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Monday, August 11, 2025

Parkinson's disease


Introduction
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder primarily affecting the motor system, with additional non-motor manifestations. It results from degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the striatum and disruption of basal ganglia circuitry. PD is the second most common neurodegenerative disorder after Alzheimer’s disease.

Epidemiology

  • Prevalence: ~1% of people over 60 years; incidence increases with age.

  • Mean age at onset: ~60 years (range 40–70 years).

  • Slight male predominance.

  • Most cases are idiopathic, but genetic and environmental factors contribute.

Etiology and Risk Factors

  • Idiopathic (most common): No single cause identified; multifactorial.

  • Genetic: Mutations in SNCA (α-synuclein), LRRK2, PARK2, PINK1, DJ-1, GBA.

  • Environmental: Pesticide exposure, rural living, well water consumption.

  • Protective factors: Caffeine and smoking (epidemiological observation, not recommended for prevention).

Pathophysiology

  • Loss of dopaminergic neurons in the substantia nigra → reduced dopamine in the striatum.

  • Presence of Lewy bodies (intracytoplasmic aggregates of α-synuclein).

  • Imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) activity in the basal ganglia.

  • Progressive neuronal loss also affects other neurotransmitter systems, contributing to non-motor symptoms.

Clinical Features

1. Cardinal Motor Symptoms (often asymmetric at onset)

  • Resting tremor: “Pill-rolling,” typically 4–6 Hz, worse at rest, improves with voluntary movement.

  • Rigidity: Increased tone, “lead-pipe” or “cogwheel” quality.

  • Bradykinesia: Slowness of movement, difficulty initiating movements, reduced amplitude of repetitive movements.

  • Postural instability: Impaired balance, increased risk of falls (usually later in disease).

2. Other Motor Signs

  • Shuffling gait with reduced arm swing.

  • Hypomimia (masked facies).

  • Hypophonia (soft speech).

  • Micrographia (small handwriting).

3. Non-Motor Symptoms (may precede motor onset)

  • Anosmia (loss of smell).

  • Constipation.

  • Sleep disorders (REM sleep behavior disorder, excessive daytime sleepiness).

  • Autonomic dysfunction (orthostatic hypotension, urinary urgency).

  • Cognitive impairment, depression, anxiety, hallucinations (in advanced disease).

Diagnosis
PD is diagnosed clinically; no definitive laboratory test exists.

Criteria

  • Diagnosis requires bradykinesia plus either rest tremor or rigidity.

  • Supportive features: Asymmetry at onset, good initial response to dopaminergic therapy, presence of levodopa-induced dyskinesias.

  • Exclude alternative causes (atypical parkinsonism, drug-induced parkinsonism).

Investigations (to support diagnosis or exclude mimics)

  • MRI brain: Usually normal in idiopathic PD, but rules out structural lesions.

  • Dopamine transporter (DAT) SPECT scan: Shows reduced striatal uptake in PD (not always necessary).

Management

Treatment is symptomatic, aimed at improving motor and non-motor symptoms and maintaining quality of life. Therapy is individualized based on age, symptom severity, and functional impairment.

1. Non-Pharmacological

  • Patient and family education.

  • Physical therapy: Balance, gait, strength training.

  • Occupational therapy: Activities of daily living.

  • Speech therapy: For hypophonia and swallowing difficulties.

2. Pharmacological

a. Levodopa preparations (most effective for motor symptoms)

  • Levodopa + carbidopa (e.g., 100/25 mg) orally 3–4 times daily; dose titrated to symptom control.

  • Levodopa + benserazide as an alternative.

  • Side effects: Nausea, orthostatic hypotension, hallucinations, dyskinesias, motor fluctuations (wearing-off, on–off phenomenon) after long-term use.

b. Dopamine agonists (younger patients, early disease, or adjunct to levodopa)

  • Pramipexole: 0.125 mg orally three times daily, titrated up.

  • Ropinirole: 0.25 mg orally three times daily, titrated.

  • Rotigotine: Transdermal patch starting at 2 mg/24 h.

  • Side effects: Somnolence, hallucinations, impulse control disorders.

c. MAO-B inhibitors (mild disease or adjunct)

  • Selegiline: 5 mg orally twice daily.

  • Rasagiline: 1 mg orally once daily.

  • Modest symptomatic benefit; may delay motor complications.

d. COMT inhibitors (prolong levodopa effect)

  • Entacapone: 200 mg orally with each levodopa dose.

  • Tolcapone: Less used due to hepatotoxicity risk.

e. Amantadine

  • 100 mg orally 1–2 times daily; reduces dyskinesias and has mild antiparkinsonian effects.

f. Anticholinergics (younger patients with tremor-predominant disease; avoid in elderly due to cognitive side effects)

  • Trihexyphenidyl: 1–2 mg orally once or twice daily, titrated.

3. Surgical Treatment

  • Deep brain stimulation (DBS): Electrodes implanted in the subthalamic nucleus or globus pallidus interna; indicated in advanced disease with motor fluctuations or dyskinesias refractory to medical therapy.

Complications

  • Motor: Wearing-off phenomena, dyskinesias.

  • Non-motor: Dementia, psychosis, autonomic instability.

  • Falls and fractures.

Prognosis

  • PD is progressive, with rate of progression varying widely.

  • Life expectancy can be near-normal with optimal management, though disability accumulates over years.

  • Non-motor symptoms often become the most disabling aspect in late stages




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