J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.6.557 on 1 June 1979. Downloaded from

Journal ofNeurology, Neurosurgery, and Psyc,iatry, 1979, 42, 557-562

Myokymia and impaired muscular relaxation with continuous motor unit activity

F. D. LUBLIN, P. TSAIRIS, L. J. STRELETZ, R. A. CHAMBERS, W. F. RIKER, A. VAN POZNAK, AND S. W. DUCKETT From the Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, and Departments of Neurology, Pharmacology, and Anesthesiology, Cornell University Medical College, New York, USA

SUMMARY We have studied two cases of the syndrome of myokymia and impaired muscular relaxation with continuous motor unit activity. Both patients complained of muscle twitching, weakness, stiffness, and hyperhydrosis during their illness. Myokymia was present over the entire body in both. On repetitive testing of muscle strength each patient showed initial fol- lowed by increasing strength as he continued his efforts. Both patients improved on phenytoin therapy at high blood levels. Nerve conduction velocities were decreased. Electromyograms showed continuous electrical activity at rest which persisted during sleep and spinal anaesthesia Protected by copyright. but was diminished by curare. Intravital staining with methylene blue in one case demonstrated sprouting and beading of motor nerve terminals with multiple innervation of muscle fibres. The neurophysiological and pathological findings in these two cases indicate an abnormality of peripheral nerve in this disorder.

Over the last 16 years sporadic reports of the Case reports clinical syndrome of myokymia and impaired muscular relaxation (, pseudomyo- CASE 1 tonia) have defined a picture of generalised mus- Two years before being studied, this 51 year old cular stiffness, continuous undulating contractions man noticed twitching of the muscles of his upper of broad strips of muscle (myokymia), hyper- extremities. There followed stiffness of his fingers, hydrosis, and often weakness. The characteristic slurring of speech, tightness of the facial muscles, finding on electromyography is continuous motor numbness and tingling of his fingertips, and in- 300 mg per day, unit activity at rest. Several reports have sug- creased perspiration. Phenytoin, http://jnnp.bmj.com/ gested an abnormality of peripheral nerve in this was started with immediate improvement in his disorder (Wallis et al., 1970; Welch et al., 1972; symptoms. After six months of phenytoin therapy Irani et al., 1977). he noticed difficulty arising from his knees. When We present clinical, neurophysiological, and walking up a flight of steps, half way up his pathological findings in two patients with this strength diminished, then gradually returned as he syndrome. In both, the pattern of weakness is neared the top. His family history and past history unusual, and is characterised by initial fatigue, were unremarkable. There was no history of ex- to toxins. Physical examination was per- followed by gradual increase of strength with re- posure on September 27, 2021 by guest. petitive efforts. These cases provide additional evi- formed after one week without phenytoin. There dence of an abnormality of peripheral nerve in was generalised hyperhydrosis. He was mildly dys- this disorder. arthric. Myokymia was present over the face, trunk, and extremities. There was no atrophy or percussion myotonia. The hands were held in carpal , and relaxation of grip was pro- Address for reprint requests: Dr Fred D. Lublin, Department of longed. Strength was diminished in all muscle Neurology, Jefferson Medical College, 1025 Walnut Street, Phila- delphia, Pa 19107, USA. groups. On testing strength, there was rapid Accepted 22 November 1978 fatigue after brief effort and improvement with 557 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.6.557 on 1 June 1979. Downloaded from

558 F. D. Lublin et al rest. If testing was prolonged, after five or six charges on percussion or on movement of the repetitions, the initial fatigue was gradually re- needle. Voluntary muscular contractions produced placed by increasing power reaching almost nor- initially a normal interference pattern. As he mal levels. Tendon and skin reflexes were all tired, there was reduction in the number of motor absent. Appreciation of pain and vibration was unit potentials in the interference pattern with minimally decreased distally. each individual unit potential appearing normal. The interference pattern returned to normal as Laboratory studies strength improved with exercise. The changes in Results of routine studies were normal. His basal the interference pattern were not as dramatic as metabolic rate was +41%. Thyroid function tests the changes in strength that occurred on repetitive were normal. The level of serum creatine phos- testing. Cessation of voluntary effort was followed phokinase (CPK) was 23 units (normal, 0-12). by a five to 15 seconds after-discharge, and then by Cerebrospinal fluid protein level was 1.5 and an electrically silent period of one to three minutes 1.3 g/l. before resumption of spontaneous activity. The after-discharge was not seen after cessation of re- Electrophysiology petitive forceful contractions. Ischaemia decreased Nerve conduction velocities, motor and sensory, the spontaneous activity at rest. The continuous were slowed (Table 1). Neuromuscular trans- motor unit activity persisted during sleep and mission studies revealed no increment or decre- spinal anaesthesia. Intravenous curare (1.8 mg) ment in evoked responses at stimulation rates of markedly diminished the continual electrical ac- 2, 20, 50, or 100 per second. Needle electromyo- tivity. Intravenous edrophonium (Tensilon, 2 mg) graphy (EMG) at rest demonstrated continuous produced a brief burst of electrical activity fol- electrical activity of full and fractionated motor lowed by mild improvement in stiffness for one unit potentials firing at a variable rate of 2 to 50 or two minutes. Larger doses produced no changes. Protected by copyright. per second (Fig. 1). Occasional couplets and multi- plets were seen. There were no myotonic dis- Histology Biopsy samples of external intercostal muscle and nerve were studied with light and electron micro- Table 1 Nerve conduction studies-case 1 scopy and histochemical staining with ATPase, Nerve Distal latency Conduction velocity succinyl dehydrogenase, and acid phosphatase. (ms) (metres/second) These studies revealed only an abundance of Left Right Normal Left Right Normal satellite cells in muscle. Median (motor) 7.2 6.0 2.5-4.6 31.5 33.5 49-79 Median (sensory) 6.2 5.3 1.6-4.0 Course Ulnar (motor) 4.0 4.2 2.4-3.5 34.0 35.0 47-75 Phenytoin at a dosage of 600 to 700 mg/day with Ulnar (sensory) 3.5 3.4 1.9-2.8 blood levels of 25 to 34 ,ug/ml resulted in a Peroneal (motor) 5.6 2.5-7.0 32.0 41-59 Posterior tibial marked diminution of the myokymia and con- (motor) 6.5 3.5-6.9 31.5 41-53 tinuous motor activity, with loss of stiffness. The Sural (sensory) 3.0 2.5-4.0 37.5 41-59 reflexes and strength returned to normal. The http://jnnp.bmj.com/

I I on September 27, 2021 by guest.

Fig. 1 Needle electromyography at rest in case I demonstrating continuous electrical activity of full and fractioned motor unit potentials (amplitude: 100 ,uV/cm; time scale: 100 ms/cm). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.6.557 on 1 June 1979. Downloaded from

Myokymia and impaired muscular relaxation with continuous motor unit activity 559 BMR decreased to -5%. Despite the high blood Electrophysiology levels of phenytoin, there were no clinical signs of Table 2 gives an outline of the nerve conduction toxicity. This clinical improvement has lasted for velocities and latencies. Motor nerve conduction 30 months. Decreasing the dosage of phenytoin velocities were slowed significantly. Distal sensory results in a return of weakness first and then latencies of the right median nerve were normal. stiffness. Segmental testing of motor conduction velocity of the right ulnar nerve demonstrated slowing CASE 2 throughout its course. Repetitive stimulation of A 31 year old man noticed twitching of his facial the ulnar nerve produced a decrementing response muscles five years before examination, followed of 50% at a stimulus rate of 50 per second (Fig. 2). over two years by twitching of the muscles of the No change was observed at lower stimulus rates. trunk and extremities. One year before admission Needle electromyography revealed continuous he noticed weakness of his grip and stiffness in his motor unit activity at rest (Fig. 3) and during hands and feet, and then progressive generalised spinal anaesthesia as in case 1. Ischaemia de- weakness. He had noticed some increase in per- creased the activity. Intravenous edrophonium spiration. He was treated for syphilis 12 years be- (Tensilon, 10 mg) produced no change in the fore admissicn, and had been an abuser of intra- clinical picture or the EMG. venous amphetamine. On examination there was moderate hyperllydrosis. He was mildly dysarthric. There was myckymia over the face, trunk, and Table 2 Nerve conduction studies-case 2 extremities wlhile awake and asleep. There was no Nerve Distal latency Conduction percussion myotonia. Strength was markedly di- (ms) velocity minished in all groups, and he needed help to (metres/second) walk. On testing strength, there was an initial Record Normal Protected by copyright. rapid fatigue which improved with rest. When Record Normal testing was prolonged, strength improved after 10 Right median (motor) 7.5 2.4-4.6 39 48-70 Right median (sensory) 2.4 2.2-3.4 to 15 repetitions but he never regained full power. Right ulnar (motor)- Deep tendon reflexes were depressed. Sensory test- supraclavicular fossa to above elbow 60 68-75 ing was normal. Right ulnar (motor)- above elbow to below elbow 28 45-75 Laboratory studies Right ulnar (motor)- Routine studies were normal as was his thyroid below elbow to wrist 5.5 1.8-4.2 38 45-75 function. The serum CPK level was 615 units Right peroneal (motor) 8.0 3.4-6.8 32 38-65 (normal, 0-90). Spinal fluid studies were normal. Right sural (sensory) Unobtainable http://jnnp.bmj.com/

Fig. 2 Decrementing response observed in case 2 on stimulating the ulnar nerve at a rate of 50/second (amplitude: 100 ,uV/cm; time scalc: on September 27, 2021 by guest. 200 ms/cm). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.6.557 on 1 June 1979. Downloaded from

560 F. D. Lublin et al

Fig. 3 Needle electromyagaphy at rest in case 2 revealiig . continuous electrical activity (amplitude: 100 ,uV/cm; time scale: 200 ms/cm).

Histology of the action improved, slowly reaching normal or Biopsy of the peroneus brevis muscle and the nearly normal power. That this is not part of a musculocutaneous nerve of the leg, using the tech- "warming up" process by which stiffness may be Protected by copyright. nique of Coers and Woolf (1959), revealed no relieved in this and myotonic disorders (Brown, significant abnormalities on light and electron 1974) is suggested by its occurrence when weak- microscopy. Muscle histochemistry with ATPase, ness (case 2) or phenytoin (case 1) had abolished succinyl dehydrogenase, acid phosphatase, and the stiffness. Transient fatigue with improvement cholinesterase stains were normal. Intravital after repetition has been described as an infre- methylene blue staining (Coers and Woolf, 1959) quent occurrence in myotonia congenita (Aminoff demonstrated beading and collateral sprouting of et al., 1977; Brown, 1974); however, the weakness terminal motor nerve fibres and multiple inner- of that disorder is maximal after rest whereas vation of muscle fibres with varying morphology strength was improved by rest in both our cases. of the endplates (Fig. 4). The EMG data in our cases are similar to those in other reports. At rest there was continuous Course electrical activity, of full and fractionated unit The patient was treated with phenytoin, 500 mg/ potentials, firing with variable frequency. This day, reaching blood levels of 34 to 45 ,ug/ml. On activity persisted during sleep and spinal

this regimen he has gradually regained strength, anaesthesia and was diminished by curare in case 1. http://jnnp.bmj.com/ his reflexes have increased, and his myokymia has During activity, the interference pattern re- diminished. The slowing of the nerve conduction flected the degree of weakness appreciated velocities and decrementing response to repetitive clinically. The main abnormal feature was the stimulation have not changed with therapy. There forming of an after-discharge after a single are no signs of phenytoin toxicity. Improvement maximal contraction. This after-discharge was not has lasted for 24 months. seen when strength had been restored by repetitive contractions.

Discussion Stimulation of the peripheral nerves has been on September 27, 2021 by guest. reported to show slowing of motor conduction Both patients fit the syndrome of "myokymia and velocity (Wallis et al., 1970; Waerness, 1974; Irani impaired relaxation with continuous motor unit et al., 1977) and prolonged motor latencies (Isaacs, activity." They differ in two main respects-their 1961). Both of our cases had marked slowing of weakness is more severe than has been described, nerve conduction velocities. In one case we found and the weakness is relieved by repetitive activity. slowing of conduction over the length of the ulnar In our cases the initial effect of exertion, for nerve from plexus to wrist. The only evidence in example, flexion of the elbow, was to aggravate any way suggestive of a junctional disorder is our the weakness. If the patient persisted, the strength finding of a decrementing response at stimulation J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.6.557 on 1 June 1979. Downloaded from

Myokymia and impaired muscular relaxation with continuous motor unit activity 561

Fig. 4 Terminal motor nerve fibres in case 2 demonstrating beading and collateral sprouting. Methylene blue, original magnification X400.

rates of 50/s in one case. This may be due to and amphetamine abuse; however, there was no fatigue of a damaged nerve (Simpson, 1962). We clear association between these problems and his found no incrementing response as is seen in the which progressed despite myasthenic syndrome (Lambert and Rooke, 1965). his discontinuation of drug abuse.. Protected by copyright. Nerve and muscle biopsies have shown normal Both phenytoin and carbamazepine have been muscle fibres in most cases. Lesions of the sural shown to be effective therapy for this disorder nerve have been reported in two cases. Segmental (Isaacs, 1961; Wallis et al., 1970; Welch et al., demyelination was reported by Welch et al. (1972) 1972). Our cases improved remarkably with and degenerative changes in a few fibres were phenytoin but required high doses to achieve noted by Wallis et al. (1970). maximal improvement. They tolerated high pheny- In motor nerves the terminal fibres have been toin blood levels (24-45 ttg/ml) without any signs found abnormal by Isaacs and Frere (1974) and in of toxicity. our case 2. Mertons and Zschocke (1965) reported no abnormality of the motor nerve terminals in We acknowledge gratefully the collaboration of their one case. We were unable to find neuro- Dr T. Lentz and Dr G. Pappas, and we thank Dr muscular junctions in sections prepared for G. Klingon for allowing us to study his patient. electron microscopy in our and other laboratories. This work was supported in part by PHS Grant Reduced numbers of vesicles and complex con- 5MOlRR00047. voluted synaptic clefts on electron microscopy are http://jnnp.bmj.com/ described in one case (Sroka et al., 1975). References The balance of the evidence-the involuntary activity, the depressed reflexes, the proliferation Aminoff, M. J., Layzer, R. B., Satya-Murti, S., and and branching of the terminal motor nerve fibres, Faden, A. I. (1977). The declining electrical the abnormalities of conduction velocity-suggest response of muscle to repetitive nerve stimulation. that there is a lesion in the peripheral motor nerve. in myotonia. Neurology (Minneapolis), 27, 812- The aetiology of this disorder is unknown. Most 816. cases Brown, J. C. (1974). Muscle weakness after rest in have no clear precipitating agent. Wallis on September 27, 2021 by guest. et al. (1970) reported one case after exposure to myotonic disorders: an electrophysiological study. the herbicide, dichlorophenoxyacetic acid (2, 4-D), Journal of Neurology, Neurosurgery, and Psychiatry, and an animal model of this disorder produced by 37, 1336-1342. exposure to the drug Coers, C., and Woolf, A. L. (1959). The Innervation 2-azaridinyl ethanol (2A-E). of Muscle: a Biopsy Study, pp. 1-11. Blackwell Neuromyotonia has been associated with occult Scientific Publications: Oxford. (Waerness, 1974). One case has been Irani, P. F., Purohit, A. V., and Wadia, N. J. (1977). reported of myokymia localised to those muscles The syndrome of continuous muscle fiber activity. innervated by an injured nerve (Medina et al., Acta Neurologica Scandinavica, 55, 273-288. 1976). Our case 2 had a history of treated syphilis Isaacs, H. (1961). A syndrome of continuous muscle- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.42.6.557 on 1 June 1979. Downloaded from

562 F. D. Lublin et al fibre activity. Journal of Neurology, Neurosurgery, lower motor neuron. Developmental Medicine and and Psychiatry, 24, 319-325. Child Neurology, 4, 55-64. Isaacs, H., and Frere, G. (1974). Syndrome of con- Sroka, H., Bomstein, M., and Sandbank, U. (1975). tinuous muscle fiber activity. South African Ultrastructure of the syndrome of continuous muscle Medical Journal, 10, 1601-1607. fibre activity. Acta Neuropathologica, 31, 85-90. Lambert, E. H., and Rooke, E. D. (1965). Myasthenic Waerness, E. (1974). Neuromyotonia and bronchial state and lung cancer. In The Remote Effects of carcinoma. Electromyography and Clinical Neuro- Cancer on the Nervous System, pp. 67-80. Edited physiology, 14, 527-535. by W. R. Brain and F. Norris. Grune and Stratton: Wallis, W. E., Van Poznak, A., and Plum, F. (1970). New York. Generalized muscular stiffness, and Medina, J. L., Chokroverty, S., and Reyes, M. (1976). myokymia of peripheral nerve origin. Archives of Localised myokymia caused by peripheral nerve Neurology (Chicago), 22, 430-439. injury. Archives of Neurology (Chicago), 33, 587- Welch, L. K., Appenzeller, O., and Bicknell, J. M. 588. (1972). Peripheral neuropathy and myokymia, sus- Mertons, H. G., and Zschocke, S. (1965). Neuro- tained muscular contraction, and continuous motor myotonia. Klinische Wochenschrift, 43, 917-925. unit activity. Neurology (Minneapolis), 22, 161-169. Simpson, J. A. (1962). The clinical physiology of the Protected by copyright. http://jnnp.bmj.com/ on September 27, 2021 by guest.