Myotonia: Recognition, Evaluation, and Differential Diagnosis

ABSTRACT

Myotonia is a non‐neurotypical muscle physiology of sarcolemmal hyperexcitability due to alterations in the structure and/or function of ion channels in the muscle cell membrane. This hyperexcitability can be observed electrically as spontaneous myotonic discharges during needle electromyography. Myotonic discharges consist of continuous sequential fibrillation or positive sharp wave morphology potentials which exhibit unstable, gradually changing, firing frequencies and amplitudes. In myotonic disorders, a clinical correlate of muscle stiffness is often present. Myotonic disorders are broadly divided into myotonic dystrophies (Types 1 and 2) and non‐dystrophic myotonias (myotonia congenita, paramyotonia congenita, and sodium channel myotonias). The myotonic dystrophies are systemic disorders of dysregulated RNA splicing clinically exhibiting fixed weakness, cataracts, diabetes and cardiac disease. Non‐dystrophic myotonic disorders are due to specific sarcolemmal ion channel genetic variants and generally clinically limited to muscle stiffness (myotonia) sometimes with muscle weakness which can be fixed or periodic. Although electrical myotonia is a distinctive feature of myotonic disorders, it is nonspecific and may occur in other neuromuscular conditions. Widespread myotonic discharges strongly suggest a myotonic disorder or a handful of other conditions including necrotizing autoimmune myopathy, some toxic myopathies, Pompe disease and several congenital myopathies. This monograph reviews clinical myotonia and mimics, electrical myotonic discharges, electrodiagnostic testing in myotonic disorders and clinical features of myotonic disorders and other myopathies with myotonia.

Abbreviations

DM1

myotonic dystrophy type 1

DM2

myotonic dystrophy type 2

EMG

electromyography

hyperKPP

hyperkalemic periodic paralysis

hypoKPP

hypokalemic periodic paralysis

LET

long exercise test

MC

myotonia congenita

PMC

paramyotonia congenita

SET

short exercise test

1. Introduction

Myotonia can be both a symptomatic clinical feature and an electrical phenomenon on electromyography (EMG). The basis of myotonia is pathologically prolonged depolarizations of the muscle fibers due to alterations in ion channel conductance. This leads to repetitive muscle fiber‐generated potentials after a single nerve stimulus. The pathophysiology can be primary or secondary dysfunction of chloride or sodium channels as discussed below. Primary myotonic disorders are defined as myopathies with both clinical and electrical myotonia. This includes myotonic dystrophies and non‐dystrophic myotonias. There are also myopathies where subclinical electrical myotonia is a common finding.

Patients with myotonic disorders commonly present with one of three symptoms: (a) stiffness (the subjective perception of clinical myotonia), (b) fixed weakness (associated myopathy), or (c) episodic weakness (attacks of paralysis). A patient history of “stiffness” is the prevailing clinical feature of non‐dystrophic myotonias, while myotonic dystrophies are usually characterized by fixed weakness. The weakness can be proximal in myotonic dystrophy type 2 (DM2), mimicking limb‐girdle muscle dystrophies (LGMD) or acquired myopathies. The fixed weakness is usually distal in myotonic dystrophy type 1 (DM1), occasionally causing diagnostic confusion with other inherited distal myopathies or even polyneuropathies. The ptosis and facial weakness in DM1 must be differentiated from myasthenia gravis and other muscle diseases such as oculopharyngeal muscular dystrophy. Mild fixed weakness can also occur in recessive myotonia congenita (MC) and long‐standing periodic paralysis. Episodic weakness with myotonia occurs in hyperkalemic periodic paralysis (hyperKPP) and occasionally paramyotonia congenita (PMC).

In this monograph, we (1) discuss the semiology of myotonia and its mimics, (2) describe specialized electrodiagnostic testing applicable to the primary myotonic disorders, and (3) briefly review neuromuscular disorders with myotonia.

2. Clinical Myotonia

Patients with clinical myotonia often describe muscle stiffness that improves with repeated use of the muscle, the so‐called “warm‐up phenomenon.” Myotonia can be clinically observed by delayed relaxation of muscle after voluntary contraction (a classic example is handgrip myotonia) or percussion (classically at the thenar eminence, Figures 1 and 2; Video S1). An individual patient's history may occasionally reveal non‐classical locations of myotonia that can be reproduced on examination [1]. For example, some patients may have elicitable percussive myotonia in proximal muscles (cited references include videos) [2, 3]. Eyelid myotonia is another common examination finding that can be demonstrated by asking the patient to repeatedly close the eyes tightly. After the first closure, there may be a lag in eye opening, which will improve with repeated efforts. Similarly, handgrip myotonia may be demonstrated on examination (Figure 3 and Video S2). Paramyotonia can be considered a clinical variant of myotonia that occurs with PMC. The key differentiation is that paramyotonia worsens, instead of improves, with repeated exercise. Both clinical myotonia and clinical paramyotonia are associated with electrical myotonic discharges.

FIGURE 1.

Percussion myotonia of the thenar muscles. The examiner is preparing to strike the thenar muscles with a reflex hammer in the first panel. Note the subsequent dimpling of muscles in the thenar muscle group. This dimpling is due to sustained contraction (myotonia) of thenar muscles evoked by direct muscle percussion. Figure reproduced with permission from Pourmand R, editor: Neuromuscular diseases: Expert clinicians' views. Boston: Elsevier; 2001. Elsevier.

FIGURE 2.

Percussion myotonia of the wrist extensor muscles. The examiner is preparing to strike the wrist extensor muscle group with a reflex hammer in the first panel. Note subsequently that the wrist is “hung up”. This “hang up” is due to sustained contraction (myotonia) of wrist extensor muscles evoked by direct muscle percussion. Figure reproduced with permission from Pourmand R, editor: Neuromuscular diseases: Expert clinicians' views. Boston: Elsevier; 2001. Elsevier.

FIGURE 3.

Handgrip myotonia. The patient has been asked to forcibly squeeze the examiner's fingers and then to open the hand as quickly as possible. There is difficulty letting go of the examiner's fingers as shown in the second panel. Figure reproduced with permission from Pourmand R, editor: Neuromuscular diseases: Expert clinicians' views. Boston: Elsevier; 2001. Elsevier.

There are conditions that mimic clinical myotonia. Patients with peripheral nerve hyperexcitability, for example, Issac's syndrome, can have an examination finding of handgrip myotonia. This is mediated by neuromyotonia (peripheral nerve‐generated) and not true myotonia (muscle‐generated). Percussive myotonia does not occur in this condition. Needle EMG will clearly differentiate these conditions [4]. Another myotonia‐mimic is the rare hereditary myopathy known as Brody disease. Individuals with this condition have muscle stiffness and may have delayed relaxation on examination. The stiffness is classically described as exercise or cold‐induced (potentially mimicking PMC as discussed below). The pathophysiology is due to variants in ATP2A1, which lead to a prolonged release of calcium from the sarcoplasmic reticulum. With EMG, these conditions can be distinguished as Brody disease does not have electrical myotonia [5, 6].

Percussive myoedema is another examination finding that can be confused with percussive myotonia. The elicited sign appears quite similar to myotonia; however, patients will often report significant associated pain [7]. Importantly, this is an electrically silent phenomenon if one observes this during insertion of an EMG needle. It can be seen in hypothyroid myopathy and may be of similar pathophysiologic origin to delayed relaxation of deep tendon reflexes [8, 9]; however, not every patient will have an identifiable neuromuscular condition [7]. Myotonia and paramyotonia are usually not difficult to clinically distinguish from muscle cramps that present with a sudden and painful focal muscle contracture [10]. Although myotonia and paramyotonia are classically painless, many patients with myotonic conditions will note chronic muscle pain [11, 12, 13, 14].

3. Electrical Myotonia

Electrical myotonia as identified on EMG is a distinct type of spontaneous discharge elicited by needle insertion or movement (Figure 4 and Video S3). The origin of myotonia is thought to be repetitive potentials of muscle origin following a single nerve stimulation. On the oscilloscope, the electrodiagnostic medicine specialist will observe the myotonic discharge as a repeating potential with morphology similar to a fibrillation potential or positive sharp wave potential. The potential is unstable and will wax and wane in both amplitude and frequency. This produces a sound often compared to a dive‐bomber or revving engine. The amplitude and frequency of the individual potentials, which are constantly changing within a single discharge, have broad ranges of 10–1000 μV and 15–150 Hz [15]. Myotonic discharges can be differentiated from widespread denervation with many potentials of similar morphology by the characteristic waxing and waning of amplitude and frequency [16]. Occasionally, one may see a “waning discharge” that appears as myotonic discharges, except they continually decrease in amplitude and frequency without ever increasing. These waning discharges may be a subtype of myotonia and can be often seen in DM2 [17] although waning discharges may not be as specific as myotonic discharges in an undifferentiated patient [16]. Myotonic discharges should not be confused with other spontaneous discharges that consist of repetitive potentials. Like myotonia, some of these originate from the muscle, such as complex repetitive discharges (CRDs), while others are driven by repetitive firing of the motor neuron or its axon, i.e., myokymia, neuromyotonia and cramps. Importantly, audible waning does not define a waning discharge, and one must visually inspect the discharge to identify both waning amplitude and frequency. A stable frequency with decreasing amplitude is common due to various discharges sampled during continual needle movement or occasionally a complex repetitive discharge, described below.

FIGURE 4.

Myotonic discharge. A myotonic discharge consists of repetitive discharges resembling fibrillation potentials or positive sharp waves. They are recorded after needle insertion, after voluntary muscle contraction or after muscle percussion, and are due to independent, repetitive discharges of single muscle fibers. The amplitude and frequency of the potentials must both wax and wane to be identified as myotonic discharges. This change produces a characteristic musical sound in the audio display of the electromyography due to the corresponding change in pitch, which has been likened to the sound of a “dive bomber.” Figure reproduced with permission from Daube J, AAEM minimonograph #11: Needle examination in clinical electromyography. John Wiley & Sons.

Complex repetitive discharges (Figure 5) are repetitive potentials, complex in appearance, with a wide range of frequencies (5–100 Hz). CRDs are thought to represent a fibrillation potential (i.e., spontaneous muscle fiber discharge) followed by ephaptic transmission to other muscle fibers [16] although this has recently been questioned [15]. They are usually of regular rhythm unless there are competing “pacemaker” fibers, that is, two nearby fibrillation potentials. The amplitude does not usually vary as in myotonic discharges. The sound is “machine‐like,” such as that of a jackhammer [15, 16]. Some electrodiagnostic medicine specialists will differentiate simple repetitive discharges (SRDs), although it is unclear if the physiologic origin or clinical association substantially differs from CRDs.

FIGURE 5.

Complex repetitive discharge. A complex repetitive discharge is a polyphasic or serrated action potential that may begin spontaneously or after a needle movement. They have a uniform frequency, shape, and amplitude, with abrupt onset, cessation, or change in configuration. Amplitude ranges from 100 μV to 1 mV and frequency of discharge from 5 to 100 Hz. Complex repetitive discharge is the most widely accepted term, though these potentials have also been referred to as bizarre high‐frequency discharge, bizarre repetitive discharge, bizarre repetitive potential, near constant frequency trains, pseudomyotonic discharge, and synchronized fibrillation. Figure reproduced with permission from Daube J & Rubin D, Needle electromyography. John Wiley & Sons.

Although similarly named to myotonia with the prefix “myo‐,” myokymic discharges are different in both origin and morphology. Myokymia is observed as semi‐rhythmically occurring “bursts” of electrical activity with intervening relative electrical silence (Figure 6). The bursts consist of repetitive firing of a single motor unit action potential (MUP). Within each burst, the MUP fires between 5 and 60 Hz while the bursts themselves are less than 2 Hz. The sound is often likened to “marching soldiers,” with each burst representing a step during the march [15, 16].

FIGURE 6.

Myokymic discharge. A myokymic discharge is a group of motor unit action potentials that fire repetitively and may be associated with clinical myokymia. The recording shows various examples of myokymic discharges at different sweep speeds. Figure reproduced with permission from Daube J & Rubin D, Needle electromyography. John Wiley & Sons.

Neuromyotonic discharges (Figure 7) consist of spontaneous repetitive firing of a single MUP. They are unique as the potential fires at a very high frequency, usually above 150 Hz (range from 100 to 300 Hz). These discharges cannot sustain themselves, so they abruptly decrease in amplitude, producing a “pinging” sound [15, 16]. They are thought to originate at the peripheral nerve terminal/axons, based on their termination by a local peripheral nerve blockade but not by sleep or general anesthesia [4]. Clinically, neuromyotonia may be associated with handgrip pseudomyotonia but percussion‐induced sustained muscle contraction is not seen [15].

FIGURE 7.

Neuromyotonic discharge. A neuromyotonic discharge is a burst of motor unit action potentials that originate in the motor axons firing at high rates (150–300 Hz) for a few seconds, and often start and stop abruptly. The amplitude of the response typically wanes. Discharge may occur spontaneously or be initiated by needle movement, voluntary effort, and ischemia or percussion of a nerve. Two examples are shown in different muscles. Figure reproduced with permission from Daube J, AAEM minimonograph #11: Needle examination in clinical electromyography. John Wiley & Sons.

Cramps are rarely captured on EMG, except when the gastrocnemius muscle is tested (personal observation). They originate in the motor neurons and not the muscle fibers like myotonia. Clinically, there will be a sudden painful involuntary contraction. Electrically, they are identified by repetitive semi‐rhythmic MUPs which are high frequency, often between 40 and 75 Hz, but occasionally up to 150 Hz. The frequency and the number of MUPs increase gradually during the development of the cramp and subside gradually as the cramp fades (Figure 8); however, this is much more subtle than the defining waxing‐waning of myotonia [15, 16]. An alert patient will, almost universally, alert the electrodiagnostic medicine specialist to the cramp.

FIGURE 8.

Cramp discharge. A cramp discharge arises from the involuntary repetitive firing of motor unit action potentials at a high frequency (up to 150 Hz) in a large area of muscle, usually associated with painful muscle contraction. Both the discharge frequency and the number of motor action potentials firing increase gradually during development, and both subside gradually with cessation. Figure reproduced with permission from Doaube J, AAEM minimonograph #11: Needle examination in clinical electromyography. John Wiley & Sons.

4. Additional Electrodiagnostic Testing in Evaluation of Myotonia

Several additional electrodiagnostic tests may aid in making or confirming the diagnosis of a myotonic disorder or periodic paralysis. These include repetitive nerve stimulation (RNS), the “short” and “long” exercise tests (SET, LET), and the provocative cold test (Table 1). Although these tests may seem antiquated given the wide availability of genetic testing, performing these tests to fully define the electrophysiologic phenotype may be useful in diagnostically challenging cases, for example, helping resolve variants of unknown significance (VUS) in CLCN1 or SCN4A. These tests are complementary to assessing for electrical myotonia. For example, a decrement on 10 Hz RNS may be present when electrical myotonia is not observed during a needle EMG examination [18].

TABLE 1.

Specialized electrodiagnostic testing of myotonic disorders.

	Myotonic dystrophy	Myotonia congenita	Paramyotonia congenita	Hyperkalemic periodic paralysis	Neurotypical
10 Hz RNS	Decrement in DM1	Decrement in recessive myotonia congenita (Becker)	Unknown	Unknown	< 10% decrement
Short exercise test	> 20% CMAP amplitude decrease post‐exercise (immediate) that rapidly recovers in 30–60 s	> 20% CMAP amplitude decrease post‐exercise (immediate) that rapidly recovers in 30–60 s; enhanced decrement at 15°C–20°C	> 20% CMAP amplitude decrease post‐exercise (the max decrement can be delayed by 30 s) that returns to baseline over > 60 s. May worsen on subsequent trials. Substantially enhanced decrement at 15°C–20°C.	Normal or nonspecific	±10% change in CMAP amplitude post‐exercise that returns to baseline within 10–20 s
Long exercise test	Unknown	~SET; immediate > 20% decrement CMAP amplitude and rapid recovery over 1 min.	~SET; > 20% CMAP amplitude decrement by about 1‐min post‐exercise. May be persistently decreased CMAP amplitude at 20–40 min post‐exercise due to delayed recovery.	Progressive decrease in CMAP amplitude that is maximal 20–40 min post exercise (> 40% decrement). Same finding is seen in hypoKPP.	Up to 40% decrease that is immediate or within 5 min post‐exercise
EMG	Myotonia (may see waning discharges in DM2)	Myotonia at room temperature; ↑ myotonic discharges at 15°C–20°C	Myotonia at room temperature. ↓ myotonic discharges and ↓ MUPs at 15°C–20°C. If intermediate cooling, may observe spontaneous fibrillations.	Myotonic discharges in hyperKPP. No myotonia in hypoKPP.	No myotonic discharges.

Abbreviations: DM1, myotonic dystrophy type 1; DM2, myotonic dystrophy type 2; EMG, electromyography; hyperKPP, hyperkalemic periodic paralysis; hypoKPP, hypokalemic periodic paralysis.

4.1. Repetitive Nerve Stimulation

It has long been recognized that in some myotonic syndromes, RNS at 10 Hz for 5–10 s often leads to a decrement in the compound muscle action potential (CMAP) amplitude [19, 20]. The presence of a CMAP decrement in the channelopathies likely varies by specific genetic variant as well as by temperature of the limb [18, 21]. It may be most commonly seen in recessive MC [19, 21, 22], although some suggest that it may also be a typical finding in DM1 [16]. The presence of a decrement is not thought to be due to a neuromuscular junction defect but rather due to pathologically slow repolarization of the muscle fiber in the setting of impaired chloride conductance [23]. Most authors have used an intermediate rate of RNS (10 Hz) to increase testing sensitivity [19, 20]; however, some have advocated for usage of a slow rate (3 Hz) with a much longer duration of the train of stimuli [22].

4.2. Short Exercise Testing

The SET is performed by recording supramaximally stimulated CMAPs after voluntary maximal isometric contraction for 10 s [24]. Recording from the abductor digiti minimi of the hand (ADM) with ulnar nerve stimulation is probably easiest [24] and the sole described method in some texts [15, 16]; however, recording the extensor digitorum brevis of the foot (EDB) with peroneal nerve stimulation is also an accepted method [24, 25]. First, a few pre‐exercise CMAPs are obtained to establish a baseline amplitude. A CMAP is obtained immediately after brief exercise and at 10‐s intervals until the CMAP amplitude returns to baseline. A neurotypical response is an initial minimal change (< 10% of baseline) of CMAP amplitude, which will return to baseline amplitude within 10–20 s (Figure 9). If a different response is expected, two repetitions of the SET with 60 s of rest between trials may increase the diagnostic yield.

FIGURE 9.

Short exercise testing. Short exercise testing screens for myotonia congenita and paramyotonia congenita physiology. It may provide value in helping resolve genetic variants of unknown significance. This graph illustrates typical CMAP amplitudes obtained from motor NCS up to 1 min after 10 s of maximal isometric exercise. Figure in SVG file. Artwork original and drawn by author J.C. based on prior art by author T.M.M.

Patients with PMC, due to some SCN4A variants, have a > 20% progressive decrement in CMAP amplitude that returns very slowly to baseline (> 60 s). This decrease in amplitude may worsen and become profound upon a second or third trial [24, 26]. This is the electrophysiological equivalent of worsened weakness with exercise that defines paramyotonia. In patients with myotonia attributed to chloride channel dysfunction, that is, MC or DMs, an immediate decrease in CMAP amplitude after exercise is also seen; however the CMAP returns to baseline within 30–60 s. A single exercise trial tends to produce a larger CMAP amplitude decrease in MC relative to PMC [24, 26]. This larger amplitude drop with relatively rapid recovery correlates with the transient paresis in MC as discussed below. When performing SET, occasionally there may be several repetitive CMAPs of decreasing amplitude following a single nerve stimulation. These have been termed post‐exercise myotonic potentials (PEMPs) and can be seen in PMC and occasionally MC [24, 26]. In the sodium‐channel myotonias (a SCN4A variant allelic disorder), the SET is either neurotypical or shows non‐specific changes [24, 26]. In hyperKPP (another SCN4A variant allelic disorder), an increase in CMAP amplitude is occasionally noted [24]. In hypokalemic periodic paralysis (hypoKPP), which lacks myotonia, the SET is typically normal [24].

4.3. Long Exercise Testing

For the LET, a supramaximally stimulated CMAP is recorded from the ADM pre‐exercise, and optionally every 1 min, during 5 min of voluntary maximal isometric exercise. A few seconds break from the exercise is recommended every 30–60 s to prevent muscle ischemia. A post‐exercise CMAP is obtained every minute for the initial 5 min post‐exercise and then every 5 min for an additional 40–45 min of rest [24, 26].

During the LET, a prominent CMAP amplitude decrement can occur in neurotypical patients; this typically occurs immediately or within 5 min post‐exercise [27]. The upper limit of normal for the decrease in CMAP amplitude is controversial. Generally, allowing up to a 40% decrease in CMAP amplitude is the accepted threshold for determining a normal response [15, 27]; however, some have used a less stringent threshold of 20% decrement [24] while others have suggested that a 40% decrement may not be completely specific for pathology in an ethnically diverse cohort [26]. One described approach is using the 40% cutoff and lowering it to 25% in individual cases if there is a very high pre‐test probability [16].

For both hyperKPP and hypoKPP, the LET is very helpful in supporting the diagnosis [15] with a reported sensitivity of ~70% for genetically confirmed periodic paralyses. The sensitivity likely correlates with the frequency of paralysis attacks [28]. The typical LET finding is a delayed and progressive decline of the CMAP amplitude with the nadir occurring around 20 to 40 min post‐exercise (Figure 10). Immediately after exercise, an increased CMAP amplitude (HyperKPP) or no change (HypoKPP) can be observed [24, 26]. If the LET is performed in PMC, a persistently decreased CMAP amplitude may be seen at 20–40 min post‐exercise; however, the overall trend will be progressive recovery or stability of the CMAP amplitude after the first minute post‐exercise. PMC and MC do not exhibit progressive decrement over 20–40 min as seen in the periodic paralyses (Figure 10) [26].

FIGURE 10.

Long exercise testing. Long exercise testing (LET) screens for periodic paralysis. It is of particular value in genetically cryptic forms of hypokalemic periodic paralysis as well as helping resolve genetic variants of unknown significance. This graph illustrates typical CMAP amplitudes obtained from motor NCS up to 40 min after 5 min of maximal isometric exercise (a short break is given after every 30–60 s of exercise to avoid ischemic complications). Figure in SVG file. Artwork original and drawn by author J.C. based on prior art by author T.M.M.

4.4. Provocative Cold Test

Pre‐cooling the limb, termed the “provocative cold test”, increases SET sensitivity for PMC and MC. Additionally, cooling the limb prior to needle EMG adds specificity for differentiating PMC and MC (see below). Briefly, the limb to be tested with electrodes attached is wrapped in a plastic bag and immersed in ice water for 10 min. The resulting typical cutaneous temperature is 15°C–20°C [29]. Although a post‐cooling pre‐exercise CMAP needs to be obtained, this is only useful as a baseline prior to exercise. A cold limb will have an approximately 20% decrease in CMAP amplitude (with corresponding prolonged duration) due to delayed sodium channel inactivation. Normal values for baseline CMAP changes after cooling are not established and there are not clearly differences between neurotypical and myotonic disorder physiology [30].

When the SET is performed after provocative cooling, patients with PMC will demonstrate a much larger decrement than if the SET was performed at room temperature [30]. A smaller enhancement of the SET decrement is also seen for autosomal dominant MC [30]. Although cooling usually enhances the typical MC or PMC pattern, at least one PMC variant (SCN4A p.Q270K) has a different SET pattern with cooling. This variant exhibits a MC‐like pattern at room temperature (post‐exercise CMAP amplitude has rapid return to baseline) but has a typical PMC pattern when the limb is cold (the post‐exercise CMAP amplitude takes greater than 60 s to return to baseline) [30].

If needle EMG is performed after fully cooling the limb (15°C–20°C), PMC typically shows fewer MUPs with incomplete interference patterns, decreased myotonic discharges and even electrical silence [29, 31]. If the limb is only mildly cooled in PMC (28°C–30°C), fibrillation potentials may be seen [32]. In contrast, needle EMG of cooled limbs in MC remains relatively unchanged and the electrical myotonia may seem more pronounced [29, 31].

5. A Possible Role for Ultrasonography in Myotonia Evaluation

As neuromuscular ultrasound has become more integrated into the electrodiagnostic medicine specialist's toolbox, there has been growing interest in using ultrasound to evaluate for myotonia. This may be of utility in challenging cases or where genetic testing is not available. Abraham and colleagues [33] described an approach for ultrasonography evaluation of percussive myotonia. Relaxation time after percussion of the thenar eminence was measured by the number of ultrasound frames (visual estimation was found to be unreliable). Sixteen patients with genetically confirmed myotonic dystrophy (DM) or channelopathy could be distinguished from 16 control individuals with 88% sensitivity and 100% specificity. Svačina and colleagues [34] subsequently described an alternative method where tissue doppler ultrasound was used to measure the tissue velocity of muscle relaxation (flexor digitorum superficialis; FDS) after the patient clenched their fist for 5 s and then immediately spread their fingers. Tissue velocity of muscle contraction (extensor digitorum communis; EDC) was also evaluated in a separate trial. Comparing 12 patients with DM to 20 control participants, the sensitivities of FDS relaxation and EDC contraction were only 50% and 75%, respectively; however both muscles had 95% specificity. Another group reported using shear wave elastography being useful in a small study [35].

6. Differentiating the Myotonic Syndromes

6.1. Classification Scheme for the Myotonic Syndromes

Broadly, the differential diagnosis of myotonic syndromes can be divided into disorders with both electrical myotonia and clinical‐manifest myotonia and those with only electrical myotonia (Table 2). Within the first group, a further distinction can be made between the myotonic dystrophies with progressive weakness and systemic features and the channelopathies with minimal fixed weakness and no systemic features. Careful evaluation of specific clinical features, exercise testing and focused genetic testing can lead to a diagnosis in the majority of cases. Even in the era of NGS panels, DM must be thoughtfully clinically screened for, as it is a repeat expansion disorder that may not be part of all phenotype specific genetic panels.

TABLE 2.

Myotonic diseases and related conditions.

	Clinical myotonia	Electrical myotonia
Myotonic dystrophy	Yes	Yes, most individuals. Waning variant discharges commonly seen in DM2
Myotonia congenita	Yes	Yes, most individuals
Paramyotonia congenita	Yes	Yes, most individuals
Sodium channel myotonias	Yes	Yes, most individuals
Hyperkalemic periodic paralysis	Yes	Yes, most individuals
Hypokalemic periodic paralysis	No	No
Schwartz–Jampel syndrome	Yes	Yes, likely most individuals have myotonic‐like discharges which may occasionally appear morphologically closer to neuromyotonic discharges and may be present at rest without needle movement
Pompe disease	No	Yes, commonly, especially paraspinal muscles and tensor fascia latae
Some congenital myopathies: myofibrillar myopathies (MYOT, DES, LDB3, FLNC), centronuclear myopathy (DNM2)	No	Yes, likely common
Autoimmune mediated necrotizing myopathies	No	Yes, common
Toxic Myopathies: cyclosporine, colchicine, hydroxychloroquine, 2,4‐D	No	Yes, likely common
Myoedema	Mimics percussive myotonia	No, electrically silent
Brody disease	Mimics handgrip myotonia	No, electrically silent
Issac's disease	Mimics handgrip myotonia	No, neuromyotonic discharges

Abbreviations: DM2, myotonic dystrophy type 2; EMG, electromyography.

6.2. Disorders With Both Clinical and Electrical Myotonia

6.2.1. Mechanistic Overview of the Myotonic Dystrophies

The DMs are some of the most common muscular dystrophies. Globally, it is estimated that 9.99 per 100,000 people have a DM, of which, 93% are DM1 and the remainder DM2 [36]. In a large cohort of over 50,000 consecutive births in New York state, there were 47.6 per 100,000 neonatal dried blood spot samples with a pathogenic repeat expansion predicted to cause DM1 [37]. Due to founder effects, the prevalence of DM1 is especially high in Northeastern Quebec, with a rate of 137 per 100,000 [38].

Both adult‐onset DM1 and DM2, at a clinical level, share common clinical features of progressive muscle weakness (with some differences in pattern as discussed below), myotonia, early‐onset cataracts and diabetes. The pathogenic genetic variant in DM1 is a trinucleotide CTG repeat expansion in the 3′ untranslated region (UTR) of DMPK (encodes a protein kinase) on 9q. In DM2, it is a pathogenic expansion of a tetranucleotide CCTG repeat in intron 1 of CNBP1 (encodes an RNA binding protein) on 3q. Both DMs exhibit clinical anticipation, although genetic correlates have been better studied in DM2. Significant genetic anticipation was classically thought to be maternal in DM1 [39] but some recent data suggests anticipation may be more common with paternal transmission [40, 41]. Anticipation may be typically maternal in DM2 [42, 43].

The pathophysiologic mechanisms in these two diseases have significant overlap and both are fundamentally “splicopathies”, defined by altered RNA splicing of multiple genes; however, there are key distinctions that give rise to specific phenotypic differences including potential age of onset. In DM1, somatic instability of the repeat expansion has been well described. Worse disease severity is predicted by both a higher inherited number of CTG repeats and the rate of somatic expansion [44]. The regulatory mechanisms of the somatic expansion rate are not clear but appear to be relatively correlated across multiple tissues in a single individual [45]. The presence of variant repeats where the CTG repeat is interrupted by other trinucleotide sequences predicts a mild disease phenotype, possibly mediated by a slower rate of somatic expansion [46]. Somatic instability is suspected to contribute to DM2 pathophysiology but has not been definitively demonstrated [47].

In both DM1 and DM2, the pre‐mRNA product of the repeat expansion sequesters RNA binding proteins known as muscleblind‐like RNA binding proteins (MBNL1, MBNL2, MBNL3) [48]. MBNLs regulate RNA splicing by interacting with the mRNAs of multiple genes. Disruption of this multifunctional regulatory role leads to diverse pleotropic effects [49]. Loss of function of MBNL1 in animal models is sufficient to cause myotonia, cataracts and myopathy [50]. It has been suggested that the relatively more mild phenotype of DM2 may be at least partially explained by competitive binding of another RNA binding protein (rbFOX1) to the CCUG repeat, thereby decreasing MBNL sequestration [51]. Decreased levels of MBNL1 lead to CLCN1 (sarcolemmal chloride channel) alternative splicing, resulting in a partial loss of function, which gives rise to myotonia via sarcolemmal hyperexcitability [52]. Similarly, insulin resistance in DM is due to alternative splicing of the insulin receptor gene (INSR) [53, 54]. The mechanism of early cataracts is not entirely defined. In mice, heterozygous loss of SIX5, a homeobox gene physically located adjacent to the DMPK 3′ UTR, is associated with cataracts [55]; however, complete knock‐out of MBNL1 also causes cataracts [50] presumably through altered splicing of an unidentified mRNA.

At the time of writing this monograph, there are no U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved disease modifying therapies for DM1 nor DM2. As elsewhere reviewed, the broad therapeutic mechanisms under study either reduce the toxic repeat expanded RNA or increase the amount of free splicing regulator proteins. There are also several small molecules under study to modulate the pathophysiology resulting from alternations in splicing [56]. Currently, Avidity Biosciences (San Diego, California, USA)'s AOC10001 is the closest pharmaceutical lead to potentially gaining FDA approval and a Phase 3 trial is currently being conducted (NCT06411288) [57]. Even in the absence of disease modifying therapy, there is critical need for multidisciplinary management of DM. The exact details are outside the scope of this monograph and we recommend review of published guidelines (see references) [58, 59, 60].

6.2.1.1. Clinical Features of Myotonic Dystrophy Type 1

There are 3 main phenotypes of DM1 based on age of onset. These include congenital, childhood and adult‐onset forms.

The congenital form is defined by prenatal or neonatal onset. Common prenatal findings include polyhydramnios in approximately one‐half and decreased fetal movements in one‐third. One‐half of cases will have low APGAR scores of less than seven at 5 min leading to the need for mechanical ventilation [61]. Prenatal brain magnetic resonance imaging (MRI) findings have been case reported [62]. In the neonatal period, three‐quarters are affected by feeding difficulties usually requiring a nasogastric tube. Other common features include clubfoot, cryptorchidism and ventriculomegaly [61]. There are detailed consensus recommendations for management [59]. Importantly, although modern infantile mortality is probably around 10% [61], a progressive improvement in proximal strength occurs over childhood development [59]. In addition to the physical manifestations, congenital DM is associated with decreased intellectual ability, autistic‐like features, and disruptions in sleep [63]. As individuals age, they eventually develop progressive weakness and myotonia more typical of adult onset DM1 [64].

The childhood form is an intermediate‐severity phenotype that shares many features with congenital DM1. It is defined as DM with onset between age 4 weeks of age and 10 years of age. A juvenile form with onset from 10 to 18 years of age is also sometimes defined [65]. Both congenital and childhood DM consensus management guidelines are published together [59].

Adult‐onset DM1 demonstrates progressive weakness in a characteristic pattern. The classic features include both craniobulbar, axial and symmetric distal limb weakness and atrophy. Ptosis, temporal wasting, and facial weakness are typical; however, ocular motility is usually spared. The facial weakness may lead to a “tenting” appearance of the mouth. Changes in articulation and swallowing dysfunction may occur. There may be weakness of both neck flexors and neck extensors which in combination with axial weakness may give rise to camptocormia. The distal limb weakness tends to affect finger function as well as ankle dorsiflexion [39, 66]. Symptomatic myotonia is relatively mild but is a key elicitable examination finding by percussion of the thenar eminence [67]. Well‐established systemic features include frontal balding, early cataracts and multiple endocrine changes including diabetes mellitus, sleep disordered breathing, and gastrointestinal hypomotility [39, 66].

The leading cause of mortality in patients with DM1 is respiratory insufficiency. Pulmonary mechanics testing with a forced vital capacity (FVC) is recommended every 6 months. Vaccinations should be kept up to date. Co‐management with a pulmonologist may be needed in some cases and referrals to sleep medicine should be considered if there is concern for sleep disordered breathing [58]. There is also variable cardiac involvement in at least half of DM1 patients including both atrial and ventricular arrhythmias, slowed conduction and cardiomyopathy. Cardiac dysrhythmias are the second most common cause of DM1‐related mortality. At diagnosis, every patient with DM should undergo a 12‐lead ECG and cardiac imaging. Regular monitoring is required, and patients should be co‐managed by a cardiologist [60]. Another possible cause of mortality is an increased risk of malignancy. This is thought to be especially true for thyroid cancers (seen in two independent cohorts) and both CNS glial tumors and choroidal melanoma (each seen in a single cohort with a hazard ratio greater than 15) [68, 69]. Although increased clinical vigilance, especially with skin examinations, is important, there is not currently evidence for enhanced cancer surveillance beyond age‐appropriate routine screening [58].

In additional to the physical syndrome, there is neuropsychiatric involvement with progressive cognitive changes [70, 71, 72]. A neurodegenerative process is supported by the observation that serial MRIs demonstrate progressive white matter changes with diffusion tensor imaging (DTI) [73, 74]. Alternative splicing also occurs in the brain of individuals with DM1 [75] and changes in MAPT expression may underlie this neurodegeneration. Recently, a small study of autopsied individuals with DM1 reported tau aggregates in a similar distribution, but more advanced than expected for primary age‐related tauopathy (PART). In addition, there was substantial glial deposition of tau (3R‐isoform) in the brainstem which may be specific for DM1 [76]. In addition to these cognitive features, it has long been described that there are often non‐neurotypical personality traits present. Although not completely consistent, increased paranoia is commonly reported in various cohorts [77, 78, 79, 80]. Apathy and fatigue are also fairly often noted [39].

6.2.1.2. Clinical Features of Myotonic Dystrophy Type 2

DM2, also known as proximal myotonic myopathy (PROMM), is less well studied but shares many of the features of DM1 and the same management strategies apply. It is generally a milder disease relative to DM1. Although historically a congenital form of DM2 has not been widely acknowledged [39], multiple groups have recently reported on the existence of congenital DM2, likely as a result of anticipation with maternal transmission [42, 43]. Key differences of adult‐onset DM2 include the distribution of weakness which tends to be proximal in the lower limbs, especially involving the hip flexors and extensors. Arm involvement may be proximal but distal predominance is typical as seen in DM1 [39, 81].

Importantly for the electrodiagnostic medicine specialist, DM1 and DM2 exhibit several differences in the needle EMG examination with respect to the anatomical distribution of myotonic discharges and the morphology of the discharges. While myotonic discharges are elicited in essentially all DM1 patients with FDI sampling and over 90% of needle movements evoke myotonia, this drops to approximately 80% and 55%, respectively in DM2. The highest yield muscle to sample for myotonic discharges may be the tibialis anterior (TA) in DM2. The reported sensitivity of recording myotonic discharges while sampling the TA at near 100% although the success of any single needle movement is approximately 50% [17]. Although DM1‐associated myotonic discharges usually meet have the classical appearance of waxing‐waning myotonia, one‐quarter of DM2 patients may have “waning” myotonic discharges that exclusively wane in frequency and amplitude [17]. These should be differentiated from SRDs and CRDs which may audibly wane due to decreasing amplitude but will retain a stable frequency while “waning.” CRDs and SRDs may change frequency, but these frequency changes are few and abrupt. Similarly, moving the needle during an SRD/CRD will lead to an audible waxing or waning due to a change in amplitude dependent on needle proximity to the myogenic discharge generator.

DM2 may be less well recognized due to its propensity to initially have nonspecific clinical presentations. One such presentation is chronic myalgia associated with allodynia over muscles [82]. Perhaps not surprisingly, one group noted an enrichment for DM2 in a cohort of patients with fibromyalgia [83] although this not common enough to warrant CNBP1 expansion testing for fibromyalgia patients without additional features of DM2 [84]. Another well‐described feature that may be seen is calf hypertrophy [81]. Unless additional features of the myotonic dystrophies are recognized, this may lead many clinicians to order a muscular dystrophy genetic testing panel, which may not include repeat expansion disorders, thus leading to a delay in diagnosis. Likely unique to DM2 is a reported higher incidence of autoimmune diseases [85, 86]; however, both DM1 and DM2 have been reported to have some immune alterations with a lower level of total concentration of serum IgG as well as lower lymphocytes than control populations [87, 88, 89].

6.2.2. Non‐Dystrophic Myotonias

The “non‐dystrophic myotonias” are myopathies grouped together based on minimal dystrophic changes and the presence of both clinical and electrical myotonia. These diseases are hereditary and caused by functional alterations in ion channels that regulate for ion conductance across the sarcolemma (Table 3). The clinical overlap is substantial, and it is frequently only possible to define the exact disorder with time‐intensive exercise testing in the electrodiagnostic laboratory or correlation with previously described pathogenic variant(s) in one of a few ion channel encoding genes; although, some pathogenic variants have multiple associated phenotypes. If one of these sarcolemmal channelopathies is suspected, it may be reasonable to defer specialized exercise testing and use a phenotype targeted genetic panel to confirm the diagnosis. These are important disorders with which to be familiar with as they are likely more common than previously thought [90]. Oftentimes affected individuals will have significant diagnostic delays, for example, within an international cohort (Western Europe and North America) of 94 patients with hyperKPP, there was a mean diagnostic delay of over 19 years and an average of 4 health care providers seen prior to diagnosis [91].

TABLE 3.

The nondystrophic myotonias and periodic paralyses.

	Myotonia congenita	Paramyotonia congenita	Hyperkalemic periodic paralysis	Sodium channel myotonias	Hypokalemic periodic paralysis
Genetic variant(s)	Monoallelic CLCN1 variants (dominant negative function) or biallelic CLCN1 variants (loss of function)	Monoallelic SCN4A gain of function variants			CACNA1S or SCN4A monoallelic variants
Pathophysiology	Reduced function of normal chloride channel conductance	Sodium channel conductance is prolonged due to closure deficit or opening			Channel has resting leakage
Typical clinical presentation	Muscle stiffness with warm‐up phenomenon	Muscle stiffness with exacerbation with exercise or cold	Muscle weakness with rest after exercise, fasting, hyperkalemia	Variable; several forms have muscle stiffness with specific triggers	Muscle weakness with rest after exercise, carbohydrate‐rich meals, hypokalemia

6.2.2.1. CLCN1 : MC Is due to Loss of Function of Chloride Conductance

MC is secondary to genetic variant(s) in CLCN1 which encodes the subunit of the dimeric CLC‐1 chloride channel protein expressed on skeletal muscle sarcolemma. MC can be inherited either by monoallelic dominant negative variants or biallelic loss of function variants. In “Thomsen's disease,” MC is inherited in an autosomal dominant pattern; the pathogenic variant encodes a protein subunit that forms a dimer with a functional subunit but renders the channel nonfunctional. Alternatively, when the loss of function variant subunit lacks the ability to form dimers, then MC is inherited in an autosomal recessive pattern and called “Becker's disease.” Becker's disease tends to be more severe, likely due to a more complete loss of functional chloride channels [13]. The exact biology is complex and multiple models of electrophysiology have been proposed [13]; some variants (e.g., truncated subunit ClC‐1 p.R894*) may cause autosomal dominant disease in some families and autosomal recessive disease in other families [92].

The phenotypic spectrum of MC is broad, ranging from individuals who are asymptomatic to individuals born with substantial congenital symptoms. The classical symptomatic description of MC is muscle stiffness or the perception of weakness that improves with repeated activity. This has been dubbed the “warm‐up phenomenon.” [13] Once individuals with this condition have “warmed up”, they may perform activities at a neurotypical or advanced level, including competitive sports. Parents may occasionally interpret and describe weakness and clumsiness in addition to or instead of stiffness. Affected children appear “athletic” with increased muscle bulk, presumably because of the sustained muscle activity. The symptoms often improve with age but do not completely disappear. In the recessive form, myotonia tends to be more severe than the dominant form, and transient weakness upon initiation of exercise often occurs. In comparison with PMC (discussed in the next section), myotonia is appreciated in the limbs more prominently than the orbicularis oculi and patient‐reported cold‐sensitivity is not as common [13, 93].

6.2.2.2. SCN4A : The Phenotypic Spectrum of a Gain of Function in Sodium Conductance

Pathogenic variants in SCN4A encoding the sodium channel type 4 subunit alpha protein can cause an overlapping spectrum of disorders. The SCN4A related disorders are usually inherited in an autosomal dominant pattern. The specific functional alteration of the channel leads to differing phenotypes that includes PMC, hyperKPP or sodium channel myotonias [13]; however, genotypic‐phenotypic correlations are far from perfect. The pathophysiologic basis of these disorders is prolonged activation of the sodium channel leading to sarcolemmal hyperexcitability.

PMC has similarities to MC as they share a chief symptom of muscle stiffness. The etymology of “paramyotonia” is derived from “paradoxical myotonia” because this phenotype is classically differentiated from MC by a worsening of symptoms with exercise. Importantly, this historical feature is not completely specific and some patients with genetically defined PMC may report a warm‐up improvement as in MC. While the predominant symptom is usually stiffness worsened by repeated exercise, some individuals with PMC can also have paralytic attacks like those seen in hyperKPP (discussed below). The major factor provoking stiffness in PMC is cold temperature [13]. EMG consistently demonstrates myotonic discharges; however concurrent neuromyotonia‐like discharges have been reported in PMC [26]. There is likely a small amount of SCN4A expression in peripheral nerve [94], but the source of these neuromyotonia‐like discharges in PMC is not known. Of note, as discussed above, individuals with the p.Q270K variant have a temperature‐dependent response to the SET [30].

Hyperkalemic periodic paralysis is characterized by attacks of weakness after exposure to provoking factors. The age of onset (defined by first paralytic attack) is bimodal with peaks in the neonatal period and 5 years of age with the first attack usually occurring by adulthood [91]. Typical triggers include rest after exercise, cold exposure, psychological stress, fasting and potassium‐rich foods [95]. About one‐fifth and one‐quarter of women report menstruation and pregnancy as triggers respectively [91]. Vague prodromal symptoms, such as fatigue, are common in the preceding 24 h. Most report prodromal symptoms, such as hyperhidrosis, in the 20 min preceding an attack of paralysis [91]. The paralytic attacks often occur daily or weekly and are generally on the order of minutes to hours although longer attacks lasting several days may occur. Typically, the weakness is not disabling; however one‐fifth to one‐third may have severe paralysis [91, 95]. The attack most commonly affects limb and sometimes facial muscles with respiratory function being subjectively affected in one‐quarter [91]. Ictal‐potassium levels are normal to elevated with a reported range of 4.0 to 6.8 mEq/L [95]. Needle EMG demonstrates myotonia in approximately 75% of HyperKPP patients [95]. Outside of attacks, it is common to have clinical myotonia [91]. Additionally, although less prominent symptomatically [91], many affected have a mild progressive myopathy [96, 97] which affects quality of life [91]. The histopathological correlates of hyperKPP are nonspecific but commonly includes vacuoles and tubular aggregates [95, 98].

Severe neonatal episodic laryngospasm (SNEL) is now named as a distinct SCN4A allelic disorder [13]. It often presents with episodic cyanotic apnea in the first month of life. It may be misdiagnosed as gastroesophageal reflux or laryngomalacia. Carbamazepine has been reported to be an effective treatment. Oftentimes individuals develop an athletic appearance and over childhood have an evolving presentation that eventually appears identical to PMC [99, 100, 101].

Myasthenic congenital myopathy is another neonatal, potentially life‐threatening, presentation with intermittent respiratory failure, bulbar paresis, ptosis, and fatigable limb weakness. This disorder has been reported to be phenotypically similar to congenital myasthenic syndrome due to CHAT deficiency; however, it is due to biallelic loss of function SCN4A variants [102, 103].

“Sodium‐channel myotonias” is an umbrella term for additional SCN4A‐related myotonic disorders that do not present with the typical PMC or HyperKPP phenotype. These include myotonia fluctuans, acetazolamide‐responsive myotonia, myotonia permanens and cold aggravated myotonia. Subtyping these highly overlapping entities may be challenging and, to some extent, a subjective determination. They are described for historical reasons as well as to illustrate the clinical spectrum of sodium‐channel myotonia.

Myotonia fluctuans presents with fluctuating myotonia that may improve initially with exercise (as in MC) but also occurs during rest after exercise and consumption of high‐potassium foods. As a differentiating point from hyperKPP, patients with myotonia fluctuans do not have objective weakness despite myotonia‐related stiffness. The phenotype of the described acetazolamide‐responsive myotonia (ACZ‐M) is very similar to myotonia fluctuans with provoked myotonia without weakness. The main differentiation is that individuals with ACZ‐M are relatively much more sensitive to dietary triggers than exercise‐related provocation. The SCN4A p.I1160V variant has been reported in association with ACZ‐M [104]. Cold‐aggravated myotonia (C‐M) is another episodic myotonia which is often painful and, as the name states, is often, but not always, triggered by exposure to cold. The warm‐up phenomenon may be present and rest after exercise may also provoke myotonia. Like the other sodium channel myotonias, weakness is infrequent in C‐M. Electrical myotonia is reported to be present in all affected individuals, and acetazolamide is typically not helpful. Several variants have been reported including p.L266V, p.L1436P, p.M1476I and p.A1481D [105, 106, 107, 108]. The SET is normal for p.L1436P and p.M1476I [107, 109] but p.L266V exercise testing has not been reported and could theoretically display a temperature‐sensitive pattern on the SET similar to the neighboring p.Q270K variant [110]. Myotonia permanens is a term that has been used in the literature to describe SCN4A p.G1306E variants which may present with variable phenotypes, including SNEL and early childhood‐onset severe painful stiffness. The clinical myotonia may be aggravated by different factors but is present continuously, hence the designation “permanens” [111, 112].

The above disorders should be differentiated from hypokalemic periodic paralysis which, although often discussed with myotonic disorders, is NOT a myotonic disorder and lacks both clinical and electrical myotonia. HypoKPP is associated with monoallelic pathogenic variants in either CACNA1S or SCN4A. Despite the genetic heterogeneity, these variants are considered together on the basis of similar presentation, LET results and absence of myotonia. Pathophysiologically, HypoKPP is due to a defect in conductance regulation leading to leakage through the affected ion channel [113]. The episodic paralysis tends to be more severe and longer duration relative to hyperKPP. Some authors suggest that a two‐hour attack duration may be of some utility to separate hypoKPP and hyperKPP although substantial overlap exists. While it is an exceptional patient with hyperKPP that has a paralytic attack lasting days, this is not atypical in hypoKPP [114]. As the disorder name, hypoKPP, implies, the serum potassium is low during paralytic attacks. A mild progressive proximal myopathy may develop overtime. Triggers of attacks include large and carbohydrate‐rich meals (as opposed to fasting in hyperKPP) and rest after exercise (also seen in hyperKPP) [13, 114]. The LET will demonstrate a delayed decrement similar to that seen in hyperKPP [26]. Needle EMG may show myopathic changes with absence of myotonia [95]. Muscle biopsy, if performed, may show vacuolar changes and tubular aggregates, similar to hyperKPP [95, 98].

The related Andersen–Tawil syndrome (ATS) is defined by a constellation of hypoKPP, specific cardiac electrical features (often ventricular arrhythmias) and certain dysmorphic features. It is associated with variants in the KCNJ2 gene which encodes the potassium channel Kir2.1. This classic triad is not always completely present, and a sizable proportion of patients do not have an identifiable genetic variation [114]. Although the causal genetic variants are not yet known in these cases, it has been reported that variants in other genes, such as KCNJ5 (encodes Kir3.4), may alter the function of the Kir2.1 channel in association with an ATS phenotype [115].

Another described hypoKPP is thyrotoxic periodic paralysis. This has been defined as hypoKPP in the setting of thyrotoxicosis and has been associated with specific genetic variants in multiple potassium channels [114]. Although described as a hypoKPP, the pathophysiology may be different [116]. It is thought that the thyrotoxic state uncovers a mildly defective ion channel that otherwise would function normally [117]. Outside of thyrotoxicosis, these described genetic variants are not thought to be symptomatic.

6.2.3. Schwartz–Jampel Syndrome

The gene HSPG2 encodes perlecan, a widely distributed extracellular matrix protein with pleotropic roles [118]. There are three described overlapping clinical syndromes with skeletal dysplasia and muscle pathology. All are caused by biallelic variants in HSPG2. Dyssegmental dysplasia Rolland–Desbuquois type (DDRH) and dyssegmental dysplasia Silverman–Handmaker type (DDSH) are predominantly characterized by skeletal dysplasia [119], while Schwartz Jampel Syndrome type 1 (SJS1) has milder skeletal dysplasia, relatively more prominent myopathic symptoms and often electrical and/or clinical myotonia [120]. Clinically, there is muscle stiffness as well as grip and percussive myotonia; however, the “myotonia” in SJS1 is likely not true myotonia which is defined by sarcolemmal hyperexcitability. This becomes more apparent with needle EMG where the “myotonic” discharge is present at rest without needle movement (true myotonia is provoked by needle movement) and is of constant frequency and amplitude (true myotonia is unstable). Furthermore, unlike in true myotonia, neuromuscular junction blockade (with curae toxin) eliminates the “myotonia” [121] thereby implying a localization more proximal than the sarcolemma. The neuromuscular junction is suspected to be the source of these spontaneous discharges as one of percelan's roles is to anchor acetylcholinesterase in the neuromuscular junction (NMJ) [122]; however, pathological involvement of the motor neuron axon has been also suggested [123].

There is also a described Schwartz Jampel Syndrome type 2 (SJS2) with “myotonic” discharges and clinical myotonia. This less well‐known disorder is caused by biallelic loss of function variants in LIFR. The SJS2 phenotype includes specific skeletal dysplasias, identical to the allelic disorder Stuve‐Wiedemann syndrome which lacks myotonia. Some have argued SJS2 is merely an expanded phenotype of Stuve‐Wiedemann syndrome. Of note, in LIFR‐associated disorders, episodic hyperthermia can occur that is severe and not anesthetic induced [124, 125] The clinical myotonia in SJS2 is present at birth unlike SJS1 where it typically becomes clinically apparent later in childhood [126]. Similarly to SJS1, curae toxin eliminates the “myotonia” in SJS2 [125].

6.2.4. Symptomatic Management of Clinical Myotonia

Clinical myotonia can cause perceptions of weakness and sometimes be painful. Pharmaceutical treatment can help in decreasing the symptomatic burden of affected patients. Details of potentially effective therapies are discussed in current guidelines [13, 58]. Here we review mexiletine and lamotrigine, both of which have randomized controlled trials (RCTs) supporting their use.

Mexiletine is the most well‐studied drug and has a significant amount of supportive data for its ability to reduce myotonia. Its historical use was primarily in cardiology and mexiletine is classified as a class IB antiarrhythmic due to its ability to inhibit the open state of voltage gated sodium channels. In DM1, there is level 1 evidence that mexiletine 150 mg three times daily reduces handgrip myotonia; however, there was no evidence in these RCTs that mexiletine improved quality of life or pain in the DM1 patient population. One RCT found no benefit on multiple patient‐reported outcomes while two RCTs, at this dose and a higher dose respectively, did not study patient‐reported outcomes [127, 128]. Given that mexiletine affects cardiac conduction, there has been some concern about its usage in DM1 [60]; however, there has not been a signal of harm due to cardiac events in DM1 patients receiving mexilitine [127, 128]. DM2 has not been studied rigorously; however, a retrospective small case series demonstrated mexiletine is probably tolerated similarly [129]. Expert opinion is that initiation of mexiletine for symptomatic relief of myotonia in both DM1 and DM2 is reasonable following multidisciplinary discussion between the co‐managing neurologist and cardiologist and review of recent 12‐lead EKG [60, 130]. In the nondystrophic myotonias, there is level 1 evidence that mexiletine 200 mg three times daily reduces patient perceived stiffness and improves quality of life. There was some heterogeneity in enrollment criteria between the RCTs; however, there did not appear to be a difference in benefit between MC and PMC subgroups [131, 132].

Due to the cardiac effects of mexiletine, additional drugs have been investigated for efficacy in clinical myotonia. Lamotrigine is a sodium channel blocker historically available for non‐cardiac indications and has been investigated for use in myotonia. In one RCT of lamotrigine titrated to 300 mg daily in patients with nondystrophic myotonias, there was a benefit seen on both objective myotonia measures and patient‐reported outcomes [133]. A more recent non‐inferiority trial compared mexiletine 600 mg total daily dose and lamotrigine 250 mg total daily dose in nondystrophic myotonias. Although there appeared to be a similar benefit for both lamotrigine and mexiletine, the study did not meet its primary endpoint of demonstrating non‐inferiority of lamotrigine compared with mexiletine on a patient‐reported outcome of myotonia [134]. Lamotrigine may also have class I antiarrhythmic effects and the prescribing information was revised by the FDA in 2020, based on in vitro data and individual case reports, to include a potential risk of cardiac arrhythmias and conduction alterations [135]; however, this has been controversial due to a lack of concerning safety signal in larger populations [136].

6.3. Diseases With Subclinical Electrical Myotonia

A fundamental point is that electrical myotonia is not specific. Although some conditions, as described below, commonly have electrical myotonia, there are many neuromuscular diseases that will occasionally have electrical myotonia. In these other disorders, myotonia generally tends to be less widespread in multiple sampled muscles. Neurogenic processes can occasionally have electrical myotonia. Among muscle diseases, electrical myotonia is reported to be found in 11% of dermatomyositis, 20% of sporadic inclusion body myositis, 14% of LGMD and 8% of mitochondrial myopathies [137].

6.3.1. Late‐Onset Pompe Disease

Late‐onset Pompe disease (late‐onset acid maltase deficiency; LOPD) is a classic example of subclinical electrical myotonia. It is reported that three‐fourths of patients have electrical myotonia in at least one muscle if a comprehensive EMG examination is performed. The paraspinal muscles have been historically described as the most sensitive area to assess for electrical myotonia but the tensor fasciae latae may be equally sensitive [138]. The most prominent features on presentation of LOPD are progressive proximal limb and girdle weakness (may mimic LGMD) with respiratory involvement. The hip adductors tend to be one of the weakest muscle groups on examination. Occasionally, LOPD can present with isolated neuromuscular respiratory failure. Cardiac involvement is less prominent in LOPD relative to infantile‐onset; however, the EKG may show a pre‐excitation pattern (Wolff‐Parkinson‐White). LOPD is a multisystem disease and patients may have additional manifestations including small fiber neuropathy and gastrointestinal symptoms [139]. Additional CNS involvement including a risk of ischemic stroke is increasingly being described [140].

Serum creatine kinase levels are often moderately increased (reported range is normal to 3000 s units/L) and EMG commonly demonstrates a myopathic pattern variably with increased spontaneous activity [141]. Biopsy of skeletal muscle demonstrates a vacuolar myopathy with periodic acid Schiff (stains polysaccharides including glycogen) positive vacuoles and acid phosphatase (stains lysosomes) positive granules. The diagnosis should be confirmed with genetic sequencing of GAA. Supportive testing is useful for screening prior to genetic testing, VUS resolution or when genetic testing is nonrevealing but there is a high clinical suspicion [142]. Supportive tests include direct measurement of alpha glucosidase (GAA) activity on nonfixed muscle tissue, cultured fibroblasts or dried blood spots. Urinary elevation of glucose tetrasaccharides is supportive but not completely sensitive nor specific [143]. The more malignant infantile form of the disease presents with cardiomyopathy and CNS involvement.

There are now multiple FDA approved enzyme replacement therapies (ERT) available. Algucosidase alfa was first approved in 2006 for infantile‐onset disease and approval was expanded to LOPD in 2010 [143]. ERT has been shown to improve both motor and respiratory manifestations and prolong survival. European consensus guidelines recommend treating all patients with a diagnosis of LOPD except patients who have no residual function that could be stabilized with ERT as well as (controversially) pre‐symptomatic patients [142, 144]. In 2021, a glycosylated form of ERT (avalglucosidase alfa‐npgt) was FDA approved in patients older than 1 year. By conjugation with mannose‐6‐phosphate (M6P) containing oligosaccharides, the enzyme achieves enhanced uptake into lysosomes [145, 146]. In 2023, another M6P conjugated ERT was FDA approved (cipaglucosidase‐alfa‐atga) to be administered with a small‐molecule enzyme stabilizer (miglutstat). The FDA approval for this ERT is narrow and it is approved only for patients with LOPD, weighing at least 40 kg, who are “not improving” on current ERT [145, 146, 147, 148, 149]. The relative efficacy of these newer glycosylated ERTs remains a significant point of uncertainty [147]. Although improvements have been made to drug delivery, ERT is still considered a disease‐modifying therapy and not curative. Patients require every 2 weeks infusions and antibody‐mediated resistance to ERT sometimes develops. Beyond the skeletal muscle, it is notable that none of the FDA‐approved ERT are delivered into the CNS which represents another opportunity for future development of therapies [147].

6.3.2. Congenital Myopathies

There are some congenital myopathies that have been historically described to demonstrate electrical myotonia during needle EMG examination. The exact likelihood of finding myotonic discharges with these myopathies is hard to determine due to the disease rarity; however, it is thought to be significantly more common when compared to all congenital myopathies generally.

Myofibrillar myopathies refers to about a dozen hereditary myopathies considered together on the basis of muscle histopathology which arises due to alterations of the myofibril Z‐disk [148]. This categorization is problematic in the postgenomic era due to overlapping clinical taxonomies [149]. For example, some genes can be typically associated with defining histopathologic findings of myofibrillar aggregates and rimmed vacuoles but demonstrate phenotypic heterogeneity [150, 151]. The presence of electrical myotonia has not fully been characterized in the various myofibrillar myopathies; however, electrical myotonia has been reported in association with pathogenic variants in MYOT (myotilin), DES (desmin), LDB3 or ZASP (LIM domain‐binding 3), and FLNC (filamin C) [152].

Centronuclear myopathy (CNM) is another histopathological categorization. These myopathies have been variably called “myotubular” myopathies; however in modern taxonomies, “myotubular” is typically reserved for the X‐linked myopathy (X‐MTM) due to MTM1 variants [98]. Similar to myofibrillar myopathies, there are roughly 10 genes with significant clinical heterogeneity [153]. Patients with pathogenic variants in DNM2 (dynamin 2), one of the most common genetic etiologies of centronuclear myopathy, have been reported to have electrical myotonia [154, 155]. Electrical myotonia in association with X‐linked myotubular myopathy is often described in textbooks and the authors have clinically observed this association; however, the only published case report of “myotubular myopathy” with myotonia was not genetically confirmed [156] and may have been DNM2‐releated CNM [157, 158]. DNM2‐associated centronuclear myopathy may present at any age with typically diffuse and symmetric weakness although there can occasionally be some asymmetry. In 1/3 to 1/2 of patients, there will be soft voice, ptosis and/or opthalmoparesis [158].

6.3.3. Acquired Myopathies

Acquired myopathies associated with electrical myotonia include necrotizing autoimmune myopathies (NAM) and specific toxidromes. In NAM, greater than half of patients will have myotonic discharges on needle EMG examination. This is even higher in patients exposed to statins; however electrical myotonia is still seen in over one‐third of statin‐naive NAM [137, 159]. Within an individual patient, the electrical myotonia may be limited to specific muscles or diffuse. The paraspinals and routinely sampled proximal arm muscles (deltoid, biceps, triceps) are reported to have the highest yield [137].

Electrical myotonia can be caused or enhanced by specific small molecules. For the majority of these, the myotonia occurs in the context of a toxic myopathy. One classic example of a toxic myopathy with myotonia is colchicine. Colchicine is an immunomodulatory medication that is prescribed for gout and other specific inflammatory conditions. Chronic use in the setting of reduced renal clearance may result in progressive proximal myopathy that has been associated with electrical and/or clinical myotonia [160, 161, 162]. Cyclosporine, an immunosuppressant medication, has been reported to cause a myopathy [163]. In one patient that was taking cyclosporine and colchicine, both clinical and electrical myotonia was found which improved with discontinuation of cyclosporine [164]. The antimalarial drugs chloroquine and hydroxychloroquine, which are used in rheumatologic conditions, are associated with a vacuolar myopathy that may be under‐recognized [165]. The needle EMG demonstrates fibrillation potentials in most patients and electrical myotonia sometimes [166]. Of possible interest, some animal model research has suggested a potentially beneficial mechanism for chloroquine in DM1 [167].

The non‐selective beta blocker propranolol has been occasionally associated with electrical myotonia but it is unclear if this is due to exacerbation of relatively mild cases of DMs [168, 169]. The mechanism is unclear; propranolol is theoretically beneficial in myotonic disorders as it is thought to have sodium channel inhibitory activity including on Nav1.4 (the protein product of SCN4A) [170]. Of possible relevance, propranolol has been associated with a modestly increased risk of myopathy, suggesting mild myotoxicity [171]. It is unknown if other beta blockers have a similar effect; beta blockers, as a medication class, are generally considered safe in DMs specifically [60]. Of note, propranolol is contraindicated in Pompe disease as it may make enzyme replacement therapy less effective [172, 173].

Historically, the cholesterol lowering drug azacosterol (20,25‐diazacholestenol) was well known to be associated with myotonia [174]; it has not been available since the 1970s. Other cholesterol lowering medications including statins and fibrates have a theoretical risk of myotonia that has not been well studied outside of NAM as discussed above [175, 176, 177]. A common herbicide, 2,4‐dichlorophenoxyacetate (often labeled as “2,4‐D”) is used widely including in many residential lawn grass products sold in garden stores; it has been long recognized that myotonia can be experimentally induced in animals exposed to 2,4‐D [178] and there is a report of unintentional exposure leading to both clinical and electrical myotonia in a dog [179]. There is not enough evidence to determine if myotonia occurs in humans or not; however clinical signs of neuromuscular irritability are reported with 2,4‐D ingestion [180].

7. Conclusions

For the electrodiagnostic medicine specialist, recognizing the associated clinical and EMG characteristics of myotonia and paramyotonia greatly aids the ability to make a specific neuromuscular diagnosis. During routine electrodiagnostic testing, a few additional historical details and a brief physical examination may provide a specific diagnosis that can be confirmed with genetic sequencing or suggest further investigations. In the clinic, due to the advent of genetic sequencing panels, the most important clinical distinction in hereditary myotonic myopathies may be determining if the disease is likely to be a dystrophic (i.e., requiring repeat expansion testing) myotonia or a nondystrophic myotonia.

Author Contributions

Jesse I. Crayle: writing – original draft, writing – review and editing. Timothy M. Miller: writing – original draft, writing – review and editing, supervision. Muhammad Al‐Lozi: writing – original draft, writing – review and editing, supervision.

Disclosure

This material serves as an update and expansion of content originally authored by Muhammad Al‐Lozi, MD and Timothy M. Miler, MD, PhD, and published in Muscle & Nerve. https://doi.org/10.1002/mus.880100704.

Ethics Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of Interest

Dr. Miller has had licensing through Ionis and C2N, and has a relationship as a consultant for Ionis, Biogen, and Arbor Bio. All relevant financial relationships have been mitigated according to ACCME standards. The editor served as a consultant for Biogen and Insmed. In accordance with ACCME requirements, all relevant financial relationships have been mitigated.

Peer Review Statement

This paper underwent peer review by the AANEM Clinical Publications Review Committee and review by the Muscle & Nerve editor.

Supporting information

Video S1: Percussion myotonia. The examiner demonstrates percussion myotonia of the thenar eminence. This is a typical finding in certain myotonic conditions especially myotonic dystrophy. Video original and taken by author M.A. with edits by author J.C.

Video S2: Handgrip myotonia. The examiner demonstrates handgrip myotonia. The patient is able to improve the myotonic stiffness by exercise (warm‐up phenomenon). Video original and taken by author M.A. with edits by author J.C.

Video S3: Electrical myotonia. Electromyography of a single patient demonstrates frequent myotonic discharges. Myotonia is defined by its continually changing frequency and amplitude in an exponential pattern. Video original and taken by author M.A. with edits by author J.C.

Crayle J. I., Al‐Lozi M., and Miller T. M., “Myotonia: Recognition, Evaluation, and Differential Diagnosis ,” Muscle & Nerve 74, no. 4 (2026): 1174–1195, 10.1002/mus.70250.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.