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Therapeutic Management of Late-Stage Parkinson’s Disease: Review of the Movement Disorder Society’s Guidelines
Parkinson’s disease (PD) was originally described in 1817 by English surgeon James Parkinson, who referred to the condition as “shaking palsy.”1 PD is the second most common neurodegenerative disease in adults, following Alzheimer’s disease.2 PD is estimated to afflict approximately 1 million Americans, or about 1% of the US population older than 60 years.3,4 This number is likely to double in the next 15 to 20 years as baby boomers continue to age.5
PD is uncommon before the age of 40, and its prevalence and incidence increases steadily thereafter.5,6 The incidence is higher among men than women,7 but all races and ethnic groups are affected.4 Although therapy can ameliorate the symptoms of PD and improve both the quality of life and life expectancy, PD continues to be associated with progressive disability and increased mortality.8,9 FDA-approved medications to treat PD are summarized in Table 1.
The cardinal signs of PD are resting tremor, rigidity, bradykinesia, and postural instability. Other common signs include micrographia (small handwriting), mask-like facial expressions, shuffling gait, and muffled speech. Motor complications of PD are outlined and defined in Table 2. Neuropsychiatric complications and autonomic disturbances are also commonly seen.
Although PD cannot yet be cured, early diagnosis and treatment can extend patients’ lives, improve their mobility and function, and enhance their quality of life. Clinical guidelines can help clinicians effectively manage PD in their patients. Numerous clinical guidelines for the management of PD exist, including by AMDA–Dedicated to Long Term Care Medicine, the American Academy of Neurology, the National Institute for Health and Clinical Excellence, and other organizations; thus, determining which guidelines to follow may be challenging for clinicians. We review one of the most recently published PD guidelines, which was released by the Movement Disorder Society’s Task Force on Evidence-Based Medicine in Movement Disorders and appeared in the European Handbook of Neurological Management.10,11 These guidelines are unique because they were composed following a comprehensive review of the existing literature, including other guidelines, and outline level of evidence for most recommendations. While these guidelines may have some degree of bias, which we will discuss later in this article, they nevertheless provide solid recommendations that can help guide clinical practice. We also provide a case scenario that demonstrates how the guidelines can be applied in the long-term care setting.
Case Scenario
The patient is a 75-year-old white man who has been a nursing home resident for 3 years. The patient’s medical history includes PD, which was diagnosed 10 years earlier, and mild hypertension. The patient’s current medications include selegiline 5 mg twice daily and carbidopa-levodopa every 6 hours to control his PD symptoms, and hydrochlorothiazide 25 mg daily to treat his hypertension.
The nursing staff report that the resident sustained multiple falls and has demonstrated increasing disorientation in the previous few months. He has also required more redirection and has worsening memory. During the day, the patient has increased tremors and stiffness in his upper extremities, but these symptoms are relieved by his next dose of carbidopa-levodopa.
On physical examination, the patient’s supine blood pressure is 120/80 mm Hg. When moved to a sitting position, he reports severe vertigo, and a decline in systolic blood pressure of 40 mm Hg is noted. He has bilateral resting hand tremors, mild rigidity in his upper extremities, and a slow, shuffling, unsteady gait. His Mini-Mental State Examination score is 20. What treatment options are available to manage this patient’s illness? Following a review of the guidelines, we outline potential treatment options for this case scenario.
Guideline Methods and Potential Limitations
Guidelines for the therapeutic management of PD were initially published by the Movement Disorder Society’s Task Force on Evidence-Based Medicine in Movement Disorders in two chapters of the European Handbook of Neurological Management in 2006 and were updated in late 2010.10,11 In one chapter, Oertel and colleagues10 address the pharmacologic, neurosurgical, and nonpharmacologic/non-neurosurgical management of early-stage PD.In the other chapter, the authors11 provide guidelines for the symptomatic control of motor and nonmotor problems in late-stage PD, outlining pharmacologic and nonpharmacologic treatments, as well as preventive and symptomatic therapies.While important potential outcomes are considered, a formal cost analysis for various options was not conducted. Because of the large volume of evidence and the detailed, comprehensive nature of the recommendations, this article will be limited to the updated guidelines related to patients with late-stage (complicated) PD, which have practical value for busy, practicing long-term care professionals treating residents who have this disease.
The guideline authors searched Medline, the full database of the Cochrane Library, and the International Network of Agencies for Health Technology Assessment for articles published up to September 2009 to gather evidence. Databases were searched for existing guidelines and management reports, requests were made to the European Federation of Neurological Societies (EFNS) for its guidelines, and reference lists from selected articles were checked. The search resulted in more than 100 recommendations and 530 references. The authors failed to define explicit inclusion and exclusion criteria for collected evidence, which may have introduced selection bias into the recommendations. Although the resulting guidelines are comprehensive, too many recommendations were made and there was a lack of focus on tackling individual symptoms of the disease. Both of these factors may diminish the usefulness of these guidelines in clinical practice.
The guidelines were authored by the Movement Disorder Society’s 20-member Task Force on Evidence-Based Medicine in Movement Disorders. The original author group members met in June 2008 and May 2009 to develop a strategy for revising the original guidelines, and additional members were asked to join the author group. Two authors reviewed publications relating to each section of the original document, graded the evidence, and made necessary revisions. The authors stated their departmental affiliations, country of origin, and potential conflicts of interest, but failed to divulge their academic titles, educational affiliations, or clinical areas of expertise. A task force dominated by specialty group members could add significant bias to the recommendations. Author groups that have a balance of practicing generalists, specialists, and researchers are more likely to produce objective guidelines. The absence of a formal process of deliberation may have produced additional guideline bias, and consideration of patient preferences in guideline development was not apparent.
The authors gathered pertinent articles published up to September 2009, and the guidelines were published in late 2010; thus, the evidence was current. Although some evidence was gathered from the 1970s, most references were dated within 5 to 10 years of guideline publication. The guidelines were not subjected to an external review by an objective group of professionals, and their applicability in clinical practice was not determined.
More than 100 recommendations were included in the final guidelines. Individual recommendations were preceded by a comprehensive review of evidence, which we do not discuss in this article. The strength of evidence and rating of recommendations were classified according to EFNS guidance.12
Recommendations for Late-Stage PD
What follows is a summary of the guidelines for the management of various symptoms of late-stage (complicated) PD. We indicate the level of evidence behind many recommendations, which range from a level A to a level C. Level A recommendations are those for which solid scientific evidence shows the benefits of a treatment to substantially outweigh its potential risks. Level B recommendations indicate that a fair amount of scientific data show the benefits of a treatment to outweigh its potential risks. Level C recommendations indicate that while fair scientific evidence suggests that there are benefits provided by a treatment, the balance between the benefits and risks is too close to make general recommendations; thus, such treatments need to be carefully weighed on a case-by-case basis. “Good practice points” (GPPs) were used to indicate recommendations that are not based on research evidence, but which nevertheless represent sound clinical guidance.
Symptomatic Control of Motor Complications
For patients with motor fluctuations during the “wearing-off” phase of treatment, adjustment of levodopa dosing (GPP), switching to a controlled-release formulation of levodopa (level C), addition of dopamine agonists (level B/C), or adding amantadine or an anticholinergic (GPP) is recommended. Addition of catechol-o-methyltransferase (COMT) inhibitors or monoamine oxidase isoenzyme type B (MAO-B) inhibitors is also recommended, but a rating level is not stated. The addition of rasagiline to selegiline should be avoided (level C) because of cardiovascular safety issues.
If oral therapy for patients with severe predictable motor fluctuations fails, deep brain stimulation of the subthalamic nucleus (STN; level A) or administration of subcutaneous apomorphine via a Penject injection (level A) or pump (level C) is recommended. Alternate delivery routes or formulations of levodopa, such as oral dispersible levodopa for a delayed ON period (level B) or levodopa/carbidopa enteric gel via percutaneous gastrostomy (level C), may also be considered.
For patients with peak-dose dyskinesia, Oertel and colleagues11 recommend adding amantadine (level A), reducing individual levodopa dose size (level C), or discontinuing/reducing the dose of MAO-B inhibitors/COMT inhibitors (GPP). The addition of atypical antipsychotics, such as quetiapine (level C) or clozapine (level C), is recommended. The potential serious adverse events of clozapine limit its use (GPP). Nonpharmacologic therapies, such as deep brain stimulation of the STN (level A) and continuous subcutaneous infusion of apomorphine (level C), may also be considered.
Biphasic dyskinesia may be managed by using the strategies for peak-dose dyskinesia (GPP) or by administering larger, less frequent doses of levodopa (GPP). OFF-period and early morning dystonias may be managed by the usual strategies for the wearing-off phenomenon (GPP), including use of additional doses of levodopa or dopamine agonist therapy, use of deep brain stimulation of the STN (level A), or administration of botulinum toxin (GPP). The use of visual or auditory cues for freezing during the OFF period (level C) is also recommended.
Oertel and colleagues11 concluded that there was insufficient evidence to recommend specific oral medical therapies for patients with unpredictable ON-OFF periods. However, they note that strategies described for wearing-off and for dyskinesia may be used for patients with unpredictable ON-OFF episodes (GPP).
Neuropsychiatric Complications
For patients with dementia, Oertel and colleagues11 recommend discontinuing potential aggravators, such as anticholinergics (level B), amantadine (level C), tricyclic antidepressants (level C), tolterodine and oxybutynin (level C), and benzodiazepines (level C).The addition of the cholinesterase inhibitors rivastigmine (level A), donepezil (level A), and galantamine (level C) is recommended. Because of the hepatotoxicity of tacrine, its use is not recommended (GPP). If cholinesterase inhibitors are not tolerated or effective, use of memantine is recommended (level C).
The authors make several recommendations for patients with psychosis. Controlling triggering factors such as infection and electrolyte disorders (GPP), reducing polypharmacy (GPP), and reducing use of antiparkinsonian drugs (GPP) should be considered. The addition of the atypical antipsychotics clozapine (level A) and quetiapine (GPP), and the cholinesterase inhibitors rivastigmine (level B) and donepezil (level C), is recommended. Olanzapine (level A), risperidone (level C), and aripiprazole (GPP) are not recommended. Typical antipsychotics should not be used, although no level of evidence rating is provided for this recommendation.
For patients with depression, the authors recommended optimizing antiparkinsonian therapy (GPP) and using tricyclic antidepressants (level B) or selective serotonin reuptake inhibitors (SSRIs; GPP). Adverse effects are less likely with SSRIs than with tricyclic antidepressants (GPP). No recommendation for the “new” antidepressants—mirtazapine, reboxetine, or venlafaxine—could be made due to limited data on these agents.
Autonomic Dysfunction
Oertel and colleagues11 recommend that orthostatic hypotension be managed by having patients avoid aggravating factors, such as large meals, alcohol, exposure to a warm environment, and drugs known to cause orthostasis. General measures, such as increased salt intake, use of elastic stockings, exercise, advising patients about postprandial effects, and tilting the head of the bed up at night, are recommended without a rating level. Drug therapy, such as midodrine (level A) and fludrocortisones (GPP), is also recommended. Urinary disturbances may be managed by optimization of night-time dopaminergic therapy (GPP) and use of anticholinergic drugs (GPP).
Recommendations for PD patients with gastrointestinal motility problems and erectile dysfunction are comprehensive but consist primarily of GPPs. The use of polyethylene glycol solution (level A) and fiber supplements such as psyllium (level B) for constipation and sildenafil for erectile dysfunction (level B) are recommended.
Sleep Disorders
Recommendations for common clinically significant sleep disorders are extensive. Level A recommendations include use of transdermal rotigotine, oral pramipexole, and sustained-release ropinirole. Modafinil is recommended for daytime somnolence (level B). Addition of a standard or slow-release dose of levodopa (level B) and deep brain stimulation of the STN (level B) are recommended for the treatment of sleep problems. Clonazepam (level C) is recommended for the treatment of rapid eye movement sleep behavior disorder in PD patients.
Resolution of the Case Scenario
Because the case patient is experiencing many of the complications of late-stage PD, the Task Force’s guidelines and recommendations are applicable to him. The patient’s motor fluctuations are characteristic of the wearing-off phenomenon. Switching from a standard-release to a controlled-
release formulation of levodopa may improve his symptoms. Dopamine agonists, COMT inhibitors, or both may be added if his symptoms do not improve.
The cholinesterase inhibitors rivastigmine, donepezil, or galantamine may be used to manage the case patient’s dementia. Tacrine use should be avoided because of its hepatotoxicity. The addition or substitution of memantine may be considered if the cholinesterase inhibitors are not tolerated or are not effective. If the case patient was receiving anticholinergics, amantadine, tricyclic antidepressants, tolterodine, oxybutynin, or benzodiazepines, discontinuing these medications should be considered because of their propensity to impair cognitive function.
The case patient’s orthostatic hypotension, which may be contributing to his increasing number of falls, can be managed using general measures, such as avoiding the aggravating factors previously described, increasing his salt intake, tilting the head of his bed up at night, use of elastic stockings, and possibly discontinuing his diuretic. Pharmacologic therapy with midodrine may be tried if these measures fail.
Conclusion
The treatment of residents with PD presents a significant challenge to the practicing long-term care professional. Multiple treatment options are available to manage this disease, and it is especially important to systematically evaluate the signs and symptoms, extent of disease, and symptom duration before initiating therapy. As the illness progresses, practitioners must carefully individualize, monitor, and modify numerous, complicated treatment strategies to provide the highest quality of care for residents with this chronic and progressive neurodegenerative disease. Use of comprehensive guidelines, such as those by the Movement Disorder Society’s Task Force on Evidence-Based Medicine in Movement Disorders, may help guide clinical decision-making.
The authors report no relevant financial relationships.
Dr. Aggarwal is faculty attending, Department of Family Medicine, Brookhaven Hospital, Patchogue, NY. Dr. Cervo is medical director, Long Island State Veterans Home, Stony Brook, NY, and associate professor of clinical medicine, Stony Brook University, Stony Brook, NY.
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