AAEE minimonograph #27: Differential diagnosis of myotonic syndromes

Streib, Erich W.

doi:10.1002/mus.880100704

Cited by 127 publications

(87 citation statements)

References 70 publications

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“…16 The time to recovery of baseline function may worsen with age in affected patients. 3 Muscle histology is not needed for diagnosis. Laboratory testing typically shows mildly elevated creatine phosphokinase (CPK) levels; potassium levels can be normal, low, or elevated.…”

Section: Thomsen's Myotonia Congenitamentioning

confidence: 99%

“…Tendon reflexes, cerebellar function, and sensation are normal. 3 Paramyotonic stiffness and subsequent paralysis may be provoked by immersion of the hand in cold water for 15 min, followed by exercise. 8 A wash cloth soaked in cold water and placed over a patient's eyes may also produce symptoms.…”

Section: Paramyotonia Congenitamentioning

confidence: 99%

“…Myotonic discharges by definition last 500 ms or longer and should be identified in at least three areas of an individual muscle outside of an endplate region. 3 The sound produced by myotonic discharges during electrophysiological study is one of the most distinct in electromyography and has been likened to the sound of such things as a World War II dive bomber, a motorcycle motor, and a chain saw. 4 A myotonic potential appears on an EMG study as a positive wave or brief spike potential, typically occurring in trains of discharges.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13] Long or short exercise testing as a part of the electrodiagnostic evaluation of a patient with myotonia may also prove useful in differentiating those with nondystrophic myotonia from other myotonic disorders. 2 The long exercise test is implemented by having a patient maximally contract an intrinsic hand muscle for 4 to 5 min, with periods of relaxation every 15 to 20 s. 3 This exercise is followed by a series of recordings at set time intervals, to analyze the amplitude and duration of the evoked compound muscle action potential (CMAP). Similarly, short exercise testing requires 5 to 10 s of maximal isometric contraction of an intrinsic hand muscle followed by a series of recordings of evoked CMAPs at set time intervals.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, short exercise testing requires 5 to 10 s of maximal isometric contraction of an intrinsic hand muscle followed by a series of recordings of evoked CMAPs at set time intervals. 3 Both cold immersion testing and exercise testing have limitations in establishing the diagnosis of a nondystrophic myotonia. Limited studies are available to establish the reliability and reproducibility of either type of testing in the same individuals over time, and there are no studies in kindreds with known genetic mutations that have established the usefulness of cold immersion and exercise testing in family members with mild or no symptoms.…”

Section: Introductionmentioning

confidence: 99%

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The Nondystrophic Myotonias

Heatwole

Moxley

2007

Neurotherapeutics

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Summary:The nondystrophic myotonias are a heterogeneous set of rare diseases that demonstrate clinical myotonia, electrical myotonia, or both. These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy. The present article reviews each of the nondystrophic myotonias by exploring the unique clinical features, electrodiagnostic findings, diagnostic criteria, gene mutations, and response to pharmacologic therapy. These diseases are divided into those with chloride channel dysfunction (the myotonia congenita disorders) and those with sodium channel dysfunction (paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis with myotonia). The variants that occur in each of these conditions are commented on. The differentiating features of the nondystrophic myotonias are summarized, and their predominant clinical, electrodiagnostic, and genetic characteristics are tabulated. For a comprehensive review of pertinent research and studies with application to diagnosis and treatment of individuals with nondystrophic myotonic disorders, the present article is best read in the context of other articles in this issue, especially those on ion channel physiology (Cannon) and pharmacology (Conte-Camerino), and on hyperkalemic periodic paralysis (Lehmann-Horn).

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Section: Thomsen's Myotonia Congenitamentioning

confidence: 99%

Section: Paramyotonia Congenitamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Nondystrophic Myotonias

Heatwole

Moxley

2007

Neurotherapeutics

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Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia

Statland

Bundy

Rayan

et al. 2012

JAMA

166

173

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Context Non-dystrophic myotonias (NDM) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally-limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in case studies and one single blind trial. As is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. Objective To determine the effects of mexiletine for symptoms and signs of myotonia in NDM. Design, Setting, and Participation Fifty-nine patients with NDM participated in a randomized, double-blind, placebo-controlled two-period crossover study conducted between December 23, 2008 and March 30, 2011 at 7 neuromuscular referral centers in 4 countries, as part of the NIH-funded Rare Disease Clinical Research Network. Intervention Oral 200 mg mexiletine or placebo capsules three times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1 week wash-out between periods. Main Outcome Measures Patient-reported stiffness recorded on an interactive voice response diary (IVR) was the primary endpoint (1 ‘minimal’ to 9 ‘worst ever experienced’). Secondary endpoints included IVR-reported changes in pain, weakness, and tiredness, clinical myotonia assessment, quantitative grip myotonia, Individualized Neuromuscular Quality of Life (INQoL, percent of maximal detrimental impact), SF-36, electrophysiological exercise testing, and needle EMG. Results Mexiletine significantly improved patient-reported stiffness on the IVR. Because of a statistically significant interaction between treatment and period for this outcome, primary endpoint is presented by period (period 1 means were mexiletine 2.53 versus placebo 4.21, difference −1.68, 95% Confidence Interval [CI] −2.66, −0.706, P<0.001; period 2 means were mexiletine 1.60 versus placebo 5.27, difference −3.68, 95% CI −3.85, −0.139, P=0.04). Mexiletine improved the INQoL QOL score (mexiletine 14.0, placebo 16.7, difference −2.69, 95% CI −4.07, −1.30, P<0.001) and decreased handgrip myotonia on clinical exam (seconds: mexiletine 0.164, placebo 0.494, difference −0.330, 95% CI −0.633, −0.142, P<0.001). The most common adverse effect was gastrointestinal (9 mexiletine, 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 placebo, 1 mexiletine). One serious adverse event was determined to be not study-related. Conclusion In this preliminary study of patients with NDM, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. Trial Registration Clinicaltrials.gov identifier: NCT 00832000

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Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials

Stunnenberg

Raaphorst

Groenewoud

et al. 2018

JAMA

131

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IMPORTANCE In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. OBJECTIVE To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. DESIGN, SETTING, AND PARTICIPANTS A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. INTERVENTIONS Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. MAIN OUTCOMES AND MEASURES Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. RESULTS Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). CONCLUSIONS AND RELEVANCE In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.

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AAEE minimonograph #27: Differential diagnosis of myotonic syndromes

Cited by 127 publications

References 70 publications

The Nondystrophic Myotonias

The Nondystrophic Myotonias

Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials

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