Parkinson's Disease: Epidemiology and Pathophysiology

Parkinson's Disease (PD) Overview

• Parkinson's disease is characterized by bradykinesia, tremor at rest, rigidity, and postural instability, affecting the extrapyramidal system

Epidemiology

• In the US, 1 million individuals are affected
• PD prevalence rises with age; 0.5% of the population in their 60s and 2.5% of those 80 years or older are affected
• PD impacts more males than females

Etiology

• The exact etiology is unknown and occurs sporadically
• Lower risk is associated with smoking cigarettes and caffeine consumption
• Pesticide exposure and genetic forms of parkinsonism are associated with mitochondrial dysfunction and oxidative stress

Pathophysiology

• Loss of dopaminergic neurons from the substantia nigra pars compacta (SNc) to the striatum (caudate nucleus and putamen)
• Neuronal projections from SNc to the striatum form the nigrostriatal pathway
• The basal ganglia (including the substantia nigra, striatum, globus pallidus, and subthalamic nucleus) controls voluntary movement
• The striatum signals the substantia nigra pars reticulata (SNr) by dopamine 1 (D₁) direct and dopamine 2 (D₂) indirect pathways
• D₁ receptor activation stimulates striatal GABAergic neurons
• D₂ receptor activation inhibits striatal GABAergic neurons
• PD results in decreased dopaminergic activation of D₁ and D₂ receptors, resulting in a net inhibitory tone on the thalamus

Lewy Bodies

• Lewy bodies are cytoplasmic filamentous aggregates composed of α-synuclein, associated with adjacent gliosis
• Lewy bodies in the following indicate the premotor stage of PD: medulla oblongata, locus coeruleus, raphe nuclei, enteric nervous system, and olfactory bulb
• Lewy bodies correlate with mood changes and peripheral symptoms
• Motor symptoms emerge with Lewy pathology development in the midbrain (SNc)
• In advanced stages, Lewy pathology can spread to the cortex

Clinical Presentation

• Bradykinesia with either reduced resting tremor, rigidity, or postural instability
• Other motor symptoms include hypomimia and micrographia
• Tremor is present, most commonly in the hands, and begins unilaterally before progressing bilaterally
• Rigidity is characterized by increased muscular resistance during passive range of motion, typically affecting the neck and extremities

Diagnosis

• Clinical diagnosis based on presence of bradykinesia and either tremor, rigidity, or postural instability
• Diagnosis exclusion of other parkinsonism or tremor conditions
• No lab tests to diagnose PD
• Pharmacotoxicity should be ruled out
• Other signs include asymmetry of motor symptoms, unilateral onset, progressive disorder, resting tremor, good response to L-dopa, at least 5 years of response to L-dopa and presence of L-dopa dyskinesias

Pharmacotoxicity

• Antiemetics like metoclopramide (dopamine and serotonin agonist) and prochlorperazine
• First-generation antipsychotics have a higher risk than second-generation ones: chlorpromazine, fluphenazine, haloperidol, olanzapine, risperidone, thioridazine

Differential diagnosis

• Including essential tremor, other drug-induced conditions, environmental toxins, infections, metabolic disorders, neoplasms, strokes, traumatic lesions, normal-pressure hydrocephalus
• Parkinsonian syndromes include corticobasal ganglionic degeneration, multiple-system atrophy, progressive supranuclear palsy
• Familial autosomal dominant and recessive parkinsonism

Treatment

• Goal is to improve motor and nonmotor symptoms
• Initiate treatment when the disease starts to interfere with daily living activities, employment, or quality of life

General treatment approach

• Under 65: Consider rasagiline, dopamine agonist
• Over 65: Consider anticholinergics
• If tremor is present, consider carbidopa/levodopa; otherwise, dopamine agonist before carbidopa/levodopa
• Physical therapy, with consideration of surgery if motor issues develop

Parkinson's Disease Medications: General Considerations

• Lowest effective antiparkinson dosage should be given
• Optimize carbidopa/L-dopa regimen before adding adjunctive agents
• MAO-B inhibitors (e.g., rasagiline) can be an initial monotherapy for mild functional impairment
• Dopamine agonists are better for motor control in cases of mild to moderate impairment
• If patients are older, cognitively impaired, or have a moderate to severe impairment, carbidopa/L-dopa is better than a dopamine agonist
• All patients require carbidopa/L-dopa

Motor Fluctuations Management

• Administer carbidopa/L-dopa more often
• Add a COMT inhibitor, MAO-B inhibitor, or dopamine agonist
• A carbidopa/L-dopa dose decrease as well as amantadine can help treat carbidopa/L-dopa–induced dyskinesias

Surgery

• Consider when patients experience frequent motor fluctuations or disabling dyskinesia/tremor despite medical optimization
• Deep-brain stimulation (DBS) with implanted neurostimulator is a preferred surgical modality

Anticholinergics

• With the degeneration of nigrostriatal dopamine neurons, striatal cholinergic interneuron activity increases and contributes to tremor
• Options: Benztropine and Trihexyphenidyl
• Side effects: Should be closely monitored, especially in elderly population (blurred vision, confusion, constipation, dry mouth, impaired memory, urinary retention, sleepiness)

Amantadine, an NMDA-Receptor Antagonist

• Management of tremor, bradykinesia, rigidity, and also L-dopa-induced dyskinesia
• Normal dosing is immediate-release 100 - 400mg daily for CrCl values of 50mL/min or greater
• With CrCl at 30-50 mL/min, the dose is 100mg daily; with CrCl between 15-29 mL/min the dose is 100mg every other day
• For CrCl values under 15 mL/min or with Hemodialysis, the dose is 200mg every 7 day
• Side effects include confusion, hallucinations, dizziness, and dry mouth; livedo reticularis may also be a side effect

Carbidopa/Levodopa (L-dopa)

• Levodopa converts to dopamine; Carbidopa prevents peripheral levodopa breakdown
• 75 mg/day of carbidopa is needed to sufficiently inhibit peripheral activity of L-amino acid decarboxylase
• Carbidopa/L-dopa maintenance is 25/100mg three times daily
• In patients with severe PD, tolerated doses are approximately 1000 - 1500mg per day
• Can discolor bodily fluids and cause priapism; long-term use leads to motor complications

Motor response assessment

• "Off" means poor motor control (tremor, rigidity, slowness)
• "On" means good motor control
• Adding entacapone, rasagiline, or safinamide can extend the duration of action of levodopa or consider a dopamine agonist, patch or ER formulation for overnight coverage
• For rapid relief, subcutaneous apomorphine or inhaled levodopa are options

Managing delayed or non-existent responses ("no-on")

• Chew or crush tablet and drink with a full glass of water, or use ODT formulation on empty stomach
• Add subcutaneous apomorphine
• A drug free-period or ‘drug holiday’ may help decrease unpredictable off states

Episodic Akinesia (Freezing) Treatment

• Physical therapy coupled with assistive walking devices or sensory cues

Dyskinesias Treatment

• Lower the dosage of carbidopa/L-dopa, or add amantadine

“Off Period" Dystonia

• Can be treated with sustained release dopamine agonists before bedtime, long-acting carbidopa/L-dopa or baclofen
• A or B type Botulinum toxin can also treat persistent focal dystonias

Levodopa drug interactions

• Levodopa is contraindicated with non-selective MAO inhibitors (isocarboxazid, phenelzine, and tranylcypromine)
• Can also interact with antipsychotics and metoclopramide
• Avoid with iron and protein-rich meals as they decrease absorption

Foscarbidopa/foslevodopa (Vyalev)

• Approved for Parkinson's treatment on Oct 17, 2024

Monoamine Oxidase B (MAO-B) Inhibitors

• Action: Selective MAO-B inhibition interferes with dopamine degradation, increasing dopaminergic activity for up to 1 hour
• Do not combine meperidine, cyclobenzaprine, linezolid or St. John’s wort because of potential serotonin syndrome
• Do not combine with dextromethorphan
• Avoid combining with serotonergic antidepressants, allow a 2-week washout period

Selegiline (MAO-b Inhibitor)

• Hepatic metabolism leads to L-methamphetamine and L-amphetamine
• ODT formulation bypasses first-pass metabolism, which improves its effects
• Agitation, orthostatic hypotension sleep issues can arise as side effects

Rasagiline/safinamide (MAO-b Inhibitor)

• Minimal neurological and gastrointestinal side effects
• There is a risk of tyramine toxicity which can lead to adverse effects; thus, advise against foods such as cheeses, sauerkraut, soy sauce, and beer

Catechol-O-Methyltransferase (COMT) Inhibitor Action and Agents

• Inhibit peripheral conversion of L-dopa to dopamine, increasing L-dopa quantity
• For “wearing off”, adds 1-2 hours “on” time, requires carbidopa/levodopa dose reduction by 10–30%
• Entacapone is hepatotoxic
• Entacapone 200mg given with carbidopa/L-dopa up to 8 times a day
• Brownish-orange coloring of the urine as well as late-developing diarrhea can occur

Dopamine agonist

• Action: Stimulates dopamine receptors D1, D2, D3, can be monotherapy for mild-moderate PD plus reduces “off” time when combined with carbidopa/L-Dopa
• Options: Pramipexole, Ropinirole, Rotigotine, and Apomorphine
• For younger patients, dopamine agonists are preferred over carbidopa/L-dopa because of motor complications
• In elderly patients, dopamine agonists used with caution because of side effects

Dopamine Agonist Adverse Effects

• Titrate dose gently to reduce nausea, confusion, drowsiness, hallucinations, lower extremity edema, and orthostatic hypotension
• Can induce dyskinesias; less common, serious effects include sleep attacks and paraphilia
• Manage delusion and hallucinations with dose reduction, or using quetiapine, clozapine or pimavanserin

Apomorphine (Dopamine Agonist)

• Synthetic derived from morphine
• Rapid “on” achieved within 20 minutes via subcutaneous administration
• Premedicate with trimethobenzamide due to nausea effects
• Inject at sites of the upper arm, thigh, and abdomen

Pramipexole (Dopamine Agonist)

• Initiate dosages with 0.125mg TID, titrate weekly using 0.125mg per dose to a max of 4.5mg per day
• Renally cleared so adjust if needed
• Postural deformity and rhabdomyolysis can arise as side effects

Ropinirole (Dopamine Agonist)

• Initiate at 0.25mg TID and titrate to therapeutic goal
• CY1A2 drug interactions such as absorption inhibition with cigarette smoke should be evaluated

Rotigotine (Dopamine Agonist)

• Administer via the patch with location rotated to minimize skin issues
• Caution with sensitivity to sulfates; hyperhidrosis can also arise

Evaluation and Monitoring

• Stable treatment evaluated every 3-6 months and when adjustments are made, efficacy and side effects should be monitored within two weeks

Patient case: Lori Tanner, 63 y.o with PD

• Chief Complaint: Her tremor makes it difficult to type on the computer, and she is now slower with most tasks

• HPI: Experienced a worsening tremor in the right hand, slow movements, and stiff muscles. She also complains of insomnia, constipation, depressed mood, lack of pleasure in her usual activities, and loss of sense of smell

• PMH: GERD and a broken left wrist in the past

• FH: Has a maternal history of Alzheimer's and osteoporosis, and her father had an ischemic stroke

• SH: No vices, and has been married for 23 years

• ROS: Admits to some occasional crying spells and low mood

• Meds: Calcium Carbonate, and Pantoprazole

• PE: Noticeable decreased facial movement and some yellow scales at her eyebrows; UPDRS score of 15 and somewhat slow handwriting were also tests performed

• Labs are average

• Assessment and plan are required