Parkinsons disease

Isra

Definition

• Parkinson’s disease is a progressive neurodegenerative disorder due to loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the basal ganglia

Pathophysiology

manifestations appears when 70% of neuron is dead

• Loss of dopaminergic neurons in substantia nigra pars compacta
• Lewy bodies (α-synuclein aggregates) (inclusion body) not pathognomonic
• Imbalance of dopamine vs acetylcholine → motor symptoms → stimulatory neurotransmitter
• Multifactorial: genetic, oxidative stress, toxins, DM Smoking, CO

dead neuron under microscope

Clinical Features

Motor Symptoms (TRAP) in one side (asymmetrical)

• Tremor (resting, pill-rolling) from side → most common + Rigid → the: cholinergic antagonist
• Rigidity (cogwheel/lead pipe) due to loss of dopamine → slow
• Akinesia/bradykinesia → start monotonous speech / micrographia
• Postural instability (usually late feature) slow pitch
• gait (narrowed, shuffling)

Non-Motor Symptoms

• Depression, anxiety
• Autonomic: constipation, urinary frequency, orthostatic hypotension
• Cognitive decline → Parkinson’s dementia → late feature
• Sleep disorders (REM behavior disorder)
• Hyposmia (early) Anosmia/

Differential Diagnosis of Parkinson’s Disease

1. Other Parkinsonian Syndromes

• Drug-induced parkinsonism: Caused by antipsychotics (haloperidol, risperidone) or antiemetics (metoclopramide). Features: symmetric, no resting tremor, improves after stopping drug.
• Vascular parkinsonism: Due to multiple small strokes. Features:, gait disturbance > tremor, hyperreflexia and poor levodopa response.
• Normal Pressure Hydrocephalus (NPH): Triad of gait disturbance, urinary incontinence, and dementia. Imaging shows enlarged ventricles with normal pressure.
• Essential tremor: Action/postural tremor (not resting), improves with alcohol, no rigidity or bradykinesia.

2. Parkinson-Plus Syndromes (Atypical Parkinsonism)

• Multiple System Atrophy (MSA): Parkinsonism + autonomic failure + cerebellar signs.
• Progressive Supranuclear Palsy (PSP): Early falls, vertical gaze palsy, axial rigidity.
• Corticobasal Degeneration (CBD): Asymmetric rigidity, apraxia, alien limb, cortical sensory loss.
• Dementia with Lewy Bodies (DLB): Early dementia, visual hallucinations, fluctuating cognition, parkinsonism

1. Apraxia

Definition: Inability to perform a learned purposeful movement despite:

• Intact intellect
• Normal strength
• Normal sensation
• Normal coordination
• Patient understands the command

2. Alien limb syndrome

Definition: A limb (usually the hand) moves on its own, without the patient’s control.

3. Other Neurological Disorders

• Wilson’s disease: Young onset, psychiatric symptoms, liver disease, Kayser–Fleischer rings.
• Huntington’s disease: Chorea, behavioral changes, family history.
• Post-encephalitic parkinsonism: Rare, history of encephalitis

Red flags against idiopathic Parkinson’s disease

• Poor or no response to levodopa
• Early postural instability or falls
• Rapid progression
• Early autonomic failure or dementia
• Symmetrical onset

Investigations

• Clinical diagnosis (UK Brain Bank criteria)
• MRI: usually normal, used to exclude other causes “Stroke, NPH”
• DAT-SPECT: ↓ striatal dopamine uptake

TJBR

• T → tremor (resting)
• S → dyskinesia
• B → Bradykinesia
• R → Rigidity (lead pipe, cogwheel)
• Writing (micrographia)
• Reading (monotonous speech)

Tremor causing drugs → β agonist, Lithium (so, ask in hx)

Pharmacological Management

1. Levodopa + Carbidopa

• Mechanism: Levodopa is a precursor of dopamine, crosses BBB → converted to dopamine. Carbidopa inhibits peripheral DOPA decarboxylase → ↑ central dopamine.
• Example: Sinemet®
• Side effects: [Nausea, vomiting, orthostatic hypotension, Arrhythmias], if ↑ dopa in periphery (centrally) dyskinesias, on-off fluctuations, [hallucinations, Schizophrenic like sx) if ↑ dopa centrally

due to down regulation of receptors

2. Dopamine Agonists

• Mechanism: Direct stimulation of dopamine receptors (D2 > D3).
• Examples: Pramipexole, Ropinirole.
• Side effects: Nausea, hypotension, hallucinations, impulse control disorders (gambling, hypersexuality), sleep attacks.

Used when end of dose phenomena occur

= end of dose phenomena

hypertension (↑ dopamine peripherally will enter neuron → nore epinephrine will go out & work on α receptor)

in other Action potential → dopamine will be released → hypotension

3. MAO-B Inhibitors

• Mechanism: Inhibit monoamine oxidase-B → ↓ dopamine breakdown in CNS.

• Examples: Selegiline, Rasagiline

• Side effects: Insomnia, hypertension (rare), nausea, vomiting

• MAO B → breaks down dopamine

• MAO A → breaks down serotonin & NE

4. COMT Inhibitors

• Mechanism: Inhibit COMT → prolong Levodopa half-life.
• Examples: Entacapone, Tolcapone.
• Side effects: Diarrhea, orange urine, hepatotoxicity (Tolcapone)., hallucination

in ↑ MAO B inhibitor MAO A will be affected too (less selectivity loss) → ↑ NE + serotonin → HTN → insomnia

• COMT enzi → in periphery: convert Levodopa into 3-O-methyl dopa (not cross BBB)
• Centrally: breaks down dopa
• So, once inhibited → more dopa enter the brain

5. Amantadine

• Mechanism: Enhances dopamine release, inhibits reuptake; NMDA receptor antagonist → inhibit glycolated glutamate receptor
• Example: Amantadine (Symmetrel®).
• Side effects: Livedo reticularis, edema, confusion, hallucinations.

6. Anticholinergics

• Mechanism: Block muscarinic receptors → restore balance between dopamine & acetylcholine. Control tremor more

• Examples: Trihexyphenidyl, Benztropine.

• Side effects: Dry mouth, blurred vision, urinary retention, constipation, confusion (avoid in elderly).

• Antiviral

• → no Ca²⁺ will enter → no death of neuron

• DDx:

  • Physiological in newborn
  • APA
  • Surgeon complaining of tremors
  • Dry sandy eyes, mydriasis, tachycardia

عصب و عيار

Good luck

End of dose phenomena treated by SAP

• S → Selegiline → MAO B inhibitor
• A → Apomorphine
• R → Ropinirole
• Dopamine agonist

Post drug → hx

Post stroke → hx

Pyramidal post stroke → hyperreflexia, plantar drift

Parkinson plus syn

• multiple system Atrophy (big danger) → BP, horizontal nystagmus
• progressive Supranuclear palsy → Bilateral disease, poor response to levodopa, young, vertical nystagmus
• Corticobasal degeneration → glabellar tap, loss of cortical sensation
• Lewy body dementia → visual hallucination, fluctuating cognition, early dementia

others:

• Wilson → Kayser Fleischer ring, jaundice
• Huntington → FR, early with new generation, AD
• Essential tremor → action tremor, voice tremor, improves with alcohol, treated by BB blocker