With Time, The Pathology of PD Spreads Throughout the Brain

With Time, The Pathology of PD Spreads Throughout the Brain Braak s staging of Parkinson s disease pathology dm co sn mc hc fc 1 Hubert H. Fernandez, MD, FAAN Professor of Medicine (Neurology) Cleveland Clinic Lerner College of Medicine Head, Section of Movement Disorders Center for Neurological Restoration Cleveland Clinic, Neurological Institute Cleveland, OH Cheryl H. Waters, MD, FRCPC Albert B. and Judith L. Glickman Professor Division of Movement Disorders Columbia University New York, NY co, coeruleus-subcoeruleus complex; dm, dorsal motor nucleus of the glossopharyngeal and vagal nerves; fc, first-order sensory association areas, premotor areas, as well as primary sensory and motor fields; hc, high-order sensory association areas and prefrontal fields; mc, anteromedial temporal mesocortex; sn, substantia nigra STAGES OF PD 2 3 4 5 6 Braak H, et al. Cell Tissue Res. 2004;318:121-134. Parkinson s Disease (PD) Epidemiology Motor Features of PD Uncommon before age 50 years 1 Annual incidence (all ages): 8.6 to 19.0/100,000 2 Incidence increases dramatically with age: approximately 100/100,000 over age 70 years 3 Prevalence in individuals older than 65 years: approximately 1% 4 More common in men 5 Incidence of PD by age 90% Age 50 and under Greater than age 50 1. Van Den Eeden SK, et al. Am J Epidemiol. 2003;157:1015-1022. 2. Twelves D, et al. Mov Disord. 2003;18:19-31. 3. von Campenhausen S, et al. Eur Neuropsychopharmacol. 2005;15:473-490. 4. Fahn S. Ann N Y Acad Sci. 2003;991:1-14. 5. Taylor KS, et al. J Neurol Neurosurg Psychiatry. 2007;78: 905-906. 10% Cardinal features Rest tremor Rigidity Bradykinesia Postural instability Other motor features Masked face Shuffling gait Freezing Micrographia Dystonia Cramps 1

Autonomic Non-Motor Features of PD Constipation Hyperhidrosis Urinary dysfunction Sexual dysfunction Sialorrhea Psychiatric disorders Depression/Anxiety Apathy Fatigue Sleep disorders Insomnia REM behavior disorder Cognitive Dementia Psychosis Clinical Features that May Suggest a Diagnosis Other than PD Poor response to adequate dosages of levodopa Early onset of postural instability Axial more than appendicular rigidity Early dementia Supranuclear gaze palsy Profound autonomic dysfunction Significant limb dystonia prior to levodopa exposure Wenning GK, et al. J Neurol Neurosurg Psychiatry. 2000;68:434-440. Differential Diagnosis of PD Dopamine Transport Imaging (DaTscan ) Essential Vascular Drugs Tremor Progressive Supranuclear Palsy Multi- System Atrophy Toxins Secondary Idiopathic Parkinson s Disease Parkinson- Plus Other Normal Abnormal Encephalitis Other Alzheimer s Disease Lewy Body Disease Corticobasal Degeneration Neurodegenerative parkinsonism (ALL) Essential tremor Drug-induced parkinsonism Vascular parkinsonism Psychogenic Dopamine transport imaging differentiates between parkinsonian disorders with and without dopamine deficiency 2

Treatment Goals Can Exercise Slow PD Progression? Exercise Therapy Is Effective in Improving Activities of Daily Living Slowing disease progression Controlling symptoms Preserving quality of life Smith AD, et al. Exp Neurol. 2003;184:31-39. Tajiri N, et al. Brain Res. 2010;1310:200-207. Hackney ME, Earhart GM. Parkinsonism Relat Disord. 2009;15:644-648. Agents Recently or Currently Being Tested for Disease-Modifying Properties No Coenzyme Q10 Pramipexole Results Pending Creatine Inosine Isradipine Exercise Maybe Rasagiline Olanow CW, et al. N Engl J Med. 2009;361:1268-1278. Massachusetts Medical Society. Used with permission. Blood Brain Barrier Sites of Action of PD Drugs Substantia Nigra levodopa DA DDC COMT dopamine levodopa 3 OMD carbidopa amantadine COMT inhibitors: tolcapone entacapone MAO B inhibitors: selegiline rasagiline ACh Striatum GABA Dopamine agonists: bromocriptine pramipexole ropinirole rotigotine Anticholinergics: trihexyphenidyl benztropine Adapted from www.wemove.org 3

Considerations in the Initial Management of PD Control of disability Favorable side-effect profile Optimal long-term strategy Cost Case Example 1 (Cont d) Examination reveals increased tone bilaterally, right greater than left; a rest tremor on the right; and bradykinesia in some tasks on the right. Right arm swing is depressed while walking. MRI normal, DaTscan-decreased uptake in the corpus striatum, especially on the left side. How would you treat this patient? Case Example 1 A 37-year-old male presents to your office with tremor of right hand for 4 to 5 years. He also has decreased manual dexterity on right and right foot cramping. He has a family history that is positive for essential tremor. His past medical history is unremarkable. Levodopa Clearly Beneficial as a Treatment of PD Change in total unified PD rating scale by dose of levodopa Fahn S, et al. N Engl J Med. 2004;351:2498-2508. Massachusetts Medical Society. Used with permission. 4

Levodopa Associated With Risk of Motor Complications Dyskinesia Peak dose End of dose Motor fluctuations End-of-dose wearing off Unpredictable on-off Yo-yo-ing 100 Adapted from: Schrag A, et al. Mov Disord. 1998;13:885-894. 75 50 25 40% BY 5 YEARS 100% BY 10 YEARS 0 1 2 3 4 5 6 7 8 9 10 Time from Initiation of Therapy (years) Impulse Control Disorder (ICD) in PD Results from a multi-center study of 3000 patients ICDs were identified in 13.6% of PD patients overall: 17.1% of patients taking a dopamine agonist (DA) alone 6.9% of patients on levodopa, and not taking a DA Types of ICDs 5.7% compulsive buying 5.0% problem/pathologic gambling 4.3% binge eating disorder 3.5% compulsive sexual behavior Weintraub D, et al. Arch Neurol. 2010;67:589-595. Incidence rate for first occurrence (per 1000 person-years) Incidence (%) 200 150 100 50 50 0 0 Occurrence of Dyskinesia: Initial Dopamine Agonist Therapy Dyskinesia Dystonia On/off Lees AJ, et al. Neurology. 2001;57(9):1687-1694. Levodopa Ropinirole Dyskinesia Levodopa Bromocriptine Dyskinesia before suppl levodopa Disabiling dyskinesia Incidence (%) Rascol O, et al. N Engl J Med. 2000;342(20):1484-1491. Incidence (%) Oertel WH, et al. Mov Disord. 2006;21(3):343-353. Parkinson Study Group. JAMA. 2000;284(15):1931-1938. MAO-B Inhibitors for Early PD Indications: monotherapy in early PD; add on to levodopa Available dosage: 1 mg tablet daily Benefits: mild symptomatic improvement; well tolerated Side effects: minimal; potential drug interactions Symptomatic treatment effect of rasagiline on total UPDRS at 6 months IMPROVEMENT Mean change from baseline in total UPDRS score 5.0 4.0 3.0 2.0 1.0 0.0 Rasagiline 1 mg Rasagiline 2 mg Placebo -0.13 P <.001 0.51 P <.001 Parkinson Study Group. Arch Neurol. 2002;59(12):1937-1943. 4.07 UPDRS: Unified Parkinson's Disease Rating Scale 5

Treatment-Emergent Adverse Events With Rasagiline Monotherapy* Percentage of Patients 90 80 70 60 50 40 30 20 10 0 Placebo Rasagiline 1 mg/d Advanced Parkinson s Disease *Adverse-event incidence >5%; between-group differences not statistically significant Adapted from: Parkinson Study Group. Arch Neurol. 2002;59(12):1937-1943. AAN Practice Guidelines for Treatment of Early PD When symptomatic therapy is required: MAO-B inhibitors may be used. Either dopamine agonists or levodopa may be used when dopaminergic therapy is required. Levodopa provides better immediate symptomatic relief. Agonists have lower risk of motor complications, particularly dyskinesias. Agonists may carry a higher side effect profile. Miyasaki JM, et al. Neurology. 2002;58(1):11-17. Issues in Advanced PD Reduced quality of life 1 Functional impairment Higher risk of depression and cognitive impairment 2 Higher risk for comorbidities 2 Increased medical expenses 2 Caregiver burden and risk of early nursing home placement 2,3 1. Dodel RC, et al. Pharmacoeconomics. 2001;19:1013-1038. 2. Parashos SA, et al. Mayo Clin Proc. 2002;77:918-925. 3. Carter JH, et al. Mov Disord. 1998;13:20-28. 6

Problems in Advanced PD Causes of Falls Motor Neuropsychiatric Autonomic Postural instability Freezing Dyskinesia Hypotension Other neurological problems Environmental Motor Problems Fluctuations Dyskinesias Freezing of gait Falls Clinical Effect Schematic of Possible Changes in Clinical Effect in Patients as PD Progresses Diminishing Duration of Target Levodopa Response Early PD Dyskinesia Threshold Response Threshold Clinical Effect Moderate PD Dyskinesia Threshold Response Threshold Clinical Effect Advanced PD Dyskinesia Threshold Response Threshold 2 4 6 Levodopa Time (h) Levodopa 2 4 6 Time (h) Levodopa 2 4 6 Time (h) Target Response Adapted with permission from: Obeso JA et al. In: Olanow CW, Obeso JA, eds. Beyond the Decade of the Brain. Vol 2. Dopamine agonists in early Parkinson s disease. Tunbridge Wells, UK: Wells Medical Ltd;1997:11-35. 7

Definition of Terms On state relatively good overall function and mobility corresponding to the medication working Off state relatively poor overall function and mobility corresponding to the medication not working Dyskinesias involuntary, nontremor movements Troublesome dyskinesias may be painful, impair balance, or are excessive to the point of causing impairment in coordination or general function Parkinson Study Group. Arch Neurol. 2005;62:241-248. Frequency of Levodopa-Induced Dyskinesia and Response Fluctuations by Age % Patients 100 80 60 40 20 0 Age at Onset (years) 21-40 (dyskinesias) 21-40 (fluctuations) 40+ (dyskinesias) 40+ (fluctuations) 0 1 2 3 4 5 Duration of Levodopa Treatment (years) Kostic V, et al. Neurology. 1991;41:202-205. n=25 in each group Treatment of Dyskinesia Peak dose or end of dose Treatment options include: Amantadine Clozapine (rarely used) Experimental therapy Deep Brain Stimulation (DBS) Mechanism: NMDA receptor antagonist, dopamine releasing agent Indications: Early PD, dyskinesias, fatigue Benefits: Mild symptomatic benefit, effective for dyskinesias Side effects: Leg swelling, livedo reticularis, neuropsychiatric, interacts with anticholinergics Amantadine Total dyskinesia Maximal dyskinesia UPDRS IVa dyskinesia UPDRS III motor off UPDRS III motor on Snow BJ, et al. Clin Neuropharmacol. 2000;23(2):82-85. Amantadine vs placebo for levodopa-induced dyskinesias Amantadine* Placebo* P value 22.0 (13.2) 29.0 (12.6) 0.004 5.2 (2.6) 6.3 (2.2) 0.02 3.2 (1.6) 4.3 (1.5) 0.02 38.4 (14.8) 41.7 (13.0) 0.04 22.3 (12.1) 23.4 (9.0) 0.44 NS *Mean score (SD) Wilcox signed-rank test 8

Case Example 2 A 65-year-old female with PD for 4 years is taking carbidopa/levodopa 25/100 QID. She is experiencing regular and predictable wearing off of the effect, 1½ hours prior to each dose. With this wearing off she gets painful foot dystonia and shortness of breath, as well as a return of her PD symptoms. How would you manage this patient? Examples of Other Off Symptoms Slowness of thinking Irritability Fatigue Drenching sweats Constipation Urinary urgency Abdominal bloating Pain Wearing Off Definition: Re-emergence of features of Parkinson s disease at end of dose May be motor or non-motor Case Example 2: Wearing Off Treatment Options Extended-release levodopa More frequent dosing of levodopa COMT inhibitors: entacapone or tolcapone Dopamine agonists MAO-B inhibitors Anticholinergics Botulinum toxin injection 9

Agents Commonly Used in the Management of PD Incidence of Non-Motor Symptoms of PD Levodopa COMT Inhibitors Tolcapone Entacapone MAO-B Inhibitors Selegiline Zydis selegiline Rasagiline Dopamine Agonists Pramipexole Ropinirole Bromocriptine Apomorphine Rotigotine Other Amantadine Anticholinergics ANS. dysfunction 80% Dementia 78% Sleep disorders * 66% Urogenital dysfunction 57-83% Gastrointestinal symptoms * 50-95% Fatigue 50% Orthostatic hypotension 50% Depression * 40-50% Pain 40-50% Impulse control disorders 7-14% *Identified as possible pre-motor symptoms ANS: autonomic nervous system Reichmann H, et al. Expert Opin. Pharmacother. 2009;10(5):773-784. Chaudhuri K, et al. Lancet Neurology. 2006;5:235-245. Non-Motor Features of PD Autonomic Constipation Hyperhidrosis Urinary dysfunction Sexual dysfunction Sialorrhea Psychiatric disorders Depression/anxiety Apathy Fatigue Sleep disorders Insomnia REM behavior disorder Cognitive Dementia Psychosis AAN Recommendations for Treatment of Non-motor Symptoms of PD Parameter Dementia Recommendation Donepezil should be considered Rivastigmine should be considered Evidence Level* Depression Amitriptyline may be considered C Insufficient evidence for other treatments U Fatigue Methylphenidate may be considered C Erectile Dysfunction Sildenafil citrate (50 mg) may be efficacious C Constipation Polyethylene glycol may be considered Insufficient evidence to support/refute the use of botulinum toxin Zesiewicz TA, et al. Neurology. 2010;74:924-931. Miyasaki JM, et al. Neurology. 2006;66:996-1002. B B C U *Evidence level was based on the AAN s classification scheme : Off-label use 10

AAN Recommendations for Treatment of Non-motor Symptoms of PD (cont d) Parameter Orthostatic Hypotension Urinary Incontinence Anxiety REM Behavior Disorder (RBD) Insomnia Recommendation Insufficient evidence to support/refute treatment in PD Insufficient evidence to support/refute treatment in PD Insufficient evidence to support/refute the treatment of anxiety with levodopa Insufficient evidence to support/refute the treatment of RBD Clonazepam and melatonin are often used in the general population Insufficient evidence to support/refute the benefit of levodopa/carbidopa on objective sleep parameters that are not affected by motor status Insufficient evidence to support/refute the benefit of melatonin on the treatment of poor sleep quality Zesiewicz TA, et al. Neurology. 2010;74:924-931. Miyasaki JM, et al. Neurology. 2006;66:996-1002. Evidence Level* *Evidence level was based on the AAN s classification scheme : Off-label use U U U U U U Case Example 3 A 75-year-old male retired physician comes to your office with PD and hallucinations. He is seeing deceased relatives in his house and accusing his wife of having an affair. His medications for PD include carbidopa/levodopa 25/100 QID. He continues to suffer from slowness and some disability. How would you manage this patient? Neuropsychiatric Management of Psychotic Symptoms Cognitive impairment and dementia Psychosis Compulsive disorders Depression Apathy Anxiety Rule out causes of mental status changes Infection Electrolyte imbalance Medications Modify PD regimen Reduce PD medications to minimum tolerable, yet effective dose Discontinue, if necessary Evaluate risk/benefit of atypical antipsychotic Priority of modification Anticholinergics Amantadine MAO-B inhibitors Dopamine agonists COMT inhibitors Levodopa/carbidopa 11

Therapy for Cognitive Impairment in PD Depression Cholinesterase inhibitors Memantine? Avoid anticholinergics Atypical neuroleptics Caregiver support CHANGE FROM BASELINE IN ADAS-cog SCORE -2.5-2.0-1.5-1.0-0.5 0 0.5 P =.002 RIVASTIGMINE (n=329) PLACEBO (n=161) P <.001 1.0 0 16 24 WEEK BASELINE DETERIORATION IMPROVEMENT Severe depression is unusual. Suicide is unusual. Weight loss, fatigue, insomnia can be due to PD or depression. Difficult to differentiate. Emre M, et al. New Engl J Med. 2004;351(24):2509-2518. Massachusetts Medical Society. Used with permission. Case Example 3 (Cont d) He is likely to have mild underlying dementia. He cannot lower his levodopa because he is quite impaired from the PD. His wife should get counseling. He should be treated with a cholinesterase inhibitor and an atypical antipsychotic (quetiapine and clozapine ONLY). Treatment of Depression in PD Very few studies have been conducted. Most antidepressants work, but very few randomized clinical trials exist. Caution with the side effects of antidepressants (low blood pressure, dry mouth, confusion and sedation with the tricyclics, and increased tremor and impotence with the SSRIs). 12

% decrease in the MADRS score -30-40 -70 Summary of PD Depression Double-Blind Studies Citalopram or desipramine vs placebo 1 Baseline Day 14 Day 30 Desipramine Placebo Citalopram Citalopram and desipramine both more effective than placebo, but significant shortterm effect (at 14 days) only with desipramine 1. Devos D, et al. Mov Disord. 2008;23(6):850-857. 2. Menza M, et al. Neurology. 2009;72(10):886-892. HAM-D change 0-4 -8-12 Nortriptyline or paroxetine CR vs placebo 2 Weeks from baseline Placebo Paroxetine Nortriptyline 0 2 4 84 Nortriptyline was superior to placebo; paroxetine was not Sleep Disorders Insomnia and sleep fragmentation Nightmares, hallucinations REM behavior disorder Sleep apnea Excess daytime sleepiness and sleep attacks Frequent urination PD immobility SAD-PD: Efficacy SAD-PD: Study of Antidepressants in PD Mean 12-Week in HAM-D Score (N=115) Comparison Effect 95% CI P-value Paroxetine vs Placebo -6.2 (-9.7, -2.7).0007 Venlafaxine vs Placebo -4.2 (-7.8, -0.6).02 Autonomic Dysfunction Constipation Urinary problems Sexual problems Orthostatic hypotension Sweating Pain Dysphagia Seborrhea Richard IH, et al. Neurology. 2012;78(16):1229-1236. 13

Orthostatic Hypotension Eliminate blood pressure medications. Try to stop PD medications (ie, dopamine agonists): Fludrocortisone Midodrine Pyridostigmine Domperidone (outside of US) Other Autonomic Problems Gastrointestinal (GI) Treat constipation No good treatments for gastroparesis Genitourinary (GU) Urinary anticholinergics may cause confusion and hallucinations Alpha adrenergic blocking agents may cause hypotension Gastrointestinal (GI) Problems Drooling Dysphagia Weight loss Gastroparesis Constipation Mild symptoms, no disability Does not yet need treatment When to Consider DBS Early Mild Moderate Advanced Symptoms with some disability May need treatment but not yet levodopa Worsening symptoms Need for levodopa ± adjunctive therapy TIME TO CONSIDER DBS Beginning of complications from disease and treatment Increasing disability despite therapy Complications of disease and treatment 14

Time Best Medical Therapy (BMT) vs DBS On without troublesome dyskinesia On with troublesome dyskinesia Patient Motor Diary Outcomes BMT change from baseline to 6 mos (n=134) DBS change from baseline to 6 mos (n=121) Mean difference between BMT vs DBS P value 0.1 4.6-4.5 <.001-0.3-2.6 2.3 <.001 Off 0.1-2.4 2.5 <.001 Asleep 0.3 0.4-0.1.66 Future Directions in PD Treatment Treat or restore function in advanced disease. Treat dyskinesia. Prevent development of motor complications. Treat nondopaminergic features. Neuroprotective treatments? Adapted from: Weaver FM, et al. JAMA. 2009;301:63-73. Adverse Events from DBS 40% of patients in study receiving DBS had a serious adverse event, including: Up to 3 months following DBS Fall (P =.02) Pain (P =.04) Confusional state (P <.001) Speech disorder (P =.004) Headache (P <.001) 4-6 months following DBS Dystonia (P =.02) Fall (P =.03) Question 1 Would dopamine agonists still be an option for Parkinson s patients with dementia and/or psychosis who have worsening motor symptoms? Weaver FM, et al. JAMA. 2009;301:63-73. 15

Question 2 Can deep brain stimulation (DBS) be considered in older patients? Question 4 In male patients with Parkinson s disease, if they suffer from postural hypotension is there an alternative to sildenafil for erectile dysfunction? Question 3 Are there effective treatments available for sialorrhea in patients with Parkinson s disease? Question 5 Why are only quetiapine and clozapine recommended for the treatment of psychosis in patients with Parkinson s disease? For these drugs, what are the starting doses? 16

Question 6 What are the best ways to assess and manage dysphagia in patients with Parkinson s disease? Question 8 What are the indications for botulinum toxins in Parkinson s disease? Question 7 Is there a maximum/ceiling dose of: Carbidopa/levodopa in patients with end-stage Parkinson s disease? Quetiapine in managing psychosis in Parkinson s disease? Question 9 Is the rotigotine patch a viable option for early Parkinson s disease? Is it an alternative to levodopa in those with advanced disease? 17

Question 10 How do you define a poor response to levodopa? Question 12 Does DBS necessitate changes in prior medical therapy? STN: subthalamic nucleus GPi: Globus Pallidus Pars Interna Question 11 Is there a hereditary component to Parkinson s disease? 18