Neuropsychiatric disturbances in Parkinson’s disease

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

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

3. 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

4. Mov Disord, 2004

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

6. 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

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

8. Dementia Age Disease duration Ocular dysfunction Axial PD Depression Sleep disordersDaytime somnolence Abnormal REM DA agonists Risk factors

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

10. Risk factors for hallucinations Association with family history

11. 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).

12. % Inzelberg et al, Am J Med Gen, 2004 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).

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

14. 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 Analyzed Variables

15. 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?

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

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

18. Patient characteristics Hallucinations No hallucinations • N 76 (32%) 158 • Men 30 % 37 % n.s. • Age 76+7 71+10 <0.0001 • PD yrs 8+5 7+6 n.s. • Tremor 68 % 72 % n.s.

19. Treatment Hallucinations No hallucinations • L-Dopa use 96 % 77 % <0.05 • L-Dopa (yrs) 5+6 6+5 n.s. • Daily dose(mg) 598+216 382+288 <0.01 • DA use 63 % 61 % n.s. • N drugs 2+1 2+1 n.s.

20. Risk factors Hallucinations No hallucinations • Demented 49 % 17 % <0.0001 • MMSE score 23+5 28+2 <0.0001 • Family history 18 % 4 % <0.001 of dementia

21. 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

22. 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.

23. 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).

24. Phantom phenomena or double crush ?

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

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

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

29. 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 Thank you