Parkinson s Disease and Treatment Options for the Younger Adult David E. Riley, M.D. Chair, Medical Education InMotion April 22, 2016 Case Presentation - 1 A 57-year-old woman had Tremor of her right hand off and on for 3 months Tremor mainly while reading or watching television Handwriting has become small Trouble beating an egg with her right hand Her family had noted A loss of facial expression She doesn t swing her right arm when she walks Case Presentation - 2 On exam, she showed Reduced blinking and facial expression Soft, monotonous voice General lack of movement Activated rigidity in the right upper limb Slowness of repetitive movements with the right hand Tremor of the right hand when she walks
James Parkinson s monograph Core clinical features: Tremor Rigidity Akinesia Postural disturbances Tremor Rest tremor (characteristic) Occurs in repose 3-7 Hz (slow) TIP: Watch for rest tremor while walking, or during tasks of concentration (e.g., arithmetic, reciting months backward) Action tremor (less common) Occurs with muscle activation 6-11 Hz (fast) Rigidity Muscle tone: Increased passive resistance A sign clinicians elicit, not a symptom Unlike spasticity, uniform in antagonists, throughout a joint range, regardless of speed TIP: Accentuated by contralateral activity Cogwheeling : correlated with tremor, not rigidity
Akinesia Akinesia : from the Greek for lack of movement Impairment of voluntary movement Typically causes most of the disability in PD Akinesia 3 components: Bradykinesia (decreased speed of movement) e.g. Slow initiation and execution of all movement Hypokinesia (decreased amplitude of movement) e.g. Micrographia, decreased arm swing, short stride Oligokinesia (decreased quantity of movement) e.g. Reduced blink and facial expression TIP: Tendency to progressive fatigue with repetition Micrographia
Postural Disturbances Flexion posture Disorder of equilibrium Exam: Test for retropulsion Pull backward on shoulders Normal: recover balance in 2 steps Parkinsonism vs. Parkinson s Parkinsonism a syndrome consisting of Tremor Rigidity Akinesia Postural disturbances Parkinsonism vs. Parkinson s Parkinson s Disease A degenerative disease with characteristic motor and non-motor clinical features, epidemiology, evolution, prognosis, treatment and pathology Parkinson s disease is the most common cause of parkinsonism, but not the only cause
Non-Motor Features Cognitive (dementia, excess somnolence) Autonomic (constipation, orthostatic hypotension, incontinence, sexual or sweat dysfunction) Sensory (restless legs, loss of smell) Miscellaneous (depression, REM-sleep behavior disorder) Premotor Features May precede motor onset by decades Strongest evidence established for: Olfactory deficit Constipation REM-sleep behavior disorder Excess daytime somnolence Depression, anxiety Savica et al. Arch Neurol 2010; 67: 798-801 Lang. Mov Disord 2011; 775-783 A Redefinition of PD Preclinical PD Pathology present; no clinical findings Premotor PD Early non-motor symptoms and signs Motor PD Classic motor manifestations Stern M, et al. Mov Disord 2012; 27: 54-60
Epidemiology Affects approximately 1 million patients in USA Prevalence: 0.3% of general population 1-3% of those older than 65 years Average age of onset is 60 years most notice first symptoms in their 50s or 60s ~5% of PD patients develop first symptoms before age 40, ~15% before age 50 ( young-onset PD, or YOPD) Typical Clinical Course Starts in one limb Dominant:non-dominant = 3:2 Progresses slowly over months and years Typically first to the other limb on the same side Eventually becomes bilateral, but remains worse on the side first affected Tremor, rigidity and akinesia early; postural instability late Etiology Multiple gene mutations now associated with PD Genetic factors play a larger role in patients with young-onset PD Environmental insults probably play a role in patients with PD onset after age 50 Excessive protein ( -synuclein) accumulation is found in all cases of PD
How is PD different for younger adults? Definition of young-onset PD Usually defined as onset < 40 or < 50 years But definitions vary widely Here I use < 50 years old, unless stated Etiology: More frequent (+) family history Onset < 50: risk of PD in sibs Sibs at risk of also developing PD < 50 y.o. Barrett et al. Mov Disord 2015; 30: 733-5 How is PD different for younger adults? Delayed diagnosis of PD with onset < 45 y.o. Mean 15 additional months until diagnosis in PD patients Higher number of visits to neurologists prior to dx Higher number of lab investigations prior to dx Rana et al. J Neurol Sci 2012; 323: 113 116 Usually need care beyond initial doctor s career How is PD different for younger adults? Course: Progression is slower Mortality Life expectancy (LE) closer to normal in relative, but not absolute, terms e.g., onset age 25-39: lose 22% LE, or 11 years; onset age > 64: lose 44% LE, or 4 years Wickremaratchi et al. Eur J Neurol 2009; 16: 450 6
How is PD different for younger adults? Increased rates of: onset with non-tremor symptom dystonia (at onset or during treatment) levodopa-induced dyskinesias depression, anxiety Clinical manifestations and complications: Lower rates of early gait difficulty falls, freezing dementia autonomic disturbances Mehanna et al. Park Rel Dis 2014; 20: 530-4 Pagano et al. Neurology 2016; 86: 1 8 Wickremaratchi et al. Eur J Neurol 2009; 16: 450 6 How is PD different for younger adults? Psychosocial effects more likely to become unemployed or retire early negative effects on finances, role functioning, social contacts, self-esteem experience more family and marital problems have higher depression scores rate their quality of life as worse than do patients with older onset with similar disease severity may need more support of family members Schrag A, et al. Mov Disord 2003; 18: 1250-6 Schrag A, Schott J. Lancet Neurol 2006; 5: 355 63 Pathology Gross: Pallor of substantia nigra Microscopic: Loss of > 50% of substantia nigra neurons In surviving neurons, cytoplasmic inclusions called Lewy bodies Lewy bodies contain α-synuclein Loss of substantia nigra neurons results in loss of dopamine in nigrostriatal tract
Lewy Body A Chemical Balancing Act In the basal ganglia, dopamine is in dynamic equilibrium with acetylcholine Dopamine Acetylcholine Antiparkinsonian drugs either compensate for missing dopamine, or antagonize acetylcholine Currently Available Medications Anticholinergics Amantadine Carbidopa/Levodopa Dopamine agonists MAO (monoamine oxidase) inhibitors COMT (catechol-o-methyl transferase) inhibitors
Anticholinergic Drugs Trihexyphenidyl (Artane ) preferred by movement disorder specialists due to lower rate of sedation Benztropine (Cogentin ) Diphenhydramine (Benadryl ) all available as generics Anticholinergic Drugs Good for relief of tremor, little else The most notorious for causing cognitive side effects (memory loss, psychosis, confusion) Poorly tolerated by elderly patients Also cause dry mouth, blurred vision, other antimuscarinic effects Main indication: for young patients (< 60 years) whose predominant symptom is resting tremor Amantadine Antiviral drug with uncertain mechanism of antiparkinsonian effect Hubsher G, et al. Neurology 2012; 78: 1096-9 Modest benefit for all symptoms Second worst for causing cognitive effects Other adverse effects: Dry mouth Livedo reticularis Pedal edema
Case Presentation - 3 Our patient initially declined any symptomatic treatment After 6 months, she reported an increase in slowness with activities of daily living A trial of amantadine 100 mg b.i.d. produced satisfactory improvement Case Presentation - 4 Our patient reported increased symptoms 6 months later These responded to an increase in amantadine to 100 mg t.i.d. However, she soon developed swelling of her legs associated with a mottled appearance of her skin Amantadine was discontinued Amantadine One option for patients with mild symptoms May have more prolonged benefit than generally acknowledged Effective symptomatic treatment for levodopa-induced dyskinesias
Levodopa Marketed in U.S.A. in combination with carbidopa as Sinemet to reduce nausea Carbidopa has no anti-pd effect; pure antinauseant 1975: Sinemet = sine + emesis Initially formulated in carbidopa/levodopa ratio of 1:10 Now the standard ratio is 1:4 Current U.S.A. Formulations Sinemet (carbidopa/levodopa tablets) ratios: 10/100, 25/100, 25/250 Sinemet CR (controlled-release carbidopa/levodopa tablets) ratios: 25/100, 50/200 Parcopa (orally disintegrating carbidopa/levodopa tablets) ratios: 10/100, 25/100, 25/250 Stalevo (carbidopa/levodopa tablets plus entacapone): 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 Rytary (capsules contain both immediate-release and extended-release beads of carbidopa-levodopa): 23.75/95, 36.25/145, 48.75/195, 61.25/245 Duopa (enteral suspension of carbidopa-levodopa): 4.63/20 per ml (in cartridges of 100 ml) Benefits of Levodopa The most effective drug in the treatment of motor manifestations of PD the cornerstone of treatment of PD for >40 years Virtually all (94%) patients with confirmed PD experience clinically significant benefit Associated with reduced disability compared to the pre-levodopa era Possibly associated with decreased mortality compared to the pre-levodopa era
Micrographia response to levodopa 2006 2008 2010: Sinemet 25/100 two tablets t.i.d. Limitations of Levodopa Only one common early side effect: nausea Two problems with levodopa as PD progresses: 1. Fluctuations in symptom severity due to premature wearing off of benefit prior to the next dose 2. Involuntary movements (dyskinesias) Both fluctuations and dyskinesias are more common in younger patients Dopamine Agonists Act by direct stimulation of the postsynaptic dopamine receptors Molecular structure similar to dopamine Effective against most principal PD manifestations Tremor Akinesia Rigidity
Dopamine Agonists Currently available in the U.S.A.: Pramipexole (Mirapex ): 3 times a day extended-release (Mirapex ER ): once daily Ropinirole (Requip ): 3 times a day extra-long-acting (Requip XL ): pill once daily Apomorphine (Apokyn ): injectable as needed Rotigotine (Neupro ): skin patch once daily Micrographia response to medication January 2009 Prior to treatment August 2010 Ropinirole XL 8 mg daily Levodopa vs. Dopamine Agonists Side Effects Levodopa Nausea Dyskinesias Fluctuations Dopamine agonists Hallucinations/ psychosis Sedation Impulse-control disorders Edema Orthostatic hypotension
Dopamine Agonists Two main concerns with long-term dopamine agonist therapy: Sudden sleep attacks, concern with driving Impulse-control disorders Gambling Compulsive buying Hypersexuality, promiscuity Binge eating 17.1% on DA agonists vs. 6.9% not taking; OR 2.7 Weintraub et al. Arch Neurol 2010; 67: 589-595 COMT & MAO-B Inhibitors Catechol-O-methyl transferase and Monoamine oxidase B enzymes break down dopamine Inhibitors of these enzymes allow dopamine molecules to survive longer Useful in patients with PD experiencing end-ofdose wearing off with levodopa Side effects similar to increasing levodopa MAO-B Inhibitors Selegiline (Eldepryl ) One size: 5 mg, max 5 mg b.i.d.; generic available Very modest symptomatic benefit Initially thought that selegiline slows progression in PD, but later disproved Orally dissolving selegiline (Zelapar ) 1.25 mg Rasagiline (Azilect ) 0.5 mg or 1 mg; once-a-day dosing, generic not available yet Many times more potent than selegiline Effective treatment for motor fluctuations Also approved for solo use
COMT Inhibitors Tolcapone (Tasmar ) Three doses daily More potent than entacapone Requires liver function monitoring Entacapone (Comtan ) 200 mg taken with each dose of levodopa Less effective than tolcapone No laboratory surveillance required Available in combination with carbidopa/levodopa (Stalevo ) Initial Pharmacologic Treatment - Mainstream Approach - Use anticholinergics, amantadine or rasagiline for milder symptoms Use levodopa or dopamine agonists when disability occurs Under 60 years old Maximize use of non-dopaminergic drugs Use dopamine agonists before levodopa Over 70 years old, prefer levodopa Long-Term Pharmacologic Treatment Principles Use minimum dose that provides satisfactory benefit TIP: In general, use small doses of multiple drugs, rather than large doses of any single drug Polypharmacy has become the norm in PD Lack of drug interactions permits this At each visit, be attentive to: Possible side effects Gaps of time in symptom relief Non-motor complications
Case Presentation - 5 Off amantadine, our patient felt severely impaired, and her tremor was more prominent than ever Due to her age (still under 60), she began pramipexole At a dose of pramipexole 1 mg t.i.d., she did well for 2 years After 2 years, she required the addition of Sinemet She said she had trouble tolerating Sinemet initially, especially the morning dose A pharmacy brochure had instructed her to take it on an empty stomach, and she became violently ill Management of PD Complications in Younger Adults Motor Fluctuations 1. Shorten levodopa dose interval, or increase dose quantity 2. Extended-release levodopa preparations 3. Protein redistribution diet 4. Increase/add dopamine agonist 5. Add COMT inhibitor; MAO-B inhibitor 6. Amantadine 7. Surgical approaches Management of PD Complications in Younger Adults Peak-Dose Dyskinesias 1. Reduce levodopa dose 2. Reduce or eliminate levodopa boosters MAO and COMT inhibitors 3. Substitute for levodopa with other antiparkinsonian medications 4. Trial of amantadine 5. DBS Surgery
Deep Brain Stimulation (DBS) Current surgical procedure of choice for PD Reduces patients dependence on medication Provides more consistent symptom control Does not produce benefit beyond the best results from medication, except for tremor Deep Brain Stimulation (DBS) Current surgical procedure of choice for PD Reduces patients dependence on medication Provides more consistent symptom control Does not produce benefit beyond the best results from medication, except for tremor Patients most likely to benefit from DBS: Young Tolerate surgery better, longer benefit Suffering from dyskinesias and fluctuations Tremor unresponsive to medication Duopa Surgical Enhancement of Medication Delivery Carbidopa/levodopa enteral suspension Administered directly into the small intestine via PEG- J (percutaneous endoscopic gastrostomy with jejunal extension) Pump provides continuous levodopa supply for 16 hours At night, pump disconnected and patients take oral meds Indicated for treatment of motor fluctuations
Other Treatment Options Hypophonia Lee Silverman Voice Therapy Balance Physical therapy specialists Common PD Management Issue Sudden Deterioration! In parkinsonism (motor function) or In cognitive function (confusion, hallucinations) Parkinson s disease is slowly progressive Sudden deterioration indicates a superimposed condition Most likely: urinary tract infection, often asymptomatic Also: other infections, new medications Parkinson s Disease in General Medicine
Prediagnostic PD in Primary Care Prediagnostic presentations of Parkinson s disease in primary care: a case-control study Schrag A, et al. Lancet Neurol 2014; 14: 57 64 Retrospective database review of 8,166 with PD vs. 46,755 non-pd 5 years prior to dx, higher incidence in future PD patients of: tremor, balance impairments, constipation, hypotension, erectile dysfunction, urinary dysfunction, dizziness, fatigue, depression, and anxiety 10 years prior to dx, higher incidence in future PD patients of: tremor, constipation Autonomic Dysfunction Cardiovascular dysfunction Gastrointestinal dysfunction Genitourinary dysfunction Sweating dysfunction Autonomic - Cardiovascular Blood pressure instability Wide swings in BP throughout the day often spiking over 200 systolic BP fluctuation > 100 mmhg observed in 64.9% of PD patients (by ambulatory monitoring) Tsukamoto et al. Brain and Behavior 2013; 3: 710 714 Nighttime hypertension Long-term trend toward low BP Mandates to control high BP cause physicians to treat minor cases leading to more frequent bouts of low BP
Autonomic - Cardiovascular As PD progresses, watch for: Resolution of prior hypertension Orthostatic hypotension Drugs for PD, esp. dopamine agonists, can aggravate the tendency to low BP Postprandial hypotension Syncope BP Target Recommendation The risks of supine hypertension in this setting are largely statistical and long-term, whereas those of orthostatic hypotension are real and immediate. Therefore, at our centre, we set a goal of a systolic blood pressure while standing of at least 100 mm Hg, in the morning. Goldstein D. Compr Physiol 2014; 4: 805 826 Autonomic - Gastrointestinal - Constipation - The most common autonomic complication of PD Increased colonic transit time may worsen with disease progression Contributing factors Physical inactivity Delayed stomach transit Diminished fluid intake Some antiparkinsonian medications
Autonomic - Genitourinary Bladder Storage failure Urinary urgency Urinary frequency Urinary incontinence Bladder Voiding failure Urinary retention, may lead to infection Impotence Medical Comorbidities of PD Bone metabolism and joint diseases Osteoporosis 25-hydroxy-vitamin D3 deficiency Fractures Especially increased risk of hip/femoral fracture Frozen shoulder Low back pain Spinal deformity (camptocormia, Pisa syndrome) Poorer outcomes from shoulder and hip surgery Medical Comorbidities of PD Cancer Overall lower incidence of, and mortality from, cancer in PD Strong association: melanoma Higher risk in both patients and relatives Also increased risk: prostate, thyroid Reduced risk: colorectal, lung, pancreas, stomach
Medical Comorbidities of PD Other comorbidities Traumatic injuries other than fractures Deep vein thrombosis Associated with wheelchair use and postural abnormalities Malnutrition Medical Side Effects of PD Medications Orthostatic hypotension: dopamine agonists Peripheral edema: dopamine agonists, amantadine Nausea: levodopa Diarrhea: COMT inhibitors Constipation: anticholinergics Urinary retention: anticholinergics Common Errors in PD Management Levodopa Formulations A patient started Sinemet 25/100 and developed nausea. He was switched to the lower dose of Sinemet 10/100. The second number in carbidopa/levodopa formulations lists the mg content of the active ingredient (levodopa); the first is carbidopa Carbidopa is added to levodopa only to reduce nausea Thus switching a patient from 25/100 to 10/100 does not represent a lower dose of antiparkinsonian medication Paradoxically, patients suffer more side effects from 10/100 tablets than 25/100 tablets
Common Errors in PD Management Instigation of Nausea A patient started Sinemet 25/100. She followed the pharmacy directive not to take the medication with food. She developed nausea. Pharmacies often take a one-size-fits-all approach to PD Interference from protein is only a significant consideration in patients with dose-related fluctuations Instruct patients to ignore any pharmacy directive that contradicts your recommendation to take Sinemet with food at the beginning Common Errors in PD Management Treatment of Nausea A patient started Sinemet 25/100 and developed nausea. He was prescribed metoclopramide (Reglan ). Metoclopramide, prochlorperazine (Compazine ) and other antinauseants are dopamine receptor blockers. They aggravate PD. 4 remedies for nausea caused by levodopa Initiate carbidopa/levodopa after meals Take extra carbidopa 25 mg tablets Ondansetron (Zofran ); inactive at dopamine receptors Definitive Rx: domperidone (not dispensed in U.S.A.) Common Errors in PD Management Treatment of Hallucinations A patient began seeing people in the house who were not there. A physician prescribed risperidone. Risperidone, haloperidol, and most other antipsychotics are dopamine receptor blockers. They aggravate PD. Consider the following sequence of interventions Look for evidence of occult infection, especially UTI Withdraw anticholinergics, then amantadine, then dopamine agonists Prescribe a cholinesterase inhibitor (rivastigmine, donepezil)* Consider quetiapine or clozapine for an antipsychotic *Off-label
Lifestyle Intervention Physical Activity Physical activity: all forms are beneficial for PD patients Exercise Traditional, especially stretching Tai chi, yoga Dance (tango, ballroom, Irish set dancing, etc.) Sports (cycling, boxing, kayaking) Patients should be told: Exercise/activity is as important for PD as taking meds So find something they are willing to do regularly, and do it! Exercise, dance, sports, voice classes 5 days/week All led by certified instructors Support groups for patient and partners Bimonthly lectures by physicians and other professionals And much more all free of charge! Check us out at beinmotion.org Conveniently located near I-480 and I-271
Recommended Reading Calne S, Kumar A. Young onset Parkinson s disease: Practical management of medical issues. Parkinsonism and Related Disorders 2008; 14: 133 142 Calne S, et al. Psychosocial issues in youngonset Parkinson s disease: Current research and challenges. Parkinsonism and Related Disorders 2008; 14: 143 150