What is Parkinson's disease, including its assessment, pathophysiology, and pharmacology?

Parkinson's Disease: Assessment, Pathophysiology, and Pharmacology

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by four cardinal motor symptoms: bradykinesia, resting tremor, rigidity, and postural instability, resulting from the depletion of dopaminergic neurons in the substantia nigra. 1, 2

Pathophysiology

Neurodegeneration

• PD results from progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta that project to the striatum 1
• Symptoms typically appear after approximately 40-50% of dopaminergic neurons have been lost, with an estimated interval of 5 years between initial neuronal loss and symptom appearance 1, 2
• PD is classified as a synucleinopathy, characterized by neuronal deposits of Lewy bodies (predominantly composed of alpha-synuclein and ubiquitin) 1

Progression Pattern

• Initial Lewy body deposition involves the medulla oblongata, pontine tegmentum, and olfactory system
• Later involvement affects the substantia nigra and other deep gray nuclei (corresponding to the onset of clinical symptoms)
• Final stage involves deposition of Lewy bodies in the cerebral cortex 1

Clinical Assessment

Cardinal Motor Symptoms

1. Bradykinesia - slowness of movement
2. Resting tremor - 4-6 Hz tremor that decreases or disappears during voluntary movement
3. Rigidity - increased muscle tone and resistance to passive movement
4. Postural instability - impaired balance and coordination 1, 2

Non-Motor Symptoms

• Autonomic dysfunction (orthostatic hypotension, urinary urgency/incontinence, constipation, sexual dysfunction)
• Cognitive impairment and dementia
• Behavioral changes
• Sleep disorders (including REM sleep behavior disorder)
• Olfactory dysfunction
• Excessive sweating 1, 2

Diagnostic Approach

• Diagnosis is primarily clinical, as there is no definitive diagnostic test 2
• Features suggesting diagnoses other than idiopathic PD include:
  • Absence of rest tremor
  • Early occurrence of gait difficulty and postural instability
  • Early dementia or hallucinations
  • Early dysautonomia
  • Ophthalmoparesis or ataxia
  • Poor or no response to levodopa 2

Differential Diagnosis

• Multiple system atrophy (MSA)
• Progressive supranuclear palsy (PSP)
• Corticobasal degeneration (CBD)
• Vascular parkinsonism
• Drug-induced parkinsonism
• Essential tremor 1

Pharmacological Management

Dopamine Replacement Therapy

• Levodopa (L-DOPA): The most effective treatment for PD motor symptoms
  • Crosses the blood-brain barrier and is converted to dopamine in the brain
  • Administered with carbidopa (peripheral decarboxylase inhibitor) to:
    • Reduce peripheral conversion to dopamine
    • Decrease required levodopa dose by about 75%
    • Increase plasma levels and half-life of levodopa
    • Reduce nausea and vomiting 3, 4
  • Pharmacokinetics:
    • Without carbidopa: plasma half-life ~50 minutes
    • With carbidopa: plasma half-life ~1.5 hours 3, 4

Common Medication Side Effects

1. Motor complications:

   • Dyskinesias (involuntary movements)
   • Motor fluctuations ("wearing-off" phenomenon)
   • "On-off" phenomena 5

2. Extrapyramidal side effects:

   • Dystonia (spastic contractions of muscle groups)
   • Drug-induced parkinsonism (bradykinesia, tremors, rigidity)
   • Akathisia (severe restlessness) 1

3. Long-term complications:

   • Tardive dyskinesia (involuntary movements, particularly orofacial)
   • Tardive dystonia 1

Advanced Treatment Options

For patients with medication-resistant symptoms or complications:

• Deep brain stimulation
• Levodopa-carbidopa enteral suspension therapy 5

Monitoring and Supportive Care

Nutritional Monitoring

• Regular monitoring of nutritional status, body weight, and vitamin levels (particularly vitamin D, folic acid, and vitamin B12) is recommended throughout disease course 1, 2
• Malnutrition is common, affecting about 15% of community-dwelling PD patients, with another 24% at medium or high risk 1

Dysphagia Screening

• Dysphagia affects more than 80% of PD patients during disease course
• Screening recommended for all patients with:
  • Hoehn & Yahr stage above II
  • Weight loss
  • Low BMI
  • Drooling or sialorrhea
  • Dementia
  • Any signs of swallowing difficulties 2

Disease Course and Prognosis

PD is heterogeneous with different progression rates:

• Diffuse malignant subtype (9-16% of PD patients): Prominent early motor and non-motor symptoms, poor medication response, faster progression
• Mild motor-predominant PD (49-53% of patients): Mild symptoms, good response to dopaminergic medications, slower progression
• Intermediate subtype: Features between the above two 5

Risk factors for increased mortality include:

• Older age at diagnosis
• Higher levodopa equivalent daily dose/body weight
• Comorbid conditions (especially cardiovascular disease)
• Poor nutritional status 2