© 2006 American Academy of Neurology Practice Parameter: Diagnosis and Prognosis of New Onset Parkinson Disease (An Evidence-Based Review) American Academy of Neurology Quality Standards Subcommittee O. Suchowersky, MD; S. Reich, MD; J. Perlmutter, MD; T. Zesiewicz, MD; G. Gronseth, MD; W.J. Weiner, MD

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© 2006 American Academy of Neurology Presentation Objectives To define key issues in the diagnosis of Parkinson’s disease (PD) To define features influencing progression To make evidence-based recommendations

© 2006 American Academy of Neurology Overview Background/Epidemiology Gaps in PD care AAN guideline process Diagnosis of PD Prognosis of PD Summary Recommendations for Future Research

© 2006 American Academy of Neurology Background PD a neurodegenerative disorder Caused by a loss of dopaminergic neurons in the substantia nigra and other dopaminergic and nondopaminergic areas of the brain

© 2006 American Academy of Neurology Descriptive Epidemiology of Parkinson Syndrome Incidence –5–24/10 5 worldwide (ref) –20.5/10 5 USA (ref) Prevalence –57–371/10 5 worldwide (ref) –300/10 5 USA/Canada (Strickland & Bertoni, 2004) –Prevalence of PS/PD rising slowly with aging population

© 2006 American Academy of Neurology Gaps in PD Care PD is a complex disease and hard to diagnose clinically, especially in the early stages –No simple diagnostic test available About 5-10% of patients with PD misdiagnosed (Hughes et al., 1992)

© 2006 American Academy of Neurology Gaps in PD Care Up to 20% of patients have alternative diagnoses at autopsy –Multiple system atrophy (MSA) –Progressive supranuclear palsy (PSP) –Alzheimer disease-type pathology

© 2006 American Academy of Neurology Seeking Answers How do we find the answers to the questions that arise in daily practice? In order to keep up to date, need to read 29 articles a day, 365 days a year (Didsbury, 2003) Or find someone who has found and summarized the relevant data for you

© 2006 American Academy of Neurology American Academy of Neurology Guideline Process Clinical Question Evidence Conclusions Recommendations

© 2006 American Academy of Neurology Clinical Question Question should address an area of quality concern, controversy, confusion, or variation in practice Question must be answerable with sufficient scientific data –Potential to improve clinical care and patient outcomes

© 2006 American Academy of Neurology Literature Search/Review: Rigorous, Comprehensive, Transparent Search Review abstracts Review full text Select articles Relevant Complete

© 2006 American Academy of Neurology AAN Level of Recommendations A = Established as effective, ineffective, or harmful for the given condition in the specified population B = Probably effective, ineffective, or harmful for the given condition in the specified population C = Possibly effective, ineffective, or harmful for the given condition in the specified population U = Data is inadequate or conflicting; given current knowledge, treatment is unproven

© 2006 American Academy of Neurology AAN Level of Recommendations A = Requires two consistent Class I studies B = Requires one Class I study or two consistent Class II studies C = Requires one Class II study or two consistent Class III studies U = Studies not meeting criteria for Class I through Class III

© 2006 American Academy of Neurology Clinical Questions 1.Which clinical features and diagnostic modalities distinguish PD from other parkinsonian syndromes? 2.Which clinical features predict rate of disease progression?

© 2006 American Academy of Neurology Methods Literature Search: –MEDLINE, EMBASE, CINHAL, and Cochrane Database of Systematic Reviews ( ) Only articles written in English included –Second MEDLINE search (1966 through Aug. 2004) –Another search using the bibliographies of retrieved articles and knowledge of the expert panel extending to January 2005

© 2006 American Academy of Neurology Methods At least two authors reviewed each paper Risk of bias determined using the classification of evidence for each study (Class I–IV) Strength of practice recommendations linked directly to level of evidence (Level A–U) Conflicts of interests disclosed

© 2006 American Academy of Neurology Literature Search/Review: Diagnosis of PD 31 articles 176 articles Exclusion criteria: -Studies not including at least 10 subjects with PD and 10 in the comparison group -Articles that were off topic -Review articles

© 2006 American Academy of Neurology Literature Search/Review: Prognosis of PD 7 articles 59 articles Exclusion criteria: -Articles published before 1990 because of changes in the case definition of PD -Articles that were off topic -Review articles

© 2006 American Academy of Neurology Diagnosis of PD

© 2006 American Academy of Neurology Clinical Question 1 Which clinical features and diagnostic modalities distinguish PD from other Parkinsonian syndromes?

© 2006 American Academy of Neurology Diagnosis of PD Categories: –Clinical –Acute challenge testing –Radiological evaluation –Neurophysiological testing –Biochemical testing –CSF examination –Olfactory testing

© 2006 American Academy of Neurology Diagnosis of PD: Clinical Features Four articles that addressed the diagnostic accuracy of clinical features helpful in distinguishing PD from other forms of parkinsonism –Three class II studies –One class III study

© 2006 American Academy of Neurology Diagnosis of PD: Clinical Examination AuthorTypeCohort Size SpectrumDiagnostic Predictor Reference Standard for PD Colosimo et al 1995 Case control Class 3 MSA(16); PD(20); PSP(16) NarrowRapid progression; symmetry; no tremor; poor response to dopa; autonomic dysfunction Autopsy Jankovic et al 2000 Retrospective cohort Class (DATATOP cohort) NarrowPoor response to levodopa, atypical clinical features Clinical assessment (up to 6 yrs), autopsy, imaging

© 2006 American Academy of Neurology Diagnosis of PD: Clinical Examination AuthorTypeCohort Size SpectrumDiagnostic Predictor Reference Standard for PD Wennings et al 2000 Case control Class 2 MSA(38); PD (100) BroadClinical exam, med side effects Autopsy Wennings et al 1999 Case control Class 2 MSA(15); PD(11); DLB(14); PSP(24); CBD(13) BroadTime to onset of falling from onset of symptoms Autopsy

© 2006 American Academy of Neurology Factors that predict against PD and are supportive of other parkinsonian syndromes in early stages of disease (Level B) –Symmetry of motor signs –Lack of tremor –Poor response to levodopa –Falls early in course –Dysautonomia early in course –Rapid progression (to H & Y III within 1 year) Recommendation for Diagnosis of PD

© 2006 American Academy of Neurology Diagnosis of PD: Clinical Features Longitudinal follow-up important –Lack of autonomic, oculomotor, cognitive abnormalities at 5 years supports PD

© 2006 American Academy of Neurology Diagnosis of PD: Levodopa/Apomorphine Challenge Response to chronic levodopa therapy an important factor in distinguishing PD from a parkinsonian syndrome Acute dopaminergic challenge may have similar predictive value –Levodopa –Apomorphine

© 2006 American Academy of Neurology Diagnosis of PD: Levodopa/Apomorphine Challenge Two articles that addressed the predictive value of levodopa/apomorphine challenge in distinguishing PD from other forms of parkinsonism –One class I study –One class II study

© 2006 American Academy of Neurology Diagnosis of PD: Levodopa/Apomorphine Challenge AuthorTypeCohort SizeDiagnostic Predictor Reference Standard for PD SpecificitySensitivity Rossi et al 2000 cohort survey Class 2 PD(83);MSA(28) ;PSP(6);unknwn (17) UDPRS change after apomorphine challenge 1.5 or 4.5 mg or dopa 25/250 dopa apo 1.5mg apo 3 apo % 66% 64% 67% 77% 71% 77% Merello et al 2002 cohort survey Class 1 PD(55);nonPD(2 7-- VP(5),MSA(4);E T(4); drug-induced(3); PSP(3);CBD(3); unknwn(3);DLB( 3)) 30% improve on UPDRS 3 after dopa 25/250 f/u of 24 mos for clinical diagnosis and chronic response to dopa 81%71%

© 2006 American Academy of Neurology Recommendation for Levodopa/Apomorphine Challenge Both levodopa and apomorphine challenge tests should be considered when diagnosis of PD in doubt (Level B)

© 2006 American Academy of Neurology Diagnosis of PD: Levodopa/Apomorphine Challenge 30% false positive and negative rates Acute levodopa challenge response a reliable predictor of chronic response to levodopa Pretreatment with domperidone* in drug naïve patients recommended * domperidone is not available in the United States

© 2006 American Academy of Neurology Diagnosis of PD: Olfaction Olfaction frequently impaired in PD Three Class II studies identified

© 2006 American Academy of Neurology Diagnosis of PD: Olfactory Testing AuthorClassCohort Size TestResults Doty et al, 1993 IIPSP (21) PD (21) NC (21) UPSITPSP similar to NC PD abn (p<0.001) Mueller et al, 2002 IIPD (37) MSA, PSP, ET (13) Sniffin Sticks PD had anosmia Wenning et al, 1995 IIPD (118) MSA (29) PSP (15) CBD (7) NC (123) UPSITPD>MSA>PSP/CBD/NC Sensitivity 77% Specificity 85%

© 2006 American Academy of Neurology Recommendation for Olfactory Testing Olfaction testing should be considered to distinguish PD from PSP and CBD (Level B) –UPSIT or “Sniffin’ Sticks tests Differences between PD and MSA not as pronounced

© 2006 American Academy of Neurology Diagnosis of PD vs. Other Parkinsonisms Not useful (Level C) GH stimulation by clonidine Electro-oculography SPECT scanning

© 2006 American Academy of Neurology Diagnosis of PD vs. Other Parkinsonisms Insufficient Evidence (Level U) Urodynamics Autonomic testing Urethral/anal EMG MRI, FDG PET, brain sonography

© 2006 American Academy of Neurology Prognosis of PD

© 2006 American Academy of Neurology Clinical Question 2 Which clinical features predict the rate of disease progression?

© 2006 American Academy of Neurology Prognosis of PD Prognostic factors examined: –Age at disease onset –Sex –Cognitive and motor symptoms Seven studies –Six Class II –One Class III

© 2006 American Academy of Neurology Recommendations for the Prognosis of PD In patients with newly diagnosed PD, the following should be used to predict more rapid rate of motor progression (Level B): –Older age at onset as an initial symptom –Rigidity/hypokinesia as an initial symptom

© 2006 American Academy of Neurology Recommendations for the Prognosis of PD Predictors of faster rate of motor progression (Level C): –Postural instability/gait difficulty –Male sex –Presence of associated comorbidities Stroke, visual, auditory

© 2006 American Academy of Neurology Recommendations for the Prognosis of PD Predictors of earlier nursing home placement and decreased survival (Level C) –Older age at onset –Dementia –Poor responsiveness to dopaminergic meds

© 2006 American Academy of Neurology Recommendations for the Prognosis of PD Predictors of earlier cognitive decline and dementia (Level B): –Older age at onset –Initial hypokinesia/rigidity

© 2006 American Academy of Neurology Recommendations for the Prognosis of PD Tremor as a presenting symptom may be used to predict a more benign course and longer therapeutic benefit to levodopa (Level C)

© 2006 American Academy of Neurology Summary Improving accurate diagnosis –Clinical features predictive of other forms of parkinsonism: Early falls Poor response to levodopa Symmetry of motor manifestations Lack of tremor Early autonomic dysfunction

© 2006 American Academy of Neurology Summary Levodopa or apomorphine challenge and olfactory testing may be helpful in distinguishing PD from other forms of Parkinsonism

© 2006 American Academy of Neurology Summary Predictive factors for more rapid motor progression, nursing home placement, and shorter survival time –Older age at onset of PD –Associated comorbidities –Presentation with rigidity and bradykinesia –Decreased dopamine responsiveness

© 2006 American Academy of Neurology Recommendations for Future Research Other techniques to improve diagnostic accuracy and address disease progression (neuroimaging, levodopa challenge tests) Long term follow-up and autopsy confirmation to determine accuracy of new diagnostic tests (genetic screening)

© 2006 American Academy of Neurology Recommendations for Future Research Methods for presymptomatic testing to identify patients at risk of developing PD Knowledge of disease progression

© 2006 American Academy of Neurology To access the full guideline please visit: AAN.com/Guidelines

© 2006 American Academy of Neurology Questions, Comments?

© 2006 American Academy of Neurology Thanks for your participation!