What is the differential diagnosis and treatment approach for a patient with suspected neuromuscular disease, including conditions like muscular dystrophy, Amyotrophic Lateral Sclerosis (ALS), myasthenia gravis, or peripheral neuropathy?

Differential Diagnosis of Neuromuscular Disease

When evaluating suspected neuromuscular disease, begin with serum creatine kinase (CK) measurement and clinical localization to distinguish between anterior horn cell disease (ALS), peripheral neuropathy, neuromuscular junction disorders (myasthenia gravis), and myopathy (muscular dystrophy, inflammatory myopathy), as each category requires distinct diagnostic pathways and has dramatically different treatment implications for mortality and quality of life.

Initial Clinical Localization

Key Clinical Features to Identify

• Pattern of weakness distribution: Proximal weakness suggests myopathy or neuromuscular junction disorder; distal weakness suggests neuropathy or motor neuron disease 1
• Presence of sensory symptoms: Sensory involvement indicates peripheral neuropathy or sensory ganglionopathy, effectively excluding pure myopathy or neuromuscular junction disorders 1
• Fatigability: Worsening weakness with repetitive activity strongly suggests myasthenia gravis or Lambert-Eaton myasthenic syndrome 2
• Bulbar symptoms: Dysphagia, dysarthria, and facial weakness indicate impending respiratory compromise in inflammatory myopathies or suggest ALS 3
• Age and tempo of progression: Rapidly progressive proximal weakness over weeks to months in adults suggests immune-mediated necrotizing myopathy (IMNM) or polymyositis; childhood onset with delayed walking (>16-18 months) or Gowers' sign suggests Duchenne muscular dystrophy 4, 3

Algorithmic Diagnostic Approach

Step 1: Initial Laboratory Screening

Obtain these tests in all patients with suspected neuromuscular disease:

• Creatine kinase (CK) and aldolase: Markedly elevated CK (>10× normal) suggests IMNM or muscular dystrophy; moderate elevation (3-10× normal) suggests polymyositis/dermatomyositis; normal CK with elevated aldolase suggests glycogen storage diseases, mitochondrial myopathy, or dermatomyositis 4, 5, 3
• Transaminases (AST/ALT): Can be elevated in muscular dystrophy (muscle origin, not liver); consider DMD before liver biopsy in any male child with unexplained transaminase elevation 4
• Complete blood count, ESR, CRP: For inflammatory conditions 4
• Thyroid function and vitamin D: To exclude endocrine causes of myopathy 4, 3

Step 2: Specialized Testing Based on CK Results

If CK markedly elevated (>10× normal):

• Genetic testing for dystrophinopathies (DMD/Becker): Dystrophin deletion/duplication testing first, then genetic sequencing if negative 4
• Myositis-specific antibodies: Anti-SRP (indicates necrotizing myopathy with poor prognosis), anti-HMGCR (statin-associated or autoimmune necrotizing myopathy) 3
• Check for myoglobinuria to assess rhabdomyolysis risk 3

If CK moderately elevated (3-10× normal):

• Myositis-specific antibodies panel: Anti-Jo-1 and anti-synthetase antibodies (anti-PL-7, anti-PL-12, anti-EJ, anti-OJ), anti-Mi2 (dermatomyositis with cutaneous features) 4, 3
• Examine for cutaneous manifestations of dermatomyositis: heliotrope rash, Gottron's papules, V-sign, shawl sign 5
• Nailfold capillaroscopy: Assess for dilated capillary loops and dropout patterns characteristic of inflammatory myopathy 4

If CK normal but aldolase elevated:

• Consider glycogen storage diseases (Types IIIa, IV, V, VII) 5
• Assess for dermatomyositis features first, including cutaneous manifestations 5
• Consider mitochondrial myopathy (look for ragged red fibers on muscle biopsy) 5

Step 3: Electrodiagnostic Studies

EMG and nerve conduction studies are essential to localize the site of pathology:

• Myopathic pattern: Polyphasic motor unit potentials of short duration and low amplitude; early recruitment 4, 5
• Neuropathic pattern: Large amplitude, long duration motor units; reduced recruitment 4
• Neuromuscular junction disorder: Repetitive nerve stimulation showing decremental response in myasthenia gravis; single-fiber EMG for jitter analysis if high suspicion despite normal RNS 4
• Motor neuron disease: Fibrillation potentials, positive sharp waves, fasciculations with chronic neurogenic changes 1

Critical pitfall: EMG does not reliably detect metabolic myopathies; further workup with muscle biopsy and metabolic testing is required if suspected 4

Step 4: Advanced Imaging

MRI of affected muscle groups:

• Detects muscle inflammation and edema (T2-weighted/STIR sequences) to guide biopsy site selection 4, 5
• Quantifies disease activity in inflammatory myopathies 4
• Must be interpreted by expert radiologist using standardized protocols 4

Step 5: Muscle Biopsy

Indications for muscle biopsy:

• Atypical presentation or absence of rash in suspected inflammatory myopathy 4
• Normal genetic testing in suspected muscular dystrophy 4
• Suspected metabolic or mitochondrial myopathy 4
• To distinguish DMD from milder Becker phenotype when genetic testing is positive 4

Biopsy should include:

• Immunocytochemistry and immunoblotting for dystrophin (for dystrophinopathies) 4
• Gomori trichrome stain to identify ragged red fibers (mitochondrial myopathy) 5
• Standardized scoring tool for inflammatory changes in suspected JDM 4
• Expert histopathological interpretation is mandatory 4

Step 6: Genetic Testing

Whole exome sequencing (WES) is increasingly first-line for suspected hereditary neuromuscular disease:

• Increases diagnostic yield when other technologies fail 6
• Useful for identifying dual diagnoses in complex cases 6
• Precise genetic diagnosis is now the gold standard for DMD and enables access to mutation-specific therapies 4

Common pitfall: Many single nucleotide variants of "unknown significance" can emerge with NGS, complicating genotype-phenotype interpretation; clinical correlation is essential 7

Disease-Specific Diagnostic Pathways

Suspected Myasthenia Gravis

• Clinical features: Fluctuating weakness, ptosis, diplopia, bulbar symptoms worsening with activity 2
• Acetylcholine receptor antibodies: Positive in 85-90% of generalized MG 4
• Repetitive nerve stimulation: Decremental response >10% diagnostic 4
• Single-fiber EMG: Most sensitive test; abnormal if >10% of fiber pairs show increased jitter or impulse blockade 4
• Edrophonium (Tensilon) test: Rapid improvement in weakness within minutes, though less commonly used now 2

Suspected ALS

• Clinical features: Progressive weakness, fasciculations, muscle atrophy, hyperreflexia with upper and lower motor neuron signs 8, 1
• EMG: Widespread denervation with fibrillations, positive sharp waves, fasciculations in multiple limb regions 1
• Riluzole 50 mg twice daily: Only FDA-approved disease-modifying therapy; extends survival by approximately 60-90 days 8
• Respiratory function monitoring: Forced vital capacity, negative inspiratory force to detect impending respiratory failure 8

Suspected Duchenne Muscular Dystrophy

• Screening trigger: Not walking by 16-18 months, Gowers' sign, unexplained transaminase elevation in male child 4
• CK levels: Markedly elevated (often 10-100× normal) 4
• Genetic testing sequence: Dystrophin deletion/duplication testing first (detects ~65% of cases), then full gene sequencing 4
• Glucocorticoids: Pharmacological mainstay; improves strength and delays loss of ambulation 4
• Cardiac monitoring: Echocardiogram at diagnosis or by age 6 years, then maximum 24-month intervals until age 10, annually thereafter 4

Suspected Inflammatory Myopathy (Rapidly Progressive)

This represents a medical emergency requiring urgent evaluation:

• Immediate priorities: Measure respiratory function (negative inspiratory force, vital capacity) as respiratory failure can develop suddenly 3
• Check troponin and ECG: Myocarditis can be life-threatening 3
• If severe weakness (Grade 3-4): Initiate methylprednisolone 1-2 mg/kg IV daily while awaiting confirmatory testing 3
• Consider plasmapheresis: For acute or severe disease, but do not perform immediately after IVIG as it removes the immunoglobulin 3
• Anti-SRP myopathy: Indicates necrotizing myopathy with acute onset, dilated cardiomyopathy, and poor response to standard immunosuppression 3

Critical Pitfalls to Avoid

• Do not delay respiratory assessment in inflammatory myopathies: Respiratory muscle involvement can rapidly progress to life-threatening failure 3
• Do not assume hereditary myopathy based on age alone: Inflammatory myopathies commonly present in the third decade 3
• Do not consider DMD diagnosis before liver biopsy in male children with elevated transaminases: AST/ALT are produced by muscle, not just liver 4
• Do not use atropine routinely in myasthenia gravis: It masks signs of cholinergic crisis from pyridostigmine overdosage, which can be fatal 2
• Do not increase anticholinesterase dosing without distinguishing myasthenic crisis from cholinergic crisis: Both present with severe weakness, but cholinergic crisis requires immediate drug withdrawal, not escalation 2
• Do not rely on EMG alone for metabolic myopathies: It does not detect them reliably; muscle biopsy and metabolic testing are required 4

Cardiac and Respiratory Monitoring

All neuromuscular diseases require systematic cardiac and pulmonary surveillance:

• Cardiac assessment: Echocardiogram and ECG at diagnosis; frequency depends on specific disease (annually for DMD after age 10) 4
• Pulmonary function: Baseline and serial monitoring; chest X-ray and HRCT if concern for interstitial lung disease 4
• Swallow function: Formal assessment including speech/language therapy evaluation, video fluoroscopy in all patients with bulbar symptoms 4