Part 1 of a 6-Part Series

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1 Release Date: April 1, Termination Date: April 1, Estimated time to complete this 6-part newsletter series: 3.0 hours. For additional updates, go to Awake and Involved: Addressing Excessive Daytime Sleepiness in Patients with Parkinson s Disease Part 1 of 6: Overview of Parkinson s Disease Dear Colleague: Sleep dysfunction, although common in the elderly, is more frequent and more severe in patients with Parkinson s disease (PD). Almost all patients with PD have disrupted sleep and almost half are excessively sleepy during the daytime. Sleep dysfunction harms patients and their caregivers by interfering with social interactions, work performance, driving, independence, psychological well-being, and tolerance to antiparkinsonian medications. The aims of this series of six Treatment Reporters are twofold: to help neurologists understand the complex etiology of sleep problems and excessive daytime sleepiness (EDS) in patients with PD and to offer treatment options. This issue begins with an overview of PD. With the help of a panel of specialists in Parkinson s disease and sleep, we will go on to cover such topics as clinical assessment of the PD patient for sleep problems and risk factors that predispose PD patients to sleep disorders. We will review the complex differential diagnosis of EDS, focusing on sleep disturbances, medications, and pathophysiology. We will then present therapeutic strategies for managing these problems, including sleep hygiene recommendations, treatment of sleep disorders, adjustment of current medications, and the use of agents designed to promote wakefulness. Sincerely, Charles H. Adler, MD, PhD Professor of Neurology Chair, Mayo Clinic Division of Movement Disorders Mayo Clinic Scottsdale Scottsdale, Arizona Introduction Parkinson s disease (PD) is estimated to affect 1 million Americans, with about 60,000 new cases diagnosed each year. 1 The prevalence of PD is expected to increase in the next decades as the baby boomer population ages. Specific causes of PD have not been identified, but advanced age, male sex, family history, and environmental toxins are known risk factors. Parkinson s disease may display either autosomal dominant or recessive Michael J. Thorpy, MD Director Sleep-Wake Disorder Center Montefiore Medical Center Bronx, New York inheritance. Studies in twins suggest that genetics may be a factor in young-onset PD, while the environment may play a more significant role in older-onset PD. These factors may result in PD by enhancing excessive accumulation of intracellular protein and extracellular protein aggregates, resulting in cell death. 1,2 Pathology Selective neuronal cell death results in depigmentation of the substantia nigra as well as depletion of dopamine in the striatum, especially in the dorsal and Part 1 of a 6-Part Series Watch Your Mail for the Next Issue! Learning Objectives This activity has been designed for neurologists who treat patients with Parkinson s disease. After completing these activities, the physician should be able to: Describe the burden of illness that excessive daytime sleepiness imposes on patients with PD. Recognize the possible etiologies of excessive daytime sleepiness in patients with PD. Employ effective measures to assess sleepiness to inform clinical decision making Examine pharmacotherapies aimed at reducing excessive daytime sleepiness in patients with PD. Incorporate new approaches to the management of excessive daytime sleepiness in PD patients to maximize quality of life and patient satisfaction. CME Information Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. This 6-part newsletter is planned and produced as an independent CME activity in accordance with the ACCME Essential Areas and Policies. Projects In Knowledge designates this educational activity for a maximum of 3.0 Category 1 credits toward the AMA Physician s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. Successful completion for 3.0 hours of CME credit requires a passing score of 70% or higher on the posttest. Full instructions for submission are included on the posttest accompanying this CME newsletter. Disclosure The Disclosure Policy of Projects In Knowledge requires that the faculty participating in a CME activity disclose to the audience any significant relationship they may have with a pharmaceutical or medical equipment company, product, or service that may be mentioned as part of their presentation, as well as any relationship with the commercial supporter of this activity. Charles H. Adler, MD, PhD, has received grant/research support from Cephalon, Inc, Elan Pharmaceuticals, GlaxoSmithKline, Pharmacia & Upjohn, and Teva Pharmaceuticals USA; and is a consultant for Elan Pharmaceuticals, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, and Pharmacia & Upjohn. Michael J. Thorpy, MD, is on the speakers bureau of Cephalon, Inc, Orphan Medical Inc, and Sanofi- Synthelabo. The opinions expressed during this 6-part activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge or the commercial supporter. This activity may include a discussion of therapies that are unapproved for use or investigational, ongoing research, or preliminary data. This CME activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the prerogative of the physician caring for the patient. This independent CME activity is supported by an educational grant from Cephalon, Inc. Copyright 2003, Projects In Knowledge, Inc. Secaucus, NJ All rights reserved. Download this 6-part series Awake and Involved: Addressing Excessive Daytime Sleepiness in Patients with Parkinson s Disease available at

2 REPORTER SM : NEUROLOGY intermediate putamen. The Lewy body, an intracytoplasmic eosinophilic inclusion in the pigmented nuclei of the brain stem, is the pathologic hallmark of PD. Neuropathologic changes can also be seen in the locus ceruleus and cerebral cortex. Since there are no diagnostic tests that are definitive for PD, a final diagnosis can only be made by autopsy. Motor Features The diagnosis of PD continues to be based on signs and symptoms, requiring at least two of three cardinal signs: resting tremor, bradykinesia, and rigidity. A fourth cardinal sign, postural instability, usually develops later in the illness. 3,4 Tremor, the most obvious symptom of PD, is usually asymmetric and exacerbated by stress and fatigue. Bradykinesia is often the most troubling symptom, slowing the patient in many activities of daily living. Other symptoms include hypophonia, micrographia, drooling, masked facies, difficulty with dressing, bathing, and feeding, reduced arm swing, flexed posture, and shuffling gait. At first, the subtlety of these signs and similarity to features of normal aging can make the diagnosis of early disease more difficult. Rigidity of passive joint movement is characteristic of PD and is mainly a cogwheel rigidity (ratchet-like movement). Symptoms generally change and worsen over time. Non-motor Features For many patients, the non-motor features of PD can be even more disabling than their motor problems. 1 Depression, psychosis, pain, and cognitive impairment can greatly interfere with independence, activities of daily living, and quality of life. More than 90% of patients with PD experience autonomic symptoms, such as paroxysmal sweating, orthostatic hypotension, constipation, bladder retention, nocturia, impotence, and hypothermia. Sleep/wake alterations affect almost all patients and are particularly disruptive to patients coping with PD, as will be described in the next Treatment Reporter. Differential Diagnosis The differential diagnosis of PD encompasses a variety of neurodegenerative and metabolic conditions (Table 1). 5 Parkinsonism refers to a set of clinical signs and symptoms that are typical of PD, but can be due to other causes, which must be ruled out before making a diagnosis of idiopathic PD. Parkinson s disease tremor of the hands can be distinguished from essential tremor because it occurs predominantly at rest and may also affect the jaws and legs, while essential tremor of the hands occurs more with action and often affects the voice and head/neck. Although arm tremor and mild cogwheel rigidity can be seen in both disorders, bradykinesia is usually a sign of PD. Drug-induced parkinsonism is one of the most critical to consider in the differential diagnosis, because it is iatrogenic and can be treated by withdrawal of the offending medication. Clues to drug-induced parkinsonism include: 1) subacute symptoms with bilateral onset, and rapid progression; 2) early postural tremor; and 3) concurrent choreo-athetoid dyskinesias, especially of the face and mouth. 5 Medications that can cause parkinsonism include antipsychotic agents, combination antidepressant/antipsychotics, anti-emetics, and dopaminedepleting drugs. Dementia and parkinsonism frequently coexist and may present either simultaneously or in sequence. Disorders, such as dementia with Lewy bodies, corticobasal degeneration, or vascular parkinsonism may present with early onset of dementia. 3,5 In PD, memory loss and other cognitive difficulties are a relatively DAs minor late-onset component in contrast to AD. Rigidity, bradykinesia, and gait disorders have been described in up to 50% of AD patients. Without reliable biologic markers, idiopathic PD may be misdiagnosed. Even at noted PD centers, only about 80% of parkinsonism cases are correctly diagnosed with idiopathic PD during life. 6 The best predictors of a pathologic diagnosis of PD include unilateral onset of symptoms, including rest tremor, and either bradykinesia or rigidity, as well as a good initial response to levodopa. Computed tomography or MRI do not reveal any specific changes related to PD, although they can rule out conditions that require different management. 3 Treatment Options Pharmacotherapy Algorithms have been developed to aid in the diagnosis and treatment of PD (Fig. 1). 1,3,7 Pharmacotherapy for PD should be individualized and the dose titrated to maximize the therapeutic response while minimizing side effects. Treatment response is also an essential component of the long-term management of PD, as adjunctive therapy or combination therapy may be required. Nonpharmacologic interventions, including education, exercise, nutrition, and support, should also be provided. Deciding when to start pharmacotherapy may reflect a clinician s preferences. Some advocate early treatment to Nonpharmacologic treatment Addition drugs Anticholinergics Amantadine Combination therapy L-DOPA COMT inhibitors Parkinson s Disease Mild Disability Pharmacologic Treatment Functional impairment Yes Marked disability Drug modification to improve efficacy and reduce side effects No Surgery Figure 1. Management of Parkinson s disease. With permission of Lippincott Williams and Wilkins. 2

3 TREATMENT REPORTER Awake and Involved: Addressing Excessive Daytime Sleepiness in Patients with Parkinson s Disease provide patients with early maximal clinical benefit while others prefer to delay treatment to minimize the risk of developing long-term motor complications. Most agree that the decision when to start pharmacotherapy usually coincides with the onset of functional impairment as defined for each patient. 1 For patients with functional impairment, levodopa or dopaminergic agonists (DAs) are recommended for initial pharmacotherapy. Combining levodopa with a DA is recommended by some specialists. Anticholinergic medications Anticholinergic agents (eg, trihexyphenidyl, benztropine) are infrequently used because of cognitive muscarinic side effects and limited efficacy. 1,8 However, younger patients with early PD may derive some benefit. Anticholinergic therapy in older patients, especially those with cognitive dysfunction, is not recommended. Amantadine Because its antiparkinsonian benefits are limited, amantadine may be used for patients with early PD as it has mild symptomatic benefits. Some clinicians find it beneficial to reduce levodopainduced dyskinesias in advanced PD. Disadvantages include amantadine s potential for development of tolerance, neuropsychiatric/cognitive side effects, ankle edema, and livedo reticularis (skin mottling). 1,8 Selegiline Selegiline is a selective MAO type B inhibitor that has mild symptomatic benefit in early PD, but is primarily used as an adjunct to levodopa in advanced patients with motor fluctuations. The major side effects include nausea, insomnia, hallucinations, and worsening of levodopa-related dyskinesias. Recent evidence does not support a neuroprotective effect for selegiline. 1,8 Dopamine agonists In the United States, two ergot-derived DAs (bromocriptine pergolide) have been used for many years to treat PD and recently two non ergot-derived DAs (pramipexole ropinirole) have been introduced. 1 Compared with levodopa, DAs do not require any metabolic steps to provide a therapeutic effect, they do not compete with plasma amino acids for transport across the blood-brain Table 1. Differential Diagnosis of Parkinson s Disease. Neurodegenerative Hereditary Disorders Disorders with Associated with Other Symptomatic Parkinsonian Features Parkinsonism Disorders Drug-induced Progessive supranuclear palsy Wilson s disease Essential tremor Toxin-induced Multiple system atrophy Huntington s disease Psychogenic Vascular Alzheimer s disease Dentatorubral-pallidoluysian atrophy Structural lesions Diffuse Lewy Machado-Joseph body disease disease Hydrocephalus Infections Metabolic Posttraumatic With permission. Corticobasal degeneration barrier and they have a longer half-life. Dopamine agonists are effective for the treatment of tremor, bradykinesia, and rigidity. Dopaminergic agonists were originally approved for use as adjuncts to levodopa in patients with advanced PD who experience motor complications. More recently, they have been shown to be quite effective as monotherapy in the treatment of early PD. Levodopa may then supplement DA therapy to enhance symptom control. Side effects associated with DAs include EDS and sleep attacks. These unintended sleep episodes are associated with all dopaminergic agents, including levodopa. Other adverse effects include hypotension, hallucinations or psychosis, nausea and vomiting, and edema of the legs. Dopaminergic agonists may rarely cause dyskinesias as monotherapy but can do so when added to levodopa treatment. Levodopa/carbidopa Levodopa/carbidopa, the most effective medication for treating PD motor symptoms, has been the cornerstone of PD pharmacotherapy for the past 30 years. Morbidity and mortality due to PD have been reduced by the use of levodopa, and virtually all patients with confirmed, idiopathic PD will eventually be treated with levodopa with clinically significant benefit. Levodopa may be used throughout the course of PD. Since dopamine cannot cross the blood-brain barrier, its precursor, levodopa, is used. Levodopa has a short elimination half-life and, when used alone, is converted to dopamine in the periphery. This produces nausea and vomiting and reduces the amount of levodopa that can penetrate the blood-brain barrier. The decarboxylase inhibitor carbidopa prevents peripheral levodopa metabolism and enhances CNS absorption. As with all PD medications, levodopa dose should be started low and gradually increased to minimize acute side effects. The lowest dose of levodopa that provides a satisfactory clinical response should be used. Despite its benefits, significant adverse events are associated with levodopa treatment. Acutely, patients may develop nausea, vomiting, lightheadedness, and hallucinations. Of most concern is the development of motor fluctuations and dyskinesias (see below). As PD progresses, the response to treatment with levodopa often begins 3

4 to fluctuate, becoming increasingly correlated with fluctuations in plasma concentrations. 1,7 COMT-inhibitors Catechol-O-methyltransferase (COMT) inhibitors (tolcapone, entacapone) inhibit peripheral metabolism of levodopa, thereby extending its half-life and increasing CNS absorption. Using levodopa with a COMT inhibitor decreases the variability in levodopa concentrations and reduces motor fluctuations. This has the clinical benefit of decreased off time and increased on time for patients with motor fluctuations. Dyskinesia is the most common side effect, and may be controlled by a 15% to 30% reduction in levodopa dose. Other side effects are diarrhea, abdominal cramps, and pain. Because of the risk for liver toxicity, tolcapone s use has been severely restricted, and entacapone is preferred. 1,8,9 Motor Fluctuations and Dyskinesias Many patients eventually notice that their 4 Early 3 5 hours Moderate hours Advanced Figure 2. Motor fluctuations and dyskinesias related to levodopa therapy. With permission of Lippincott Williams and Wilkins. motor response to oral medications begins to fluctuate and dyskinesias appear. This phenomenon rises from 3% after 12 months of treatment to 70% after more than 9 years. 10 Motor complications and dyskinesia may be related to changes in the firing frequency of basal ganglia output neurons and effects of these changes on thalamic and cortical motor areas. Motor fluctuations consist of alternations between on periods during which patients have relatively good mobility and motor function, and off periods during which the patients have suboptimal or no response to medication. Several types of motor fluctuations may develop as the disease progresses, including end-of-dose wearing off, delayed on response, dose failures, and unpredictable responses. Dyskinesias usually begin as a twisting, posturing, or cramping of the toes or feet on awakening ( off state dystonia) or as a choreiform disorder of the side of the body most affected by PD ( on state dyskinesia). Patients with dyskinesias usually are those who are very responsive to dopaminergic medications. Peak-dose dyskinesia associated with PD usually begins after the dose of dopaminergic medication has been absorbed and brain/blood levels have peaked. As PD progresses, the therapeutic window for eliciting a motor response to References medication without causing a dyskinetic response is compressed (Fig. 2). 11 Carefully titrating the dose of the dopaminergic medication, discontinuing selegiline or COMT inhibitors, adding amantadine, or surgery in extreme cases may be useful. 7,8,12 Surgery Surgical options for PD generally fall within three categories: ablative, stimulating, and restorative. Pallidotomy, an ablative procedure, results in a consistent, long-lasting, and dramatic amelioration of contralateral dyskinesia in 90% of patients. Deep brain stimulation is based on observations indicating that high-frequency stimulation of specific brain sites can simulate the effects of a destructive lesion. Deep brain stimulation of the subthalamic nucleus and the globus pallidus pars interna both provide comparable benefits, including management of tremor. Restorative procedures, such as fetal cell transplants, are still in the experimental stages. Conclusion Patients with PD present with a constellation of clinical symptoms that change as the disease progresses. Optimal management must include accurate diagnosis, recognition of the wide variety of complex treatment issues, and choice of the best therapeutic options individualized for each patient. Treatment goals should focus on symptom control and improved quality of life. TX 1. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson s disease (2001): treatment guidelines. Neurology. 2001;56(suppl 5):S1-S Lang AE, Lozano AM. Parkinson s disease. First of two parts. N Engl J Med. 1998;339: Guttman M, Kish SJ, Furukawa Y. Current concepts in the diagnosis and management of PD. CMAJ. 2003;168: Marjama-Lyons JM and Koller WC. Parkinson s disease: update in diagnosis and symptom management. Geriatrics. 2001;56: Adler CH. Differential diagnosis of Parkinson s disease. Med Clin N Am. 1999;83: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55: Jankovic JJ. Therapeutic strategies in Parkinson s disease. In: Jankovic JJ, Tolosa E, eds. Parkinson s Disease and Movement Disorders. 4th Edition. Philadelphia, Pa: Lippincott Williams and Wilkins; Chapter Uitti RJ. Advancing Parkinson s disease and treatment of motor complications. In: Adler CH, Ahlskog JE, eds. Parkinson s Disease and Movement Disorders: Diagnosis and Treatment Guidelines for the Practicing Physician. Totowa, New Jersey: Humana Press; Chapter Kurth MC, Adler CH. COMT inhibition: a new treatment strategy for Parkinson s disease. Neurology. 1998;50(5 suppl 5):S Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations estimated from the cumulative literature. Mov Disord. 2001;16: Obeso JA et al. Dopamine agonists in early Parkinson s Disease. In: Olanow CW, Obeso JA, eds. Beyond the Decade of the Brain Vol 2. Kent, UK: Wells Medical Ltd; 1997: Adler CH. Relevance of motor complications in Parkinson s disease. Neurology. 2002;58:S

5 CME Posttest Part 1 of 6: Overview of Parkinson s Disease CME Instructions Awake & Involved: Addressing Excessive Daytime Sleepiness in Patients with Parkinson s Disease To receive documentation of your participation in this six-part CME activity (for which each newsletter equals.50 hours of CME credit) for a total of 3.0 hours of CME credit, please complete the following steps: 1. Read each newsletter carefully. 2. Complete the CME Posttest included in each of the newsletters. 3. Mail or fax each of your completed CME Posttests to Projects In Knowledge, One Harmon Plaza, 6th Floor, Secaucus, NJ 07094; fax: * *Successful completion for 3.0 hours of CME credit requires a passing score of 70% or higher on each of the 6 posttests. After you have submitted all 6 posttests, you will be issued a CME certificate for 3.0 hours of CME credit. If your score is lower than 70% on any individual posttest, you will be notified by mail and given an opportunity to retake that test. Name Degrees/Credentials Mailing Address City State ZIP Phone Office Fax Please indicate your answers below. 1. The best predictors of a pathologic diagnosis of PD do not include: a. Unilateral onset of symptoms c. Bilateral onset of symptoms b. Good initial response to levodopa d. Bradykinesia 2. Selegiline should not be used: a. For patients with early PD c. For its neuroprotective effect b. As an adjunct to levodopa in advanced PD patients d. For patients with motor fluctuations 3. Unlike dopamine agonists, levodopa is not associated with sleep attacks. a. True b. False 4. Treatment options for a patient with peak-dose dyskinesia should not include: a. Titrating the dose of dopaminergic medication c. Raising the dose of entacapone b. Discontinuing selegiline d. Pallidotomy Thank you for your participation PT