Diagnosis and Treatment of Parkinson Disease

Educational Objectives

The goal of this program is to improve management of Parkinson disease (PD). After hearing and assimilating this program, the clinician will be better able to:

1. Apply diagnostic criteria for patients suspected to have PD.
2. Identify adverse effects associated with medications prescribed for PD.
3. Optimize initiation of medications for PD based on patient characteristics.

Summary

Background: Parkinson disease (PD) is a progressive motor disorder which occurs secondary to dopamine depletion in the substantia nigra, which leads to hypokinesis; primary PD is idiopathic in nature; head trauma, chronic use of antipsychotic medications, and exposure to pesticides may cause secondary parkinsonism; PD is more common among men than women

Presentation

Motor symptoms: resting tremor — a “pill-rolling tremor” occurs when the muscles are relaxed and disappears with voluntary movement or during sleep; tremor occurs at a rate of 4 to 6 cycles/sec and usually is unilateral at onset, with progression to bilateral involvement; ≈30% of people with PD do not experience tremors at disease onset; bradykinesis — affects fine motor skills (eg, writing [becomes smaller], blinking [rate decreases, causes a “staring effect”]) in early PD; gait is slow but can be sped up in response to external cues; rigidity — excessive and continuous contraction of the muscles leads to stiff joints; passive extension and flexion of the forearms causes asymmetrical “lead pipe” or “cogwheel” rigidity; often affects the neck and shoulders prior to the face and extremities; eventually affects the whole body; postural instability — occurs in late stages of PD; patients have impaired balance, falls, diminished arm swing, and retropulsion (inability to stop active motion); rapid shuffling steps and a forward-flexed posture are seen when walking

Nonmotor features: are often related to autonomic dysfunction; can occur years before diagnosis; include, eg, orthostatic hypotension, excessive sweating, urinary incontinence, altered sexual function, gastric dysmotility, constipation, diplopia, impaired smell, paresthesias

Diagnosis: the United Kingdom Parkinson Disease Society Brain Bank criteria for diagnosis include bradykinesia (required for diagnosis), the presence of ≥1 other symptom (rigidity, resting tremor, or postural instability), plus ≥3 supportive diagnostic criteria (unilateral onset, progressive symptoms, clinical course of ≥10 yr, or response to levodopa for ≥5 yr); definitive diagnosis can be made using brain biopsy (not clinically used); magnetic resonance imaging can be used to exclude, eg, basal ganglion stroke; clinicians rely on clinical presentation for diagnosis; PD symptoms only appear after loss of ≥65% of dopaminergic neurons in the substantia nigra; the premotor phase can last 2 to 5 yr before motor symptoms appear

Dopamine replacement: main treatment; delay use as long as possible to maximize benefits (which decrease with time), and initiate when symptoms significantly interfere with the patient’s life; as dopamine cannot be directly administered (because it does not cross the blood-brain barrier), levodopa (L-dopa) is used; conversion of L-dopa to dopamine outside the brain results in adverse effects (eg, nausea, vomiting, orthostatic hypotension); carbidopa is a peripheral decarboxylase inhibitor; compared with L-dopa alone, carbidopa-levodopa provides fewer drug interactions; adverse effects include nausea, hallucinations, and sleep disturbances; treatment starts with an immediate-release preparation dosed 25 mg/100 mg 3 times daily with meals, and the dose is slowly titrated upward; following dose stabilization, long-acting preparations can be used to manage “on-off” periods; an infusion pump can be used to continuously deliver L-dopa directly into the small intestine for sustained effect; an inhaled L-dopa preparation provides quick relief during “off” episodes, though some patients find the inhaler difficult to use; L-dopa is initially effective for 5 to 6 hr, though dose benefits shorten over time, causing fluctuations between “on” and “off” states; dyskinesias may develop with long-term use of dopaminergic medications

Dopamine agonists: bind to dopaminergic receptors in the brain to improve motor function; dopamine agonists are less potent than L-dopa but can delay motor fluctuations and dyskinesias; adverse effects include, eg, nausea, dizziness, postural hypotension, edema, drowsiness, sudden sleep attacks, impulse control disorders (eg, pathological gambling, compulsive shopping, aggressive sexual behaviors) are reversible upon discontinuation

Monoamine oxidase B (MAO-B) inhibitors: inhibit the breakdown of dopamine; MAO-B inhibitors are useful as monotherapy for early-stage motor symptoms and delay the need for L-dopa; MAO-B inhibitors are less effective and impart more adverse effects than L-dopa

Catechol-O-methyltransferase (COMT) inhibitors: inhibit an enzyme that breaks down L-dopa; COMT inhibitors are added to L-dopa when the effects of L-dopa start to wear off between doses; monitoring of liver function testing is required

Adenosine A_2A receptor antagonists: improve motor function; potentially extend daily “on” time by ≤1 hr when added to L-dopa, though less effective in doing so when compared with COMT inhibitors

Fourth-line treatments (eg, amantadine, trihexyphenidyl, benztropine): typically only used if newer medications are not helpful

Deep brain stimulation (DBS): useful in patients with severe motor fluctuations and dyskinesias not responding to medication; electrodes are usually implanted in the substantia nigra; DBS is most beneficial in mid-stage PD

Treatment initiation: starting with a dopamine agonist is preferable for individuals <65 yr of age to delay the need for L-dopa; starting with L-dopa might be more practical for individuals of older age or with cognitive impairment or multiple comorbidities

Management of disease progression: patients typically report speech and swallowing problems, gait issues, falls, autonomic dysfunction, gastrointestinal dysmotility, sleep disorders, and hallucinations (≤60% of individuals with hallucinations develop dementia); acetylcholinesterase inhibitors have no clear benefit for slowing cognitive decline or decreasing falls; a systematic review demonstrated efficacy of selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy in improving symptoms of depression; one study demonstrated that nortriptyline may be more effective than SSRIs for depression and can also improve sleep abnormalities, but can worsen cognitive issues and increase fall risk; evidence suggests electroconvulsive therapy may help refractory depression and improve some Parkinson symptoms; pimavanserin — recently approved by the United States Food and Drug Administration for treatment of hallucinations and delusions in PD psychosis; a selective serotonin inverse agonist with no dopamine-blocking activity (unlike traditional antipsychotics, which block dopamine), avoiding worsening of motor symptoms; monitoring with electrocardiography is necessary, as pimavanserin can prolong the QT interval

Impacts on quality of life: patients report cognitive issues, communication problems, fatigue, sleep problems, poor emotional well-being, sexual dysfunction, self-image, social withdrawal, eating difficulties, and weight loss; as PD progresses, symptoms worsen because of continued loss of dopaminergic neurons; average life expectancy after diagnosis is 15 yr

Readings

Chou K. In the clinic. Parkinson disease. Ann Intern Med. 2012;157(9):ITC5-1-ITC5-16. doi:10.7326/0003-4819-157-9-201211060-01005. View Article; Desai H, Senaratne M, Swami S, et al. Implications of pimavanserin in patients with dementia-related psychosis: a systematic review. J Med Sci. 2024;44(3):103-110. doi:10.4103/jmedsci.jmedsci_277_23. View Article; Faouzi J, Corvol JC, Mariani LL. Impulse control disorders and related behaviors in Parkinson's disease: risk factors, clinical and genetic aspects, and management. Curr Opin Neurol. 2021;34(4):547-555. doi:10.1097/WCO.0000000000000955. View Article; Postuma R, Poewe W, Litvan I, et al. Validation of the MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2018;33(10):1601-1608. doi:10.1002/mds.27362. View Article; Thaler A, Alcalay RN. Diagnosis and medical management of Parkinson disease. Continuum (Minneap Minn). 2022;28(5):1281-1300. doi:10.1212/CON.0000000000001152. View Article.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Baldor reported nothing relevant to disclose. Members of the planning committee reported nothing relevant to disclose. Dr. Baldor's lecture includes information related to the investigational or off-label use of a therapy, product, or device.

Acknowledgements

Dr. Baldor was recorded exclusively for Audio Digest. Audio Digest thanks the speakers and Keck School of Medicine of the University of Southern California for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

FP723502

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.