The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study.

Mexiletine is the only drug with proven effect for treatment of non-dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non-dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non-dystrophic myotonias. In this, randomized double-blind, placebo-controlled, two-period cross-over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8-week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013-003309-24). We included 26 patients (10 females, 16 males, age: 19-74 years) from 13 November 2013 to 6 July 2015. Twenty-two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5-1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2-1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient-related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment-naive patients with non-dystrophic myotonias.

Aerobic training in myotonia congenita: Effect on myotonia and fitness.

INTRODUCTION: Exercise has not been investigated in myotonia congenita (MC). We investigated whether regular aerobic training can reduce myotonia and improve fitness. METHODS: Untrained patients with MC (age: 24-62 years; n = 6) completed 28 ± 3 sessions of 30-minute cycle ergometer training at 75% of maximal capacity for 11 ± 1 weeks. Fitness was evaluated by maximal oxygen uptake. The level of myotonia was assessed by the Myotonia Behavior Scale, 14 step stair test, timed up and go test, and hand and eye closure-open tests. RESULTS: Training increased fitness by 9% (95% confidence interval [CI], 1-17%; P = 0.02) and maximal workload by 10% (95% CI, 3-18%; P = 0.03). None of the myotonia tests changed in a clinically meaningful way. CONCLUSIONS: Regular endurance training improves fitness and maximal workload performance in patients with MC. The lack of creatine kinase elevations indicates that muscle damage did not occur. Improved fitness, however, did not change myotonic symptoms in this small cohort. Muscle Nerve 56: 696-699, 2017.

Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study.

In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of postexercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients [7 women and 10 men, aged 33 ± 11 yr (18-52), body mass index: 22 ± 3 kg/m(2) (16-26)] and 8 healthy matched controls [3 women and 5 men, age 33 ± 13 years (19-54), body mass index: 23 ± 3 kg/m(2) (19-27)], muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions, with and without oral postexercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 ± 1 µmol phenylalanine/min) vs. rest (8 ± 1 µmol phenylalanine/min, P = 0.02), enhancing net muscle protein loss. In contrast, postexercise protein-carbohydrate supplementation reduced protein breakdown, abolished net muscle protein loss, and increased the muscle FSR in patients (0.04 to 0.06%/h; P = 0.03). In conclusion, postexercise protein-carbohydrate supplementation reduces skeletal mixed-muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that postexercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of postexercise protein-carbohydrate supplementation are warranted in these conditions.

Muscle phenotype in patients with myotonic dystrophy type 1.

INTRODUCTION: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. METHODS: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na(+)-K(+) pump content. RESULTS: Muscle strength correlated with a decline in Na(+)-K(+) pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na(+)-K(+) pump content. Histopathologically, we found few centrally placed nuclei (range 0.2-6.9%). CONCLUSIONS: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1.

High-intensity training in patients with spinal and bulbar muscular atrophy.

OBJECTIVE: Long duration, moderate-intensity exercise is not well tolerated in patients with spinal and bulbar muscular atrophy (SBMA). This study investigated whether patients with SBMA can benefit from high-intensity training (HIT). METHODS: Ten patients with SBMA were randomized to 8 weeks of supervised HIT [n = 5; age = 50 (25-63) years] followed by 8 weeks of self-training or 8 weeks of no training followed by 8 weeks of non-supervised HIT [n = 5; age = 50 (26-54) years]. Training consisted of 2 × 5-min exercise periods with 1-min cyclic blocks of intermittent maximal intensity exercise on an ergometer bike. Maximal oxygen capacity (VO2max) and workload (Wmax) were measured before and after training by incremental exercise tests. Plasma creatine kinase levels, self-rated muscle pain, muscle fatigue, and activity level were monitored throughout the training period. RESULTS: Eight patients completed training. One patient dropped out after 5 weeks of training for private reasons. Another patient was excluded after 4 weeks due to lack of compliance. Eight weeks of training increased both VO2max (1.9 ± 2.3 ml min-1 kg-1; p = 0.04) and Wmax (15.6 ± 17.9 W; p = 0.03) in the 8 patients who completed training. There were no changes in plasma creatine kinase levels, self-reported muscle pain or muscle fatigue activity level after training. CONCLUSION: This pilot study suggests that high-intensity training is safe and improves fitness in patients with SBMA. Unlike low- and moderate-intensity training, HIT is efficacious and favored over other training forms by the patients.

Relationship between muscle inflammation and fat replacement assessed by MRI in facioscapulohumeral muscular dystrophy.

OBJECTIVE: Unlike most muscular dystrophies that progress symmetrically at a constant rate, facioscapulohumeral muscular dystrophy (FSHD) is characterized by stepwise, asymmetric progression of muscle wasting, and weakness. Muscle tissue is progressively replaced by fat; however, its relation to preceding inflammation is unclear. In this longitudinal study of FSHD, we assessed muscle inflammation and fat replacement and their relation quantitatively. We also investigated whether fat replacement in muscle varies along its length. METHODS: Forty-five patients with FSHD were evaluated twice, 14 months apart. Using MRI sequences with short TI inversion recovery (STIR), we quantified the degree of STIR hyperintensity in muscles (≥ 2 SD above control intensity). STIR hyperintensities (STIR+) suggest edema or inflammation. We used Dixon MRI to quantify fat content. RESULTS: Of 370 thigh muscles, 83 were STIR+ at baseline and 103 at follow-up. The highest frequency of STIR+ was seen in muscles with inter-mediate fat content (40-60% fat). The progression of fat replacement was higher in STIR+ muscles (5.0 ± 4.0%) vs. STIR- muscles [2.3 ± 3.3% (P < 0.0001)]. In addition, muscles with severe STIR+ at baseline had a higher fat replacement progression than muscles with milder STIR+ (R = 0.39, P = 0.001). The fat content was higher in the distal part vs. proximal part of most muscles (P < 0.05). However, the progression of the fat replacement was uniform along the length of all the muscles. CONCLUSION: Muscles with STIR+, indicating inflammation, have a faster progression of fat replacement than STIR- muscles, and the fat replacement progression correlated with the severity of STIR+.

High-intensity interval training in facioscapulohumeral muscular dystrophy type 1: a randomized clinical trial.

Increasing evidence suggests that high-intensity training (HIT) is a time-efficient exercise strategy to improve fitness. HIT has never been explored in neuromuscular diseases, likely because it may seem counterintuitive. A single session of high-intensity exercise has been studied without signs of muscle damage in facioscapulohumeral muscular dystrophy type 1 (FSHD1). We aimed to determine whether HIT is safe and effective in FSHD1 in a randomized, controlled parallel study. Untrained adults with genetically verified FSHD1 (n = 13) able to perform cycle-ergometer exercise were randomized to 8 weeks of supervised HIT (n = 6) (3 × 10-min cycle-ergometer-HIT/week) or 8 weeks of usual care (n = 7). Following this, all participants performed 8 weeks of unsupervised HIT (3 × 10-min cycle-ergometer-HIT/week). Primary outcome was fitness, maximal oxygen uptake/min/kg body weight. Furthermore, workload, 6-min walk distance, 5-time sit-to-stand time, muscle strength, and daily activity levels were measured. Pain, fatigue, and plasma-CK were monitored. Twelve patients completed the randomized part of the study. Plasma-CK levels and pain scores were unaffected by HIT. Supervised HIT improved fitness (3.3 ml O2/min/kg, CI 1.2-5.5, P < 0.01, n = 6, NNT = 1.4). Unsupervised HIT also improved fitness (2.0 ml O2/min/kg, CI 0.1-3.9, P = 0.04, n = 4). There was no training effect on other outcomes. Patients preferred HIT over strength and moderate-intensity aerobic training. It may seem counterintuitive to perform HIT in muscular dystrophies, but this RCT shows that regular HIT is safe, efficacious, and well liked by moderately affected patients with FSHD1, which suggests that HIT is a feasible method for rehabilitating patients with FSHD1.

Mitochondrial DNA mutation load in a family with the m.8344A>G point mutation and lipomas: a case study.

Studies have shown that difference in mtDNA mutation load among tissues is a result of postnatal modification. We present five family members with the m.8344A>G with variable phenotypes but uniform intrapersonal distribution of mutation load, indicating that there is no postnatal modification of mtDNA mutation load in this genotype.

MRI as outcome measure in facioscapulohumeral muscular dystrophy: 1-year follow-up of 45 patients.

There is no effective treatment available for facioscapulohumeral muscular dystrophy type 1 (FSHD1), but emerging therapies are under way that call for a better understanding of natural history in this condition. In this prospective, longitudinal study, we used quantitative MRI to assess yearly disease progression in patients with FSHD1. Ambulatory patients with confirmed diagnosis of FSHD1 (25/20 men/women, age 20-75 years, FSHD score: 0-12) were tested with 359-560-day interval between tests. Using the MRI Dixon technique, muscle fat replacement was evaluated in paraspinal, thigh, and calf muscles. Changes were compared with those in FSHD score, muscle strength (hand-held dynamometry), 6-minute-walk-distance, 14-step-stair-test, and 5-time-sit-to-stand-test. Composite absolute fat fraction of all assessed muscles increased by 0.036 (CI 0.026-0.046, P < 0.001), with increases in all measured muscle groups. The clinical severity FSHD score worsened (10%, P < 0.05), muscle strength decreased over the hip (8%), neck (8%), and back (17%) (P < 0.05), but other strength measures, 6-minute-walk-distance, 5-times-sit-to-stand-test, and 14-step-stair-test were unchanged. Changes in muscle strength, FSHD score, and fat fraction did not correlate. This first study to systemically monitor quantitative fat replacement longitudinally in FSHD1 shows that MRI provides an objective measure of disease progression, often before changes can be appreciated in strength and functional tests. The study indicates that quantitative MRI can be a helpful end-point in follow-up and therapeutic trials of patients with FSHD1.

Disturbed right ventricular diastolic function in patients with systemic sclerosis: a Doppler tissue imaging study.

BACKGROUND: Cardiopulmonary involvement in patients with systemic sclerosis (SSc) carries a poor prognosis, mainly due to pulmonary hypertension and right-heart failure. To date, right ventricular (RV) involvement has not been studied in detail. We therefore assessed RV function in patients with SSc and related the findings to the clinical features of the disease. METHOD: Twenty-six consecutive patients (21 women) with SSc (mean age, 56 +/- 15 years [+/- SD]) and 25 healthy, age-matched control subjects (21 women) were studied. Doppler echocardiography including Doppler tissue imaging was used to evaluate cardiac function. Pulmonary function was also studied. RESULTS: Compared with control subjects, RV free wall thickness (5.8 +/- 1.7 mm vs 3.7 +/- 1.1 mm, p < 0.001) and right atrial (RA) systolic area (15.9 +/- 3.7 cm2 vs 13.0 +/- 2.3 cm2, p < 0.01) were increased in patients with SSc, while the global early diastolic/atrial component velocity ratio was reduced (1.2 +/- 0.4 vs 1.7 +/- 0.6, p < 0.01). The global isovolumic relaxation time (IVRT) [64 +/- 23 ms vs 39 +/- 13 ms, p < 0.001] and regional IVRT (83 +/- 40 ms vs 46 +/- 24 ms, p < 0.001) were prolonged in patients vs control subjects, whereas the RV global filling time was reduced (454 +/- 122 ms vs 548 +/- 104 ms, p < 0.01). RV systolic function and pulmonary pressures at rest were similar in the two groups, but the pulmonary artery acceleration time was reduced (119 +/- 34 ms vs 141 +/- 29 ms, p < 0.05) in patients compared to control subjects. Left ventricular function did not differ between the two groups. CONCLUSION: Patients with SSc exhibit altered RV diastolic function together with an increase in RV wall thickness and RA area. These findings appear to be early markers of RV disturbance, probably in response to intermittent pulmonary arterial hypertension.

Aerobic training and postexercise protein in facioscapulohumeral muscular dystrophy: RCT study.

OBJECTIVE: To investigate the effect of regular aerobic training and postexercise protein-carbohydrate supplementation in patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: In this randomized, double-blind, placebo-controlled parallel study, we randomized untrained men (n = 21) and women (n = 20) with FSHD (age 19-65 years) to 2 training groups-training with protein supplement (n = 18) and training with placebo supplement (n = 13)-and a nonintervention control group (n = 10). We assessed fitness, walking speed, muscle strength, questionnaires, and daily activity levels before and after 12 weeks of interventions. Training involved 36 sessions of 30-minute cycle-ergometer training. After each session, patients drank either a protein-carbohydrate or placebo beverage. RESULTS: In the trained participants, fitness, workload, and walking speed improved (10% [confidence interval (CI) 4%-15%], 18% [CI 10%-26%], 7% [CI 4%-11%], respectively, p < 0.001, number needed to treat = 2.1). Self-assessed physical capacity and health (Short Form-36) also improved. Muscle strength and daily activity levels did not change with training. Protein-carbohydrate supplementation did not result in further improvements in any tests compared to training alone. CONCLUSIONS: This randomized, controlled study showed that regular endurance training improves fitness, walking speed, and self-assessed health in patients with FSHD without causing muscle damage. Postexercise protein-carbohydrate supplementation does not add any further improvement to training effects alone. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that regular aerobic training with or without postexercise protein-carbohydrate supplementation improves fitness and workload in patients with FSHD.

Bezafibrate in skeletal muscle fatty acid oxidation disorders: a randomized clinical trial.

OBJECTIVE: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. METHODS: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise. RESULTS: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise. CONCLUSION: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates in disorders of FAO do not translate into clinically meaningful effects in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.

Blocked muscle fat oxidation during exercise in neutral lipid storage disease.

OBJECTIVE: To determine whether impaired exercise capacity in neutral lipid storage disease with myopathy is solely caused by muscle weakness or whether a defect in energy metabolism (blocked fat oxidation) may also play a role. DESIGN: We studied a 37-year-old woman with neutral lipid storage disease with myopathy, who cycled while lipid oxidation was assessed using U-(13)C palmitate tracer dilution technique. The effect of a glucose infusion during exercise was also studied. SETTING: Neuromuscular research unit. RESULTS: The exercise-induced increase in fat oxidation was virtually abolished in the patient. Treatment with intravenous glucose infusion improved maximal oxygen uptake from 23 to 27 mL × kg(-1) × min(-1), and maximal workload from 75 to 100 W. CONCLUSIONS: These results demonstrate that in addition to fixed weakness, neutral lipid storage disease with myopathy is also characterized by a profound block in fat oxidation, which limits exercise tolerance.

Selective iron supplementation based on serum ferritin values early in pregnancy: are the Norwegian recommendations satisfactory?

BACKGROUND: The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement. In the latter group the efficacies of two iron preparations of different strengths and types were compared. METHODS: Ninety-three women had been given advice only (Group I) and were enrolled in the project at 6 weeks postpartum. Two hundred and thirty-three women enrolled at their second antenatal visit and were given advice plus iron supplement; those with s-ferritin <60 microg/L were randomized to a daily dose of 1) 60 mg Fe2+ (Ferromax) or 2) 3.6 mg heme iron plus 24 mg Fe2+ (Hemofer), and started taking the supplement at once if s-ferritin <20 microg/L or at 20 weeks if 20-60 microg/L. In addition to hemoglobin as routine, s-ferritin was measured in all the women at 6 weeks postpartum. RESULTS: At 6 weeks postpartum median s-ferritin was 28 and 34 microg/L in Groups I and II, respectively, and a significantly higher mean s-ferritin (46.5 vs. 37.3 microg/L; p < 0.05) was found in women taking the highest dose. There were no correlations between s-ferritin in early pregnancy and at 6 weeks postpartum. Peripartum blood loss was the main indicator for iron status at 6 weeks postpartum. CONCLUSION: Iron supplementation based on iron status early in pregnancy, with 60 mg ferrous iron or 27 mg iron containing heme, resulted in adequate iron stores at 6 weeks postpartum among 75% or 70% of the women, respectively. However, 6 weeks were not sufficient to rebuild iron stores in women with large peripartum blood loss.