PARKINSON’S DISEASE Diagnosis & Treatment Options University of South Carolina School of Medicine March 27, 2014 Dale R.Hamrick, MD PO Box Columbia, SC (803)

Cardinal Characteristics Resting tremor Bradykinesia Rigidity Postural instability

Beware the Old Man (or woman) Difficulty initiating movement (akinesia) Small amplitude movements (hypokinesia) Reduced motor velocity (bradykinesia) Loss of postural reflexes Stooped body posture

Additional Signs & Symptoms Micrographia Masked face Slowing of ADLs Stooped, shuffling gait Decreased arm swing when walking

Additional Signs and Symptoms Difficulty arising from a chair Difficulty turning in bed Hypophonic speech

Non-Motor Symptoms Neuropsychiatric Depression Anhedonia Attention deficit Hallucinations Delusions Obsessional behavior Cognitive disorder Sleep disorders Restless legs Periodic limb movements REM behavior disorder Excessive daytime somnolence Vivid dreaming Non-REM sleep-related movement disorders Insomnia

Non-Motor Symptoms Autonomic symptoms Bladder urgency, nocturia, frequency Sweating Orthostatic hypotension Hypersexuality Erectile impotence hypotestosterone state GI symptoms Sialorrhea Ageusia Dysphagia Reflux Vomiting Nausea Constipation Fecal incontinence

Non-Motor Symptoms Sensory Pain Paresthesia Olfactory disturbance Other Fatigue Diplopia Blurred vision Seborrhea Weight loss

Epidemiology Incidence 5-24/ 10 5 worldwide (USA: 20.5/10 5 ) Incidence of PS/PD rising slowly with aging population Prevalence /10 5 worldwide (USA/Canada 300/10 5 ) 35%-42% of cases undiagnosed at any time Onset mean PS 61.6 years; PD 62.4 years rare before age 30; 4-10% cases before age 40

What Happened?

Mortality in PS Reduced life expectancy Mean survival after onset ~ 15 years longer in non-demented PD cases longer with L-dopa use PD survival >MSA, PSP The most common causes of death: pulmonary infection/aspiration, urinary tract infection, pulmonary embolism and complications of falls and fractures

Atypical Parkinsonism Early onset of, or rapidly progressing, dementia Rapidly progressive course Supranuclear gaze palsy Upper motor neuron signs Cerebellar signs—dysmetria, ataxia Urinary incontinence Early symptomatic postural hypotension

Progressive supranuclear palsy Supranuclear downgaze palsy, square wave jerks Upright posture/frequent falls Pseudobulbar emotionality Furrowed brow/stare

Corticobasal degeneration Unilateral, coarse tremor Limb apraxia/limb dystonia/alien limb

Multiple system atrophy Shy-Drager syndrome Autonomic insufficiency—orthostasis, impotence Striatonigral degeneration Tremor less prominent Olivopontocerebellar atrophy Cerebellar signs

Diffuse Lewy Body Disease Early onset of dementia Delusions and hallucinations Agitation Alzheimer’s disease Dementia is the primary clinical syndrome Rest tremor is rare

Hydrocephalus-induced Parkinsonism Normal pressure hydrocephalus Clinical triad: parkinsonism/gait disorder urinary/fecal incontinence dementia

Drug Classes in PD Dopaminergic agents Levodopa Dopamine agonists COMT inhibitors MAO-B inhibitors Anticholinergics Amantadine

Levodopa Most effective drug for parkinsonian symptoms First developed in the late 1960s; rapidly became the drug of choice for PD Large neutral amino acid; requires active transport across the gut and blood-brain barriers

Levodopa (cont’d) Rapid peripheral decarboxylation to dopamine without a decarboxylase inhibitor (DCIs: carbidopa, benserazide) Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations

Amantadine Antiviral agent; PD benefit found accidentally Tremor, bradykinesia, rigidity & dyskinesias Exact mechanism unknown; possibly: enhancing release of stored dopamine inhibiting presynaptic reuptake of catecholamines dopamine receptor agonism NMDA receptor blockade Side effects —autonomic, psychiatric mg/day

Treatment Options Preventive treatment No definitive treatment available Symptomatic treatment Pharmacological Surgical Non-motor management Restorative—experimental only Transplantation Neurotrophic factors

Levodopa-Induced Dyskinesias Most common is “peak dose” dyskinesia disappears with dose reduction Choreiform, ballistic and dystonic movements Most patients prefer some dyskinesias over the alternative of akinesia and rigidity

COMT Inhibitors Newest class of antiparkinsonian drugs: tolcapone, entacapone Potentiate LD: prevent peripheral degradation by inhibiting catechol O-methyl transferase Reduces LD dose necessary for a given clinical effect

COMT Inhibitors (cont’d) Helpful for both early and fluctuating Parkinson’s disease May be particularly useful for patients with “brittle” PD, who fluctuate between off and on states frequently throughout the day

Dopamine Agonists: Distinguishing Features Directly stimulate dopamine receptors No competition with dietary amino acids Longer half-life than levodopa Monotherapy or adjunct therapy May delay or reduce motor fluctuations & dyskinesias associated with levodopa May be neuroprotective “The Patch” – rotigotine (Neupro)

DAs: Common Adverse Effects Nausea, vomiting Dizziness, postural hypotension Headache Drowsiness & somnolence Dyskinesias Confusion, hallucinations, paranoia

Clinical Decision-Making in Early PD Disease severity degree of functional impairment impact on quality of life Age of patient comorbidities risk of acute drug intolerance risk of long-term complications Neuroprotection

Initial Therapy: The Elderly Patient Shorter treatment horizon Lower risk of long-term complications Higher likelihood of comorbidities Carbidopa/Levodopa: well tolerated, effective Use adjunctive medications cautiously Avoid sedating medications

Initial Therapy: The Young Patient Long-term treatment horizon Increased risk of long-term complications Increased patient responsibilities Dopamine agonist monotherapy Levodopa-sparing strategies Putative neuroprotective strategies Role of levodopa is not adequately defined

Levodopa: Guidelines in Early PD Start low and increase slowly Titrate dosage to efficacy (~ mg/day) Immediate release Controlled release Acute side effects: nausea, dizziness, somnolence

Managing Early Complications: Wearing Off/Mild Dyskinesia For pts on DA monotherapy: elevate dosage of agonist add LD, w/ or w/o COMT inhibitor For pts on LD: add DA, COMT inhibitor, or MAO inhibitor reduce LD dosage use combination of immediate and CR

Managing Early Complications: Altered Mental States Confusion, sedation, dizziness, hallucinations, delusions Reduce or eliminate CNS-active drugs of lesser priority anticholinergics – sedatives amantadine – muscle relaxants hypnotics – urinary spasmodics Reduce dosage of DA, COMT inhibitor, or LD

Surgical Treatments for Parkinson’s Disease Ablative thalamotomy pallidotomy Electrical stimulation VIM thalamus, globus pallidus internus, sub-thalamic nucleus Transplant autologous adrenal, human fetal, xenotransplants, genetically engineered transplants

Deep Brain Stimulation (DBS) High frequency, pulsatile, bipolar electrical stimulation Stereotactically placed into target nucleus Exact physiology unknown, but higher frequencies mimic cellular ablation, not stimulation

Psycho-Social Aspects of Parkinson's disease Chronic, progressive, incurable Off the wall cures Depression (like stroke, assume they all are depressed) Housing – the move to the NH Children and their fears Resuscitation issues Artificial nutrition issues

Other Parkinson’s Meds MAO Inhibitors rasagaline selegilene zydis carbidopa/levodopa rotigotine patch

Hoehn and Yahr Staging 1. Unilateral disease only 2. Bilateral mild disease, with or without axial involvement 3. Mild-to-moderate bilateral disease, with first signs of deteriorating balance 4. Severe disease requiring considerable assistance 5. Confinement to wheelchair or bed unless aided