Sintomi non-motori nel Parkinson

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1 Sintomi non-motori nel Parkinson Angelo Antonini Centro Parkinson - ICP Milano, Italia

2 Segni e sintomi della malattia di Parkinson Sintomi non-motori iniziali Perdita di interesse e di motivazione Depressione Dolore muscolare articolari Vertigine Disturbi vegetativi Sintomi motori iniziali Riduzione nei movimenti spontanei Impaccio nei movimenti fini Ipofonia Tremore a riposo Sintomatologia motoria completa Rigidità Bradicinesia Tremore a riposo Instabilità posturale

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4 First NMS at onset (N = 1307) Articular/Muscular Pain Fatigue Anxiety Depression Apathy Gastro-intestinal symptoms Behavioural sleep disturbances (REM) Weight variation Genitourinary symptoms Anhedonia Cognitive symptoms Sexual dysfunction Other Hallucination 11.4% 8.7% 7.1% 6.4% 5.4% 5.1% 4.3% 4.0% 1.5% 1.2% 28.2% 25.3% 24.9% 23.6% 0% 10% 20% 30% 40% 50% Antonini et al. Neurol Sciences 2008; Barone et al. submitted

5 Prolonged lack of therapy is associated with worsening quality of life Grosset D, et al. J Neurol Neurosurg Psychiatry 2007;78:465-9

6 Relationship between NMS frequency and severity of disease (N = 1072) Disease Severity as Hoehn and Yahr score NMS Pain Urinary Sleep dysfunction Fatigue Apathy Loss of attention Skin Psychiatric Respiratory Gastrointestinal Antonini et al. Neurol Sciences 2008; Barone et al. submitted

7 Relevance of MMSE on frequency of NMSs RESPIRATORY (*) 16% 33% PSYCHIATRIC (*) 65% 85% SKIN 23% 32% ATTENTION/MEMORY (*) APATHY (*) FATIGUE (*) 27% 41% 56% 56% 76% 77% SLEEP 63% 73% CARDIOVASCULAR 14% 19% URINARY 56% 67% PAIN GASTRO INTESTINAL (*) 60% 66% 59% 74% MMSE SCORE ² 23.8 MMSE SCORE > 23.8

8 Depression is the clinical variable most impacting on quality of life Grosset et al. Mov Disord 2005

9 Presence of depressive symptoms determines therapy initiation in early PD Ravina B, et al. Neurology 2007;69:342-7

10 Depression and cognition are the main predictors of physical decline in PD: DATATOP retrospective evaluation Marras C, et al. Movement Disorders 2008

11 Unraveling depression in Parkinson s Disease Small number of PD patients treated for depression PRIAMO: 169/1072 (14%), Danish survey 4565/ (19.9%) Most current studies are open-label Depression affects quality of life and patientt selfperception of motor function (Kulisewsky Eur J Neurol 2008) Different scales relate differently to overall view of depression (Barone PRODEST 2008) Antonini A, Europ J Neurol 2008

12 PRODEST-PD (PROfile of Depressive SympToms in Parkinson s Disease) Multinational, cross-sectional survey with outcome measures from rating scales in the defined trial population (n=1016). The depression rating scales used: HADS, HAMD- 17, BDI-1A. To relate symptoms of depression with cognition, mood, motivation and motor behavior, the following rating scales are used: FAB (cognitive), DSM-IV (mood parts A, B, C, E) and UPDRS-III (PD/motor symptoms). Barone P, et al. Poster P854, 12 th Annual International Congress of Parkinson s Disease and Movement Disorders, Chicago, IL, USA, June 22-26, 2008

13 Pramipexole Depression Study International, double-blind, randomized, placebo-controlled clinical trial. Objective: To investigate the efficacy of pramipexole, compared with placebo in treating Parkinson s disease patients with stable motor function and depressive symptoms. The efficacy of pramipexole vs. placebo will be based on the change from baseline in the Beck Depression Inventory (BDI) total score after 12 weeks of treatment. Methods 296 entered PD patients (age yrs) from 76 active centers in 13 European countries Inclusion Criteria: Modified Hoehn and Yahr stage I to III; Stable motor function (without motor fluctuations or dyskinesia); On antiparkinsonian therapy (except DAs) at least previous 4 wks; Depressive symptoms (GDS) Results: Expected by end of 2008 Barone P, et al. Poster P601, 12 th Annual International Congress of Parkinson s Disease and Movement Disorders, Chicago, IL, USA, June 22-26, 2008; BI data on file.

14 Most common site of pain in PD vs. controls Site of pain starting at or after reference age Neck Odds ratio* (95% Confidence interval) p 1.1 (0.5 to 2.3), p=0.75 Shoulder 2.8 (1.4 to 5.8), p=0.004 Arm 1.7 (0.9 to 3.8) p=0.08 Back 1.9 (1.1 to 3.4), p=0.02 Leg or foot 1.9 (1.1 to 2.9), p=0.03 * Adjusted for age sex, referral center, education, depression, and medical conditions associated with pain Defazio G, et al. Arch Neurol 2008 (in press)

15 Frequency of chronic pain in PD and control subjects Pain PD patients (n=402) Control subjects (n=317) P All types 281 (70%) 199 (63%) 0.04 Dystonic 27 (6%) 0 <0.001 Non dystonic 268 (64%) 199 (63%) 0.28 Defazio G, et al. Arch Neurol 2008 (in press)

16 Presence of dystonic pain is associated with more severe PD symptoms Dystonic pain (n=27) Non-dystonic pain (n=170) No pain (n=217) Age (years) 69.7± ± ±9.9 Sex(men/women) 16 /13 111/74 143/74 Years of schooling 7.7± ±4 8.5±3.9 Duration of disease (years) 9±8 7.7± ±10.2 Hoehn&Yahr staging 2.7±0.7 * 2.2± ±0.7 UPDRS score part III 28±11* 21±11 20±9 Levodopa daily dose (mgs) 615±363 * 458± ±352 UPDRS score part IV 4±3.4 * 2.2±3.1 2±2.9 One way Anova: * different from the other groups, p < 0.05

17 Effetto della presenza di uno specifico NMS sulla PDQ-39

18 Dolore, affaticabilità e disturbi del sonno hanno la maggiore incidenza per anno Incidence Presence at 1-y follow-up Pain Sleep Fatigue 13.4% 13.2% 12.3% 60.7% 58.4% 63.1% Attention/memory 11.3% 44.2% Gastrointestinal Urinary 10.8% 10.5% 58.1% 57.8% Skin 10.3% 25.9% Psychiatric symptoms 9.5% 59.0% Apathy 9.4% 29.7% Respiratory 9.1% 18.3% Cardiovascular 6.0% 13.0%

19 Incidenza di demenza ad un follow-up di 12-mesi (N=934) 50% 40% 38% 30% 20% 10% 7% 7% 6% 0% PSP MSA PD VP

20 Emergence of non-motor symptoms is often the first sign of wearing-off Sensory disorders Autonomic dysfunction Gastrointestinal disorders Non-motor symptoms Neuropsychiatric disorders e.g. psychosis, depression, anxiety and dementia Sleep disorders Orthostatic hypotension Urologic disorders Adler CH, Mov Disord 2005;20 Suppl 11:S23-9

21 Patient mobility becomes with disease progression increasingly dependent on peripheral levodopa bioavailability Dyskinesia Dyskinesia Dyskinesia on on on off off off

22 Wearing-off questionnaire (WOQ-19) Stacy et al. Movement Disorders 2005

23 Many patients complain of the occurrence of nonmotor symptoms associated with wearing-off Tiredness Cloudy mind or dullness in thinking Pain Panic attacks Chest discomfort Abdominal discomfort Sweating Restlessness Slowness in thinking Bladder problems Anxiety Mood changes Abnormal sensations such as: Hot/cold Aching Numbness Stacy et al. Movement Disorders 2005

24 Motor and non-motor features improved after therapy administration in patients with motor fluctuations Martinez-Martin et al. Movement Disorders 2008

25 Six-month improvement of mean non-motor scale subscores from oral levodopa to intrajejunal levodopa infusion (N = 20 pts) GI Urinary Cardiovasc Sexual Sleep Halluc Memory Depression Misc Antonini, Chaudhuri, Odin, data on file

26 Non-motor symptoms are main reason for acute PD admissions in regional hospitals Vimercate N=373 Pavia N=180 Motor Symptoms* 12% N=46 32% N=59 Non-Motor Symptoms 88% N=327 68% N=121 * Worsening disease, psychiatric complications. Courtesy Drs Braga, Pederzoli, Crespi

27 Acute hospital admissions are associated with high risk of patient death due to complications Died on first admission 19 (7%) Second admission within 1 yr 16 (6%) Total 35 (13%) Characteristics of 19 patients who died at first admission Mean age 79 yrs Cause Sepsis 3 (16%) Respiratory infection 6 (31%) Heart failure (ACC) acute infarct 5 (27%) Stroke 2 (10%) Renal Insufficiency 2 (10%) Diabetes 1 (6%) Courtesy of Dr Braga, Vimercate Hospital

28 I sintomi non-motori determinano il deterioramento clinico nella malattia di Parkinson Kempster et al. Brain 2007

29 Parkinson: ricoveri 2005 (DRG 012) Regione Dimessi Degenza media PIEMONTE VALLE D'AOSTA LOMBARDIA P.A. BOLZANO P.A. TRENTO VENETO FRIULI V.G LIGURIA EMILIA ROMAGNA TOSCANA UMBRIA MARCHE LAZIO ABRUZZO MOLISE CAMPANIA PUGLIA BASILICATA CALABRIA SICILIA SARDEGNA TOTALE ITALIA

30 Meno di 1/3 dei ricoveri acuti per Parkinson sono in neurologia N Pazienti % Medicina Interna Neurologia Ortopedia Urologia Pneumologia

31 Una migliore integrazione con i servizi territoriali domiciliari (prevenzione attiva) può portare ad una riduzione di ricoveri internistici e possibilmente di quelli chirurgici

32 Conclusioni I NMSs che riguardano comportamento e stato cognitivo sono tra i più comuni in pazienti con Parkinson Affaticabilità e dolore diventano progressivamente rilevanti con il progredire della malattia Un diverso atteggiamento terapeutico mirato a garantire una stimolazione farmacologica più stabile e una migliore gestione territoriale del paziente potrebbero ridurre i costi di degenza di questi pazienti