Transcript Presentation Slides - American Academy of Neurology

Treatment of Nonmotor Symptoms
of Parkinson Disease
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
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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© 2010 AMERICAN ACADEMY OF NEUROLOGY
Presentation Objectives
• To review the treatment of nonmotor
symptoms of Parkinson disease (PD)
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Treatment of autonomic symptoms
Treatment of sleep dysfunction
Treatment of fatigue
Treatment of anxiety
• To present evidence-based
recommendations
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Overview
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•
•
•
Background
Gaps in care
AAN guideline process
Analysis of evidence, conclusions,
recommendations
• Recommendations for future research
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
AAN Guideline Process
Clinical Question
Evidence
Conclusions
Recommendations
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Literature Search/Review
Rigorous, Comprehensive, Transparent
Complete
Search
Review abstracts
Review full text
Select articles
Relevant
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Applying This Process
to the Issue
We will now turn our attention to the guidelines.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Clinical Questions
1.
2.
3.
4.
5.
6.
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?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Clinical Questions, cont.
7.
8.
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?
9. What treatments are effective for restless legs
syndrome (RLS) and periodic limb movements of sleep
(PLMS) in PD?
10. What treatments are effective for rapid eye movement
(REM) sleep behavior disorder (RBD) in PD?
11. What treatments are effective for fatigue in PD?
12. What treatments are effective for anxiety in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Literature Review
Inclusion criteria:
- Studies on treatment of a
3,369 abstracts
nonmotor symptom in
patients with PD
- Limited to human subjects
- All foreign languages with
English abstracts
Exclusion criteria:
46 articles
© 2010 AMERICAN ACADEMY OF NEUROLOGY
- 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
AAN Classification of Evidence
for 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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for 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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for 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.***
© 2010 AMERICAN ACADEMY OF NEUROLOGY
AAN Classification of Evidence
for 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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 1: What treatments are effective
for sexual dysfunction in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 2: What treatments are effective
for OH in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 3: What treatments are effective
for urinary incontinence in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 4: What treatments are effective
for gastrointestinal symptoms in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 5: What treatments are effective
for other autonomic symptoms in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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,3 which concluded that botulinum toxin should
be considered for drooling (Level B).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 6: What treatments are effective
for EDS in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 7: What treatments are effective
for insomnia in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 8: Is surgical treatment of PD
with DBS of the STN effective treatment for
insomnia?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
 DBS STN is not currently used to treat sleep disorders.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 9: What treatments are effective
for RLS and PLMS in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
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.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 10: What treatments are effective
for REM RBD in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
 Data regarding the treatment of RBD in PD are
insufficient.
Recommendation:
 There is insufficient evidence to support or refute the
treatment of RBD (Level U).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
 The antiepileptic drug clonazepam and melatonin are
often used to treat RBD in the general population.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 11: What treatments are effective
for fatigue in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
 Methylphenidate is possibly useful in treating fatigue in
patients with PD (one Class II study).
Recommendation:
 Methylphenidate may be considered in patients with
fatigue (Level C).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
 Methylphenidate has the potential for abuse.4 Although
there is no current evidence to suggest such a risk in
PD, patients with PD do have a risk for dopamine
dysregulation syndrome and impulse control disorders
that share many clinical and functional imaging features
with addiction.
 Regarding sleep disorders, there are currently no
controlled studies on treatment for sleep apnea, sleepdisordered breathing, parasomnia, and sleepwalking.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Analysis of Evidence
Question 12: What treatments are effective
for anxiety in PD?
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Conclusion/Recommendation
Conclusion:
 Data regarding the treatment of anxiety in PD are
insufficient.
Recommendation:
 There is insufficient evidence to support or refute the
treatment of anxiety in PD with levodopa (Level U).
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Clinical Context
 Although randomized controlled trials of antianxiety
agents in patients with PD are lacking, their
pharmacologic action and widespread clinical use are
consistent with benefit in anxiety. Antianxiety
medications have been associated with ataxia, falls, and
cognitive dysfunction.
 Controlled studies of treatment for other psychological
symptoms, including obsessive behaviors, gambling,
delusions, decreased motivation, apathy, and
concentration difficulties, are lacking.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Future Research
• Although common, nonmotor symptoms of PD are
underdiagnosed. There is a paucity of research
concerning treatment of nonmotor symptoms in PD.
• A concerted and multidisciplinary effort needs to be
made towards finding treatments for nonmotor
symptoms in PD. The NMS Quest study5 established a
valid and reliable questionnaire to identify nonmotor
symptoms in PD.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Future Research, cont.
• Additionally, a revised version of the Unified Parkinson’s
Disease Rating Scale will include an expanded section
to assess nonmotor symptoms.6 These tools should
assist in screening and early identification of nonmotor
symptoms in PD.
• There are few dedicated controlled trials of drugs to treat
nonmotor symptoms in PD. Such trials are urgently
required.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Future Research, cont.
• These symptoms include the following:
• Sleep disorders (including sleepiness, sleep apnea, sleep
disordered-breathing, parasomnia, RBD, sleepwalking, sleep
attacks, insomnia, EDS, sudden onset of sleep, RLS, PLMS, vivid
dreaming, and fatigue)
• Autonomic symptoms (including OH, orthostasis, constipation,
incomplete bowel emptying, fecal incontinence, nausea, vomiting,
heat intolerance, urinary frequency, urinary incontinence, urinary
urgency, nocturia, sweating, hypersalivation, drooling, seborrhea,
sexual dysfunction in men and women, hypersexuality, ED, and
impotence)
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Future Research, cont.
• Psychological symptoms (including anxiety, obsessive behaviors,
delusions, decreased motivation, apathy, and decreased
concentration
• Sensory dysfunction (including smell, olfaction, taste, saliva,
paresthesias, and visual disturbances)
• Other nonmotor symptoms (including weight loss, anorexia, and
leg edema)
© 2010 AMERICAN ACADEMY OF NEUROLOGY
References
1. Shulman LM, Taback RL, Bean J, Weiner WJ. Comorbidity of the
nonmotor symptoms of Parkinson's disease. Mov Disord.
2001;16(3):507-510.
2. Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Nonrecognition of depression and other non-motor symptoms in
Parkinson's disease. Parkinsonism Relat Disord. 2002;8(3):193197.
3. Naumann M, So Y, Argoff CE, et al. Assessment: Botulinum
neurotoxin in the treatment of autonomic disorders and pain (an
evidence-based review): report of the Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology.
Neurology 2008;70(19):1707-1714.
4. Llana ME, Crismon ML. Methylphenidate: increased abuse or
appropriate use? J Am Pharm Assoc 1999;39(4):526-530.
© 2010 AMERICAN ACADEMY OF NEUROLOGY
References, cont.
5. Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric
properties of a novel non-motor symptoms scale for Parkinson’s
disease: Results from an international pilot study. Mov Disord
2007;22(13):1901-1911.
6. Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder
Society-sponsored revision of the Unified Parkinson’s Disease
Rating Scale (MDS-UPDRS): Process, format, and clinimetric
testing plan. Mov Disord. 2007;22(1):41-47.
For a complete list of references, please access the
full guidelines at www.aan.com/guidelines
© 2010 AMERICAN ACADEMY OF NEUROLOGY
Questions/Comments
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Thank you for your participation!
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