MBBS 1st Professional Examination Answer

Case Clues

• 60-year-old male
• Difficulty initiating motor activity (hypokinesia/akinesia)
• Resting tremor while sitting
• No change in facial expression despite change in emotion (masked facies / hypomimia)

i) Probable Diagnosis

"The hallmark clinical features of Parkinson disease include tremor, rigidity, and bradykinesia, usually of asymmetric onset." - Textbook of Family Medicine 9e

ii) Pathophysiology with Diagram

Basic Anatomy

• Striatum (Caudate + Putamen) - receives input
• Globus Pallidus interna (GPi) - main output nucleus (inhibitory, GABAergic)
• Globus Pallidus externa (GPe)
• Substantia Nigra pars compacta (SNpc) - dopamine source
• Subthalamic Nucleus (STN)
• Thalamus (VL nucleus) - relay to motor cortex

Normal Physiology - Two Pathways

• Cortex → Striatum → D1 receptors activated by dopamine → GPi inhibited → Thalamus disinhibited → Motor cortex activated → Movement facilitated

• Cortex → Striatum → D2 receptors activated → GPe inhibited → STN disinhibited → GPi excited → Thalamus inhibited → Motor cortex suppressed

Pathophysiology in Parkinson's Disease

"Parkinson disease results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The fibers to the putamen (part of the striatum) are most severely affected." - Ganong's Review of Medical Physiology, 26e

1. Direct pathway underactive (D1 not stimulated) → GPi not inhibited → excess inhibition of thalamus
2. Indirect pathway overactive (D2 not inhibited → GPe inhibited → STN disinhibited → GPi over-excited) → even more inhibition of thalamus

Pathophysiology Diagram

NORMAL                              PARKINSON'S DISEASE
                                    (Loss of SNpc dopamine)
Cortex                              Cortex
  |                                   |
Striatum ←─ SNpc (DA)             Striatum ←✗─ SNpc (↓↓DA)
  |                                   |
  ├─[Direct] D1 → GPi↓ →          ├─[Direct] D1 not stimulated
  |           Thalamus↑ →          |           GPi overactive →
  |           Movement              |           Thalamus↓↓
  |                                 |
  └─[Indirect] D2 → GPe↓ →        └─[Indirect] D2 not inhibited
              STN↓ → GPi↓ →                    GPe inhibited →
              Thalamus↑                         STN overactive →
                                                GPi ↑↑ →
                                                Thalamus ↓↓↓
                                                   |
                                                Motor Cortex SUPPRESSED
                                                = HYPOKINESIA / AKINESIA

iii) Clinical Features of Parkinson's Disease

A. Cardinal Motor Features ("TRAP")

B. Other Motor Features

• Masked facies (hypomimia) - reduced facial expression despite emotional changes (as in this case)
• Micrographia - progressively smaller handwriting
• Hypophonia - soft, monotonous voice
• Shuffling gait - narrow-based, festinating (accelerating, bent forward)
• Reduced arm swing during walking
• Drooling (sialorrhoea)
• Dysphagia - swallowing difficulty (oral, pharyngeal, or esophageal phase)
• Reduced eye blinking (normal ~20/min; reduced in PD)
• Freezing of gait - sudden inability to continue walking

C. Non-Motor Features

• Anosmia (loss of smell) - often an early sign
• Depression / anxiety / apathy
• Autonomic disturbances - orthostatic hypotension, constipation, urinary dysfunction, sexual dysfunction
• Sleep disturbances - REM sleep behavior disorder (RBD)
• Cognitive impairment / dementia - late stage
• Sensory disturbances - pain, paresthesias

"The absence of motor activity and the difficulty in initiating voluntary movements are striking. There is a decrease in the normal, unconscious movements such as swinging of the arms during walking, the panorama of facial expressions related to the emotional content of thought and speech." - Ganong's, 26e

iv) Two Drugs Used to Reduce Hypokinesia

1. Levodopa (L-DOPA) - combined with Carbidopa

• Mechanism: Levodopa is the precursor of dopamine. Unlike dopamine itself, L-dopa crosses the blood-brain barrier and is then converted to dopamine in the striatum by DOPA decarboxylase.
• Carbidopa (a peripheral decarboxylase inhibitor) is combined to prevent peripheral conversion, reducing side effects and increasing CNS availability.
• Most effective drug for bradykinesia/hypokinesia.
• Limitation: Beneficial effects wane after 5-7 years as neuronal degeneration progresses.

"More dramatic improvement is produced by administration of L-dopa. Unlike dopamine, this dopamine precursor crosses the blood-brain barrier and helps repair the dopamine deficiency." - Ganong's Review of Medical Physiology, 26e

2. Dopamine Agonists (e.g., Bromocriptine, Pramipexole, Ropinirole)

• Mechanism: Directly stimulate dopamine receptors (D1, D2) in the striatum, bypassing the need for surviving dopaminergic neurons.
• Used as monotherapy in younger patients or as adjuncts to levodopa.
• Bromocriptine (ergot-derived) was the classical agent; Pramipexole and Ropinirole (non-ergot) are now preferred.

Note for exams: Anticholinergic drugs (e.g., Benztropine, Trihexyphenidyl) help with tremor by restoring the dopamine-acetylcholine balance but have less effect on hypokinesia specifically. The question asks specifically about drugs reducing hypokinesia, so L-dopa + Carbidopa and Dopamine agonists are the correct answer.

Summary Table