Cardinal Features An Overview of • Parkinsonism Parkinson’s Disease 9 Bradykinesia 9 Rigidity 9 Tremor Punit Agrawal, DO • Classically at rest Division of Movement Disorders 9 Postural instability OSU Dept of Neurology • Typically a late symptom Illustration of Parkinson's Disease by Sir William Richard Gowers 1886. (http://commons.wikimedia.org/wiki/File:Sir_William_Richard_Gowers_Parkinson_Disease_sketch_1886.jpg) • Parkinson’s Disease accounts for about 85% of patients with features of parkinsonism - (wemove.org)

Parkinson’s Disease Cardinal Features of Parkinsonism - Bradykinesia

• In 1817 James Parkinson • Delayed motor initiation (1755-1824) described Parkinson’s disease. • Slowed voluntary movement • Rapid fatigue with repetitive movements • Shuffling gait • Micrographia • Decreased dexterity • Hypomimia (decreased facial expression)

Parkinson J (1817) An essay on the Shaking palsy. Sherwood, Neely and Jones, London • Hypophonia (low voice volume)

1 Cardinal Features of Cardinal Features of Parkinsonism - Parkinsonism - Tremor Postural Instability • Loss of postural reflexes • Classically, a 3-7 Hz rhythmic resting • Retropulsion tremor that commonly presents with opposition of forefinger and thumb. • Increased difficulty turning with increased incidence of falls • Hands, legs, lips/chin. • Often the most disabling and least • Rest tremor typically increases with walking and distraction, but decreases with responsive to medications attention or with action. • Not typically present as an early features of Parkinson’s disease.

Parkinson’s Disease can cause Cardinal Features of numerous other symptoms including Parkinsonism - Rigidity many non-motor MOTOR NON-MOTOR • Bradykinesia • Constipation • Involuntary increase in muscle tone • Rigidity • Anosmia (loss of smell) Cardinal • Tremor • Excessive drooling Features • Gastroesophageal Reflux • Postural instability • Lead pipe or cogwheel • Depression/ Anxiety • Micrographia (small writing) • Cognitive changes/dementia • In mild disease, can augment with • Decreased dexterity • Sleep disturbance activation of opposite limb (Froment’s • Hypomimia (“Masked Face”) • Seborrheic dermatitis • Postural changes • Bladder urgency/frequency maneuver) • Festination/Freezing of gait • Sweating spells • Speech changes • Hypotension • Dysphagia (trouble • Sexual dysfunction swallowing)

2 Pathological Hallmark of PD Braak Staging of Lewy Bodies Classic hallmark is degeneration of dopamine from the pars compacta plus intracytoplasmic proteinaceous inclusions (Lewy bodies). Per decade of life, there is an estimated 9-13% loss of Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459. dopamine neurons. Stage 1 - Lewy bodies (LB) first form within the olfactory bulb and dorsal motor nucleus of the vagal nerve. Motor symptoms do not Stages 2 and 3 - LB pathology expands into additional brain stem nuclei (e.g., locus appear until there is a lost of coeruleus and substantia nigra). about 70% of dopaminergic Stages 5 and 6 - Pathology extends into the cerebral cortex. neurons from this area. More commonly recognized clinical symptoms arise during Stages 4 to 6 when the http://www.smbs.buffalo.edu/pth600/IMC-Path/y2case/y2ans18.htm pathology involves significant regions of the substantia nigra and related brain areas.

PD Pathology Epidemiology • PD also associated with extensive pathology in • As many as 1.5 million people in the US have non dopamine cells: Parkinson’s disease. 9 Cholinergic neurons in the of • Approximately 60,000 Americans are diagnosed Meynert and dorsal motor nucleus of vagus with Parkinson's disease each year. 9 Norepinephrine neurons in the locus ceruleus • Affects 1.5 -2.0 % of people over the age of 60 9 Serotonin neurons in the midline raphe years. 9 plus many other cells in the cortex, spinal • Onset of symptoms is typically 60-70 years of cord, and peripheral autonomic system. age, but up to 15 % of people with PD are diagnosed before the age of 50. • Pathology in the dorsal motor nucleus and 9 These estimates do not account for cases of olfactory regions may predate dopaminergic cell PD that are unreported, undiagnosed or loss in the substantia nigra pars compacta. misdiagnosed.

Forno LS. Neuropathy of Parkinson’s Disease. J Neuropathol Exp Neurol 1996;55:259-272. Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459. National Parkinson’s Disease Foundation, Inc. 2007

3 NINDS Parkinson’s Etiology Disease Criteria (aka Gilman Criteria) • The cause is not known, and with most cases of • Group A: (at least 2 needed) disease being sporadic. 9 Resting tremor* • However, there is a suspected strong link to 9 Bradykinesia* 9 Rigidity genetic and environmental factors. 9 Asymmetric onset • Risk factors included family history, increasing 9 Postural instability age, rural living, well water, exposure to • Group B: Suggests alternative diagnosis: pesticides/herbicides, and repeated head injury. 9 Early postural instability 9 Early freezing of gait • Some studies have suggested smoking decreases 9 Hallucinations risk of development of Parkinson’s disease with 9 Early dementia no good explanation. 9 Gaze palsy 9 Early, severe dysautonomia 9 Previous condition/drugs known to cause parkinsonism

Parkinsonism – Diagnosis of PD Differential Diagnosis • Parkinson’s disease is a clinical diagnosis based • Parkinsonism does not equal Parkinson’s disease. on history and exam findings. • The differential for parkinsonism include: • The diagnosis of parkinsonism is classified as: 9 Atypical Parkinsonian Syndromes 9 Most Likely - 2 of 4 present cardinal features, 9 Secondary Parkinsonism with 1 being resting tremor or rigidity. • Vascular • Medication induced 9 Probable – isolated rest tremor or rigidity • Infectious alone. • Metabolic/Toxic 9 Possible - either bradykinesia or postural 9 Dementia syndromes instability 9 Other Hereditary degenerative disease 9 Psychogenic

4 Features that may suggest cause of parkinsonism other than Atypical Parkinsonian Parkinson’s disease Syndromes 9 Symmetric symptoms 9 Early balance/gait trouble or falling 9 Early symptoms of cognitive dysfunction or dementia symptoms • Progressive Supranuclear Palsy that precede onset of features of parkinsonism or within 1 year of motor symptoms. • Cortico-basalganglionic Degeneration 9 Minimal to no response to levodopa 9 History of exposure to drugs reported to cause parkinsonism - Neuroleptics • Multiple System Atrophy - Lithium - Depakote 9 MSA type P: (Striatonigral Degeneration) -Other 9 MSA type A: (Shy-Drager Syndrome) 9 Stepwise progression or history of CVA 9 Apraxia or alien limb phenomena 9 MSA type C: (Olivopontocerebellar Atrophy) 9 Vertical gaze palsy 9 Upper motor symptoms on exam

Testing? Progressive Supranuclear Palsy • There is no diagnostic test used to diagnose PD • Neuroimaging and blood tests are useful to rule out other • Fairly symmetrical symptoms possible conditions if tremor or history/exam is atypical with features that may suggest a diagnosis other than • Early onset of gait trouble with falls Parkinson’s Disease: • Axial rigidity 9 Work up may include: • Thyroid profile • Early dysarthria and gaze impairment • Ceruloplasmin/Serum copper 9 Vertical gaze palsy • Brain imaging • Frontal lobe dementia • EMG/NCV • Minimal tremor • Confirmation of a diagnosis of Parkinson’s disease can be made at autopsy • Minimal to no response to levodopa.

5 Corticobasalganglionic Secondary Parkinsonism

• Vascular Degeneration • Usually history of acute onset or step wise progression • Predominant gait trouble and possible cognitive deficits • Cortical apraxia and possible alien hand • Supported by brain MRI findings of previous infarcts • Medication induced syndrome 9 Typically dopamine blocking agents, but others have been more more commonly reported as well • Rigidity and bradykinesia with minimal to Metaclopramide Neuroleptics Phenothiazines no tremor Reserpine Butyrophenones SSRI Amiodarone Diltiazem Valproic acid • Dystonic limb posturing early in disease. Lithium • Infectious • Very asymmetric • Postencephalitic, syphlis • Metabolic/Toxic • Minimal to no response to levodopa. • Hypothyroidism, hepatocerebral degeneration, hypoxia, carbon monoxide, carbon disulphide, cyanide, MPTP.

Multiple Systems Atrophy Other causes of

• MSA –type P (Striatonigral Degeneration): Parkinsonism 9 Akinetic rigid parkinsonism with minimal response to levodopa • Other Hereditary degenerative diseases • MSA – type A (Shy-Drager Syndrome): 9 Huntington’s Disease (juvenille), Wilson’s disease, Neuroacanthocytosis 9 Akinetic rigid parkinsonism with early prominent autonomic dysfunction (papillary changes, postural • Dementia syndromes hypotension, urinary incontinence, cardiac arrhythmia, upper airway obstruction) 9 Significant cognitive issues or dementia prior to or within a year of parkinsonian motor • MSA – type C (Olivopontocerebellar Atrophy): symptoms 9 Parkinsonism with cerbellar ataxia, abn eye movements, retinal degeneration, pyramidal tract • Diffuse Disease dysfunction. May be familial in an autosomal dominant pattern • Alzheimer’s disease

6 Parkinsonian Medications Levodopa • Approved by FDA in 1970 • Parkinsonian medications increase dopamine • Levodopa is the cornerstone of treatment of Parkinson’s activity via precursor levodopa, dopamine Disease motor symptoms, despite all the other available agonists or blockage of enzymatic breakdown medications! (MAO-B inhibitors) • Levodopa provides anti-parkinsonian benefit over the entire course of the disease. 9 Parkinsonian medications can alleviate motor • When levodopa is given alone, a large amount is changed symptoms of bradykinesia, rigidity, and to dopamine outside the brain and leads to excessive side tremor to a certain degree. effects. Further, only 1-5% of the ingested levodopa is available for the brain. 9 Other motor symptoms have mild or no • Levodopa is combined with a DOPA decarboxylase response inhibitor (Carbidopa in the USA) which lessens 9 Non-motor symptoms rarely benefit from conversion to dopamine outside the brain making up to parkinsonian medications 10% available for the brain. • Taking levodopa with foods rich in protein interferes with absorption.

PD Medications by LEVODOPA Classes DRUG NAME: AVAILABLE IN: • PD medications are divided in classes based on mechanism of action. 9 Levodopa – Crosses into the brain and is then converted to Standard carbidopa/levodopa 10/100, 25/100, and 25/250 dopamine (Sinemet®) mg 9 MAO-B Inhibitors – Decreases dopamine breakdown 9 Dopamine Agonist– Mimics dopamine thus stimulating dopamine Controlled release 25/100 and 50/200 mg receptors so less dopamine is needed carbidopa/levodopa (Sinemet CR®) 9 COMT Inhibitors – Prevent the breakdown of levodopa 9 Anti-cholinergics – Decreases need for dopamine stimulation and mostly helps tremor only Oral disintegrating tablet 10/100, 25/100, and 25/250 carbidopa/levodopa (Parcopa®) mg • Potential side effects that can occur with any Parkinsonian medication: 9 Sleepiness - Nausea, diarrhea, constipation • The dose must be tailored to the individual patient. 9 Vivid dreams - Psychosis/Confusion • Typical dosing initially 3 or 4 times a day. Less frequent or irregular 9 Dyskinesia - Lightheadedness dosing can lead to early onset of motor complications.

7 Carbidopa/levodopa: Complications of levodopa • Levodopa related motor fluctuations typically develop 2-5 side effects years after initiation of levodopa. • Common reported potential • Other serious potential side 9 Decrease duration of response -“Wearing-off”. side effects: effects: 9 Upset stomach 9 Dyskinesia 9 Hypotension 9 Nausea/vomiting • Peak dose dyskinesia 9 Cardiac arrhythmias 9 Headaches • Diphasic dyskinesia 9 Psychosis 9 Visual disturbances • Off state dyskinesia 9 Dizziness 9 Anemia. • Dystonic posturing 9 Change in mentation 9 Inconsistent response with possible no “on”. 9 Sleep disturbances • Young onset PD patients are more likely to have motor fluctuations given the duration of having symptoms of 9 Motor complications disease. • Dyskinesia • The development of these are thought to be related to: • End of dose wearing off • Disease progression • Unpredictable • Changes in receptors response

Levodopa Slows Overall COMT Inhibitors

Clinical Progression of PD Enzymes that break down levodopa: Nutt et al 1994. Gordin et al 2002 1 ) DDC – DOPA Decarboxylase 2) COMT - Catechol-O-methyltransferase Stalevo PI, 2003 Percentage of Patients With Stage 4 or Stage 5 Disability or Death Over a 15-Year Follow-up Period 100

• Rate of clinical 90 Untreated Patients 80 progression is Patients Treated With L-dopa

s 70

t

slowed n

e

i 60

t

a

P 50

f

o • Life expectancy 40

% is substantially 30 increased 20 10 0 1 to 5 Years 6 to 10 Years 11 to 15 Years

Years of Follow-Up This medication allows for more levodopa to reaches the brain, and prolonged duration of each dose Poewe & Wenning. Neurology. 1996;47(6 suppl 3):S146-S152. Schematic of Dual Inhibition of DDC* and COMT Enzyme Pathways

8 Catechol-O-methyltransferase Anticholinergics (COMT) INHIBITORS DRUG NAME: AVAILABLE IN: DOSE RANGE: • Tolcapone (Tasmar®): 100 and 200 mg 9 Has both central and peripheral action Benztropine (Cogentin®) 0.5, 1, and 2 mg 0.5 – 6 mg/day 9 Dose is 100mg or 200mg dose three times a day 9 Has a “black box warning” associated with fatal liver failure Trihexyphenidyl (Artane®) 2 , 5 mg and 1-15 mg/day 9 Requires monitoring of ALT/AST levels: 2mg/5mL elixer – Prior to starting – Every 2−4 weeks for the first 6 months * Diphenhydramine 25, 50 mg and 25-100 mg/day – At intervals deemed clinically relevant thereafter (Benadryl®) 12.5mg/5mL elixer • Entacapone (Comtan®): 200 mg 9 Mostly peripheral action *Secondary action of this medication 9 200 mg dose must be taken with levodopa 9 Increases availability of levodopa in the plasma • These medications can specifically lessen tremor. 9 Limit 8 a day • Common side effects include confusion, trouble thinking clearly, • Carbidopa/Levodopa/Entacapone (Stalevo®): 50, 75, 100, 125, 150 and 200 blurred vision, dry mouth, constipation, and lightheadedness. 9 Convenience for patients 9 Limited to 8 daily doses due to entacapone

Amantadine COMT inhibitors: Side Effects • This is an antiviral agent approved in 1966, also found to alleviate some motor symptoms of PD in patient in 1969. • More commonly reported SE: • Amantadine (Symmetrel®): 9 100 mg pill or 50 mg/ 5 mL solution 9 Upset stomach 9 Dose: 200-300 mg/day (100 mg PO twice or three times a day. (Max dose 500-600mg/day) 9 Diarrhea • The exact mechanism of action is unknown; however, it appears to have several properties including: 9 Discoloration of urine • anticholinergic effect • enhancing dopamine release 9 Sleep disturbance • anti-glutamatergic (NMDA) effect • This is one medication that can specifically lessen dyskinesia and smooth 9 Dizziness out motor fluctuations of levodopa. • Generally well tolerated 9 Headaches Potential Side Effects 9 Dyskinesia - Dry mouth - Depression/Anxiety - Blurred vision - Hallucinations/Psychosis/Confusion 9 Orthostasis - Leg swelling - Livedo reticularis - Dizziness - Vivid dreams

9 Dopamine Agonists DA agonist: side effects DRUG NAME: AVAILABLE IN:

Ropinirole (Requip®) 0.25, 0.5, 1, 2, 3, 4, and 5 mg • More commonly reported • Other adverse reactions Pramipexol (Mirapex®) 0.125, 0.25, 0.5, 1, and 1.5 mg SE: that are reported

Ropinirole extended release 2, 4, and 8 mg 9 Upset stomach 9 Obsessive- (Requip XL®) 9 Dizziness compulsive behaviors *Bromocriptine (Parlodel®) 2.5, 5, and 10 mg (like compulsive 9 Headache Apomorphine (Apokyn®) 0.2 mL – 0.6 mL (10 mg/mL) gambling) - Injectable only 9 Dyskinesia 9 Sudden sleep attacks - Used for rescue only. 9 Peripheral edema * Not primarily used for PD 9 Confusion • These activate various dopamine receptors, bypassing degenerating dopamine neurons. 9 Hallucinations/psycho • Longer half-lives than levodopa sis • Need to be titrated over several weeks and the response is not as sudden as with levodopa therapy.

Dopamine Agonists Apomorphine (Apokyn®) • It is a older very potent dopamine agonist with rapid onset of action and a very short half life. • Can be used alone in early PD or as adjunctive • It is only used for therapy in later PD rescue during periods of “off” times in • Dopamine agonist often are considered as initial between doses of treatment for young-onset patients (< 50). levodopa. • Administered by 9 It may help prolong the possible onset of subcutaneous injection. levodopa-induced motor fluctuations. • Associated with • Dopamine agonists should be used with caution ignificant gastrointestinal upset in the elderly patients (>70) or anyone with 9 Must pretreat with an anti-emetic. cognitive (thinking) problems at baseline. • Other potentital side effect: Concern for higher risk of side effects. 9 Lightheadedness (Orthostatic hypotension) 9 Sleepiness

10 Selective MAO-B Inhibitors MAO enzyme inhibitor:

DRUG NAME: AVAILABLE DOSES: side effects • Blocks the enzyme Selegiline 5 mg (MAO-B) that breaks • Potential side effects: (Eldapryl®) down dopamine after it 9 Nausea is released from the cell. 9 GI upset • This allows for 9 Dizziness Zydis Selegiline 1.25 mg dopamine to be present longer and have a 9 Headaches (Zelpar®) greater effect. 9 Dry mouth • Used for initial therapy or adjunctive therapy. 9 Dyskinesias 9 Sleep disturbance 0.5 and 1 mg • Possible neuro- Rasagiline protective: Still being 9 Hallucination (Azilect®) investigated 9 Orthostasis 9 Hypertension

MAO enzyme inhibitors Selective MAO-B Inhibitors - Caution

• Standard selegiline is dosed twice a day (morning and noon). • Hypertensive crisis through tyramine reaction: • Zelapar and rasagiline are dosed once a day. 9 AKA: “cheese effect” (red wines, aged foods) • Rasagiline is more selective, more potent, and has less 9 This occurs with doses of MAO-B Inhibitors peripheral side effects. greater than recommended doses (selectivity • Zelapar® dissolves rapidly on the tongue, and absorbed is lost) into the blood stream bypassing first pass metabolism of • Contraindicated with Meperidine (Demerol®) the liver. This allows for a lower dose and lessens peripheral side effects. • Caution advised with the class of anti- depressants “Selective Serotonin Re-uptake Inhibitors”

11 Neurosurgical Approach Neuroprotective Strategies • Cell death presumed to be from several • Deep Brain Stimulation pathophysiologic factors, including: 9 Oxidative Stress • Pallidotomy 9 Mitochondrial dysfunction • Gene Therapy – being investigated 9 Excitotoxicity • ?Stem Cell? 9 Inflammatory cytokines • ?Tissue Transplant? 9 Trophic factor deficiency 9 Signal mediated apoptosis

Deep Brain Stimulation Neuroprotective Strategies

• Neuroprotective? • Helps with levodopa 9 Vitamin E responsive symptoms 9 CoEnzyme Q10 • Lessens motor 9 Vitamin C complications of 9 Creatine levodopa therapy 9 Anti-inflammatory agents 9 Exercise

12 Tx Non-Motor Symptoms • Dementia: • Bladder dysfunction 9 Cholinesterase inhibitors 9 Urologist evaluation (donezepil, rivastigmine, 9 Anticholinergic urological agents galantamine) • Sexual dysfunction 9 NMDA antagonist (memantine) 9 Hormone levels • Psychosis 9 Erectile dysfunction medications 9 Review medications and check for other health problems • Depression / Anxiety 9 Reduce or wean medications 9 SSRIs, Buproprion, SNRIs, TCA more likely to cause cognitive • Sleep issues 9 Sleep study 9 Quetiapine or Clozapine 9 Diphenhydramine, Valerian, • Swallowing / speech Melatonin 9 Speech therapy 9 Sleep hygiene practices 9 Daily voice/speech exercises 9 Trazadone, Remeron, Ambien, 9 Modified diet Rozerem • Constipation • Orthostasis 9 Fluid, salt, compression hoses, 9 Fluids, fiber, stool softener raised head of bed. 9 Lower or wean anti- hypertensives 9 Midodrine, fludrocortisone

Strategies in Treatment of disease

• Global Approach

• Education Exercise Cognition • Drug treatment to reduce Education severity of symptoms and Mood improve quality of life Other Health issues Sleep • Adapt lifestyle to maintain Nutrition function in daily life activities Social Activitis Medication • Non-pharmacologic Activities interventions are extremely important • Daily exercises • Physical Therapy • Speech Therapy • Assistance devices

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