Review and Management of Common Nonmotor Symptoms of Parkinson’s Disease

Release Date: January 1, 2011

Expiration Date: January 31, 2013

FACULTY:

Lindy D. Wood, PharmD
Fellow in Geriatrics College of Pharmacy Washington State University/Elder Services
Spokane, Washington

Joshua J. Neumiller, PharmD, CDE, CGP, FASCP
Assistant Professor, College of Pharmacy Washington State University/Elder Services Spokane, Washington

Stephen M. Setter, PharmD, CDE, CGP, FASCP
Associate Professor, College of Pharmacy Washington State University/Elder Services
Spokane, Washington

Erin K. Dobbins, PharmD
Clinical Instructor/Consultant Pharmacist College of Pharmacy Washington State University Family Home Care & Hospice
Liberty Lake, Washington

FACULTY DISCLOSURE STATEMENTS:

Lindy Wood receives grant funding from and serves as a consultant to Teva Neuroscience, Inc. Joshua Neumiller receives grant funding from Teva Neuroscience, Inc. Stephen Setter receives grant funding and serves as a consultant and on the speaker’s bureau for Teva Neuroscience, Inc. Erin Dobbins has no conflicts of interest to report in relation to this manuscript. This program contains discussion of off-label use of medications.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data..

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-11-001-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
CE Customer Service: (800) 825-4696 or cecustomerservice@jobson.com

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To discuss common nonmotor features of Parkinson’s disease and present potential pharmacologic and nonpharmacologic treatments.

OBJECTIVES:

After completing this activity, participants should be able to:

  1. Recognize and differentiate between motor and nonmotor symptoms of Parkinson’s disease.
  2. Explain the impact that pharmacologic therapy for Parkinson’s disease motor symptoms may have on nonmotor symptoms.
  3. Identify and recommend pharmacologic and nonpharmacologic treatment interventions for nonmotor symptoms of Parkinson’s disease.

Although most pharmacists immediately identify the motor manifestations of Parkinson’s disease (PD)—tremor, rigidity, bradykinesia, and postural instability—the nonmotor symptoms of the disease often go unrecognized. Examples of these nonmotor symptoms include depression, dementia, psychosis, swallowing and gastrointestinal disorders, orthostatic hypotension, urinary dysfunction, sleep disorders, and numerous other challenges (see TABLE 1).1,2 These symptoms are generally unresponsive to common pharmacologic agents used for the motor problems in PD, many of which can actually exacerbate nonmotor symptoms.1,2 For example, dopamine agonists or levodopa may induce hallucinations or orthostatic hypotension, two common nonmotor symptoms of PD. Given the frequency of patient contact and the familiarity with therapies commonly used to treat nonmotor symptoms, the pharmacist is in a unique position to enhance the management of people with PD. This article will focus on the following nonmotor symptoms of PD: depression, cognitive impairment, psychosis, sleep disturbances, swallowing disorders, sialorrhea, gastrointestinal disorders, and orthostatic hypotension.

tbl1

 

Depression While major depressive disorder tends to be rare in PD, minor depression is common, affecting 40% to 70% of patients. It often manifests prior to the diagnosis of PD and does not correlate with the degree of PD severity.3-6 There is no gold standard for the treatment of depression in PD, since large, randomized, placebo-controlled trials in patients with concomitant depression and PD are lacking. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) seem to work well for many patients. A pharmacist should be aware that SSRIs have been implicated in worsening motor function in PD, so careful monitoring of PD motor symptoms should be in place if an SSRI is initiated.4 Due to their anticholinergic properties, TCAs may actually improve motor symptoms such as tremor; however, other anticholinergic side effects, including cognitive impairment, dizziness, and constipation, must be weighed carefully.3,4,7 Nonpharmacologic approaches to depression, including cognitive behavioral therapy and counseling, may also be of benefit.1,8

Cognitive Impairment

Some degree of cognitive impairment is often present in newly diagnosed PD patients, and its development seems inevitable, with 85% of patients exhibiting cognitive impairment 15 years after diagnosis of PD.9,10 When cognitive impairment becomes significant enough that it affects social or occupational functioning, it is termed dementia.11 Approximately 30% to 40% of patients with PD will develop Parkinson’s disease dementia (PDD).12-14 Many patients with PDD will also present with depression, which is a strong risk factor for impaired cognitive function in PD.15 Also commonly occurring in PDD are psychosis and hallucinations, which are four times more common in patients with dementia versus patients with nondemented PD.13 The development of dementia in a patient with PD is often a precursor for nursing home placement and impending mortality.13,16

fig1

A thorough medication review should be conducted prior to initiating a new medication for cognition. First, anticholinergic medications (benztropine, trihexyphenidyl) should be assessed and discontinued if possible.17 Next, amantadine, dopamine agonists (pramipexole, ropinirole), and monoamine oxidase B (MAOB) inhibitors (selegiline, rasagiline) should be discontinued or decreased in dose, in that order.17,18 First-line treatment for PDD should be an acetylcholinesterase inhibitor unless contraindicated.19-23 All medications in this class (donepezil, galantamine, and rivastigmine) have shown benefits in PDD, but to date, rivastigmine is the only agent with FDA approval for PDD.20-23 Despite documented benefit of these medications, their effects are generally not robust. A Cochrane Review meta-analysis found that only about 15% of patients had a clinically meaningful benefit from rivastigmine therapy.24 Acetylcholinesterase inhibitors should be titrated slowly from a low dose, outlined in TABLE 2, depending on patient tolerance.25 Side effects include gastrointestinal upset, diarrhea, bradycardia, syncope, and hip fractures.20-23,26 There is currently insufficient evidence to recommend the use of memantine in this population.18,27

tbl2

 

Psychosis

People with PD often experience visual hallucinations, commonly of people or small animals, and “sense of presence” illusions in which they imagine something is present or see something out of the corner of their eye.28 Often these experiences are benign and do not bother the patient or their family or caregivers. If the patient experiences a loss of contact with reality, generally described as psychosis, or the hallucinations or delusions become bothersome, treatment is necessary.

The dopaminergic medications used to treat PD may cause or worsen psychosis. It appears that psychosis affects up to 10% of patients not being treated with dopaminergic therapies, while about 40% of patients receiving dopaminergic therapy experience psychosis.29,30 Thus, the first step in treating psychosis is to assess the patient’s medications. Just as for cognitive impairment, anticholinergic medications should be decreased or discontinued if possible.28 The medications should then be reduced or discontinued in the following order: MAO-B inhibitors, amantadine, dopamine agonists, catechol O-methyltransferase inhibitors (entacapone, tolcapone), and levodopa.28 As the dopamine agonists cause hallucinations more commonly than levodopa, it is often preferred to discontinue the agonist, even if that means the levodopa must be increased to compensate for reduced motorsymptom control.17

If additional treatment is required after a medication review and subsequent changes, quetiapine or clozapine are the preferred antipsychotic agents for a person with PD.31,32 The other atypical antipsychotics and all first-generation antipsychotics have increased potential to worsen the motor symptoms of PD and should be avoided.31,32 Although clozapine is extremely effective for treating psychosis in PD without worsening motor function, its use requires frequent monitoring for agranulocytosis, a rare side effect. This leads most clinicians to use quetiapine as first-line therapy.33 TABLE 2 includes recommended dosages of clozapine and quetiapine to be titrated to effect as tolerated. Of note, both clozapine and quetiapine may exacerbate other nonmotor symptoms of PD, including orthostatic hypotension and sedation.

Sleep Disturbances

Sleep disturbances are a common complaint in PD, and one-third of patients with PD rated their sleep problems as moderate to severe in one study.34 A variety of sleep disturbances may occur in PD, including rapid eye movement (REM) sleep behavior disorder (RBD), restless legs syndrome (RLS), excessive daytime sleepiness (EDS), and somnolence or insomnia due to medications. Like other nonmotor manifestations of PD, sleep disturbances like RBD often precede the diagnosis of PD.35

RBD is characterized by jerking and/or violent limb and body movements during REM sleep. This condition is dangerous to both the patient and his or her bed partner, as the patient often acts out dreams or may strike something with a limb.36 Contrary to RBD, RLS is characterized by discomfort and an intense urge to move the legs while awake. Evidence indicates that RLS is more prevalent in patients with PD than in the general population and tends to follow, rather than precede, a PD diagnosis.37

Fifty percent of patients with PD report EDS, which could be caused or worsened by many factors, including dopaminergic medications.38 The dopamine agonists and levodopa have been associated with EDS and sudden onset of sleep.39 This is particularly worrisome for patients who drive and take dopamine agonists, as sudden “sleep attacks” have contributed to several automobile accidents.39 Pharmacists must be vigilant in counseling patients taking dopamine agonists about this possible side effect and should encourage them to stop driving if they begin falling asleep during activities in which they are normally alert.

Many other medications may contribute to sleep disturbance, highlighting the need for a comprehensive medication review. Either insomnia or somnolence could be caused by various antidepressants, depending on the agent and dosage used. It is particularly important that a pharmacist question patients with sleep disturbance about their use of OTC medications or herbals, many of which are touted for their soporific properties. Anticholinergic medications, including those used for PD, or the OTC agent diphenhydramine often cause substantial sedation and may produce a hangover effect if used for sleep.40

A variety of pharmacologic treatment options are available if further intervention is required. If a patient is waking up during the night due to a PD symptom such as increased rigidity, adding a dose of controlledrelease carbidopa/levodopa or a dopamine agonist prior to bedtime may be effective. No particular agent has been proven to be the preferred one for treating the sleep disturbances in PD. Patient- and medication-specific factors, clinician preference, drug interactions, and cost must all be considered.

Swallowing Disorders and Sialorrhea

Dysphagia, or difficulty swallowing, afflicts anywhere from 18.5% to 100% of patients with PD and is not necessarily associated with PD severity.41,42 Dysphagia leads to aspiration in many patients, a risk factor for the most common cause of death in PD patients: pneumonia.42,43 Dangerously, people with PD often experience “silent” aspiration, or aspiration not accompanied by symptoms like coughing, which makes them especially vulnerable to complications.41 Dysphagia may also lead to weight loss and poorer quality of life for a patient with PD.44 Many patients, unfortunately, are unaware of their dysphagia, with studies showing impaired swallowing in over 50% of subjects, even though many reported no difficulty.45

The management of dysphagia should be interdisciplinary, involving the use of a speech therapist who can perform swallowing evaluations and training for the patient with PD. It is important to also rule out other causes of dysphagia or coughing, including gastrointestinal reflux disease or other gastrointestinal ailments.46 There are many lifestyle techniques that can be implemented during mealtimes to optimize swallowing and hinder aspiration; these are outlined in TABLE 3.

tbl3

 

Although many patients with PD experience sialorrhea, or drooling, this is not due to overproduction of saliva. Rather, a diminished swallowing response is actually to blame for the accumulation of saliva seen particularly in more advanced stages of PD.46 Making matters worse, people with PD often posture themselves with a forward head tilt, which can worsen drooling.46 This accrual of saliva in the mouth, particularly if accompanied by difficulty with swallowing, increases the risk of aspiration in the patient with PD. Although drooling may be treated with anticholinergic medications like antihistamines, the risks often outweigh the benefits for many patients. Some neurologists will target the salivary glands with botulinum toxin, which has been proven useful in clinical settings for the treatment of sialorrhea.47

Gastrointestinal Dysfunction

Often underappreciated are the gastrointestinal symptoms of PD, including gastroparesis and constipation, which affect about 70% to 80% of patients with PD.48 Gastroparesis may lead to nausea, early feelings of fullness, and anorexia. Unfortunately, dopaminergic therapies targeted to the motor symptoms of PD may exacerbate gastroparesis or constipation.48

Constipation may be treated effectively through the regular use of OTC bowel agents, listed in TABLE 3, in addition to the usually recommended treatments of increased fluid, fiber, and physical activity. Patients seeking treatment for gastroparesis must be particularly careful to avoid metoclopramide, a commonly used gastrointestinal prokinetic agent, as it may worsen PD motor symptoms.49 Domperidone, a peripheral dopamine blocker unable to cross the blood-brain barrier, effectively treats gastroparesis without worsening motor symptoms.49 Although not FDA approved in the United States, domperidone is approved in over 50 other countries, and physicians in the U.S. may file an investigational new drug application with the FDA to allow the use of domperidone in treatment-resistant patients.50

Orthostatic Hypotension

Though up to 50% of patients with PD suffer from orthostatic hypotension (OH), many do not experience symptomatology of OH, including dizziness, weakness, and syncope.40,51 The criteria for OH are a drop in systolic blood pressure of at least 20 mmHg and a drop in diastolic blood pressure of at least 10 mmHg upon standing after 15 minutes in a supine position.52 OH is often observed in more severe stages of PD.51 Medications used to treat PD, particularly dopamine agonists, can also cause or worsen pre-existing OH. Additionally, other medications that a patient with PD may be taking, such as TCAs, anticholinergics, or antipsychotics, may contribute to OH.

Many nonpharmacologic strategies exist for treating OH. First, increasing fluid and salt intake may be effective for increasing blood pressure.53 The patient’s use of antihypertensives and diuretics should also be re-evaluated for their necessity. Additionally, wearing compression stockings, increasing caffeine use, elevating the head of the bed, crossing one’s legs, and avoiding alcohol, extreme heat, and sudden postural changes may improve OH.53 If further treatment is indicated, fludrocortisone or midodrine can be very effective for OH, though careful monitoring must be in place to avoid hypertension that could be induced by these agents.53 Fludrocortisone is a mineralocorticoid that reduces OH by increasing plasma volume, whereas midodrine increases vasoconstriction as an alpha-1 receptor agonist.51,53 Nonsteroidal anti-inflammatory drugs may also present an option for OH, though the risks of these medications must be considered. 53 Lifestyle interventions and pharmacologic therapy for OH are summarized in TABLE 4.

tbl4

 

Conclusion

Patients with PD are faced with a host of challenges extending beyond the traditional motor symptoms of the disease. Depression, cognitive impairment, and hallucinations, in addition to problems with swallowing, gastrointestinal function, and sleep, are widespread in PD and poorly impact quality of life. While many people with PD see specialists for the management of their disease, these nonmotor issues are often left unaddressed due to lack of awareness or limited appointment time. A pharmacist is generally more accessible to a patient and may offer practical recommendations and advice, including both pharmacologic and nonpharmacologic strategies, to manage common nonmotor symptoms.

CASE STUDY

Elizabeth, a long-time customer of your pharmacy, is a 68-year-old woman with a history of hypertension, hypercholesterolemia, and depression. Her blood pressure has been maintained at the target of <140/90 mmHg for the last few years on the combination of hydrochlorothiazide 25 mg po daily, lisinopril 20 mg po daily, and amlodipine 10 mg po daily. A few months ago, she reported that her cholesterol had decreased to 190 mg/dL thanks to changes in diet, a new walking regimen, and the simvastatin 40 mg po daily she fills at your pharmacy. She has also been filling the SSRI sertraline 100 mg po daily for depression for the last several years.

One afternoon Elizabeth presents with a new prescription for ropinirole 0.25 mg po three times daily. She tells you she was recently diagnosed with Parkinson’s disease (PD) by a neurologist, who wrote this prescription. As you dispense the ropinirole, you take extra time with Elizabeth, explaining the side effects of this new medication. You pay particular attention to the side effect of somnolence and explain to Elizabeth that if she falls asleep unexpectedly, she should avoid driving and notify you or the neurologist. The following week, you see Elizabeth in the bowel remedies aisle of your pharmacy, and you head out to see how she is doing. She is glad to see you, as she carefully examines various stool softeners. She explains that while she’s always tended toward constipation, she’s even more “plugged up” since starting the ropinirole. You explain that constipation is common in PD and that the ropinirole could be making it worse. Next, you help Elizabeth select an appropriate product.

About a year and a half later, Elizabeth comes to the pharmacy after an appointment with her neurologist. She has a new prescription for carbidopa/levodopa 25/100 mg po three times daily, explaining that the “ropinirole just wasn’t working as well anymore.” You notice Elizabeth looks quite a bit leaner and ask if she has lost weight. She explains that she has lost some weight, although not intentionally, explaining, “I just don’t feel as hungry and the food seems to catch in my throat.” You mention that PD can cause difficulty with swallowing and recommend that she talk to her neurologist about this and consider asking for a speech therapy consult. You also mention that a local PD organization has a singing group that meets once a month to strengthen their voices and help with their swallowing. Elizabeth is relieved to hear that other people with PD experience these problems and that there are actions she can take to treat them.

Over the next several years, Elizabeth continues to be a regular customer, filling her increasing doses of carbidopa/levodopa. About 10 years after her diagnosis of PD, you see Elizabeth gradually struggling more and more. She takes short, shuffling steps up to the pharmacy counter and appears considerably more unsteady and frail. Worrying about her risk of falling and fractures, you

take care to counsel her about the importance of adequate calcium and vitamin D. She tells you that while she has only fallen once or twice, she does tend to feel very dizzy, particularly when she gets up from bed in the morning or after her afternoon nap. You take her blood pressure at the pharmacy, and it is 107/72 mmHg. She has continued to take the hydrochlorothiazide, lisinopril, and amlodipine that were started so long ago. After telling Elizabeth that a drop in blood pressure is a common problem in PD, you recommend that she discuss her blood pressure medications with her primary care provider (PCP) to reassess if she still needs all of them, and you offer to fax the PCP regarding your concern. You show Elizabeth a pair of compression stockings out in the pharmacy and fill her in on other lifestyle modifications she can make to help relieve orthostasis.

The next time Elizabeth is in the pharmacy, she is accompanied by her son, Matthew. This time, Elizabeth’s prescription is for donepezil 5 mg po daily. Matthew informs you that Elizabeth’s mind “isn’t as sharp as it used to be,” so the neurologist recommended this medication. Filling the donepezil, you educate Matthew about the common side effects of this class of medications, including nausea, diarrhea, and a slowed heart rate. Before Elizabeth and Matthew leave the pharmacy, you ask, as you always do, about herbal or OTC medication use. Elizabeth says the only nonprescription medications she takes are her multivitamin, calcium two times daily, and lately Tylenol PM to help her sleep. You recommend that she discontinue the Tylenol PM, considering that its robust anticholinergic and antihistaminic effects could impair cognition, and you advise her to follow up with her PCP for assessment of insomnia.

Matthew comes in a couple of years later, without Elizabeth, and presents a prescription for risperidone 1 mg to be given to Elizabeth in the evening. He tells you that Elizabeth is now living at a nursing home where she frequently hallucinates, and that her behavior has become increasingly aggressive. You note that the nursing home’s provider wrote for the risperidone, and you tell Matthew that there might be a better agent for Elizabeth, considering her PD. You phone the provider and recommend quetiapine, to be started at a dose of 12.5 mg po and titrated as tolerated to effect. You also mention that due to quetiapine’s sedative properties, it may also help Elizabeth sleep. The provider accepts your recommendation and Matthew thanks you for being thorough.

The next time you see Matthew, he has no prescriptions. He explains that he just stopped in to tell you of his mother’s death and to thank you for all the compassion you showed to Elizabeth. He tells you how fondly she always spoke of you and that she was always grateful for the time you took with her.

 

REFERENCES

  1. Truong DD, Bhidayasiri R, Wolters E. Management of non-motor symptoms in advanced Parkinson disease. J Neurol Sci. 2008;266:216-228.
  2. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15(suppl 1):14-20.
  3. Lieberman A. Depression in Parkinson’s disease—a review. Acta Neurol Scand. 2006;113:1-8.
  4. Slaughter JR, Slaughter KA, Nichols D, et al. Prevalence, clinical mani festations, etiology, and treatment of depression in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2001;13:187-196.
  5. Leentjens AF, Van den Akker M, Metsemakers JF, et al. The incidence of depression preceding the onset of Parkinson’s disease: a register study. Mov Disord. 2003;18:414-418.
  6. Tandberg E, Larsen JP, Aarsland D, et al. The occurrence of depression in Parkinson’s disease. A community based study. Arch Neurol. 1996;53:175-179.
  7. Cummins JL. Depression and Parkinson’s disease: a review. Am J Psychiatry. 1992;149:443-454.
  8. Hely MA, Morris JG, Reid WG, et al. Sydney Multicenter Study of Parkinson’s disease: non-L dopa-responsive problems dominate at 15 years. Mov Disord. 2005;20:190-199.
  9. Muslimovic D, Post B, Speelman JD, et al. Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology. 2005;65:1239-1245.
  10. Emre M. Treatment of dementia associated with Parkinson’s disease. Parkinsonism Relat Disord. 2007;13:S457-S461.
  11. American Psychiatric Association. Diagnostic and Statistic Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Press; 1997.
  12. Emre M. Dementia associated with Parkinson’s disease. Lancet Neurol. 2003;2:229-237.
  13. Hobson P, Meara J. Risk and incidence of dementia in a cohort of older subjects with Parkinson’s disease in the United Kingdom. Mov Disord. 2004;19(9):1043-1049.
  14. Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson’s disease. Mov Disord. 2005;20(10):1255-1263.
  15. Giladi N, Treves A, Paleacu D, et al. Risk factors for dementia, depression and psychosis in long-standing Parkinson’s disease. J Neural Transm. 2000;107:59-71.
  16. Hely MA, Reid WG, Adena M, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord. 2008;23(6):837-844.
  17. Fahn S, Jankovic J. Nonmotor problems in Parkinson’s disease. In: Principle and Practice of Movement Disorders. 2nd ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2007:193-204.
  18. Gauthier S. Pharmacotherapy of Parkinson disease and dementia and Lewy Body dementia. Front Neurol Neurosci. 2009;24:135-139.
  19. Rongve A, Aarsland D. Management of Parkinson’s disease dementia: practical concerns. Drugs Aging. 2006;23(10):807-822.
  20. Litvinenko IV, Odinak MM, Mogil’naya VI, et al. Efficacy and safety of galantamine (reminyl) for dementia in patients with Parkinson’s disease (an open controlled trial). Neurosci Behav Physiol.2008;38(9):937-945.
  21. Poewe W, Wolters E, Emre M, et al. Long-term benefits of rivastig mine in dementia associated with Parkinson’s disease: an active treatment extension study. Mov Disord. 2005;21(4):456-461.
  22. Muller T, Welnic J, Fuchs G, et al. The DONPAD-study treatment of dementia in patients with Parkinson’s disease with donepezil. J Neural Transm. 2006;71(suppl):27-30.
  23. Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord. 2006;21(11):1899-1907.
  24. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson’s disease dementia. Cochrane Database Syst Rev. 2006, Issue 1. Art.No.: CD004747. DOI: 10.1002/14651858.CD004747.pub2.
  25. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2009. www.clinicalpharmacology.com. Updated February 2009.
  26. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its conse quences in patients with dementia receiving cholinesterase inhibitors. Arch Intern Med. 2009;169:867-873.
  27. Aarsland D, Ballard C, Walker Z, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a doubleblind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8:613-618.
  28. Zahodone LB, Fernandez HH. Pathophysiology and treatment of psychosis in Parkinson’s disease. Drugs Aging. 2008;25(8):665-682.
  29. Hasnain M, Vieweg WV, Baron MS, et al. Pharmacological management of psychosis in elderly patients with Parkinsonism. Am J Med. 2009;122:614-622.
  30. Ecker D, Unrath A, Kassubek J, et al. Dopamine agonists and their risk to induce psychotic episodes in Parkinson’s disease: a case-control study. BMC Neurol. 2009;9:23-28.
  31. Reddy S, Factor SA, Molho ES, et al. The effect of quetiapine on psychosis and motor function in Parkinsonian patients with and without dementia. Mov Disord. 2002;17(4):676-681.
  32. Friedman JH, Factor SA. Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord. 2000;15(2):201-211.
  33. Schneider F, Althaus A, Backes V, et al. Psychiatric symptoms in Parkinson’s disease. Eur Arch Psychiary Clin Neurosci. 2008;258(suppl 5):55-59.
  34. Tandberg E, Larsen JP, Karlsen K. A community-based study of sleep disorders in patients with Parkinson’s disease. Mov Disord. 1998;13:895-899.
  35. Gagnon J, Bedard M, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology.2002;59:585-589.
  36. Comella CL, Nardine TM, Diederich NJ, et al. Sleep-related violence, injury and REM sleep behavior disorder in Parkinson’s disease. Neurology. 1998;51:526-529.
  37. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol. 2002;59:421-424.
  38. Hobson DE, Lang AE, Martin WR, et al. Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA. 2002;287:455-463.
  39. Frucht S, Rogers JD, Greene PE, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology. 1999;52:1908-1910.
  40. Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson’s disease. Parkinsonism Relat Disord. 2007;13:323-332.
  41. Coates C, Bakheit AM. Dysphagia in Parkinson’s disease. Eur Neurol. 1997;38:49-52.
  42. Miller N, Noble E, Jones D, et al. Hard to swallow: dysphagia in Parkinson’s disease. Age Ageing. 2006;35:614-618.
  43. Morgante L, Salemi G, Meneghini F, et al. Parkinson disease survival: a population-based study. Arch Neurol. 2000;57:507-512.
  44. Plowman-Prine EK, Sapienza CM, Okun MS, et al. The relationship between quality of life and swallowing in Parkinson’s disease. Mov Disord. 2009;24(9):1352-1358.
  45. Fuh JL, Lee RC, Wang SJ, et al. Swallowing difficulty in Parkinson’s disease. Clin Neurol Neurosurg. 1997;99:106-112.
  46. Johnston BT, Li Q, Castell JA, Castel DO. Swallowing and esophageal function in Parkinson’s disease. Am J Gastroenterol. 1995;90(10):1741-1746.
  47. Ondo WG, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson’s disease. Neurology. 2004;62:37-40.
  48. Jost WH. Gastrointestinal motility problems in patients with Parkinson’s disease. Effects of antiparkinsonian treatment and guidelines for management. Drugs Aging. 1997;10:249-258.
  49. Ahmad N, Keith-Ferris J, Gooden E, et al. Making a case for dom peridone in the treatment of gastrointestinal motility disorders. Curr Opin Pharmacol. 2006;6:571-576.
  50. Reddymasu SC, Soykan I, McCallum RW. Domperidone: review of pharmacology and clinical applications in gastroenterology. Am J Gastroenterol. 2007;102:2036-2045.
  51. Mathias CJ. Cardiovascular autonomic function in parkinsonian patients. Clin Neurosci. 1998;5:153-166.
  52. Goldstein DS. Dysautonomia in Parkinson’s disease: neurocardiological abnormalities. Lancet Neurol. 2003;2:669-675.
  53. Pathak A, Senard JM. Pharmacology of orthostatic hypotension in Parkinson’s disease: from pathophysiology to management. Expert Rev Cardiovasc Ther. 2004;2(3):393-403..

Back to Top


  Take Test  |  View Questions