1.09, SE( ) = 0.34), indicating that tissue transplants led to improvement in “on” scores. There were not enough studies to investigate whether variation in study characteristics might be responsible for the heterogeneity in the study effects (See Figure 11).

Conclusions of Surgery Meta-Analyses. Pallidotomy resulted in significant improvement in “off” scores and insignificant improvement in “on” scores. DBS of GPi and STN resulted in significant improvement in “off” scores, but no significant change in “on” scores. Thalamic DBS resulted in no significant change in “off” or “on” scores. Fetal cell transplantation resulted in significant improvement in both “off” and “on” scores.

The mean “off” effect size for pallidotomy (0.77) is lower than the mean effect size for DBS of the GPi (1.31). This implies that DBS of the GPi may be better than pallidotomy in controlling PD symptoms in the “off” state. Without head-to-head RCTs, however, any conclusions are tentative at best. It is also worthwhile to note that there are other possible benefits to surgery, such as reduction of dyskinesias and motor fluctuations, that could not be investigated in these meta-analyses. Finally, while current results of tissue transplantation are promising, too few studies have been done on fetal brain surgery to make any more than tentative conclusions about its effectiveness, and the recent RCT comparing tissue transplant to sham surgery raised important questions regarding the long-term safety of the procedure.¹⁰³

Psychiatric Treatment

There were ten accepted studies and one kin concerning treatment of psychiatric disorders in patients with advanced PD. Six studies were UCSs (n=114), two were RCTs (n=57), and two were retrospective observational studies (n=221). Eight studies were graded as level III evidence, and two were level II. Quality score could only be calculated for two studies, and was four in one study²⁶² and two in the other.²⁶³

Six accepted studies evaluated the efficacy of the atypical antipsychotic medication clozapine in managing PD patients with psychosis.^{264 – 269} None were RCTs. Four were UCSs (n=93), lasting from 12 to 24 months.^{264 – 267} Over seventy-five percent of patients in these studies demonstrated improvement in their psychotic behavior on a daily dose of 6.25 to 150 mg clozapine. The main adverse events reported were sialorrhea (reported in zero to 59 percent of patients), sedation (reported in two to 53 percent of patients), and confusion (reported in zero to 82 percent of patients). There were no reported cases of agranulocytosis. In the two retrospective reviews, charts of 221 PD patients on clozapine for control of psychotic symptoms were reviewed.^{268, 269} Patients received clozapine for one to 76 months (mean duration 15.2 months). There was a decrease in the number of patients with agitation, delirium, delusions, dementia, depression, visual hallucinations, psychosis sundowning, insomnia, vivid dreams, daytime napping, disorientation, memory loss, and abulia, although none of these symptoms resolved completely in all patients. Forty-six of 221 patients (20.8 percent) withdrew from the drug due to adverse events. The most common adverse events were somnolence, amnesia, delirium, sialorrhea, and orthostatic hypotension. Granulocytopenia was reported in six patients, but all resolved with discontinuation of the drug, and there were no cases of agranulocytosis.

The efficacy and safety of risperidone,²⁷⁰ quetiapine,²⁷¹ piracetam,²⁶³ and citalopram²⁶² were evaluated in one study each. In a UCS of ten patients with advanced PD, cognitive decline and psychiatric symptoms, patients were treated with low doses of the atypical antipsychotic drug risperidone for 16 to 48 weeks (mean 34.8 weeks).²⁷⁰ While there was improvement in psychiatric symptoms in most subjects, two patients discontinued risperidone due to worsening of parkinsonism, and two developed delirium. The small size and uncontrolled design of this study does not allow conclusions to be drawn regarding the efficacy and safety of risperidone.

Quetiapine, another atypical antipsychotic, was openly administered for 12 months to 11 PD patients with psychosis.²⁷¹ Only five of the 11 patients completed one year of treatment. Withdrawals were due to dizziness, falling, obstipation, cerebrovascular accident, and lack of efficacy. Four of the five patients who completed the trial had improvement in their psychotic symptoms, particularly visual hallucinations. The small trial size and high dropout rate make these results difficult to interpret.

Piracetam, a drug that is structurally similar to γ-aminobutyric acid, was investigated in an RCT of 20 patients who were randomized to piracetam or placebo for 24 weeks, for treatment of intellectual impairment.²⁶³ There were no significant effects on any motor or cognitive features of PD.

Thirty-seven PD patients suffering from major depression participated in an RCT comparing citalopram, a serotonin-specific reuptake inhibitor (SSRI), to placebo.²⁶² After six, ten, 14, 26, 39, and 52 weeks, the citalopram was well tolerated, but no more efficacious than placebo.

Ancillary Treatment

Of the 20 studies ultimately accepted, the majority were RCTs (k=13, t=28, n=866). Three were single-blinded, and the others were not blinded. There were two nRCTs (t=4, n=73), two cross-sectional studies (t=2, n=20), and three UCSs (n=90). Studies were graded as level I (k=2), II (k=11), or III (k=7) evidence, where I is best. The mean quality score for the 13 RCTs was 1.5 of a possible 5, where 5 is best, reflecting low quality.

Genetics

Due to the lack of prospective trials regarding genetic testing for PD, it was decided that the genetics review would be presented as a summary of recent articles on the topic, including review articles. Evidence for the existence of a genetic component for PD has been reported since the 1880s, when a neurologist described a family history of PD in up to 15 percent of his patients.^{293, 294} However, experts currently believe that most cases of PD are sporadic, and that family history does not appear to confer increased risk of developing PD.²⁹⁵

Early twin studies showed low concordance rates, and argued against a genetic etiology of PD. More recent studies have refuted this claim.²⁹⁵ In a study of nearly 200 twin pairs in which at least one twin had PD, there was increased concordance in monozygotic twins, but only in patients who were diagnosed with PD before age 50.²⁹⁶ The authors concluded that genetics do not appear to play a major role in PD with typical age of onset (age > 50), but may be more important for cases with younger age of onset (≤ 50).

Another twin study evaluated the [18-F] fluorodopa PET scans of 34 patients and their monozygotic or dizygotic twins who did not have PD.²⁹⁷ Ten of the 18 monozygotic twins and three of the 17 dizygotic twins had PET scans that showed decreased uptake of fluorodopa in the striatum, consistent with PD, although none of them had clinical evidence of PD. Subjects were followed for up to seven years after their initial evaluation. All asymptomatic monozygotic co-twins showed progressive loss of dopaminergic function over seven years, and four developed clinical PD, but none of the dizygotic twin pairs became clinically concordant. This study suggests that there is a substantial genetic component to the etiology of PD that has been unrecognized because standard clinical diagnostic criteria are insufficiently sensitive. It also shows that functional imaging modalities, such as [F-18] Fluorodopa PET, may be useful tools for future studies of genetic or environmental risk factors for PD.

In an epidemiologic study using a comprehensive genealogic computerized database of over 600,000 Iceland residents over the past 11 centuries, all relatives of PD patients were traced, to examine the evidence for a genetic component of PD risk.²⁹⁸ Risk ratios (RRs) were calculated for the relatives of all 772 PD patients, and also for the subgroup of PD patients with late-onset PD (n=560). Siblings of PD patients had the highest RRs (6.3 for all PD patients, 6.7 for patients with late-onset PD), followed by offspring (3.0 and 3.2, respectively), and nieces and nephews (2.3 and 2.7, respectively). The results of this study suggest that there may be a substantial genetic contribution (at least in this highly interrelated ethnic population), not only in patients with “young-onset” disease (as has been the finding in twin studies), but also in PD patients with typical age of onset.

Mutations associated with PD have been identified in several genes, and it appears that different mutations can produce the same parkinsonian phenotype. The α-synuclein gene on chromosome 4q21–23, and the parkin gene on chromosome 6q25–27 have been studied extensively.²⁹⁴ α-synuclein is a protein that has been identified as a major component of Lewy bodies and a part of the amyloid plaque in AD.²⁹⁵ A point mutation in the α-synuclein gene has been identified in some cases of autosomal dominant familial PD in families of Greek or Italian descent.²⁹⁴ Many mutations in the parkin gene are associated with early-onset, autosomal-recessive PD in Japanese and European families^{299 – 302} while other parkin mutations may be associated with a protective factor for sporadic (non-familial) PD.³⁰³

It is likely that other genes will be identified that are involved with familial PD, but the currently available evidence suggests that the vast majority of PD cases are not familial, and have no known associated genetic component.²⁹⁵ When more information is known about the specific genetic abnormalities in PD patients, specific intracellular genetic manipulation may become possible, with the goal of treating, curing, and even preventing PD.^{304, 305}

Standardize methods of reporting results

Standardization of reporting results facilitates inter-study comparisons. Given the unlikely probability that any one study will conclusively demonstrate the efficacy of a given treatment, it becomes very important for authors to make sure that their results are both clear and complete enough to allow future synthesis with other important studies in the field.

The reliability and validity of the UPDRS has been widely documented, and it is currently the most common instrument used to measure the progression of PD. Investigators should report baseline, endpoint, and change in UPDRS scores, along with their respective standard deviations. While some researchers only report the motor subscore, and it is important that the ADL score be reported as well. Many researchers reported much of this data in figures, making estimates of means imprecise, and estimation of standard deviations almost impossible. Unless researchers report change score standard deviations, the added certainty those researchers achieve by controlling for an individual's pre-test data will not be directly available to future researchers.

The CAPIT committee recommended that surgical studies report UPDRS scores (“off” and “on”), H&Y stages (“off” and “on”), Dyskinesia Rating Scale (“on”), timed tests of motor function (“off” and “on),” and self-reporting diary. We enthusiastically endorse these recommendations, for studies of pharmacological and ancillary as well as surgical treatments, because standardized reporting of baseline and outcome data can only enhance the ability to build an evidence base regarding the optimal treatment of PD.

Duration and severity of “on” and “off” periods are useful parameters to follow, particularly in patients with advanced PD. These could not be meta-analyzed, due to the widely divergent methods used in reporting. “On” and “off” time should be consistently reported, using a standardized method.

Patient withdrawal should preferably be modeled using the sophisticated statistical methods currently published and in development for the problem;³⁰⁶ when these methods cannot be employed, researchers should use ITT/LOCF and record whether they do so. When researchers deem LOCF findings inappropriate, they should explain how they are accounting for patient withdrawal and whether their findings are sensitive to how patient withdrawal is handled.

Adequately power studies

Many of the studies meta-analyzed had very small sample sizes. While one of the benefits of meta-analysis is that a synthesis of inadequately powered studies can yield interesting findings, such meta-analyses require large numbers of studies in order to make conclusive findings. Researchers should make sure to power their efficacy studies appropriately.

Report L-dopa usage

The number of patients who receive L-dopa, and their doses, should be clearly stated. Many studies mentioned whether L-dopa treatment was allowed, and failed to report how many patients needed such treatment, or what their average dose was. Given that most treatments incorporate L-dopa into the regimen, and given that an important treatment outcome is whether an additional drug allows for a decrease in L-dopa dose, data regarding actual L-dopa usage are quite important in evaluation.

Include patients with comorbidities in clinical trials

In clinical practice, clinicians see patients with numerous comorbidities in addition to PD. As nearly all of the studies excluded patients with serious illnesses, the generalizability of study results is limited.

Include more elderly patients and members of different racial and ethnic groups in clinical trials

As the body of evidence increases in size, the power to detect difference in efficacy of treatment based on certain characteristics increases. More detailed description of patients enrolled in studies could help researchers to identify which treatments may be more efficacious in patients of different age, gender, or ethnic background.

Perform studies that include patients with younger onset of disease

Only three of the 356 treatment arms in the database reported mean age of disease onset as less than 50. While PD is mainly a disease of the elderly, it does occur in young patients as well, and it would be inappropriate to assume that patients with early onset of PD should necessarily be treated the same as patients with older onset of PD. More studies of younger patients are needed to determine whether different treatment is appropriate in this population.

Evaluate use of combinations of tests in diagnosing PD

Preliminary evidence suggests that the PD test battery may be helpful in diagnosing PD. More research should be done looking at combinations of tests for diagnosing PD.

Improve quality and duration of studies of ancillary treatments for PD

Further studies of PT, OT, speech therapy, and other nonpharmacologic and nonsurgical modalities should be of longer duration and should measure standardized, clinically meaningful outcomes.

Report family perceptions relating to patient care

Families are one of the most important resources for managing patients. They play an important role in the results of an intervention by their participation as well as their interpretation of the success. Family caregiver perceptions should be included in research as an independent variable and should be included systematically as an important endpoint.

Continue research on genetic components of PD risk

Important new developments in genetic susceptibility for PD are likely to have a major impact on the diagnosis and management of PD. Information on these topics should be collected and included in an update of this systematic review. Studies of genetic abnormalities in PD patients should continue, to help identify which patients are appropriate for genetic testing.

Perform long-term studies on efficacy of surgical procedures

The literature indicates that research is needed on the efficacy of surgical outcomes in patients 65 years of age and over. The literature also indicates that research is needed to evaluate long-term efficacy and safety in the areas of DBS and tissue transplantation.

Unified Parkinson Disease Rating Scale (UPDRS)¹

The UPDRS is a rating tool to follow the longitudinal course of Parkinson's Disease. A total of 199 points are possible. 199 represents the worst (total) disability, 0 indicates no disability.

UPDRS is made up of three distinct subscales:

1. Mentation, behavior, and mood

2. Activities of daily living (ADL) during “off” and “on” periods

3. Motor function during “on” periods

A fourth subscale is also sometimes used:

1. IV. Complications of therapy (In the past week)

Sections composing each subscale are usually 0–4 points.

These scores are calculated by interviewing the patient. Some sections require multiple grades assigned to each extremity.

AIMS Score (Abnormal Involuntary Movements Scale)²

This scale requires the examiner to observe the patient sitting quietly at rest and again while the patient carries out selected motor tasks (mouth opening, tongue protrusion, finger taps, and walking, among others). Seven body areas are rated: muscles of facial expression, lips and perioral area, jaw, tongue, upper and lower extremities, and trunk. A five-point scheme ranging from 0 (normal) to 4 (severe) is used to assess each body part. The worst dyskinesias seen in each body part are rated for the intensity of the movement and the chosen rating score is reduced by one point if that body region has dyskinesias during the quiet rest phase of the observation. There are also three global rating scales to complete: overall severity, incapacitation for the patient, and the patient's awareness of the dyskinesias. Finally, two interview questions for the patient concentrate on dental hygiene and the wearing of dentures.

Activities of Daily Living (ADL)³

The ADL scale measures the impact of PD on 14 categories, including:

• Speech

• Salivation

• Swallowing

• Handwriting

• Cutting food and handling utensils

• Dressing

• Hygiene

• Turning in bed and adjusting bedclothes

• Falling

• Freezing when walking

• Walking

• Left-sided tremor

• Right-sided tremor

• Sensory complaints.

Each category is scored on a 0–4 scale, with 0 indicating normal or unaffected functioning, and 4 signifying a patient who is helpless or non-ambulatory. For example, the response scale for cutting food and handling utensils is as follows:

• 0 = Normal

• 1 = Somewhat slow and clumsy, but no help needed

• 2 = Can cut most foods, although clumsy and slow; some help needed

• 3 = Food must be cut by someone, but can still feed slowly

• 4 = Needs to be fed

The scores for the 14 categories are summed to give an overall ADL score. The overall score ranges from 0 to 56, with higher scores reflecting greater disability and the need for assistance.

Barthel Index⁴

Full credit is not given for an activity if the patient needs even minimal help/supervision. A score of 0 is given when patient cannot meet criteria as defined.

1. Feeding

   1. (10 pts). Independent; feeds self from tray or table; can put on assistive device if needed; accomplishes feeding in reasonable time.

   2. (5 pts). Assistance necessary with cutting food, etc.

   3. (0 pts). Cannot meet criteria

2. Moving (from wheelchair to bed and return)

   1. (15 pts). Independent in all phases of this activity.

   2. (10 pts). Minimal help needed or patient needs to be reminded or supervised for safety of 1 or more parts of this activity.

   3. (5 pts). Patient can come to sitting position without help of second person but needs to be lifted out of bed and assisted with transfers.

   4. (0 pts). Cannot meet criteria

3. Personal Toilet

   1. (5pts). Can wash hands, face; combs hair, cleans teeth. Can shave (males) or apply makeup (females) without assistance; females need not brain or style hair.

   2. (0 pts). Cannot meet criteria

4. Getting On and Off Toilet

   1. (10 pts). Able to get on and off toilet, fastens/unfastens clothes, can use toilet paper without assistance. May use wall bar or other support if needed; if bedpan necessary patient can place it on chair, empty, and clean it.

   2. (5 pts). Needs help because of imbalance or other problems with clothes or toilet paper.

   3. (0 pts). Cannot meet criteria

5. Bathing Self

   1. (5 pts). May use bath tub, shower or sponge bath. Patient must be able to perform all functions without another person being present.

   2. (0 pts). Cannot meet criteria

6. Walking on Level Surface

   1. (15 pts). Patient can walk at least 50 yards without assistance or supervision; may use braces, prostheses, crutches, canes, or walkerette but not a rolling walker. Must be able to lock/unlock braces, assume standing or seated position, get mechanical aids into position for use and dispose of them when seated (putting on and off braces should be scored under dressing). 15

   2. (10pts). Assistance needed to perform above activities, but can walk 50 yards with little help.

   3. (0 pts). Cannot meet criteria

7. Propelling a Wheelchair

   Do not score this item if patient gets score for walking.

   1. (5 pts). Patient cannot ambulate but can propel wheelchair independently; can go around corners, turn around maneuver chair to table, bed toilet, etc. Must be able to push chair 50 yards.

   2. (0 pts). Cannot meet criteria

8. Ascending and Descending Stairs

   1. (10 pts). Able to go up and down flight of stairs safely without supervision using canes, handrails, or crutches when needed and can carry these items as ascending/descending.

   2. (5 pts). Needs help with or supervision of any of the above items.

   3. (0 pts). Cannot meet criteria

9. Dressing/Undressing

   1. (10 pts). Able to put on, fasten and remove all clothing; ties shoelaces unless necessary adaptions used. Activity includes fastening braces and corsets when prescribed; suspenders, loafer shoes and dresses opening in the front may be used when necessary.

   2. (5 pts). Needs help putting on, fastening, or removing clothing; must accomplish at least half of task alone within reasonable time; women need not be scored on use of brassiere or girdle unless prescribed.

   3. (0 pts). Cannot meet criteria

10. Continence of Bowels

    1. (10 pts). Able to control bowels and have no accidents. Can use a suppository or take an enema when necessary (as for spinal cord injury patients who have had bowel training)

    2. (5 pts). Needs help in using a suppository or taking an enema or has occasional accidents.

    3. (0 pts). Cannot meet criteria

11. Controlling Bladder

    1. (10 pts). Able to control bladder day and night. Spinal injury patients must be able to put on external devices and leg bags independently, clean and empty bag, and must stay dry day and night.

    2. (5 pts). Occasional accidents occur, cannot wait for bed pan, does not get to toilet in time or needs help with external device.

    3. C(0 pts). Cannot meet criteria.

Beck Depression Inventory⁵

This is a twenty question survey to be completed by the patient. Answers are scored on 0 to 3 scale, 0 = minimal, and 3 = severe.

1. Sadness

2. Hopelessness

3. Past failure

4. Anhedonia

5. Guilt

6. Punishment

7. Self-dislike

8. Self-blame

9. Suicidal thoughts

10. Crying

11. Agitation

12. Loss of interest in activities

13. Indecisiveness

14. Worthlessness

15. Loss of energy

16. Insomnia

17. Irritability

18. Decreased appetite

19. Diminished concentration

20. Fatigue

21. Lack of interest in sex

<15 = Mild Depression

15–30 = Moderate Depression

>30 = Severe Depression

Brief Psychiatric Rating Scale (BPRS)⁶

This scale consists of 24 symptom constructs, each to be rated in a 7-point scale of severity ranging from 1 (not present) to 7 (extremely severe). Total score ranges from 24–168, with higher scores indicating more severe psychosis.

1. Somatic concern

2. Anxiety

3. Depression

4. Suicidality

5. Guilt

6. Elated

7. Grandiosity

8. Suspiciousness

9. Hallucinations

10. Unusual thought content

11. Bizarre behavior

12. Self-neglect

13. Disorientation

14. Conceptual disorganization

15. Blunted affect

16. Emotional withdrawal

17. Motor retardation

18. Tension

19. Uncooperativeness

20. Excitement

21. Distractibility

22. Motor hyperactivity

23. Mannerisms and posturing

Columbia University Rating Scale (CURS)⁷

This scale was presented in 1970 by researchers from Columbia University who used it in their initial L-dopa trials. Total scores range from 0–65, 0 is normal and 65 is maximum disability. This scale was a modification of the Webster scale (see page C22), which was published in 1968. In addition to the activities measured in the Webster scale, this scale also measures salivation, arising from a chair, postural stability and rapid movements of fingers, hands and feet. Subsequent modifications of this scale include NYU Scale and Kings College Hospital Scale.

1. Facial Expression

   • 0 = Normal

   • 1 = Minimal hypomimia, could be normal ‘poker face’

   • 2 = Slight but definitely abnormal dimunition of facial expression

   • 3 = Moderate hypomimia

   • 4 = Masked or fixed facies with severe or complete loss of facial expression

2. Seborrhea

   • 0 = Normal

   • 1 = Greasy forehead, no dermatitis

   • 2 = Mild dermatitis, erythema, and scaling

   • 3 = Moderate dermatitis

   • 4 = Severe dermatitis

3. Sialorrhea

   • 0 = None

   • 1 = Slight but definite excess of saliva in pharynx (patients may be unaware of it); no drooling

   • 2 = Moderately excessive saliva with minimal drooling, if any

   • 3 = Marked excess of saliva with some drooling

   • 4 = Marked drooling, requiring special measures

4. Speech Disorder

   • 0 = Normal

   • 1 = Slight loss of expression, diction, and/or volume

   • 2 = Monotone, slurred but understandable

   • 3 = Marked impairment, difficult to understand

   • 4 = Unintelligible

5. Arising from chair (with straight back)

   • 0 = Normal

   • 1 = Slow

   • 2 = Pushes self up from arms or seat

   • 3 = Tends to fall back and may have to try several times but can get up without help

   • 4 = Unable to arise without help

6. Posture

   • 0 = Normal erect

   • 1 = Not quiet erect, slightly stooped, could be normal for older people

   • 2 = Moderate simian posture, definitely abnormal

   • 3 = Marked simian posture with kyphosis

   • 4 = Severe flexion with extreme abnormality of posture

7. Postural Stability (If Romberg is normal, judge response to sudden posterior displacement produced by push of sternum)

   • 0 = Normal

   • 1 = Retropulsion, but recovers unaided

   • 2 = Absence of postural response; would fall if not caught

   • 3 = Very unstable, tends to fall

   • 4 = Unable to stand without assistance

8. Gait Disturbance

   • 0 = Freely ambulatory, good stepping, turns readily

   • 1 = Walks slowly, may shuffle with short steps; no festination or propulsion

   • 2 = Walks with great difficulty, with festination, short steps; shows freezing and pulsing but requires little or no assistance

   • 3 = Severe disturbance, requires frequent assistance

   • 4 = Cannot walk, even with help

9. Tremor (Head and four limbs are scored separately; maximum score = 20.)

   • 0 = Absent

   • 1 = Slight and infrequently present

   • 2 = Moderate in amplitude but only intermittently present

   • 3 = Moderate and present most of the time

   • 4 = Marked in amplitude and present most of the time

10. Finger Dexterity (Tested in both hands; maximum score = 8; patients taps thumb with forefinger, then with each finger in rapid succession.)

    • 0 = No dysfunction

    • 1 = Slightly slow, may be normal

    • 2 = Definite dysfunction

    • 3 = Very slow with frequent errors

    • 4 = Unable to perform test

11. Succession Movements (Tested in both hands; maximum score = 8; patient taps knees alternatively with palm and dorsum of hands.)

    • 0 = No dysfunction

    • 1 = Slightly slow; may be normal

    • 2 = Definite dysfunction

    • 3 = Very slow with frequent errors

    • 4 = Unable to perform test

12. Foot Tapping (Tested in both feet; maximum sore = 8; using heel as fulcrum, patients taps floor with ball of foot.)

    • 0 = Normal

    • 1 = Slightly slow

    • 2 = Slow

    • 3 = Markedly slow

    • 4 = Unable to perform test

13. Bradykinesia (Combining both slowness and poverty of movement in general.)

    • 0 = None

    • 1 = Minimal slowness giving movement a deliberate character

    • 2 = Mild degree of slowness and poverty of movements; definitely abnormal

    • 3 = Moderate slowness; occasional hesitation on initiating movements and arrests of ongoing movements

    • 4 = Marked slowness and poverty of movement; frequent freezing and long delays in initiating movements

Dyskinesia Rating Scale⁸

Several variations of the rating scale for dyskinesia are used. This Dyskinesia Scale Score is the arithmetic mean of the intensity and duration scores, and is only assessed in the “on” state.

The intensity score is given as score and definition:

• 0 = absent

• 1 = minimal severity: patient is not aware of dyskinesias

• 2 = patient is conscious of the presence of dyskinesias but there is no interference with voluntary motor acts

• 3 = dyskinesias may impair voluntary movements but patient is normally capable of undertaking most motor tasks

• 4 = intense interference with movement control, and daily life activities are greatly limited

• 5 = violent dyskinesias, incompatible with any normal motor task

  The duration score is given as score and definition:

• 0 = absent

• 1 = only present when carrying out motor tasks

• 2 = present between 25–50% of waking hours

• 3 = present between 51–75% of waking hours

• 4 = present between 76–99% of waking hours

• 5 = continuous throughout the day, 100%

Hamilton Depression Scale (HAM-D)⁹

This is a twenty one question survey to be completed by a physician. The range is 0–64 points, higher score = more severe depression.

• 1. Depressed mood (0 to 4)

• 2. Feelings of guilt (0 to 4)

• 3. Suicide (0 to 4)

• 4. Insomnia

• • 5. Early (0 to 2)

  • 6. Middle (0 to 2)

  • 7. Late (0 to 2)

• 8. Work activities (0 to 4)

• 9. Retardation to stupor (0 to 4)

• 10. Agitation (0 to 2)

• 11. Fear (0 to 4)

• 12. Anxiety (0 to 4)

• 13. Gastrointestinal symptoms (0 to 2)

• 14. Systemic somatic symptoms (0 to 2)

• 15. Decreased libido or menstrual disturbance (0 to 2)

• 16. Hypochondiasis (0 to 4)

• 17. Weight loss (0 to 2)

• 18. Diminished insight (0 to 2)

• 19. Symptom diurnal variation (1 to 2)

• 20. Feelings of unreality (0 to 4)

• 21. Paranoid symptoms (0 to 3)

• 22. Obsessive Compulsive Symptoms (0 to 2)

10–13: Mild depression

14–17: Moderate depression

>17: Severe depression

Hoehn and Yahr Clinical Staging Scale¹⁰

Stages I–V, lower stage indicates better function.

Stage I.

Unilateral involvement only, usually with minimal or no functional impairment.

Stage II.

Bilateral or midline involvement, without impairment of balance.

Stage III.

First sign of impaired righting reflexes. This is evident by unsteadiness as the patient turns or is demonstrated when he is pushed from standing equilibrium with the feet together and eyed closed. Functionally the patient is somewhat restricted in his activities but may have some work potential depending upon the type of employment. Patients are physically capable of leading independent lives, and their disability is mild to moderate.

Stage IV.

Fully developed, severely disabling disease; the patient is still able to walk and stand unassisted but is markedly incapacitated.

Stage V.

Confinement to bed or wheelchair unless aided.

Modified Hoehn and Yahr Staging

Stage 0 = No signs of disease.

Stage 1 = Unilateral disease.

Stage 1.5 = Unilateral plus axial involvement.

Stage 2 = Bilateral disease, without impairment of balance.

Stage 2.5 = Mild bilateral disease, with recovery on pull test.

Stage 3 = Mild to moderate bilateral disease; some postural instability; physically independent.

Stage 4 = Severe disability; still able to walk or stand unassisted.

Stage 5 = Wheelchair bound or bedridden unless aided.

This rating system has been largely replaced by the Unified Parkinson's Disease Rating Scale (UPDRS).

Levodopa Equivalent Units (LEU)¹¹

Conversion formula:

100 LEU = 100 mg regular L-dopa, given with a peripheral decarboxylase inhibitor = 133 mg L-dopa plus DCI in controlled-release tablets = 10 mg bromocriptine = 1 mg pergolide mesylate.

Mini-Mental Status Exam (MMSE)¹²

Range 0–30, lower scores indicate more severe impairment.

This scale is widely used for assessing cognitive mental status. As a clinical instrument, the MMSE has been used to detect impairment, follow the course of an illness, and monitor response to treatment. While the MMSE has limited specificity with respect to individual clinical syndromes, it represents a brief, standardized method by which to grade cognitive mental status. It assesses orientation, attention, immediate and short-term recall, language, and the ability to follow simple verbal and written commands. Furthermore, it provides a total score that places the individual on a scale of cognitive function.

Northwestern University Disability Scale (NUDS or NWUDS)¹³

Clinical experience suggested that the symptoms of Parkinson's Disease make themselves felt most frequently in the areas of walking, personal hygiene, dressing, eating and feeding, and speaking. These five areas constitute the range of this scale. It was decided to assign a maximum of 20 points to each of the five sub-scales, in this way a total of 100 points is possible, so that the degree of disability may be expressed as a percentage. Lower score represents greater disability.

Phenyl Ethyl Alcohol or Detection Threshold (PEA)¹⁴

Detection threshold is a measure of the lowest concentration of a particular olfactory stimulus required to activate peripheral receptors and trigger the perception of the stimulus. To assess olfactory threshold, ascending (10^-7 -1 mol) dilutions of phenyl-ethyl-alcohol are administered; the threshold value is defined as the lowest concentration that is perceived.

Parkinson Psychosis Rating Scale (PPRS)¹⁵

This scale was designed to assess the severity of specific symptoms of levodopa-induced psychosis in patients with Parkinson's disease.

Visual Hallucinations

1. Absent

2. Mild: Occasional; complete or partial insight; nonthreatening

3. Moderate: Frequent; absence of full insight; can be convinced; may be threatening

4. Severe: Persisitent hallucinations; no insight; associated with heightened emotional tone, agitation, agression

Illusions and Misidentification of Persons

1. Absent

2. Mild: Occurring infrequently

3. Moderate: Occurring very often

4. Severe: Occurring persistently

Paranoid Ideation (persecutory and/or jealous type)

1. Absent

2. Mild: Associated with suspiciousness

3. Moderate: Associated with tension and excitement

4. Severe: Accusations of family members, aggression and/or lack of cooperation (i.e., refusal to eat and/or take medication)

Sleep Disturbances

1. Absent

2. Mild: Associated with anxiety

3. Moderate: Night terrors with recurrent awakening and feeling of danger

4. Severe: Nightmares with recurrent awakenings, associated with agitation and confusion

Confusion

1. Absent

2. Mild: Disorientation in time/place/person

3. Moderate: Confusion combined with impaired attention/concentration/ registration/recall/interruption of goal-directed actions

4. Severe: Very confused with or without delirium

Sexual Preoccupation

1. Absent

2. Mild: Thoughts, dreams, worry about sexual competence

3. Moderate: Increased demand for sexual activity

4. Severe: Violent sexual impulsiveness

8–12: Mild disease

13–18: Moderate disease

19–24: Severe disease

Proposed Diagnostic Criteria for Parkinson's Disease¹⁶

Criteria for POSSIBLE diagnosis of Parkinson disease:

Criteria for PROBABLE diagnosis of Parkinson disease:

At least 3 of the 4 features in Group A are present

AND

None of the features in Group B is present (note: symptom duration of at least 3 years is necessary to meet this requirement)

AND

Substantial and sustained response to levodopa or a dopamine agonist has been documented

Criteria for DEFINITE diagnosis of Parkinson disease:

All criteria for POSSIBLE Parkinson disease are met

AND

Histopathologic confirmation of the diagnosis is obtained at autopsy***

*Group A features: Characteristic of Parkinson disease

1. Resting tremor

2. Bradykinesia

3. Rigidity

4. Asymmetric onset

**Group B features: Suggestive of alternative diagnoses

1. Prominent postural instability in the first 3 years after symptom onset

2. Freezing phenomena in the first 3 years

3. Hallucinations unrelated to medications in the first 3 years

4. Dementia preceding motor symptoms or in the first year

5. Supranuclear gaze palsy (other than restriction of upward gaze) or slowing of vertical saccades

6. Severe, symptomatic dysautonomia unrelated to medications

7. Documentation of a condition known to produce parkinsonism and plausibly connected to the patient's symptoms (such as suitably located focal brain lesions or neuroleptic use within the past 6 months)

***Proposed criteria for histopathologic confirmation of Parkinson disease:

1. Substantial nerve cell depletion with accompanying gliosis in the substantia nigra

2. At least 1 Lewy body in the substantia nigra or in the locus ceruleus (note: it may be necessary to examine up to 4 nonoverlapping sections in each of these areas before concluding that Lewy bodies are absent)

3. No pathologic evidence for other diseases that produce parkinsonism (eg, progressive supranuclear palsy, multiple system atrophy, cortical-basal ganglionic degenration)

Schwab & England Activities of Daily Living Scale (S&E) or (SEADL)¹⁷

Range 0–100%, with higher % meaning less severe disease

The rating can be assigned by the rater or by the patient.

• 100%-Completely independent. Able to do all chores without slowness, difficulty, or impairment.

• 90%-Completely independent. Able to do all chores with some slowness, difficulty, or impairment. May take twice as long.

• 80%-Independent in most chores. Takes twice as long. Conscious of difficulty and slowing.

• 70%-Not completely independent. More difficulty with chores. 3 to 4X along on chores for some. May take large part of day for chores.

• 60%-Some dependency. Can do most chores, but very slowly and with much effort. Errors, some impossible.

• 50%-More dependant. Help with 1/2 of chores. Difficulty with everything.

• 40%-Very dependant. Can assist with all chores but few alone.

• 30%-With effort, now and then does a few chores alone of begins alone. Much help needed.

• 20%-Nothing alone. Can do some slight help with some chores. Severe invalid.

• 10%-Totally dependant, helpless.

• 0%-Vegetative functions such as swallowing, bladder and bowel function are not functioning. Bedridden.

Sickness Impact Profile (SIP)¹⁸

The Sickness Impact Profile (SIP) is a general quality of life scale. It consists of 136 items (statements) which measure 12 distinct domains of quality of life:

• Ambulation

• Movement and mobility

• Body care

• Social interaction

• Communication

• Alertness

• Emotional behavior

• Sleep

• Eating

• Work

• Household management

• Recreation

The SIP can be administered by an interviewer or by the patients themselves. Although it is easy to administer and score, it is relatively time-consuming, taking approximately 30 minutes to complete.

Patients identify those statements which describe their experience. Each item is weighted depending on the severity of dysfunction. For each category, the scores are summed and expressed as a percentage of the maximum score possible. Higher scores represent greater dysfunction. Although scores can be calculated for each of the 12 individual domains, three summary scores are typically calculated and reported: total score (includes all domains), a physical score (ambulation, body care, and movement and mobility), and a psychosocial score (emotional behavior, social interaction, alertness, and communication).

UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria¹⁹

1. Diagnosis of PARKINSONIAN SYMPTOMS:

   BRADYKINESIA (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions).

   And at least one of the following:

   1. a. muscular rigidity

   2. b. 4–6 Hz rest tremor

   3. c. postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction.

2. Exclusion criteria for Parkinson's disease:

   1. history of repeated strokes with stepwise progression of Parkinsonian features

   2. history of repeated head injury

   3. history of definite encephalitis

   4. oculogyric crises

   5. neuroleptic treatment at onset of symptoms

   6. more than one affected relative

   7. sustained remission

   8. strictly unilateral features after three years

   9. supranuclear gaze palsy

   10. cerebellar signs

   11. early severe autonomic involvement

   12. early severe dementia with disturbances of memory, language and praxis

   13. Babinski sign

   14. presence of a cerebral tumor or communicating hydrocephalus on CT scan

   15. negative response to large doses of levodopa (if malabsorption excluded)

   16. MPTP exposure

3. Supportive prospective criteria for PARKINSON'S DISEASE. Three or more required for diagnosis of definite Parkinson's Disease.

   1. unilateral onset

   2. rest tremor present

   3. progressive disorder

   4. persistent asymmetry affecting the site of onset most

   5. excellent response (70–100%) to levodopa

   6. severe levodopa-induced chorea

   7. levodopa response for 5 years or more

   8. clinical course of 10 years or more

University of Pennsylvania Smell Identification Test (UPSIT)¹⁴

This is a standardized tool that has been widely used in the evaluation of patients affected by neurodegenerative disorders. This “scratch and sniff” test consists of 40 multiple-choice items. The range of scores is 0–40, 40 being the best score. The patient is required to mark one of the four alternatives even if no smell is perceived. To establish the meaning of a given individual's test score, it is compared to scores from normal persons of equivalent age and gender using tables providing an easy-to-interpret measure of an individual's performance. In this classification scheme, anosmia is defined as total inability to perceive qualitative odor sensations, whereas microsmia is defined operationally as decreased ability to smell. Microsmia can be further subdivided into “severe,” “moderate,” and “mild” classes. The 40-item UPSIT can be used in both clinical and experimental settings to test patients affected by PD and related disorders.

Webster's Parkinson's Disease Rating Scale (WPDRS)²⁰

This scale was developed as a simple rating scale that can be used to evaluate the degree of total parkinsonian disabilities. It applies a gross clinical rating to each of the 10 listed items, assigning value rating of 0–3 for each item, where 0 = no involvement and 1, 2, and 3 are equated to early, moderate, and severe disease, respectively. Scores range from 0 to 30, and decline represents decrease in severity of PD signs. Values of 1 to 10 indicate early illness; 11 to 20, moderate disability; and 21 to 30, severe or advanced disease.

Bradykinesia of Hands - Including Handwriting

• 0 = No involvement.

• 1 = Detectable slowing of the supination-pronation rate, evidenced by beginning difficulty in handling tools, buttoning clothes, and with handwriting.

• 2 = Moderate slowing of supination-pronation rate, one or both sides, evidenced by moderate impairment of hand function. Handwriting is greatly impaired, micrographia present.

• 3 = Severe slowing of supination-pronation rate. Unable to write or button clothes. Marked difficulty in handling utensils.

Rigidity

• 0 = Non-detectable.

• 1 = Detectable rigidity in neck and shoulders. Activation phenomenon is present. One or both arms show mild, negative, resting rigidity.

• 2 = Moderate rigidity in neck and shoulders. Resting rigidity is positive when patient not on medication.

• 3 = Severe rigidity in neck and shoulders. Resting rigidity cannot be reversed by medication.

Posture

• 0 = Normal posture. Head flexed forward less than 4 inches.

• 1 = Beginning poker spine. Head flexed forward up to 5 inches.

• 2 = Beginning arm flexion. Head flexed forward up to 6 inches. One or both arms raised but still below waist.

• 3 = Onset of simian posture. Head flexed forward more than 6 inches. One or both hands elevated above the waist. Sharp flexion of hand, beginning interphalangeal extension. Beginning flexion of knees.

Upper Extremity Swing

• 0 = Swings both arms well.

• 1 = One arm definitely decreased in amount of swing.

• 2 = One arm fails to swing.

• 3 = Both arms fail to swing.

Gait

• 0 = Steps out well with 18–30 inch stride. Turns about effortlessly.

• 1 = Gait shortened to 12–18 inch stride. Beginning to strike one heel. Turn around time slowing. Requires several steps.

• 2 = Stride moderately shortened - now 6–12 inches. Both heels beginning to strike floor.

• 3 = Onset of shuffling gait, steps less than 3 inches. Occasional stuttering-type or blocking gait. Walks on toes-turns around very slowly.

Tremor

• 0 = No detectable tremor found.

• 1 = Less than one inch of peak-to-peak tremor movement observed in limbs or head at rest or in either hand while walking or during finger to nose testing.

• 2 = Maximum tremor envelope fails to exceed 4 inches. Tremor is severe but not constant and patient retains some control of hands.

• 3 = Tremor envelope exceeds 4 inches. Tremor is constant and severe. Patient cannot get free of tremor while awake unless it is a pure cerebellar type. Writing and feeding himself is impossible.

Facies

• 0 = Normal. Full animation. No stare

• 1 = Detectable immobility. Mouth remains closed. Beginning features of anxiety or depression.

• 2 = Moderate immobility. Emotion breaks through at markedly increased threshold. Lips parted some of the time. Moderate appearance of anxiety or depression. Drooling may be present.

• 3 = Frozen facies. Mouth open ¼ inches or more. Drooling may be severe.

Seborrhea

• 0 = None.

• 1 = Increased perspiration, secretion remaining thin.

• 2 = Obvious oiliness present. Secretion much thicker.

• 3 = Marked seborrhea, entire face and head covered by thick secretion.

Speech

• 0 = Clear, loud, resonant, easily understood.

• 1 = Beginning of hoarseness with loss of inflection and resonance. Good volume and still easily understood.

• 2 = Moderate hoarseness and weakness. Constant monotone, unvaried pitch. Beginning of dysarthria, hesitancy, stuttering, difficult to understand.

• 3 = Marked harshness and weakness. Very difficult to hear and to understand.

Self-Care

• 0 = No impairment.

• 1 = Still provides full self-care but rate of dressing definitely impeded. Able to live alone and often still employable.

• 2 = Requires help in certain critical areas, such as turning in bed, rising from chairs, etc. Very slow in performing most activities but manages by taking much time.

• 3 = Continuously disabled. Unable to dress, feed himself, or walk alone.

Objective

To conduct a systematic review of the literature to assess the quantity and quality of available evidence regarding diagnosis and treatment of Parkinson's disease (PD).

The following 12 specific questions will be addressed in the systematic review:

1. What are the results of neuroimaging studies (CT, MRI, PET, SPECT) or other diagnostic tests in determining the diagnosis of PD?

2. What are the results of L-dopa challenge in PD? What is the accuracy, sensitivity and specificity of this test for diagnosing PD?

3. What is the efficacy of medication used to treat early PD? What is the efficacy of initial treatment with L-dopa vs. a dopamine agonist?

4. What is the evidence for neuroprotection with selegiline, Vitamin E, or Vitamin C?

5. 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?

6. What are the outcomes of treatment for patients who experience motor fluctuations and/or dyskinesias while taking L-Dopa?

7. What serious adverse events are associated with medications used to treat PD?

8. What are the outcomes of treatment of PD patients with psychotic symptoms or non-psychotic behavioral and psychological dysfunction?

9. When is surgery performed on PD patients? What types of surgeries are performed and what are their outcomes?

10. What are the outcomes of rehabilitation in PD?

11. What are the results of recent review articles regarding diagnosis and genetic testing in PD.

12. 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, co-morbidities, gender, race, ethnicity, or income level?

Background

The topic “Parkinson's Disease” was nominated by the American Academy of Neurology (AAN) to assist in answering several key questions of diagnosis and management of patients with this disease.

PD is a progressive disorder of the central nervous system characterized clinically by tremor, rigidity, and bradykinesia. PD affects 1% of the population over age 60, and up to 2.5% over age 70.¹ Mayo Clinic researchers have estimated the lifetime risk of developing PD at 7.5%.² This could have serious health and economic implications as the baby boom generation ages. Annual societal costs related to PD were estimated in 1994 to be $20 billion,¹ and are likely to be much higher now and in the future.

The design and interpretation of all prevention and treatment studies are made more difficult by the fact that PD has a variable and unpredictable clinical course. Furthermore, numerous outcome measures and formats have been developed, which complicate efforts to pool results across studies.³

The twelve key questions can be broken down into 4 basic categories: diagnosis, pharmacological treatment, (early and late), surgical treatment, and other modalities.

Not all “parkinsonism” is PD. The incidence of misdiagnosis has been estimated at up to 24% of patients.⁴ The goal of this portion of the task order is to establish the evidence base of clinical trials that present sensitivity and specificity data pertaining to clinical and neuroimaging tests that are used to diagnose PD.

Treatment may be subdivided into early, overall, and late treatment, although there is significant overlap between the categories.

The standard treatment for PD has been levodopa (L-DOPA), which, once it reaches the brain, is converted to dopamine to correct the deficiency which characterizes PD. L-DOPA has been a mainstay of therapy since its introduction 40 years ago. However, questions of when to initiate therapy, and long term neurotoxicity, remain chief concerns to patients and practitioners. Several other drugs are often used, either in combination with L-DOPA to enhance its effects, or instead of L-DOPA, when its efficacy wanes or when response fluctuations or toxicity become unmanageable. These can be categorized chiefly as anticholinergics or dopamine agonists. Although there were very few new agents introduced for nearly 3 decades after the introduction of L-DOPA, several new agents, such as new dopamine agonists and the catechol-O-methyl transferase (COMT) inhibitors, with different mechanisms of action have recently been approved by the FDA. None, however, including L-DOPA, have been shown to impact the natural history of PD. They are useful for symptom control only, primarily motor dysfunction.

Research into agents capable of preventing or slowing progression of the disease is currently underway. These include antioxidants such as Vitamin E and coenzyme Q-10, the monoamine oxidase inhibitors selegiline and rasagiline, and glutamate antagonists such as riluzole.

The role of invasive methods such as pallidotomy and deep brain stimulation as additional treatment options require expert assessment. Neural growth factors and neural cell implants (fetal cells from humans or animals, and genetically engineered stem cells) are the focus of increasingly intense research efforts.

The safe and effective use of co-medications to treat depression, psychosis, and cognitive changes of PD is also the subject of considerable new research.

The role of non-pharmacologic interventions, such as physical rehabilitation therapy, remains uncertain.

The goal of this portion of the task order is to review the evidence base of clinical trials pertaining to the treatment of PD. Given that PD is a chronic condition, and that patients stay on medications for years, the most clinically relevant data will come from long-term trials. For this reason, only trials of greater than or equal to 24 weeks duration will be accepted. Furthermore, the most useful data for analysis concerning pharmacological treatment of PD will be in randomized controlled trials (RCTs); therefore, only RCTs will be accepted for studies pertaining to pharmacological treatment. Studies pertaining to surgery and rehabilitation will not be limited to RCTs.

Genetic testing of relatives of patients with early onset PD is another area of current controversy. This is an area where there would be limited information to be derived from RCTs or even clinical trials; therefore, review articles pertaining to Genetics and PD will be reviewed and summarized for the Final Report.

Methods

MetaWorks will apply the latest and established best methods in the evolving science of review research.^5–9

A flow diagram outlining the systematic review process is located in Attachment A.

The following tasks will proceed sequentially, and a project timeline has previously been submitted.

Statistical Analyses

Statistical analyses will be performed as the data permit. The search criteria for the 12 questions have been restricted to allow us to select only those studies most likely to contribute data that could be analyzable. Further details of analysis will be developed later in an analysis plan.

However, we also note that several questions are related to management of patients with PD. Studies in the literature addressing clinical practice or medical management are typically very limited, and will probably only allow for descriptive analysis.

Synthesis & Reporting

This task involves bringing together all of the evidence into a coherent report and presenting the raw data in a tabular format as well as performing both qualitative and quantitative data syntheses as data permit and as protocol objectives require.

Meta Works will prepare and submit to the TOO evidence tables for each step in the causal pathways, as data permits.

Technical Experts

MetaWorks will identify a TEP through networking with our nominating partner, our academic collaborators, professional organizations and relevant consumer groups. The TEP will be composed of six to eight individuals with specific expertise in general neurology, PD, neurosurgery, internal medicine, and at least one consumer representative. The TEP will review and provide timely feedback to all draft Work Plans and deliverables on an ongoing basis. MetaWorks will consult with these individuals as appropriate in carrying out the tasks required under this task order.

Peer Review

In addition to the TEP described above, MetaWorks will identify up to 12 additional individuals who are experts in the topic area, to serve as peer reviewers of the draft evidence report. These individuals will be chosen from the fields of neurology, general practice and internal medicine, as well as consumers who have experienced PD. These individuals will be sought from professional organizations which have been instrumental in developing guidelines in aspects of PD treatment or diagnosis, such as the American Academy of Neurology. Consumers will be sought from consumer groups such as the National Parkinson Foundation Inc., the Parkinson's Disease Foundation, Inc., the Parkinson's Institute and others active in PD initiatives.

Names of potential reviewers will come from our technical expert panel, the nominating partner, LDI, AHRQ, and from the literature being reviewed by the project team. The profile of the peer review group will be similar to that of the TEP, and may also include representatives from manufacturers of the medications and diagnostics included in the evidence report.

A copy of the draft evidence report will be sent to each peer reviewer, along with a reviewer's form to be completed and returned to MetaWorks. This form will contain a checklist of items to be assessed as well as provide room for free-form text comments. The form will be pre-screened by the TEP and the TOO prior to being sent to the peer reviewers. Reviewers will be given 3 weeks to respond, after which they will be contacted. All feedback will be stored in a project folder at MetaWorks. A statement of response to each reviewer's comments will be prepared and stored with each reviewer's comments. This response will also be returned to the reviewer.

A summary of the main comments and responses will be prepared and shared with the TOO. Reviewer comments and additional analyses and text resulting from the response to reviewer critique will be incorporated into the final iteration of the evidence report.

Implementation and Dissemination

An implementation plan will be prepared with the nominator, the American Academy of Neurology. Dissemination will occur via AHRQ. MetaWorks/LDI will prepare a manuscript describing key aspects of the work for publication in peer reviewed journals. Abstracts of same may also be submitted for presentation at professional meetings.

References

Work Plan Acceptance

Attachment A: MetaWorks Flow Diagram

Attachment B: Levels of Evidence

1. Evidence based on randomized controlled clinical trials (or meta-analysis of such trials) of adequate size to ensure a low risk of incorporating false-positive or false-negative results.

2. Evidence based on randomized controlled trials that are too small to provide level I evidence. These may show either positive trends that are not statistically significant or no trends and are associated with a high risk of false-negative results.

3. Evidence based on nonrandomized, controlled or cohort studies, case series, case-controlled studies or cross-sectional studies.

4. Evidence based on the opinion of respected authorities or that of expert committees as indicated in published consensus conferences or guidelines.

5. Evidence which expresses the opinion of those individuals who have written and reviewed these guidelines, based on their experience, knowledge of the relevant literature and discussion with their peers.

These 5 levels of evidence do not directly describe the quality or credibility of evidence. Rather, they indicate the nature of the evidence being used. In general, a randomized, controlled trial has the greatest credibility (level I); however, it may have defects that diminish its value, and these should be noted. Evidence that is based on too few observations to give a statistically significant result is classified as level II. In general, level III studies carry less credibility than level I or II studies, but credibility is increased when consistent results are obtained from several level III studies carried out at different times and in different places.

Decisions must often be made in the absence of published evidence. In these situations it is necessary to use the opinion of experts based on their knowledge and clinical experience. All such evidence is classified as “opinion” (levels IV and V). Distinction is made between the published opinion of authorities (level IV) and the opinion of those who have contributed to these guidelines (level V). However, it should be noted that by the time level V evidence has gone through the exhaustive consensus-building process used in the preparation of these guidelines, it has achieved a level of credibility that is at least equivalent to level IV evidence.

from: The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ 1998:158

Attachment C: Jadad Quality Score Assessment

Please read the articles and try to answer the following questions (see attached instructions):

1. Was the study described as randomized (this includes the use of words such as randomly, random, and randomization)?

2. Was the study described as double-blind?

3. Was there a description of withdrawals and drop outs?

Scoring the items:

Either give a score of 1 point for each ‘yes’ or 0 for each ‘no’. There are no in-between marks.

Give an additional point if:	For question 1, the method to generate the sequence of randomization was described and it was appropriate (table of random numbers, computer generated, coin tossing, etc.)
and/or:	If for question 2 the method of double-blinding was described and it was appropriate (identical placebo, active placebo, dummy, etc.)
Deduct 1 point if:	For question 1, the method to generate the sequence of randomization was described and it was inappropriate (patients were allocated alternately, or according to date of birth, hospital number, etc.)
and/or:	For question 2 the study was described as double-blind but the method was inappropriate (e.g., comparison of tablet vs.injection with no double dummy)

Objective

The objective of this Task Order is to conduct a systematic review of the literature to assess the quantity and quality of available evidence regarding diagnosis and treatment of Parkinson's Disease (PD).

Project Status to Date

Thirteen key questions were posed by the Agency for Healthcare Research and Quality (AHRQ) and the American Academy of Neurology (AAN). After a preliminary review of the literature, MetaWorks and the Leonard Davis Institute (LDI) worked collaboratively to modify the original key questions, making them more amenable to answers by systematic literature review. The content of the revised questions is unchanged; however, they are now worded differently. In general, where the original questions asked about what kinds of testing or treatment “should” be done, or “what is the role” of a particular test or treatment, the modified questions ask “what are the results,” or “what is the evidence.”

Causal pathways relevant to the key objectives of this project were developed to help guide the literature review. Many of the elements included in the causal pathways are controversial, particularly the use of MAO-B inhibitors for neuroprotection, and the question of when L-Dopa should be started. One of the goals of this Task Order is to identify the weight of the available evidence regarding these and other issues.

After numerous discussions with representatives from AHRQ, AAN, and LDI, final decisions were made regarding the composition of the Technical Expert Panel (TEP) for this project. The TEP is composed of four neurologists/PD experts, one neurosurgeon/PD expert, one general neurologist, one general internist, and one PD patient, who is a cardiologist. This multidisciplinary approach will provide valuable feedback from a variety of perspectives.

The Work Plan and Causal Pathways were sent to all members of the TEP for review on September 19, 2000. Feedback was requested by October 16, 2000, and has been received from 7 of the 8 members of the TEP.

Based on preliminary assessment of the literature, relevant databases, input from collaborating partners, and feedback received from the TEP, the Work Plan and the Causal Pathways have been modified accordingly.

Twenty people have been invited to participate in the project as Peer Reviewers of our draft evidence report. To date, seven have accepted. More potential peer reviewers are being contacted, with an ultimate goal of at least twelve peer reviewers, from multiple disciplines.

To date, 957 abstracts have been identified from the Medline search, 397 from the Current Contents search, and 590 from the Cochrane Library search, yielding a total of 1,944 citations. After 614 duplicates were identified, a total of 1,330 abstracts were downloaded into Reference Manager at MetaWorks.

Level I screening of all abstracts for exclusion criteria has been completed, and resulted in 560 potential accepted studies. Full papers are being retrieved for all accepted abstracts.

Level 2 screening of the full articles for inclusion and exclusion criteria is nearly complete. All studies that are rejected at Level 2 are required to be reviewed by a second researcher, to insure that there is 100% consensus regarding which studies are to be rejected. Manual bibliography checks of all accepted studies are currently underway, in search of potential accepts that may not have been identified by electronic searches.

After Level 2 screening is complete, data extraction of the accepted articles will commence. The Revised Work Plan describes, in great detail, the remaining steps in the systematic review process. The draft Evidence Report will be submitted to AHRQ by July 2, 2001.

Causal Pathway: Diagnosis of Parkinson's Disease Legends

¹Principal Symptoms Present:

*Two or more present, one of which is resting tremor or bradykinesia

1. Rigidity affecting one or more limbs, cogwheel in nature

2. Resting, postural tremor most often asymmetrical, 3–7 Hz, hands preferentially affected

3. Bradykinesia (akinesia, hypokinesia)

4. Postural/Gait disturbance often appears late in disease

²Principal Symptoms May Be Present:

*One or more may be present

1. Rigidity affecting one or more limbs, may or may not be cogwheel in nature

2. Tremor may be asymmetrical, but frequently bilateral and higher frequency (5–12 Hz). Head, voice, tongue, palate, leg and/or trunk tremor may occur

3. Bradykinesia

4. Postural/Gait disturbance

³Secondary Symptoms May Be Present:

1. Psychiatric symptoms (depression, anxiety, psyshosis)

2. Autonomic dysfunction (sexual dysfunction, orthostatic hypotension)

3. Gastrointestinal dysfunction (constipation, weight loss, dysphagia)

4. Urologic dysfunction

5. Speech and swallowing problems

6. Falls

7. Sleep disturbances

8. Visual disturbances

9. Cognitive dysfunction (dementia)

10. Olfactory dysfunction

11. Difficulty writing

⁴Secondary Symptoms May Be Present:

(as above)

⁵Radiology/Laboratory Tests not as useful in diagnosis:

Results of computed tomography (CT), magnetic resonance imaging (MRI), cerebrospinal fluid analysis, and electroencephalography (EEG) are usually normal and of little diagnostic asistance.

Positron-emission tomography (PET scan) using radio-labeled dopa may be helpful in confirming a diagnosis.

⁶Radiology/Laboratory Tests helpful in diagnosis of other conditions:

CT, MRI useful to eliminating other disease processes such as tumors, strokes, hydrocephalus, etc. Laboratory investigation should be performed when atypical symptoms exist, there is a strong family history or early age of onset.

Causal Pathway: Treatment of Parkinson's Disease Legends

For all medications, start with low dose, increase dose slowly until:

symptoms abate OR

maximum dose is reached OR

intolerable side effects occur.

Only make one medication change at a time.

¹ MAO-B Inhibitors: Monoamine oxidase B inhibitors (for neuroprotection):

² Seligiline, Rasagiline

³ Dopamine Agonists : Bromocriptine, Pergolide, Pramipexole, Andropinrole,

⁴ Cabergoline, Ropinirole, Apomorphine (activate dopamine receptors)

⁵ Other Modalities: Rehabilitation, Physical Therapy, Occupational Therapy, Speech Therapy, Counseling, Dietary Changes.

⁶ L-DOPA/PDI: Levodopa/Carbidopa (peripheral decarboxylase inhibitor)

⁷ Disabling tremor: may occur any time during the course of the disease.

⁸ COMT inhibitors: Catechol-O-methylransferase inhibitor: Tolcapone, Entacapone

⁹ Anticholinergic agents: Trihexylphenidyl, Benztropine, Procyclidine

¹⁰ Surgical interventions: pallidotomy, thalamotomy, deep brain stimulation, fetal nigral implants.

¹¹ Atypical Neuroleptic agents: Clozapine, Olanzapine, Quietipine

Many aspects of this causal pathway are controversial, including when to initiate therapy with L-DOPA, and when to use other agents. Monitoring for toxicities should be done throughout treatment, and is not specifically mentioned in this pathway. Similarly, physical therapy, counseling, speech therapy, and rehabilitation should start as soon as PD is diagnosed, and continue indefinitely.

The causal pathways are not clinical practice guidelines, nor are they algorithms for decisions in patient care. They have been constructed solely for use as guides during this systematic review of the literature.

Interpretation of Standardized Mean Differences

Standardized mean differences (δs) are used to represent the difference between two groups when the groups are measured on differently scaled measures across many studies. For instance, in the pharmacological studies, patients are evaluated on as many as seven different measures. A standardized mean difference between groups is simply the mean difference re-scaled so that all measures have the same variance and standard deviation in scores. If we make the assumption that these scales or subscales measure roughly the same construct (past validity studies make this a safe assumption for the scales in question),¹ meta-analysis of standardized mean differences (also commonly referred to as “effect sizes” in this report) becomes both possible and theoretically meaningful.

The value of the standardized mean difference might be best considered as the degree of overlap between the distributions of treatment and control group scores. Because delta (δ) is the standardized score of the treatment group mean in the control group distribution, we can calculate approximately what proportion of the control group scores are less than the average score in the treatment group.² The table below summarizes percentages for a range of effect sizes.

Thus, someone undergoing a treatment (e.g., bromocriptine) that has an expected effect size of .50 would expect that his symptoms afterwards would be better than 70 percent of those who underwent the “control” procedure (e.g., L-dopa alone).

Even small effects can be important, depending on the importance of the outcome. In past medical studies, small but statistically significant effect sizes have been deemed important enough to prematurely end double-blinding: the 1987 study of the effect of aspirin on reducing the risk of heart attacks found an effect size for aspirin over placebo equivalent to a standardized mean difference of .07.³

Calculation of Change Score Standard Deviations

While many studies reported both baseline and outcome data (from which change score means can be calculated), only a few studies (most from the Parkinson's Study Group) reported change score standard deviations. Because controlling for pre-test differences was desired, and the “change score” standardized mean difference was desirable as a meta-analytic outcome, we estimated change score standard deviations when the data was not directly available.

This estimation was possible due to the studies that reported pre-test means and standard deviations, post-test means and standard deviations, and change score means and standard deviations. This data was available for 25 treatment arms, and it allowed for the calculation of 25 pre/post-test correlations. Figure 1 demonstrates that the time between pre-test and post-test scores was strongly related to the correlation between pre-test and post-test scores. In fact, the relationship was strong enough (R²=.77) to make imputation of the pre/post-test correlation possible. The method used gave slightly more conservative (i.e., lower) correlations than those implied by the figure. For studies with a treatment duration of 10 months or less, a correlation of .8 was used to estimate the change-score standard deviation; .6 was used for those between 10.1 months and 20 months; .4 for those between 20.1 months and 30 months; .2 for those between 30.1 months and 40 months; and .1 for those studies of longer duration. The formula used was

Figure 1. Time of evaluation versus pre-test post-test correlation

Peer Reviewer Form

On the following page, please provide:

1. A brief explanation of both positive and negative answers;

2. Suggestions for improvement of the content or format of this review;

3. Suggestions for additional analyses of this dataset worth including in this report, or in future reports.

**We would prefer that you complete and return this form electronically. However, you may also fax the form back to us, or fax back an annotated version of the draft report if you prefer. Contact information is provided below.

Thank you in advance for your time in completing this form and giving us your feedback. We value your input and greatly appreciate your efforts. Please send the completed form and comments to MetaWorks by July 30, 2001.

Contact:

Rhoda P. Estok, RN, BSN, CNOR

Metaworks Inc.

E-mail: restok@metawork.com

Phone: (781) 395-0700 x254

Fax: (781) 395-7336

Pharmacological Treatment

The Parkinson Study Group conducted a 10-week, multicenter, double-blind RCT comparing placebo with various doses of pramipexole as monotherapy in 264 patients with early PD.¹The trial did not meet the inclusion criteria for this review, due to its short duration; however, only two studies of pramipexole in early PD are included in the database, and this study is mentioned here for comparison. Pramipexole was well tolerated, and resulted in total UPDRS scores that were significantly improved compared with placebo. Studies of longer duration are necessary to confirm these favorable results.

A French, multicenter, open-label RCT compared tolcapone with bromocriptine in 146 PD patients who experienced “wearing-off” or “on/off” fluctuations on L-dopa/PDI.²As the trial lasted only eight weeks, it did not meet the inclusion criteria for this review, but it is the only direct comparison of tolcapone and bromocriptine, and therefore deserves mention. After eight weeks, patients in both groups had similar degrees of motor disability and “on/off” time. Patients in the tolcapone group were able to reduce their daily L-dopa dose more than were patients in the bromocriptine group. The side effect profile varied between the two groups. Studies of longer duration are necessary before conclusions can be made regarding a comparison of the efficacy and safety of bromocriptine and tolcapone.

Three double-blinded, placebo-controlled RCTs that were rejected because of insufficient study duration were readdressed upon the recommendation of a TEP member. One was the French selegiline multicenter trial (FSMT), a three-month study which showed that selegiline was statistically superior to placebo in improving symptoms in patients with early PD.³One study reported that pergolide monotherapy had superior efficacy to placebo in a three-month study of patients with early PD.⁴One six-week study of patients with “wearing-off” phenomenon on L-dopa assessed different doses of tolcapone in addition to L-dopa.⁵The addition of tolcapone reduced the “wearing-off” phenomenon. While all of these studies are important, their short duration precludes our ability to statistically compare the results of these studies to other studies in the database, and they remained in the “unaccepted studies” log.

A few studies have been performed using GM1 ganglioside, a normal constituent of nerve cell membranes, in human PD patients.⁶,⁷,⁸None of the studies met the criteria for acceptance for this review; only one was an RCT, and the study duration was less than 24 weeks. The study is, nevertheless, mentioned in this review, as GM1 represents a new category of pharmacologic treatment for PD that may receive further attention among researchers, although no studies published after 1998 were found.

After an initial intravenous test dose of GM1 1000 mg or placebo, 48 patients with mild to moderate PD were randomized to self-administered GM1 100 mg or placebo subcutaneously twice a day for 16 weeks.⁸Forty-five patients completed the study, and no withdrawals were related to the safety or efficacy of GM1. The main adverse events were injection site reaction, including rash, erythema, or swelling, in ten GM1 patients and one placebo patient, and insomnia in five GM1 patients and two placebo patients. Twelve placebo patients and three GM1 patients complained of fatigue. The UPDRS motor scores improved a mean of 7.5 points after 16 weeks of GM1, while remaining essentially unchanged in the placebo patients. Twenty-one patients elected to continue to take GM1 in an open-label extension of the RCT.⁷Eighteen of these 21 patients continued to have UPDRS motor scores better than baseline, while three had worse scores. Patients who took GM1 continuously for two years showed the greatest improvement from their baseline UPDRS motor scores. Three patients who were followed after they discontinued GM1 at the end of the double blind trial all developed worsening of their UPDRS motor scores.

Anticholinergic Drugs

No trials of anticholinergic drugs met the inclusion criteria for this systematic review. In order to present the available information on this category of drugs, eight studies that were rejected for inclusion into the database but are pertinent to anticholinergic drugs in PD are mentioned here. The most recent studies are discussed first.

A cross-sectional study of the prevalence of dementia in PD was performed on 70 consecutive PD outpatients at a clinic of a university hospital.⁹Patients with dementia had received anticholinergic drugs for significantly longer than patients who were not mentally impaired, leading the authors to conclude that anticholinergic drugs should be avoided in PD patients with cognitive decline.

One study tested the cognitive function of 13 patients with newly diagnosed PD, before and after two weeks of treatment with trihexyphenidyl.¹⁰No patients were demented at baseline, and no significant change was seen in neuropsychological testing before and after the trihexylphenidyl. Given the short duration of the trial and the lack of cognitive impairment at baseline, it is difficult to draw any conclusions from this study.

In a retrospective analysis of 113 PD patients at a movement disorder clinic, the memory performance of patients taking anticholinergics was not significantly different from that of patients on dopaminergic medications alone.¹¹This observation held true for patients with early, middle, or advanced disease. The presence of dementia at baseline was not reported, and may confound these findings, as other studies have suggested that anticholinergics impair cognitive function in patients who are already impaired at baseline.¹²

A study of 78 PD patients showed that patients with PD for > 3 years had memory performance that was worse than controls, and patients on benzhexol had dosage-dependent memory impairment compared to patients on L-dopa alone.¹³The authors concluded that memory is impaired in PD, and benzhexol contributes to the memory decline.

Most studies of anticholinergics were published prior to 1990. In a placebo-controlled, double-blind cross-over study published in 1981, 29 men with PD for one year, on stable doses of L-dopa/PDI, were treated with 10 weeks of benztropine or placebo, followed by a five-week washout period, then 10 weeks of the opposite treatment.¹⁴The authors reported that qualitative and quantitative evaluations showed small but statistically significant improvements for rigidity, finger tapping speed, and ADL for patients on benztropine, compared with patients on placebo. No patients had dementia at baseline. Patients on benztropine had a ten percent decrease in one of the five cognitive measures tested, two patients complained of memory problems, poor concentration, irritability and confusion, and two patients experienced hallucinations. All adverse effects were reportedly mild and reversible with decreasing the medication dose. Interpretation of this study is limited by its short duration, the absence of results prior to cross-over, and the difficulty in comparing their evaluations with today's UPDRS scores.

A study published in 1978 evaluated 20 patients with early PD who were taking trihexyphenidyl.¹⁵L-dopa/PDI was openly added for eight weeks. All patients improved in bradykinesia, tremor, rigidity, and disability scale. The authors concluded that adding L-dopa/PDI to anticholinergics improves the therapeutic response in PD. This study is mainly of historic interest, as practitioners at that time were hesitant to use L-dopa, and were often treating PD patients with anticholinergics alone.

A double-blinded RCT comparing L-dopa plus trihexyphenidyl to L-dopa plus placebo was published in 1974.¹⁶There was no significant difference between the two groups, indicating that L-dopa alone was equivalent to L-dopa plus trihexyphenidyl.

The literature contains limited data regarding the efficacy and safety of anticholinergics in PD. Anticholinergics played an important role in the treatment of PD prior to the development of L-dopa, but their current role is limited to young, cognitively intact PD patients who have resting tremor as the predominant symptom.¹⁷

Surgery

One study compared overall effects of unilateral vs. bilateral STN in patients with advanced PD.¹⁸The study was not accepted into the database because no baseline data was reported on the ten patients in the study. They all underwent bilateral STN electrode implants, and the UPDRS scores of nine patients were assessed six months postoperatively, off medication, with stimulation off, on unilaterally, and on bilaterally. For all parameters measured, bilateral stimulation resulted in the greatest improvement, although unilateral STN DBS also led to moderate improvement in all PD symptoms.

One study that was published too late to meet the inclusion criteria for this systematic review was an RCT comparing the outcomes of embryonic tissue transplantation to sham surgery.¹⁹The active group consisted of 20 patients who underwent transplantation of human embryonic mesencephalic tissue containing dopamine neurons into their putamens. A control group of equal size underwent sham surgery, in which burr holes were drilled into their skulls, without penetration of the dura. The mean subjective global rating scores reported by patients one year after surgery were not significantly different between the two groups. The mean total UPDRS “off” scores one year postoperatively improved in the transplantation group compared to the control group, but the difference was not statistically significant (p=0.11). Patients ≤ 60 in the active group had significantly better UPDRS total, motor, rigidity, and bradykinesia scores than patients in the sham surgery group. Patients > 60 in the active group showed mild, not statistically significant improvement in UPDRS total scores, but no improvement in bradykinesia. Tremor did not improve in either age group.

The transplanted embryonic dopamine neurons survived well, as evidenced by 18F-fluorodopa PET scans in 19 transplant recipients, and autopsies in two transplant recipients who died of causes unrelated to their surgeries. Five of the younger patients who initially responded well to transplants developed severe, refractory dystonia and dyskinesia after the first year after transplantation. The researchers postulated that the transplanted embryonic dopamine neurons were producing too much dopamine in these patients.

While the initial results of embryonic tissue transplantation appeared promising in the younger patients, the development of late dystonia and dyskinesia clearly showed that this procedure is not a panacea for PD patients.

Psychological

ThePSYchosis andCLOzapine inParkinson'S Disease (PSYCLOPS) trial examined the effects of clozapine on dopaminergic-induced psychosis.²⁰As the trial lasted only four weeks, it did not meet the criteria for acceptance into our database, however, the study is worthy of mention due to the paucity of information on treatment of patients with antiparkinsonian drug-induced psychosis. Sixty PD patients with hallucinations or delusions induced by antiparkinsonian drugs were randomized to receive low-dose clozapine (n=30) or placebo (n=30). Dosage was titrated between 6.25 and 50 mg daily, depending on clinical response. In the treatment of schizophrenia, clozapine is generally prescribed at a much higher dosage of 300 to 900 mg daily.Patients in the clozapine group showed improvement in all measures of psychosis, and had no worsening of motor symptoms. There was a statistically significant improvement in tremor in the patients in the clozapine group. During the four weeks of the trial, one patient on clozapine developed leukopenia, and one discontinued clozapine due to sedation. In an open-label extension of the trial, another patient developed leukopenia, and six patients died. The investigators did not believe that any of the deaths were related to clozapine use. While these results are promising, RCTs of longer duration are needed, particularly to evaluate adverse events.