Hilbert JE, Ashizawa T, Day JW, Luebbe EA, Martens WB, McDermott MP, Tawil R, Thornton CA, Moxley RT 3rd.
Diagnostic odyssey of patients with myotonic dystrophy.
J Neurol. 2013 Oct;260(10):2497-504. doi: 10.1007/s00415-013-6993-0. Epub 2013 Jun 27.
Abstract/Text
The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.
D'Ambrosio ES, Gonzalez-Perez P.
Cancer and Myotonic Dystrophy.
J Clin Med. 2023 Mar 1;12(5). doi: 10.3390/jcm12051939. Epub 2023 Mar 1.
Abstract/Text
Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. Dominantly inherited CTG and CCTG repeat expansions in DMPK and CNBP genes cause DM type 1 (DM1) and 2 (DM2), respectively. These genetic defects lead to the abnormal splicing of different mRNA transcripts, which are thought to be responsible for the multiorgan involvement of these diseases. In ours and others' experience, cancer frequency in patients with DM appears to be higher than in the general population or non-DM muscular dystrophy cohorts. There are no specific guidelines regarding malignancy screening in these patients, and the general consensus is that they should undergo the same cancer screening as the general population. Here, we review the main studies that investigated cancer risk (and cancer type) in DM cohorts and those that researched potential molecular mechanisms accounting for DM carcinogenesis. We propose some evaluations to be considered as malignancy screening in patients with DM, and we discuss DM susceptibility to general anesthesia and sedatives, which are often needed for the management of cancer. This review underscores the importance of monitoring the adherence of patients with DM to malignancy screenings and the need to design studies that determine whether they would benefit from a more intensified cancer screening than the general population.
日本神経学会：筋強直性ジストロフィー診療ガイドライン 2020.
Gadalla SM, Lund M, Pfeiffer RM, Gørtz S, Mueller CM, Moxley RT 3rd, Kristinsson SY, Björkholm M, Shebl FM, Hilbert JE, Landgren O, Wohlfahrt J, Melbye M, Greene MH.
Cancer risk among patients with myotonic muscular dystrophy.
JAMA. 2011 Dec 14;306(22):2480-6. doi: 10.1001/jama.2011.1796.
Abstract/Text
CONTEXT: 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.
OBJECTIVE: To quantitatively evaluate cancer risk in patients with MMD, overall and by sex and age.
DESIGN, SETTING, AND PARTICIPANTS: 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.
MAIN OUTCOME MEASURES: Risks of all cancers combined and by anatomic site, stratified by sex and age.
RESULTS: 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.
CONCLUSION: Patients with MMD identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites.
Wahbi K, Bassez G, Duchateau J, Salort-Campana E, Vicart S, Desaphy JF, Labombarda F, Sellal JM, Deharo JC.
Expert opinion on mexiletine treatment in adult patients with myotonic dystrophy.
Arch Cardiovasc Dis. 2024 Jun-Jul;117(6-7):450-456. doi: 10.1016/j.acvd.2024.03.001. Epub 2024 Apr 15.
Abstract/Text
In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.
Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.
Logigian EL, Martens WB, Moxley RT 4th, McDermott MP, Dilek N, Wiegner AW, Pearson AT, Barbieri CA, Annis CL, Thornton CA, Moxley RT 3rd.
Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1.
Neurology. 2010 May 4;74(18):1441-8. doi: 10.1212/WNL.0b013e3181dc1a3a.
Abstract/Text
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.
Wood L, Cordts I, Atalaia A, Marini-Bettolo C, Maddison P, Phillips M, Roberts M, Rogers M, Hammans S, Straub V, Petty R, Orrell R, Monckton DG, Nikolenko N, Jimenez-Moreno AC, Thompson R, Hilton-Jones D, Turner C, Lochmüller H.
The UK Myotonic Dystrophy Patient Registry: facilitating and accelerating clinical research.
J Neurol. 2017 May;264(5):979-988. doi: 10.1007/s00415-017-8483-2. Epub 2017 Apr 10.
Abstract/Text
Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional "snapshot" analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry's primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment.
Matsumura T. Oral and dental problems at bedside of patients with progressive muscular dystrophy. IRYO - Japanese J Natl Med Serv. 一般社団法人 国立医療学会; 2007 Dec 20;61(12):781–785.
Ono S, Kurisaki H, Sakuma A, Nagao K.
Myotonic dystrophy with alveolar hypoventilation and hypersomnia: a clinicopathological study.
J Neurol Sci. 1995 Feb;128(2):225-31. doi: 10.1016/0022-510x(94)00244-i.
Abstract/Text
We present a case of myotonic dystrophy accompanied by alveolar hypoventilation and hypersomnia. Case history, pulmonary function tests, polygraphic recording, and multiple sleep latency test, concomitant with a restrictive ventilatory abnormality, suggested a central origin of alveolar hypoventilation and hypersomnia in our case. The most significant neuropathological findings were in the tegmentum of the brain stem. Severe neuronal loss and gliosis were observed in the midbrain and pontine raphe, particularly in dorsal raphe nucleus and superior central nucleus. Pontine and medullary reticular formation also showed a marked cell loss and fibrillary gliosis. The alveolar hypoventilation and the hypersomnia in our case may be attributed to these morphological abnormalities, and would appear to be central in nature.
Rubinsztein JS, Rubinsztein DC, Goodburn S, Holland AJ.
Apathy and hypersomnia are common features of myotonic dystrophy.
J Neurol Neurosurg Psychiatry. 1998 Apr;64(4):510-5. doi: 10.1136/jnnp.64.4.510.
Abstract/Text
OBJECTIVES: Myotonic dystrophy is a disease characterised by myotonia and muscle weakness. Psychiatric disorder and sleep problems have also been considered important features of the illness. This study investigated the extent to which apathy, major depression, and hypersomnolence were present. The objective was to clarify if the apathy reported anecdotally was a feature of CNS involvement or if this was attributable to major depression, hypersomnolence, or a consequence of chronic muscle weakness.
METHODS: These features were studied in 36 adults with non-congenital myotonic dystrophy and 13 patients with Charcot-Marie-Tooth disease. By using patients with Charcot-Marie-Tooth disease as a comparison group the aim was to control for the disabling effects of having an inherited chronic neurological disease causing muscle weakness. Standardised assessment instruments were used wherever possible to facilitate comparison with other groups reported in the medical literature.
RESULTS: There was no excess of major depression on cross sectional analysis in these patients with mild myotonic dystrophy. However, apathy was a prominent feature of myotonic dystrophy in comparison with a similarly disabled group of patients with Charcot-Marie-Tooth disease (clinician rated score; Mann Whitney U test, p=0.0005). Rates of hypersomnolence were greater in the myotonic dystrophy group, occurring in 39% of myotonic dystrophy patients, but there was no correlation with apathy.
CONCLUSION: These data suggest that apathy and hypersomnia are independent and common features of myotonic dystrophy. Apathy cannot be accounted for by clinical depression or peripheral muscle weakness and is therefore likely to reflect CNS involvement. These features of the disease impair quality of life and may be treatable.
Ono S, Kanda F, Takahashi K, Fukuoka Y, Jinnai K, Kurisaki H, Mitake S, Inagaki T, Nagao K.
Neuronal cell loss in the dorsal raphe nucleus and the superior central nucleus in myotonic dystrophy: a clinicopathological correlation.
Acta Neuropathol. 1995;89(2):122-5. doi: 10.1007/BF00296355.
Abstract/Text
A quantitative study of neurons in the dorsal raphe nucleus (DRN) and the superior central nucleus (SCN) was performed in seven patients with myotonic dystrophy (MyD), five of whom showed hypersomnia, and in eight age-matched controls. The densities of neurons in the DRN and the SCN were significantly lower in MyD patients with hypersomnia than in MyD patients without hypersomnia and control subjects. There was an appreciable positive correlation in the density of neurons between the DRN and the SCN in all MyD patients. These data suggest that the neuronal loss of the DRN and the SCN is associated with the presence of hypersomnia in MyD.
Antonini G, Morino S, Fiorelli M, Fiorini M, Giubilei F.
Selegiline in the treatment of hypersomnolence in myotonic dystrophy: a pilot study.
J Neurol Sci. 1997 Apr 15;147(2):167-9. doi: 10.1016/s0022-510x(96)05328-2.
Abstract/Text
Patients with myotonic dystrophy frequently complain of hypersomnolence, a symptom which seriously restricts their social life. The pathogenesis of this symptom is a matter of debate: it has been attributed to both alveolar hypoventilation and pathological changes in the brainstem. As selegiline has been shown to reduce the number of sleep attacks in nacrolepsy, we tested whether hypersomnolence in myotonic dystrophy would respond to the same treatment. Ten patients with myotonic dystrophy received selegiline/placebo (20 mg daily) in a double-blind crossover trial. We monitored daytime sleepiness by means of a multiple sleep latency test. Treatment appeared to be well tolerated but did not alter hypersomnolence in myotonic dystrophy. Further studies to assess the effect of higher doses of selegiline are warranted.
Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D.
Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial.
Clin Ther. 2009 Aug;31(8):1765-73. doi: 10.1016/j.clinthera.2009.08.007.
Abstract/Text
BACKGROUND: Myotonic muscular dystrophy type 1 (MMD1) is the most common form of adult MD, with a mean prevalence of 1 in 8000. Excessive daytime sleepiness (ie, hypersomnia) is a common complication of MMD1.
OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of modafinil for the treatment of hypersomnia in adults with MMD1.
METHODS: This multicenter, prospective, randomized, double-blind, placebo-controlled study consisted of a prerandomization period (90 to 2 days before randomization) and a 4-week randomization period in which patients were assigned to receive either active treatment (modafinil 300 mg/d) or placebo. The study was conducted at 3 clinics in France between February 2000 and June 2002. Adult patients aged > or =18 years, with genetically proven MMD1, an Epworth Sleepiness Scale (ESS) score >10, and a mean latency to sleep onset < or =8 minutes measured by the Multiple Sleep Latency Test (MSLT) were eligible. The primary efficacy end point was the Maintenance of Wakefulness Test (MWT) score at 4 weeks. Secondary end points included the mean MSLT score and scores from the ESS, physician's assessment of the therapeutic effect and the patient's global self-assessment via visual analog scale, the 17-item Hamilton Depression Rating Scale, and the Short Form Health Survey (SF-36) quality-of-life assessment.
RESULTS: A total of 28 patients (15 men, 13 women; mean [SD] age, 40 [12.7] years [range, 18-69 years]; 100% white; modafinil group, 13; placebo group, 15) completed the study without protocol violations. Of the 28 patients with MMD1 included in the analysis, 21 had adult-onset MMD1. At 4 weeks, the mean MWT score was 16.4 (3.3) minutes in the modafinil group and 15.8 (3.8) minutes in the placebo group (P = NS). At the end of the randomization period, there were no significant between-group differences in any secondary outcome. A total of 8 patients (4 in each group) reported > or =1 adverse event, including digestive, neurologic, and skin symptoms. Weight loss was reported in 1 patient (2 kg).
CONCLUSION: In this small study conducted in an adult population with MMD1 and a high prevalence of hyper-somnia, modafinil had no significant effects on daytime somnolence measured using objective MWTs.
de Swart BJ, van Engelen BG, Maassen BA.
Warming up improves speech production in patients with adult onset myotonic dystrophy.
J Commun Disord. 2007 May-Jun;40(3):185-95. doi: 10.1016/j.jcomdis.2006.06.005. Epub 2006 Jul 14.
Abstract/Text
UNLABELLED: This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls were examined, using a protocol that requires subjects, to speak continuously for at least 10 min. In MD patients, warming up led to an increase in speech rate and a decrease in speech variability without causing signs of fatigue or exhaustion as a result of prolonged and intensive use of the speech musculature. No significant changes were found in the controls. After warming up, MD patients achieved a habitual speech rate in reading and reciting similar to that of healthy controls.
LEARNING OUTCOMES: As a result of this activity the reader will learn that 1. In contrast to most neuromuscular disorders, speech production in patients with adult onset myotonic dystrophy improves by activity. 2. Myotonia in speech musculature in patients with adult onset myotonic dystrophy can be reduced by instructing them to warm up their muscles by repetitive movements. 3. Warming up is a valuable intervention because it improves the velocity and fluency of speech production without aggravating the signs of flaccid dysarthria.
Nitz J, Burns Y, Wuthapanich N, Jackson R.
A study of repeated lateral pinch grip in myotonic dystrophy.
Physiother Res Int. 1999;4(1):1-11. doi: 10.1002/pri.1999.4.1.1.
Abstract/Text
BACKGROUND AND PURPOSE: Subjects with myotonic dystrophy present with progressive muscle weakness, myotonia and fatigue. The aim of this study was to determine whether there was a difference in response to fatiguing exercise in myotonic dystrophy individuals compared to normal subjects. If no difference was found, a similar response to a physiotherapy exercise programme as seen in normal subjects might be expected.
METHOD: Ten individuals with myotonic dystrophy were compared to eight normal subjects in their response to ten repetitions of maximal lateral pinch grip efforts each five seconds in duration and separated by a ten-second rest. The root mean square (RMS) values, initial median frequency (Fmed) and slope of the median frequencies were recorded by electromyography (EMG) for the first dorsal interosseus, flexor pollicis brevis, flexor digitorum profundus and extensor digitorum communis muscles in the forearm and hand. Simultaneously, the rate of grip development, rate of grip release and work done during each grip effort were recorded by dynamometer. The RMS values for all muscles from subjects with myotonic dystrophy increased over the ten repetitions.
RESULTS: The initial Fmed for all myotonic dystrophy muscles was lower than for the normal subjects. The Fmed slopes for the first and last repetition showed no significant difference to the normal subjects. Rate of grip development was no different between groups over ten repetitions. Rate of grip release was slower and work done less for the individuals with myotonic dystrophy.
CONCLUSION: Results suggest the main difference between muscles affected by myotonic dystrophy and normal ones was the smaller size of muscle fibres. The increase in rate of grip release that was found is supportive of the 'warm-up' phenomenon. This appears to indicate that muscles affected by myotonic dystrophy could benefit from standard physiotherapeutic exercise methods.
小林寿子. 神経疾患の装具療法について. 義装会誌2014；30：6-10.
Aldehag A, Jonsson H, Lindblad J, Kottorp A, Ansved T, Kierkegaard M.
Effects of hand-training in persons with myotonic dystrophy type 1--a randomised controlled cross-over pilot study.
Disabil Rehabil. 2013 Oct;35(21):1798-807. doi: 10.3109/09638288.2012.754952. Epub 2013 Mar 12.
Abstract/Text
PURPOSE: To investigate the effects of a hand-training programme on grip, pinch and wrist force, manual dexterity and activities of daily living, in adults with myotonic dystrophy type 1 (DM1).
METHOD: In this randomised controlled trial with a crossover design, 35 adults with DM1 were, after stratification for grip force, assigned by lot to two groups. Group A started with 12 weeks of hand training, while group B had no intervention. After a wash-out period of 12 weeks, where none received training, the order was reversed. The Grippit® was used as primary outcome measure and the hand-held Microfet2™ myometer, the Purdue Pegboard, the Canadian Occupational Performance Measure (COPM) and the Assessment of Motor and Process Skills (AMPS) were secondary outcome measures. Assessments were performed before and after training and control periods, i.e. four times altogether.
RESULTS: Ten persons dropped out and 13 had acceptable adherence. Intention-to-treat analyses revealed significant intervention effects for isometric wrist flexor force (p = 0.048), and for COPM performance (p = 0.047) and satisfaction (p = 0.027). On an individual level, improvements were in general showed after a training period.
CONCLUSION: The hand-training programme had positive effects on wrist flexor force and self-perception of occupational performance, and of satisfaction with performance. No evident detrimental effects were shown.
IMPLICATIONS FOR REHABILITATION: Myotonic dystrophy type 1 (DM1) is a slowly progressive neuromuscular disease characterised by myotonia and muscle weakness and wasting. People with DM1 are often concerned about their ability to carry out ADL and to participate in, e.g. work, sports and hobbies when they gradually become weaker. This pilot study showed that a hand-training programme improved wrist flexor force and self-perception and satisfaction of occupational performance. Resistance training of hand muscles with a silicon-based putty can be a therapy option for people with DM1 in clinical practise.
Brembilla-Perrot B, Schwartz J, Huttin O, Frikha Z, Sellal JM, Sadoul N, Blangy H, Olivier A, Louis S, Kaminsky P.
Atrial flutter or fibrillation is the most frequent and life-threatening arrhythmia in myotonic dystrophy.
Pacing Clin Electrophysiol. 2014 Mar;37(3):329-35. doi: 10.1111/pace.12260. Epub 2013 Oct 9.
Abstract/Text
BACKGROUND: Several arrhythmias were reported in myotonic dystrophy (MD).
OBJECTIVES: To evaluate the prevalence of atrial fibrillation (AF) and atrial flutter (AFL) in MD and the clinical consequences.
METHODS: One hundred sixty-one patients, mean age 41 ± 14 years, were referred for a type 1 MD. All patients were asymptomatic except four patients and followed during 5 ± 4 years. Electrocardiogram (ECG), echocardiography assessing left ventricular ejection fraction, and Holter monitoring were obtained and repeated.
RESULTS: Twenty-seven patients (17%) presented sustained (>1 hour) AF (n = 15) or AFL (n = 12); two of them presented syncope-related 1/1 AFL. In one of them, 16 years of age, cardiac defibrillator was implanted for a diagnosis of ventricular tachycardia, but the true diagnosis was established after inappropriate shocks. AFL ablation was performed in five patients, but four developed AF. The other seven patients with AFL developed AF. During the follow-up, 22 patients died (14%) from cardiac and respiratory failure; eight patients with AF/AFL died (30%) while only 14 without AF/AFL died (10%; P < 0.01). Univariate analysis indicated that age >40 years (death: 48 ± 14 vs 40 ± 8 in alive patients), abnormal ECG, and occurrence of AF/AFL were significant factors of death. At multivariate analysis, AF at ECG (odds ratio: 3.12) and age >40 (odds ratio: 3.14) were the sole independent variables predicting death.
CONCLUSIONS: AF and AFL were frequent in MD and increased mortality. AFL could present as 1/1 AFL with a poor tolerance and a risk of misdiagnosis despite frequent conduction disturbances. This arrhythmia could explain wide QRS tachycardia occurring in MD and interpreted as VT.
©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.
Russo V, Nigro G, DI Meo F, Papa AA, Cioppa ND, Proietti R, Russo MG, Calabrò R, Politano L.
The effect of atrial preference pacing on atrial fibrillation electrophysiological substrate in Myotonic Dystrophy type 1 population.
Acta Myol. 2014 Dec;33(3):127-35.
Abstract/Text
P-wave dispersion is a non invasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of atrial fibrillation. The relationship between P-wave dispersion (PD) and atrial fibrillation (AF) in Myotonic dystrophy type 1 (DM1) patients is still unclear. Atrial Preference Pacing (APP) is an efficient algorithm to prevent paroxysmal AF in patients implanted with dual-chamber pacemaker. Aim of our study was to evaluate the possible correlation between atrial preference pacing algorithm, P-wave dispersion and AF burden in DM1 patients with normal cardiac function underwent permanent dual-chamber pacemaker implantation. We enrolled 50 patients with DM1 (age 50.3 ± 7.3; 11 F) underwent dual-chamber pacemaker implantation for various degree of atrioventricula block. The study population was randomized following 1 months stabilization period to APP algorithm features programmed OFF or ON. Patients were assessed every 3 months for the first year, and every 6 months thereafter up to 3 years. At each follow-up visit, we counted: the number of premature atrial beats, the number and the mean duration of AF episodes, AF burden and the percentage of atrial and ventricular pacing. APP ON Group showed lower number of AF episodes (117 ± 25 vs. 143 ± 37; p = 0.03) and AF burden (3059 ± 275 vs. 9010 ± 630 min; p < 0.04) than APP OFF Group. Atrial premature beats count (44903 ± 30689 vs. 13720 ± 7717 beats; p = 0.005) and Pwave dispersion values (42,1 ± 11 ms vs. 29,1 ± 4,2 ms, p = 0,003) were decreased in APP ON Group. We found a significant positive correlation between PD and AF burden (R = 0,8, p = 0.007). Atrial preference pacing algorithm, decreasing the number of atrial premature beats and the P-wave dispersion, reduces the onset and perpetuator factors of AF episodes and decreases the AF burden in DM1 patients underwent dual chamber pacemaker implantation for various degree of atrioventricular blocks and documented atrial fibrillation.
Alsaggaf R, Pfeiffer RM, Wang Y, St George DMM, Zhan M, Wagner KR, Amr S, Greene MH, Gadalla SM.
Diabetes, metformin and cancer risk in myotonic dystrophy type I.
Int J Cancer. 2020 Aug 1;147(3):785-792. doi: 10.1002/ijc.32801. Epub 2019 Dec 19.
Abstract/Text
Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well-established agent for the management of T2D, is thought to have cancer-preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age-, sex- and clinic-matched cohort of 12,318 DM1-free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18-10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06-3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91-1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72-1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.
© 2019 UICC.
Khan ZA, Khan SA.
Myotonic dystrophy and pregnancy.
J Pak Med Assoc. 2009 Oct;59(10):717-9.
Abstract/Text
Myotonic dystrophy is the most common neuromuscular disease in adults with a prevalence of 2.4-5.5 per 100,000. Here we describe two cases of DM and discuss their obstetric complications. Our first case concerns a 39 year old multipara whose pregnancies were complicated by recurrent abdominal pain, polyhydramnios and post partum haemorrhage which was attributed to DM. In our second case we discuss the management of a 27 year old woman with dichorionic, di-amniotic twins. Chorionic Villous Sampling at 11 weeks revealed one of the fetuses, a male; to be afflicted by DM. Selective termination of the affected twin was performed. Unfortunately, she developed severe oligohydramnios and chronic liquor leak. This resulted in the intra-uterine death of the second twin 5 days later. Our cases highlight the importance of prenatal diagnosis and prompt genetic counselling. A multidisciplinary team approach is required in the management of such high risk cases.
Zaki M, Boyd PA, Impey L, Roberts A, Chamberlain P.
Congenital myotonic dystrophy: prenatal ultrasound findings and pregnancy outcome.
Ultrasound Obstet Gynecol. 2007 Mar;29(3):284-8. doi: 10.1002/uog.3859.
Abstract/Text
OBJECTIVE: The objective of this study was to assess the maternal and prenatal ultrasound findings and outcome in pregnancies complicated by congenital myotonic dystrophy Type 1 (DM1).
METHODS: A retrospective chart review of all patients with a diagnosis of DM1 and pregnancy presenting to the Oxford Radcliffe Hospital between 1990 and 2004 was undertaken. Obstetric case notes were reviewed and details of all pregnancies obtained. This included data on prenatal diagnostic tests and obstetric ultrasound scans performed as well as pregnancy complications and pregnancy outcome. Maternal and fetal CTG expansion size was also recorded where available. Maternal genetic case notes were reviewed for details of maternal grip myotonia.
RESULTS: Sixty pregnancies among 26 couples in which one of the parents was a carrier of DM1 were identified during the study period. These resulted in 36 (60%) pregnancies affected by congenital DM1 and 19 (31.7%) unaffected pregnancies. There were four miscarriages and one termination of pregnancy for non-medical reasons. Nineteen of the 36 affected pregnancies ended in termination following the antenatal diagnosis of congenital DM1 by either chorionic villus sampling (CVS) or amniocentesis. In the remaining 17 affected pregnancies (16 singleton and one twin) there was one miscarriage of an affected fetus with co-existing Down syndrome and eight perinatal deaths. The principal cause of perinatal death was respiratory failure in the early neonatal period. Antenatally noted clinical/sonographic abnormalities in these pregnancies included polyhydramnios (100%), talipes (26.6%) and borderline ventriculomegaly (13.3%). Uni- or bilateral talipes was noted at delivery in 10 of 16 (62.5%) neonates. Maternal grip myotonia was present in all but one of these cases.
CONCLUSION: The antenatal findings of polyhydramnios and talipes should prompt a search for maternal grip myotonia. If present, definitive testing for congenital DM1 should be considered.
Argov Z, de Visser M.
What we do not know about pregnancy in hereditary neuromuscular disorders.
Neuromuscul Disord. 2009 Oct;19(10):675-9. doi: 10.1016/j.nmd.2009.07.004. Epub 2009 Aug 18.
Abstract/Text
Only sparse information is available concerning the relationship between pregnancy and hereditary neuromuscular disorders. This review deals with several issues like the effects of such conditions on female fertility (myotonic dystrophy type 1 and mitochondrial disorders), on the risk to the fetus (myotonic dystrophy type 1 and Charcot-Marie-Tooth disease), on the ability to carry pregnancy and its complications (markedly increased preterm labor in myotonic dystrophies and spinal muscular atrophy), on the labor and its possible need for interventions (myotonic dystrophy type 1, facioscapulohumeral dystrophy and Charcot-Marie-Tooth disease). It also discusses the question of pregnancy effects on the course of the inherited neuromuscular disorders (myotonic dystrophies, spinal muscular atrophy, facioscapulohumeral dystrophy, Charcot-Marie-Tooth disease, congenital myopathy and limb-girdle muscular dystrophy). The aim of this critical review is to point at pregnancy-related problems that need further research.
Awater C, Zerres K, Rudnik-Schöneborn S.
Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients.
Eur J Obstet Gynecol Reprod Biol. 2012 Jun;162(2):153-9. doi: 10.1016/j.ejogrb.2012.02.020. Epub 2012 Mar 28.
Abstract/Text
OBJECTIVE: Information about pregnancy and delivery in hereditary neuromuscular disorders (NMD) is limited and largely restricted to small case series and single case reports. Further data of obstetric histories in clinically and genetically defined subgroups are required.
STUDY DESIGN: We reviewed the obstetric histories of 178 patients with myotonic dystrophy type 1 (DM1) and 2 (DM2), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), and congenital myopathy (CM) by means of questionnaires and medical reports. Patients were recruited in the period 1992-2010 after they had at least completed one pregnancy. A total of 380 pregnancies resulting in 315 children were documented.
RESULTS: Compared to the normal German population, the number of miscarriages and hypertensive diseases in pregnancy was not increased in the cohort. Patients with NMD delivered more frequently by vaginal operations (8.9-18.2%) and by cesarean births with significantly high rates in DM1 (36.7%) and SMA (42.4%). Preterm deliveries were recorded in 30.7% of DM1, 12.6% of DM2, and 29.4% of SMA gestations. Abnormal fetal presentation occurred significantly more frequently in DM1 (34.6%) and LGMD (26.7%) deliveries and was a feature of chairbound patients. Considering a possible influence of pregnancy on the disease course, about half of LGMD, one-third of SMA, and one fifth of CMT patients reported a deterioration of symptoms in pregnancy. Neonatal outcome was favorable in all NMD but DM1, where infantile morbidity and mortality is often but not exclusively related to congenitally affected children.
CONCLUSION: Our data are important for obstetric care and genetic counseling of women with NMD who are contemplating pregnancy.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Rudnik-Schöneborn S, Zerres K.
Outcome in pregnancies complicated by myotonic dystrophy: a study of 31 patients and review of the literature.
Eur J Obstet Gynecol Reprod Biol. 2004 May 10;114(1):44-53. doi: 10.1016/j.ejogrb.2003.11.025.
Abstract/Text
OBJECTIVES: Myotonic dystrophy can be associated with increased obstetric risks, but the maternal contribution for gestational outcome is difficult to establish considering the varying degrees of severity and the influence of fetal factors.
STUDY DESIGN: We analyzed the pregnancy course and outcome of 31 women with classic myotonic dystrophy, who delivered a total of 66 children. In addition, 93 gestations from the literature were reviewed.
RESULTS: As most patients were not aware of their diagnosis at reproductive age, often the first indication of the maternal disease was a severely affected child (39%). Miscarriages and pre-eclampsia did not increase. Ectopic pregnancies occurred in 4%, placenta previa in 9% of gestations, while postpartum hemorrhage due to uterine atonia was only reported twice. Severe urinary tract infections were reported for 19% of the patients, but were only rarely encountered in the literature. Preterm labor, before 34 weeks, occurred in 19% of gestations and was often, but not exclusively attributed to congenitally affected fetuses in contrast to polyhydramnios (17%). Labor abnormalities of all three stages were frequent, increasing the number of operative deliveries (cesarean section rate 36%). Perinatal mortality was 15% and mainly related to congenitally affected children.
CONCLUSIONS: The risk for obstetric complications and urinary tract infections increases for pregnant patients with myotonic dystrophy. They need constant obstetric monitoring. It is hoped that a better awareness of the clinical picture might help to improve gestational outcome in myotonic dystrophy.
Ogoyama M, Takahashi H, Kobayashi Y, Usui R, Matsubara S.
Ritodrine-induced rhabdomyolysis, infantile myotonic dystrophy, and maternal myotonic dystrophy unveiled.
J Obstet Gynaecol Res. 2017 Feb;43(2):403-407. doi: 10.1111/jog.13211. Epub 2016 Dec 17.
Abstract/Text
A primiparous pregnant woman in remission of myositis suffered very acute-onset ritodrine-induced rhabdomyolysis. At 29 gestational weeks, ritodrine was administered for threatened preterm labor. Just 3 h later, she complained of severe limb muscle pain, with serum creatinine phosphokinase elevated to 32 019 U/L and myoglobinuria. The muscle pain disappeared immediately after ceasing administration of ritodrine. At 31 weeks, premature rupture of the membranes occurred, necessitating cesarean section, yielding a baby with weak tonus, and the presence of infantile muscle diseases was suspected. Genetic analysis of the infant confirmed myotonic dystrophy (dystrophia myotonica, DM), which prompted us to perform maternal genetic analysis, confirming maternal DM. Ritodrine can induce rhabdomyolysis even in the prodromal phase with a mild phenotype of DM. A literature review suggested that ritodrine-induced rhabdomyolysis may be likely to occur more acutely after ritodrine administration in DM compared with non-DM mothers.
© 2016 Japan Society of Obstetrics and Gynecology.
Nasu K, Sugano T, Yoshimatsu J, Narahara H.
Rhabdomyolysis caused by tocolysis with oral ritodrine hydrochloride in a pregnant patient with myotonic dystrophy.
Gynecol Obstet Invest. 2006;61(1):53-5. doi: 10.1159/000088531. Epub 2005 Sep 23.
Abstract/Text
Drug-induced rhabdomyolysis during pregnancy is extremely rare. We report here a rare case of ritodrine-hydrochloride-induced rhabdomyolysis in a pregnant patient with myotonic dystrophy. A 32-year-old primigravida was admitted because of premature labor at 31 weeks of gestation. She had been diagnosed as having myotonic dystrophy by electromyographic investigations and abnormal serum creatinine phosphokinase (CPK) levels. Tocolysis was initiated with oral ritodrine hydrochloride (15 mg/day) alone. There was a prompt response to the ritodrine hydrochloride. Three days after administration began, serum CPK levels had become markedly elevated to 10,897 mg/dl and myoglobinuria was detected (1,800 ng/dl), suggesting the presence of rhabdomyolysis. There was no evidence of worsening of the myotonic symptoms. Tocolysis was stopped immediately, and the laboratory data improved gradually. At 37 weeks of gestation, she spontaneously delivered a healthy male baby. Rhabdomyolysis has been recognized as a complication of tocolytic therapy with ritodrine hydrochloride. Therefore, beta-adrenergic agents should be used with great care, especially for patients with myotonic dystrophy, because of these agents' tendency to aggravate or precipitate myotonia and to induce rhabdomyolysis.
Copyright 2006 S. Karger AG, Basel.
Matsuda Y, Nagayoshi Y, Kirihara N.
Rhabdomyolysis during prolonged intravenous tocolytic therapy.
J Perinat Med. 2002;30(6):514-6. doi: 10.1515/JPM.2002.080.
Abstract/Text
A patient with twin gestation was hospitalized because of preterm labor and treated with intravenous ritodrine hydrochloride and magnesium sulfate. After more than 5 weeks of therapy, the patient developed muscle pain, which was diagnosed as rhabdomyolysis.
Verriello L, D'Amico D, Pauletto G, Gigli GL, Bergonzi P.
Rhabdomyolysis caused by tocolytic therapy with ritodrine hydrochloride.
Neuromuscul Disord. 2009 Oct;19(10):718-20. doi: 10.1016/j.nmd.2009.06.364. Epub 2009 Jun 24.
Abstract/Text
We report a case of rhabdomyolysis with severe generalized weakness and muscle pain after administration of ritodrine hydrochloride, in a pregnant patient without history of neuromuscular disease. Laboratory tests showed an increase of blood CK value and myoglobinuria. An electromyography was performed, revealing a typical myogenic pattern and diffuse denervation activity. Muscular biopsy allowed to rule out inflammatory and metabolic myopathy. After delivery, the patient underwent intensive rehabilitation with progressive improvement of her clinical situation, until complete recovery. Three months later, both neurological assessment and CK levels were normal. This case highlights that rhabdomyolysis has to be considered even in patient treated with ritodrine alone and without history of neuromuscular disease. Therefore, muscular symptoms and CK levels should be monitored in women treated with ritodrine for premature labour.
Catanzarite V, Gambling D, Bird LM, Honold J, Perkins E.
Respiratory compromise after MgSO4 therapy for preterm labor in a woman with myotonic dystrophy: a case report.
J Reprod Med. 2008 Mar;53(3):220-2.
Abstract/Text
BACKGROUND: MgSO4 is widely used for tocolysis. Serious complications are rare as long as dosing is carefully monitored. Adverse effects in muotonic dustrophy have not been previously described.
CASE: A 35-year-old woman, gravida 1, para 0, was hospitalized with suspected mild myotonic dystrophy, polyhydramnios and preterm labor at 33 weeks. MgSO4 infusion rapidly resulted in respiratory compromise. Muscular strength returned to baseline after the infusion was stopped. Mother and infant proved to have myotonic dystrophy.
CONCLUSION: The choice of tocolytic medication in maternal myotonic dystrophy is problematic. Beta-2 sympathomimetics have been reported to precipitate myotonia. This case illustrates the potential for MgSO4 to cause respiratory embarrassment. Indomethacin may be the tocolytic of choice in myotonic dystrophy.
Mathieu J, Allard P, Gobeil G, Girard M, De Braekeleer M, Bégin P.
Anesthetic and surgical complications in 219 cases of myotonic dystrophy.
Neurology. 1997 Dec;49(6):1646-50. doi: 10.1212/wnl.49.6.1646.
Abstract/Text
The objective of this study was to assess the frequency, type, and severity of perioperative complications after a first surgery under general anesthesia in patients with myotonic dystrophy (DM) and to measure the association with suspected risk factors. Numerous cases of perioperative complications in DM patients have been reported. Hazards have been associated with the use of thiopentone, suxamethonium, neostigmine, and halothane. A retrospective study of perioperative complications was conducted for 219 DM patients who had their first surgery under general anesthesia at the Chicoutimi Hospital. The overall frequency of complications was 8.2% (18 of 219). Most complications (16 of 18) were pulmonary, including five patients with acute ventilatory failure necessitating ventilatory support, four patients with atelectasis, and three patients with pneumonia. Using multivariate analysis, we found that the risk of perioperative pulmonary complications (PPC) was significantly higher after an upper abdominal surgery (odds ratio (OR), 24.4; 95% CI, 4.0 to 149.3) and for patients with a severe muscular disability, as assessed by the presence of proximal limb weakness (OR, 14.1; 95% CI, 1.5 to 134.4). The likelihood of PPC was not related to any specific anesthetic drug. Because of the increased risk of PPC, careful monitoring during the early postoperative period, protection of upper airways, chest physiotherapy, and incentive spirometry are mandatory in all symptomatic DM patients, particularly those with a severe muscular disability or those who have undergone an upper abdominal surgery.
Petri H, Mohammad BJY, Kristensen AT, Thune JJ, Vissing J, Køber L, Witting N, Bundgaard H, Christensen AH.
Natural history of cardiac involvement in myotonic dystrophy type 1 - Emphasis on the need for lifelong follow-up.
Int J Cardiol. 2024 Jul 1;406:132070. doi: 10.1016/j.ijcard.2024.132070. Epub 2024 Apr 21.
Abstract/Text
BACKGROUND: Cardiac involvement represents a major cause of morbidity and mortality in patients with myotonic dystrophy type 1 (DM1) and prevention of sudden cardiac death (SCD) is a central part of patient care. We investigated the natural history of cardiac involvement in patients with DM1 to provide an evidence-based foundation for adjustment of follow-up protocols.
METHODS: Patients with genetically confirmed DM1 were identified. Data on patient characteristics, performed investigations (12 lead ECG, Holter monitoring and echocardiography), and clinical outcomes were retrospectively collected from electronic health records.
RESULTS: We included 195 patients (52% men) with a mean age at baseline evaluation of 41 years (range 14-79). The overall prevalence of cardiac involvement increased from 42% to 66% after a median follow-up of 10.5 years. There was a male predominance for cardiac involvement at end of follow-up (74 vs. 44%, p < 0.001). The most common types of cardiac involvement were conduction abnormalities (48%), arrhythmias (35%), and left ventricular systolic dysfunction (21%). Only 17% of patients reported cardiac symptoms. The standard 12‑lead ECG was the most sensitive diagnostic modality and documented cardiac involvement in 24% at baseline and in 49% at latest follow-up. However, addition of Holter monitoring and echocardiography significantly increased the diagnostic yield with 18 and 13% points at baseline and latest follow-up, respectively. Despite surveillance 35 patients (18%) died during follow-up; seven due to SCD.
CONCLUSIONS: In patients with DM1 cardiac involvement was highly prevalent and developed during follow-up. These findings justify lifelong follow-up with ECG, Holter, and echocardiography.
CLINICAL PERSPECTIVE: What is new? What are the clinical implications?
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
