Myotonia

Etiology

The presentation of myotonia can result from a diverse array of etiologies. The most common myotonic disorder is myotonic dystrophy type 1, resulting from a trinucleotide repeat on the dystrophia myotonica protein kinase (DMPK) gene that has varying protein consequences depending on the length of the repeat. The next most common disorders are the myotonic channelopathies, led by myotonia congenita in prevalence, which results from defects in electrolyte channels that cause resulting skeletal muscle overexcitability. 

1. Dystrophic Myotonias

• Myotonic dystrophy type 1 (CTG trinucleotide repeat on DMPK gene) [2]
• Myotonic dystrophy type 2 (CCTG tetranucleotide repeat on CNBP gene) [2]

2. Non-dystrophic Myotonias

• Myotonia congenita (CLCN1 gene, chloride channelopathy) [3]
• Paramyotonia congenita (SCN4A gene, sodium channelopathy) [3]
• Sodium channel myotonias (SCN4A gene, sodium channelopathy) [3]

3. Periodic Paralyses 

• Hypokalemic periodic paralysis type 1 (CACNA1S gene, calcium channelopathy) [3]
• Hypokalemic periodic paralysis type 2 (SCN4A gene, sodium channelopathy) [3]
• Hyperkalemic periodic paralysis (SCN4A gene, sodium channelopathy) [3]
• Andersen-Tawil syndrome (KCNJ2 gene, potassium rectifying channelopathy) [3]

Epidemiology

Dystrophic Myotonias

• Myotonic dystrophy type 1 is the most common myotonic disorder overall, with a prevalence of 1 in 8,000 [2]
• Myotonic dystrophy type 2 is a rare disorder with unknown prevalence estimated to be between 1 to 9 in 100,000 [2]

 Non-dystrophic Myotonias

• Myotonia congenita is the most common non-dystrophic myotonia, with a prevalence ranging from 0.2 to 7.3 per 100,000 [4]
• Paramyotonia congenita has a prevalence of approximately 1 in 250,000 [4]
• Hypokalemic periodic paralyses have a prevalence of 13 in 100,000 [4]

• Hyperkalemic periodic paralyses have a prevalence of approximately 1 in 200,000 [4]
• Andersen-Tawil syndrome has a prevalence of approximately 1 in 1,000,000 [4]

History and Physical

A patient presenting with myotonia would be expected to describe an impaired and delayed relaxation of a muscle after contraction. The patient may also describe symptoms such as pain, weakness, and fatigue due to prolonged muscle contraction. Depending on the specific myotonia involved, the patient may present with abnormal muscle appearance, including muscle hypertrophy or under-development. Episodic muscle weakness may also be reported. Classically, the patient will also report muscle stiffness that improves with activity, called a ‘warm-up’ phenomenon. However, the warm-up phenomenon is absent in less common etiologies of myotonia, such as paramyotonia congenita and myotonia dystrophy type II.[5]

In Dystrophic Myotonias, systemic symptoms will also frequently be present. Depending on the mutation and protein involved, you can expect to see patients reporting blurred vision from cataracts, hyperglycemia from insulin resistance, facial dysmorphisms, which can include a distinctive "carp-shaped" mouth or bone abnormalities on x-ray.[3] The presence of systemic systems with the classic myotonia symptoms described above and normal electrolytes should raise suspicion for Dystrophic Myotonia.

Hyperkalemic Periodic Paralysis patients would be expected to present within the first decade of life with complaints of episodic muscle paralysis lasting from 1 to 4 hours. Reported triggers could include rest after exercise, consumption of potassium-rich foods, fasting, stress, and fatigue. Respiratory muscle involvement could be seen in severe cases. Patients will typically recover to full strength between episodes but may develop weakness later in life.[4] If the patient has had routine laboratory work in the past, they may report a history of hyperkalemia.

In contrast, a patient with Hypokalemic Periodic Paralysis would typically present with episodes of muscle weakness that most commonly occur at night or early in the morning. The attacks can last from hours to days, with variable severity from mild weakness to profound paralysis. The attacks can be of any frequency, from multiple per day to only a few in a lifetime. Attack triggers can include carbohydrate-rich foods, alcohol, stress, exercise, menstruation, and medications, including insulin and corticosteroids. With severe hypokalemia, ocular, bulbar, or respiratory muscles can be involved.[6]

Evaluation

Evaluation of suspected myotonia should involve the exclusion of other more common pathologies that may present similarly, followed by confirmatory testing if negative. The patient will most commonly present with muscle hypertrophy, a positive family history, and muscle stiffness with repeated activity. The creatine kinase may be elevated. Abnormal thyroid function should be ruled out due to a similar presentation. Other etiologies, such as inflammatory or toxic myopathies, should be considered in the right clinical context. Testing for dystrophic and non-dystrophic myotonia will require a needle electromyogram (EMG) study, with long and short exercise testing. However, genetic testing is the gold standard and can identify over 130 mutations known to result in non-dystrophia myotonia.[2]

For a patient with suspected hypokalemic or hyperkalemic period paralysis, evaluation should include a laboratory test demonstrating high or low levels of potassium in the blood, along with the history & physical rxam findings noted in that section above. The patient should first be evaluated for other more common causes of increased or decreased serum potassium. At a minimum, the patient should be evaluated for renal dysfunction, iatrogenic causes of hypo/hyperkalemia, gastrointestinal loss, and basic endocrine function. Confirmatory testing for the periodic paralyses also requires needle electromyogram studies or genetic testing, with genetic testing as the gold standard.[3][7][8]

Treatment / Management

Treatment of myotonia resulting from the dystrophic and non-dystrophic myotonias is not well established. However, mexiletine has been demonstrated to have efficacy in the relief of myotonia in myotonic dystrophy type I and non-dystrophic myotonias. The recommended dosage is 200 mg three times daily, with an ECG evaluation of QT interval before administration. Other medications have been suggested for the treatment of myotonia, including imipramine, taurine, and clomipramine, but the evidence is too weak to recommend at this time.[9](A1)

In addition to pharmacologic management of myotonia, trigger avoidance in non-dystrophic myotonias such as avoiding cold exposure and strenuous exercise can provide significant patient relief. In dystrophic myotonias, targeted therapies designed to reduce the systemic symptoms of the disease can significantly alleviate patient discomfort. Given that systemic systems in dystrophic myotonias vary widely by patient, treatment choice will vary as well and will depend on the particular system involved.

Treatment of patients with periodic paralysis should focus on avoiding known triggers and stabilizing serum potassium. Patients should reduce stressful situations such as nightshift work, irregular meals, abnormal sleep-wake cycles, high-carbohydrate meals, and prolonged rest after exercise. In hyperkalemic periodic paralysis, patients should adhere to a diet low in potassium-rich foods and diuretic use. In hypokalemic periodic paralysis, patients should increase potassium intake by adhering to a diet rich in potassium-rich foods. If conservative management fails, both types of periodic paralysis can be treated with carbonic anhydrase inhibitors such as dichlorphenamide or acetazolamide, with dichlorphenamide as first-line due to fewer side effects.[10][11]

Differential Diagnosis

Myotonia can be differentiated from mimicking conditions by a thorough history, physical exam, and basic laboratory testing. Hypothyroidism is one such condition that can present similar to myotonia. However, the patient would likely not describe an episodic muscle weakness. However, routine thyroid function laboratory studies should be performed in any patient being considered for a diagnosis of myotonia to rule out an atypical presentation. Likewise, electrolyte abnormalities can temporarily present similarly to myotonia, and in particular similar to the hyper/hypokalemic periodic paralyses. However, the patient would again not likely suffer such a condition on an episodic basis over an extended period of time, and further workup may reveal a source of electrolyte disturbance.

Prognosis

Non-dystrophic myotonias have generally been regarded to have a benign prognosis. However, data is limited due to the relative rarity of the illnesses. The severity of illness is thought to be best correlated with the acuity of the patient’s reported pain and fatigue. In dystrophic myotonias, the severity of illness is best predicted by the severity of the systemic symptoms involved. Given that myotonic dystrophy type 1 and 2 can often present with significant systemic symptoms, the morbidity of a patient’s disease can be severe. However, myopathy is thought to be most severe in the periodic paralyses and can worsen with age and result in permanent severe myopathy.

Complications

All myotonias can result in worsening or more significant myopathy over time, particularly the periodic paralyses. In addition, dystrophic myotonias can result in significant systemic symptoms, including cataracts, insulin resistance, facial dysmorphisms. Patients can also suffer iatrogenic harm, as most medications used to treat myotonia have significant side effect profiles.