In an adult with unexplained muscle bulk, how should true muscular hypertrophy be evaluated and managed?

Hypertrophia Musculorum Vera: Evaluation and Management

What is Hypertrophia Musculorum Vera?

Hypertrophia musculorum vera is an extremely rare condition characterized by true muscle fiber enlargement without underlying myopathy, dystrophy, or neurogenic disease—it represents isolated, unexplained muscle hypertrophy as the sole clinical finding. 1 This entity must be distinguished from the far more common pseudohypertrophy (fatty or connective tissue infiltration) and secondary hypertrophy from identifiable causes. 2

Critical First Step: Exclude Cardiac Involvement

Before pursuing a neuromuscular workup, you must immediately obtain a 12-lead ECG and transthoracic echocardiogram to exclude hypertrophic cardiomyopathy (HCM), as this carries significant mortality risk and fundamentally changes management. 3

• Cardiac screening is mandatory because:
  • HCM affects 1 in 500 adults and can present with skeletal muscle findings 4
  • LV wall thickness ≥15 mm on echo defines HCM in adults and requires specific management to prevent sudden cardiac death 3, 5
  • ECG abnormalities (LVH voltage criteria, ST-T changes, pathological Q-waves) are present in 75-95% of HCM patients 4
  • First-degree relatives require cascade screening if HCM is identified 6, 4

Systematic Diagnostic Approach to Unexplained Muscle Bulk

Step 1: Determine True Hypertrophy vs. Pseudohypertrophy

Obtain MRI of the affected muscles as the gold standard imaging modality to distinguish true muscle fiber enlargement from fatty/connective tissue infiltration. 7

• True hypertrophy shows: Enlarged muscle that is isointense with normal muscle on all MRI sequences, well-defined margins, normal contour 7
• Pseudohypertrophy shows: Excessive fat interspersed throughout muscle on MRI, often with paradoxical weakness 2, 7
• Ultrasound can supplement MRI by demonstrating diffuse muscle mass enlargement without edema 8

Step 2: Identify Underlying Myopathic Causes

Perform electromyography (EMG) and nerve conduction studies to detect myopathic or neurogenic patterns that explain the hypertrophy. 8

• Look for polyphasic, large motor unit potentials suggesting chronic denervation with reinnervation 8
• EMG findings consistent with myotonia (dive-bomber discharges) point to myotonia congenita, where true hypertrophy from repetitive muscle activity is characteristic 2
• Neuromyotonia patterns indicate continuous muscle fiber activity causing work hypertrophy 2

Obtain muscle biopsy from the hypertrophied muscle if EMG is abnormal or diagnosis remains unclear. 8

• Biopsy findings to assess:
  • Marked fiber size variation without inflammation or fiber loss suggests congenital monomelic hypertrophy 8
  • Central nuclei in >25% of fibers indicates centronuclear myopathy, which can present with pseudohypertrophy in adults 9
  • Type 2 fiber predominance and hypertrophy occurs in myotonia congenita 2
  • Fatty infiltration confirms pseudohypertrophy rather than true hypertrophy 9, 7

Step 3: Screen for Neurogenic Causes

Paradoxically, denervation can cause muscle hypertrophy rather than atrophy—evaluate for radiculopathy, peripheral neuropathy, or spinal cord pathology. 1, 7

• Obtain MRI of the spine (cervical for upper extremity, lumbar for lower extremity) to identify:
  • Spinal stenosis causing chronic denervation 7
  • Herniated disc with nerve root compression 7
  • Tethered cord or spina bifida 7
• Denervation hypertrophy is rare but well-documented in sciatica, hypertrophic neuritis, and progressive spinal muscular atrophy 1
• EMG will show denervation potentials (fibrillations, positive sharp waves) with chronic reinnervation changes 7

Step 4: Exclude Endocrine and Metabolic Causes

Order thyroid function tests (TSH, free T4) and IGF-1 level, as hypothyroidism and acromegaly classically cause true muscle hypertrophy. 1

• Hypothyroidism causes diffuse muscle hypertrophy with delayed muscle relaxation (pseudomyotonia) 1
• Acromegaly produces muscle hypertrophy from chronic growth hormone excess 1
• Both conditions are reversible with treatment of the underlying endocrine disorder 3

Step 5: Consider Infiltrative Processes

If imaging shows muscle enlargement with abnormal signal characteristics, evaluate for:

• Cysticercosis: Travel history, eosinophilia, characteristic "rice grain" calcifications on imaging 1
• Sarcoidosis: Systemic symptoms, elevated ACE level, chest imaging 1
• Amyloidosis: Cardiac involvement, macroglossia, periorbital purpura 3

Diagnosis of Hypertrophia Musculorum Vera (Diagnosis of Exclusion)

Hypertrophia musculorum vera can only be diagnosed after systematically excluding all identifiable causes of muscle hypertrophy through the above workup. 1

• This represents true muscle fiber enlargement as the sole clinical finding 1
• No underlying myopathy, dystrophy, neurogenic disease, endocrine disorder, or infiltrative process is present 1
• The mechanism remains unknown 1
• It may be congenital (present from birth/early childhood) or acquired 8

Management Approach

For true hypertrophia musculorum vera with no identifiable cause, management is conservative and focused on monitoring for complications:

• No specific treatment exists for idiopathic true muscle hypertrophy 1
• Serial clinical examinations every 6-12 months to assess for:
  • Development of weakness (suggests evolving myopathy)
  • Progression of hypertrophy
  • Emergence of systemic symptoms
• Repeat EMG and consider repeat biopsy if clinical deterioration occurs 8
• Genetic counseling if family history suggests hereditary pattern 8
• Physical therapy to maintain range of motion if hypertrophy causes functional limitation 8

For secondary causes identified during workup, treat the underlying condition:

• Myotonia congenita: Mexiletine or other sodium channel blockers to reduce myotonia 2
• Endocrine myopathies: Hormone replacement or suppression as appropriate 1
• Denervation hypertrophy: Address underlying neurologic lesion (decompression surgery for stenosis/disc herniation) 7

Critical Pitfalls to Avoid

• Never assume muscle bulk is benign without cardiac evaluation—missing HCM can result in sudden cardiac death 3, 4
• Do not rely on clinical examination alone to distinguish true hypertrophy from pseudohypertrophy—MRI is essential 7
• Recognize that muscle enlargement with weakness is pseudohypertrophy until proven otherwise, as this paradoxical combination points to dystrophy or infiltrative disease 2
• Do not miss denervation hypertrophy—always obtain spine imaging when EMG shows denervation in hypertrophied muscles 7
• Remember that "hypertrophia musculorum vera" is extraordinarily rare—exhaust the differential diagnosis before accepting this label 1