2. Neuropsychiatric disturbances in Parkinson’s disease Rivka Inzelberg, MD Dept. of Neurology, Movement Disorders Clinic Hillel Yaffe Medical Center, Hadera & Technion, Haifa, Israel

3. Variable constellation- not necessarily continuum 61 % > 1 psychiatric symptom Depression, apathy Anxiety, panic Sleep disorders Hallucinations Psychotic symptoms Delirium, agitation

4. Hallucinations in PD Frequent in medicated PD patients On a background of clear sensorium Types usually visual auditory (Inzelberg et al., 1998) tactile (Fenelon et al., 2002) gustatory (Holroyd et al., 2001) cenesthetic (Jimenez-Jimenez et al., 1997) From “An artist’s view of drug-induced hallucinations” Eserbach, Mov Disord, 2003

5. Mov Disord, 2004

6. Risk for nursing home placement Relative risk 1 2 2.5 15 Goetz et al., Neurology, 1993

7. Risk factors for hallucinations in PD N=216 patients- 39.8 % hallucinations Risk factors Cognitive impairment Daytime somnolence – sleep wake cycle Long PD duration Fenelon et al, Brain,2000

8. Follow-up study In a year additional 15 % started to hallucinate Risk factors Severe sleep disturbances Ocular disorders High axial motor score Maindreville, et al, Mov Disord 2005

9. Risk factors Dementia Age Disease duration Ocular dysfunction Axial PD Depression Sleep disorders Daytime somnolence Abnormal REM DA agonists

10. Observations Treatment alone cannot explain their occurrence L-Dopa levels peaks do not correlate hallucinations

11. Risk factors for hallucinations Association with family history

12. Family history and PD course PD patients with positive family history of PD might have a different disease course (de la Fuente-Fernandez et al, 1998, Inzelberg et al, 1998, 2004).

13. Mean duration of disease until dementia: 10.1+6.0 years for FH and 4.7+4.5 yrs for NFH (p=0.0022). Mean age FH was 72.5+10.6 and of NFH 74.1+10.5 yrs (p>0.1). % Inzelberg et al, Am J Med Gen, 2004

14. Patients 276 consecutive PD patients Outpatient Movement Disorders Clinic Parkinson’s disease was diagnosed in all cases according to standard criteria

15. Analyzed Variables Disease variables Age Age of PD onset Disease duration L-Dopa treatment duration L-Dopa dose Number of antiparkinsonian drugs Dementia -DSM- IV MMSE Family history PD Tremor Dementia

16. Hallucination questionnaire 1. Have you ever had hallucinations in the past or present? Y/N 2. Type...visual, auditory, tactile, other 3. Content, description 4. Mood congruent?

17. Hallucinations 158 43 76 N=276, N=234 reliable information Mean age :76 + 11 years Mean age at disease onset 66 + 13 years (32 %)

18. 65 People 65 People 1 Tree Branches 1 Tree Branches 3 Animals 3 Animals 1 Tactile 1 Tactile 6 Auditory 6 Auditory 76 (all) Visual 76 (all) Visual Hallucination Types

19. Patient characteristics Hallucinations No hallucinations N76 (32%)158 Men30 %37 %n.s. Age76+771+10<0.0001 PD yrs 8+57+6n.s. Tremor 68 %72 %n.s.

20. Treatment Hallucinations No hallucinations L-Dopa use 96 %77 %<0.05 L-Dopa (yrs)5+66+5n.s. Daily dose(mg)598+216382+288<0.01 DA use63 %61 %n.s. N drugs2+12+1 n.s.

21. Risk factors Hallucinations No hallucinations Demented49 %17 % <0.0001 MMSE score23+528+2<0.0001 Family history 18 %4 %<0.001 of dementia

22. Results The stepwise regression procedure chose the dementia and positive family history of dementia as most prominent risk factors (p<0.001) for hallucinations. Other variables namely, age, L-Dopa treatment and dose, disease duration, family history of PD or presence of tremor were not explanatory variables. Paleacu and Inzelberg, Neurology, 2005

23. A genetic trend ? Hallucinations – in the presence of an environmental stimulus (dopaminergic treatment) might be a heritable phenotype. The psychotic phenotype aggregates in siblings of Alzheimer’s disease and Huntington’s disease patients.

24. No relationship with hallucinations Dopamine receptor variants show no association with hallucinations (Makoff et al., 2000, Kaiser et al, 2003). No relationship between ApoE4 & hallucinations (Inzelberg et al, 2000). No relationship with COMT (low, intermediate and high metabolizers) (Camicioli, et al. 2005).

25. Phantom phenomena or double crush ?

26. Visual dysfunction in PD Longer VEP Abnormal pattern ERG Decreased contrast sensitivity Decreased color discrimination – blue green Decreased amount DA in retina-postmortem

28. RNFL thickness * Inferior retinal quadrant microns ** * p<0.05 ** p<0.01 Inzelberg et al., 2004

29. An integrative model Adapted from Diedreich et al, Mov Disord 2005 Defective retinal DA function Poor visual performance Partial visual deprivation Cognition ? Compensation – visual memory contents Visual hallucinations REM Sleep-wake cycle Genetic predisposition

30. Thank you Diana Paleacu, MD Abarbanel Mental Health Center, Batyam, Israel Edna Schechtman, PhD Ben Gurion University, Beer Sheva, Israel Funded by a grant of the Israel Ministry of Helath, Chief Scientist Rosa Strugatsky, MD, Neurology Department, Hillel Yaffe Medical Center Avinoam Ophir, MD Opthalmology Department, Hillel Yaffe Medical Center, Hadera