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Myotonic dystrophy: Treatment and prognosis

Myotonic dystrophy: Treatment and prognosis
Literature review current through: Jan 2024.
This topic last updated: Sep 26, 2022.

INTRODUCTION — Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are autosomal dominant, multisystem disorders characterized by skeletal muscle weakness and myotonia, cardiac conduction abnormalities, iridescent cataracts, and other abnormalities.

The management and prognosis of patients with DM will be reviewed here. Other aspects of DM are discussed separately. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

BACKGROUND — The genetics, clinical features, and diagnosis of DM are reviewed here briefly and discussed in detail elsewhere. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

DM1 results from an expansion of a cytosine-thymine-guanine (CTG) trinucleotide repeat in the 3'-untranslated region of the DM1 protein kinase (DMPK) gene. DM2 is caused by an expansion of a cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat located in intron 1 of the CCHC-type zinc finger nucleic acid binding protein (CNBP, also known as ZNF9) gene. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Genetics'.)

The diagnosis of DM can usually be made clinically in a patient with the characteristic presentation and a positive family history. Genetic testing for an expanded CTG repeat in the DMPK gene is the gold standard for confirming the diagnosis of DM1. Testing for the CCTG repeat in the ZNF9 (CNBP) gene is appropriate if DM1 testing is negative. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Diagnosis'.)

MANAGEMENT AND DM PHENOTYPE — DM1 and DM2 are multisystem disorders characterized by skeletal muscle weakness and myotonia, cardiac conduction abnormalities, cataracts, and other abnormalities. However, the age of onset, presentation, and severity and progression of symptoms vary according to DM phenotype. There are congenital, childhood, classic (adult-onset), and mild forms of DM1, whereas only an adult-onset form of DM2 is recognized. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Phenotypes' and "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Clinical features'.)

Certain aspects of management differ according to phenotype, as outlined in the sections that follow.

Congenital DM1 — Infants with congenital DM1 often present with respiratory and feeding difficulties and may require neonatal intensive care and ventilatory support. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Congenital DM1'.)

Respiratory involvement is the leading cause of death in the neonatal period. Need for support longer than four weeks usually indicates a poor prognosis for survival, and the mortality rate exceeds 25 percent [1-3]. Nasal continuous positive airway pressure (N-CPAP) can facilitate weaning infants with DM1 from endotracheal mechanical ventilation and minimize morbidity associated with prolonged intubation [4].

Because feeding difficulties are common during the first two years of life, children with congenital DM1 are at increased risk for aspiration and may benefit from feeding evaluation. Survivors usually are able to suck and swallow adequately for oral nutrition by 8 to 12 weeks of age [5]. However, gastrostomy tube insertion is often necessary during the first six months of life to maintain nutrition and prevent aspiration pneumonia.

Childhood DM1 — The childhood (juvenile) form of DM1 typically presents before the age of 10 years with cognitive and behavioral problems. Over time, affected children develop muscle symptoms and disability that is similar to severe adult-onset classic DM1. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Childhood DM1'.)

Cognitive and psychosocial assessments are important aspects of management [6]. Special education, psychotherapy, social support, and vocational skills training can help to improve function, although there are no high-quality trials evaluating these approaches. In some cases, pharmacotherapy for issues such as attention deficit disorder, anxiety, or mood disorders may be beneficial.

Management of childhood DM1 is otherwise similar to that of classic (adult-onset) DM1, including routine surveillance for and treatment of the multiple neurologic and systemic manifestations, such as progressive muscle weakness, cardiac abnormalities, dysphagia, respiratory involvement, and sleep disorders (table 1).

Classic DM1 — The classic form of DM1 becomes symptomatic during the second to fourth decade of life. Major clinical manifestations include (but are not limited to) skeletal and respiratory muscle weakness, myotonia, cataracts, cardiac arrhythmias, and excessive daytime sleepiness (EDS). Multidisciplinary surveillance and management of these and other issues is optimal (table 1); specific issues are outlined below. (See 'Specific management issues' below.)

Mild DM1 — The mild form of DM1 is characterized by mild weakness, myotonia, and cataracts. Onset is usually after age 40 years. Though generally not debilitating, surveillance for cataracts and potentially serious manifestations of DM1, such as cardiac conduction abnormalities, is advisable.

DM2 — The onset of DM2 ranges from the second to the seventh decades, and the condition often presents with prominent muscle pain, myotonia, weakness, or cataracts. In most cases, proximal muscle weakness predominates, particularly involving the hip girdle muscles. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'DM2'.)

Although DM2 generally is less severe than classic DM1, it can progress to disability and is associated with an increased risk of cardiac conduction disease and other serious complications. Therefore, management is similar to that of classic DM1 (table 1).

SPECIFIC MANAGEMENT ISSUES — There is no disease-modifying therapy available for the treatment of DM. Thus, treatment is symptomatic. The systemic (non-neuromuscular) manifestations of DM are the most treatable aspects of the disease. A number of tests and evaluations are useful in the surveillance and management of patients with DM1 and DM2 (table 1). Because the disease is multifaceted and variable, its management requires an interdisciplinary approach among health professionals and involves many different skills and services from community resources [7,8]. Recommendations regarding management are based more on consensus and clinical experience than on evidence from randomized controlled trials.

Muscle involvement — The natural history of DM1 is that of gradual progression in weakness. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Skeletal muscle weakness'.)

The management of physical disability depends on the distribution and severity of muscle weakness and is best provided by a multidisciplinary team including neurologists, physiatrists, and occupational and physical therapists. Consensus-based care guidelines recommend annual evaluation for mobility, balance, and falls; activities of daily life, including self-care; and activities in home, school, work, and community [8].

Initially, molded ankle-foot orthoses are helpful in preventing foot-drop and enhancing gait stability. Over time, patients may find that a walker is necessary to navigate distances with confidence and safety, and in the later stages of the illness, a wheelchair may be required, especially for longer distances outside of the home. Accordingly, the sequential and often combined use of ankle-foot orthoses, walkers, and wheelchairs in concert with multidisciplinary interventions (addressing the compromised vision, fatigue, and visuospatial deficits of patients with DM1) are important in maintaining health and safety in these patients.

Neck muscle weakness is common in DM1, affecting both flexor and extensor groups, and tends to cause head-drop; this symptom may be ameliorated by a fitted collar. Eye lid crutches or blepharoplasty may be helpful for troublesome ptosis encountered in DM1.

In DM2, progression and severity of weakness are less pronounced than in DM1. When necessary, the assistive devices described for DM1 are likely to be helpful.

Exercise training — Moderate-intensity strength training for DM1 has been assessed in only a few small randomized trials [9,10]. There was no clear evidence of benefit or harm [11].

A smaller study on the effects of aerobic training in 12 patients with DM1 for 12 weeks on a cycle ergometer noted that patients increased maximal oxygen uptake by 14 percent and increased maximal workload by 11 percent [12]. However, 5 of 17 patients who were originally enrolled dropped out of the study because of low compliance, and 3 of the 12 who completed the study did not follow the original training schedule. Thus, such approaches to fitness are likely to be most appropriate for a relatively small subset of patients with DM1 who exercise under supervision.

In the absence of evidence that exercise is effective for improving muscle strength, we suggest that patients with DM engage in low-intensity exercise, to the extent that they are capable and without undue physical stress. We also suggest that exercise include gentle stretching actions at selected joints, such as dorsiflexion at the ankles, extension at the knees, and abduction at the hips, which may attenuate the tendency for tendon shortening and joint contractures. This recommendation is based upon the intuitive sense that stretching and exercise may be systemically beneficial, and upon evidence that low-intensity exercise is not harmful.

Since exercise can precipitate serious arrhythmias, some have suggested exercise testing with electrocardiographic (ECG) monitoring as part of the routine evaluation of young patients with DM1 [13]. Congestive heart failure has also been reported in a young DM1 patient following daily excessive physical activity [14]. We suggest exercise testing with ECG monitoring prior to beginning an exercise training program in patients with DM1. In patients with cardiac symptoms or abnormal regular or stress test ECG, a decision regarding the safety of exercise training should be made by a cardiologist. Cardiology consultation is also recommended in adults with DM1 or DM2 prior to beginning an exercise program.

Muscle pain — In DM2, muscle pain can be a persistent and troubling symptom and is often a presenting manifestation of the disease. Muscle pain may also affect some patients with DM1. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Muscle pain'.)

Pharmacologic agents that may be effective for this problem include nonsteroidal anti-inflammatory drugs, gabapentin, tricyclic antidepressants, mexiletine, and low-dose glucocorticoids, such as oral prednisone 5 mg on alternate days [15]. We begin management with ibuprofen or naproxen as needed, along with gabapentin up to 300 mg three times per day.

Myotonia — Symptoms of myotonia in patients with DM1 can be sufficiently pronounced to prompt treatment. Myotonic symptoms in DM2 are less likely to require therapy. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Muscle pain'.)

For adults with myotonic symptoms that require treatment (typically in DM1), we suggest initial therapy with mexiletine 450 mg daily in three divided doses. In children and adolescents, in whom myotonia may occasionally need to be treated, mexiletine (1.5 to 3.0 mg/kg every 8 to 12 hours) may be used with careful follow-up. Because of the rare proarrhythmic effects of mexiletine in those with underlying ventricular arrhythmias, it is best to obtain a cardiology consultation before beginning therapy with mexiletine, particularly for patients with DM1 who have current or remote cardiac symptoms or for those with an abnormal baseline ECG [16]. Mexiletine is contraindicated in patients with second- and third-degree heart block. Ataxia, coordination abnormalities, and dizziness are relatively common side effects, and ongoing hematologic, liver function, and cardiac monitoring must be performed. (See "Major side effects of class I antiarrhythmic drugs".)

The clinical experience of treating myotonia has involved a variety of medications, including phenytoin, mexiletine, procainamide, propafenone, flecainide, and carbamazepine, all of which are sodium channel blockers and share the potential to increase weakness while reducing myotonia [17,18]. However, there are few high-quality data:

In several small, double-blind, randomized controlled trials involving patients with DM1, treatment with mexiletine (at either 450 mg or 600 mg daily, given in three divided doses) was superior to placebo for improvement in grip relaxation time [16,19]. Mexiletine was well tolerated in these trials and was not associated with any serious adverse effects or cardiac conduction abnormalities.

An earlier systematic review published in 2006 found 10 small randomized controlled trials that evaluated the effectiveness of 12 different treatments for myotonia in patients with DM and other myotonic disorders [20]. However, the quality of the trials was generally poor, and a meta-analysis was not possible.

Historically, quinine and procainamide were used to treat myotonia, but their use is no longer recommended because they exhibit adverse effects on cardiac conduction, to which patients with DM may be especially vulnerable.

Cardiac disturbances — Cardiac conduction disturbances and tachyarrhythmias occur in DM1, and to a lesser extent in DM2. In some instances, cardiac arrhythmias may occur as a very early manifestation of the disease. More details on the specific cardiac abnormalities and their clinical manifestations are discussed in detail separately. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Cardiac abnormalities'.)

We typically refer our patients to a cardiologist for ongoing care and follow-up, in parallel with neurology clinic visits. Significant cardiac involvement is often asymptomatic. In accord with 2017 guidelines from the American Heart Association (AHA), we recommend a careful cardiac history (seeking evidence for palpitations, blackouts, syncope, and dyspnea), examination (ascertainment for bradyarrhythmia, ectopic beats, mitral valve prolapse, and atrial fibrillation), ECG, echocardiography, and ambulatory ECG monitoring at the time of DM diagnosis, regardless of symptoms (table 1) [21]. Patients with a normal left ventricular ejection fraction should be reevaluated yearly by examination, ECG, and ambulatory ECG monitoring, and every two to four years by echocardiography.

Patients with palpitations, dizziness, syncope, non-sinus rhythm, PR interval >240 msec, QRS duration >120 msec, or second- or third-degree atrioventricular (AV) block should be evaluated at least annually and also considered for invasive electrophysiology study in anticipation of possible pacemaker or implantable cardioverter-defibrillator (ICD) placement. Permanent pacemaker placement is indicated for most patients with second- and third-degree AV block and all patients with symptoms related to the resulting bradycardia. (See "Second-degree atrioventricular block: Mobitz type I (Wenckebach block)" and "Second-degree atrioventricular block: Mobitz type II" and "Third-degree (complete) atrioventricular block".)

In addition, a clinical case can be made for permanent pacemaker implantation in an asymptomatic patient if there is documentation of serial lengthening of the PR interval or QRS duration, or an electrophysiologic study to determine the HV interval could be performed to establish a more definitive indication for device implantation. However, this remains somewhat controversial, primarily because available data are limited. One of the largest studies was a retrospective analysis of 486 adults from the DM1 Heart Registry who had a PR interval >200 msec or a QRS duration >100 msec or both [22]. The study compared 341 patients who were treated with an invasive strategy (electrophysiologic study and permanent pacemaker if the interval from the His bundle to the right ventricle [HV interval] was >70 msec) with 145 patients who had noninvasive management. In the unadjusted analysis, there was a trend toward longer nine-year survival in the invasive compared with the noninvasive group (77 versus 70 percent), but the difference was not statistically significant (hazard ratio [HR] 0.74, 95% CI 0.47-1.16). However, in several different analyses that adjusted for between-group differences in baseline characteristics, the longer survival associated with the invasive strategy was statistically significant, with adjusted HRs ranging from 0.47 (95% CI 0.26-0.84) to 0.61 (95% CI 0.38-0.99). This finding was mainly due to a significantly lower incidence of sudden death associated with the invasive strategy. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Neuromuscular diseases'.)

Guidelines from the AHA note that it is reasonable to consider ICD placement in select patients with neuromuscular disease, particularly those in which arrhythmia may be a predominant feature (including DM1), after thoughtful discussion and decision-making, which should be individualized and based on the overall medical status and options for management [21]. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Neuromuscular diseases'.)

Respiratory function and sleep — Respiratory complications and sleep-related breathing abnormalities are common in DM1 but are less frequent and severe in DM2. These problems are discussed in detail separately. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Respiratory function'.)

Accordingly, an important aspect of respiratory management in DM1 is to gauge effectiveness of gas exchange by clinical signs (comfort level, respiratory rate, oxygen saturation, auscultation for air entry into the lung bases) and observation for evidence of diaphragmatic paralysis and pneumonia.

In adults with DM1, we often follow up the clinical assessment by obtaining forced vital capacity (FVC) measurements (table 1), and use the values of serial FVC results in concert with clinical findings to follow respiratory status. In the absence of data upon which to base specific recommendations, we suggest that FVC be measured annually in asymptomatic adult subjects but more regularly in those with dyspnea or previously documented reduction in FVC.

Patients should be vaccinated for pneumonia and influenza [8]. Respiratory infections should be evaluated and treated promptly, as patients with DM1 are at increased risk for respiratory decompensation.

In patients demonstrated to have alveolar hypoventilation, regular use of incentive spirometry and a cough assist device may help to counteract the tendency for atelectasis and hypercarbia and reduce the risk of pneumonia.

Obstructive sleep apnea (OSA) may coexist with central hypoventilation, especially in those at highest risk due to coexisting obesity. The hypersomnia of DM1 may be aggravated by alveolar hypoventilation and the sleep apnea syndrome but is not entirely reversed by continuous positive airway pressure (CPAP) management [23]. Thus, it is critical to assess the quality of sleep in patients with DM1, probing for whether there is nocturnal restlessness, unexplained awakenings, and loud snoring punctuated by occasional awakenings and gasping for breath, all of which should suggest the presence of a sleep-related respiratory disorder and lead to further study with a polysomnographic evaluation (table 1) that will reveal a more specific diagnosis [23]. Patients with DM who have sleep apnea may present with only daytime sleepiness and occasionally orthopnea, perhaps due to diaphragm weakness [24,25]. Some patients can have central apneas and may benefit from adaptive servo-ventilation. (See "Central sleep apnea: Treatment", section on 'Patients with hypoventilation-related CSA'.)

Noninvasive positive airway pressure ventilation (NIPPV) may be helpful in correcting sleep apnea, improving hypoventilation, and assisting diaphragm weakness. Bilevel positive airway pressure ventilation (BiPAP) is better tolerated by patients with weakness of the chest wall and diaphragm who cannot overcome expiratory forces. NIPPV may also be used symptomatically during the day to rest weak respiratory muscles and to improve dyspnea. In rare instances, the progressive loss of respiratory drive and the increasing severity of diaphragm and chest wall muscle weakness creates a situation in which NIPPV no longer provides adequate respiratory support and tracheostomy may be considered.

Children with childhood (juvenile) DM may not be able to cooperate for reliable pulmonary function testing. However, most adolescent patients can be tested, and a baseline FVC and forced expiratory volume in one second (FEV1) measurement is suggested for adolescent patients. Periodic testing is not needed for most pediatric patients with DM1, but we suggest annual or twice yearly pulmonary tests in adolescents with dyspnea or reduced baseline FVC and/or FEV1 values. We also suggest pulmonary function tests as part of preoperative evaluation if general anesthesia is anticipated. (See 'Risk of anesthesia' below.)

Infants with congenital DM1 often require continuous ventilatory support. (See 'Congenital DM1' above.)

Excessive daytime sleepiness — Given the limited evidence from randomized controlled trials, we suggest a trial of modafinil (200 mg twice daily) for adult patients with DM and severe excessive daytime sleepiness (EDS).

A 2006 systematic review found only three trials that had evaluated the effectiveness of pharmacologic therapy for EDS in DM [26].

Modafinil was evaluated in two trials that included a total of 60 adults with DM [27,28]. Both trials suggested that modafinil was modestly beneficial for the treatment of daytime sleepiness, as assessed by the Epworth Sleepiness Scale, and was well tolerated. (See "Quantifying sleepiness", section on 'Epworth Sleepiness Scale (ESS)'.)

Selegiline failed to show any benefit for hypersomnolence in one trial of 11 patients with DM, but major methodologic flaws precluded definitive conclusions [29].

The systematic review identified no trials that evaluated the use of pharmacologic agents for EDS in children with DM [26]. Methylphenidate (20 mg single daily dose) was found to reduce EDS in a later (2012) three-week, placebo-controlled, randomized crossover trial of 24 adults with DM1 [30].

Cataracts — Slit-lamp examination to detect cataracts is appropriate at the time of diagnosis and periodically thereafter (table 1), as dictated by symptoms in patients with DM1 or DM2. In the congenital form of DM1, cataracts are uncommon before the age of 10 [1].

Corrective surgery is indicated if symptoms from the cataract interfere with activities of daily living. Surgery is needed in a substantial minority of patients. In one series of 164 patients with DM1, cataract surgery was carried out in 21 (13 percent) [1], and in another series of 234 patients with DM2, cataract extraction was performed in 75 (32 percent) [31].

The evaluation and treatment of cataracts is discussed in detail elsewhere. (See "Cataract in adults".)

Dysphagia and nutrition — Swallowing assessment is an important part of the management of patients with DM1 (table 1), as dysphagia is a risk factor for aspiration pneumonia and poor nutrition (see "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Gastrointestinal involvement'). In childhood DM1 in particular, dysphagia may lead to poor weight gain.

Formal evaluation by a speech and swallow therapist is appropriate for those with symptomatic dysphagia, and referral to a nutritionist may be useful for advice regarding calorie supplementation. Assessment by gastroenterology specialists may also be helpful for some adult or pediatric patients with dysphagia. Intestinal pseudo-obstruction has been reported in patients with DM [32]; it may be severe enough to require either a temporary or permanent ileostomy.

Similarly, children with congenital DM1 are at increased risk for aspiration and may benefit from a feeding evaluation. In infants with poor gastric motility, metoclopramide, which decreases the threshold of smooth muscle for the action of acetylcholine, may be beneficial [33].

One of the major problems faced by patients with DM1 is fatigue, which in turn leads to reduced nutritional intake. Advice to eat smaller meals more frequently may help to overcome the problem of fatigue. Problems with aspiration may be managed by modifying the consistency of foods, which is mostly accomplished by thickening of liquids, as well as by sleeping with the head of the bed elevated. Pharyngeal muscle myotonia, sometimes triggered by cold liquids, may impair swallowing and might be relieved by avoiding cold liquids.

Lip-strengthening exercises can increase maximal lip force and endurance but do not improve dysarthria, saliva control, or eating and drinking ability in children and adolescents with DM1 [34]. They can complement speech and dysphagia therapies but cannot replace them.

Endocrinopathies — Patients with DM, especially those with DM2, are at increased risk for insulin resistance and diabetes. A fasting blood glucose and hemoglobin A1C are suggested at baseline and annually. Thyroid-stimulating hormone (TSH) and free T4 should be assessed at baseline and every two to three years thereafter to screen for hypothyroidism.

Primary hypogonadism and erectile dysfunction are common in men with DM1 and less common in DM2. Clinicians should inquire about erectile dysfunction and treat low testosterone in symptomatic men. Cardiovascular risks and side effects associated with some medications used to treat erectile dysfunction should be considered. (See "Treatment of male sexual dysfunction".)

Risk of anesthesia — We recommend that patients with DM, particularly those with DM1, avoid general anesthesia when possible. Many experts believe that the combination of neuromuscular, cardiac, and respiratory abnormalities places patients with DM1 at particular risks of complications from general anesthesia.

In observational case series or case reports, most [35-40] but not all [41] reports suggest that patients with DM are at high risk for pulmonary complications with general anesthesia. Patients with DM1 or DM2 may have cardiac conduction system abnormalities such as supraventricular and ventricular arrhythmias; laryngeal and pharyngeal muscle weakness may predispose to aspiration. In addition, myotonia may be precipitated by hypothermia, shivering, or mechanical or electrosurgical stimulation. The higher sensitivity to sedatives and anesthetic induction and neuromuscular blocking agents (NMBAs) may result in cardiovascular and respiratory complications [42,43]. Intellectual impairment, cognitive dysfunction, and/or hypersomnolence may further affect anesthetic emergence [8].

Regional anesthesia may be appropriate for some procedures, and for some patients with DM1. For patients who must have general anesthesia, preoperative assessments of cardiac and pulmonary function may identify patients at particularly high risk for surgery, and close monitoring for postoperative apnea may reduce the risk of complications [1].

When sedation is necessary, we suggest use of a short-acting agent such as propofol, and avoidance of long-acting sedatives such as the benzodiazepines [44]. In planning the anesthetic approach, the risk of aspiration with sedation must be considered; for some patients, general anesthesia with endotracheal intubation for airway protection will be preferred.

Rapid sequence induction and intubation is indicated for general anesthesia for patients at high risk of aspiration, including those with DM. However, succinylcholine should be avoided, due to the potential to cause diffuse muscle contraction and, in severe cases, trismus, laryngospasm, and the inability to manage the airway [45,46]. Alternatives to succinylcholine include rocuronium (0.9 to 1.2 mg/kg intravenously), or a high-dose remifentanil intubation. (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Neuromuscular blocking agents (NMBAs)'.)

The response to nondepolarizing NMBAs is variable in these patients and may depend on the degree of muscle wasting. Thus, doses should be titrated and guided by neuromuscular monitoring with a peripheral nerve stimulator, preferably using a quantitative device. Electrical stimulation with a peripheral nerve stimulator could theoretically cause myotonia and be misinterpreted as reversal of neuromuscular block, although this phenomenon has not been reported. (See "Monitoring neuromuscular blockade", section on 'Quantitative monitoring'.)

Administration of neostigmine for NMBA reversal has reportedly caused diffuse muscle contraction [47], presumably related to increased acetylcholine sensitivity in myotonic muscle. To avoid administration of neostigmine, an intermediate-acting drug (eg, cisatracurium) can be used if surgery will last long enough for spontaneous recovery. As an alternative, rocuronium or vecuronium can be used and reversed with sugammadex. (See "Clinical use of neuromuscular blocking agents in anesthesia".)

These points and additional recommendations to mitigate risk are detailed in expert guidelines from the Myotonic Dystrophy Foundation [48]:

Preoperatively evaluate pulmonary, cardiac, and gastrointestinal DM features in addition to its neurologic and neuromuscular effects.

Use regional anesthesia when possible to reduce or eliminate the need for general anesthesia.

Avoid premedications (eg, sedatives and opioids) to the extent possible.

Keep the patient warm.

Consider precautionary application of defibrillator/pacer pads.

On induction, anticipate aspiration and avoid the use of succinylcholine.

Adhere to strict extubation criteria. Given DM effects on central nervous system, gastrointestinal, ventilatory, and pharyngeal function, prepare the patient for prolonged postanesthesia mechanical ventilation, commonly after having fully regained consciousness.

Prepare the patient for prolonged ventilatory assistance, for example by prior initiation of BiPAP with a mask that is immediately available postanesthesia.

Plan for continuous peripheral arterial oxygen saturation (SpO2) and ECG monitoring postanesthesia until the patient fully regains preoperative status, or longer if analgesics or sedatives are used in the postanesthesia period.

Manage postoperative pain with nonsteroidal anti-inflammatory drugs, regional techniques, and acetaminophen, and without opioids when possible.

Encourage aggressive pulmonary toilet after anesthesia, including by use of a mechanical cough-assistance device if necessary.

Patients with myotonias, including DM, are not at increased risk of malignant hyperthermia with anesthesia. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Muscle diseases compatible with malignant hyperthermia-triggering agents'.)

The data regarding patients with DM2 are limited but suggest little or no increased risk with general anesthesia. In a retrospective report of 121 patients with DM2 who had 340 operations under general anesthesia, the frequency of severe complications was <1 percent [49]. An observational study of patients with DM2 reported that none experienced problems during general anesthesia, but did not state how many patients had such anesthesia [31].

Risk of statins — It is unknown whether statins increase the risk of muscle symptoms and signs in patients with DM1 and DM2. However, statin use is associated with adverse muscle effects. Among the general population, statin-associated myalgia and myopathy occur with a frequency of 2 to 11 percent, while severe myonecrosis and clinical rhabdomyolysis are much rarer (0.5 and <0.1 percent, respectively) (see "Statin muscle-related adverse events", section on 'Epidemiology'). However, individuals with metabolic muscle disorders are more likely to experience statin-induced myopathic effects (see "Statin muscle-related adverse events", section on 'Preexisting neuromuscular disorders'). Therefore, a cautious approach seems warranted in patients with DM.

We suggest that patients with DM1 and DM2 who are treated with statins should have close monitoring of statin dose, potential myopathic symptoms, and serum creatine kinase levels. Statin use should be abandoned in favor of another lipid management strategy if an increase in statin-related muscle symptoms and signs develop. Of note, statin-induced muscle symptoms may be difficult to distinguish from the muscle pain associated with DM2 [18].

Genetic counseling — DM1 is inherited in an autosomal dominant manner, and therefore the offspring of an individual with a premutation (a phenotypically normal person with a mutable gene of CTG repeat size 35 to 49) or offspring of a phenotypically involved individual (abnormal gene with CTG repeat size of ≥50) with a frank mutation has a 50 percent chance of inheriting the mutant allele [50]. There is no evidence of preferential transmission of the mutated allele [51].

Disease-causing DM1 alleles may expand in length during gametogenesis, resulting in the transmission of longer CTG repeats that may be associated with earlier onset and more severe disease phenotype than observed in the parent, the phenomenon of anticipation. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Genetics'.)

Importantly, when the disease is transmitted by a male, the mean intergenerational variation in size of the CTG repeat is minimal (56 CTG repeats); however, when the mother is the affected parent, the mean intergenerational expansion is very high (948 CTG repeats), explaining why the expanded CTG repeat in congenital DM1 is inherited most often from the mother [51,52].

The risk of giving birth to a child with congenital DM is related to intergenerational amplification; the estimated risk is 60 to 100 percent if the maternal expansion is >900 repeats, and <12 percent if the expansion is <600 [53]. However, these estimates have wide confidence limits, making risk assessment difficult [50].

Maternal expansion is the underlying basis for the observation that congenital DM infants typically have an affected mother. Although it is common for neonatal cases (those with congenital DM) to be born from symptomatic mothers with multisystem involvement, it is also not unusual for the mother of a neonate affected with congenital DM to be asymptomatic, and subsequently be found to have an abnormal CTG expansion [51].

The following individuals are at risk and should be referred for genetic counseling, even if they are asymptomatic [50]:

Parents of an affected individual (ie, proband). Because almost all CTG expansions in the DMPK gene are inherited and new mutations are rare, both parents should be tested to identify the one with the allele in the abnormal range (>34 CTG repeats). Parents may appear unaffected because symptoms are sometimes hard to recognize in mild DM1, or may be truly asymptomatic and have a minimally expanded CTG repeat. Parents with an expanded CTG allele should receive recurrence risk counseling.

Couples with one affected spouse or a spouse at risk who plan to have children; they should be informed about the genetic risk to their future offspring, the availability of prenatal and/or preimplantation genetic testing, and the available reproductive options.

Other family members of an affected parent diagnosed by molecular DMPK testing. First-degree family members have a 50 percent risk of being affected with DM1.

Siblings of a proband who are approaching childbearing age. The risk to each sibling is 50 percent if one parent of a proband has an expanded CTG allele.

Offspring of a proband, even if asymptomatic. All offspring have a 50 percent chance of inheriting the expanded CTG allele. These individuals are at risk of having children with DM1. The allele may expand further during gametogenesis if inherited maternally, producing a more severely affected child.

Other family members of a proband. The risk depends upon the genetic status of the proband's parent. The risk of being affected with DM1 may be as high as 50 percent for other family members.

Genetic testing — Prenatal testing is available for pregnancies at risk for DM1 by analysis of DNA extracted from fetal cells obtained by amniocentesis at 15 to 18 weeks gestation, or chorionic villus sampling at 10 to 12 weeks gestation. It is important that molecular confirmation of the diagnosis (CTG expansion in the DM1 gene locus) be undertaken before prenatal testing is performed, and it is best that molecular diagnosis not only be confirmed in symptomatic parents but also that evidence of mutant alleles be sought in the asymptomatic parent [51].

For testing of symptomatic and at-risk asymptomatic children and adults, several points are germane with regard to DM1:

As a general rule, patients with larger CTG expansions in circulating leukocytes have an earlier onset of more severe symptoms. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Phenotypes'.)

The probability of developing an asymptomatic or mild phenotype is nearly 100 percent for patients with expansions of ≤100 CTG repeats [53].

For the patients with DM1 and a repeat size between 100 and 2000, there is great variation (table 2). The severity of the disease may be hard to predict on the basis of CTG repeat allele size, particularly in the 100 to 1000 CTG repeat range, because of significant overlap between phenotypes (mild, classic, childhood, and congenital) [54,55].

With 400 repeats, the risk of mild, moderately severe, and severe disease is 19, 72, and 9 percent, respectively [53].

Most patients with classic DM1 have between 100 and 1000 CTG repeats.

In children with congenital DM1, the CTG repeat size is usually ≥1000, though in some cases the CTG repeat size is between 730 and 1000 [56].

In those with ≥2000 repeats, usually infants and children, the likelihood of developing a severe phenotype is >90 percent [53].

In DM2, testing of at-risk asymptomatic adults can determine whether an individual has a CCTG expansion and, thus, whether he or she is at risk to develop the disease. Probands with de novo mutations have not been reported, and all affected individuals whose biological parents have been tested have had one parent with a CCTG repeat expansion. In contrast to DM1, the repeat size cannot predict age of onset, severity, or clinical symptoms. Again, in contrast to DM1, there is an absence of a congenital (severe) form of the disease. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Genetics'.)

The other notable difference between DM1 and DM2 is the behavior of the repeat size, which tends to contract when passed to the next generation in DM2 families (and tends to expand in DM1 transmissions), and then increases as the individual ages. However, there is no maternal or paternal predilection in DM2 for repeat size contraction or expansion. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Genetics'.)

As in DM1, prenatal testing for pregnancies at 50 percent risk for DM2 is possible when the presence of a mutation has been confirmed in an affected parent. However, such testing is not commonly done for a condition like DM2 that typically has an adult onset and does not have a major impact on the intellect.

Pregnancy — Women with DM1 have an increased risk of miscarriage, preterm delivery, and prolonged labor due to poor uterine contraction. Patients should be referred to a high-risk obstetrics provider where available for prenatal care and delivery [8]. (See "Neurologic disorders complicating pregnancy", section on 'Muscle disease'.)

LIFE EXPECTANCY — Life expectancy is clearly reduced for patients with congenital DM1, and is likely reduced for patients with childhood DM1 and classic (adult-onset) DM1 [18,55,57,58]. Respiratory and cardiac diseases are the most common causes of death. Younger age of onset, more severe muscle weakness, and cardiac arrhythmia may be associated with an increased risk of death.

In the DM2 population, the absence of a congenital form, the lack of association with any developmental abnormalities or severe childhood symptoms, and the relatively mild extramuscular manifestations (compared with DM1) suggest that life expectancy is unlikely to be compromised to the extent that it may be in patients with classic DM1.

The reduced life expectancy associated with DM1 is illustrated by the following reports:

In a study of 115 patients with congenital DM1, life-table data suggested that the likelihood of death before 18 months of age was 25 percent, while the likelihood of survival into the mid-thirties was 50 percent [59]. Up to 20 percent of patients died either suddenly or of documented cardiac arrhythmias.

A longitudinal cohort study of 367 patients with DM1 with a median age of 33 (range 2 to 80) at baseline were followed for 10 years [57]. During the course of the study, 75 patients (20 percent) died. The main causes of death were pneumonia (43 percent), cardiovascular disease or sudden death (31 percent), and neoplasia (8 percent). The overall mean age at death was 53 years. Using age-matched general population mortality rates as a comparator, the standardized mortality ratio (a ratio of observed to expected deaths) for those with DM was significantly increased to 7.3 (95% CI 5.8-9.1).

In another longitudinal study of 408 patients with DM1 who were followed for a mean of 5.7 years, there were 81 deaths (20 percent), and the mean age at death was 54 years [60]. The most common cause of death, affecting 32 of 81 patients (40 percent), was progressive neuromuscular respiratory failure. Twenty-seven patients (33 percent) died suddenly. Independent risk factors for sudden death were severe conduction system abnormality on baseline electrocardiogram (ECG; relative risk [RR] 3.3, 95% CI 1.24-8.78) and a clinical diagnosis of atrial tachyarrhythmia (RR 5.18, 95% CI 2.28-11.77). Independent risk factors for death from progressive neuromuscular respiratory failure were patient age, severe proximal muscle weakness, heart failure, and atrial tachyarrhythmia.

Cardiac conduction disturbances can progress rapidly and are associated with mortality in DM. In a cohort of 30 patients with DM1 who were followed over a 17-year period, the baseline ECG sum of the PR interval plus QRS duration of ≥320 msec was the best predictor of mortality [61]. All survivors had a PR plus QRS time of <320 msec. However, among the 15 patients who died, the cause was respiratory in 10 and cardiac in 3. In another study of 70 patients with DM1, independent positive predictors of PR and QRS prolongation during long-term follow-up were paroxysmal atrial flutter or fibrillation, older age, and larger CTG repeat expansions [62].

A separate issue that contributes to reduced life expectancy and increased morbidity is a tendency for medical care to be fragmented or deficient for DM1 patients and families. This phenomenon may result from two main factors [7]:

The complex manifestations of DM1, including neuromuscular, behavioral, emotional, and cognitive disturbances, contribute to suboptimal education levels, employment problems, and diminished income when compared with the general population, and accordingly compromise the daily activities and social roles of patients with this disease.

The variable multisystem presentations and complications of DM1 pose diagnostic and management challenges for the medical community.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Muscular dystrophy (The Basics)")

Beyond the Basics topics (see "Patient education: Overview of muscular dystrophies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystem disorders characterized by skeletal muscle weakness and myotonia, cardiac conduction abnormalities, cataracts, and other abnormalities. The age of onset, presentation, and severity and progression of symptoms vary according to DM phenotype. No disease-modifying therapy is available, and treatment is symptomatic. (See 'Management and DM phenotype' above and 'Specific management issues' above.)

Depending to some degree upon the phenotype, most patients with DM1 and DM2 may need cardiac evaluations for arrhythmia and cardiomyopathy; forced vital capacity (FVC) for respiratory muscle weakness; polysomnography for sleep disorders; ophthalmologic examination for cataracts; swallowing assessment for dysphagia; cognitive and psychosocial assessments for intellectual, attentional, and psychiatric disorders; and endocrine testing for diabetes and hypothyroidism (table 1).

Infants with congenital DM1 often present with respiratory and feeding difficulties and may require neonatal intensive care and ventilatory support. Neonates and children with congenital DM1 are at increased risk for aspiration and may require a feeding evaluation and gastrostomy tube feeding. (See 'Congenital DM1' above.)

The childhood (juvenile) form of DM1 typically presents with cognitive and behavioral problems. Cognitive and psychosocial assessments and interventions are important aspects of management, which is otherwise similar to that of classic DM1. (See 'Childhood DM1' above.)

In the classic (adult-onset) form of DM1, clinical manifestations include (but are not limited to) skeletal and respiratory muscle weakness, myotonia, cataracts, cardiac arrhythmias, and excessive daytime sleepiness (EDS). Multidisciplinary management is optimal. (See 'Classic DM1' above.)

The mild form of DM1 is generally not debilitating, but surveillance for cataracts and potentially serious manifestations of DM1, such as cardiac conduction abnormalities, is advisable. (See 'Mild DM1' above.)

DM2 generally is less severe than classic DM1 but can progress to disability and is associated with an increased risk of cardiac conduction disease and other serious complications. Management is similar to that of classic DM1. (See 'DM2' above.)

Management of physical disability may involve the use of assistive devices. For adolescent and adult patients with DM1 and adults with DM2 who are able to participate, have a normal electrocardiogram (ECG), and are free from cardiac symptoms, we suggest low-intensity exercise training as tolerated and without undue physical stress (Grade 2C). For patients with cardiac symptoms or an abnormal baseline ECG, we suggest exercise testing with ECG monitoring prior to beginning an exercise training program, since exercise can trigger arrhythmias. In this group of patients, a decision regarding the safety of exercise training should be made by a cardiologist. (See 'Muscle involvement' above and 'Exercise training' above.)

For occasional adult patients who have severe myotonia that interferes with function, we suggest initial therapy with mexiletine 450 or 600 mg daily in three divided doses (Grade 2C). For children with severe myotonia, we suggest oral mexiletine 1.5 to 3.0 mg/kg every 8 to 12 hours (Grade 2C). Adults and children should have a cardiology evaluation for risk assessment before starting treatment with mexiletine. (See 'Myotonia' above.)

For adult patients with DM1 and severe EDS, we suggest a trial of modafinil (200 mg twice daily) (Grade 2B). (See 'Excessive daytime sleepiness' above.)

Average life expectancy is reduced for patients with congenital DM1, childhood DM1, and classic (adult-onset) DM1, whereas average life expectancy is probably normal or near normal for patients with DM2. (See 'Life expectancy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David A Chad, MD, who contributed to an earlier version of this topic review.

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