What are the differential diagnoses for a 19-year-old male with a two-year history of episodic lower-extremity weakness?

Differential Diagnosis for Episodic Lower Limb Weakness in a 19-Year-Old Male

The most critical diagnoses to consider in a young male with two years of episodic lower extremity weakness are periodic paralysis (particularly thyrotoxic or hypokalemic forms), early-onset muscular dystrophy, and metabolic channelopathies, with periodic paralysis being the most likely given the episodic nature and age of presentation. 1, 2

Immediate Life-Threatening Conditions to Exclude

Periodic Paralysis Syndromes

• Thyrotoxic hypokalemic periodic paralysis (THPP) presents with recurrent episodes of generalized muscular weakness, especially affecting the legs, associated with hypokalaemia and hyperthyroidism, and can cause fatal cardiovascular and respiratory complications. 1
• Episodes are often precipitated by high carbohydrate intake, rest after exercise, or stress. 1, 2
• Diagnosis requires checking serum potassium during an episode, thyroid function tests (TSH, free T4), and ECG to assess for arrhythmias. 1
• Hypokalemic periodic paralysis (non-thyrotoxic form) typically presents with episodic weakness triggered by carbohydrate consumption, with a strong family history pattern affecting multiple relatives. 2

Guillain-Barré Syndrome

• Although typically monophasic rather than episodic over two years, Guillain-Barré syndrome causes rapidly progressive bilateral leg weakness starting distally and ascending to arms and cranial muscles, with markedly reduced or absent reflexes, reaching maximal disability within approximately two weeks. 3
• The two-year episodic history makes this diagnosis less likely, but atypical variants should be considered if there is any acute-on-chronic worsening. 3

Neuromuscular and Genetic Causes

Muscular Dystrophy

• Duchenne or Becker muscular dystrophy can present in late adolescence with proximal muscle weakness, calf hypertrophy, and difficulty with running or athletic activities. 4
• Check serum creatine kinase (CK) levels—significantly elevated CK (>1000 U/L) suggests muscular dystrophy. 4
• Becker muscular dystrophy is allelic to Duchenne but presents in older children with milder phenotype and can manifest episodically with exertion. 4
• Approximately one-third of cases represent new mutations without family history. 4

Metabolic Myopathies

• Vacuolar myopathy associated with hypokalemic periodic paralysis shows T-tubule dilation on electron microscopy and can present with episodic weakness over many years. 2
• Acid maltase deficiency (glycogen storage disease) should be considered in the differential of vacuolar myopathy. 2
• Mitochondrial myopathies can present with episodic weakness and require muscle biopsy showing "ragged red fibers" on Gomori trichrome stain. 4

Spinal Cord Pathology

Tethered Cord Syndrome

• Tethered cord syndrome in teenagers presents with progressive muscle weakness, gait disturbances, and difficulties with running or keeping up during athletic activities. 4
• Symptoms may include back and/or leg pain that varies in character (dull, sharp, lancinating, or dysesthetic) and is aggravated by spinal flexion/extension or walking. 4
• Patients often have a history of subtle abnormalities dating to early childhood, including being "slow" athletically or having chronic constipation. 4
• A characteristic feature is sudden appearance of new pain or neurologic deficits after back stretching events (falls, vigorous sports, trauma). 4
• Look for cutaneous markers overlying the spine (dimples, hair tufts, hemangiomas) on physical examination. 4

Spinal Vascular Malformations

• Spinal dural arteriovenous fistula can present with variable lower extremity weakness that fluctuates day-to-day and is exacerbated by walking or bending forward. 5
• MRI may show cord edema and dilated peri- and intramedullary vessels; diagnosis requires spinal angiography (DSA). 5
• This is a rare but underreported condition that requires detailed history regarding symptom exacerbation patterns. 5

Inflammatory and Autoimmune Causes

Idiopathic Inflammatory Myopathies

• Polymyositis or dermatomyositis typically presents with proximal muscle weakness affecting lower extremities more than upper, though episodic presentation over two years would be atypical. 4
• Check CK, aldolase, and consider autoantibody testing (anti-Jo-1, anti-Mi2, anti-SRP). 4
• Muscle biopsy shows inflammatory infiltrates invading muscle fibers, distinguishing this from muscular dystrophy. 4

Diagnostic Approach Algorithm

Initial Laboratory Testing

1. Serum potassium during an episode (critical for periodic paralysis diagnosis). 1, 2
2. Thyroid function tests (TSH, free T4) to exclude thyrotoxic periodic paralysis. 1
3. Creatine kinase (CK) level—if >1000 U/L, pursue muscular dystrophy workup with genetic testing for dystrophin gene. 4
4. Complete metabolic panel including calcium, magnesium, phosphate. 6
5. ECG to assess for arrhythmias associated with electrolyte disturbances. 1

Physical Examination Priorities

• Muscle bulk assessment for calf hypertrophy (muscular dystrophy) or atrophy ("saber shins" suggesting chronic denervation). 4
• Gower maneuver testing—inability to rise from floor without pushing up with arms indicates proximal weakness. 4
• Deep tendon reflexes—diminished or absent suggests lower motor neuron disorder; hyperreflexia suggests upper motor neuron pathology. 4
• Cutaneous examination of back for dimples, hair tufts, or vascular malformations suggesting tethered cord. 4
• Sensory examination for distal-to-proximal sensory loss or "suspended" sensory deficits. 4

Advanced Diagnostic Testing

• Electromyography (EMG) is indicated to differentiate myopathic (short duration, low amplitude polyphasic potentials) from neuropathic patterns and to guide muscle biopsy site selection. 4, 6
• Spinal MRI if history suggests tethered cord (back pain, bladder/bowel symptoms, cutaneous markers) or spinal vascular malformation (symptom exacerbation with walking/bending). 4, 5
• Muscle biopsy if CK elevated or EMG shows myopathic pattern—look for vacuolar changes, inflammatory infiltrates, dystrophin absence, or mitochondrial abnormalities. 4, 2
• Genetic testing for CACN1AS or SCN4A mutations if periodic paralysis suspected. 2

Critical Clinical Pitfalls

• Do not assume normal strength between episodes excludes serious pathology—periodic paralysis and early muscular dystrophy can have completely normal examinations interictally. 1, 2
• Do not miss thyrotoxicosis—THPP is rare in Western populations but carries significant mortality risk from cardiac arrhythmias and respiratory failure if untreated. 1
• Do not overlook family history—many genetic myopathies and periodic paralyses have autosomal dominant inheritance affecting multiple family members, though new mutations occur in one-third of cases. 4, 2
• Do not attribute symptoms to deconditioning or psychiatric causes without objective testing—young males with episodic weakness often have their symptoms dismissed before reaching correct diagnosis. 1, 5
• Do not perform muscle biopsy without EMG guidance—sampling error is common, and EMG identifies the most affected muscle for optimal diagnostic yield. 4