To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1).
Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait ...instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1.
We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials.
There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment.
Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1.
This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.
The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management ...based on analysis of evidence.
To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy.
Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification, and areas for future research are defined.
Seven class I studies and numerous less rigorous trials all demonstrated that corticosteroid treatment for 6 months with prednisone (0.75 or 1.5 mg/kg/day) increased muscle strength, performance, and pulmonary function and significantly slowed the progression of weakness. Two class I trials examined the effect of lower dosage of prednisone (0.30 and 0.35 mg/kg/day), demonstrated lesser but similar benefits, and showed a lower frequency of side effects (e.g., weight gain). The only significant side effects in all class I trials were weight gain and development of a cushingoid facial appearance. One longer-term trial of daily prednisone (0.3 to 0.7 mg/kg/day), a class III study, showed prolongation of functional ability and slower progression of weakness in patients during 3 years of treatment. One class IV, open trial of alternate-day prednisone (2 mg/kg for 2 months, then two-thirds dose every other day) extended ambulation by approximately 2 years in treated compared with untreated patients. Deflazacort, a corticosteroid similar in structure to prednisone, produced similar improvement in muscle strength and function with a similar side effect profile.
Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with Duchenne dystrophy and should be offered (at a dose of 0.75 mg/kg/day) as treatment. If side effects require a decrease in prednisone, tapering to dosages as low as 0.3 mg/kg/day gives less robust but significant improvement. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of Duchenne dystrophy in countries in which it is available. Benefits and side effects of corticosteroid therapy need to be monitored. The offer of treatment with corticosteroids should include a balanced discussion of potential risks.
To update the 2005 American Academy of Neurology (AAN) guideline on corticosteroid treatment of Duchenne muscular dystrophy (DMD).
We systematically reviewed the literature from January 2004 to July ...2014 using the AAN classification scheme for therapeutic articles and predicated recommendations on the strength of the evidence.
Thirty-four studies met inclusion criteria.
In children with DMD, prednisone should be offered for improving strength (Level B) and pulmonary function (Level B). Prednisone may be offered for improving timed motor function (Level C), reducing the need for scoliosis surgery (Level C), and delaying cardiomyopathy onset by 18 years of age (Level C). Deflazacort may be offered for improving strength and timed motor function and delaying age at loss of ambulation by 1.4-2.5 years (Level C). Deflazacort may be offered for improving pulmonary function, reducing the need for scoliosis surgery, delaying cardiomyopathy onset, and increasing survival at 5-15 years of follow-up (Level C for each). Deflazacort and prednisone may be equivalent in improving motor function (Level C). Prednisone may be associated with greater weight gain in the first years of treatment than deflazacort (Level C). Deflazacort may be associated with a greater risk of cataracts than prednisone (Level C). The preferred dosing regimen of prednisone is 0.75 mg/kg/d (Level B). Over 12 months, prednisone 10 mg/kg/weekend is equally effective (Level B), with no long-term data available. Prednisone 0.75 mg/kg/d is associated with significant risk of weight gain, hirsutism, and cushingoid appearance (Level B).
To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD).
This phase III, double-blind, randomized, placebo-controlled, multicenter ...study evaluated muscle strength among 196 boys aged 5-15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995.
All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis.
After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED.
This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.
Background and purpose
Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined.
...Method
Information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure were collected from 266 DM patients who were enrolled in the US National Institutes of Health National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members.
Results
Seventy‐seven subjects reported having skin tumors that were either benign (n = 31), malignant (n = 32) or both (n = 14). Female gender odds ratio (OR) = 2.27, 95% confidence interval (CI) 1.02–5.05, P = 0.04, older age (OR = 1.10, 95% CI 1.05–1.16, P < 0.001) and DM1 subtype (OR = 3.42, 95% CI 1.27–9.26, P = 0.02) were associated with a malignant skin tumor. The associations between malignant skin tumors and known risk factors light eye color (OR = 1.62, 95% CI 0.78–3.39, P = 0.20), light skin complexion (OR = 1.31, 95% CI 0.63–2.73, P = 0.48) and moderate/extensive face freckles (OR = 1.47, 95% CI 0.50–4.34, P = 0.49) were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR = 4.28, 95% CI 0.91–19.95, P = 0.06, and OR = 2.19, 95% CI 0.67–7.09, P = 0.19, for sunburn with and without blistering, respectively).
Conclusions
Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. It is recommended that DM patients adhere to sun exposure protective behavior.
To quantitate improvement in hand‐grip myotonia and muscle strength (i.e., the “warm‐up” phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric ...contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand‐grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm‐up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm‐up = 0). In DM1, 70% of warm‐up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm‐up was highly correlated with the severity of myotonia, and with day 2 warm‐up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm‐up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm‐up in force output. Muscle Nerve, 2005
Background and purpose
Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic ...heterogeneity, the broad range of non‐muscular manifestations and the usual delays in the diagnosis of DM1.
Method
Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first‐degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer‐related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering.
Results
A total of 467 deaths and 337 cancers were reported amongst 1737 first‐degree DM1 relatives. Mortality risk amongst relatives reported as DM1‐unaffected was comparable to that of the general population standardized mortality ratio (SMR) 0.82, P = 0.06, whilst significantly higher mortality risks were noted in DM1‐affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk.
Conclusion
There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease‐specific clinical care and surveillance.
Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal ...atrophy, insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation is cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.
In 2005, the American Academy of Neurology and the Child Neurology Society published a practice parameter, based primarily on studies that involved 6 to 18 months of treatment, indicating that ...prednisone has a beneficial effect on muscle strength and function in patients with Duchenne muscular dystrophy and recommended that corticosteroids be offered (prednisone 0.75 mg/kg/d and deflazacort 0.9 mg/kg/d) as treatment. Recent reports emphasize that longer term treatment with corticosteroids (greater than 3 years) produces important sustained benefits in neuromuscular function without causing major side effects. This review highlights these reports and indicates that long-term corticosteroid therapy (1) prolongs ambulation by 2 to 5 years, (2) reduces the need for spinal stabilization surgery, (3) improves cardiopulmonary function, (4) delays the need for noninvasive nasal ventilation, and (5) increases survival and the quality of life of patients with Duchenne muscular dystrophy. Educational, vocational, and other social counseling is now a vital part of management for Duchenne muscular dystrophy.
Myotonic muscular dystrophy (MMD) is an autosomal-dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may ...be at increased risk of malignancy, putative risks that have never been quantified.
To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age.
We identified 1658 patients with an MMD discharge diagnosis in the Swedish Hospital Discharge Register or Danish National Patient Registry between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed up from date of first MMD-related inpatient or outpatient contact to first cancer diagnosis, death, emigration, or completion of cancer registration.
Risks of all cancers combined and by anatomic site, stratified by sex and age.
One hundred four patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during postdischarge follow-up. This corresponds to an observed cancer rate of 73.4 per 10,000 person-years in MMD vs an expected rate of 36.9 per 10,000 person-years in the general Swedish and Danish populations combined (standardized incidence ratio SIR, 2.0; 95% CI, 1.6-2.4). Specifically, we observed significant excess risks of cancers of the endometrium (n = 11; observed rate, 16.1/10,000 person-years; SIR, 7.6; 95% CI, 4.0-13.2), brain (n = 7; observed rate, 4.9/10,000 person-years; SIR, 5.3; 95% CI, 2.3-10.4), ovary (n = 7; observed rate, 10.3/10,000 person-years; SIR, 5.2; 95% CI, 2.3-10.2), and colon (n = 10; observed rate, 7.1/10,000 person-years; SIR, 2.9; 95% CI, 1.5-5.1). Cancer risks were similar in women and men after excluding genital organ tumors (SIR, 1.9; 95% CI, 1.4-2.5, vs SIR, 1.8; 95% CI, 1.3-2.5, respectively; P = .81 for heterogeneity; observed rates, 64.5 and 47.7 per 10,000 person-years in women and men, respectively). The same pattern of cancer excess was observed first in the Swedish and then in the Danish cohorts, which were studied sequentially and initially analyzed independently.
Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.
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