BORDEAUX MDS WINTER SCHOOL FOR YOUNG NEUROLOGISTS HOW TO EVALUATE MOTOR COMPLICATIONS IN PARKINSON'S DISEASE T. Henriksen Tove Henriksen, MD MDS Clinic University Hospital of Bispebjerg, Copenhagen
MOTOR COMPLICATIONS Beginning of 1970s on-of syndrome was described (Markham 1974) Wearing off: short duration response Motor benefit within 45-90 minutes after intake, lasts for a few hours Parallels the rise and fall of plasma-dopa Wearing off On-off: sudden change in motor capacity Unpredictable Apparently unrelated to L-dopa intake and plasma levels T. Henriksen Muenter, 1971
DEFINITIONS OF DYSKINESIAS Dyskinesiatype Clinical picture Duration On-off status Off -(period) dystonia Biphasic dyskinesia Dystonia Variable Off Chorea or ballistic Limited T. Henriksen Intermediate Peak dosedyskinesia Chorea Variable On Mouradian MM in Managing Advanced Parkinson s Disease: The role of continuous dopaminergic stimulation. Aquilonius and Lees (Ed). 2008.
Pre-clinical studies of motor complications Pulsatile levodopa treatment is a cause of motor complications Study Finding Juncos et al, 1989 30-day intermittent levodopa, but not continuous levodopa treatment, produced behavioural sensitisation in 6-OHDA rats Bibbiani et al, 2005 Continuous apomorphine infusion improved motor function in primates for up to 6 months without dyskinesias Intermittent apomorphine produced dyskinesias within 7-10 days of treatment Blanchet et al, 2001 Dyskinesias <10 days of intermittent dopaminergic treatment in MPTP-treated primates Only 3 of 6 primates developed dyskinesias with continuous dopaminergic stimulation, but complications diminished in intensity Schmidt et al, 2008 In unilateral 6-OHDA lesioned rats, pulsatile levodopa injections (1-2/day) caused contraversive rotations and AIMs Pulsatile (1-2/day) injections of the dopamine agonist rotigotine resulted in more contraversive rotations than a slow release formulation Stockwell et al, 2009 Continuous rotigotine delivery (via osmotic minipump) produces less dyskinesias than pulsatile rotigotine administration (twice daily) in MPTP-treated primates Stockwell et al, 2010 Switching from pulsatile levodopa or rotigotine administration to continuous rotigotine infusion reduced the severity and duration of dyskinesias in primates T. Henriksen Juncos JL, et al. Ann Neurol 1989;25(5):473-8. Bibbiani F, et al. Exp Neurol 2005;192(1):73-8. Blanchet PJ, et al. Adv Neurol 2001;86:337-44. Schmidt WJ, et al. J Neural Transmiss 2008;115(10):1385-92. Stockwell KA, et al. Exp Neurol 2009;219(2):533-42. Stockwell KA, et al. Exp Neurol 2010;221(1):79-85.
POTENTIAL MECHANISMS UNDERLYING PULSATILE LEVODOPA-INDUCED DYSKINESIAS Large peaks-and-troughs of extracellular dopamine: Rise and decline of levodopa and dopamine levels in the striatal extracellular fluid correlate with the timing of AIMs Larger increases in striatal levodopa and dopamine in dyskinetic 6-OHDA lesioned rats than in non-dyskinetic animals Chronic levodopa treatment may alter dopamine regulation and metabolism in striatum and may lead to treatment-related adaptations T. Henriksen Serotonergic system: Treatment with serotonin autoreceptor agonists blunts the peak in extracellular dopamine levels in dyskinetic rats Removal of serotonin afferents blocks levodopa-induced dyskinesias in 6-OHDA lesioned rats Thus, dysregulated dopamine release from serotonergic neurons likely play a key role in dyskinesia development Cenci MA, Lundblad M. J Neurochem 2006;99(2):381-92. Lindgren H et al. J. Neurochem 2010;112(6):1465-76. Carta M, et al. Brain 2007;130(7):1819-33.
AETIOLOGY OF DYSKINESIAS: WHAT WE HAVE LEARNED FROM THE LABORATORY T. Henriksen Adapted from Thanvi B, et al. Postgrad Med J 2007;83:384-88
MOTOR FLUCTUATIONS Levodopacarbidopa intestinal gel (LCIG) Erratic gastric emptying Bloating Late on No on Hyperkinesias T. Henriksen Apomorphine DBS
MOTOR COMPLICATIONS IN PARKINSON S DISEASE Frequently develop following chronic pulsatile levodopa treatment Motor complications manifest as motor fluctuations and dyskinesias After 4 to 6 years of oral levodopa treatment: 12% to 60% of patients develop motor fluctuations 8% to 64% of patients develop dyskinesias After 9 to 15 years: 61% to 96% of oral levodopa-treated patients develop dyskinesias Risk factors: Levodopa exposure Duration Dosage Age of onset Gender Disease duration T. Henriksen Ahlskog JE and Muenter MD. Mov Disorder 2001;16:448 458. Encarnacion EV and Hauser RA. Eur Neurol 2008;60:57-66.
EVALUATION, HOW? Pt/carer information PD diary, patient/carer/staff Compliance Subjective errors due to difficulty differentiating between symptoms Lack sensitivity to detect sensitivity over time (Papapetropolis 2012) Clinical evaluation, observation Rating scales Historical information, recall bias Physical examination, limited snapshot Wearable motion sensors/mobile devices ACC Tremor Pen Smart Phone Parkison KinetiGraph GYRO EMG StepWatch Activity Monitor T. Henriksen
RATING SCALES Abnormal Involuntary Movement Scale (AIMS), focuses on anatomical distribution and intensity of dyskinesia Rush Dyskinesia Rating Scale (RDRS) focuses on objective assessments of functional disability during prescribed tasks Lang Fahn Scale (LF) focuses on patient perceptions Rating Unified Parkinson s Disease Scale (UPDRS) Part IV assesses historical information on dyskinesia duration and has an overall assessment of intensity. Scale Obeso Scale the dyskinesia rating protocol, recommended in the Core Assessment Program for Intracerebral Transplantation (CAPIT) later modification (CAP-SIT). Home-based patient-completed diaries with designations of dyskinesia that vary from scale to scale dyskinesia present vs absent, dyskinesia divided into troublesome and nontroublesome Parkinson Disease Dyskinesia Scale (PDD-26) patient self-assessment scale. The Unified Dyskinesia Rating Scale (UDysRS) combines patient-based assessments of dyskinesia with objective evaluations of disability and impairment from dyskinesias. T. Henriksen
PARKISON KINETIGRAPH (PKG) T. Henriksen
PATIENT DIARY T. Henriksen
MDS-UDYSRS T. Henriksen
ACKNOWLEDGEMENT This presentation incorporates the Unified Dyskinesia Rating Scale (UDysRS), which is owned and outlicensed by the International Parkinson and Movement Disorder Society (MDS). Permission to reproduce the UDysRS in this presentation was granted by MDS.
MDS-UPDRS T. Henriksen