treatment of Parkinson disease.pdf - ARTICLE The scientific and clinical basis for the treatment of Parkinson disease(2009 C Warren Olanow MD FRCPC

treatment of Parkinson disease.pdf - ARTICLE The scientific...

This preview shows page 1 out of 136 pages.

You've reached the end of your free preview.

Want to read all 136 pages?

Unformatted text preview: ARTICLE The scientific and clinical basis for the treatment of Parkinson disease (2009) C. Warren Olanow, MD, FRCPC Matthew B. Stern, MD Kapil Sethi, MD Address correspondence to Dr. C. Warren Olanow, Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place, Annenberg 14-94 New York, NY 10029 [email protected] ABSTRACT Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1–2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. NEUROLOGY 2009;72 (Suppl 4):S1–S136 Parkinson disease (PD) is named in honor of James Parkinson, whose monograph entitled “An Essay on the Shaking Palsy,” written in 1817, provided an enduring description of the clinical features of this disorder.1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.3 INTRODUCTION The cardinal clinical manifestations of PD are resting tremor, rigidity, bradykinesia, and gait dysfunction (table 1). It is now appreciated that PD is also associated with many nonmotor features, includ- Table 1 Classic motor features of PD Cardinal features Additional features Resting tremor Micrographia Rigidity Masked facies Bradykinesia Decreased blinking Gait disturbance/postural instability Freezing Flexed posture PD ⫽ Parkinson disease. From the Department of Neurology (C.W.O.), Department of Neuroscience (C.W.O.), and Bendheim Parkinson’s Disease Center (C.W.O.), Mount Sinai School of Medicine, New York, New York; Parkinson’s Disease and Movement Disorder Center (M.B.S), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Department of Neurology (K.S.), Division of Movement Disorders, Medical College of Georgia School of Medicine, Augusta, Georgia. Supported by independent grants from Teva Neuroscience, Boehringer Ingelheim, Novartis/Orion, and Solvay Pharmaceuticals. Disclosure: C.W.O. has served as a consultant for Boehringer Ingelheim, Teva, Novartis/Orion, Solvay, Merck-Serono, Ceregene, Eisai, Schering-Bayer and the welding defense. M.B.S. serves as a consultant for Boehringer Ingelheim, Novartis, Ipsen, and Teva. K.S. has served as a consultant for Novartis, GlaxoSmithKline, Boehringer Ingelheim, Schering Plough, Biogen, Teva, Solvay, Valeant, and Ipsen. Neurology® supplements are not peer-reviewed. Information contained in Neurology® supplements represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®. Copyright © 2009 by AAN Enterprises, Inc. S1 Figure 1 Classic pathology of PD. The left panel illustrates the marked reduction in neuromelanin pigment in the substantia nigra pars compacta (SNc) in a patient with PD (bottom) compared with a normal individual (top). The middle panel illustrates the marked reduction in dopaminergic neurons in the SNc of a patient with PD (bottom) compared with a normal individual (top). The right panel depicts a surviving dopamine neuron containing a Lewy body using hematoxylin and eosin (H&E) stain. Note that the Lewy body has a dense core (representing proteinaceous material) surrounded by a pale halo (comprised of ␣-synuclein and neurofilaments). Courtesy of Dr. Dan Perl. ing autonomic dysfunction, pain and sensory disturbances, mood disorders, sleep impairment, and dementia (see discussion in the nondopaminergic and nonmotor features section, page S70). Pathologically, PD is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) coupled with intracytoplasmic proteinaceous inclusions known as Lewy bodies (figure 1). It is also now appreciated that PD is associated with extensive nondopaminergic pathology, which involves cholinergic neurons of the nucleus basalis of Meynert, norepinephrine neurons of the locus coeruleus, serotonin neurons in the midline raphe, as well as neurons in the cerebral cortex, brainstem, spinal cord, and peripheral autonomic nervous system.4 Indeed, recent studies suggest that nondopaminergic pathology, particularly in the dorsal motor nucleus and olfactory regions, precedes the onset of dopaminergic pathology in the SNc.5 The introduction of levodopa in the late 1960s represented a major therapeutic advance in the management of PD.6 Levodopa treatment provides meaningful benefit to most patients with PD, and is associated with improvement in activities of daily living, independence, employability, and survival. However, long-term treatment with levodopa is complicated by the development of adverse events (AEs) that include motor fluctuations, dyskinesias, and neuropsychiatric complications.7,8 Additional medical and surgical therapies that have been developed for PD to date have focused primarily on treating or preventing levodoparelated motor complications, and do not provide beneS2 Neurology 72 (Suppl 4) May 26, 2009 fits that are superior to what can be achieved with levodopa. Because of these advances, motor complications seem to represent less of a problem today than they did in the past. The nondopaminergic features of the disease (e.g., freezing, falling, and dementia) are not well controlled with dopaminergic therapies and now represent the major source of disability for most patients with advanced PD.9 Thus, despite levodopa treatment and the considerable success that has been achieved in treating motor complications, patients with PD still experience severe disability. This has spurred an intensive effort to develop “neuroprotective” or “disease-modifying” treatments that can slow, stop, or reverse disease progression. This effort has been aided by the identification of a number of gene mutations that are associated with the development of familial and even sporadic cases of PD. In recent years, there has been an explosion of laboratory studies aimed at better defining the molecular basis of cell death in PD, and identifying novel targets for potential symptomatic and neuroprotective interventions.10-12 Physicians who treat the patients with PD must now, more than ever, assimilate an enormous body of scientific and clinical information to optimally manage patients with this complex disorder. In 1994,13 1998,14, and 2001,15 groups of movement disorder experts published an algorithm (decision tree) for the management of PD, with the intent of considering treatment options and providing therapeutic recommendations for practicing physicians who treat patients with PD. These monographs reviewed the available therapies, the scientific rationale for choosing them, and the decision-making processes involved in selecting treatment for an individual patient. Alternative treatment strategies were considered and areas of controversy identified. It is 7 years since the most recent of these publications, and in this time considerable new information relevant to the treatment of PD has become available. Thus, we believe it is timely to publish an updated, comprehensive review of PD therapy and the underlying scientific basis for considering the various treatment alternatives. From the laboratory perspective, there have been advances in identifying the cause of PD, the pathogenesis of how nerve cells die, the pathophysiology of the normal and dopamine-depleted basal ganglia, and the physiologic and molecular basis of levodopa-related motor complications. New gene mutations have been identified in patients with familial PD, as well as in individuals with typical sporadic PD. Increasingly, evidence indicates that there are many different causes of PD,16 and, indeed, that sporadic PD might be the result of a complex interaction among multiple genetic and environmental factors that may vary in different individuals. New information has become available on the mechanism responsible for levodopa-induced motor complications and the potential value of therapies that provide more continuous dopaminergic stimulation (CDS). Clinically, many new therapeutic interventions have been studied, and several of these are now on the market and available for the treatment of patients with PD. Specifically, there is new information with respect to the role of rasagiline, dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors in early treatment; new agents that treat motor complications; the role of deep brain stimulation (DBS); infusion therapies; putative neuroprotective agents; and novel trial designs that attempt to sort out confounding symptomatic from disease-modifying effects. In addition, experimental studies suggest potential therapeutic benefits from stimulation of novel surgical targets, as well as from cell-based and gene delivery approaches. Furthermore, the importance of nonmotor and nondopaminergic features of the disease has become apparent. Indeed, it is possible that olfactory impairment, REM behavior disorder (RBD), and constipation might be early features of PD that antecede the onset of the classic motor features of the disease. These developments have expanded our knowledge, provided new treatment options, and improved our ability to treat patients with PD in different stages of the disorder. We have revised our previous algorithm (decision tree) to take this new information into account. We continue to consider the advantages and disadvantages of various therapeutic agents, to highlight clinical controversies, and to provide our personal opinions. Where material in the 2001 supplement remains current and applicable, it was not changed. Where new information has become available, particularly from prospective, double-blind, controlled clinical trials, it has been incorporated and our treatment approaches modified accordingly. This monograph is designed to aid physicians in identifying and selecting treatment options for patients in various stages of PD and in the management of the various problems that can ensue. This monograph builds on the evidence-based medicine guidelines provided by organizations, such as the Movement Disorder Society and the American Academy of Neurology.17-19 We try to evaluate the results of current studies in light of existing scientific information and to describe how this body of information can be used to make informed decisions. We recognize that physicians are often called upon to institute therapies despite a lack of adequate clinical and scientific information. We also recognize that the treatment of PD is highly individual and that the physician must use his or her best judgment and consider the wishes of the patient in making therapeutic decisions. In many instances, there may be alternative approaches that are equally valid, and an effort has been made to point these out. This monograph is not intended to represent a single way of treating PD, but rather to point out many different treatment options and the strengths and weaknesses of the underlying clinical data and scientific rationale. It is our hope that this publication will be of use to clinicians, managed care organizations, and other healthcare providers as they try to incorporate a large body of clinical and scientific information into the difficult and complex decision-making processes involved in caring for patients with PD. The differential diagnosis of PD is listed in table 2.20 PD is the most common form of parkinsonism, accounting for about 75% of cases seen in the office of a movement disorder specialist. Historically, PD was diagnosed based on the presence of two of three cardinal features—tremor, rigidity, and bradykinesia—and pathologically by degeneration of dopaminergic neurons in the SNc coupled with the presence of Lewy bodies. However, studies performed at the London Brain Bank found that in 100 consecutive cases diagnosed as having PD in life, the diagnosis was not confirmed at autopsy in 24%.21 A retrospective analysis of this population found that the clinical features that were most likely to accurately predict PD pathology were parkinsonism associated with resting tremor, asymmetry, and good response to levodopa.22 Similar observations were made based on MRI studies.23 In a subsequent study of 73 consecutive patients diagnosed as having PD by neurologists using these criteria, postmortem confirmation of the clinical diagnosis was made in all but one (98.6%) case.24 Thus, a diagnosis of PD can be made with a high level of confidence in a patient with parkinsonism who has resting tremor, prominent asymmetry, and good response to levodopa. Each patient with PD does not necessarily manifest all of these features. An estimated 30% of patients with PD do not have resting tremor. Patients with a tremor-dominant form of PD tend to have a relatively benign course, whereas those who present with an akinetic-rigid form of the disease have more rapid progression and are more likely to ultimately be diagnosed as having atypical parkinsonism.25 There are also occasional examples of pathologically confirmed cases of PD that were misdiagnosed as having an atypical form of parkinsonism during life.21 Recent studies have emphasized that PD is associated with a variety of nonmotor features and that pathology is widespread and extends beyond the nigrostriatal system. Of particular interest are studies suggesting that nonmotor features of PD may antedate the development of the classic motor features of MANAGEMENT OF PD Diagnosis. Neurology 72 (Suppl 4) May 26, 2009 S3 Table 2 Differential diagnosis of PD PD ⫽ Parkinson disease; MSA-P ⫽ multiple system atrophy-parkinsonian; MSA-C ⫽ multiple system atrophy-parkinsonian cerebellar. the disorder. Thus, individuals with a combination of constipation, RBD, and anosmia may not only be at increased risk for developing PD, they may already have an early form of the disease.26 On the basis of these findings, it is likely that cases will be diagnosed at earlier stages in the future and that current diagnostic criteria will need to be further amended. Clinical diagnostic accuracy is less precise for patients with atypical parkinsonism than for those with PD. Although it is usually possible to identify that a patient has an atypical parkinsonism, it may be difficult to diagnose the precise subtype. The clinical features that best predict that a patient has an atypical parkinsonism are early onset of prominent speech and gait dysfunction, postural instability, axial greater than appendicular rigidity, absence of resting tremor, prominent autonomic dysfunction, and poor or unsustained response to levodopa. The presence of prominent and symptomatic orthostatic hypotension or concomitant cerebellar signs should raise the possibility of multiple system atrophy (MSA).27 Although features may overlap, recent nomenclature favors dividing MSA into those with predominant parkinsonian (MSA-P) or cerebellar (MSA-C) features. Pathologically, MSA is characterized by striatal and/or cerebellar degeneration associated with ␣-synuclein deposits in glial cells (glial cytoplasmic inclusions). Progressive supranuclear palsy (PSP) is characterized by features of an atypical parkinsonism, with impairment in vertical eye movements, particularly down gaze, hyperextension of the neck, and early falling.28 Slowing of S4 Neurology 72 (Suppl 4) May 26, 2009 vertical saccades or the presence of a prominent stare with marked reduction in blink rate may be early features and should raise suspicion that a patient with atypical parkinsonism might have PSP. Some patients with PSP may strongly resemble patients with PD in the early stages of their illness and have a positive response to levodopa. Pathologically, PSP is characterized by degeneration in the SNc, other brainstem regions, and the pallidum, coupled with prominent tau-positive neurofibrillary tangles. Subgroups of PSP have been defined that have prominent Lewy bodies in the SNc.29 Some have argued that this is a separate condition referred to as PSP–Parkinson, in contrast to the more classic form of the illness, which is referred to as PSP–Richardson. Atypical parkinsonism in the presence of asymmetric focal rigidity and cortical features, such as myoclonus, apraxia, or alien limb phenomenon, should raise the possibility of corticobasal ganglionic degeneration.30 Parkinsonism can also be a feature of a variety of other conditions, including Huntington disease (particularly young-onset Westphal variant), Hallervorden-Spatz disease, Wilson disease, and dopa-responsive dystonia. A discussion of these conditions is beyond the scope of this monograph, but it is important to consider these conditions in the differential diagnosis of an atypical parkinsonism. Some clinicians use a “levodopa challenge” to try and differentiate PD from atypical parkinsonism. We find this not to be particularly helpful because patients with PD with mild clinical features may not show much of a benefit from levodopa, whereas pa- tients with atypical parkinsonism may show some benefit from the drug, particularly in the early stages of the disease. Furthermore, animal studies suggest that even a single dose of levodopa might prime the dopamine-depleted basal ganglia for the subsequent development of dyskinesia.31 On the basis of these considerations, most experts recommend against performing this procedure as a diagnostic test.32 Secondary forms of PD can also occur. Druginduced parkinsonism is the most common secondary cause and can closely resemble PD. Diagnosis can usually be made by taking a careful history and evaluating the effects of drug withdrawal. Neuroleptic agents used in the management of psychiatric disorders are the most common cause of secondary parkinsonism. It is important to appreciate that some neuroleptic agents are used primarily to treat nonpsychiatric problems, such as emesis (e.g., prochlorperazine [Compazine] and promethazine [Phenergan]) and other gastrointestinal disorders (e.g., metoclopramide [Reglan]). Other drugs that have been reported to induce or worsen parkinsonism include dopamine uptake ...
View Full Document

  • Winter '16
  • SNC

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture

  • Left Quote Icon

    Student Picture

Stuck? We have tutors online 24/7 who can help you get unstuck.
A+ icon
Ask Expert Tutors You can ask You can ask You can ask (will expire )
Answers in as fast as 15 minutes