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Continuous Muscle Fiber Activity Raymond G. Auger, M.D.

gin often is not significantly altered by sleep o r general anesthesia. Nerve block does not influence the abnormal muscle contractions if it is produced proximal to the origin of the abnormal muscle activity, but block of neuromuscular transmission totally abolishes the abnormal activity.

CLINICAL PRESENTATION Involuntary muscle contraction persisting during sleep is a constant feature of these conditions. Usually, this is associated with a n undulation o f t h e overlying skin d u e to continuous muscle contraction, a clinical phenomenon termed "myokymia." 'Fhere is often a delay of relaxation after muscle contraction, similar to that seen in association with myotoriic dystrophy; when this occur-s in association with sustained muscle contraction and generalized rnyokymia, the term "neuromjwtonia" has been applied:' At times, excessive sweating mav be seen; this is probably due to the heat engendered by sustained muscle contraction. In some cases, carpopedal spasm resembling tetany may be seen despite riorlnal calcium and magnesium metabolism. . t h e term "normocalcernic tetany" has been applied to this condition." 'I'he degree of disability experienced by patients with one of these disorders is variable. Some patients are severely disabled, whereas in others the complaints are minor, the abnormal activity being attributed to "nervousness." Although the condition is usually generalized, in some patients it can be localized to only a few muscles. T h e state of the rnyotatic reflexes is variable; sorne patients have normal reflexes, whereas in others the tendon reflexes are depressed. This probably depends on whether o r not the patient has a n associated peripheral neuropathy.

Consultant. Ikpat-tment of' Neurology, hlayo (:link and Ma)o Fountlation; Assistant I'rof'esso~- 01' Neurology, Mayo Medical School; Rochester, Minnesota. Reprint requests: Dr. Auger, Mayo Cliriic, 200 First Street SU', Rocheaier, MN 55905. Copyright 0 1991 by 'l'hieme Medical Publishers, l n c . , 381 Park Avenue South, Ncw York, N Y 100 16. All rights reserved.

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'I'he phrase "continuous muscle fiber activity" has been applied to a heterogeneous group of conditions that share the feature of sustained involuntary muscle contraction d u e to hyperactivity of peripheral nerve motor axons.'-:' Although it is a misnomer because the same name could be applied to sustained activity from sources other than the peripheral nerves, the name has been quite firmly established in the literature. Similarly, the eponym "Isaacs' syndrome" has received wide usage even though similar conditions were described many years before Isaacs' initial description of this disorder. T h e literature reveals that these syndromes involve different diseases that vary in clinical prcsentation, associated electrophysiologic abnormalities, and rnorphologic findings. They share the feature of involuntary sustained muscle contraction, occasionally associated with sensory abnormalities. Kelated syndromes include neuromyotonia, IsaacsMerton syndrome, quanta1 squander syndrome, generalized myokymia, pseudornyotonia, normocalcemic tetany, neurotonia, continuous motor unit activity, and chorCe fibrillaire d e Morvan. I n a previous discussion of the subject, we used the phrase "sustained involuntary muscle activity of peripheral nerve origin," which more accurately describes the process. These conditions may be confused with central disorders such as the stiff-man syndrome o r with primary muscle disorders causing cramps o r myotonia. Usually this differentiation can be made clinically, but in sorne of these disorders further studies are required, including electrornyography (EMG) and nerve conduction studies. In selected cases general anesthesia, spinal anesthesia, peripheral nerve block, o r neuromuscular block may be required before a definite diagnosis can be made. Sustained muscle activity of peripheral nerve ori-

CON'I'INUOUS MUSCLE FIBER AC~'IVITY-AUGER

I. Not associated with clinical or electromyographic evidence of peripheral neuropathy A. Hereditary B. Acquired 1. ldiopathic 2. Associated with exposure to toxins 3. Associated with intrathoracic tumors II. Associated with peripheral neuropathy A. Hereditary B. Acquired 1. ldiopathic 2. Associated with exposure to toxins 3. Associated with intrathoracic tumors 4. Associated with inflammatory neuropathies Ill. Chondrodystrophic myotonia (Schwartz-Jampel syndrome) IV. Tetany from known metabolic causes A. Hypocalcemia 6 . Hypomagnesemia V. Myokymic discharges after plexus irradiation or peripheral nerve injury VI. Localized myokymia after nerve injury VII. Facial myokymia VIII. Miscellaneous

CLASSIFICATION These conditions do not stem from a single disease process but are heterogeneous, representing the response of the peripheral nerve to several different insults, each of which alters nerve function and induces spontaneous motor axon activity. Table I presents a classification of these disorders, and the discussion that follows describes the various diseases in this fran~ework.

NOT ASSOCIATED WITH CLINICAL OR ELECTROMYOGRAPHIC EVIDENCE OF PERIPHERAL NE UROPATHY

Hereditary In 1952, SheaffQescribed a hereditary illness in a father and four of his sons, all of whom had generalized muscle twitching. In 1972, Jusic et a17 reported on a family with 12 affected members who had persistent muscle cramps involving mainly the lower limbs. EMG showed continual waxing and waning electrical discharges, which were not affected by spinal anesthesia or nerve block and persisted during sleep. There was no benefit from the use of carbamazepine. In 1975, Van Dyke et aI8 described a family with periodic ataxia who also had persistent myokymia. EMG showed continuous spontaneous activity of motor units occurring at rest. Similar families have been described by Hanson et al,' Gancher and Nutt,"' and Brunt and von Weerden." In 1976, Isgreenvescribed a patient who had prolonged attacks of tetany with normal calcium and magnesium metabolism. Other members of the family were similarly affected, and some had recurrent seizures. In 1977, Hartlage et all2 described a family whose members had painless stiffening of the leg muscles and constant rippling movements of their muscles even during sleep. In 1983, Ashizawa et allVescribed a family with seven members who had persistent vermiform

Figure 1. Three superimposed response traces from stimulation of ulnar nerve with recording from abductor digiti minimi. Repetitive discharges are seen after initial M response. (From Auger et aI.l4 Reprinted with permission.)

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Table 1. Classification of Peripheral Nerve Disorders Causing Sustained Involuntary Muscle Activity

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twitching and episodic stiffness in the lower extremities. EMG demonstrated the continuous firing of motor units, usually in a rhythmic pattern. Improvement occurred with phenytoin or carbamazepine therapy. In 1984, Auger et all" studied six patients in two unrelated families who had generalized myokymia and recurrent muscle stiffness. Repetitive discharges followed motor nerve stimulation (Fig. l ) , and EMG demonstrated spontaneous recurrent bursts of motor unit activity. Within a burst, the firing rate was high (150 to 300 Hz). T h e clinical and EMG abnormalities improved after treatment with carbamazepine or phenytoin. One patient also obtained benefit from sodium valproate. In 1984, McGuire et all5 described a family with continuous motor unit activity presenting as muscle stiffness and rigidity in early childhood. In most of the families that have been described, the mode of inheritance appeared to be autosomal dominant.

Acquired

IDIOPATHIC. Most of the cases of continuous muscle fiber activity that have been described are idiopathic, including the cases described by Isaacs.' His original cases were a 12-year-old boy with generalized stiffness (Fig. 2) and an adult with similar findings. Isaacs recognized that the clinical and electrophysiologic findings in these patients differed from those in myotonia. He later described a 20-year-old man with a similar presentation.%ll three patients responded well to phenytoin or carbamazepine therapy. In a later article describing a 14-year follow-up of the two original cases, it was noted that the manifestations of the disease were less prominent with time and that treatment could be d i s c o n t i n ~ e d . ~ Reports of other patients are in this category as ~ell.l"-'~

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Figure 2. Photograph of original patient described by Isaacs. Note the stiff posture and contraction of muscles. (From Isaacs.' Reprinted with permission.)

thoracic tumors has also been implicated. WalshZ7 described neuromyotonia in a patient with an anterior mediastinal tumor. T h e type of tumor was unknown, but the authors suspected on clinical grounds that it was a bronchogenic carcinoma. Partanen et alZ8identified a patient with neuromyotonia and normocalcemic tetany who had a small cell carcinoma of the lung. Halbach et aly9 deASSOCIATED WITH EXPOSURE TO TOXINS. Exposure to toxins has been implicated in some scribed two patients with thymoma who had gencases. Mitsumoto et alZ3described a patient with eralized myokymia as well as excessive sweating generalized myokymia who had received gold and intermittent psychotic behavior. These patreatment for rheumatoid arthritis. They noted tients had increased acetylcholine receptor antithat this condition had been described' in the body titers with no evidence of a block of neuroFrench literature as "chorCe fibrillaire d e Mor- muscular transmission. T h e symptoms improved van."24Similar abnormalities have been associated after thymectomy and immunosuppressive treatwith mercury i n t ~ x i c a t i o n . ~ V h e rhas e been one ment in one case. Litchy and Auger"" observed a report of generalized myokymia associated with similar patient with a thymoma who had evidence the use of clofibrate, but this has not been con- of sustained involuntary muscle activity. T h e involuntary muscle activity did not improve after firmed."j thymectomy, but there was a good initial response ASSOCIATED WITH INTRATHORACIC TUMORS. A paraneoplastic syndrome associated with intra- to phenytoin and subsequently to carbamazepine.

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SEMINARS I N NEUROLOGY

(:ON'I'INUOUS MUSCLE FIBEK ACTIVITY-AUGER

Hereditary In 1959, Gamstorp and Wohlfartsl described two patients who had generalized myokymia associated with probable Charcot-Marie-Tooth disease. In 1969, Avanzini et al"' described a chronic familial neuropathy with frequent cramping and EMG evidence of frequent motor unit potential discharges. In 1979, Lance et al":' described two members of' a family with Charcot-Marie-Tooth disease who had frequent muscle spasms and cramps and a pattern on EMG that was classified as neuromyotonia. Microneurography of cutaneous nerve fascicles suggested that abnormal spontaneous activity arose from sensory as well as motor axons. I n 198 1, Lazaro et al" described a family who had frequent muscle cramps associated with painful posturing of the hands and feet. In 1984, Vasilescu et al" described three members of a family with Charcot-Marie-Tooth disease associated with f'asciculations, cramps, myokymia, impaired muscle relaxation, and percussion myotonia. One of the patients responded to sodium valproate. In 1989, Serratrice et a P d e s c r i b e d a patient with Charcot-Marie-Tooth disease who also had sustained involuntary muscle activity that responded to carbamazepine.

In 1980, Warrnolts and Mendell" described a patient with a mild chronic sensorimotor peripheral neuropathy who also had sustained involuntary muscle activity. T h e abnormality occurred only in response to passing nerve impulses. Voluntary activity generated involuntary high-frequency discharges of motor unit potentials, which persisted briefly after relaxation (Fig. 3). Repetitive afterdischarges also occurred after stimulation of the motor nerves. 'They applied the term "neurotonia" to this condition. There was a poor response to phenytoin therapy. In 198 1, Coers et al"" reported on two patients with sustained involuntary muscle activity who had diminished nerve conduction velocities. ASSOCIATED WITH EXPOSURE TO TOXINS. In 1970, Wallis et a14" described a patient who had generalized muscular stiffness, fasciculations, and rnyokymia of peripheral nerve origin. It was postulated that this may have been related to exposure to 2,4-dichlorophenoxyacetic acid. In 1972, Black et a14' described an infant with sustained involuntary muscle activity who had increased tissue levels of dichlorodiphenyldichloroethylene (DDE), which is a metabolite of DDT (dichlorodiphenyltrichloroethane).

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ASSOCIATED WITH PERIPHERAL NEUROPATHY

PARANEOPLASTIC SYNDROME ASSOCIATED WITH INTRATHORACIC TUMORS. In 1974, Waerness4' described a patient with a peripheral neuropathy and sustained involuntary muscle activity who had a bronchogenic carcinoma. Phenytoin given intravenously had no effect on the abnormal activity. See also Garcia-Merino et

ASSOCIATED WITH INFLAMMATORY NEUROPAAcquired

IDIOPATHIC. In 1972, Welch et al" described a 22-year-old woman with generalized myokymia and sustained involuntary muscle activity.

In 1978, Valenstein et a14"escribed diffuse myokymia and muscle hypertrophy in a patient with chronic recurrent polyneuropathy. Muscle hypertrophy presumably was related to sustained involuntary muscle activity.

THIES.

Figure 3. Burst of repetitively firing motor unit potentials activated by mild voluntary contraction of biceps brachii. (From Warmolts and Mendell.3BReprinted with permission.)

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CHONDRODYSTROPHZC MYOTONIA

This is also known as Schwartz-Jarnpel syndrome (see article by Pascuzzi in this issue of Seminars). It is characterized clinically by the combination of dwarfism, blepharophimosis, kyphoscoliosis, and flexion contractures of' the limbs. Clinical myotonia is present, and the EMG may show myotonic discharges. Some of the abnormal activity is due, in part, to peripheral nerve hyperexcitability, because much of the abnormal spontaneous activity can be abolished by blockade of the ' is in contradistincneuromuscular j ~ n c t i o n . ~This tion to the myotonic electrical activity seen in the myotonic muscular dystrophies, which persists after blockade of the neuromuscular junction.

TETANY FROM KNOWN METABOLIC CAUSES

Tetany from metabolic causes, including hypocalcernia and hypomagnesemia, was studied by Denny-Brown4' and Kugelberg"' who demonstrated that the tetanic muscle spasms arose from proximal nerve trunks. They noted the occurrence of doublets and multiplets with voluntary contraction. As tetany develops, more and more nlotor units are recruited until the oscillogl aphic screen is filled with high-frequency motor unit discharges and a high-pitched sound is heard from the loudspeaker. MYOKYMZC DISCHARGES AFTER ZRRADZATZON

In 1981, Albers et a15" described myokymic discharges in limbs after radiation therapy for metastatic cancer. 'These abnormalities are associated with damage to the brachial or lumbosacral plexus after radiation treatment and are considered relatively specific in this scenario, enabling the differentiation from neoplastic infiltration of the plexus in most cases. LOCALIZED MYOKYMIA AFTER NERVE INJURY

Medina et ali' described a case of localized myokyrnia involving the leg after damage to the tibia1 nerve from a gunshot wound. Involuntary motor unit discharges were apparent, sometimes firing as doublets or multiplets. T h e hypertrophy of the calf that has been reported in association with S- 1 radiculopathy probably arises from a similar mechani~m."~

RIGHT ORBICULARIS ORlS MUSCLE

LEFT ORBlCULARl S ORlS MUSCLE , I ( !1

, , , ' , 1 1 '

Figure 4. Facial myokymia. Spontaneous activity, showing regularly recurring bursts of motor unit potentials, each burst firing independently of the others. (From Daube et a1.53Reprinted with permission.)

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In 1978, Korczyn et al"' described a patient with decreased motor nerve conduction ;elocity who had sustained involuntary muscle activity associated with muscular hypertrophy. T h e patient also had thickened peripheral nerves. Various d r u g therapies were tried, including phenytoin, baclofen, and dantrolene, without sustained improvement. In 1982, Brick et a145described two patients with inflammatory polyradiculopathy and generalized myokymia. They demonstrated that the myokymia was accentuated by lowering the amount of ionized calcium by either hyperventilation o r plasma exchange. In 1987, Hosokawa et al" described three patients with diabetic neuropathy and limb myokymia who also had neuromyotonia.

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C O N T I N U O U S MUSCLE FIBER ACTIVITY-AUGER

Facial myokymia is characterized clinically by the presence of continuous vermicular movements of the muscles supplied by the facial nerve. It is usually unilateral but may be bilateral. Its EMG counterpart is the presence of regularly recurring bursts of motor units, each burst firing independently. T h e rate of discharge within a burst is 25 to 60 Hz. 'There are 3 to 10 units within a burst, and the burst itself recurs every 0.5 to 3 seconds (Fig. 4). This abnormality is usually seen in association with intrinsic brainstem lesions, such as in multiple sclerosis and tumors, although it can also be seen in association with extra-axial tumors in the region of the cerebellopontine angle. It has also been reported in association with inflammatory polyradiculoneuropathies.""

MISCELLANEOUS

Localized myokymia with no history of nerve injury or irradiation has been noted. A case limited to the upper extremities has been de~cribed.~"n another case, the myokymic activity was multifocal, involving the right orbicularis oris, right thenar muscles, and left supraspinatus.iVredominant in-

volvement of the laryngeal muscles also has been

ELECTROPHYSIOLOGY NERVE CONDUCTION STUDIES

The results of nerve conduction studies vary, depending on whether or not there is an associated peripheral neuropathy and whether the disturbance of peripheral nerve function is on the basis of axonal degeneration or segmental demyelination. With axonal degeneration, the conduction velocity may be at lower limits of normal or slightly decreased, whereas with segmental demyelination the conduction velocity may be profoundly decreased and a conduction block may be apparent. Repetitive afterdischarges are frequently recorded in muscle after stimulation of a motor nerve (Figs. 1, 3). Bursts of repetitively firing motor unit potentials also may be activated by voluntary contraction (Fig. 3). Sensory nerve studies may be normal or abnormal, depending on whether or not there is an associated peripheral neuropathy. In some patients with these disorders, paresthesia may be present, suggesting hyperactivity of sensory as well as motor axons. In the family reported by Lance et microneurography demonstrated that spon-

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FACIAL MYOKYMIA

Figure 5. Spontaneous activity recorded from first dorsal interosseous muscle with concentric needle electrode. Highfrequency myokymic discharges are evident. (From Auger et aI.l4 Reprinted with permission.)

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Figure 6. Spontaneous discharge of motor unit at high frequency in patient with sustained involuntary muscle activity of peripheral nerve origin.

CONCENTRIC NEEDLE ELECTRODE EXAMINATION

Examination of involved muscle demonstrates spontaneous motor unit activity, sometimes occurring in regularly recurring myokymic bursts (Fig. 5). Within each burst the frequency of motor unit discharge may be high, sometimes from 150 to 300 Hz ("high-frequency myokymic discharges")." In other cases the abnormal discharges may occur at irregular intervals and last for different durations (Fig. 6). T h e abnormal discharges usually persist during sleep and general anesthesia. They also may persist after proximal nerve block if they arise from nerve terminals, as they often do. However, they always disappear after block of the neuromuscular junction with curare. With voluntary contraction, some motor units may fire as doublets or multiplets. Buchtha15' reviewed some of these features.

PATHOLOGY

264

As is expected from the heterogeneity of these diseases, the pathologic features vary. In diseases in which there is an associated peripheral neuropathy, muscle biopsy shows neurogenic abnormalities, including grouped muscle fiber atrophy. If a nerve biopsy is done, nonspecific changes of axonal degeneration and segmental demyelination may be seen. Askanas et a158 noted the presence of abnormal-appearing Schwann cells with large membrane-bound vacuoles in one patient with sustained involuntary muscle activity and a peripheral neuropathy. Oda et a15Vemonstrated the presence of terminal axonal sprouting in a muscle biopsy specimen from a patient with this disorder. Sroka et al"' demonstrated enlargement of the myoneural junction, ramification of the synaptic clefts, and the absence of synaptic vesicles in the nerve terminals. O n the other hand, Liitschg et al" demonstrated marked atrophy of the postsynaptic regions and widened synaptic clefts.

PATHOPHYSIOLOGY T h e mechanism leading to hyperactivity of the peripheral nerves in these syndromes is unknown. Some investigators have been struck by the similarity between these syndromes and findings in dystrophic- mice, in which ephaptic activation and spontaneous discharges originate in a zone of closely packed, unmyelinated axons in spinal nerve roots."' Although the mechanism is unknown, an abnormality of the sodium or potassium channels in peripheral nerve membrane best explains the clinical features, EMG findings, and response to treatment.

TREATMENT Phenytoin or carhamazepine therapy is effective in most, but not all, cases. Phenytoin appears to have a stabilizing effect on all cell membranes, including those of peripheral nerves.""-" "'Thereis considerable evidence that this effect results directly or indirectly from the decreased flux of sodium ions during action potentials. Carbamazepine probably acts by decreasing sodium conductance in nerve membranes. Sodium valproate therapy may be successful in patients who do not respond to phenytoin or carbamazepine or in those who are intolerant of these drugs.66 The duration of treatment varies. In some patients, treatment may be required indefinitely, whereas in others it may be possible to discontinue treatment if the patient remains free of symptoms. In a 14-year follow-up of Isaacs' original cases, treatment had been discontinued with no recurrence of symptoms.%essation of treatment is most likely to be successful in acquired as opposed to hereditary cases.

REFERENCES 1. Isaacs H . A syndrome of continuous muscle-fiber activity. 1 Neurol Neurosurg Psychiatry 1961;24:319-25

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taneous electrical activity also occurred in sensory axons.

2. Isaacs H. Continuous muscle fiber activity in an Indian male with additional evidence of terminal motor fibre abnormality. ,I Neurol Neurosurg Psychiatry 1967; 30: 126-33 3. lsaacs H, Heffron JJA. T h e syndrome of 'continuous muscle-fiber activity' cured: further studies. J Neurol Neurosurg Psychiatry 1974;37: 123 1-5 4. Mertens H-G, Zschocke S. Neuromyotonie. Klin Wochenschr 1965;43:917-25 5. Isgreen WP. Norniocalcemic tetany: a problem of erethism. Neurology 1976;26:825-34 6. Sheaff HM. Hereditary myokymia: syndrome o r disease entity associated with hypoglycemia and disturbed thyroid function. Arch Neurol Psychiatry 1952;68:236-47 7. Iusic A, Dogan S, Stojanovic V. Hereditary persistent distal cramps. J Neurol Neurosurg Psychiatry 1972; 35:370-84 8. Van Dyke DH, Griggs KC, Murphy MI, Goldstein MN. Hereditary myokymia and periodic ataxia. J Neurol Sci 1975;25:109-18 9. Hanson PA, Martinez LB, Cassidy R. Contractures, continuous muscle discharges, a n d titubation. Ann Neurol 1977;1:120-4 10. Gancher ST, Nutt J G . Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov Disord 1986; 1:239-53 11. Brunt ERP, von Weerden TW. Familial paroxysmal kinesigenic ataxia and continuous myokymia. Brain 1990;113:1361-82 12. Hartlage PL, Swift 'I'K, Sackellarcs J C , Branch CL. ' r h e "stiff child" syndrome: hereditary niuscle stiffness with continuous muscle-fiber activity. (Abstr.) Neurology 1977;27:348 13. Ashizawa T, Butler IJ, Harati Y, Roongta SM. A dominantly inherited syndrome with continuous motor neuron discharges. Ann Neurol 1983; 13:285-90 14. Auger RG, Daube JR, Gomez MR, Larnbert EH. Hereditary form of sustained muscle activity of peripheral nerve origin causing generalized myokymia and muscle stiffness. Ann Neurol 1984; 15: 13-2 1 15. McGuire SA, Tomasovic J.1, Ackerman N J r : Hereditary continuous muscle fiber activity. Arch Neurol 1984; 41 :395-6 16. Denny-Brown D, Foley JM: Myokymia a n d the benign fasciculation of muscular cramps. Trans Assoc Am Physicians 1948;61:88-96 17. Gardner-Medwin D, Waltori J N . Myokymia with impaired muscular relaxation. Lancet 1969; 1:127-30 18. Hughes KC, Matthews WB. Pseudo-myotonia a n d myokymia. J Neurol Neurosurg Psychiatry 1969;32: 11-4 19. Schultze F. Beitrage zur Muskelpathologie. Dtsch Z Nervenheilkd 1894;6:65-75 20. Claes C. A clinical and neurophysiological study of a mixed type of myotonia and sporadic tetany. J Neurol Sci 1966;3:265-83 21. Greenhouse AI-1, Bicknell J M , Pesch RN, Seelinger DF. Myotonia, myokymia, hyperhidrosis, a n d wasting of muscle. Neurology 1967; 17:263-8 22. Barron SA, Heffner RR. Continuous muscle fiber activity: a case with unusual clinical features. Arch Neurol 1979;36:520-1 23. Mitsurnoto H , Wilbourn A J , Subramony SH. Generalized myokymia and gold therapy. Arch Neurol 1982; 39 ~449-50 24. Roger H, Alliez 1 , R o g e r s . La chorke fibrillaire d e Morvan: bilan d e 70 observations dont 30 personnelles. Rev Neurol (Paris) l953;88: 164-73 25. Gil R, Lcfi.vre JP, Neau JP, Guillard 0, H u h A. Choree fibr-illaire d e Morvan et syndrome acrodynique aprks u n traitenient mercuriel. Rev Neurol (Paris) 1984;140: 728-33 26. Teravainen H , Makitie J . Myokymia, unusual side-effect otclofibrate. (Letter.) Lancet 1976;2: 1298 27. Walsh JC. Neuromyotonia: a n unusual presentation of intrathoracic malignancy. J Neurol Neurosurg Psychiatry 1976;39: 1086-91

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