1. Surgical management: DBS and effects on gait, posture and falls overview Miguel Coelho, MD Neurology Department, Hospital Santa Maria Clinical Pharmacology Unit, IMM, Lisbon Portugal 25 September 2014 2nd Annual Allied Health Professional Summer School

2. Financial Disclosure Nothing to declare.

3. Outline Indications for DBS in PD. Overall efficacy of DBS for advanced PD. Safety of DBS for advanced PD. DBS effects on gait, posture and falls.

4. Levodopa-induced motor complications Levodopa-induced motor complications (MC): high incidence in PD patients treated with L-dopa. General rule: ~ 40-50% after 5 yrs of L-dopa. Consist of motor fluctuations & dyskinesias. High impact on disability and QoL. Difficult to manage and complex drug regimens. Ahlskog & Muenter 01; Schrag & Quinn 00; Marras 04

5. Indications for DBS in PD PD with disabling MC refractory to best medical treatment. Disabling tremor refractory to medical treatment. Off dystonia. Neither curative nor disease-modifying. Benefit on QoL (mostly motor sub-domains; in those ≤ 65 yrs-old) Bronstein 11; Lang 06; Deuschl 06; Hilker R et al 05; Kleiner-Fisman et al 06; Pahwa et al 06; Derost et al 07

6. Candidates for DBS in PD  70-75 years. Good response to L-dopa (best predictor). Indepedent on ADL during ON. No or few axial non-LD-responsive motor signs. Bronstein 11; Lang 06

7. Candidates for DBS in PD No Dementia. No severe treatment-resistant depression or other severe psychiatric disorder. Psychosis should be carefully assessed (drug- induced ?). Realistic expectations & good social support. Bronstein 11; Lang 06

8. Efficacy of DBS Superior to best medical therapy (BMT). Overall efficacious and safe on long-term (10 years), except axial signs. Improves QoL. STN or GPi. Schuepbach 13; Odekerken 13; Castrioto 11; Deuschl 06; Williams 10; Weaver 09; Follett 10;

9. Efficacy of DBS Motor Benefit: – Off periods in 30-60%. – “On without dyskinesias” in 45%. – Disability of dyskinesias in 50-60%. – in parkinsonism severity (UPDRS motor off) in 40- 50%. Odekerken 13; Castrioto 11; Deuschl 06; Williams 10; Weaver 09; Follett 10; Shupbach 07; Anderson 05; Parkinson Study Group 01; Limousin 96;

10. Efficacy of DBS Motor Benefit: – ADL (UPDRS II off) in 20-40%. – Levodopa Equivalent Dose (LED) in 40-50%. –STN > GPi Odekerken 13; Castrioto 11; Deuschl 06; Williams 10; Weaver 09; ; Follett 10; Krack 03; Kleiner-Fisman et al 06; Pahwa et al 06; Derost et al 07; Shupbach et al 07; Anderson et al 05; Parkinson Study Group 01; Limousin 96;

11. Krack 03 Rodriguez-Oroz 05

12. Safety of DBS Safety: –High frequency of clinical relevant AEs (11%). –Increase concern with safety. –Neuropsychiatric side effects. –Axial side effects (gait \ balance \ speech) Videnovic 08; Kleiner-Fisman et al 06; Pahwa et al 06;

13. Procedure and hardware-related AEs Videnovic 08

14. Stimulation independent \ disease progression AEs Videnovic 08

15. DBS on gait, posture and falls The effects of DBS on balance and gait are difficult to interpret because they are complex behaviors that may or may not be sensitive to LD or DBS, and many postoperative observations are anecdotal. Aspects of gait and speech that improve with LD therapy improve with DBS; however, these may later worsen with disease progression. There was consensus that STN DBS can worsen speech and gait in some patients whose symptoms may be improved by altering stimulation parameters. Bronstein 11

16. DBS on gait, posture and falls Does DBS improve gait, posture and falls? –Short-term –Long-term –Compare to what? dopa-sensitive signs? Can DBS deteriorate axial symptoms in the short term? STN vs Gpi?

17. Does DBS improve gait, posture and falls? Rodriguez-Oroz 05 Stim ON

18. Krack 03 Stim on +Med off

19. Follett 10 Odekerken 13 Stim on med off med on

20. Castrioto 11

21. Can DBS deteriorate axial symptoms in the short term? Castrioto 11 Med off

22. Schuepbach, Earlystim 13 24 months

23. Weaver 09 Williams 10, PD SURG UK 12 months

24. Rodriguez-Oroz 05

25. Okun, 12 STN; control with no stimulation till 3 months

26. Adams 11 Ferraye 08

27. Umemura 10

28. Is there a difference between STN and GPi? St. George 10 Meta-regression of 11 studies

29. Follett 10

30. Moro 10 Multicentre study with blinded and unblided assessments at 5-6 yrs FU N = 51

31. Odekerken 13 Stim on med off med on AEs

32. Rodriguez-Oroz 05 Stim ON STN GPI

33. Gait & Posture & Falls DBS improves gait and balance comparing on\off stimulation in the short and medium-term. DBS effect on these signs < apendicular. But DBS seems to worsen falls compared to baseline in a subset of patients. But DBS seems to worsen gait compared to baseline in a subset of patients.

34. Gait & Posture & Falls STN might be worse than GPi. Different test conditions (i.e med on\dbs off) Diverse clinical & laboratory outcomes among “axial symptoms umbrella”: different results.