Optimizing the Treatment of Parkinson's Disease: Patient-specific - PDF document

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations Outline   Epidemiology of Parkinson’s Disease (PD) Treatment of PD   Non-pharmacologic treatment Pathology Optim izing the Treatm ent of   Dopaminergic treatment Making the diagnosis of PD  Motor fluctuations  Clinical features of PD Parkinson's Disease  Treatment of selected non-motor features  Motor features of PD Patient-specific Considerations  Non-motor features  Indicators for the need to refer to a  Pre-motor features specialist Pravin Khem ani, MD  Natural history of PD  Surgical and niche treatments for PD Associate Professor, Movement Disorders Department of Neurology and Neurotherapeutics University of Texas Southwestern Dallas, TX London, 1 8 1 7 Pathology Braak’s Hypothesis Epidem iology of PD Spread of Synucleinopathy Direct and indirect costs associated with PD exceed $20 billion annually in United States Braak et al. Neurobiol Aging 2003;24:197-211. Dorsey et al. Neurology 2007;68:384-386. Van Den Eeden et al. Am J Epidemiol 2003;157:1015-1022. 1

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations Making the Diagnosis of PD DaTscan  PD remains a clinical diagnosis based on recognition of the three cardinal signs  Rest tremor  Bradykinesia  Limb rigidity  DaTscan is a diagnostic tool which can indicate if nigral dopaminergic degeneration is present or not, but it is not specific for PD, and patients should receive a neurologic consultation before considering DaTscan  DaTscan is generally recommended when suspicion exists for neuroleptic induced or psychogenic parkinsonism or when an atypical tremor is present Normal PD Motor Features of PD Associated Motor Features • 70% of patients  Stooped posture Resting tremor 1,2 • “Pill-rolling” tremor in hands • Can involve lips, chin, jaw, legs  Small handwriting  Decreased arm swing • 80% to 90% of patients Bradykinesia 1,3,4 • Most disabling symptom of PD  Cramping  Difficulty swallowing • >90% of patients Rigidity 1,4  Changes in facial expression • “Cogwheel” (fluctuating) or “lead pipe” (continuous)  Shuffling • Indicative of advanced-stage PD Postural instability 1 • Frequent cause of falls 1. Jankovic. J Neurol Neurosurg Psychiatry . 2008;79:368-376. 2. Bhidayasiri. Postgrad Med J . 2005;81:756-762. 3. Berardelli et al. Brain . 2001;124(pt 111):2131-2146. 4. Weintraub et al. Am J Manag Care . 2008;14(2 suppl):S40-S48. Non-m otor Features of PD Pre-m otor Features • Depression in up to 40% of patients  Constipation, anosmia, REM sleep behavior disorder, depression Psychiatric disorders 1 • Anxiety in ~30% of patients  Presence of alpha-synuclein in colonic mucosa is controversial • Mild cognitive impairment Cognitive disorders 1,2 • Dementia in 15% to 40% of patients • >70% of patients Sleep abnormalities 1,3 • REM sleep behavior disorder • Constipation Autonomic dysfunction 1,3 • Orthostatic hypotension Sensory 3 • Olfactory dysfunction Control PD PD Control Miscellaneous 1,2 • Fatigue and weight loss Shannon, KM et al. Mov Disord 2012;27:716-719. 1. Thanvi et al. Postgrad Med J . 2003;79:561-565. 2. Fahn and Sulzer. NeuroRx . 2004;1:139-154. Antunes et al. Mov Disord 2016;31:1567-1570. 3. Jankovic. J Neurol Neurosurg Psychiatry . 2008;79:368-376. 2

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations Natural History of PD Progression of Motor Sym ptom s 1 2 Symptoms on one Bilateral side of the 3 symptoms; body only no balance Impaired 4 postural impairment Severe reflexes; disability, yet 5 physically still able to independent Wheelchair walk or stand bound or unassisted bedridden Increasing disability; decreasing independence Hoehn and Yahr Staging Non-pharm acologic Treatm ent  Education: it is essential that the patient understands the natural history of the disease and treatment options  Emotional and social support: depression and needs for care must be addressed early on  Exercise is critical and may slow the progression of the disease  Tai Chi, boxing, cycling, aerobic exercise, resistance training are all helpful  In animal studies, the mechanism of exercise-induced benefit appears Treatm ent of PD to be the elaboration of brain growth hormones  Nutrition: weight loss is common and should be addressed Chaves da Silva et al. J Neurol Sci. 2016;363:5-15. Non-dopam ineric Drug Treatm ent for PD Dopam inergic Treatm ent of PD  Anticholinergics  Direct or indirect stimulation of striatal dopamine receptors is the primary pharmacologic treatment for PD  Benztropine and trihexyphenidyl are most commonly used  Most effective in ameliorating rigidity and tremor; little or no effect on bradykinesia  Categories of dopaminergic treatment  Serious side effects such as visual blurring, urinary hesitancy, and memory  Levodopa impairment are common, especially in elderly patients  Dopamine agonists  Amantadine  Monoamine oxidase inhibitors  C-O-Methyl transferase (COMT) inhibitors  Exerts anticholinergic effects, NMDA antagonism, and inhibits dopamine reuptake  Produces a mild to moderate antiparkinsonian effect  While very effective for the major motor features of PD, some clinical  Side effects include ankle edema and livido reticularis, and when combined with symptoms do not respond well including balance impairment and non- levodopa, hallucinations are common motor PD features  The best-studied drug for inhibiting levodopa-induced dyskinesia 3

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations Levodopa I m pact of Levodopa on Mortality  By far the most clinically effective drug for the symptoms of Parkinson’s disease, introduced in 1975 as carbidopa/levodopa  Helpful in alleviating all of the three cardinal symptoms (tremor, rigidity, bradykinesia)  When started early in the disease it can produce a dramatic and smooth clinical response lasting years  Uptake and conversion to dopamine allows storage and release in a physiologic fashion Hoehn MM. Adv Neurol . 1986;45:457-461. Levodopa Dose Response Levodopa Adverse Effects Fahn S et al. N Engl J Med . 2004;351:2498-2508. Fahn S et al. N Engl J Med . 2004;351:2498-2508. Levodopa’s Lim itation is Short Half-life Levodopa Recom m endations  As levodopa is the most effective drug for PD, it should be  Short half-life of levodopa leads used in almost all patients at some point in the disease to pulsatile stimulation of DA  Always use the lowest dose of levodopa that is sufficient to receptors which alters BG control PD symptoms signaling resulting in dyskinesia  To minimize the risk of nausea, avoid 10/100 preparation; generally one needs a 1:4 ratio of carbidopa to levodopa  Always give levodopa a minimum of 3 times daily to reduce plasma levodopa fluctuations  Consider treatment with carbidopa/levodopa extended release due to longer half-life 4

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations Dopam ine Agonists Available Dopam ine Agonists  Symptomatic efficacy is moderate (second in power to levodopa) Ropinirole Pramipexole Ropinirole XL Pramipexole ER Rotigotine Apomorphine  Because of their long half-lives, these drugs produce more Class Non-ergot Non-ergot Non-ergot Non-ergot Non-ergot Non-ergot physiologic receptor stimulation and have been shown to delay Half-life 8-12 hours 6 hours 24 hours 24 hours Continuous 1 hour the onset of dyskinesia Oral Oral Oral Oral Patch Injection Delivery  Slow upward dose titration is the key to achieving adequate Dosing 0.25 - 8 mg 0.125 – 1.5 mg 2-24 mg 0.375 - 4.5 mg 2-8 mg daily 2-6 mg doses for full efficacy; side effects may prevent optimal dosing TID TID once daily once daily SC PRN  When used in addition to levodopa in fluctuators, they result in a 2-3 hour reduction in off time per day Agonist Side Effects I m pulse Control Disorders  Sedation 20 Dopamine Agonist (n=2040) 17.1 ‡ No Dopamine Agonist  Sleep attacks (n=1050) Current ICD, % 15  GI side effects (nausea and vomiting) 10  Orthostatic hypotension 7.2 6.9 6.4 5.6 4.4 5  Leg edema 3.5 2.9 2.3 1.6 1.7 1.7  Compulsive behaviors (impulse control disorders) 0 Any ICD Problem/pathologic Pathologic gambling Compulsive sexual Compulsive buying Binge-eating gambling only behavior disorder ICD Type Weintraub et al. Arch Neurol. 2010;67:589-595. COMT I nhibitors MAO-B I nhibitors  By blocking peripheral degradation of levodopa, these drugs potentiate the effect of  Work by blocking breakdown of dopamine inside the brain levodopa and lengthen its half-life thus enhancing the effect of both endogenous and  Entacapone and tolcapone are available, but tolcapone almost never used due to exogenous dopamine idiosyncratic liver toxicity  Rasagiline, selegiline and safinamide currently available  Rasagiline and selegiline produce symptomatic effects in monotherapy and when used with levodopa  Safinamide has anti-glutaminergic properties and reduces dyskinesia in animal models, but this finding was not confirmed in humans Shapira et al. JAMA Neurol. 2017;74:216-224. 5