Treatment of Nonmotor Symptoms of Parkinson Disease

1. Report of the Quality Standards Subcommittee of the American Academy of Neurology Theresa A. Zesiewicz, MD, FAAN; Kelly L. Sullivan, MSPH; Isabelle Arnulf, MD; K. Ray Chaudhuri, MD; John C. Morgan, MD, PhD; Gary S. Gronseth, MD, FAAN; Janis Miysaki, MD, MEd, FAAN; Donald J. Iverson, MD, FAAN; William J. Weiner, MD Treatment of Nonmotor Symptoms of Parkinson Disease

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3. Presentation Objectives • To review the treatment of nonmotor symptoms of Parkinson disease (PD) • Treatment of autonomic symptoms • Treatment of sleep dysfunction • Treatment of fatigue • Treatment of anxiety • To present evidence-based recommendations

4. Overview • Background • Gaps in care • AAN guideline process • Analysis of evidence, conclusions, recommendations • Recommendations for future research

5. Background • Nonmotor PD symptoms can be as troublesome as motor symptoms and impact activities of daily living, though they are often underrecognized by health care professionals.1,2 • The nonmotor symptoms reviewed for this guideline are the following: • Autonomic dysfunction: gastrointestinal disorders, orthostatic hypotension, erectile dysfunction (ED), sweating, urinary abnormalities • Sleep disorders: restless legs syndrome, periodic limb movements of sleep, excessive daytime sleepiness, insomnia, REM sleep behavior disorder, obstructive sleep apnea • Fatigue • Anxiety

6. Gaps in Care • Limited evidence was identified per symptomatic treatment area studied (autonomic dysfunction, sleep disorders, and fatigue). • Regarding use of modafinil for excessive daytime sleepiness, evidence was stronger for subjective assessment than for objective assessment. • Treatment of nonmotor symptoms is a little-understood area of care that requires more and better research. • Evidence for treatment of some nonmotor symptoms (e.g., hypotension) is stronger in disease areas other than PD.

7. AAN Guideline Process Clinical Question Evidence Conclusions Recommendations

8. Clinical Questions • The first step in developing guidelines is to clearly formulate questions to be answered. • Questions address areas of controversy, confusion, or variation in practice. • Questions must be answerable with data from the literature. • Answering the question must have the potential to improve care/patient outcomes.

9. Complete Search Review abstracts Review full text Select articles Relevant LiteratureSearch/Review Rigorous, Comprehensive, Transparent

10. AAN Classification of Evidence • All studies rated Class I, II, III, or IV • Five different classification systems: • Therapeutic • Randomization, control, blinding • Diagnostic • Comparison to gold standard • Prognostic • Screening • Causation

11. AAN Level of Recommendations • A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. • B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. • C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. • U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. • Note that recommendations can be positive or negative.

12. Translating Class to Recommendations • A = Requires at least two consistent Class I studies.* • B = Requires at least one Class I study or two consistent Class II studies. • C = Requires at least one Class II study or two consistent Class III studies. • U = Studies not meeting criteria for Class I through Class III.

13. Translating Class to Recommendations, cont. * In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

14. Applying This Processto the Issue We will now turn our attention to the guidelines.

15. Clinical Questions 1. What treatments are effective for sexual dysfunction in PD? • What treatments are effective for orthostatic hypotension (OH) in PD? • What treatments are effective for urinary incontinence in PD? • What treatments are effective for gastrointestinal symptoms in PD? • What treatments are effective for other autonomic symptoms in PD? • What treatments are effective for excessive daytime somnolence (EDS) in PD?

16. Clinical Questions, cont. • What treatments are effective for insomnia in PD? • Is surgical treatment of PD with deep brain stimulation (DBS) of the subthalamic nucleus (STN) effective treatment for insomnia? • What treatments are effective for restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) in PD? • What treatments are effective for rapid eye movement (REM) sleep behavior disorder (RBD) in PD? • What treatments are effective for fatigue in PD? • What treatments are effective for anxiety in PD?

17. Methods • MEDLINE, EMBASE, and SCI • 1966 through November 2006 (see guideline for search terms) • Manual searches made until August 2008 • Relevant, fully published, peer-reviewed articles

18. Methods, cont. • At least two authors reviewed each article for inclusion. • Risk of bias was determined using the classification of evidence for each study (Classes I–IV). • Strength of practice recommendations were linked directly to levels of evidence (Levels A, B, C, and U). • Conflicts of interest were disclosed.

19. 3,369abstracts 46 articles Literature Review • Inclusion criteria: • Studies on treatment of a nonmotor symptom in patients with PD • Limited to human subjects • All foreign languages with English abstracts • Exclusion criteria: • Articles not peer-reviewed • Articles unrelated to PD or treatment of nonmotor PD symptoms • Articles related to treatment of cognitive or mood disorders in PD or treatment of sialorrhea with botulinum toxin

20. AAN Classification of Evidencefor Therapeutic Intervention • Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: • a. concealed allocation • b. primary outcome(s) clearly defined • c. exclusion/inclusion criteria clearly defined • d. adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

21. AAN Classification of Evidencefor Therapeutic Intervention • e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required* 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority. 2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment. (e.g. for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). 3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. 4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

22. AAN Classification of Evidencefor Therapeutic Intervention, cont. • Class II:A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a-e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. • Class III:All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.***

23. AAN Classification of Evidencefor Therapeutic Intervention, cont. • Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion. **Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three are missing, the class is automatically downgraded to Class III. ***Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

24. Analysis of Evidence Question 1: What treatments are effective for sexual dysfunction in PD?

25. Conclusion/Recommendation Conclusion: • Sildenafil citrate (50 mg) is possibly efficacious in the treatment of ED in PD (one Class II study). Recommendation: • Sildenafil citrate may be considered in patients with PD with ED (Level C).

26. Clinical Context • A complete medical evaluation should determine whether other treatable causes of ED may be present, including other medical conditions or side effects of medications. The United States Food and Drug Administration (FDA) has approved sildenafil citrate as a medication to treat impotence.

27. Analysis of Evidence Question 2: What treatments are effective for OH in PD?

28. Conclusion/Recommendation Conclusion: • Data are insufficient to make a recommendation on the use of indomethacin, fludrocortisones, pyridostigmine, or domperidone in treating OH in PD. Recommendation: • There is insufficient evidence to support or refute treatments of OH in PD (Level U).

29. Clinical Context • Randomized controlled trials of mineralocorticoids, alpha-sympathomimetics, and pyridostigmine in patients with PD are lacking. However, their pharmacologic action is consistent with improvement in OH. The only medications that are currently FDA-approved to treat OH are midodrine and L-threo-dihydroxyphenylserine (L-threo-DOPS; Droxidopa), an orally active synthetic precursor of norepinephrine.

30. Analysis of Evidence Question 3: What treatments are effective for urinary incontinence in PD?

31. Conclusion/Recommendation Conclusion: • Data for the treatment of urinary incontinence with apomorphine or DBS are insufficient. Recommendation: • There is insufficient evidence to support or refute treatments of urinary incontinence in PD (Level U).

32. Clinical Context • Although randomized controlled trials of anticholinergics in patients with PD are lacking, their pharmacologic action and widespread clinical use are consistent with benefit in urinary incontinence. Anticholinergics have been shown to cause confusion in patients with PD.

33. Analysis of Evidence Question 4: What treatments are effective for gastrointestinal symptoms in PD?

34. Conclusions/Recommendations Conclusions: • Isosmotic macrogol (polyethylene glycol) possibly improves constipation in PD (one Class II study). Data are insufficient regarding the use of botulinum toxin for constipation in PD. Recommendations: • Isosmotic macrogol (polyethylene glycol) may be considered to treat constipation in PD (Level C). • There is insufficient evidence to support or refute the use of botulinum toxin to treat constipation in PD (Level U).

35. Clinical Context • Although randomized controlled trials of treatments for constipation in patients with PD are lacking, their pharmacologic action and widespread clinical use are consistent with benefit in constipation. Additionally, nonpharmacologic treatments such as increased water and dietary fiber intake have shown clinical benefit in relieving constipation. Drugs used to treat many conditions, including PD, can cause constipation.

36. Analysis of Evidence Question 5: What treatments are effective for other autonomic symptoms in PD?

37. Evidence • Controlled trials evaluating treatment for other autonomic symptoms, including heat intolerance, urinary frequency, urinary urgency, nocturia, sweating, hypersalivation, drooling, seborrhea, hypersexuality, and leg edema, are lacking. • The use of botulinum toxin as a treatment for sialorrhea was reviewed as part of a previous AAN practice parameter,3which concluded that botulinum toxin should be considered for drooling (Level B).

38. Analysis of Evidence Question 6: What treatments are effective for EDS in PD?

39. Conclusions Conclusions: • For patients with PD and EDS, modafinil is effective in improving patients’ perception of wakefulness (two Class I studies), but is ineffective in objectively improving EDS as measured by objective tests (two Class I studies).

40. Recommendations Recommendations: • Modafinil should be considered for patients to improve their subjective perception of EDS (Level A). There is insufficient evidence to support or refute a safety benefit in patients with PD with EDS who engage in activities where sleepiness poses a potential danger (e.g., driving) (Level U). It should be noted that patients who are treated with modafinil may experience an improvement in sleep perception without an actual improvement in objective sleep measurements.

41. Analysis of Evidence Question 7: What treatments are effective for insomnia in PD?

42. Conclusion Conclusion: • Levodopa/carbidopa improved sleep-associated motor symptoms that may contribute to insomnia, but data demonstrating an improvement in objective sleep parameters or sleep satisfaction are insufficient. Melatonin is established as effective in improving patients’ perception of sleep quality (two Class I studies) but data are conflicting regarding objective improvement in sleep quality as measured by polysomnography (PSG).

43. Recommendations Recommendations: • There is insufficient evidence to support or refute the benefit of levodopa on objective sleep parameters that are not affected by motor status (Level U). • There is insufficient evidence to support or refute the treatment of poor sleep quality with melatonin (Level U).

44. Analysis of Evidence Question 8: Is surgical treatment of PD with DBS of the STN effective treatment for insomnia?

45. Conclusion Conclusion: • DBS STN therapy possibly improves sleep quality in patients with advanced PD (Class III studies). However, none of the studies performed DBS STN to treat insomnia as a primary symptom.

46. Clinical Context • DBS STN is not currently used to treat sleep disorders.

47. Analysis of Evidence Question 9: What treatments are effective for RLS and PLMS in PD?

48. Conclusion Conclusion: • Levodopa/carbidopa probably decreases the frequency of spontaneous nighttime leg movements (one Class I study). Data regarding the use of non-ergot dopamine agonists to treat RLS and PLMS specifically in patients with PD are insufficient.

49. Recommendations Recommendations: • Levodopa/carbidopa should be considered to treat PLMS (Level B). • There is insufficient evidence to support or refute the treatment of RLS and PLMS with non-ergot dopamine agonists (Level U).

50. Clinical Context • Data on the use of dopamine agonists to treat RLS and PLMS specifically in patients with PD are lacking. The dopamine agonists ropinirole and pramipexole are the only FDA-approved agents for the treatment of moderate to severe primary RLS.