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pX '2 o 7 3 430 t A \. \ Generalized Muscular Stiffness, Fasciculations, and Myokymia of Peripheral Nerve Origin W illiam E. Wallis, M D ; Alan Van Poznak, M D; and Fred Plum, M D, N ew York y veloped hands. A one year cal terbi protectiv herbicide thesias 1 stiffness work. T 1 week, bu v- gressed o ing his g GJ time he creased i S' fore ente ? rienced n H is sym] ; temperai' neurologi was urirc asthma. ] did not re H is bio rate 80 b- T h e PERIPHERAL nerve disorders, un like central nervous system and muscle dis eases, have not been widely recognized as causes of generalized muscular stiffness. Isaacs,1-2 in 1961 and 1967, reported three patients with an entity of generalized mus cular stiffness, fasciculations, continual elec tromyographic (EM G) activity at rest and depressed deep tendon reflexes. The muscu lar stiffness and' continual EMG activity were abolished by curare but persisted dur ing spinal anesthesia and after peripheral nerve blocks, suggesting that the syndrome was due to isolated, spontaneous, peripheral nerve hyperactivity. Isaacs also discovered that diphenylhydantoin (DPH ) induced a substantial and sustained decrease in the muscular stiffness. Similar cases were re ported by Mertens and Zschocke3 and by Levy et al,1 both groups confirming the effects of spinal anesthesia and curare. Mer tens and Zschocke3 also found carbamazepine as effective as D P H in treatment. Sig- Subraitted for publication Sept 8, 1969; accepted Oct 25. From the departments of neurology (Drs. Wallis and Plum) and anesthesiology (Dr. Van Poznak), New York Hospital-Comell Medical Center, New York. ; Reprint requests to Department of Neurology, New York Hospital-Comell Medical Center. New York 10021 (Dr. Plum). ; wald et al,5 Gardner-Medwin and Walton, and Hughes and Mathews7 have reported apparently identical patients; however, these cases did not undergo investigation to deter mine the peripheral nerve origin of the con dition. Despite the convincing pharmacolog ical evidence that localized the source of the stiffness to the peripheral nervous system, no abnormality was found in the motor conduction velocities in the one patient where this was studied,2 and none of the reported patients has undergone nerve biop sy. The etiology is unknown. This paper reports two patients similar to those described by Isaacs1-2 and offers new neurophysiological and histological evidence relating the disease to the peripheral nerves. The etiology is discussed in view of similar animal experimental models which can be produced with exposure to certain chemi cals8'11 including a herbicide dichlorophenoxyacetic acid (2,4-D), a compound to which one of our patients was exposed. A prelimi nary report has been made.12 Report of Cases CASE 1.-- A 21-year-old Puerto Rican man presented to the New York Hospital complain ing of difficulty walking. H e had been well until two years earlier when over two days he de- Fig : Arch N eurol-- Voi 22, M a y 1970 GENERALIZED MUSCULAR STIFFNESS--WALLIS ETiAL 431 `It, f ` f and Walton,6 have reported however, these ation to detergin of the con' pharmacologs source of the arvous system, in the motor e one patient i none of the ne nerve biop- vcloped painful paresthesias in his feet and', ture 98.6 F (37 C), and respirations 26 breaths hands. A t the time he had been employed for ^per minute and slightly labored. He was well one year spraying sugar cane fields with chemi developed and nourished, and his skin was cal herbicides containing 2,4-D. He utilized no warm with marked engorgement of the super- \ protective mask or clothing and handled the ficial veins. He perspired heavily at rest. No herbicide freely. Three days after the pares cataracts or frontal baldness were present Aus thesias began, he developed painful muscular cultation of the chest revealed a few scattered Blifiness in all four limbs and was forced to stop inspiratory wheezes, but results of the general work. The pain disappeared over the next physical examination were otherwise normal. week, but the muscular stiffness gradually pro H e was intellectually in ta c t T he remainder gressed over the nejft two years, severely impair of his neurological examination disclosed abnor ing his gait and manual dexterity. During this malities limited to changes in motility, skeletal time he noted diffuse muscular twitching, in muscle function, and the deep tendon reflexes. creased sweating, and fatigue. One month be The man was bent forward and visibly stiff in fore entering the New York Hospital he expe all his skeletal muscle groups. H e was muscu- rienced mild dysphagia and exertional dyspnea. larly well developed but thin, and the forearms His symptoms were not affected by changes in tapered towards the wrist, appearing moder temperature. There was no family history of ately atrophied (Fig 1). H is hands were held in neurological disease. His past medical history fixed, flexed positions, and his feet were plantar was unremarkable except for mild bronchial flexed in the equinovarus position. When he asthma. Despite many previous lacerations he tried to walk he moved with deliberate slowness did not recall receiving tetanus immunization. but much effort, as if in a slow motion film, or His blood pressure was 120/70 mm Hg, heart trying to pull himself through some great ex rate 80 beats per minute and regular, tempera- ternal resistance. T he facial, masse ter, trunk, Fig 1.-- N ote posture o f hands and rig h t foot. M u sculature is tense and well developed (case 1). ents similar to md offers new 3gical evidence ipheral nerves, /iew of similar which can be certain chemi dichlorophenoound to which sed. A prelimi- 3 rto Rican man spital complaini been well until vo days he de- Arch Neurol--Vol 22, May 1970 432 GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL 1 GEi and extremity muscles all contracted visibly with fine and coarse twitching and rippling adventitious movements when he placed him self completely at rest. Passive flexion of the limbs met with a steady uniform resistance which gradually increased as the arc of move ment increased. The speed and range of volun tary movement were limited in the jaw, ex tremity, and respiratory muscles, and what muscular contraction was accomplished cost great effort so that he fatigued quickly and perspired even more. After prolonged muscular contraction, muscular relaxation was alow and incomplete. This phenomenon was particularly prominent in relaxing the grip; however, per cussion myotonia was not present. During sleep, the muscular stiffness persisted. No ten don jerks could be obtained, but the cutaneous abdominal and cremasteric reflexes were brisk. No Babinski signs or other pathological reflexes were present. Sphincter function and results of the sensory examination were normal. The complete blood count, urinalysis, serum electrolyte analyses, serum calcium/phosphorous, magnesium, blood urea nitrogen, two-hour post prandial blood glucose, fasting blood glucose, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, serum lactic dehydrogenase, serum creatine phosphokinase, chest and skull roentgenograms, stool guaiac, stool for parasites and ova, electroencephalogram, electrocardiogram, and lumbar puncture find ings were all within normal limits. Elec trophysiolog leal and Ncuropharmncological Investigations.-- Electrom yography.-- All majoKmusclc groups were sampled with a con centric needle electrode and standard amplify ing equipment and disclosed similar findings. No myotonic response was present on insertion or movement of the needle or on percussion of muscle. At rest, continual waxing and waning electrical discharges were present with only occasional widely separated periods of electrical silence (Fig 2) lasting three to five seconds. T he activity consisted of both normal-appear ing motor units and periodic bursts of repeti tive short duration (2 msec or less) action potentials of variable amplitude and usually a diphasic and stereotyped configuration (Fig 3). M any of the normal-appearing motor units corresponded to visible fasciculations in the vicinity of the needle. The interference pattern was full and the motor units under voluntary control appeared normal. Peripheral N erve B lock.-- Electromyography of the first dorsal interosseous muscle showed a substantial but by no means complete reduction in the abundant electrical activity at rest after blocking of the ulnar and median nerves with 1% procaine (Fig 2). The effectiveness of the block was tested by stimulating both nerves at the elbow without producing an evoked electri cal response in the muscle. All distal sensory and motor function of ulnar and median nerves was absent clinically after the block. Spinal and general anesthesia were induced after first fully explaining the invprocedure to the consent. Muscle an formed under anestl of 1% lidocaine (X? the subarachnoid sj producing complete legs and anesthesia t was detected in eitl the EM G activity. E with 500 mg of i thiopental sodium v. muscular stiffness or C u ra re.-- Adm inisl intravenously produt taxation and electrica R ep etitive N erve .* to 30 cps supramaxii delivered to the m< while the evoked re; the abductor pollicis electrodes. N o signil the am plitude of evok< M otor Conduction performed using sur over muscle while sti supramaximally. AH ties were either slighi . range of normal (Tabl Histological Studi light microscopic exan sy taken from the r; stained with hematoxy Nerve Biopsy.--Tb Fig 2.-- EMG recordings from first dorsal interos taneous m uscle activity is m oderately reduced; bottom nerve was biopsied a seous muscle. Top tracing, Resting record dem onstrat ing continuous skeletal m uscle discharge; m iddle trace, recorded after ulnar and median nerve block; spon- trace, recorded on separate occasion after giving pa tient 1 gm DPH, spontaneous activity greatly reduced. Calibrated: horizontal, 1 second; vertical, IOOjiv. cally. A small numbei undergone severe de; .G the majority of the ren sheaths appearing inti' cular abnormalities wei Other Investigation; rate was + 9 5 but tl (PB I) value was non* tests revealed restricts (Table 2). Fluoroscop; m otility studies of thr mal. A urine sample ( serum contained no < tetanus. Treatment.-- Diazep; 10 mg, three times da infusion of magnesium duced no improvement ministration previously D P H were administer six-hour period while serial D P H blood levels No EM G or clinical chi DPH dose of 750 mg  ET AL nnd Ncuropharmacn-Elcctrom yography.-- AJ1 ere sampled with a con2 and standard amplify sclosed similar findings, was present on insertion -edle or on percussion of mal waxing and waning vere present with only -ated periods of electrical g three to five seconds. of both normal-appear:>eriodic bursts of repeti2 msec or less) action amplitude and usually a jed configuration (Fig 3). .1-appearing motor units le fasciculations in the The interference pattern or units under voluntary ial. Blocks-- Electromyography ;rosseous muscle showed a means complete reduction rical activity at rest after and median nerves with . The eflectiveness of the timulating both nerves at oducing an evoked electrimuscle. All distal sensory f ulnar and median nerves after the block. Spinal and *re induced after first fully is m oderately reduced; bottom rate o ccasion after g ivin g paneous activity greatly reduced, second; vertical, lOOjiv. GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL 433 explaining the investigational nature of the procedure to the patient and obtaining his consent. Muscle and nerve biopsy w ere\performed under anesthesia. Ten cubic centimeters of 1% lidocaine (Xylocaine) were injected into the subarachnoid space at the L-3 interspace producing complete voluntary paralysis of the legs and anesthesia to the T-10 level; no change was detected in either the clinical stiffness or the EMG activity. Deep anesthesia was induced with 500 .m g of intravenously administered thiopental sodium without any change in the muscular stiffness or the EMG. Curare.-- Administration of 10 mg of curare intravenously produced complete muscular re laxation and electrical silence on the EMG. R epetitive N erve Stim u la tio n.--Trains of 10 to 30 cps supramaximal electrical stimuli were delivered to the median nerve at the wrist while the evoked response was recorded from the abductor pollicis brevis muscle with surface electrodes. N o significant change occurred in the amplitude of evoked potentials. M otor Conduction Velocities.-- Studies were performed using surface recording electrodes over muscle while stimulating the nerve trunk supramaximally. A ll motor conduction veloci ties were either slightly below or in the lower range of normal (Table 1). Histological Studies.-- M uscle B iopsy.-- A light microscopic examination of a muscle biop sy taken from the right vastus lateralis and stained with hematoxylin-eosin was normal. Nerue B iopsy.--The right aural (sensory) nerve was biopsied and examined microscopi cally. A small number of individual fibers had undergone severe degenerative changes with the majority of the remaining fibers and myelin sheaths appearing intact. Inflammatory or vas cular abnormalities wer lacking. Other Investigations.--The basal metabolic rate was +95 but the protein-bound iodine (PBI) value was normal. Pulmonary function tests revealed restrictive chest wall dysfunction (Table 2). Fluoroscopy of the diaphragm and motility studies of the small bowel were nor mal. A urine sample contained no 2,4-D. The serum contained no detectable antibodies to tetanus. Treatment.--Diazepam in oral doses of up to 10 mg, three times daily, and an intravenous infusion of magnesium sulfate 0.32 m g/kg pro duced no improvement. Using methods of ad ministration previously described,13 1,500 mg of DPH were administered intravenously over a six-hour period while a continual EMG and serial DPH blood levels were obtained (Fig 4). No EMG or clinical changes were noted until a DPH dose of 750 mg was reached, and1 the (a) (b) (c) /W M /W VW 1 H I- (d) 10 msec M llW iilM IOO^iv Fig 3.-- Tracing from resting EMG records (case 1). (a) Short duration units resem bling fibrillatio ns which, however, disappeared after .curarization; (b) norm al appearing action potentials; (c) repetitive norm al-ap pearing sterotyped action potentials; (d) calibrations. V arious co m b in atio ns o f a, b, and c were present In resting EMG. blood level was 13/rg/ml. (A D P H blood level of 10 to 15/rg per milliliter usually provides effective anticonvulsant action.) Following this, the muscular stiffness and associated EM G ac tivity progressively decreased until maximal improvement was achieved at a dose of 1 gm of D P H (blood level 17/tg/rol). No further change occurred as the dose was increased to 1.5 gm and the blood level to 25pg/ml. Occasional fasciculations and scant spontaneous electric activity persisted after treatment (Fig 2). Coinciding with the subsidence of sponta neous EM G activity, the patient improved markedly in his gait, breathing, and ability to move (Table 2). The previously absent stretch reflexes reappeared. T he excess sweating, ve nous engorgement, and hypermetabolism disap peared. The entire improvement persisted after initiating 0.3 gm D P H therapy daily. After one month of treatment, the DPH was discontinued and three days later all of his pretreatment symptoms and findings returned. Restitution of D PH at 0.3 gm daily produced a remission which lias now lasted eight months. The de- Arch Neurol-- Vol 22. May" 1970 434 GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL i GENERA Table 1.-- Motor Conduction Velocities in Case 1 M eters/Second Nerve M edian U ln a r Com m on peroneal T ib ia l Left 42 44 33 37 Right N orm al (35) 39 40-58 39 40-60 36 43-57 34 40-55 Table 2.-- Comparison Before and After iTreatment I--n Cas--e 1 -- Before DPH Treatm ent After DPH Treatm ent B asal M etabolic Raje + 9 5 D iaphoresis | 1 Superficial venous engorgem ent Intense M arked Pulm onary functions (% p redicted values) Forced expiratory volu m e (1 sec) 33% Vital capacity 43% M axim um breathing capacity 26% +20 N orm al N orm al 68% 67% 81% formities of the hands and feet gradually disap peared (ilh physical therapy. Case 2 \ - A 30-year-old farmer's wife was healthy and free from neurological symptoms until the age of 26 years when painful pares thesias began in her hands followed by a pro gressive stiffness of all four extremities. These symptoms progressed during the -next year, but her only limitations were in fine movements of the hands and in rapid walking. A t the age of 28, at the Auckland Hospital of New Zealand, a muscle biopsy was normal and an EM G con tained continuous motor unit discharges at rest. The results of a lumbar puncture and studies of muscle enzymes in serum were normal. Her physicians noted difficulty in muscular relaxa tion, generalized muscle stiffness, fasci culatiom, and depressed muscle stretch reflexes. She was discharged without treatment but her muscle stiffness improved moderately over the next two years. She denied exposure to herbicides or industrial toxins. There was no fam ily history of neurological disease. Cold weather did not affect the muscular stiffness, but she did note improvement with repeated exercise. She was examined by one of us (W.W.) in October 1968. Her blood pressure was 120/75 Fig 4.-- Resting EM G activity at various DPH blood levels. Note that depression of EMG activity begins with a DPH dose of 750 mg and a blood level of 1 3/ig/m l. M a x i mal im provem ent occurred w ith a dose of 1,000 mg and a blood level of 17/rg/m l. Full interference 23 Time (hours) mm Hg, heart rale 80 b regular, and her temper The general physical ex: I markable except for obesi 'i. tually normal. The only n ties were in the motor .* findings similar to, but mil patient in case 1. She wal i and could knit and perft ments with difficulty. Non lender, but the calves a were m ildly hypertrophiet in slight plantar flexion, flexed and claw-like. Th uniformly resistant to pas ably contracted at rest, hi lations were visible and major muscle groups in t movements as well as the muscles persisted durir myotonia was absent, bu ness improved after act m ent She initially had muscles after a vigorous don jerks were 1+ and : the ankles where they c despite reinforcement. T he following laborato complete blood count, u gehogram, serum elect phorus, and PBI. EMG.-- T he right abi and both tibialis anterior using a concentric needle EM G was almost continu long runs and intermitti This activity was interru] riods of electrical silence onds. The motor units amplitude and duration short duration (2 msec oi pearing units. T he interfe and those motor units ui appeared normal. Treatment was initiate of 1,000 mg of orally adi in divided doses over 48 1 orally four times daily. N stiffness of fasciculations dose was increased to 6( without improvement. S signs of D PH toxicity d therefore, an abnormalit; or absorption was suspc< was begun on carbama times daily, and impro' Following treatment, m\ eluding the posture in hi normal except for the p< Arch Neurol--Voi 22, May 1970 / T AL feet gradually disapiy. farmer's wife was urological symptoms when painful pares* 3 followed by a pror extremities. These ig the next year, but n fine movements of liking. A t the age of al of New Zealand, a and an EM G con* lit discharges at rest, icture and studies ofi were normal. Her in muscular relaxa'fitness, fasciculations, ich reflexes. She was ent but her muscle .tely over the next sure to herbicides or as no family history jld weather did not 55, but she did note exercise. ne of us (W.W.) in pressure was 120/75 iression of 'm l. Maxi* 17/jg/m l. Full inlerference .5gm IV M G activity resi 3 Electrical silence GENERALIZED MUSCULAR STIFFNESS-- WALLIS ET AL 435 mm Hg, heart rate 80 beats per minute 'and numbers of fasciculationk. The ankle tendon regular, and her temperature 98.6 F (37 3^. jerks could now be obtained easily. The general physical examination was u n r e\ markable except for obesity. She was intellec tually normal. The only neurological abnormal Comment * ities were in the motor system which showed findings similar to, but milder than, those of the patient in case 1. She walked slowly and stiffly and could knit and perform other fine move ments with difficulty. None of her muscles were lender, but the calves and thenar eminences P athophysiology-H ie pharmacologic and physiologic evidence indicates that this dis order results from isolated, spontaneous hyperactivity in various segments of the pe ripheral motor unit. A central cause is un were mildly hypertrophied. The feet were held likely since the muscular stiffness was un in alight plantar flexion, and the hands were changed by sleep, spinal anesthesia, and flexed and claw-like. The muscles were stiff, uniformly resistant to passive stretch, and palp ably contracted at rest. Myokymia and fascicu lations were visible and palpable in all the major muscle groups in the extremities. These movements as well as the stiff resistance of the muscles persisted during sleep. Percussion myotonia was absent, but her muscular stiff ness improved after active or passive move deep barbiturate anesthesia. An origin in the muscle or postsynaptic neuromuscular junction is ruled out, since curare eliminated the muscle contraction and all EMG activ ity. The decrease in EM G activity after peripheral nerve block indicates that the spontaneous activity arose from sites both distal and proximal to the nerve block. In ment She initially had difficulty relaxing the addition, many of the action potentials were muscles after a vigorous contraction. The ten abnormally brief (2 msec or less), reflecting don jerks were 1 + and symmetrical except in fractional activation of a motor unit. This the ankles where they could not be obtained despite reinforcement. The following laboratory data were normal: complete blood count, urinalysis, chest roent genogram, serum electrolytes, calcium, phos phorus, and PBI. EMG.--The right abductor pollicis brevis and both tibialis anterior muscles were sampled using a concentric needle electrode. A t rest, the suggests that some of the activity also arose in the nerve at sites beyond the major axon branching. This combination of normal and fractionated motor unit potentials is similar to the fasciculatory EMG activity evoked by neostigmine and other facilitatory drugs that act on the motor nerve terminals.8 The remarkable effect of D P H in the EMG was almost continuously active with both patient in case 1 (and in Isaacs* patients) long runs and intermittent bursts of activity. also supports the idea of a peripheral motor This activity was interrupted by occasional pe nerve disorder. D P H in standard thera riods of electrical silence lasting 10 to 15 sec onds. The motor units themselves varied in amplitude and duration and included both short duration (2 msec or less) and normal-ap pearing units. T he interference pattern was full and those motor units under voluntary control appeared normal. Treatment was initiated with a loading dose of 1,000 mg of orally administered D P H given peutic doses has little effect on peripheral nerve conduction or synaptic transmission, but does act specifically on motor nerve terminals to block posttetanic potentiation (P T P )14 in tonic muscles. In this phenome-; non a conditioning tetanic volley establishesa hyperexcitability of motor nerve terminals, such that repetitive discharges arise when in divided doses over 48 hours and then 100 mg the terminals are invaded by subsequent orally four times daily. N o change in either the single impulses. Thus, both physiological stiffness of fasciculations. occurred and the daily and pharmacological evidence favors the dose was increased to 600 mg for three days motor terminals as the site of part of the without improvement. She failed to develop peripheral nerve hyperexcitability in these signs of D P H toxicity despite this high dose; patients. In this regard it is of interest that therefore, an abnormality of D P H metabolism . or absorption was suspected. Accordingly, she was begun on carbamazepine, 250 mg f-o--u-V, times daily, and improved within 24 hours. the unmyelinated terminal region is particu larly sensitive to dysfunction and this region develops early degenerative changes follow Following treatment, muscle examination in ing experimental injury to the peripheral cluding the posture in her hands and feet was motor axon.16 1 normal except for the persistence of moderate The results of the motor conduction veloc- Arch Neurol--Voi 22, May J970 436 GENERALIZED MUSCULAR STIFFNESS--WALLIS' ET AL ities and nerve biopsy in case 1 also suggest \diseascs of the anterior horn cells,18 but they peripheral nerve disorder. The sural nerve Wn accompany a variety of conditions in biopsy is to our knowledge the only avail cluding generalized metabolic disorders10 able anatomic study of nerve in this syn and peripheral nerve lesions.20 Fascicula drome. Since motor nerve biopsy was not tions are thought to represent the sponta considered warranted, we can only speculate neous isolated discharge of individual motor that the minimal degenerative changes units;18 but it is far from clear that they found in the sensory nerve reflects a similar necessarily originate in the motor neuron process involving motor nerve fibers. soma; indeed much evidence indicates a pe Clinical Features.-- Generalized muscular ripheral source. Thus, the fasciculations that stiffness, fasciculations, and myokymia of follow the administration of neostigmine are peripheral nerve origin present three essen initiated in the distal unmyelinated termi tial clinical features which were consistently nals of the motor nerve, and even in motor present in our cases and those previously neuron disease itself some fasciculations per reported: (1) generalized muscle stiffness; sist following procaine block or anatomic (2) fasciculations; (3) myokymia. Other section of the nerve supplying the muscle in features such as depressed muscle stretch question.21 The unchanged EMG findings reflexes, joint deformities, sweating, venous after spinal anesthesia indicate that the fas engorgement, and elevated basal metabolic ciculations in the present cases originated rate were not uniformly present and are entirely in peripheral motor axons. probably epiphenomena, ie, manifestations The fasciculation is manifested clinically only of the severity of the muscle contrac as a single muscle twitch and on the EMG tion. as a single spontaneous motor unit. When The muscle stiffness was widely distribut fasciculations are multiple, closely grouped, ed and confined to the skeletal musculature. and follow one another continuously in dif Smooth and cardiac muscle as well as the ferent muscle bundles, they give the appear eye muscles were spared. The muscle stiff ance of muscle undulation rather than a. ness was continually present and in severe single twitch. These undulations were called cases, such as the patient in case 1, persisted myokymia by Schultze22 who coined the term during sleep. Difficulty in muscular relaxa to describe benign spontaneous undulating tion has been noted in many instances and contractions of the calves and thighs. Elec- has resembled the myotonia of muscle dis tromyographically, one cannot distinguish ease except for the absence of percussion the individual fasciculations accompanying myotonia and repetitive discharges on mov anterior horn cell disease from those accom ing the EMG needle. The myotonia of mus panying more peripheral dysfunction al cle disease as noted in myotonia dystrophica though the combination of a slow rate of and the myotonia" of goats is thought to be a discharge and accompanying giant poten primary muscle phenomenon since it persists tials helps electrically to localize the proxi after curarization.16-17 Landau16 believed that mal lesions while the combination of a high the difficulty in relaxation following pro rate of discharge and the presence of small longed muscular contraction observed in pa subunit potentials identifies peripheral hy tients with myotonia dystrophica represented perexcitability. Thus, peripheral hyperexci a normal lengthening reaction in muscles tation in these patients leads to fascicula stretched by persistent myotonic contraction tions which, when frequent and widespread, in antagonist muscles. Such a normal phys cause the undulations of myokymia; the lat iological mechanism may be responsible for ter is the- clinical result of the rapid and the difficulty in muscle relaxation noted in widespread repetition of the first, not a dis patients with spontaneous peripheral motor- ease itself any more than fasciculation is a axon hyperactivity. disease itself. Fasciculations are a prominent part of the I Treatment.-- With D PH or carbamaze- illness and important in distinguishing it pine :treatment, all the previously reported from other disorders producing muscular hy patients and both of our own demonstrated perLonus. The presence of muscle fascicula- j 4n immediate and remarkable decrease in lions at rest has most often been linked to muscular stiffness and improvement of hand Arch Neurol--Vol 22, May J970 and foot defo> i evident in tlv ! turned almost incapacitated manual movet feet without very likely ii peutic effect ! motor nerve ! to improve tl plained. It is volved pathoi ferent from tl although notl D P H blood Ic is possible tl absorption or responsible.22 T he therapi pine is less c D PH , carbat- treatment of t gia. It protect induced oonvu pressive effect the"spinal trij pine shares tl> at lower equi\ carbamazepinripheral nerve Etiology.-- unknown, bul sure of the pa1 2,4-D. In labo induces a rigi sembls the s> lar stiffness, f: Curare will n stiffness or threspect 2,4-D myotonia and this paper. N of isolated m< stein et al26 ai reported that neuropathy ii patients, a f` generalized i vealed no evi closed normal emulations of --similar to drugs such a<tients also rej t/ r al GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL 437 jrn cells,18 but they y of conditions inlabolic disorders1* usions.20 Fasciculajresent the sponlaof individual motor m clear that they the motor neuron nee indicates a pe*fasciculations that of neostigmine are junyelinated termiand even in motor a 2 fasciculations per- block or anatomic lying the muscle in :ed`EMG findings dicate that the fasit cases originated jot axons. anifested clinically i and on the EMG motor unit. When ie, closely grouped, continuously in dif?y give the appearion rather than a dations were called vho coined the term aneous undulating 5 and thighs. Elec- cannot distinguish ions accompanying from those accomal dysfunction alof a slow rate of lying giant potenlocalize the proxiibination of a high i presence of small fies peripheral hyripheral hyperexcileads to fasciculant and widespread, myokymia; the latof the rapid and the first, not a disi fasciculation is a 'H or carbamazeneviously reported own demonstrated rkable decrease in provement of hand and foot deformities. This was particularly lar to those of our cases, apd a colleague has evident in the patient in case 1 who re*, reported to us similar muscular stiffness, turned almost to normal from being severely "muscle twitching, and paresthesias docu incapacitated and unable to perform fine mented by his physician and lasting four manual movements or walk more than 100 months after using 2,4-D. Despite 'these feet without exhaustion. As noted, DPH suggestive observations, 2,4-D is widely used very likely induces this remarkable thera and generally thought to be nontoxic in peutic effect by depressant effects upon the workers spraying it.27 motor nerve terminals. The failure of D PH Many pharmacological agents and chemi to improve the patient in case 2 is unex cals can induce spontaneous repetitive ac plained. It is possible that her disorder in tion potentials in muscle.8*10 These include volved pathophysiological mechanisms dif anticholinesterases, the veratrine alkaloids, ferent from those in the patient in case 1, and other facilitatory drugs and poisons. although nothing else suggested it. Since Many of these chemicals induce repetitive DPH blood levels were not obtained, it also firing in the motor nerve terminals and mus is possible that an abnormality of DPH cle and thus produce states which share the absorption or metabolism may have been characteristics of myotonia and this syn responsible.23 drome. An example is the recently reported The therapeutic mechanism of carbamaze- drug, 2-azaridinyl ethanol (2 A -E ).10 This pine is less clear than that of DPH. Like drug induces continuous fasciculations; DPH, carbamazepine is effective in the nerve section abolishes these when they are treatment of epilepsy and trigeminal neural induced by small doses, but the fascicula gia. It protects animals against strychnine- tions return if the dose is raised. The fasci induced convulsions2* and has a specific sup culations are abolished by curare. No signif pressive effect upon synaptic transmission in icant effects are exerted by 2 A-E upon the the spinal trigeminal nucleus.23 Carbamaze central or autonomic nervous system, and pine shares this latter effect with D PH but D PH in therapeutic doses effectively sup at lower equivalent dose levels. The effect of presses the isolated peripheral nerve carbamazepine upon PTP in isolated pe hyperactivity.10 That the human disease can ripheral nerves is not known. be simulated so closely'in experimental ani Etiology.--The cause of this syndrome is mals suggests that in some patients it m ay. unknown, but it is worth noting the expo be a nonspecific response to peripheral sure of the patient in case 1 to the herbicide, nerves damaged by any of a variety of toxic 2,4-D. In laboratory animals 2,4-D exposure agents which might include 2,4-D or still-un induces a rigid state which superficially re identified chemicals such as 2 A-E. sembles the syndrome of generalized muscu Differential Diagnosis.-- This syndrome is lar stiffness, fasciculations, and myokymia.11 easily differentiated from other causes of Curare will not abolish either the muscular muscular stiffness. It only superficially re stiffness or the electrical activity, and in this sembles the so-called "stiff-man syndrome," respect 2,4-D poisoning resembles myogenic for which the diagnostic criteria28 include myotonia and not the syndrome described in (1) generalized muscular stiffness which dis this paper. Nevertheless, spontaneous firing appears during sleep, (2 ) a normal neuro of isolated motor nerves also occurs.11 Gold logical examination aside from the muscle stein et al211and Monarca and Di Vito27 have stiffness, (3) continual EMG activity at reported that 2,4-D can induce a peripheral rest, (4) depression of EMG activity and neuropathy in man, and one of Goldstein's muscle stiffness with general anesthesia, patients, a 65-year-old farmer, developed spinal anesthesia, and peripheral nerve generalized fasciculations. The EMG re blocks. On the basis of No. 4, the stiff-man vealed no evidence of denervation but dis-. syndrome is thought to have a central ori closed normal motor unit potentials and lasy gin, although of all the patients reported ciculations of "the grouped discharge type only one has undergone all the tests. These --similar to those that can be caused by patients are said to improve with diazepam drugs such as neostigmine." Goldstein's pa-J treatment which was without effect in the lients also reported distal paresthesias simi patient in ea sel. Arch Neurol-- Vol 22, May 1970 / 438 GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL ci This syndrome is also readily differentialed '\ Ncuromyotonia3 r \from the myotonia of muscle disease which available evidence suggests arises in the mus Pseudomyotonia5 Myokymia with impaired muscular cle membrane itself.1-17 Although some pa relaxation tients with generalized muscular stiffness and Pseudomyotonia and myokymia7 fasciculalions of peripheral nerve origin find The term "generalized muscular stiffness, it difficult to relax their muscles and show a fasciculations, and myokymia of peripheral decreased stiffness with repeated motions, . nerve origin" is admittedly cumbersome, but they demonstrate neither percussion myotonia, does convey the essential clinical and patho increased stiffness .with exposure to cold, nor other stigmata of a myopathy. Unlike the myotonia of muscle disease, generalized fasciculations are present while they are not in a logical features. Recently, the patient in case 1 returned from his native Puerto Rico, and we were able to reexamine him. Clinically, he was unchanged from his initial examination two years pre myopathy. In muscle myotonia the EMG is viously, and he still required full therapeutic generally silent at rest, responding with the levels of D P H to prevent incapacitating muscle repetitive potentials only after percussion of contraction. Dr. Thomas R. Swift recorded the the muscle or movement of the recording EMG from the abductor digiti quinti muscle needle, while in the syndrome described here, the EMG shows continual activity at rest. Finally, the EMG activity is fully blocked by curare, which it is not in the myo tonia of muscle disease.1*17 The basal ganglia disorders, pyramidal tract spasticity, muscle spasm resulting from spinal intemeuron damage,29 and tetanus after the patient had been removed from DPH for two weeks. He electronically counted the number of spontaneous muscle potentials with the muscle at rest and following successive ulnar nerve blocks at the elbow and wrist, respectively. Dr. Swift w ill publish the details subsequently, but block at the elbow reduced the potentials 53% from a resting mean and SE of 5,300 2 8 1 per minute to 3,500 6 1 0 per are not associated with fasciculations, myo minute. Block at the wrist further reduced the kymia, and depressed stretch reflexes. In number of potentials to 300 19 per minute. tetanus and muscle spasm from spinal interneuron damage, the EMG may contain con tinual activity at rest which corresponds to the visible muscle spasm29*30; however, both The results provide clear evidence that a significant amount of the spontaneous activity arose from the peripheral nerve between the two blocks. tetanus and spinal intemeuron disease are associated with hyperactive deep tendon Summary reflexes and other signs of spinal cord dys Two patients with a syndrome of general function. Tetanus is usually an acute illness ized muscular stiffness, fasciculations, and and does not last for periods of two to six myokymia of peripheral motor nerve origin years such as in our cases. are reported. The muscular stiffness was Nomenclature.--A number of patients unchanged by sleep, general anesthesia, or have been described with various combina spinal anesthesia, but was reduced by distal tions of muscle stiffness, myokymia, fascicu peripheral nerve block and abolished by cu lations, myotonia, "pseudomyotonia,'* and rare, thus confirming Isaacs' view that isolat muscle atrophy .31-54 M ost of these patients ed spontaneous firing of the peripheral mo have not undergone the pharmacological tor nerves is responsible. The configuration dissection necessary to establish firmly that of many of the electromyographic (EMG) their disorder originated in peripheral nerve action potentials and the effect of peripheral and not spinal cord or muscle, but their nerve block suggest that the action poten disease so closely resembled the present tials originate in various portions of the cases clinically that they were probably the peripheral motor axons including the nerve same. However, the rarity of the disorder, terminals. Further evidence of a peripheral and the different views of its pathogenesis nerve disorder was found in abnormal motor have led to the following names, most of nerve conduction velocities and an abnormal which either overlook the unusual pathophy sural nerve biopsy in one patient. The disor siology or utilize confusing or hybrid terms: der} is readily differentiated from other con Continuous muscle fiber activity1.2 ditions producing muscular stiffness such as *pyramidal tract r ij^nus, myogenic i^m an" syndrome {/.and carbamazepi j*decrease the resl imove the clinical ;loin probably ext |j depressing the ex j unmyelinated mo Ifi | The cause of tl damage to peripl to certain chemi oxyacetic acid (2 li P.! 1. Isaacs H: Syndi activity. J Neurol . 1961. 2. Isaacs H: Conti an Indian male with j? motor fiber activity. 30:126-131, 1967. : 3. Mertens HG, Klin Wschr 43:917-91' 1 4. Levy JA, Witti mia associada a atiri ua. Arq Neuropsyqu 5. Sigwald J, et al 115:1003-1014, 1966. 6. Gardner-Medwin with impaired muse 130, 1969. 7. Hughes RC, M and myokymia. J j 32:11-14, 1969. 8. Riker WF, Okai *1 t1o9r69n.erve terminals. . 9. Masland RL, W companying fascicula J Neurophysiol 3:269- 10. Zager RF, Md pharmacology of 2-a: Exp Ther 166:205-216 11. Eyzaguirre C, Experimental myoton The veratrinic effect(2,4-D) in the rat A112. Wallis WE, T1 (ions, myokymia anperipheral nerve disea to be published. 13. Wallis WE, K< nous diphenylhydanto itive seizures. Neurolo 14. Raines A, Slam j tional effects of diphe- neuromuscular juncti153:361-366, 1966. 15. Song SK: Ultrend-plates of skeletal Fed Proc 26:794, 1967. 16. Landau WM: myotonia. Neurology ? 17. Brown GL, Har in the goat Brain 62:3 Arch Neurol-- Vol 22, May 1970 I GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL 439 culnr .a7 * r stiffness,' peripheral rsome, but and patho*: urned from 1 ere able to unchanged years pre-' therapeutic: ting muscle corded the `HI nti muscle from D PH ounted the ntials with successive and wrist, j: the details jw reduced an and SE 610 per educed the er minute. :e that a us activity 'tween the >f generaldons, and rve origin mess was ^thesia, or . by distal ed by cuhat isolatheral mofiguration 2 (EMG) peripheral on potenis of the the nerve peripheral nal motor abnormal rhe disorither con 's such as pyramidal tract disease, parkinsonism, teta nus, myogenic myotonia, and the "stiffman" syndrome. Both diphenylhydan torn and carbamazepine ameliorate the stiffness, decrease the resting EMG activity, and re move the clinical disability. Diphenylhydantoin probably exerts its therapeutic effect by depressing the excitability of the peripheral unmyelinated motor nerve terminals. F) The cause of the disorder is unknown, but , damage to peripheral perves from exposure to certain chemicals such as dichloropbencxyacetic acid (2,4-D) may play a role. An identical experimental model can be pro duced in animals with 2-aziridinyl ethanol (2 A-E). \ This investigation was supported in part by Pub lic Health Service grants NB-05064 from the Nation al Institute of Neurological Diseases and Stroke and FR-47 from the Division of General Medical Sci ences. The patient in case 2 was referred to us by Gavin Glaegow, FRCP, and Dr. W. F. Riker made helpful suggestions. 1 Nonproprietary and Trade Names of Drug Diazepam-- VaZium. References 1. Isaacs H: Syndrome of continuous muscle fiber 18. Denny-Brown D, Pennybacker JB: Fibrilla clivity. / Neurol Neurosurg Peychiat 24:319-325, tions and fasciculations in voluntary muscle. Brain 1961. 61:311-334, 1938. ' 2. Isaacs H: Continuous muscle fiber activity in 19. Denny-Brown D, Foley JM: Myokymia and in Indian male with additional evidence of terminal the benign fasciculations of muscular cramps. Trane H motor fiber activity. J Neurol Neurosurg Peychiat Aseoc Amer Physiol 61:88-96, 1948. ; 30:126-131, 1967. 20. DeJong RN: The Neurologic Examination, ed 3. Mertens HG, Zschocke S: Neuromyotonia. 3. New York, Paul B Hoeber, 1967, p 54L i Kim Wechr 43:917-925, 1965. 21. Forster FM, Borkowski WJ, Alpers BJ: i. Levy JA, Wittig EO, Ferraz EC: Escleroder- Effects of denervation on fasciculations in human mia associada a atiridade electrics muscular contin muscle. Arch Neurol Peychiat 56:276-283, 1946. ua. Arq Neuropsyquiat 23:283-287, 1965. 22. Scbultze F: Beitrge zur Muskel pathologie. 5. Sigwald J, et al: Pseudo-myotonia. Rev Neurol Deutsche Z Nervenheilk 6:65-70, 1895. 115:1003-1014, 1966. 23. Kutt H, Haynes J, McDowell F: Some causes 6. Gardner-Madwin D,- Walton JN: Myokymia of ineffectiveness of diphenylhydantoin. Arch Neurol with impaired muscular relaxation. Lancet 1:127- 14:489-492, 1966. 130, 1969. 24. Dalessio DJ: Chronic pain syndromes and 7. Hughes RC, Mathews WB: Pseudo-myotonia disordered cortical inhibition: Effects of -tricyclic and myokymia. J Neurol Neuroturg . Peychiat, compounds. Dis Nerv Sys 28:325-328, 1967. 32:11-14, 1969. 1 25. Fromm GH, Killian JM: Effects of some 8. Riker WF, Okamoto M: Pharmacology of mo anticonvulsant drugs on the spinal trigeminal nucle tor nerve terminals. Ann Rev Pharmacol 9:173-208, us. Neurology 17:275-280, 1967. 1969. 26. Goldstein NP, Jones PH, Brown JR: Periph 9. Masland RI* Wighton RS: Nerve activity ac eral neuropathy after exposure to an ester of dicblo- companying fasciculation produced by prostigmine. rophenoxyacetic acid. JAMA 171:1306-1309, 1959. J Neurophysiol 3:269-276, 1940. 27. Monarca G, Di Vito G: Sull Intossicazi-one 10. Zager RF, McCarty LP, Standaert FG: The acuta da diserbante (acido 2-4 dichlorofenos- pharmacology of 2-aziridinyl ethanoL J Pharmacol siacetico). Folia Med! 44:480-485, 1961. Exp Ther 166:205-216, 1969. IL Eyzaguine C, Folk BP, Zierler KL, et al: Experimental myotonia and repetitive phenomena: The veratrinic effects of 2,4-dichorophenoxyacetate (2,4-D) in the rat Amer J Physiol 155:69-76, 1948. 12. Wallis WE, Plum F: Continuous fascicula tions, myokymia and muscle contraction due to peripheral nerve disease. Trane Amer Assoc Physiol, to be published. 13. Wallis WE, Kutt H, McDowell F: Intrave nous diphemylhydwntoin in treatment of acute repet itive seizures. Neurology 18:513*525, 1968. 28. Gordon critical survey EoEf ,stiJfaf nmusaznkosynDdMro,mKe.aAufmmearnJ L: M A ed 42:582-599, 1967. 29. Penry JK, Hoefnagel D, Van Den Noart 8, et al: Muscle spasm and abnormal postures resulting from damage to intemeurons in spinal cord. Arch Neurol 3:500-512, 1960. 30. Struppler A Struppler E, Adams RD: Local tetanus in man: Its clinical and neurophysiological characteristics. Arch Neurol 8:162-178, 1963. 3L Gamstorp I, Wohlfart G: A syndrome charac 14. Raines A, Standaert FG: Pre- and post-junc terized by myokymia, myotonia, muscular wasting tional effects of diphenylhydantoin at the cat soleus and increased perspiration. Acta Peychiat Seand neuromuscular junction. J Pharmacol Exp Ther 34:181-194, 1959. 153:361-366, 1966. 32. Greenhouse AH, Bichnell JM, Pesch RN, et 15. Sang SK: Ultrastructural changes of motor al: Myotonia, myokymia, hyperhydrosis and wast end-plates of skeletal muscle following denervation. ing of muscle. Neurology 17:263-268, 1967. Fed Proc 26:794, 1967. 33. Behrend RC: Zur Frage der erworbenen Myo 16. Landau WM: The essential mechanism In tonie. Deutsch Z Nervenheilk 160:22-42, 1949. myotonia. Neurology 2:369-388, 1952. 34. Cles C: A clinical and neurophysiological 17. Brown GL, Harvey AM: Congenital myotonia study of a mixed type of myotonia and sporadic in the goat Brain 62:341-363, 1939. tetany. J.Neurol Sei 3:265-283, 1966. Arch Neurol--Vol 22, May 1970 i