Parkinson's research and the future of treatments DEEP BRAIN STIMULATION: BEST PRACTICE AND MORE Francesca Morgante Institute of Molecular and Clinical Sciences, St George's University of London, London, United Kingdom
Disclosures • Dr Francesca Morgante has received honoraria as a Consultant & Advisory Boards from Medtronic and Merz. • She has received honoraria for speaking from Merz, Bial, UCB Pharma, Medtronic, Chiesi, Abbvie, Zambon. • She serves in the Editorial board of Movement Disorders, Movement Disorders Clinical Practice and Frontiers in Movement Disorders.
MILESTONES OF PARKINSON’S DISEASE STARTING TREATMENT: how to start Psychiatric modifiers Motor and non-motor fluctuations & dyskinesia Advanced PD issues leading to non-oral treatments Late stage PD: Falls, psychosis, dementia
OVERVIEW OF PD TREATMENT Education Rehabilitation about disease Medications phases Surgery Complex Infusions therapies Prevent auto-medication Falls Postural Stable Fluctuation and and addiction to DA instability phase dyskinesia medications 80 years 50 55 60 65 70 75 Stage I-II Stage II-III Stage III-IV Stage IV-V
WHAT IS BEST PRACTICE FOR DBS TREATMENT? - Recognition of the advanced phase at the right time - Correct Selection of surgical candidates - Concomitant management of medication and DBS with novel programming strategies after surgery - Multidisciplinary care from selection to follow-up
PD CLINIC SPECTRUM OVER DISEASE COURSE Symptoms due to DA treatment Symptoms mainly due + disease progression to disease progression Fluctuations and Dyskinesia • Freezing of gait • Motor fluctuations • Falls • Levodopa-induced dyskinesia • Speech disturbance • Dysphagia Non-motor symptoms modulate by DA treatment • Postural abnormalities • ICB, depression, anxiety • Gastrointestinal • Psychosis • Fatigue and Apathy • Dysautonomia • Cognitive disturbances • Sleep disorders • Cognitive Impairment
WHEN DOES THE ADVANCED PHASE START? SEVERE MOTOR FLUCTUATIONS (i.e. with gait impairment or need of assistance) FLUCTUATING PAIN SLEEP DISTURBANCES ↑ ↑ ↑ DA Medication AXIAL DISTURBANCES GASTROINTESTINAL DISTURBANCES BEHAVIOURAL DISTURBANCES (i.e. DA abuse, disabling ICD) DYSKINESIA
COMPLEXITY OF PD TREATMENT OVER THE YEARS Dietary Botulinum Antidepressants Benzodiazepines restrictions toxin Amantadine Levodopa Amantadine COMT-I Disp-Levodopa COMT-I COMT-I Levodopa MAO-I MAO-I COMT-I MAO-I Levodopa Levodopa Levodopa Levodopa Dopamine - Dopamine - Dopamine - Dopamine - Dopamine - Agonists Agonists Agonists Agonists Agonists Stage I-II Stage II-III Stage IV-V
ADVANCED PD TREATMENT: GOALS • Decrease motor fluctuations ( Off time; On time) • Decrease dyskinesias • Avoid or treat psychiatric and behavioral complications • Management of non motor symptoms (NMS), especially Non-motor fluctuations • Dopaminergic daily dose PRIMARY GOAL: IMPROVING QUALITY OF LIFE
Impaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS. Schuepbach et al, Neurology 2019
ADVANCED THERAPIES Apo Duo DBS Advanced age (<70 for DBS) +/- OK NO Mild cognitive impairment OK OK NO Dementia NO +/- NO Mild psychosis (drug-induced, visual hallucinations) +/- OK +/- Severe psychosis NO NO NO Brain MRI: atrophy OK OK NO Lack of MDT Team OK NO NO
THE IMPORTANCE OF A PATHWAY FOR ADVANCED PD AND A MDT TEAM FOR ADVANCED PD TRIAGING TO DIFFERENT ADVANCED THERAPIES – St GEORGE’S MODEL Advanced PD WORSHOPS TO Extensive Motor and with poor QoL PREPARE PD AND Non-motor CAREGIVERS TO DBS assessment Review from MDT MEETING Neuropsychiatric for symptoms including ADVANCED ADVANCED MDT ADVANCED ICD CLINIC THERAPY CLINIC THERAPIES TREATMENT Neuropsychological Discussion of the: assessment ADVT - TEAM • treatment selected • expectations Neurologists • complications Discussion of • Follow-up organization PD nurses Expectations Follow-up Neuropsychologist MDT Pathway Neurosurgeon Neuroimaging Best Medical treatment Thalamotomy
THE IMPORTANCE OF SELECTION FOR DBS
GOOD SELECTION = GOOD OUTCOME!!! Absolute selection criteria Disease Duration > 5 years (> 4 years by Early Stim) Age < 70 years Severe motor complications despite optimal medical treatment Severe disability, poor quality of life Response to Levodopa Absence of major depression Absence of active psychosis Absence of cognitive disturbances Relative Exclusion criteria Gait disturbances resistant to levodopa Severe postural instablity (in ON) Single Mild Cognitive impairment
2019 1999 How inclusion criteria were changed by recent acquisition on PD progression and management?
TOO FAR IN THE DISEASE MIGHT BE TOO LATE!
Neurostimulation for Parkinson’s Disease with Early Motor Complications DBS vs. BMT Favoring UPDRS-III off -16.4 DBS UPDRS-III on -4.5 DBS UPDRS-II off -6.2 DBS UPDRS-IV -4.1 DBS On w/o dysk +1.9h DBS SCOPA-PS -2.1 DBS LEDD -609.1 DBS BPRS -2.2 DBS Montgomery -2.4 DBS BDI -1.9 DBS All statistically different Schuepbach et al., EARLYSTIM SG, NEJM 2013
WHAT PATIENT-RELATED FACTORS MAY INFLUENCE THE CHOICE OF THERAPY? • Age and duration of disease • Cognitive and neuropsychiatric status • Medical co-morbidities • Non-motor symptoms • Presence of dysarthria • Presence of gait and balance problems Few data are available on these issues for all the 3 treatments, mainly for DBS
WHAT MAKES DBS SURGERY UNIQUE? Reduce dopaminergic daily dose (LEDD) (STN DBS in PD) Treatment may be regulated ASYMMETRICALLY Different targets for different symptoms
REDUCTION OF LEDD BY STN DBS BUT NOT BY INFUSIONAL THERAPIES Antonini et al, MDJ 2007 De Gaspari et al, JNNP 2006 Romito et al, MDJ 2008
CONSEQUENCES OF ↓ LEDD AFTER DBS DYSKINESIA BEHAVIOURAL COMPLICATIONS AND HYPERACTIVE BEHAVIOUR NON-MOTOR CONSEQUENCES OF OVERMEDICATION WITH DA DRUGS
Lhommè et al, Brain 2012 After surgery, the OFF medication motor score improved (45.2%), allowing for a 73% reduction in dopaminergic treatment
Effect of DBS on NMS in Young-onset PD T0 T6 T12 T24 p-value Post-hoc tests T0-T6=0.04 NMSS total score 58.2 ± 25.6 38.3 ± 28.03 32.9 ± 18.8 45.7 ± 31.1 0.004 T0-T12=0.01* T0-T24=0.07 Cardiovascular 1.36 ± 2.77 0.42 ± 0.78 0.58 ± 1.83 1.16 ± 2.30 0.1 T0-T6=0.0004* Sleep/fatigue 16.6 ± 8.6 5.9 ± 6.3 3.7 ± 3.3 4.4 ± 4.6 <0.0001 T0-T12=0.0004* T0-T24=0.0004* Mood/Cognition 9.4 ± 16.1 13.9 ± 17.0 10.4 ± 14.9 14.6 ± 18.0 0.2 Perception/ 0.1 ± 0.3 0.7 ± 1.4 0.3 ± 0.6 1.0 ± 3.2 0.4 hallucinations Attention/Memory 1.4 ± 3.4 3.2 ± 5.7 1.8 ± 2.8 2.5 ± 3.4 0.7 Gastrointestinal 5.6 ± 5.7 3.6 ± 7.0 3.8 ± 5.4 6.2 ± 7.6 0.09 Urinary 8.0 ± 8.0 7.0 ± 9.7 8.1 ± 7.1 11.0 ± 12.3 0.8 Sexual function 2.4 ± 4.7 1.2 ± 3.3 0.6 ± 2.7 1.4 ± 3.2 0.3 T0-T6=0.01* Miscellaneous 12.4 ± 6.9 4.5 ± 5.9 8.2 ± 8.9 7.5 ± 5.1 0.01 T0-T12=0.08 T0-T24=0.03 T0-T6=0.003* PDSS-2 22.9 ± 10.6 12.5 ± 10.5 10.8 ± 7.8 11.1 ± 9.2 <0.0001 T0-T12=0.0009* T0-T24=0.0005* Significant positive correlation at T6 between the relative change of N=18 PDSS-2 and dopamine-agonists LEDD (PMX in 10 pts) (rho=-0.49, p=0.04). Ricciardi, et al, MDJ 2018
GAIT DISTURBANCES AND DBS WHY PD PEOPLE FALL OFF? • Freezing of gait in OFF, asymmetry in gait and posture • On-Phase dyskinesia • Orthostatic syncope • Loss of postural reflexes • Severe Executive Dysfunction
DBS IMPROVE GAIT DISTURBANCES OF THE OFF PHASE 130 Hz 60 Hz Moreau et al, Neurology 2008 Bakker et al, MDS 2004
Effect of STN-DBS on FOG in PD
NOVEL DBS TECHNOLOGIES TO MANAGE ADVANCED SYMPTOMS Short pulse width - Current steering -
AIMING TO BEST PRACTICE IN ADVANCED PD MANAGEMENT WITH DBS • Redefining Advanced phase: not delaying treatment • Need of better predictors of disease progression at the time of selection: better selection • Need to work on PD people expectations before and after DBS • Need to have clear guidelines on how to program DBS based on prominent symptoms. • Need of a pathway for Neurophysiotherapy and SLT for late stage PD treated with DBS.
ACKNOWLEDGEMENTS St. George’s University of London – MDS group • Neurologists: Dominic Paviour, Lucia Ricciardi , Jan Coebergh, Mark Edwards • PD nurses: Alison Leake , Catherine Parry, Lucy Kerogoi • Clinical Research Fellows: Marianna Sarchioto, Andrea De Angelis • Neurosurgeon: Erlick Pereira • Neuropsychologist: Priyanka Pradhan • DBS group coordinator: Donna Nottage Collaborators: • Alfonso Fasano, University of Toronto • Alberto Espay, University of Cincinnati • Davide Martino, University of Calgary • Giovanni Cossu, AOU Brotzu, Cagliari • Maria Chiara Sensi, University Hospital Ferrara • Enza Maria Valente, University of Pavia • Maurizio Zibetti, Leonardo Lopiano, University of Turin St George’s DBS Team • Michele Tinazzi, University of Verona • Chiara Sorbera, IRCCS Neurolesi, Messina
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