1. Parkinson’s disease PÉCSI TUDOMÁNYEGYETEM SZEGEDI TUDOMÁNYEGYETEM PTE Neurológiai Klinika „AZ ÉLETTUDOMÁNYI-KLINIKAI FELSŐOKTATÁS GYAKORLATORIENTÁLT ÉS HALLGATÓBARÁT KORSZERŰSÍTÉSE A VIDÉKI KÉPZŐHELYEK NEMZETKÖZI VERSENYKÉPESSÉGÉNEK ERŐSÍTÉSÉRE” TÁMOP-4.1.1.C-13/1/KONV-2014-0001

2. Parkinson’s disease Deep brain stimulation PÉCSI TUDOMÁNYEGYETEM SZEGEDI TUDOMÁNYEGYETEM PTE Neurológiai Klinika „AZ ÉLETTUDOMÁNYI-KLINIKAI FELSŐOKTATÁS GYAKORLATORIENTÁLT ÉS HALLGATÓBARÁT KORSZERŰSÍTÉSE A VIDÉKI KÉPZŐHELYEK NEMZETKÖZI VERSENYKÉPESSÉGÉNEK ERŐSÍTÉSÉRE” TÁMOP-4.1.1.C-13/1/KONV-2014-0001

3. Components of a DBS system It has three major components  Implantable pulse generator  Connecting cable  Stimulating electrode TÁMOP-4.1.1.C-13/1/KONV-2014-0001

4. High frequency: functional inhibition Low frequency: functional enhancement Pathomechanism of deep brain stimulation 50Hz?? Major parameters of stimulation: amplitude (Voltage/current), pulse-width, and frequency. The effects of DBS is highle depends on the: TÁMOP-4.1.1.C-13/1/KONV-2014-0001

5. Approved indications  Tremor  Parkinson’s disease  Primary dystonia  Obsessive compulsive disorder  Partial epilepsy with or without secondary generalization Upcoming new indications  Guilles de la Tourettes syndrome  Depresion  Cluster headache  Neuropathic pain DBS indications in the EU TÁMOP-4.1.1.C-13/1/KONV-2014-0001

6. Globus pallidus p. interna Globus pallidus p. interna -Fluctuation, dyskinesia -Rigidity -Tremor (moderately) Thalamus n. ventralis int. Thalamus n. ventralis int. -Tremor reduction - Minimal effect on bradykinesia and rigidity Subthalamic nucleus Subthalamic nucleus -rigidity -tremor -bradykinesia -indirectly on dyskinesia Neurosurgical targets in Parkinson’s disease TÁMOP-4.1.1.C-13/1/KONV-2014-0001

7. Therapeutic aims in Parkinson’s disease UPDRSm score improvement by 40-60% (DBS Study Group, 2001, Volkmann et al. Ann Neurol 2004;55:871-875 Deuschl et al.N Eng J Med 2006;355:896-908.) Reduction of LED by 50-60% (Krack et al. N Eng J Med 2003;349:1925-1934) Reduction of OFF time by 61% (DBS Study Group, N Eng J Med 2001;345:956-963) Reduction of dyskinesias by 59-75% (DBS Study Group, 2001) Improved quality of life PDQ-39 by 25%, UPDRS-II by 39% (Deuschl et al, 2006) TÁMOP-4.1.1.C-13/1/KONV-2014-0001

8. ‘ON without dyskinesia‘ON’ + Dyskinesia‘OFF’ Before DBS (n=96) 49% 27% 23% After DBS (6 months) (n=91) 74%* 19% 7% * The Deep-Brain Stimulation for Parkinson’s Disease Study Group. Deep-brain stimulation of the subthalamic nucleus for the pars interna of the globus pallidus in Parkinson’s disease. N Eng J Med. 2001;345:956-63. DBS increases the ‚ON time’ by three-fold TÁMOP-4.1.1.C-13/1/KONV-2014-0001

9. Improvement in UPDRS-III (Off medication) 6-month1-year 3 years 5 years Tremor79%75%83%75% Rigiditás 58%73%74%71% Akinesia42%63%52%49% * The Deep-Brain Stimulation for Parkinson’s Disease Study Group. Deep-brain stimulation of the subthalamic nucleus for the pars interna of the globus pallidus in Parkinson’s disease. N Eng J Med. 2001;345:956-63. DBS has long-lasting efficacy on the cardinal symproms of Parkinson’s disease TÁMOP-4.1.1.C-13/1/KONV-2014-0001

10. Timing for surgery is crucial: Neither too early, nor too late! “Wearing-Off” Dyskinesia, “On-Off” Motoros Fluktuációk Postural instability, Freezing, falls, Dementia, psychotic symptoms Optimal timing Mild Moderate Severe Symptoms Severity Too earlyToo late a TÁMOP-4.1.1.C-13/1/KONV-2014-0001

11. Major predictor factors Age (over 70 years it may be less effective) Disease duration Co-morbidities (pl. hypertonia, stroke) Levodopa-test Presence and severity of levodopa-resistent symptoms Presence and severity of neurocognitive disorders Ability to use the patient programmer Having a family or care-giver Dopamine-dysregulation symptoms TÁMOP-4.1.1.C-13/1/KONV-2014-0001

12. Aim of patient selection Major aims of the preoperative evaluation are the following: - Optimal patient selection - Judge the possible benefits - Judge the possible side-effects associated with the treatment - According to international guidelines, the most optimal way to perform the evaluation is having a team including the neurologists, psychologists, psychiatrists and neurosurgeons TÁMOP-4.1.1.C-13/1/KONV-2014-0001

13. Preoperative evaluation Preoperative evaluation has 3 major parts: Verification of the clinical diagnosis of Parkinson’s disease –We have to exclude patients having secondary parkinsonisma or Parkinson Plus Syndromes Judge of severity of PD-related symptoms –Severity: Are the severity of symptoms severe enough to indicate DBS? –On levodopa test: at least 30% improvement –Further optimatisation of oral treatment are likely unable to improve the symptoms Judge the contraindications of DBS syurgery –Are there any problems which could interfere with head surgery? TÁMOP-4.1.1.C-13/1/KONV-2014-0001

14. Process of preoperative evaluation Physical examination Judge the clinical diagnosis in accordance with UK Brain Bank criteria Brain MRI (if contraindicate brain CT) Neuropsychological examination (depression, cognitive function) Levodopa-test (Based-on Unified Parkinson’s Disease Rating Scale or Movement Disorders Society-based Unified Parkinson’s Disease Rating Scale) Patient diary (ON state, ON with slight dyskinesia, ON with severe dyskinesia, OFF state, daytime sleep duration) TÁMOP-4.1.1.C-13/1/KONV-2014-0001

15. Importance of levodopa-test 70 60 50 40 30 4050607080 Average pre-operative L-dopa responsiveness (% change in UPDRS III) OFF score/ON score in percentage % Change in UPDRS III with surgery p=0.001 1 1 Kleiner-Fisman G, et al. Mov Disord 2006 2 Welter ML, et al. Brain 2002 TÁMOP-4.1.1.C-13/1/KONV-2014-0001

16. Indications for deep brain stimulation in Parkinson’s disease Indications: Pharmaco-resistant tremor (IA evidence) Severe fluctuations, which cannot managed by further optimatisation of oral treatment, disease duration >5 years, >30% improvement on levodopa-test (IA evidence) Early fluctuation ( 6 points) if age 4 years, improvement on levodopa-test >50% (IB evidence) TÁMOP-4.1.1.C-13/1/KONV-2014-0001

17. Contraindications for deep brain stimulation Severe neurocognitive impairments (dementia in accordance with DSM-V or <125 points on Mattis Dementia Rating Scale) Severe, drug-resistant depression (Beck Depression Inventory score >20 points during appropriate psychiatric treatment) Psychotic symptoms (pl. agitation, hallucinations, paranoid symptoms) Abnormality on brain MRI interfering with neurosurgery Prominent levodopa-resistant symptoms (< 30% improvement on levodopa-test) Levodopa-resistant symptoms are the dominant symptoms Reduced life-expectancy due to co-morbidities Clinical diagnosis of Parkinson’s disease cannot be made in accordance with UK Brain Bank criteria Non-compliance TÁMOP-4.1.1.C-13/1/KONV-2014-0001

18. Steps of deep brain stimulator implantation Stereoractic frame Neuronavigational system Identifying the target – Neuroimaging – Microelectrode recording – Stimulation Implanting electrodes Implanting the pulse generator TÁMOP-4.1.1.C-13/1/KONV-2014-0001

19. Microelectrode registration There are four electrodes separated by 2-2 mm. Based on the electropysiological recordings we can chose the most optimal trajectory. In this case the signals on the green and white colored positions have the typical signals for the target area. TÁMOP-4.1.1.C-13/1/KONV-2014-0001

20. Microelectrode registration Planned target based on MRI is the level of 0 mm. On this picture the electrophysiological data of level between -6 and +6 mm are shown. Signals typical for the subthalamic nucleus are found between the levels of -3 and +3 mm. TÁMOP-4.1.1.C-13/1/KONV-2014-0001

21. Clinician and patient programmers The patient can also change the stimulation setting within safe limits. TÁMOP-4.1.1.C-13/1/KONV-2014-0001

22. Case study Male, born in 1944 Rest tremor and clumsiness of extremities with left dominance occurred in 2007 (mixed-type of Parkinson’s disease) Since 2007 pramipexole (dopamine agonist) treatment Since 2010 levodopa/carbidopa/entacapone and pramipexole combination Later rotigotine patch Excessive daytime sleepiness (dopamine agonist side-effect) In 2015 deep brain stimulation therapy was initiated due to drug resistant (despite of dopamine agonist, levodopa, COMT-inhibitor combination therapy) symptoms interfering with activities of daily living TÁMOP-4.1.1.C-13/1/KONV-2014-0001

23. Preoperative state Severity of Parkinson’s disease (MDS-UPDRS): 69 points Quality of life (PDQ-39): 25,7 (higher values mean worse quality of life) TÁMOP-4.1.1.C-13/1/KONV-2014-0001

24. Postoperative state (6 months) Severity of Parkinson’s disease (MDS-UPDRS): 30 points Quality of life (PDQ-39): 8,9 (higher values mean worse quality of life) TÁMOP-4.1.1.C-13/1/KONV-2014-0001

25. Expert video Name of the expert: Norbert Kovacs, MD, PhD TÁMOP-4.1.1.C-13/1/KONV-2014-0001

26. Created by Created by: Norbert Kovács MD, PhD Zsuzsa Aschermann MD Beáta Bóné MD Lector: Komoly Sámuel MD, DSc TÁMOP-4.1.1.C-13/1/KONV-2014-0001