Congenital and Acquired Myotonia

Author(s): Heakyung Kim, MD, Hannah Aura Shoval, MD, Jahannaz Dastgir, MD

Originally published:09/22/2015

Last updated:09/22/2015

1. DISEASE/DISORDER

Definition

Myotonia is characterized clinically by a prolonged muscle contraction or a delayed muscle relaxation, often lasting several seconds.1 Electrophysiologically, myotonia is characterized on EMG by a distinctive pattern of spontaneous firing of muscle fibers waxing and waning in frequency and amplitude.2

Etiology

The majority of conditions with myotonia are hereditary (inherited genetically), with some hereditary forms being congenital and others appearing later in development. Hereditary myotonia most commonly occurs in conjunction with dystrophic and nondystrophic myopathies, but may also rarely occur with episodic ataxia syndromes.

Nonhereditary myotonia can be antibody mediated (autoimmune or paraneoplastic), occur in the setting of other conditions such as hypothyroidism, or be drug induced.

Additionally, there are other conditions with delayed relaxation that may clinically present like myotonia but do not have true electrophysiological myotonia, which may be collectively referred to as “pseudomyotonia”.10 In a recent Cochrane review of myotonia treatment, they excluded McArdle’s disease (glycogenosis type V), Hoffman’s disease (CPK elevation with muscle hypertrophy and complex spontaneous discharges sometimes including true myotonia, due to hypothyroidism), Brody’s disease (sarcoplasmic reticulum- Ca2+ATPase deficiency), neuroleptic malignant syndromes and tetanus.11 There is some controversy as to whether Schwartz-Jampel syndrome (chondrodystrophia myotonia) is considered a true form of myotonia.12,13 There are also related but distinct conditions referred to as stiff-person syndrome, with progressive rigidity and spasm with stimulation, waxing and waning with concurrent spasms of proximal muscules, showing continuous involuntary motor unit activity on EMG that is abolished during sleep, most commonly due to anti-GAD antibodies. Isaacs syndrome (aka Isaacs-Merton syndrome, neuromyotonia or pseudomyotonia) is more commonly paraneoplastic or due to peripheral nerve disorders, characterized by continuous muscle fiber activity on EMG that persists during sleep and also fasciculations, myokymia, and complex repetitive discharges. The overlap between various syndromes and etiologies can be confusing. Hereditary neuromyotonia such as Gamstrop-Wolfhart syndrome is referred to by some sources as a variant of Isaac’s syndrome, and the hyperekplexia syndromes, which are also hereditary, are sometimes referred to as stiff-baby syndrome. Treatments most successful for each of these syndromes differ substantially.

The rest of this article will focus on true myotonia with muscle membrane hyperexcitability.

Patho-anatomy/Physiology

Myotonia is caused by the hyperexcitability of skeletal muscle fibers due to alterations in voltage gated chloride, sodium, calcium, or potassium channels. In nondystrophic disorders it is a mutation in the gene that alters the Na, Cl, Ca or K channel structure and thus conductivity and function.3 In myotonic dystrophy, it is not a mutation in the gene of the channel itself but a defect in the mRNA splicing of the Cl channels leading to expression of a nonfunctional variant of the chloride channel.4 This defect in mRNA splicing may affect gene expression in other organs as well and explain why dystrophic disorders are part of a systemic disease not just localized to muscles.

Myotonia can occur in skeletal muscle, affecting neck movement, chewing, and eyelid opening.5 This can occur after initial voluntary contraction, spontaneously, or after mild stimulation such as percussion of a muscle, termed percussion myotonia.6 Myotonia can also occur in smooth muscles, which may explain symptoms of delayed pupillary response,abdominal pain, diarrhea, bloating, and dysphagia8 that can be seen in patients with myotonia.

Classification: Clinical vs. Electrical Myotonia

A number of medications can cause EMG myotonia with or without clinical myotonia. These include cardiac medications including Propranolol and lipid lowering agents such as HMG-CoA reductase inhibitors, clofibrate, and 20, 25-diazacholesterol.5 Cases induced by 20, 25-diazacholesterol can present with myotonia and cramps several months after start of medications.9 Some asthma medications, such as terbutaline, fenoterol, beta-adrenergic agonist inhalers, as well as some immunosupresants, penicillamine, cyclosporine, colchicine, monocarboxylic acids, anthracene-9-carboxylic acid, 2,4-dichlororophenoxyacetic acid5 and chloroquine can also cause myotonia. Treatment is to stop medication when clinically indicated.

Electrophysiologic myotonia may also be seen in association with other disorders:2

  1. Metabolic: acid maltase deficiency (Pompe’s disease)
  2. Inflammatory: Dermatomyositis/polymyosits
  3. Congenital: centronculear or myofibrillar myopathies
  4. Systemic disorders: malignant hyperpyrexia, drug-induced, autoimmune, or other causes of hypothyroidism.
  5. Cases of severe denervation of any etiology.5

Myotonia

Electrical and Clinical Myotonia

  1. Dystrophic Myotonia*
    1. Myotonic Dystrophy Type I
    2. Myotonic *Dystrophy type II
  2. Ion Chanel Dysfunction
    1. Cl- Channel Disorder
      1. Thomsen Myotonia Congenita.
      2. Becοker Myotonia Congenita
    2. Na+ Channel Disorder
      1. Paramyotonia Congenita
      2. Myotonia Fluctuans
      3. Myotonia Permanens
      4. Acetazolamide-Responsive Myotonia.
      5. Hyperkalemic Periodic Paralysis with Myotonia.
    3. K+ Channel Disorder
      1. Episodic Ataxia
    4. CA+2 Channel Disorder

Primarily Electrical with variable clinical myotonia

  1. Other*
  2. Medications / Agents *

Electrical Myotonia with Clinical Myotonia: Myotonic dystrophy

EPIDEMIOLOGY

According to the NIH, myotonic dystrophy, the most common condition with myotonia, affects at least 1 in 8,000 people worldwide with DM1 being the most prevalent.14 Because of the genetic nature of this condition, a founder effect contributes to the increased prevalence of DM2 in some geographical areas, most notably in Finland.15

GENETICS:

DM1 and DM2: Autosomal Dominant

DM1: chromosome 19q13.3 locus DMPK with repeat expansion of CTG. Severity of disease is roughly associated with number of repeats of CTG.

DM2: chromosome 3q21.3 locus CNBP, with repeat expansion of CCTG. Severity of DM2 is much less clearly related to the number of repeat expansions of CCTG.

CLINICAL COURSE/PROGNOSIS

DM1 16: Patients with more severe cases may be severely affected with hypotonia, clubfoot, myopathic facies and dysphagia at birth. Less severe cases of the condition becomes apparent with global developmental delays; adult onset cases typically result in disability by age 30-50yrs unless very mild with relatively few repeats. Cataracts are generally present in adults, type II diabetes is increasingly likely to develop over time, as are marked disturbances of arousal and sleep-wake cycle; cardiac conduction defects are common and respiratory insufficiency prominent at later stages, both leading to premature death.

DM2 16: Generally patients are able to function, work, and perform activity of daily living while younger than 60 unless severely debilitated by pain. Tremors are prominent. Muscle weakness becomes more severe at age 60-85 causing disability. Patients have increased coronary artery disease. Cataracts present in nearly all over the age of 20 by slit lamp examination.17 Overall, life expectancy is much closer to normal.

Specific secondary or associated conditions and complications

Myotonic dystrophies affect multiple organs of the body with dermatologic, gynecologic, cardiac, pulmonary, and neurological effects.

DM1: Excessive daytime sleepiness, gastrointestinal symptoms, endocrinopathies most commonly diabetes, hypothyroidism and hypogonadism, restrictive lung disease, a malignant hyperthermia-like reaction to anesthesia, cancer, and, in some, mild cognitive impairments17; more severe intellectual disability is more common with younger onset of clinical disease. In childhood onset, psychiatric diagnosis are common, especially phobia, mood, anxiety and attention-deficit-hyperactivity disorders.22

DM2: tremor, atherosclerosis5. Respiratory muscles are generally preserved. Cardiac, Diabetes and hearing loss are each present in 20% of patients with DM2.17

2. ESSENTIALS OF ASSESSMENT

History

Patient should be asked about symptoms of pain, cramping and weakness. Distal muscles are usually more affected and difficulty releasing grip may be noted, or patients may have successful, even subconscious, strategies for avoiding this. A thorough review of systems is needed to address all organs. Family history should include any neuromuscular disease, family history of cataracts and the age of onset, and history of heart disease or arrhythmias. Ophthalmologic history should include cataracts, especially any developing before age 50.

DM1: Adult-onset presenting with muscle weakness, myotonia and or cataracts especially in the setting of family history of similar symptoms. Childhood-onset cases often present with difficulties at school due to attentional problems and/or intellectual disability, and they eventually develop more symptoms of muscular weakness and myotonia. Congenital-onset form is the most severe form (covered elsewhere http://me.aapmr.org/kn/article.html?id=214). Be aware of the “anticipation” phenomenon, where each generation is more severely affected because of expansion of the trinucleotide repeat; many children are born to parents who are unaware they have the condition. Males may transmit the disease in milder form, as with increasing severity, their fertility is affected, but most severe cases are therefore born to affected mothers. These mothers may have myotonia and myopathic facies, are fertile but prone to deliver prematurely, and may even be cognitively affected enough that they are unable to raise their children, so that care is delegated to a grandparent who is either unaffected or very mildly symptomatic, and commonly undiagnosed.

DM2: Presentation between 8-60 yrs of age. There is no congenital form. Large variability in symptoms with some cases extremely mild with minimal if any significant effect. Pain is a prominent component. In contrast to DM1, weakness and pain are most common in proximal muscle groups, with diffuse areas of pain to palpation, and pain at rest not associated with timing of myotonia.16,17

Physical examination

Clinically, myotonia is best tested by having a patient make a tight fist and then try to open hands quickly.11 In the case of myotonia, there will be a few second delay in hand opening. Similarly, after forced eye closure there will be delay in eyelid opening.5 Percussion of thenar eminence, wrist extensors, quadriceps, gastrocnemius or tongue, are classically used to test for percussion myotonia. Symptoms of myotonia are generally aggravated by cold.

DM1: Characteristic facial appearance with frontal balding, atrophy in the temporal muscles, ptosis and tented upper lip. Distal muscles are more affected. There is often a “warm up” phenomenon where myotonia improves with repeat activation.

DM2: A “jerky”/”ratchety” quality to grip.5 Pain, unrelated to myotonia, occurring spontaneously or elicited by palpation on exam is common in proximal muscle groups. Proximal muscles are more affected than distal muscles or facial muscles. Cognitive deficits, when present, are generally mild.

Clinical Functional Assessment

Difficulty with ambulation, climbing stairs,11 manual dexterity, opening or closing eyelids11 and releasing a handshake, which can be socially embarrassing.

Laboratory Studies

Laboratory testing should include creatinine kinase, hgbA1c, follicular stimulating hormone, gamma-glutamyltransferase, albumin, white blood cell counts, total cholesterol, lactate dehydrogenase and alanine aminotransferase, IgG lymphocytes, and serum potassium.

EKG, echocardiogram and monitoring of pulmonary function are also recommended.

DM1: Elevated CPK.

DM2: CPK can be modestly elevated, but is more likely to be closer to normal. Positive rheumatological serological markers and high lipid profiles are common.

Muscle Biopsy 16: Muscle biopsy can be done if diagnosis is not clear based on the clinical picture or if genetic and electrodiagnosis evidence is not available. Muscle biopsy abnormalities are more common in dystrophic myopathies compared to more variable findings in nondystrophic myotonia, including normal, myopathic or hypertrophied muscles.

DM1: Small type I fibers, sarcoplasmic masses and ring fibers are frequent as well as internalized nuclei.

DM2: Highly atrophic type 2 fibers. Nuclear clumps.

Imaging16

MRI of muscles shows fatty hypertrophy correlating with clinical weakness. Brain MRI shows widespread white matter changes.

DM1 16: Soleus and medial gastrocnemius is most affected and affected first. Brain MRI findings are common.

DM2: Vastus latereralis is first affected.16 The involvement of erector spinae and gluteus maximus are also common.17 Milder brain MRI findings may be found in some advanced or severe cases 16.

Supplemental Assessment Tools

Electrodiagnostically, myotonia has been likened to hearing a revving engine or dive bomber airplane.2,5 Morphologically, the spontaneous muscle fiber action potentials have characteristics of positive waves or fibrillations.5 This can be stimulated by voluntary contraction, stimulation by the motor nerve or an electrode, 1 or mechanical stimulation including percussion or needle stimulation.2 Characteristic results with short and long exercise tests help to differentiate between the various causes of myotonia.

DM1: More easily evoked in most muscles compared to in DM2.5

DM2: More easily evoked in proximal muscles, such as vastus lateralis and tensor fascia lata compared to in DM1.5 Amplitudes of CMAP and myotonia increase with exercise and decrease with rest.17

Genetic testing: Diagnosis of both DM1 and DM2 is confirmed via genetic testing.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Multidisciplinary treatment with education, genetic counseling and symptom modification with physical therapy as well as close monitoring and treatment of systemic features and associated diseases. Most importantly, cardiac arrhythmias should be monitored by yearly electrocardiographic or Holter testing 5, especially for DM1.

There is currently no FDA approved medication for spasticity and there is insufficient evidence for safety and efficacy for myotonia treatment.11 According to a Cochrane review updated in 2011, while there was insufficient evidence to make any recommendations at this time, the best evidence exists for clomipramine, imipramine, both anti-depressants, as well as taurine, an amino acid.11 According to a review article in Muscle and Nerve, more recently the best evidence exists for the efficacy of mexiletine for pain control5 though anecdotally it may also be of functional benefit.

Symptoms of hypersomnolence are thought to be primarily caused by a central dysfunction of sleep regulation as opposed to sleep-related disordered breathing or sleep fragmentation, and they have been successfully treated in some cases with methylphenidate, as recommended by the American Academy of Sleep Medicine for patients with DM1.20

DM1: Special precautions are needed during anesthesia given the prevalence of cardiopulmonary involvement especially the increased risk for atelectasis, pneumonia or acute ventilatory failure. Patients have a high sensitivity to respiratory depression with benzodiazepines and opioids, and paracetamol and NSAID’s are preferred when not contraindicated fotr other reasons.21 Weak bulbar muscles, prolonged gastric emptying time, and blunted response to C02 require awake extubations, caution with postoperative noninvasive ventilation, and careful use of supplemental oxygen.21 Muscular disability can help predict patients with highest perioperative risk.21

Muscle relaxants and hyperkalemia should be avoided and regional anesthesia is preferred when possible.

Stimulant medications are commonly used to treat the circadian rhythm disturbances and attentional disorders. Visual-spatial deficits should also be evaluated as they are common in childhood onset DM1.22 Severity is associated with a greater number of CTG expansion.22

DM2: Pain is a prominent feature in DM2 and can be treated with anti-myotonic pharmaceuticals listed above. Alternatively, nonsteroidal anti-inflammatory medication and acetaminophen may provide relief.5 Patients may require referral to pain management.

Translation into Practice and Clinical Pearls:

A diagnostic workup should be considered even in patients who are taking medications with known myotonic potential as drugs can unmask an underlying disease.5 Presence of cataracts at a young age should prompt further questioning. Type of cataract diagnosed can be very helpful as the presence of iridescent posterior subcapsular opacities are almost pathognomonic for DM1.18 The average time from onset of symptoms to diagnosis is over 5 years for DM1, and over 14 years for DM2.16 The longer delay for DM2 is likely due to subtler symptoms and poor clinician awareness.16

4. CUTTING EDGE/EMERGING ISSUES AND UNIQUE CONCEPTS

Research is focused primarily on DM1. Attempts are being made to use antisense oligonucleotides that reduce transcripts from the mutant DMPK allele without affecting the DMPK protein.16 Given the similarities between DM1 and DM2, treatment of DM1 will likely be adaptable to help treat DM2.16 Treatment for the cognitive and other CNS symptoms also has less rigorous evidence available at this time.19

Patients with these conditions, particularly DM1 mutations, should be offered genetic counseling and testing. In vitro fertilization and pre-implantation diagnostic methods can significantly reduce the risk of DM1 transmission between generations.

5. GAPS IN EVIDENCE-BASED KNOWLEDGE

For DM1 and DM2, a better understanding of molecular pathomechanisms and DNA instability is needed. RNA toxicity with spliceopathy does not seem to account for all the multisystem involvement.16

REFERENCES

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  2. Preston D, Shapiro B. Electromyography and neuromuscular disorders.3rd edition London: Elsvier inc; 2013. Chapter 36- Myotonic muscle disorders and periodic Paralysis Syndromes p563- 582.
  3. Pusch M. Myotonia caused by mutations in the muscle chloride channel gene CLCN1. Hum Mutat 2002;19:423–434.
  4. Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, MoxleyRT, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 2002;10:35–44.
  5. Heatwole CR, Statland JM, Logigian EL. The diagnosis and treatment of myotonic disorders. Muscle Nerve. 2013;47(5):632–48. doi:10.1002/mus.23683.
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  7. Harvey JC, Sherbourne DH, Siegel CI. Smooth muscle involvement in myotonic dystrophy. Am J Med 1965;39:81–90.
    http://neuromuscular.wustl.edu/mother/myotox.htm#diazacholesterol
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  9. Trip J, Drost G, van Engelen BGM, Faber CG. Drug treatment for myotonia. Cochrane Database Syst Rev. 2006:CD004762. doi:10.1002/14651858.CD004762.pub2.
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    http://ghr.nlm.nih.gov/condition/myotonic-dystrophy
  12. Neurology. 1999 Jul 22;53(2):297-302. Founder mutations and the high prevalence of myotonia congenita in northern Finland. Papponen H1, Toppinen T, Baumann P, Myllylä V, Leisti J, Kuivaniemi H, Tromp G, Myllylä R.
  13. Udd B, Krahe R. The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 2012;11:891–905. doi:10.1016/S1474-4422(12)70204-1.
  14. Braddom, Randall. 4th edition. Physical Medicine and Rehabilitation. Chapter 48 Myopathic Disorders. Philadelphia, PA: Saunders 2011.
  15. Garrott HM, Walland MJ, O’Day J. Recurrent posterior capsular opacification and capsulorhexis contracture after cataract surgery in myotonic dystrophy. Clin Experiment Ophthalmol 2004; 32: 653–55.
  16. Laberge L, Gagnon C, Dauvilliers Y, Daytime sleepiness and myotonic dystrophy, Curr Neurol Neurosci Rep. 2013 Apr;13(4):340. doi: 10.1007/s11910-013-0340-9.
  17. Laberge L, Gagnon C, Dauvilliers Y. Daytime Sleepiness and Myotonic Dystrophy. Curr Neurol Neurosci Rep (2013) 13:340 DOI 10.1007/s11910-013-0340-9)
  18. Veyckemans F1, Scholtes JL., Myotonic dystrophies type 1 and 2: anesthetic care, Paediatr Anaesth. 2013 Sep;23(9):794-803. doi: 10.1111/pan.12120. Epub 2013 Feb 5.
    http://onlinelibrary.wiley.com/doi/10.1111/pan.12120/abstract
  19. Douniol M, et.al, Psychiatric and cognitive phenotype in children and adolescents with myotonic dystrophy, Eur Child Adolesc Psychiatry. 2009;18(12):705-15.
    http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04379.x/epdf
  20. Van de Meche’ et al, Treatment of hypersomnolence in myotonic dystrophy with a CNS stimulant, Article first published online: 13 OCT 2004 DOI: 10.1002/mus.880090410, Muscle & Nerve Volume 9, Issue 4, pages 341–344, May 1986.

Author Disclosure

Heakyung Kim, MD
Nothing to Disclose

Hannah Aura Shoval, MD
Nothing to Disclose

Jahannaz Dastgir, MD
Nothing to Disclose

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