Nuran Dilek

Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1

Objective: To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1). Background: 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. Methods: 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. Results: 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. Conclusions: 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. Classification of Evidence: 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.

Quantitative analysis of the warm-up phenomenon in myotonic dystrophy type 1

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

Severity, type, and distribution of myotonic discharges are different in type 1 and type 2 myotonic dystrophy.

To characterize and compare electrical myotonia in myotonic dystrophy type 1 (DM1) and type 2 (DM2), 16 patients with genetically confirmed DM1 and 17 patients with DM2 underwent standardized concentric needle electromyography of deltoid, biceps, extensor digitorum communis, first dorsal interosseous, tensor fascia lata (TFL), vastus lateralis (VL), tibialis anterior, and thoracic paraspinal muscles. Eight needle insertions per muscle were made by electromyographers blinded to DM type who recorded the presence and type of myotonia (e.g., classic waxing–waning or less specific waning discharges). Manual muscle testing was performed by a physical therapist. Overall, myotonia was more elicitable in DM1 than DM2; only in VL and TFL was myotonia more elicitable in DM2 than DM1. The major type of myotonia was waxing–waning in DM1, and waning in DM2. Four DM2 (24%), but no DM1 patients had only waning myotonia. In the arms, myotonia was distally predominant in both DM1 and DM2. In the legs, it was distally predominant in DM1, but both proximal and distal in DM2. The severity of myotonia was positively correlated with muscle weakness and with the presence of waxing and waning discharges in DM1, but with neither in DM2. Thus, myotonia is qualitatively and quantitatively different in DM1 than DM2. Except for proximal leg muscles, myotonia is more evocable in DM1 than DM2. It tends to be waxing–waning in DM1 but waning in DM2, thus making electrodiagnosis of DM2 more challenging. Its severity correlates with muscle weakness and the presence of waxing–waning discharges in DM1 but not DM2. Muscle Nerve, 2007

Computerized hand grip myometry reliably measures myotonia and muscle strength in myotonic dystrophy (DM1)

The aim of this study was to develop a reliable, sensitive, quantitative measure of grip myotonia and strength and to determine whether CTG repeat length is correlated with grip myotonia and with muscle strength in myotonic dystrophy type 1 (DM1). Three maximum voluntary isometric contractions (MVICs) of the finger flexors (i.e., handgrip) were recorded on 2 successive days using a computerized handgrip myometer in 29 genetically confirmed DM1 patients and 17 normals. An automated computer program calculated MVIC peak force (PF) and relaxation times (RTs) along the declining (relaxation) phase of the force recordings at 90%, 75%, 50%, 10%, and 5% of PF. Patients also underwent quantitative strength testing (QST) manual muscle testing (MMT). The patients had longer grip RTs and lower PFs than normals. RT (90% to 5%) was above the normal mean +2.5 SD in 25 (86%) patients. In DM1, prolongation of RT was mainly in the terminal (50% to 5%), rather than the initial (90% to 50%) phase of relaxation. PFs and RTs for each patient were reproducible on consecutive days. RTs were positively correlated with leukocyte CTG repeat length, whereas measures of muscle strength, such as PF, QST, and MMT, were negatively correlated with repeat length. We conclude that computerized handgrip myometry provides a sensitive, reliable measure of myotonia and strength in DM1 and offers a method to assess natural history and response to treatment. Muscle Nerve, 2007

Pregnancy and birth outcomes in women with facioscapulohumeral muscular dystrophy

Obstetric risk in facioscapulohumeral muscular dystrophy (FSHD) is not known. We surveyed 38 women with FSHD reporting 105 gestations and 78 live births. Review of medical records showed that pregnancy outcomes were generally favorable. The rates for low birth weight and total operative deliveries were statistically higher than the national rates in the general population. Worsening of FSHD was reported in 24% of gestations and did not usually resolve after delivery.

Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure.

Introduction: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). Methods: Initially we partnered with 278 myotonic dystrophy type‐1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test–retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. Results: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test–retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. Conclusions: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient‐reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI. Muscle Nerve 49: 906–914, 2014

Quality-of-life in Charcot–Marie–Tooth disease: The patient’s perspective

This study determines the impact of symptoms associated with Charcot-Marie-Tooth disease on quality-of-life. Charcot-Marie-Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot-Marie-Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot-Marie-Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot-Marie-Tooth, including activity limitations, pain, fatigue, hip-thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot-Marie-Tooth types. There are multiple symptoms that impact Charcot-Marie-Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot-Marie-Tooth health.

Myotonic dystrophy health index: Correlations with clinical tests and patient function

Introduction: The Myotonic Dystrophy Health Index (MDHI) is a disease‐specific patient‐reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type‐1 (DM1). Methods: We conducted a cross‐sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient‐reported outcome measures. Results: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. Conclusions: Patient‐reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients. Muscle Nerve, 2015 Muscle Nerve 53: 183–190, 2016

Visualization of the diaphragm muscle with ultrasound improves diagnostic accuracy of phrenic nerve conduction studies

Introduction: Evaluation of phrenic neuropathy (PN) with phrenic nerve conduction studies (PNCS) is associated with false negatives. Visualization of diaphragmatic muscle twitch with diaphragm ultrasound (DUS) when performing PNCS may help to solve this problem. Methods: We performed bilateral, simultaneous DUS–PNCS in 10 healthy adults and 12 patients with PN. The amplitude of the diaphragm compound muscle action potential (CMAP) (on PNCS) and twitch (on DUS) was calculated. Results: Control subjects had <38% side‐to‐side asymmetry in twitch amplitude (on DUS) and 53% asymmetry in phrenic CMAP (on PCNS). In the 12 patients with PN, 12 phrenic neuropathies were detected. Three of these patients had either significant side‐to‐side asymmetry or absolute reduction in diaphragm movement that was not detected with PNCS. There were no cases in which the PNCS showed an abnormality but the DUS did not. Conclusions: The addition of DUS to PNCS enhances diagnostic accuracy in PN. Muscle Nerve 49: 669–675, 2014

Prospective study of muscle cramps in Charcot-Marie-Tooth disease

Introduction: This study aims to assess the frequency, location, severity, duration, and fluctuation over time of muscle cramps in Charcot‐Marie‐Tooth disease (CMT). Methods: Inherited Neuropathies Consortium Contact Registry participants recorded the occurrence and characteristics of muscle cramps using an 11‐question survey administered 3 times over 8 weeks. Results: A total of 110 adult patients with CMT completed the survey. Weekly cramp frequency was 9.3 (SD 12.3), and 23% had daily muscle cramps. Twenty‐two percent reported a significant impact on quality of life. Over 8 weeks, the daily frequency and severity of muscle cramps did not change significantly. Conclusions: Patients with CMT have muscle cramps that vary little over an 8‐week period, and they may interfere with quality of life. These data may be useful in the planning of clinical trials of agents to treat adults with CMT‐associated muscle cramps. Muscle Nerve 51: 485–488, 2015