Objectives Emerging Treatments in Parkinson s s Disease 1) Describe recent developments in the therapies for Parkinson s Disease Jeff Kraakevik MD Assistant Professor OHSU/Portland VAMC Parkinson s Center of Oregon/PADRECC Pathology Substantia nigral degeneration As Parkinson s progresses it eventually affects large portions of the brain. Braak, et al. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
Parkinson s s Disease Clinical manifestations Classic symptoms Tremor Bradykinesia Rigidity Postural instability Non-motor symptoms Cognitive/psychological Autonomic -Speech/Swallowing GI -Sleep Diagnosis DaTscan Radionucleotide which tags DaT (Dopamine active transporter) Approved for PD vs ET (2012) Figure from Cummings, et al. Brain. 2011 Dopamine Carbidopa Levodopa How PD meds work Dopamine COMT MAO-B Dopamine agonist Brain COMT MAO-B inhibitors = = entacapone Carbidopa/Levodopa selegiline Agonists (Comtan), (Eldepryl), = pramipexole = Sinemet rasagaline tolcapone (Azilect) (Tasmar) (Mirapex), ropinerole (Requip) HVA PD medications Carbidopa/Levodopa = Sinemet Dopamine Agonists = pramipexole (Mirapex), ropinerole (Requip) MAO-B inhibitors = selegiline (Eldepryl, Deprenyl), rasagaline (Azilect) COMT inhibitor = entacapone (Comtan), tolcapone (Tasmar) Stalevo = C/L + entacapone
Guidelines to follow American Academy of Neurology practice parameters April 2006 Miyasaki, et al. Initiation of treatment (Jan 2002) Suchowersky, et al. Neuroprotective strategies Pahwa, et al Motor fluctuations/dyskinesia Early disease Neuroprotection Best data available reveals a trend Investigation is problematic Perhaps better goal = disease modification http://www.aan.com/go/practice/guidelines Agents with promise Co-enzyme Q10/ Creatine = OUT Phase III trials stopped NOT effective Selegiline/rasagiline (Level U) Selegiline 5 mg once to twice daily Rasagiline start 0.5 mg qd -> 1.0 mg qd Exercise (Class II evidence) Levodopa Safe/does not accelerate Disease (level B) Rasagiline Data Parkinson Study Group, Arch Neurol 2004;61:561-566. Copyright restrictions may apply.
Rasagiline Change in UPDRS Exercise Improves balance and increases overall quality of life May slow progression of disease Four components Aerobic activity Balance activity (Tai chi, Pilates, dance) Agility training Strengthening and stretching Copyright restrictions may apply. Parkinson Study Group, Arch Neurol 2004;61:561-566. Salgado, et al. Brain Sciences. 2013. http://www.mdpi.com/2076-3425/3/1/87 Exercise Tips for patient instructions Having a plan is best PT can help create plan Start small and work up Exercise in groups is more fun Athletic trainers provide longitudinal assistance Future directions Pre-symptomatic testing NET-PD study group Hormonal therapies GDNF Stem cell implantation Specific exercise programs
Neuroprotection Summary I have never been lost, but I will admit to being confused for several weeks. Daniel Boone Neuroprotection summary No clear agents/therapies yet MAO-B inhibitors have most evidence of medications Still more of a trend Exercise is important Initiation of symptomatic medication Eventually pts will need medicine Choices for early symptomatic patient Dopamine agonist (level A, Class II) Carbidopa/levodopa (level A, Class II) COMT inhibitor (?) IR no better than CR (Level B, Class II) Older medications Amantidine Anticholinergics Dopamine Agonists Impulsive disorders Common up to 15% Can be subtle Can t stop working on projects More extreme Gambling Hypersexual behaviors Shopping etc. Can lead to illegal behavior Voon, et al. Curr Opinion Neur. 2011.
ELLDOPA study Fahn, et al. N Engl J Med. 2004 Dec 9;351(24):2498-508 Ongoing Debates Pendulum has swung back to L-dopa Timing of starting therapy Continuous dopaminergic stimulation Early introduction of COMT inhibitor Dopamine agonist patch Rotigotine Ropinerole XL Pramipexole XR Duo Dopa (Not FDA approved) My preferences Young patient without cognitive impairment Dopamine agonist first-line Offer MAO-inhibitor Older person or cognitive impairment L-dopa (usually I start IR) Pharmacy cost issues DA and rasagiline are expensive Sinemet and selegiline are not
It takes a team Up to this point we focused on motor portion of PD Majority of symptoms which can cause disability are non-motor Care of these problems takes multiple discliplines Each member addresses specific needs of the patient Who is on the team? Physician Nurse coordinator Social worker Physical therapy Occupational therapy Speech therapy Others music therapy, art therapy, etc. How to make the team work Clearly defined roles Expertise in unique aspects of care in PD Clear communication Regular self-assessments of how team is functioning New research updates Medications in the pipeline Adenosine A 2a antagonists (caffeine) Istradefyline and Preledenant Both in Phase III studies 5 HT 1a agonist Pardoprunox Phase III studies MAO-B inhibitor and Glutamate release Safinamide Phase III studies Kalia, et al. Movement Disorders. 2013
Deep Brain Stimulation Update on Deep Brain Stimulation Current indications are for PD, ET, and generalized dystonia Trials ongoing into early treatment When first see motor fluctuations Frameless and imaging guided surgery http://www.youtube.com/watch?v=nc7cyadeo_c Computer-Brain interface Scheuepbach, et al. NEJM. 2013. Little et al. Ann Neurol. 2013. Shameless plug VA PADRECC developed My Parkinson s Story web series 8-10 minutes videos Follows a patient with a problem Gives practical advice on how to deal with problem http://www.youtube.com/playlist?list=p L3AQ_JVoBEyxd5tkfQG-S3p_SDYBFtJ6c Or search VA PADRECC on YouTube Conclusions Treatment options change as disease progresses Rehab can add to medication therapy Surgical treatment is beneficial in carefully selected individuals Team approach to care of Parkinson s disease is beneficial