Differential Diagnosis of Myotonic Disorders

Home , Muscular dystrophy, Myopathy, Myotonia, Myotonia congenita, Myotonic dystrophy, Neuromyotonia

AANEM MONOGRAPH ABSTRACT: The presence of myotonia and paramyotonia on clinical examination and of myotonic discharges during electrodiagnostic (EDX) studies are important for the diagnosis of certain neuromuscular conditions. The increased muscle activity of myotonia produces muscle stiffness that improves with repeated activity. Paramyotonia produces a similar symptom, but the stiffness paradoxically increases with activity. Myotonic discharges are easily recognized on EDX testing because of the waxing and waning discharges. Myotonic dystrophy and myotonia congenita share both clinical and electrodiagnostic myotonia. Paramyotonia congenita and hyperkalemic periodic paralysis are associated with clinical paramyotonia and electrical myotonia. Acid maltase deﬁciency often produces myotonic potentials without clinical evidence of myotonia or paramyotonia. The differential diagnosis of these myotonic disorders is discussed. Muscle Nerve 37: 293–299, 2008

DIFFERENTIAL DIAGNOSIS OF MYOTONIC DISORDERS

TIMOTHY M. MILLER, MD, PhD

Neurology Department, Washington University, St. Louis, Missouri, USA

Accepted 19 September 2007

DIFFERENTIAL DIAGNOSIS OF MYOTONIC ation of muscle after voluntary contraction or per- DISORDERS cussion.”1 Patients with myotonia often complain of Myotonia rarely presents clinically in isolation. It is muscle stiffness that improves with repeated use of often an additional clue to consider in a constella- the muscle, the so-called “warm-up phenomenon.” tion of more prominent signs and symptoms associ- On examination, myotonia may be apparent from ated with a disease such as myotonic dystrophy. On the first handshake, presenting with a delayed re- electromyographic (EMG) examination, myotonia lease of the hand.8,31 This can also be appreciated by presents frequently when unexpected either in ap- asking the patient to repeatedly grip and release the parent isolation or as part of a difficult neuromus- examiner’s fingers. Another helpful maneuver is to cular case. This EMG finding often becomes a key ask the patient to repeatedly close the eyes tightly. element in the diagnosis. Myotonic potentials are After the first closure, there may be lag in opening one of the most specific potentials recognized on the eyes, but this will improve with repeated efforts needle EMG. The aim of this review is to aid the (Fig. 1A). Patients with paramyotonia also complain reader in the differential diagnosis of myotonic dis- of muscle stiffness, but the stiffness often is associ- orders (Table 1). Genetic tests are available for many ated with exercise rather than improving with exer- of these disorders, although in some cases they are cise, i.e., there is no warm-up phenomenon (Fig. only available in specialized laboratories. 1B). Myotonia may be provoked by percussion of muscle, e.g., by percussion of the thenar eminence. Recognizing Myotonia Clinically. Myotonia is de- The muscle stiffens, often adducting the thumb fined clinically as the occurrence of “delayed relax- (Figs. 2, 3). Both paramyotonia and myotonia are associated with myotonic discharges on EMG. Myo- tonia and paramyotonia are usually not difficult to Available for CME credit through the AANEM at www.aanem.org. distinguish from muscle cramps that present with a Abbreviations: CMAP, compound muscle action potential; CRD, complex sudden and painful focal muscle contracture. Myo- repetitive discharge; EDX, electrodiagnostic; EMG, electromyographic; Hy- perKPP, hyperkalemic periodic paralysis; HypoKPP, hypokalemic periodic tonia and paramyotonia are typically painless. paralysis Key words: myotonia; myotonia congenita; myotonic dystrophy; paramyotonia; periodic paralysis; Schwartz–Jampel syndrome Recognizing Myotonia on Electrodiagnostic Testing. Correspondence to: American Association of Neuromuscular & Electrodi- agnostic Medicine (AANEM), 2621 Superior Dr. NW, Rochester, MN 55901; Myotonia is often easier to define on EMG examina- e-mail: [email protected] tion than on neurological examination (Fig. 4). Myo- © 2007 Wiley Periodicals, Inc. tonic potentials are caused by chronically depolar- Published online 7 December 2007 in Wiley InterScience (www.interscience. ized muscle membranes. They are spontaneous, wiley.com). DOI 10.1002/mus.20923 painless discharges with a waxing and waning of both

AANEM Monograph MUSCLE & NERVE March 2008 293 Table 1. Differential diagnosis of myotonic disorders. istic waxing that is part of the classic definition. However, these potentials may represent a subset of Clinical Myotonia and Electrical Myotonia myotonia. Logigian et al.21 found that 4 of 17 pa- Myotonic dystrophy type 1 Myotonic dystrophy type 2 (proximal myotonic myopathy) tients with genetically confirmed proximal myotonic Myotonia congenita myopathy (DM2) had only waning discharges with- Schwartz–Jampel syndrome out evidence of classic myotonic discharges. As ex- Clinical Paramyotonia and Electrical Myotonia pected, all of the 16 patients with myotonic dystro- Hyperkalemic periodic paralysis phy (DM1) in their study had classic myotonic Paramyotonia congenita Electrical Myotonia without Clinical Myotonia discharges. Acid maltase deficiency Myokymic potentials are spontaneous potentials Uncommon Causes of Myotonia that have rhythmic firing of grouped motor unit Myopathy action potentials. Typically the discharges are in Denervation Drug-induced hypothyroidism groups of 2–10 at a frequency of 2–60 Hz, with a sound like marching soldiers. Neuromyotonic discharges are secondary to continuous muscle activity firing at 100–300 Hz. The potentials do not wax and amplitude and frequency, producing a characteristic wane, but may abruptly decrease in amplitude, pro- audio profile often compared to a dive-bomber.1,2,15 ducing a “ping” sound. Neuromyotonic discharges These potentials are repetitive discharges with a rate are not affected by voluntary activity, sleep, or anes- of 20–80 Hz and are of two types: (1) biphasic spike thesia, but may be interrupted by a local blockade of potentials less than 5 ms in duration that resemble peripheral nerve, the presumed generator of the fibrillation potentials, and (2) positive waves, 5–20 discharges. Tapping on the nerve provokes neuro- ms in duration, that resemble positive sharp waves. A myotonia. Complex repetitive discharges (CRDs) are single myotonic potential may look and sound ex- repetitive complex potentials with a sudden onset actly like a fibrillation potential or positive sharp and cessation, resembling the sound of a motorboat wave, but it is the multiple runs with the character- or motorcycle. These potentials do not wax and istic waxing and waning that distinguish the dis- wane like myotonia, although the waveform shape, charges as myotonic potentials. Needle insertion and amplitude, and frequency may change during dis- movement, muscle contraction, or tapping the mus- charge. Cramps are rarely captured on EMG, but cle will often provoke the myotonia. Although single may be distinguished by their sudden painful con- myotonic potentials can resemble fibrillations or traction accompanied by high-frequency discharges, positive sharp waves, myotonic potentials are rarely which can be up to 150 Hz. The discharge frequency confused with other discharges. and the number of motor unit discharges increase Waning discharges are easily distinguished from gradually during the development of the cramp, and myotonic discharges because they lack the character- subside gradually as the cramp fades.

FIGURE 1. (A) Myotonia of the orbicularis oculi. In this series of photographs the patient is initially looking straight ahead (left), then forcibly closing her eyes (center), and finally is attempting to open her eyes as wide as possible (right). Note that the patient is unable to open her eyes because of myotonia of the orbicularis oculi muscle. This figure demonstrates classic myotonia, in which the myotonia is most severe after the first contraction. If the patient had repeated the forcible eye closures the myotonia would have “warmed up” or lessened with repeated closures. (B) Paradoxical orbicularis oculi myotonia. In this series of photographs the patient has been asked to forcibly close her eyes and then to open them fully as quickly as possible. Each photograph was taken immediately after the patient was told to open her eyes. After the first forcible eye closure (left) the patient has no difficulty in opening her eyes. Note the progressive difficulty in fully opening her eyes. After the fourth forcible eye closure (right) the patient is unable to open her eyes. (Reproduced with permission from Pourmand R, editor: Neuromuscular diseases: expert clinicians’ views. Boston: Elsevier; 2001. © Elsevier.)

294 AANEM Monograph MUSCLE & NERVE March 2008 FIGURE 2. Percussion myotonia of the thenar muscles. (A) The examiner is preparing to strike the thenar muscles with a reﬂex hammer. (B) Note the dimpling of muscles in the thenar muscle due to sustained contraction (myotonia) of the thenar muscles evoked by direct muscle percussion. (Reproduced with permission from Pourmand R, editor: Neuromuscular diseases: expert clinicians’ views. Boston: Elsevier; 2001. © Elsevier.)

Electrodiagnostic Studies That May Aid Differential Di- CMAP is tested over a 30–45-min period following 5 agnosis. Myotonia is the most useful finding on min of sustained exercise. In all forms of periodic standard EMG and nerve conduction examinations. paralysis, both genetic and metabolic (e.g., thyro- However, several specialized tests may also aid in toxic periodic paralysis), there is a decrease in CMAP making or confirming the diagnosis of a disorder over time. The CMAP decrement in patients with associated with myotonia: repetitive stimulation, the hypokalemic periodic paralysis (HypoKPP) and hy- “short” and “long” exercise tests, and the provocative perkalemic periodic paralysis (HyperKPP) differs cold test. qualitatively from the decrement in those with Repetitive Stimulation. It has long been recog- paramyotonia congenita. In paramyotonia con- nized that in myotonic syndromes repetitive stimula- genita, there is a rapid decline in CMAP amplitude tion at 5–10 Hz leads to a decrement in the com- followed by a slow increase back to baseline over the pound muscle action potential (CMAP).3,7,12,42 next 60 min. In HypoKPP and HyperKPP, the am- This decrement has been attributed to transient plitude increases immediately after exercise and inexcitability of the muscle membrane. Although then declines slowly over the course of 15–30 min. consistent with a myotonic disorder, this finding is Patients with myotonia congenita also may show a not specific. decrement on the exercise test, but this is not con- Exercise Testing. In the “short” exercise test the sistent. patient is asked to exercise briefly (10–30 s). A Cooling Test. Cold provokes the symptom of CMAP is recorded and compared with the CMAP weakness in patients with paramyotonia congenita. recorded prior to exercise. In patients with DM1, This cold effect may be reproduced in the EDX this brief period of exercise causes a decrease in the laboratory by recording the CMAP for an individual CMAP, whereas in DM2 there is no change.39 muscle before and after cooling the limb for 15–30 In the “long” exercise test both the period of min at 15°C.28,35 The CMAP decrement in paramyo- exercise and the subsequent time of recording are tonia congenita patients is typically greater than “long.” As first described by McManis et al.,24 the 75%. Cooling may initially provoke myotonia in pa-

FIGURE 3. Percussion myotonia of the wrist extensor muscles. (A) The examiner is preparing to strike the wrist extensor muscle group with a reﬂex hammer. (B) The wrist is hung up due to sustained contraction (myotonia) of wrist extensor muscles evoked by direct muscle percussion. (Reproduced with permission from Pourmand R, editor: Neuromuscular diseases: expert clinicians’ views. Boston: Elsevier; 2001. © Elsevier.)

AANEM Monograph MUSCLE & NERVE March 2008 295 leads to an increased expansion of the triplet repeat. In DM1 this may be pronounced, with a nearly asymptomatic mother giving birth to a child with a greatly expanded CTG repeat and congenital myotonic dystrophy, manifested by developmental delay and severe limb weakness. FIGURE 4. Myotonic discharge. EMG of typical myotonic dis- The diagnosis is confirmed by genetic analysis, charge demonstrating waxing and waning of both amplitude and which is performed widely. Disease onset varies from frequency. infancy to young adulthood. Incidence is 12–14 per 100,000. tients with paramyotonia congenita, but after pro- Proximal Myotonic Myopathy. DM2, known as prox- longed cooling there will be a decrease in electrical imal myotonic myopathy in Europe, is another trip- activity. let repeat disorder that shares many of the features of myotonic dystrophy. The CCTG expansion muta- DISORDERS WITH BOTH CLINICAL AND ELECTRICAL MYOTONIA tion in intron 1 of the zinc finger protein 9 gene causes DM2. DM2 is an adult-onset muscular dystrophy as- Mytotonic Dystrophy. Myotonia congenita, DM1, sociated with myotonia, proximal weakness, cata- and DM222 all share prominent clinical classic myo- racts, cardiac arrhythmias, insulin resistance, and tonia and electrical myotonia. other multisystemic features of adult-onset The best-known myotonic disorder is DM1. The DM1.13,20,36 The major distinction of DM2 is the later characteristics of this CTG-repeat disorder include onset and predominant proximal weakness. Myoto- cranial muscle wasting/weakness and distal-predom- nia is also prominent in this disorder both clinically inant limb weakness. The small temporalis muscles, and on EMG. Congenital DM2 does not occur. ptosis, and a long, lean face produce a characteristic facial appearance. Cranial muscle abnormalities may Myotonia Congenita. Myotonia is the prominent also include dysphagia, dysarthria, and sometimes clinical symptom of myotonia congenita.11,34 The eye-movement abnormalities. The limb muscle weak- severe classic myotonia causes stiffness especially ness affects distal muscles to a greater degree than when first starting an activity. Once these patients proximal muscles. Along with inclusion-body myosi- have warmed up, they may perform activities at a tis, this muscle disease has the distinction of promi- normal or advanced level, including competitive nent finger-flexor weakness. Reflexes are depressed sports. The disorder presents in early childhood and in proportion to weakness. The rate of disease pro- may be described by the parents as weakness and gression is slow; longevity is not affected in many clumsiness in addition to or instead of stiffness. De- patients, but overall life expectancy is reduced sec- spite the reported difficulties, affected children ap- ondary to respiratory diseases, cardiovascular dis- pear “athletic,” with increased muscle bulk, presum- eases, neoplasms, and sudden deaths presumably from cardiac arrhythmias.23 The manifestations out- ably because of the sustained muscle activity. The side of the nervous system are also characteristic and myotonic symptoms often improve with age but do include frontal balding, cataracts, and cardiac abnor- not completely disappear. malities. Cataracts eventually develop in nearly all Myotonia congenita is secondary to a mutation in patients. Frontal baldness is also universal. Diabetes the ClCN1 chloride channel, and may be transmit- 34 is more common in DM1, although it is not seen in ted either dominantly or recessively. Curiously, a all patients. Cardiac abnormalities are apparent on particular mutation may be recessive in some fami- echocardiogram with evidence of first-degree heart lies and dominant in others. The reasons for this are block or bundle branch block. not clear. Recessively inherited myotonia congenita Clinically, the myotonia is usually simple to dem- is referred to as Becker’s myotonia congenita and onstrate both by percussion and by asking the pa- dominantly inherited disease as Thomsen’s myoto- tient to perform physical tasks such as squeezing a nia congenita. The chloride channel defect leads to hand or opening the eyes. Sometimes the myotonic an elevation of the resting membrane potential and grip of a parent is a hint in diagnosing childhood thus a tendency toward repeated muscle contrac- myotonic dystrophy, which may be more severe in tions. Genetic testing for myotonia congenita may be children because of the phenomenon of anticipa- performed in some specialized centers, many of tion whereby triplet repeat instability in the gametes which are best located at www.genetests.org.

296 AANEM Monograph MUSCLE & NERVE March 2008 Schwartz–Jampel Syndrome. Schwartz–Jampel syn- residues affected. These mutations cause a chroni- drome, also known as chondrodystrophic myotonia, cally depolarized muscle membrane. Genetic testing is associated with severe myotonia as well as short is available for these disorders in specialized centers. stature, muscular hypertrophy, diffuse bone disease, Potassium-aggravated myotonia is also linked to a ocular and facial abnormalities, and joint contrac- sodium-channel mutation.32 In this disorder, potas- tures.27,43 Muscle stiffness is one of the first symp- sium administration “aggravates” or brings on myo- toms that presents in childhood. There is no tonia. These patients also experience episodic myo- warm-up phenomenon for the myotonia. The EMG tonia. They do not have attacks of weakness. The findings of this rare disorder more closely resemble myotonia is not sensitive to cold and is most promi- neuromyotonia or CRDs. Unlike typical myotonia, the nent ϳ20 minutes after exercise. repetitive, high-frequency discharges in this disorder When considering HyperKPP or paramyotonia do not wax and wane. Schwartz–Jampel syndrome is congenita, the main differential consideration is Hy- caused by loss-of-function mutation in the HSPG2 poKPP,10,34 which does not show any paramyotonia gene, which encodes perlecan, a heparan sulfate pro- clinically or myotonia on EMG.25 Attacks of weakness teoglycan secreted into basement membranes.26 are more prolonged in HypoKPP (lasting hours to days) and are more severe, often leaving the patient DISORDERS WITH CLINICAL PARAMYOTONIA AND unable to walk. Inherited forms of HypoKPP are ELECTRICAL MYOTONIA secondary to calcium-channel mutations. Metabolic causes are most often secondary to hyperthyroidism, Both HyperKPP and paramyotonia congenita are although chronic potassium wasting (e.g., renal tu- characterized by attacks of weakness and paramyoto- bular acidosis) may also cause episodic muscle weak- nia. Both of these dominantly inherited diseases ness. Andersen–Tawil syndrome, which is associated present in infancy or childhood and are associated with mutations in KCNJ2,30 consists of the triad of with sodium channel mutations. In HyperKPP the cardiac arrhythmias, dysmorphic features, and peri- attacks of weakness dominate the clinical picture. odic paralysis; there is no myotonia. These attacks are often provoked by resting after exercise, skipping meals, or eating foods containing MYOTONIA ONLY ON EMG, NOT PHYSICAL a high potassium content.10,25,34 The attacks occur EXAMINATION relatively frequently (one per day to one per week), are short-lived (minutes to hours), and usually are Myotonia on clinical examination is always associ- not completely disabling. Some patients complain of ated with myotonic discharges on EMG. The con- stiffness with exercise and demonstrate paramyoto- verse is also nearly always true, with one notable nia on examination. EMG studies show myotonia in exception. Acid maltase disease consistently shows myotonic potentials on EMG with absent clinical ϳ75% of HyperKPP patients.25 During the attack, myotonia.28,35 Adult-onset acid maltase deficiency the serum potassium level is often elevated. Muscle (glycogenosis type II) is a glycogen storage disease biopsy shows a vacuolar myopathy. Patients with that presents with truncal and proximal limb weak- paramyotonia congenita mainly complain of stiffness that is slowly progressive over the years. Death is ness, but also have attacks similar to those of Hy- usually caused by weakness of respiratory muscles. perKPP. One of the major factors provoking stiffness Occasionally, the presenting weakness is diaphrag- in these patients is cold temperature. EMG demon- matic. Unlike certain other glycogen storage dis- strates myotonia in all paramyotonia congenita pa- eases, the heart and liver are not enlarged. Serum tients. In both HyperKPP and paramyotonia con- creatine kinase levels are increased. EMG shows ev- genita the paramyotonia and attacks of weakness idence of multiple spontaneous discharges including decrease in middle age. In cases where periodic myotonic discharges, fibrillation potentials, positive paralysis or paramyotonia congenita are being ques- sharp waves, CRDs, and small motor unit action tioned, the exercise test and cooling test may be potentials. Diagnosis is confirmed by muscle biopsy particularly helpful. Nearly all cases of periodic pa- with periodic acid–Schiff positive vacuoles. A more ralysis are associated with mild to moderate weakness malignant form of the disease may present in infancy 6,18,19,25 in later adult life. with heart muscle and neuronal involvement. Both HyperKPP and paramyotonia congenita are secondary to mutations in the sodium-channel OTHER DISORDERS SCN4A gene. T704M and M1592V are the most common mutations in HyperKPP. In paramyotonia con- There are other disorders in which myotonia is oc- genita, R1448C and T1313M are the most common casionally recognized, although usually not as a pre-

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