What is the differential diagnosis for a patient with progressive muscle weakness, fatigue, fasciculations, and balance difficulties, with a history of steroid treatment and incomplete improvement with physical therapy and baclofen?

Differential Diagnosis for Progressive Proximal Muscle Weakness Following Prolonged Corticosteroid Use

The most likely diagnosis is steroid-induced myopathy, followed by inflammatory myopathy (polymyositis/dermatomyositis), limb-girdle muscular dystrophy (particularly dysferlinopathy), and less likely metabolic myopathies including glycogen storage diseases or mitochondrial myopathy.

Primary Differential Diagnoses (In Order of Likelihood)

1. Steroid-Induced Myopathy (Most Likely)

• The temporal relationship between 6 weeks of decadron treatment and onset of proximal muscle weakness (difficulty hanging clothes, using arms to stand) is highly characteristic of corticosteroid myopathy 1
• The low-normal CPK with proximal muscle weakness pattern strongly suggests steroid myopathy rather than inflammatory myopathy, which typically presents with elevated CPK 2, 3
• Steroid myopathy characteristically affects proximal muscles (shoulders, hips) with preserved distal strength, matching this patient's 4/5 proximal and 4+/5 to 5/5 distal strength pattern 1
• The absence of muscle enzyme elevation (normal aldolase, low-normal CPK) with EMG showing normal findings further supports non-inflammatory myopathy 2, 3

2. Inflammatory Myopathy (Polymyositis/Dermatomyositis) - Second Most Likely

• Despite negative antibodies (AChR, anti-MuSK, polymyositis panel), seronegative inflammatory myopathy remains possible as autoantibodies are absent in 20-30% of cases 2, 4
• The mildly elevated ESR while on steroids could indicate underlying inflammation, though this is non-specific 2
• However, the normal EMG/NCS strongly argues against active inflammatory myopathy, as EMG in polymyositis typically shows polyphasic motor unit action potentials of short duration and low amplitude with fibrillation potentials 2
• The normal MRI lumbar spine without muscle edema makes active inflammatory myositis less likely, as MRI typically shows muscle inflammation and edema in active disease 2, 3
• Muscle biopsy would be definitive but was not performed; this remains the gold standard for confirming inflammatory myopathy with characteristic mononuclear cell infiltration 2, 4

3. Limb-Girdle Muscular Dystrophy (LGMD), Particularly Dysferlinopathy (LGMD2B) - Third Most Likely

• Dysferlinopathy can present with asymptomatic hyperCKemia for years before weakness develops, though this patient has low-normal CPK rather than elevated 5, 6
• LGMD2B classically presents in young adults (20s-30s) with proximal pelvic girdle weakness, difficulty climbing stairs, and progressive course - matching several features here 5, 7
• The family history of undiagnosed orthopedic ailments and hypermobile EDS raises suspicion for hereditary connective tissue or muscular disorders 5, 7
• However, the acute onset temporally related to steroid use (rather than insidious progression) and normal EMG make muscular dystrophy less likely 5, 7
• Dysferlinopathy can show minimal or no dystrophic changes on muscle biopsy early in disease, with absent or reduced dysferlin on immunohistochemistry being diagnostic 5, 6

4. Metabolic Myopathies (Glycogen Storage Disease, Mitochondrial Myopathy) - Less Likely

• Glycogen storage diseases (Types IIIa, IV, V, VII) can present with elevated aldolase but normal CPK, though aldolase was normal in this patient 3
• Adult-onset acid maltase deficiency (Pompe disease/GSD Type II) can present with respiratory muscle weakness ("rib muscle weakness" sensation) and proximal myopathy mimicking polymyositis 8
• The intermittent dyspnea with sensation of "rib muscle weakness" and diaphragm soreness could suggest respiratory muscle involvement seen in metabolic myopathies 8
• Mitochondrial myopathies demonstrate ragged red fibers on Gomori trichrome stain and typically present with exercise intolerance, but the acute onset after steroid use makes this unlikely 2, 3
• The well-controlled diabetes (A1C normal range) argues against significant metabolic derangement 8

5. Myasthenia Gravis - Unlikely

• Negative AChR and anti-MuSK antibodies make myasthenia gravis very unlikely 2
• The pattern of fatigable weakness with muscle "shaking" during exercise could suggest neuromuscular junction disorder 2
• However, normal EMG/NCS without decrement on repetitive nerve stimulation effectively rules out myasthenia gravis 2
• No ocular symptoms (ptosis, diplopia) which are present in 85% of myasthenia cases 2

Critical Diagnostic Considerations

Key Clinical Features Supporting Steroid Myopathy

• Temporal onset at 6 weeks of high-dose corticosteroid therapy (decadron) 1
• Proximal > distal weakness pattern 1
• Low-normal CPK (steroid myopathy typically has normal or minimally elevated CPK) 2, 3
• Normal EMG/NCS (steroid myopathy may show normal or minimal myopathic changes) 2
• Gradual improvement with physical therapy and time (consistent with steroid myopathy recovery pattern) 1

Red Flags Requiring Further Investigation

• The progressive vision changes ("gone to shit") with blurriness over 24 months could indicate mitochondrial disease if associated with other systemic features 2
• Constipation, urinary hesitancy, and autonomic symptoms raise concern for more systemic neuromuscular disorder 2
• Balance difficulties with veering into walls suggests possible cerebellar or proprioceptive involvement beyond simple myopathy 2
• The COVID booster temporal relationship is noted but unlikely causal given the intervening steroid exposure 2

Recommended Diagnostic Algorithm

Immediate Next Steps

1. Discontinue or aggressively taper corticosteroids if clinically feasible, as continued steroid exposure will perpetuate steroid myopathy 1

2. Obtain muscle biopsy of affected proximal muscle (deltoid or quadriceps) to definitively distinguish inflammatory myopathy from muscular dystrophy 2, 4

   • Request immunohistochemistry for dysferlin, dystrophin, and inflammatory markers 5, 6
   • Request Gomori trichrome stain to evaluate for ragged red fibers (mitochondrial disease) 2, 3
   • Request assessment for type 2 fiber atrophy (characteristic of steroid myopathy) 2

3. Repeat MRI of proximal muscles (thighs, shoulders) with STIR sequences to assess for muscle edema/inflammation 2, 3

   • Active inflammatory myositis shows T2 hyperintensity and edema 2, 3
   • Chronic muscular dystrophy shows fatty replacement without edema 5, 6

Secondary Investigations if Muscle Biopsy Non-Diagnostic

1. Genetic testing for limb-girdle muscular dystrophies, particularly DYSF gene sequencing for dysferlinopathy 5, 6
2. Metabolic workup including:
   • Acid alpha-glucosidase enzyme activity (Pompe disease) given respiratory symptoms 8
   • Lactate/pyruvate levels and consider muscle biopsy for electron microscopy if mitochondrial disease suspected 2
   • Forearm exercise testing if exercise-induced symptoms predominate 3

Monitoring Parameters

1. Serial CPK and aldolase measurements off steroids - rising levels would suggest inflammatory or dystrophic process rather than steroid myopathy 3, 9
2. Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) given respiratory muscle symptoms 2, 8
3. Cardiac evaluation with troponin, ECG, and echocardiogram to exclude cardiac involvement seen in inflammatory myopathies and some muscular dystrophies 2, 9

Common Pitfalls to Avoid

• Do not assume normal CPK excludes inflammatory myopathy - approximately 10-15% of polymyositis cases have normal CPK, though aldolase is usually elevated 3
• Do not rely solely on autoantibody testing - seronegative inflammatory myopathy occurs in 20-30% of cases 2, 4
• Do not dismiss muscular dystrophy based on adult onset - dysferlinopathy commonly presents in the 20s-40s and can have minimal early biopsy changes 5, 6
• Do not overlook the baclofen as contributing to weakness - baclofen commonly causes weakness (5-15% incidence) and fatigue (2-4%), which could compound underlying myopathy 1
• Do not miss respiratory muscle involvement - this patient's dyspnea and "rib muscle weakness" warrant formal pulmonary function testing as respiratory failure is a major cause of mortality in metabolic myopathies and can occur with minimal limb weakness 8