The Shaking Palsy of 1817

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1 The Shaking Palsy of 1817 A Treatment Update on Parkinson s Disease Dr Eitzaz Sadiq Neurologist CH Baragwanath Acadamic Hospital

2 Parkinson s Disease O Premature death of dopaminergic neurons O Symptoms as a result of DA deficiency O Bradykinesia O Rigidity O Tremor O Postural instability

3 Therapeutic Goals O AIM = replace dopamine! O Maximal efficacy O Minimal side-effects

4 Pharmacological Options 1. Levodopa 2. DA agonists 3. Inhibit breakdown of DA O O COMT inhibitors MAO-B inhibitors 4. Others

5 Levodopa O Remains the Gold Standard of therapy O No other treatment has proven superior efficacy O Problems O Pharmacokinetics O Doses often limited by side-effects O? Neurotoxicity

6 O Directly stimulate DA receptors DA Agonists Pramipexole, Ropinirole, Bromocriptine O Monotherapy in mild disease O Or add-on therapy later O Ineffective in patients who have shown no therapeutic response to levodopa

7 Inhibitors of DA Metabolism

8 Inhibitors of DA Metabolism 1. MAO-B Inhibitors (Selegeline/Rasagaline) O Monotherapy in early disease (modest effect) O Add-on therapy with Levodopa O? Neuroprotective 2. COMT Inhibitors (Entacapone/Tolcapone) O Ineffective alone O Levodopa extenders

9 Others O Amantadine (Symmetral ) O Anti-viral agent O DA release, DA reuptake, Stimulate DA receptors, Anticholinergic O Moderately effective for dyskinesias

10 Others O Anticholinergics (Trihexyphenidyl, Biperiden, Orphenadrine) O Useful for tremor O Caution in elderly

11 The Bottom Line Levodopa is the most effective symptomatic therapy for Parkinson s disease

12 Is Levodopa Neurotoxic? O Possibly hastens degeneration of DA neurons O Free radicals and oxidative stress O DATATOP, STRIDE-PD Trials: O Increased motor complications (dyskinesias) O High doses O Prolonged usage (ie. Early age of onset) Should Levodopa be rationed?

13 Is Levodopa Neurotoxic?

14 Is Levodopa Neurotoxic? O CALM-PD Trial O Less dyskinesias with DA agonists O BUT, also less potent and less efficacious Recommendation: O in early-onset PD of mild/moderate severity, can start with DA agonist O BUT if symptoms not controlled, do not delay Levodopa therapy

15 Is any agent Neuroprotective? O Levodopa O ELLDOPA Trial O Questionable methodology O Rasagaline (MAO-B inhibitor) O TEMPO Trial, ADAGIO Trial O Promising data, though not universally accepted O Step in the correct direction

16 Obstacles with Oral Agents O Non-constant drug levels O Pharmacokinetics

17 Novel Routes of Delivery O Enteral O Subcutaneous O Cutaneous patches O Nasal sprays

18 Duodenal Levodopa Infusion O Less fluctuations in plasma drug levels DuoDopa O Thus less dyskinesias But O Cost! O GIT side-effects

19 O Crush daily dose of Levodopa into 1 litre juice O Sip calculated amount at fixed intervals O Danger: Overdose, DA Dysregulation Syndrome Liqui-Dopa

20 O Potent DA agonist Apomorphine O Intermittent rescue injections O OR Continuous subcutaneous infusion O Pump-driven

21 Rotigitine O DA agonist O Preparations: O Patches O Nasal spray

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23 Deep Brain Stimulation

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25 How does DBS work? DA Deep Brain Stimulation ++Stim STN ++Stim GPi Inhibition of Thalamus Thalamocortical Activity Akinesia and rigidity

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28 Limitations of DBS O Does not surpass maximal Levodopa response O If maximum dose was tolerable O Does not help axial symptoms (Eg. postural instability) O Does not help speech and swallowing problems O Speech may worsen O Cognitive concerns post-dbs O No evidence that it slows disease progression THUS, strict patient-selection is imperative

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30 The Future O Neural transplantation O Gene therapy O GDNF infusions O Nanotechnology O PD Vaccine

31 Parkinson s Disease 2014 O Levodopa is the most effective symptomatic therapy O The realistic role of other agents is: O In mild, early disease O To augment Levodopa O True neuroprotection remains debateable O Alternatives routes of drug delivery are promising O Deep Brain Stimulation is an attractive adjunct to treatment, but with limitations