Clinical and EMG Myotonia


Drug-induced myotonia: Beta-blocking drugs or diuretics, depolarizing, relaxing and anesthetic drugs, and statins may induce short-lived myotonia.

Isaacs syndrome: The disease presents early in life with most patients being < 40 years of age at the time of symptom onset. A dominant mode of inheritance in the familial form of the disease may occur. Progressive painless stiffness, cramping, and weakness are prominent features of the disease. As opposed to fasciculations, patients complain of constant myokymia (writhing movements of the muscles under the skin visualized by continuous "rippling" movements of the muscle). These persist during sleep. Hyporeflexia is also seen in a large percentage of patients. Weakness, when present, tends to be in the distal lower extremities. Autonomic involvement may also be seen with hyperhidrosis and tachycardia. Calf hypertrophy has been described in some patients. "Action" or grip myotonia may be seen. However, percussion myotonia is rare. There may be an associated neuropathy. EMG is the most valuable diagnostic test with continuous motor activity: spontaneous discharges, and rhythmical and continuous firing. The configuration of the wave forms varies, representing either motor units or single fiber discharges. Myokymia is seen electrically. This motor activity persists during sleep. Serum CK levels may be increased. No routine laboratory test is available to detect the antibodies which have been described in research studies. The diagnosis is made by the characteristic history of cramping and stiffness, which persists during sleep and the EMG findings of continuous spontaneous discharges and myokymia in the affected muscle groups. Sleep, narcosis and plexus block have no effect on the continuous motor activity, which can be blocked only succinylcholine. Plasma exchange can result in significant benefit, while the iv immunoglobulin can make symptoms worse. The differential diagnosis includes stiff-person syndrome (prominent muscle stiffness which disappears during sleep with no myokymia on EMG). Anti-GAD antibodies are found in stiff-person syndrome. Benzodiazepines are helpful in stiff-person syndrome, but have no effect in Isaacs syndrome. Phenytoin and carbamazepine are helpful for stiffness in Isaacs syndrome, while there is no effect in stiff-person syndrome. Another disease to be considered in the differential is the Schwartz-Jampel syndrome (myotonia, stiffness syndrome, dwarfism and muscle hypertrophy).

Proximal myotonic myopathy (PROMM) or myotonic dystrophy type 2 (DM2): The age of onset is in the 2nd or 4th decade of life (age range 13 – 67 years, median 48 years). This autosomal dominant multisystem disorder is characterized by a characteristic pattern of muscle weakness involving proximal leg weakness (hip flexor and extensors), neck flexors, elbow extensors, thumb and deep finger flexors, and without atrophy (as opposed to distal involvement in DM1), clinical myotonia and myalgias, and cataract (before the age of 40 years). Fluctuating or episodic muscle pain is common in patients > 50 years. Further typical features are cardiac disturbances (asystole, arrhythmias, episodic syncope, conduction block and cardiomyopathy) and hypogonadism (with elevated FSH). Early-onset male frontal balding is found in 20 – 50% of patients. Serum CK (typically less than 5x the upper limits of normal) and γ-GT are usually elevated. Diabetes is found in 23% and abnormal glucose tolerance testing shows insensitivity in 75% of patients. Muscle biopsy (vastus lateralis) is abnormal even with normal manual strength testing being normal. The disorder is linked to the DM2 locus at chromosome 3q21. Lack of mental retardation in juvenile cases, less symptomatic distal, facial and bulbar weakness and less pronounced atrophy differentiates this form of dystrophy from DM1. While distal weakness and myotonia are usually the first complaints in DM1, muscle pain, stiffness, fatigue or proximal weakness are the reasons for seeking medical advice in PROMM.


Myotonic dystrophy (DM1): MD type 1 is the most common form of adult muscular dystrophy (1/8,000). It is transmitted as an autosomal dominant trait. The severity of the disease is highly variable, with phenotypic spectrum including symptomatic or very mild affected adults. The following features are however constantly present: atrophy of the intrinsic hand muscles, facial muscle involvement, myotonia and dystrophic changes in nonmuscular tissue. In adulthood, it presents with myotonia, progressive muscle weakness and wasting affecting first distal limbs muscles or ptosis and facial weakness. Small muscles of the hands along with the extensor muscles of the forearms are often first to become atrophic. Alternatively, foot drop may be an early manifestation. Myotonia may precede the weakness by years and can be easily elicited (clinically and on EMG) in the hands and tongue after forceful contraction (action myotonia) or percussion. Typical facial appearance; hatchet-like shape of the head, frontal balding, slack eyes with ptosis, flat smile with facial and jaw weakness, and slightly forward carriage of head due to neck muscle weakness (“swan neck”). Pharyngeal and laryngeal weakness may result in monotonous nasal voice. IQ is low-normal with hostile, reticent, suspicious, uncooperative personality. Cardiomyopathy together with pneumonia (diaphragmatic weakness and alveolar hypoventilation) is the most frequent primary cause of sudden death occurring in 30% of patients. ECG changes consisting of major conduction changes, major arrhythmias or both are found in 26-48% of patients. Other characteristics dystrophic changes include lenticular opacities or cataract (slit lamp), dilatation and hypomobility of the esophagus or bowel (due to dilation), testicular and ovarian atrophy and daytime somnolence. Occasionally sensorimotor neuropathy, frontal hyperostosis and basal ganglia calcification may be found. The myotonic dystrophy locus (myotonin protein kinase or DMPK) is located on chromosome 19q13.3 (unstable trinucleotide CTG). Most patients are wheelchair bound in 20 years. If the genetic test is negative PROMM should be considered.


Myotonia congenita (Thomsen disease): This autosomal dominant chloride channel disorder is a nonprogressive, nondystrophic myotonic disorder. The age of onset ranges from the 1st - 2nd decade, but as opposed to MD1 this is an early onset myotonia. Typical complaints are difficulty releasing the grip of a handshake or opening the eyelids after squinting in bright sunlight. It is further characterized by muscle stiffness and myotonia most pronounced after a period of inactivity (exposure to cold does not worsen myotonia (paramyotonia congenita) or hyperkalemia (hyperkalemic periodic paralysis)). Percussion myotonia can be elicited by tapping of the muscle and tongue and persists for several seconds. Improvement of myotonia and movements, in general, is observed after continued exercise (‘warming up’ phenomenon). The myotonia is painless, but after prolonged activity nocturnal myalgia may develop. Thomsen disease affects the legs > face, arms. Patients may stumble and fall. Smooth muscles and heart are never affected. Intelligence is normal and no dystrophic features of MD1 are found. Thomsen disease may manifest itself first as myotonia associated with weakness during pregnancy. Small muscle potentials, myotonic discharges are present on EMG, with no CMAP decrement with cooling. Biopsy is normal. Both Thomsen and Becker disease have been linked to chromosome 7q35 in the region of the human skeletal muscle chloride channel gene (CLCN1). Mexiletine and phenytoin are effective in the treatment. Thomsen disease needs to be differentiated from Schwartz-Jampel disease (myotonia, stiffness syndrome, dwarfism and muscle hypertrophy).


Becker myotonia (generalized myotonia): Similarly to Thomsen disease, this is another form of myotonia congenita, but an autosomal recessive form. Unlike Thomsen disease, this form becomes manifest in adolescence or later and tends to be more severe. Becker myotonia starts with transient episodic muscular weakness after rest in the early teens. It first affects the legs > trunk, arms, face. Hypertrophy is invariably present in the legs, distal muscle atrophy and weakness may be found, in addition to, limited extension at the wrist (contractures). Serum CK levels may be elevated. Mexiletine and phenytoin are effective in the treatment. This form of myotonia is also the result of mutations in CLCN1 gene.


Paramyotonia congenita: This sodium channel myotonia is transmitted as an autosomal dominant disorder. Early onset myotonia, mild in character and involving mainly the orbicularis oculi, levator palpebrae and tongue, and consist of cold-induced episodes of weakness and stiffness. The attacks of periodic paralysis and myotonia are worsened by repetitive activity (paradoxical myotonia) which is especially prominent in the eyelids and are often associated with muscle pain. The weakness may be diffuse or limited to the part of the body that is cooled.  Once present, the weakness persists for hours, even after rewarming the body. Percussion myotonia can be evoked in the tongue and thenar eminence. Immersion of the arm and hand in ice water elicits both myotonia and weakness after about 30 minutes. Serum CK may be elevated. EMG shows myotonic discharges in all muscles. Biopsy is non-specific. Mexiletine and acetazolamide are effective in the treatment. The gene responsible for this disorder is SCN4A and is located at chromosome 17q.

Potassium-aggravated myotonias: These are myotonic disorders characterized by worsening of myotonia by the ingestion of potassium and response to treatment with acetazolamide. This term was recently adopted and includes disorders previously known as sodium channel myotonia (myotonia fluctuans and myotonia permanens). These disorders typically exhibit pure myotonia without sensitivity to cold or attacks of weakness.

Primary hyperkalemic periodic paralysis: This autosomal dominant disorder usually starts in the 1st decade of life. The episodes of mild to moderate weakness are more frequent but briefer in duration (minutes to hours). Their frequency tends to decline with age. Attacks of weakness occur usually before breakfast and later in the day may be precipitated by rest after exercise, immobility, potassium ingestion, irregular diet, cold exposure, or emotional stress. Weakness starts in the legs, thighs and lower back and spreads to hands, forearms and shoulders. Respiratory muscles are usually spared. Attacks last 15-60 min and recovery can be hastened by mild exercise. After an attack, weakness may persist for several days. Myotonia may occur (clinical or on EMG). Potassium is usually high or may be normal. Provacative test (2 g oral potassium load in a sugar-free liquid repeated every 2 h for 4 doses: weakness has a latency of 1-2 h). Acetazolamide and thiazide are effective in the treatment. Mutations in SCN4A gene are responsible for this sodium channel disease.

Hypothyroid myopathy: This consists of action myospasm and myokymia and of precussion myoedema and slowness of both contraction and relaxation phases of tendon reflexes. Serum CK levels are usually elevated. Although not true myotonia EMG may show myopathic pattern with bizarre high-frequency discharges. Biopsy is not very helpful.


EMG Myotonia


Emery-Dreifuss muscular dystrophies (EDMD): This disorder can be either X-linked recessive (mutation emerin gen locus Xq28) or autosomal dominant (mutation lamin A/C gene locus 1q21.2-q21.3). The age of onset is usually in the first two decades, with mild contractures, delayed developmental milestones (walking at the age of >3 years), not being able to keep pace. The key features consist of familial myopathies associated with neck extensor and limb joint contractures (elbow, heel), humeropelvic-predominant weakness, cardiomyopathy, and cardiac arrhythmia (conduction system disease).  There is no hypertrophy. Weakness affects first the upper arm and pectoral girdle muscles and later the pelvic girdle and distal muscles of the lower extremities. Occasionally, facial muscles are affected. Serum CK are moderately elevated (2-4x). EMG shows features of myopathy but non-specific with myotonic discharges and echocardiogram reduced ejection fraction. DNA studies for dystrophin Xp21.2 gene deletion, fascioscapulohumeral 4q35 deletion, and EDMD-XR gene mutation should be negative. Sudden death is a frequent occurrence.


Debrancher enzyme deficiency type III or Forbes-Cori disease (DED3): The clinical appearance of this autosomal recessive (chromosome 1p21) myopathy is highly variable. In the adult forms (starting in the 3rd and 4th decade) we differentiate several phenotypes: (1) muscular symptoms in adult years while the liver symptoms start in childhood, (2) muscle weakness starting in adult years long after liver symptoms in childhood have remitted, (3) only muscular symptoms as adults without any sign or history of liver dysfunction since childhood. Rapid fatigue and aching of muscles is a common presentation, occurring at exertion and beginning at an early age. The myopathy can also have different forms: (1) adult onset distal myopathy (distal leg weakness and intrinsic hand muscles); (2) subacute myopathy of the respiratory muscles; (3) severe generalised myopathy; and (4) minimal variant myopathy. Exercise intolerance is uncommon. Rarely, a mild polyneuropathy may be observed. The clinical course is complicated by advanced liver dysfunction and by severe cardiomyopathy. All patients have raised CK concentrations (up to 800 U/l), myogenic and neurogenic (denervation) features with pseudomytonic discharges on EMG, and markedly decreased debrancher enzyme activities in muscle or liver biopsy specimens. Leucocyte glycogen debrancher enzyme assay provides the diagnosis.


Becker muscular dystrophy: This form of dystrophy is considered to be a late onset-form of Duchenne muscular dystrophy. It occurs in about 4/100,000 male births. It is a X-linked genetic disorder practically limited to males and transmitted by females. The age of onset is varies between 5 to 45 years. It results in proximal weakness first affecting the pelvic girdle then the pretibial muscles (foot drop), and later on the pectoral muscles and upper limbs. Hypertrophy of the calves, quadriceps femoris and deltoid muscles is a consistent finding. Cardiac involvement occurs and mentation is normal. Serum CK levels are 25 to 200 x increased. EMG shows a myopathic pattern with myotonic discharges. The latter together with muscle biopsy (ELISA dystrophin measurement) should be able to differentiate this disorder from hereditary spinal muscular atrophy. Patients become wheelchair bound before the age of 30 years, but some patients live an advanced age. Female carriers (mothers of the patient) have generally calf hypertrophy, raised serum CK levels and abnormal EMG.

Hypothyroid myopathy: This consists of action myospasm and myokymia and of precussion myoedema and slowness of both contraction and relaxation phases of tendon reflexes. Serum CK levels are usually elevated. Although not true myotonia EMG may show myopathic pattern with bizarre high-frequency discharges. Biopsy is not very helpful.

Inclusion body myositis (IBM): Sporadic IBM is the most common acquired inflammatory myopathy of patients over age 50 years (typically a late middle aged man), characterized by a slowly progressive, painless, asymmetric atrophy and weakness of both proximal and distal arm and leg muscles, most prominently affecting the finger and wrist flexors in the upper extremities and the quadriceps, and tibialis anterior muscles (ankle dorsiflexion) in the lower limbs (late stage drop foot). The most common clinical presentation is proximal weakness in the legs, and distal weakness in the arms. The esophagus is the most common (25-40%) organ affected, resulting in dysphagia and aspiration pneumonia. CK levels are usually mildly elevated (300 - 600 UI/L). EMG reveals myopathic disease with true myotonic discharges and sometimes associated mild sensorimotor distal axonal polyneuropathy. Muscle biopsy (myopathic alterations with inflammatory foci, rimmed vacuoles, inclusions which stain for amyloid, and ragged red fibers) confirms the diagnosis. The disorder shows poor response to immunosuppressive therapy. The most common pitfall in diagnosing IBM is polymyositis, dermatomyositis and MND.


Stiff-person syndrome: The mean age of onset is in the early 40s (30 - 70 years of age). Insidious onset and progressive fluctuating stiffness and rigidity of predominantly axial (abdominal and thoracolumbar paraspinal muscles with difficulty in bending and turning) and, predominantly, proximal lower limb muscles (often asymmetric) and episodic painful spasm superimposed in the rigidity, often precipitated by startle, emotional, and tactile stimuli are the clinical characteristics of this rare disorder. Paroxysms of muscle spasm can be accompanied by profuse diaphoresis, hypertension, tachycardia, and extreme dysphoria. Hyperlordosis, need for cane, shortness of breath and task-specific phobias are commonly observed. EMG shows continuous muscle activity despite relaxation and abolished by iv diazepam. Stimulation (scratching) of the skin increases the motor unit activity. NCVs and distal latencies are normal. Autoantibodies against glutamic acid decarboxylase (anti-GAD65) (ELISA, Boehringer, Mannheim) in serum (>50 ng/ml psitive) and CSF are found in 90% of patients using currently available assays. CSF studies occasionally show increased IgG levels and oligoclonal bands. An association with DRb1 0301 allele has been established in 70% of patients. Three forms of the stiff-person syndrome are generally recognized: 1) autoimmune stiff-person syndrome associated with other autoimmune disorders, and with anti-GAD antibodies. In this form of the disorder, pancreatic islet cell, parietal cell, and thyroid autoantibodies are frequently found; 2) paraneoplastic stiff-person syndrome (associated with breast and small cell lung cancer) with anti-amphiphysin antibodies can be found in serum and CSF. In paraneoplastic stiff-person syndrome, anti-GAD antibodies are usually, but not always, negative; 3) idiopathic stiff-person syndrome with no detectable autoantibodies or autoimmune glandular dysfunction. Frequently, autoimmune disorders are associated with the stiff-person syndrome, including insulin-dependent diabetes mellitus (up to 30% of patients with stiff-person syndrome), thyroiditis, MG, adrenal and ovarian failure, pernicious anemia, and vitiligo. Diazepam is highly effective at reducing spasms and stiffness, but oral doses of up to 300 mg per day may be necessary in some patients. Baclofen has been used with excellent responses both orally and intrathecally with typical dosage ranges of 10-100 mg per day orally, and 50-1000 µg per day intrathecally. Other agents with reported benefit in some patients are tizanidine, methocarbamol, vigabatrin, and valproate (mainly for spasms). Botulinum toxin has been used occasionally for severe muscle spasms with dystonia. Corticosteroids, plasma exchange and iv immunoglobulin infusions may be helpful.