Approach to Proximal Muscle Weakness (PMW)

1. Neuromuscular Junction Disorders (NMJ)

• Key Characteristics:
  • History:
    • Patients often report fluctuating muscle weakness that worsens throughout the day. For example, the patient may have strength in the morning but experience a decline in strength towards the evening.
    • Difficulty with activities like combing hair, putting on shirts, or climbing stairs is common due to proximal muscle weakness.
  • Physical Examination:
    • Positive fatigability testing: Progressive weakening of muscles with repetitive use (e.g., holding the arms up or keeping eyes open).
    • Enhanced/induced ptosis: Visible drooping of the eyelid after sustained upward gaze (suggestive of Myasthenia Gravis).
    • Axial muscle weakness: Weakness in neck extensors, which may lead to a “dropped head” appearance.
    • Proximal muscle weakness in major muscle groups such as deltoids, biceps, triceps, quadriceps, and hamstrings. Normal strength in wrist and ankle flexors/extensors is often preserved.

Categories:

• Postsynaptic Disorders:
  • Myasthenia Gravis: Autoimmune disorder with antibodies targeting acetylcholine receptors. Patients present with fluctuating muscle weakness, often accompanied by ocular symptoms like ptosis and diplopia. Associated with thymomas or thymic hyperplasia.
• Presynaptic Disorders:
  • Lambert-Eaton Myasthenic Syndrome (LEMS): Caused by antibodies against presynaptic calcium channels, resulting in reduced acetylcholine release. Notable for improvement of strength with repeated contractions.
  • Botulism: A neurotoxin blocks acetylcholine release, leading to muscle paralysis and cranial nerve involvement.
  • Snake Venom: Certain neurotoxic venoms can affect neuromuscular transmission, leading to generalized weakness.

Diagnosis:

• Antibody tests: For conditions like Myasthenia Gravis (anti-AChR) and LEMS (anti-VGCC).
• Electromyography (EMG): Characteristic findings like decremental response on repetitive nerve stimulation.
• Clinical Tests: Fatigability tests and edrophonium (Tensilon) test to confirm Myasthenia Gravis.

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2. Myopathies

• Key Characteristics:
  • History:
    • Progressive proximal muscle weakness that is consistent throughout the day and does not fluctuate like NMJ disorders. Patients may have difficulty performing tasks such as combing hair, raising arms, or climbing stairs.
    • Family history or childhood onset may suggest congenital or hereditary causes.
  • Physical Examination:
    • Proximal muscle weakness without fatigability or sensory loss. Reflexes are generally normal unless atrophy is severe.
    • No changes in muscle strength with repetitive testing.

Categories:

• Congenital Myopathies:
  • Examples include Nemaline myopathy, Central core disease, and Centronuclear myopathy. These often present with hypotonia and delayed motor milestones in infancy.
• Muscular Dystrophies:
  • Conditions like Duchenne and Becker Muscular Dystrophies (Dystrophin deficiency), Emery-Dreifuss Muscular Dystrophy, and Limb-Girdle Muscular Dystrophy. Characterized by progressive muscle weakness and wasting.
• Metabolic Myopathies:
  • Glycogen storage diseases and lipid storage diseases present with exercise intolerance, muscle cramps, and progressive weakness.
• Inflammatory Myopathies:
  • Include Polymyositis, Dermatomyositis (skin changes), and Inclusion Body Myositis (usually in older adults).
• Drug & Toxin-Induced Myopathies:
  • Caused by drugs such as statins, colchicine, chloroquine, and certain toxins like tetrodotoxin.
• Electrolyte & Endocrine Myopathies:
  • Imbalances like hypokalemia, hypercalcemia, or thyroid and parathyroid disorders can present with muscle weakness.

Diagnosis:

• Elevated Creatine Kinase (CK): Indicative of muscle damage.
• Muscle biopsy: Characteristic histological findings help diagnose different myopathies.
• Genetic testing: For hereditary conditions like muscular dystrophies.
• EMG: Distinguishes myopathic from neuropathic patterns.

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3. Polyneuropathy

• Key Characteristics:
  • History:
    • Weakness associated with sensory changes, such as numbness or tingling in a "glove and stocking" distribution. There may be autonomic symptoms like orthostatic hypotension or urinary retention.
  • Physical Examination:
    • Areflexia: Loss of reflexes, especially in the ankles.
    • Sensory loss: Reduced sensation to vibration, proprioception, pain, and temperature, particularly in the distal extremities.

Categories:

• Demyelinating Polyneuropathies:
  • Conditions like Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Present with progressive weakness, sensory loss, and areflexia.
• Axonal Polyneuropathies:
  • Caused by diabetes, alcohol, and certain toxins like lead. Presents with distal weakness, atrophy, and sensory changes.
• Hereditary Neuropathies:
  • Such as Charcot-Marie-Tooth disease, which often presents with foot deformities (e.g., high arches), distal weakness, and sensory loss.

Diagnosis:

• Nerve conduction studies (NCS) and EMG: Distinguish between demyelinating and axonal neuropathies.
• Laboratory tests: To identify underlying causes like diabetes, vitamin deficiencies, or toxins.
• Cerebrospinal Fluid (CSF) analysis: High protein in GBS indicates albuminocytologic dissociation.

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Summary Table: Proximal Muscle Weakness by Etiology

This approach provides a structured and organized method for evaluating patients with proximal muscle weakness, focusing on differentiating among NMJ disorders, myopathies, and polyneuropathies based on their unique historical and clinical features.