What is the appropriate diagnostic evaluation and first‑line pharmacologic therapy for a patient presenting with myotonia?

Diagnostic Evaluation and First-Line Pharmacologic Therapy for Myotonia

For patients presenting with myotonia, confirm the diagnosis with electromyography demonstrating myotonic discharges and genetic testing for CLCN1 or SCN4A mutations, then initiate mexiletine as first-line therapy for symptomatic relief. 1, 2

Diagnostic Evaluation

Clinical Assessment

• Look for delayed muscle relaxation after voluntary contraction manifesting as muscle stiffness, pain, fatigue, and the characteristic "warm-up phenomenon" where stiffness improves with repeated muscle contractions 1, 3
• Distinguish between non-dystrophic myotonia and myotonic dystrophy by assessing for systemic features: myotonic dystrophy presents with progressive muscle weakness, cardiac conduction abnormalities, cataracts, and endocrine dysfunction, while non-dystrophic myotonia is predominantly limited to muscle stiffness without progressive weakness 1, 3
• Assess for cardiac involvement in suspected myotonic dystrophy with baseline ECG and echocardiography, as conduction abnormalities and arrhythmias are the leading cause of sudden death 4, 5

Electrophysiological Testing

• Perform electromyography (EMG) to demonstrate electrical myotonia, characterized by waxing and waning high-frequency discharges that produce the classic "dive bomber" sound 1, 6
• EMG findings are diagnostic when clinical history and examination are consistent with myotonia 1

Genetic Confirmation

• Order genetic testing for CLCN1 (chloride channel) and SCN4A (sodium channel) mutations to confirm non-dystrophic myotonia 1, 3
• Test for DMPK CTG repeat expansion if myotonic dystrophy is suspected based on systemic features, using triplet repeat-primed PCR followed by Southern blot confirmation for single alleles 4
• Genetic testing establishes the specific diagnosis, guides prognosis, and informs family counseling, though incomplete penetrance can occur even with pathogenic variants 7

Laboratory Studies

• Check serum creatine kinase, which may be mildly elevated in myotonic disorders 7
• Exclude other causes of muscle stiffness including hypothyroidism and inflammatory myopathies 6

First-Line Pharmacologic Therapy

Mexiletine for Non-Dystrophic Myotonia

• Mexiletine is the first-line treatment for symptomatic non-dystrophic myotonia with moderate-certainty evidence demonstrating significant reduction in muscle stiffness (Interactive Voice Response Diary Stiffness score improved by -3.12 points, 95% CI -3.75 to -2.49) 2
• Mexiletine improves quantitative hand grip (MD -0.11 seconds, 95% CI -0.18 to -0.04) and reduces electromyographic myotonia (MD -0.67,95% CI -0.23 to -1.11) 2
• Quality of life improves with mexiletine in non-dystrophic myotonia (SF-36 Physical Component Summary: MD 6.45,95% CI 4.32 to 8.58; Mental Component Summary: MD 6.78,95% CI 1.89 to 11.67) 2

Mexiletine for Myotonic Dystrophy

• Mexiletine likely reduces hand grip relaxation time in myotonic dystrophy (MD 1.37 seconds improvement, 95% CI 0.87 to 1.86) with moderate-certainty evidence 2
• However, quality of life measures show no significant improvement in myotonic dystrophy patients (SF-36 PCS: MD -1.40,95% CI -5.56 to 2.76) 2

Alternative: Lamotrigine

• Lamotrigine is a second-line option for non-dystrophic myotonia when mexiletine is contraindicated or not tolerated, with moderate-certainty evidence showing improvement in relaxation times (hand grip: MD 2.80 log seconds, 95% CI 2.09 to 3.51) 2
• Lamotrigine likely improves quality of life (SF-36: MD 5.00 points, 95% CI 3.12 to 6.88) with moderate-certainty evidence 2

Adverse Effects to Monitor

• Most common adverse events with mexiletine include gastrointestinal symptoms (nausea, dyspepsia), lethargy, and headache, occurring more frequently than placebo (84 vs 55 events in myotonic dystrophy trials; 94 vs 29 events in non-dystrophic myotonia trials) 2
• Lamotrigine adverse events include headache, fatigue, and rash (44 events vs 23 with placebo) 2
• Educate patients about anesthetic complications as myotonic disorders carry increased perioperative risks including malignant hyperthermia-like reactions and prolonged neuromuscular blockade 1

Critical Management Considerations for Myotonic Dystrophy

Cardiac Surveillance Protocol

• Implement annual ECG and echocardiography even when asymptomatic with normal baseline studies, as cardiac conduction disease progresses unpredictably 5
• Permanent pacemaker implantation is mandatory for third-degree or advanced second-degree AV block at any anatomical level 4, 5
• Consider pacemaker for any degree of AV block in myotonic dystrophy type 1 due to risk of rapid, unpredictable progression 5
• When pacemaker indication exists with ventricular arrhythmias or left ventricular dysfunction, implant an ICD instead of a pacemaker alone 4, 5

Medication Safety

• Avoid QT-prolonging medications including quetiapine and other antipsychotics unless absolutely necessary, as these patients already have significant cardiac conduction abnormalities and face 30% risk of sudden cardiac death 5

Common Pitfalls

• Do not rely solely on clinical examination to exclude myotonia; EMG is essential as electrical myotonia may be present without obvious clinical signs 6
• Do not assume all patients respond to mexiletine; research indicates variable response rates and some patients require alternative agents 2
• Do not overlook cardiac screening in myotonic dystrophy; conduction abnormalities are the leading cause of sudden death and require aggressive surveillance 4, 5
• Do not delay genetic testing when EMG confirms myotonia, as specific genetic diagnosis guides prognosis, family counseling, and identifies patients requiring cardiac monitoring 4, 1