With Time, The Pathology of PD Spreads Throughout the Brain
Braak’s staging of Parkinson’s disease pathology
dm co sn mc hc fc
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STAGES OF PD
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
2 3 4 5 6
Braak H, et al. Cell Tissue Res. 2004;318:121-134.
Parkinson’s Disease (PD) Epidemiology
? Uncommon before age 50 years1 ? Annual incidence (all ages): 8.6 to 19.0/100,0002 ? Incidence increases dramatically with age: approximately 100/100,000 over age 70 years3 ? Prevalence in individuals older than 65 years: approximately 1%4 ? More common in men5
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.
Motor Features of PD
Cardinal features
? Rest tremor ? Rigidity ? Bradykinesia ? Postural instability
Incidence of PD by age
10%
Other motor features
? Masked face ? Shuffling gait ? Freezing ? Micrographia ? Dystonia ? Cramps
90%
Age 50 and under Greater than age 50
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Non-Motor Features of PD
? Autonomic
– Constipation – Hyperhidrosis – Urinary dysfunction – Sexual dysfunction – Sialorrhea
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
? Sleep disorders
– Insomnia – REM behavior disorder
? Cognitive
– Dementia – Psychosis
? Psychiatric disorders
– Depression/Anxiety – Apathy – Fatigue
Wenning GK, et al. J Neurol Neurosurg Psychiatry. 2000;68:434-440.
Differential Diagnosis of PD
Essential Tremor Vascular Drugs Progressive Supranuclear Palsy Idiopathic Secondary Parkinson’s Disease Lewy Other Alzheimer’s Disease Body Disease ParkinsonPlus Corticobasal Degeneration Other MultiSystem Atrophy
Dopamine Transport Imaging (DaTscan?)
Toxins
Normal
Abnormal
Encephalitis
: Neurodegenerative parkinsonism (ALL) ; Essential tremor ; Drug-induced parkinsonism ; Vascular parkinsonism ; Psychogenic
Dopamine transport imaging differentiates between parkinsonian disorders with and without dopamine deficiency
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Treatment Goals ? Slowing disease progression ? Controlling symptoms ? Preserving quality of life
Can Exercise Slow PD Progression?
Exercise Therapy Is Effective in Improving Activities of Daily Living
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
? ?
Sites of Action of PD Drugs
Substantia?Nigra
levodopa MAO‐B?inhibitors: selegiline rasagiline amantadine Dopamine?agonists: bromocriptine pramipexole ropinirole rotigotine
Coenzyme Q10 Pramipexole
Blood Brain Barrier
Results Pending
Creatine Inosine ? Isradipine ? Exercise
? ?
DA
GABA
ACh
DDC COMT dopamine levodopa 3‐OMD
Maybe
?
Striatum
Rasagiline
carbidopa
?Massachusetts
Anticholinergics: trihexyphenidyl benztropine
Olanow CW, et al. N Engl J Med. 2009;361:1268-1278.
COMT?inhibitors: tolcapone entacapone
Medical Society. Used with permission.
Adapted?from?https://www.doczj.com/doc/005562949.html,?
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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.
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Levodopa Associated With Risk of Motor Complications
? Dyskinesia
– Peak dose – End of dose
75 100 100% BY 10 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
? Motor fluctuations
– End-of-dose wearing off – Unpredictable “on-off” – “Yo-yo-ing”
50
40% BY 5 YEARS
25
0 1 2 3 4 5 6 7 8 9
10
Time from Initiation of Therapy (years) Adapted from: Schrag A, et al. Mov Disord. 1998;13:885-894. Weintraub D, et al. Arch Neurol. 2010;67:589-595.
Occurrence of Dyskinesia: Initial Dopamine Agonist Therapy
Incidence rate for first occurrence (per 1000 person-years)
200 150 100 50 0 Dyskinesia Dystonia On/off
Lees AJ, et al. Neurology. 2001;57(9):1687-1694. Oertel WH, et al. Mov Disord. 2006;21(3):343-353.
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
Mean change from baseline in total UPDRS score
5.0 4.0 3.0 2.0 1.0 0.0
0.51 -0.13 P < .001 P < .001 Rasagiline 1 mg Rasagiline 2 mg Placebo
Incidence (%)
Levodopa Bromocriptine
4.07
Incidence (%)
0
Dyskinesia Dyskinesia before suppl levodopa Disabiling dyskinesia
Incidence (%)
50
Levodopa Ropinirole
IMPROVEMENT
Rascol O, et al. N Engl J Med. 2000;342(20):1484-1491.
Parkinson Study Group. JAMA. 2000;284(15):1931-1938.
Parkinson Study Group. Arch Neurol. 2002;59(12):1937-1943.
UPDRS: Unified Parkinson's Disease Rating Scale
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Treatment-Emergent Adverse Events With Rasagiline Monotherapy*
90 80 70 60 50 40 30 20 10 0
Percentage of Patients
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 life1 ? Functional impairment ? Higher risk of depression and cognitive impairment2 ? Higher risk for comorbidities2 ? Increased medical expenses2 ? Caregiver burden and risk of early nursing home placement2,3
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.
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Problems in Advanced PD
Causes of Falls ? Postural instability ? Freezing ? Dyskinesia ? Hypotension ? Other neurological problems ? Environmental
? Motor ? Neuropsychiatric ? Autonomic
Motor Problems
? Fluctuations ? Dyskinesias
Clinical Effect
Schematic of Possible Changes in Clinical Effect in Patients as PD Progresses
Diminishing Duration of Target Levodopa Response
Early PD Moderate PD Advanced PD Dyskinesia Threshold Response Threshold Dyskinesia Threshold Response Threshold Dyskinesia Threshold Response Threshold
Clinical Effect
? Falls
Levodopa
2
6 4 Time (h)
Clinical Effect
? Freezing of gait
Levodopa
2
4 6 Time (h)
Levodopa
2
6 4 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.
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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
100 80 Age at Onset (years) 21-40 (dyskinesias) 21-40 (fluctuations) 40+ (dyskinesias) 40+ (fluctuations)
% Patients
60 40 20 0
n=25 in each group 0 1 2 3 4 Duration of Levodopa Treatment (years) 5
Kostic V, et al. Neurology. 1991;41:202-205.
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
Amantadine
Amantadine vs placebo for levodopa-induced dyskinesias
Amantadine*
Total dyskinesia Maximal dyskinesia UPDRS IVa dyskinesia UPDRS III motor off UPDRS III motor on 22.0 (13.2) 5.2 (2.6) 3.2 (1.6)
Placebo*
29.0 (12.6) 6.3 (2.2) 4.3 (1.5)
P value?
0.004 0.02 0.02
? Indications: Early PD, dyskinesias, fatigue ? Benefits: Mild symptomatic benefit, effective for dyskinesias ? Side effects: Leg swelling, livedo reticularis, neuropsychiatric, interacts with anticholinergics
38.4 (14.8) 22.3 (12.1)
41.7 (13.0) 23.4 (9.0)
0.04 0.44 NS
Snow BJ, et al. Clin Neuropharmacol. 2000;23(2):82-85.
?Wilcox
*Mean score (SD) signed-rank test
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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, 1? 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.
Examples of Other “Off” Symptoms
? Slowness of thinking ? Irritability ? Fatigue ? Drenching sweats ? Constipation ? Urinary urgency ? Abdominal bloating ? Pain
How would you manage this patient?
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
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Agents Commonly Used in the Management of PD
? ?
Incidence of Non-Motor Symptoms of PD
ANS dysfunction . Dementia Sleep disorders * Urogenital dysfunction Gastrointestinal symptoms * Fatigue Orthostatic hypotension Depression * Pain Impulse control disorders
*Identified as possible pre-motor symptoms
Levodopa COMT Inhibitors ? Tolcapone ? Entacapone MAO-B Inhibitors ? Selegiline ? Zydis selegiline ? Rasagiline
?
?
Dopamine Agonists ? Pramipexole ? Ropinirole ? Bromocriptine ? Apomorphine ? Rotigotine Other ? Amantadine ? Anticholinergics
80% 78% 66% 57-83% 50-95% 50% 50% 40-50% 40-50% 7-14%
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
? Sleep disorders
– Insomnia – REM behavior disorder
AAN Recommendations for Treatment of Non-motor Symptoms of PD
Parameter
Dementia Depression Donepezil?
Recommendation
should be considered
Evidence Level*
B B C U C C C U
Rivastigmine should be considered Amitriptyline may be considered Insufficient evidence for other treatments Methylphenidate? may be considered Sildenafil citrate (50 mg) may be efficacious Polyethylene glycol may be considered Insufficient evidence to support/refute the use of botulinum toxin
? Cognitive
– Dementia – Psychosis
Fatigue Erectile Dysfunction Constipation
? Psychiatric disorders
– Depression/anxiety – Apathy – Fatigue
Zesiewicz TA, et al. Neurology. 2010;74:924-931. Miyasaki JM, et al. Neurology. 2006;66:996-1002.
*Evidence level was based on the AAN’s classification scheme ?: Off-label use
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AAN Recommendations for Treatment of Non-motor Symptoms of PD (cont’d)
Parameter
Orthostatic Hypotension Urinary Incontinence Anxiety REM Behavior Disorder (RBD)
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.
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
Evidence Level*
U U U
U
U U
Insomnia
Zesiewicz TA, et al. Neurology. 2010;74:924-931. Miyasaki JM, et al. Neurology. 2006;66:996-1002.
*Evidence level was based on the AAN’s classification scheme ?: Off-label use
How would you manage this patient?
Neuropsychiatric
? ? ? ? ? ? Cognitive impairment and dementia Psychosis Compulsive disorders Depression Apathy Anxiety
Management of Psychotic Symptoms
? Rule out causes of mental status changes
– Infection – Electrolyte imbalance – Medications
Priority of modification
Anticholinergics ? Amantadine ? MAO-B inhibitors ? Dopamine agonists ? COMT inhibitors ? Levodopa/carbidopa
? Modify PD regimen
– Reduce PD medications to minimum tolerable, yet effective dose – Discontinue, if necessary
? Evaluate risk/benefit of atypical antipsychotic
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Therapy for Cognitive Impairment in PD
CHANGE FROM BASELINE IN ADAS-cog SCORE
-2.0 -1.5 -1.0 -0.5 0 0.5 1.0 0 16 24
Depression
IMPROVEMENT
? Cholinesterase inhibitors ? Memantine? ? Avoid anticholinergics ? Atypical neuroleptics ? Caregiver support
-2.5
P = .002 P < .001 RIVASTIGMINE (n=329) PLACEBO (n=161)
BASELINE
? Severe depression is unusual. ? Suicide is unusual. ? Weight loss, fatigue, insomnia can be due to PD or depression. ? Difficult to differentiate.
WEEK
?Massachusetts
Emre M, et al. New Engl J Med. 2004;351(24):2509-2518.
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).
DETERIORATION
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).
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Summary of PD Depression Double-Blind Studies
Citalopram or desipramine vs placebo1
Baseline
% decrease in the MADRS score
-30
Sleep Disorders
? Insomnia and sleep fragmentation ? Nightmares, hallucinations ? REM behavior disorder ? Sleep apnea ? Excess daytime sleepiness and sleep attacks ? Frequent urination ? PD immobility
Nortriptyline or paroxetine CR vs placebo2
0
Day 14
Day 30
HAM-D change
Placebo
-4
Placebo
Paroxetine
-8
-40
Citalopram
-12 -70
Nortriptyline
0 2 4 84
Desipramine
Citalopram and desipramine both more effective than placebo, but significant shortterm effect (at 14 days) only with desipramine
Weeks from baseline
Nortriptyline was superior to placebo; paroxetine was not
1. Devos D, et al. Mov Disord. 2008;23(6):850-857. 2. Menza M, et al. Neurology. 2009;72(10):886-892.
SAD-PD: Efficacy
SAD-PD: Study of Antidepressants in PD
Mean 12-Week ? in HAM-D Score (N=115)
Comparison Paroxetine vs Placebo Effect -6.2 95% CI (-9.7, -2.7) P-value .0007
Autonomic Dysfunction
? Constipation ? Urinary problems ? Sexual problems ? ? ? ? Orthostatic hypotension Sweating Pain Dysphagia
Venlafaxine vs Placebo
-4.2
(-7.8, -0.6)
.02
? Seborrhea
Richard IH, et al. Neurology. 2012;78(16):1229-1236.
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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
Early
When to Consider DBS
Mild Moderate Advanced
? ? ? ? ?
Drooling Dysphagia Weight loss Gastroparesis Constipation
h
? Mild symptoms, no disability ? Does not yet need treatment
TIME TO CONSIDER DBS
? Symptoms with some disability ? May need treatment but not yet levodopa ? Worsening symptoms ? Need for levodopa ± adjunctive therapy ? Beginning of complications from disease and treatment ? Increasing disability despite therapy ? Complications of disease and treatment
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Best Medical Therapy (BMT) vs DBS
Patient Motor Diary Outcomes
Time BMT change from baseline to 6 mos (n=134) 0.1 DBS change from baseline to 6 mos (n=121) 4.6 Mean difference between BMT vs DBS -4.5 P value
Future Directions in PD Treatment
? Treat or restore function in advanced disease. ? Treat dyskinesia. ? Prevent development of motor complications. ? Treat “nondopaminergic” features. ? Neuroprotective treatments?
On without troublesome dyskinesia On with troublesome dyskinesia Off Asleep
< .001
-0.3
-2.6
2.3
< .001
0.1 0.3
-2.4 0.4
2.5 -0.1
< .001 .66
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.
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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?
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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?
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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?
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