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P>( 2 7 3 430 1 \. t * Generalized Muscular Stiffness, Fasciculations, and Myokymia of Peripheral Nerve Origin William E. Wallis, MD; Alan Van Poznak, MD; and Fred Plum, MD, New York 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 (D PH ) induced a substantial and sustained decrease in the muscular stiffness. Similar cases were re ported by Mertens and Zschocke8 and by Levy et al,4 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- Submitted 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-Cornell Medical Center, New York. ! Reprint requests to Department of Neurology, New York Hospital-Comell Medical Center, New York 10021 (Dr. Plum). ; wald et al,B Gardner-Medwin and Walton,8 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 biopsy. 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 P uerto R ican man presented to the N ew York H ospital complain ing of difficulty walking. H e had been well until two years earlier when over two days he de- Arch Neurol-- Vol 22, May 1970 t i l and Walton,8 have reported however, these nation to deter'gin of the con%pharmacolog ie source of the ervous system, in the motor e one patient d none of the une nerve biop- GENERALIZED MUSCULAR STIFFNESS--WA L U S ETiAL 431 velc>|>ed painful paresthesias in his feet and'v lure 98.6 F (37 C), and respirations 26 breaths hands. At the time he had been employed for \p e r 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 stiffness in all four limbs and was forced to stop inspiratory wheezes, but results of the general work. The pain disap|>eared over the next physical examination were otherwise norfnal. week, but the muscular stiffness gradually pro He was intellectually intact The 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. He was muscurienced 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). His 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. The facial, masseter, trunk. Fifl 1.-- Note posture of hands and right foot. Musculature Is tense and well developed (case 1). ients similar to and offers new ogical evidence ripheral nerves, view of similar which can be certain chemie dichlorophenpound to which >sed. A prelimi- 3 ;rlo Rican man ^spital complaind been well until wo days he de- Arch Neurol--Vol 22, May 1970 'J j'f' il [, 11 432 GENERALIZED MUSCULAR STIFFNESS-- WALLIS E T AL 1 G and extremity muscles all contracted visibly with fine and coarse twitching and rippling adventitious movements when he placed himself 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 voluntary 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 slow 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-hcrur 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. Fig 2.-- EMG recordings from first dorsal interos seous muscle. Top tracing. Resting record demonstrat ing continuous skeletal muscle discharge; middle trace, recorded after ulnar and median nerve block; spon- Eleclrophysiological and Neurophnrmacological Investigations.--Electromyography.--All majoKmuscJe 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. The 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). Many of the normal-appearing motor units corresponded tD visible fasciculations in the vicinity of the needle. The interference pattern was full and the motor units under voluntary control appeared normal. Peripheral Nerve Block.--Electromyography of the first dorsal interosseous muscle showed s 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 in procedure to the consent. Muscle a formed under anesof 1% Iidocaine (> the subarachnoid i producing compleh legs and anesthesia was delected in a' the EMG activity, with 500 mg of thiopental sodium muscular stiffness o Curare.--Adminii intravenously prodi laxation and electric Repetitive Nerve to 30 cps supramax delivered to the n while the evoked r the abductor pollicii electrodes. No sign the amplitude of evo Motor Conduclioi performed using sv over muscle while s supramaximally. A1 ties were either slig range of normal (Tal Histological Stui light microscopic exa sy taken from the stained with hematox Nerve Biopsy.--A nerve was biopsied catly. A small numb undergone severe d the majority of the n sheaths appearing in cular abnormalities w Other Investigate rate was +95 but (PBI) value was no tests revealed restrict (Table 2). Fluoroscoj motility studies of t) mal. A urine sample serum contained no tetanus. T re a tm e n t.--Diazej 10 mg, three times d infusion of magnesian duced no improvemer ministration previousl; DPH were administe six-hour period while serial DPH blood leve No EMG or clinical d DPH dose of 750 m S ET AL i GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL 433 and Nouropharmncn--Electromyography.--A11 vere sampled with a conle and standard amplifyiisclosed similar findings. was present on insertion eedle or on percussion of nual waxing and waning were present with only rated periods of electrical ng three to five seconds. i of both normal-appearperiodic bursts of repeti(2 msec or less) acLion amplitude and usually a ped configuration (Fig 3). al-appearing motor units ble fasciculations in the . The interference pattern tor units under voluntary nal. Block.--Electromyography terosseous muscle showed a i means complete reduction trical activity at rest after r and median nerves with ). The effectiveness of the stimulating both nerves at reducing an evoked electri* muscle. All distal sensory jf ulnar and median nerves after the block. Spinal and ere induced after first fully is moderately reduced; bottom arate occasion after giving pa.anaous activity greatly reduced. 1 second; vertical, 100/tv. mm 1 explaining the investigational nature*of the a procedure to the patient and obtaining his I consent. Muscle and nerve biopsy were\per- formed 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 Ihe EMG activity. Deep anesthesia was induced (b) n with 600 ,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. Repetitive Nerve Stimulation.--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 (c) Mirir the abductor pollicis brevis muscle with surface electrodes. No significant change occurred in the amplitude of evoked potentials. /l/l/l/V V W W Motor Conduction Velocities.--Studies were H I- performed using surface recording electrodes over muscle while stimulating the nerve trunk (d) 10 m sec supramaximally. All motor conduction veloci ties were either slightly below or in the lower JJUIXIlXiJLJlJO- |0/iv range of normal (Table 1). Histological Studies.--Muscle Biopsy.--A light microscopic examination of a muscle biop sy taken from the right vastus lateralis and stained with hematoxylin-eosin was normal. Nerve Biopsy.--The right sural (sensory) Fig 3.-- Tracing from resting EMG records (case 1). (a) Short duration units resembling fibrillations which, however, disappeared after .curarization; (b) normal appearing action potentials; (c) repetitive normal-ap pearing sterotyped action potentials; (d) calibrations. Various combinations of a, b, and c were present In resting EM6. nerve was biopsied and examined microscopi cally. A small number of individual fibers had blood level was 13/ig/ml. (A D PH blood level undergone severe degenerative changes with of 10 to 15pg per milliliter usually provides the majority of the remaining fibers and myelin effective anticonvulsant action.) Following this, sheaths appearing intact. Inflammatory or vas the muscular stiffness and associated EMG ac cular abnormalities wer lacking. tivity progressively decreased until maximal Other Investigations.--The basal metabolic improvement was achieved at a dose of 1 gm of rate was +95 but the protein-bound iodine DPH (blood level 17pg/ral). No further change (FBI) value was normal. Pulmonary function occurred as the dose was increased to 1.5 gm tests revealed restrictive chest wall dysfunction and the blood level to 25pg/ml. Occasional (Table 2). Fluoroscopy of the diaphragm and fasciculations and scant spontaneous electric motility studies of the small bowel were nor activity persisted after treatment (Fig 2). mal. A urine sample contained no 2,4-D. The Coinciding with the subsidence of sponta serum contained no detectable antibodies to neous EMG activity, the patient improved tetanus. markedly in his gait, breathing, and ability to Treatment.--Diazepam in oral doses of up to move (Table 2). The previously absent stretch 10 mg, three times daily, and an intravenous reflexes reappeared. The excess sweating, ve infusion of magnesium sulfate 0.32 mg/kg pro nous engorgement, and hypermetabolism disap duced no improvement Using methods of ad peared. The entire improvement persisted after ministration previously described,13 1,500 mg of initiating 0.3 gm D PH therapy daily. After one DPH were administered intravenously over a month of treatment, the DPH was discontinued six-hour period while a continual EMG and and three days later all of his pretreatment serial DPH blood levels were obtained (Fig 4). symptoms and findings returned. Restitution of No EMG or clinical changes were noted urjtil a DPH at 0.3 gm daily produced a remission DPH dose of 750 mg was reached, and" the which has now lasted eight months. The de- Arch Neurol-- Vol 22, May 1970 I t r* y'r i\ *- ii : l : ! y 'i * 1! i! i If 434 GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL \ GENERs Table 1.-- Motor Conduction Velocities in Case 1 Meters/Second Nerve Median Ulnar Common peroneal Tibial Lett Right Normal (35) 42 39 44 39 33 36 37 34 40-58 40-60 43-57 40-55 Table 2.--Comparison Before and After Treatment iq Case 1 Before DPH Treatment After DPH Treatment Basal Metabolic Rate + 9 5 Diaphoresis intense Superficial venous engorgement Marked Pulmonary functions (% predicted values) Forced expiratory volume (1 sec) 33% Vital capacity 43% Maximum breathing capacity 26% +20 Normal Normal 68% 67% 81% formities of the hands and feet gradually disa^ peared vyilh physical therapy. Case 2 \r A 30-year-old farmer's wife was healthy and free from neurological symptom 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. At 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, fasciculatiom, 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 family 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 EMG 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 13/rg/ml. Maxi mal improvement occurred with a dose of 1,000 mg and a blood level of 17pg/mf. Full interference 23 Time (hours) mm Hg, heart rate 80 ! regular, and her tempe The general physical e: markable except for obe: tually normal. The only itics were in the motor findings similar to, but m patient in case 1. She w; and could knit and per ments with difficulty. No tender, but the calves were mildly hypertrophif in slight plantar flexion flexed and claw-like. Ti uniformly resistant to pa ably contracted a t rest. 1 H lations were visible anc major muscle groups in movements as well as th muscles persisted duri myotonia was absent, b ness unproved after ar ment. She initially had muscles after a vigorou.* don jerks were 1+ and the ankles where they despite reinforcement. The following laborat complete blood count, i genogram, serum elect] phorus, and PBI. EMG.--The right a! and both tibialis anterio using a concentric needl< EMG was almost contin long runs and intermit This activity was interr nods of electrical silenc onds. The motor units amplitude and duratic short duration (2 msec < pearing units. The inter and those motor units i appeared normal. Treatment was initial of 1,000 mg of orally ac in divided doses over 48 orally four times daily. stiffness of fasciculations dose was increased to f without improvement signs of DPH loxidty therefore, an abnormal^ or absorption was suspwas begun on carbarn times daily, and impr Following treatment, n eluding the posture in ! normal except for the ; :r a l I feet gradually disap* py* I farmer's wife wai eurological symptoms when painful pares is followed by a pfo ur extremities. These ng the next year, but in fine movements of alking. At the age of Lai of New Zealand, a il and an EMG connit discharges at rest, incture and studies of n were normal. Her / in muscular relaxa`.illness, fasciculeLions, itch reflexes. She was nent but her muscle ately over the next iosure to herbicides or vas no family history 'old weather did not ess, but she did note J exercise. one of us (W.W.) in pressure was 120/75 pression of ]/m l. Maxif 17pg/ml. Full interference l.5gm (V EMG octivity at rest a Electrical silence GENERALIZED MUSCULAR STIFFNESS--WALLIN ET AL 435 mm Hg, heart rate 60 beats per minute 'fend numbers of fasciculationd. The ankle tendon rrgular, and her temperature 98.6 F (37 jerks could now be obtained easily. The general physical examination was unreV markable except for obesity. She was intellec tually normal. The only neurological abnormal Comment v 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 stiflly and could knit and perform other fine move ments with difficulty. None of her muscles were lender, but the calves and thenar eminences Pathophysiology.--The 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 slight plantar flexion, and the hands were changed by sleep, spinal anesthesia, and flexed and claw-like. The muscles were stiff, deep barbiturate anesthesia. An origin in uniformly resistant to passive stretch, and palp the muscle or postsynaptic neuromuscular ably contracted at resL Myokymia and fascicu- . junction is ruled out, since curare eliminated lations were visible and palpable in all the major muscle groups in the extremities. These movements as well as the stiff resistance of the the muscle contraction and all EMG activ, ity. The decrease in EM G activity after muscles persisted during sleep. Percussion peripheral nerve block indicates that the myotonia was absent, but her muscular stiff spontaneous activity arose from sites both ness improved after active or passive move 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 EM G 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 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. The interference pattern was full and those motor units under voluntary control appeared normal. Treatment was initialed with a loading dose of 1,000 mg of orally administered DPH given in divided doses over 48 hours and then 100 mg nerve disorder. D P H in standard thera peutic doses has little effect on peripheral nerve conduction or synaptic transmission, but does act specifically on motor nerve terminals to block posttetanic potentiation (F T P )14 in tonic muscles. In this phenome non a conditioning tetanic volley establishes a hyperexcitability of motor nerve terminals, such that repetitive discharges arise when the terminals are invaded by subsequent orally four times daily. No 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 PH toxicity despite this high dose; patients. In this regard it is of interest that therefore, an abnormality of DPH metabolism , or absorption was suspected. Accordingly, she / was begun on carbamazepme, 250 mg four/ the unmyelinated terminal region is particu larly sensitive to dysfunction and this region times daily, and improved within 24 hours. . 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.la normal except for the persistence of moderate The results of the motor conduction veloc- Arch Neurol-- Vol 22, May J970 Bit 43G ENERA LIZED MUSCULAR STIFFNESS-- WALLIS' E T AL ilies and nerve biopsy in case 1 also suggest s diseases of the anterior horn cells,18 but they peripheral nerve disorder. The sural nerve W i 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 EM G 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 terni 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.18-17 Landau18 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 / Treatment.-- With D P H 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 pertonus. The presence of muscle fascicula- -4n immediate and remarkable decrease in tions at rest has most often been linked to muscular stiffness and improvement of hand and foot defo i evident in tl* { turned almost incapacitated manual move feet without very likely i: peutic effect i motor nerve f to improve tl plained. It is volved patho ferent from t although not : D P H blood ]< is possible t. absorption oi responsible.23 T he therap pine is less < D P H , carba; treatment of < gia. It protec induced convi pressive effec the'spinal tri pine shares tl at lower equi' carbamazepir. ripheral nervt Etiology.-- unknown, bu sure of the ps 2,4-D. In lab* induces a rig sembles the s lar stiffness, f Curare will r stiffness or th respect 2,4-D myotonia anr this paper, b of isolated m stein et al-8 a reported that neuropathy i patients, a f generalized vealed no ev closed norma emulations o -- similar to drugs such a tients also rc Arch Neurol--Vol 22, May 1970 i " AL GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL 437 irn cells,18 but they / of conditions in[abolie disorders1* sions.70 Fascicularesent the sponta>f individual motor -n clear that they the motor neuron nee indicates a pefasciculations that of neostigmine are nmyelinated termiand even in motor fasciculations perolock or anatomic iying the muscle in ed EMG findings dicate that the fasit cases originated or axons. anifested clinically and on the EMG motor u n it When e, closely grouped, ontinuously in dify give the appearon rather than a lations were called ;Ho coined the term aneous undulating j and thighs. Eleccannot distinguish ons accompanying from those accomil dysfunction alof a slow rate of ying giant potenlocalize the proxibination of a high ; presence of small .les peripheral hyipheral hyperexcileads to fasciculant and widespread, myokymia; the latof the rapid and die first, not a disi fasciculation is a H or carbamazereviously reported own demonstrated rkable decrease in provement of hand and foot deformities. This was particularly lar to those of our cases, and 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, D PH 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 P H 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 vera trine alkaloids, ferent .from those in the patient' in case 1, and other fadlitatory 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 D PH 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 convulsions24 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 P H but D PH in therapeutic doses effectively sup at lower equivalent dose levels. The effect of presses the isolated peripheral nerve carbamazepine upon P T P 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 may 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 criteria*-8 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 al-fl and 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 iasj 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 tients also reported distal paresthesias simi- patient in case 1. Arch Neurol-- Vol 22. May J970 t a 438 GENERALIZED MUSCULAR STIFFNESS--WALLIS ET AL G .pyramidal tract This syndrome is also readily differentiated '\ Neuromyotonia3 jnus, myogenic from the myotonia of muscle disease which Pseudomyotonia5 man" syndrome available evidence suggests arises in the mus Myokymia with impaired muscular and carbamazep cle membrane itself.18-17 Although some pa relaxation8 \ decrease the res tients with generalized muscular stiffness and Pseudomyotonia and myokymia7 I .move the clinica fasciculations of peripheral nerve origin find it difficult to relax their muscles and show a decreased stiffness with repeated motions, they demonstrate neither percussion myotonia, The term "generalized muscular stiffncs, fasciculations, and myokymia of peripheral nerve origin" is admittedly cumbersome, but does convey the essential clinical and patho i jtoin probably ex Sj depressing the e i .unmyelinated m The cause of t increased stiffness .with exposure to cold, nor other stigmata of a myopathy. Unlike the myotonia of muscle disease, generalized fas ciculations 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 ! damage to perip r` to certain chem ..^oxyacetic acid (: myopathy. In muscle myotonia the EM G is viously, and he still required full therapeutic generally silent at rest, responding with the levels of DPH to prevent incapacitating musde '-'Ii - ; I. Isaacs H: Sync repetitive potentials only after percussion of contraction. Dr. Thomas R. Swift recorded the : activity. J Neurol the muscle or movement of the recording 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.16-17 The basal ganglia disorders, pyramidal EMG from the abductor digit! quinti muscle after the patient had been removed from DPH for two weeks. He electronically counted the number of spontaneous muscle potentials with the muscle a t rest and following successive ulnar nerve blocks a t the elbow and wrist, respectively. Dr. Swift will publish the detaib subsequently, but block at the elbow reduced 1961. . 2. Isaacs H: Con an Indian male will ? motor fiber activity 30:126-131, 1967. ' 3. Mertens HG, Klin Wachr 43:917-9 ! 4. Levy JA, W it mia assodada a atii tia. Arg Neuropaygu. tract spasticity, muscle spasm resulting from the potentials 53% from a resting mean and SE spinal intemeuron damage,2 and tetanus of 5,300 281 per minute to 3,500 610 per are not associated with fasciculations, myo minute. Block at the wrist further reduced the 5. Sigwald J, et a 115:1003-1014, 1966. 6. Gardner-Medwi with impaired mus kymia, and depressed stretch reflexes. In number of potentials to 300 19 per minule. 130, 1969. tetanus and muscle spasm from spinal inter The results provide clear evidence that a neuron damage, the EMG may contain con significant amount of the spontaneous activity . 7. Hughes RC, > and myokymia. J 32:11-14, 1969. tinual activity at rest which corresponds to arose from the peripheral. nerve between the the visible muscle spasm20-3; however, both two blocks. 8. Riker W P, Oka tor nerve terminals. 1969. tetanus and spinal intemeuron disease are associated with hyperactive deep tendon reflexes and other signs of spinal cord dys Summary Two patients with a syndrome of general 9. Masland RL, \ companying fascicul J Neurophyxiol 3:26 10. Zager RF, Me function. Tetanus is usually an acute illness ized muscular stiffness, fasciculations, and pharmacology of 2-i 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 Exp Ther 166:205-21 11. Eyzaguixro C, Experimental myoto Nomenclature.--A number of patients unchanged by sleep, general anesthesia, or have been described with various combina spinal anesthesia, but was reduced by distal The vera trimc eflec (2,4-D) in the rot / 12. W allis WE, I tions of muscle stiffness, myokymia, fascicu peripheral nerve block and abolished by cu lions, myokymia bi lations, myotonia, "pseudomyotonia," and rare, thus confirming Isaacs' view that isolat muscle atrophy.31-34 M ost of these patients ed spontaneous firing of the peripheral mo peripheral nerve dise to be published. 13. W allis WE, I* have not undergone the pharmacological tor nerves is responsible. T he configuration nous diphenylhydant 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 itive seizures. Neurol 14. Raines A, Star lional effects of diph- and not spinal cord or muscle, but their nerve block suggest that the action poten neuromuscular junct disease so closely resembled the present tials originate in various portions of the 1531361-366, 1966. IS- Song SK: UK cases clinically that they were probably the peripheral motor axons including the nerve 1; end-plates of skeleta same. However, the rarity of the disorder, terminals. Further evidence of a peripheral : Fed Proc 26:794, 19G1 and the different views of its pathogenesis nerve disorder was found in abnormal motor 16. Lnndnu WM: j; myotonia. Neurology have led to the following names, most of nerve conduction velocities and an abnormal ' 17. Brown GL, Hn which either overlook the unusual pathophy sural nerve biopsy in one patient. The disor in the goat Brain 62: 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 Arch Neurol-- Vol 22, May J970 GENERALIZED MUSCULAR STIFFNESS-- WALLIS ET AL 439 'I julur 'J 4 a* * stiffness, peripheral; -some, but tnd patho- irned from re able to unchanged years pretherapeutic. ing muscle corded the nti muscle from DPH mnted the ntials with successive and wrist, the details w reduced an and SE 610 per \ jduoed the ar minute. 'e . that a js activity tween the f generalions, and rve origin ness was thesia, or by distal 2d by cuhat isolatheral mofiguration i (EMG) peripheral on poten:s of the the nerve peripheral oal motor abnormal .Tie disorther cons such as f ; ji J ; j e I t pyramidal tract disease, parkinsonism, teta nus, myogenic myotonia, and the "stiffman" syndrome. Both diphenylhydantoin uid carbamazepine ameliorate the stiffness, decrease the resting EMG activity, and re move the clinical disability. Diphenylhydan toin probably exerts its therapeutic effect by depressing the excitability of the peripheral unmyelinated motor nerve terminals. ' The cause of the disorder is unknown, but damage to peripheral nerves from exposure to certain chemicals such as dichlorophenoxyacetic 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 N B -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 Glasgow, FRCP, and Dr. W. F. Riker made helpful suggestions: Nonproprietary and Trade Names of Drug Diazepam--Valium. . References 1. Isaacs H: Syndrome of continuous muscle fiber 18. Denny-Brown D, Pennybacker JB: Fibrilla ctivity. / Neurol N eurosurg Psychiat 24319-325, tions and fasciculations in voluntary muscle. Brain 1961. 61:311-334, 1938. Z Isaacs H: Continuous muscle fiber activity in 19. Dainy-Brown D, Foley JM: Myokymia and i *n Indian male with additional evidence of terminal the benign fasciculations of muscular cramps. Trans \ motor fiber activity. J Neurol Neurosurg Psychiat Assoc Amer Physiol 61:88-96, 1948. ; 30:126-131, 1967. 20. DeJong RN: The Neurologic Examination, ed 3. Mertens HG, Zschocke S: Neuromyotcnia. 3. New York, Paul B Hoeber, 1967, p 54L Klin Wschr 43:917-925,1965. * ' 21. Forster FM, Borkowski WJ, Alpers BJ: 4. Levy^ JA, WIttig EO, Ferraz EC: Escleroder- Effects of denervation on fasciculations in human mia assoeiada a atiridade electrics muscular contin muscle. Arch Neurol Psychiat 56:276-283, 1946. ue. Arq Neuropsyquiat 23:283-287,1966. 22. Schultze F: Beitrfige zur Muskel pathologie. 5. Sgwald J, et al: Pseudo-myotonia. Ren Neurol Deutsche Z Nervenheilk 6:65-70, 1895. 115:1003-1014,1966. . 23. Kutt H, Haynes J, McDowell F: Some causes S. Gardner-Madwin D, Walton JN : Myokymia of ineffectiveness of diphsiylhydantoin. Arch Neurol with impaired muscular relaxation. Lancet 1:127- 14:439-492, 1966. 130,1969. 24. Dalessio DJ: Chronic pain syndromes and 7. Hughes RC, Mathews WB: Pseudo-myotonia disordered cortical ihhibition: Effects of .tricyclic nd myokymia. J Neurol Neuroaurg Psychiat compounds. D is N e w Sys 28:325-328, 1967. 32:11-14, 1969. 1 25. Fromm GH, Killian JM: Effects of some 8. Riker WF, Okarooto M: Pharmaoology of mo 'antioonvulsant drugs on the spinal trigeminal nucle tor nerve terminals. Ann Peu Pharmacol 9:173-208, us. Neurology 17:275-280,1967. 1969. 20L Goldstein N P, Jones PH, Brown JR: Periph 9. Masland RL, Wighton RS: Nepve activity ac eral neuropathy after exposure to an ester of dicbJo* companying fasciculation produced by pzostigmine. rophenaxyacetic acid. JAMA 171:1306-1309,1959. I Neuropkysiol 3:269-275, 1940. 27. Monarca O, Di Vito G: Sull Intossicaxi-one 10. Zager RF, McCarty LP, Standaert FG: The acuta da diserbante (acdo 2-4 dichlorofenos* pharmacology of 2-axiridinyl ethanoL J Pharmacol siacetioo). Folia M ed 44:480-485, 196L Exp Ther 166:205-216, 1969. 28. Gordon EE, Januszko DM , Kaufman L: A IL Eyzaguirre C, Folk B P, Ziefler KL, et al: n-itni-nl survey of stiff man syndrome. Am er J M ed Experimental myotonia and repetitive phenomena: The vemtrinic effects of 2,4-dichoropbenoxyacetate (2,4-D) in the rat Amer J Physiol 155:69-76, 1948. 12. Wallis WE, Plum F: Continuous iasddila tions, myokymia and muscle contraction due to peripheral nerve disease. Trans Amer Assoc Physiol, to be published. 13. Wallis WE. Kutt H, McDowell F: Intrave nous diphenylhydantoin in treatment of acuta repet itive seizures. Neurology 18:513-525, 1968. 14. Raines A. Standaert FG: Pre- and post-junc tional effects of diphenylhydantoin at the cat soleus neuromuscular junction. J Pharmacol Exp Ther 153:361-366, 1966. 15. Song SK: Ultrastructural changes of motor end-plates of skeletal muscle following denervation. 42:582-599, 1967. 29. Penry JK, Hoefnagel D, Van Den Noort S, et al: Muscle spasm and abnormal postures resulting from damage to interneurons in spinal cord. Arch Neurol 3:500-512, 1960. 30. Strappier A, Struppler E, Adams RD: Local tetanus in man: Its clinical and neurophysiological characteristics. Arch Neurol 8:162-178, 1963. 3L Gamstoip I, Wohlfart G: A syndrome charac terized by myokymia, myotonia, muscular wasting and increased perspiration. Acta Psychiat Scand 34:181-194, 1959. 32. Greenhouse AH, Bichnell JM , Pesch RN, et al: Myotonia, myokymia, hyperhydrosis and wast 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 2:369-383, 1952. 34. Claes C: A clinical and neurophysiological 17. Brown GLs Harvey AM: Congenital myotonia study of a mixed type of myotonia and sporadic in the goat Brain 62:341-363, 1939. tetany. J.Neurol Sci 3:265-283, 1966. Arch Neurol--Vol 22, May 1970