Cathy Chuang, MD Jacobi Medical Center Department of Neurology Parkinson’s Disease Cathy Chuang, MD Jacobi Medical Center Department of Neurology

Definition of parkinsonism Parkinsonism is a syndrome manifested by any combination of the following cardinal features: 1) bradykinesia 2) resting tremor 3) rigidity 4) postural instability 5) freezing 6) flexed posture

Other associated features of parkinsonism Other common features of parkinsonism include masked facies, hypophonia, micrographia, shuffling gait with decreased armswing, and increased saliva with drooling. Common behavioral signs include decreased motivation, apathy, decreased attention span, social withdrawal, anxiety, and depression. Cognitive decline can occur in 30-40% of patients.

Differential diagnosis of parkinsonism I. Primary (idiopathic): Parkinson's disease II. Secondary (acquired): drugs, toxins, infections, vascular, trauma, hydrocephalus III. Parkinson's-plus syndromes or atypical parkinsonian syndromes: PSP, MSA, DLBD, CBGD, etc IV. Heredodegenerative parkinsonism: HD, Wilson's, Hallervorden-Spatz, Spinocerebellar ataxias, juvenile parkinsonsim (parkin gene), neuroacanthocystosis, X-linked dystonia-parkinsonism (Lubag), mitochondrial cytopathies with striatal necrosis (Leigh's disease),etc.

Diagnostic Criteria Parkinsonism requires at least 2 out of 6 cardinal features with one of them being either bradykinesia or rest tremor. Parkinson’s disease-United Kingdom Parkinson's disease society brain bank criteria and NINDS diagnostic criteria   -Supportive features: asymmetric onset, classical pill-rolling rest tremor, progressive disorder, persistent asymmetry, good response to levodopa, drug-induced dyskinesias, and clinical course > 10 yrs; lack of any atypical features   -Atypical features: symmetric onset, early falls, early hallucinations, severe dementia, autonomic features, cerebellar signs, cortical signs, gaze palsy, and lack of response to high dose of levodopa

Management of Early Parkinson’s disease If very mild disease and no disability, can opt NOT to treat with symptomatic medications. May consider possibly treating with selegiline, rasagiline, Coenzyme Q10, or anti-oxidant vitamins C and E because of theoretical possibility of slowing disease progression. Physical therapy focusing on stretching exercises should be started as soon as the diagnosis is made  

Medical Management: Early Parkinson’s disease Levodopa sparing strategy If younger patient, try to avoid using levodopa since they will be more prone to long-term complications of levodopa therapy. Start with dopamine agonist (Parlodel, Mirapex, or Requip), amantadine, or anti-cholinergic (Artane) for tremors. Selegiline (Eldepryl) or rasagiline can also provide some symptomatic benefit for mildly affected patients If older patient (>65), you can start with levodopa

Dopamine Agonists A. Ergot agonists 1. bromocriptine (Parlodel): oldest agent, may not be as effective as other agents, start with ½ of 2.5 mg tablet bid, increasing by 2.5 mg per day every 14-28 days; aim for dose of 30 mg per day 2. pergolide (Permax): recently taken off market because of valvular fibrosis

Other Dopamine Agonists B. Non-ergot agonists 1. pramipexole (Mirapex): start with ½ of 0.25 mg qhs and increase by ½ tabs q2-3 days until reach ½ tab qid; then continue increasing by ½ tab q week aiming for a dose of 1.5-4.5 mg qd 2. ropinirole (Requip): start with 0.25 mg 1 tab tid x 1 week, then 2 tabs tid x 1week, and then 3 tabs tid for 1 week; switch to 1 mg tid, and increase by 1 mg every week, aiming for 12-16 mg qd.

Dopamine Agonists: Alternative forms of delivery A. SC injection: apomorphine (Apokyn) used primarily as a rescue agent for “off” periods, needs to be given with Tigan because of nausea B. Transdermal patch: rotigotine (Neupro), applied daily for 24 hours

Side effects of dopamine agonists Common to all agonists: nausea, vomiting, sedation, lightheadedness, orthostatic hypotension, hallucination, and confusion More common in ergot agonists: St. Anthony’s fire, pulmonary/retroperitoneal fibrosis, cardiac valvulopathy (Permax) “Sleep attacks” are controversial but may be more common with Mirapex and Requip

Amantadine (Symmetrel) A mild indirect dopaminergic agent with several mechanisms of action 1.Augmentation of dopamine release from storage sites 2. Blocking of reuptake of dopamine into presynaptic terminals 3. Some anticholinergic properties 4. NMDA glutamate receptor blocking activity Starting dose is 100 mg qd and increase to bid or tid. Side effects include ankle edema, livedo reticularis, and confusion/hallucinations

Anticholinergics Main anticholinergic agent used is trihexyphenidyl (Artane) but can also try benztropine (Cogentin) Mainly effective for treatment of tremor Not well tolerated in older patients because of confusion, memory problems, and hallucinations Start Artane with 1 mg (1/2 of 2 mg tab) qd and increase by ½ tablets every 3-4 days to 2 mg tid, then increase by 2mg q week; aim for maximum dose tolerated Other side effects include sedation, dry mouth, dry eyes, and urinary retention

Sinemet (carbidopa/levodopa) Begin levodopa when symptoms become disabling or patient is unable to tolerate other medications (especially in older individuals with dementia) Levodopa is also best Rx for intractable tremors but often need to increase to higher doses (1000 mg qd or more) There are different formulations of Sinemet (25/100, 10/100, 25/250, CR 25/100, CR 50/200). Now also available as Parcopa which is oral dissolving tablet. It is best to start with 25/100, 1/2 tablet qd and increase by 1/2 tablet every week until reach a dose of 1 tab tid; continue to increase the dose as needed

Management for more advanced stages of Parkinson’s disease a) Begin levodopa when symptoms become more disabling and increase the dose gradually as tolerated, dividing the dose tid, qid, or more frequently. Switch to 25/250 strength as you reach higher doses, or use both low and high doses to titrate more gradually. b) Sinemet CR (25/100,50/200) formulation is best at bedtime when patients are having difficulty with sleeping secondary to being off in the middle of the night, but can also be added during the day in combination with immediate-release Sinemet.  c) Add levodopa to use in combination with a dopamine agonist, amantadine, or an MAO-B inhibitor (selegiline or rasagiline) to help keep the dose of levodopa low AND to smooth out motor fluctuations.

Motor complications in advanced PD 1. Wearing off 2. On-off fluctuations 3. Delayed on’s 4. Sudden off’s 5. Dyskinesias

Management of motor complications FIRST determine the problem! Ask these questions: 1. When do you take your medications? You should document exactly when and what doses of medications are taken. 2. How long does it take for your medications to start working? 3. How long does the effect last for? Does the effect wear off before the next dose? 4. Do you have any involuntary movements (dyskinesias) secondary to your medications? How long do they last and when do they occur in relation to your dose of medicine? Do they interfere with you daily activities or are they painful? 5. Is there any time of day when the medication seems to work better or worse than other times? 6. How is your Parkinson's disease in the AM when you wake up? Do you sleep well at night? If no, why not? 7. Do you take your medications with food? 8. Does the levodopa ever suddenly wear off unpredictably?

Wearing off Wearing off is when the effect of levodopa subsides or completely stops prior to the next dose. This can be managed with the COMT (catechol-O-methyl transferase) inhibitors, Comtan (entacapone) or Tasmar (tolcapone), which help to prolong the effect of Sinemet. Tasmar requires LFT monitoring and can only be used if all other drugs have been ineffective. Wearing off can also be managed by adding dopamine agonists or selegiline or rasagiline to levodopa, or adding CR Sinemet to immediate release Sinemet Sinemet can be dosed more frequently; i.e. if levodopa effect only lasts for 3 hours, then give the Sinemet every 3 hours

On-Off fluctuations On-off fluctuations can consist of delayed on's, sudden offs, deep offs or dose failures. They are very difficult to manage. If possible, ask patients to keep a diary to record fluctuations. 1. Add dopamine agonists, amantadine, rasagiline, or selegiline to smooth out or improve the response to Sinemet 2. Decrease the interval between Sinemet doses while decreasing individual doses 3. Increase the dose of Sinemet at times which seem to be most problematic 4. Liquid Sinemet to increase the intestinal absorption---this can be very effective for delayed on's. All the Sinemet tablets can be made in a daily batch of liquid Sinemet and a small amount can be taken every hour or every couple of hours. 5. Avoid taking protein during the daytime and take the Sinemet on an empty stomach. 6. Try apomorphine injections for delayed on’s or any off symptoms

Dyskinesias Dyskinesias can occur at peak doses of Sinemet or biphasically at beginning and end of dose levels of levodopa For peak dose dyskinesias, the best thing to do is decrease the dose of Sinemet. You can give Sinemet more frequently while decreasing each individual dose. If the patient is on CR, you should change to regular Sinemet which is less likely to cause dyskinesias. If Sinemet can't be decreased without compromising motor abilities, you should try to add amantadine (up to 100 mg qid) or add an agonist which will allow you to lower the Sinemet If diphasic dyskinesias, may need to increase Sinemet or add Comtan to prevent wearing off between doses

Drug-induced psychosis Drug-induced psychosis includes vivid nightmares, hallucinations, paranoia, and delusions. 1. Discontinue the offending agent if possible; amantadine, anticholinergics, and dopamine agonists are prone to causing cognitive side effects in elderly patients 2. If psychosis continues on Sinemet, then you can add Seroquel (quetiapine) or Clozaril (clozapine). Try Seroquel first because it does not require weekly CBC monitoring 3. If possible, decrease the dose of levodopa, especially at night 4. If psychosis is very severe, admit patient  

When to consider referral for surgery When patients have difficult to control motor fluctuations When patients have difficult to control dyskinesias Should probably not refer patients with significant cognitive decline; they usually do not do as well

Types of surgical intervention Subthalamic (STN) deep brain stimulation Globus pallidus interna (Gpi) deep brain stimulation Pallidotomy (Gpi) VIM Thalamic deep brain stimulation VIM Thalamotomy

Management of non-motor symptoms 1. Depression: anti-depressants including SSRI's and tricyclics, ECT can also be helpful for intractable cases.  2. Anxiety: benzodiazepines, Paxil  3. Insomnia: treating this can really benefit PD patients because they may have “sleep benefit”. Give CR at bedtime to help relieve immobility in bed, or try sleeping pill at night such as benzodiazepine or Ambien. Or treat with antidepressant if necessary. Consider Klonopin or dopamine agonist if has RLS  4. Orthostatic hypotension: increase fluid and salt intake; Ted stockings; treat with Florinef or Midodrine if very symptomatic  5. Apathy or sedation: try stimulants such as caffeine, Ritalin, Provigil.

Non-pharmacological interventions Physical therapy: this should begin early in disease course to maintain flexibility, especially focusing on stretching exercises. Continue PT throughout disease especially focusing on gait training to prevent falls Speech therapy can also be helpful for some patients with hypophonia; Swallowing evaluation for those with dysphagia Psychotherapy for patients with depression or anxiety. Supportive therapy to help cope with the illness.  

Conclusion There are many medications available for PD including levodopa, dopamine agonists, subcutaneous apomorphine, COMT inhibitors, MAO inhibitors, amantadine, and anticholinergics Choice of medication depends on age of patient, side effect profile, and specific PD problem you are addressing Management of PD differs for each patient and can require a huge amount of trial and error Don’t forget non-motor symptoms which can be just as or more disabling than motor symptoms Physical therapy is crucial for maintaining mobility and flexibility, and preventing falls Consider surgery only when unable to optimize medical therapy