PERSPECTIVE
A Hypothesis to Account for the Mary Walker Phenomenon BERNARD M. PATTEN, M.D., F.A.C.P., Houston, Texas
Certain myasthenic patients show that their skeletal muscles produce a substance during ischemic exercise which, when released into the circulation, increases muscle weakness. This phenomenon has been named after Mary Walker, the physician who popularized its demonstration. It is suggested that ischemic exercise produces lactic acid that binds calcium, reducing ionized and total serum calcium. The decreased calcium has an adverse effect on skeletal muscle function especially in patients with myasthenia gravis, where neuromuscular function is often so precarious it may be interrupted by weak inhibitors.
MYASTHENIA GRAVIS is a disease of unknown origin; its
chief symptoms are weakness and easy fatigability of skeletal muscle. It has been found that patients with myasthenia gravis have defective neuromuscular transmission, which is partially corrected by administration of anticholinesterase drugs (1) or by the administration of ACTH ( 2 ) , corticosteroids (3, 4 ) , or other agents that depress the body's immune response ( 5 ) . Because the clinical condition of the myasthenic patient closely resembles that seen in curare poisoning (6-8), investigators have, for a long time and with variable success, tested the blood of myasthenic patients for curariform substance (9-13). Their efforts were spurred by an experiment that showed that during ischemic exercise, the myasthenic patient may make a substance that, when released into the circulation, causes weakness of a nonexercised muscle (8, 10, 14-16). This experiment was popularized by Mary Walker in the early part of this century (14). The Mary Walker Experiment
When the effect of the patients' neostigmine was just beginning to wear off, although the patients were still strong, the circulation was cut off in both arms by sphygmomanometer armlets at a pressure of 200 mm Hg; the patients then briskly pronated and supinated their forearms until they tired, which took about 1 minute. While the circulation was cut off, no weakness was noted in the rest of the body, not even the eyelids; but W2 minutes after the pressure was released, the eyelids began • From the Neuromuscular Disease Division, Department of Neurology, Baylor College of Medicine, Houston, Texas.
to droop, and after 2 minutes, the patients were about as weak as they had been before their morning injection of neostigmine. As a rule, the weakness always came on IY2 minutes after the pressure was released and always appeared to be equally severe. When only one arm was fatigued by exercise with the circulation cut off and when both arms were exercised in the same way but short of fatigue with the circulation cut off, the ensuing weakness was much less. Cutting off the circulation with the armlets in position for several minutes without exercise caused some weakness, but far less than with exercise. When patients were fully under the influence of neostigmine, pronation and supination of both forearms for about 1 minute with the circulation cut off produced no obvious effect, although the patients thought that they felt a little weaker. In a normal subject, no weakness was apparent after brisk pronation and supination for 1 minute with the circulation cut off. In patients with less severe myasthenia, there was less increase in weakness. Mary Walker interpreted her experiments as showing that increased destruction, defective production, or release of acetylcholine cannot be the immediate cause of myasthenia gravis, but that something produced in the muscles themselves enters the circulation, causing the abnormal fatigability. She reasoned that anything that delays the destruction or facilitates the release of acetylcholine would be antagonistic to this curarizing substance. Since Mary Walker's demonstration, several investigators have refined the experiments and published photographs (15) and movie frames (10) of patients before and after the release of the cuffs that were occluding the circulation. Grosse-Brockhoff and Welte (8) observed development of lid ptosis and weakness in myasthenic patients after release of a tourniquet that had bound the legs while the patient had been instructed to flex and extend his legs. They also suggested that some curare-like substance is liberated in the myasthenic patient when he is fatigued. Struppler (7) noted the same phenomenon and called the effective substance "Ermiidungsstoffe," which was considered to have a curare-like action on neuromuscular transmission because it was inhibited by neostigmine. The most thorough electrophysiologic demonstration of the phenomenon was that of Tsukiyama and colleagues (16), who studied four myasthenic patients using the schema depicted in Figure 1. The right ulnar nerve was stimulated for 5 minutes after blood flow to the upper arm
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Figure 1 . Schema showing Tsukiyama's (1959) method of studying evoked muscle action potentials before and after ischemic work of right forearm muscles. The blood pressure cuff on the right arm is inflated above the systolic blood pressure. Repetitive stimulation of the ulnar nerve for 5 minutes causes the muscles supplied by the ulnar nerve distal to the stimulus to do ischemic work. Meanwhile, the hypothenar electrical activity evoked by stimulating the left ulnar nerve is recorded. One minute after the blood pressure cuff is released, a decrease in amplitude of the hypothenar potentials on the left may be seen in some myasthenic patients.
was shut off by inflating the cuff of the sphygmomanometer above the systolic pressure. Action potentials were recorded from the contralateral hypothenar muscles by means of surface electrodes attached to an amplifier and oscilloscope. After release of the cuff, no changes were observed in the evoked potentials of the hypothenar muscle after ischemic exercise of the contralateral arm in normal subjects. In myasthenic patients, on the other hand, the amplitudes of the evoked muscle action potential began to decrease soon after release of the cuff. The depression of the action potential was prominent 1 to 4 minutes after release of the strangulation, when it reached 50% to 80% of the original amplitude, and recovery was observed in the following 10 to 15 minutes. After administration of anticholinesterase, this depression of the action potential following the "strangle test" was less marked, and recovery occurred sooner. These investigators interpreted their experiments as showing that some neuromuscular blocking agent was produced in the myasthenic patients especially after exercise. Using animal nervemuscle for assay of this substance, Tsukiyama found that previous administration of anticholinesterase had no effect on the production of the myasthenic substance and that the effect of this substance becomes less pronounced in patients or animals pretreated with anticholinesterases (16). His interesting conclusion was that the presence of anticholinesterase can suppress the action of the "myasthenic substance," but cannot inhibit its production. This suggested that anticholinesterase could not be a preventive agent in the treatment of myasthenia gravis. A neuromuscular blocking agent made by muscle may explain some of the well-known clinical phenomena in myasthenia. For instance, myasthenic patients characteristically have weakness and easy fatigability brought on by 412
exercise and relieved by rest. They are worse in the late afternoon and evenings, when such a factor might be expected to have accumulated in the blood, and they are significantly improved in the mornings, when the factor might be expected to be least concentrated in the blood. Myasthenic patients may develop weakness in nonexercised muscles when other muscles are strained, thus explaining the appearance of ptosis after a patient has climbed stairs. The same phenomenon of weakness of nonexercised muscles after exercise has been observed in myasthenic dogs ( 1 7 ) . Desmedt and Borenstein (18) have devised a special method to show subclinical involvement in muscles that present no decrement or exhaustion in the regular tests. The method combines ischemia of the upper limb, produced by a cuff around the upper arm, with stimulation of the ulnar nerve at 3 stimuli per second for 5 to 7 minutes. Usually a myasthenic patient will develop clear decrement to repetitive stimulation after 7 minutes of stimulation while the circulation is still occluded. The decrements are present after release of the cuff but gradually disappear in the ensuing 18 minutes. This method supposedly allows a more critical definition of the concept of subclinical involvement and provides a sensitized method of testing for myasthenia. Naturally, the concept of a muscle-produced "myasthenic factor" would be a suitable explanation of this neurophysiologic phenomenon. The trouble with the concept of a muscle-produced "myasthenic factor" is that it does not explain the autoimmune or thymic involvement in the condition, nor does it fit in with current knowledge of the decreased amount of acetylcholine present in the neuromuscular junctions of myasthenic patients. In other words, the Mary Walker phenomenon is not compatible with current concepts of either the autoimmune or acetylcholine-deficient nature of myasthenia. To resolve this difficulty, it is postulated that muscle that is exercised under hypoxic conditions releases many substances, the principal one of which, lactic acid, has a mildly inhibiting effect on muscle function. In the normal person, the neuromuscular transmission has a large safety margin and hence is not likely to show complete block or even significant impairment when mild inhibitors are present. In the myasthenic patient, however, neuromuscular transmission has little or no safety margin, and, being precarious, it is easily interrupted by weak inhibitors. In short, results of Walker's experiments need not be considered as having fundamental significance with respect to the cause of myasthenia gravis. The Argument for the Lactic Acid Hypothesis
Lactic acid is a normal by-product of muscle metabolism, and its production and release are increased by heavy exercise or impairment of the circulation. Exercise tests done under ischemic conditions show that lactate levels are often increased to three or four times the basal levels in the exercised extremity. Exercising only one arm under ischemic conditions, instead of two, as is required for the Mary Walker test, may result in systemic lactic acidemia, as evidenced by the elevation of blood lactate in serial
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samples drawn from an antecubital vein of the unexercised arm (Table 1). Exercise of both arms under ischemic conditions would be expected to produce approximately twice the amount of lactic acid that is produced by ischemic exercise of one arm. Thus, the procedures of the Mary Walker experiment would be expected to be equivalent to a sudden injection of lactate into the circulation as the tourniquet is released. It should be noted that the time course of initial effect occurring Wi minutes after release closely approximates the circulation time to get from venous drainage of forearm muscles through the right heart, lungs, left heart, and into the arterial circulation to the nonexercised muscles, as is seen, for instance, on intravenous injection of edrophonium chloride (19). Weakness was also seen in some myasthenic patients 2 minutes after the start of an intravenous infusion of lactate. The duration of effect for 18 minutes on the basis of Desmedt's ischemic provocative test for myasthenia corresponds to the known duration of lactacidemia after intravenous infusion of lactate (20). A. V. Hill (21), in his classic experiments, showed that muscle, excited anaerobically, fails to contract when the concentration of lactic acid inside it rises to about 0 . 3 % . In the presence of oxygen, the lactic acid disappears and the muscle recovers. Under conditions in which a thin muscle in oxygen-free Ringer's solution is excited slowly to allow diffusion to remove the lactic acid as it is formed, the muscle was found to liberate two to three times as much energy as it would if diffusion were not permitted. Hill concluded that fatigue of muscle is not ordinarily due to substrate depletion, but rather to lactic accumulation. Since these experiments of Hill and Kupalov (21), it has been a common belief that accumulation of lactic acid in the blood and in the exercising muscles is one cause of fatigue and a lowered performance capacity. Karlsson and Saltin (22) concluded from their experiments that a high lactic acid concentration in the muscle tissue could be the reason for exhaustion; Klausen, Knuttgen and Forster (23) showed that high blood lactate prior to exhaustive exercise can inhibit further lactate production and cause a tendency to reduce endurance capacity and work output. Thus, if high blood lactates may adversely affect normal muscle function, it seems reasonable to assume that lactate would also have an adverse effect on the function of myasthenic muscle. The lactate hypothesis not only explains the Mary Walker phenomenon, Desmedt's ischemic provocative test for myasthenia, and the fatigue post-exercise with relief by rest, but it also might explain in part why patients feel stronger in the morning and get weaker as the day wears on: blood lactate levels are lowest in the morning and then, in general, tend to rise as the day progresses*. The lactate hypothesis is also compatible with Tsukiyama's (16) finding that prior administration of anticholinesterase has no effect on production of the substance that causes the Mary Walker phenomenon but does profoundly decrease its effect on the myasthenic patient. One would not expect anticholinesterase drugs to impair lactate produc* PATTEN BM: Personal observation.
Table 1. Serial Venous Lactate Levels After I sent3mic Exercise of Right Arm* Time
Right Arm
Left Arm
mg/100 ml
mg/100 ml
Before exercise
17.2
15.5
After exercise 1 min 2 min 4 min 6 min 10 min
36.2 44.7 46.6 44.9 43.3
18.7 17.2 21.4 20.7 18.8
* A voiunteer lay still in bed for 1 hour. Baseline blood lactate levels were drawn from indwelling catheters placed in an a ntecubital vein of each arm. A blood pressure cuff around the right arm was then inflated to 200 mm Hg (50 mm Hg above the volunteer's systo lie pressure), and the volunteer exercised his right forearm by opening; and closing his right hand as fast and for as long as he could. Afteir 1 minute and 5 seconds, when the volunteer was unable to move his hand any longer, the blood pressure cuff was deflated, and samples of v enous blood were drawn simultaneously from the catheters at 1, 2, 4, 6 , and 10 minutes after the exercise. The lactate level rose in the unexeircised left arm to a peak 38% greater than the baseline value. The peak of lactate in the unexercised left arm was 46% less than that in the ex ercised right arm, but the peak lactate levels in both arms occurred at the same time, 4 minutes after ischemic exercise.
tion, but one would expect these drugs to alter the myasthenic neuromuscular junction, making it less sensitive to the action of mild inhibitors such as lactate. The lactate hypothesis is supported by the interesting experiments of Schmidt and Chase (24), who found that there was a definite synergism between d-tubocurarine and muscular activity. After only V2 minute of intermittent but strenuous exercise, the dose of d-tubocurarine needed to produce paralysis in the rabbit was reduced by 5 0 % . A prolongation of the period of exertion to 2 minutes measurably augmented the synergism. The results confirm the experiments of Torda and Wolff (25), who showed the presence of a "curare-like" agent in the serum of blood obtained from the hind limbs of anesthetized cats after tetanic stimulation of the sciatic nerve. In this respect it should be noted that fatigued muscles of healthy subjects behave like slightly curarized muscles as far as summation of stimuli (26-28), posttetanic potentiation of single twitches (29), and response to tetanizing currents (29, 30) are concerned. To investigate the possible role of lactate in producing weakness, the effects of intravenous lactate infusions in patients with myasthenia gravis were compared with the effects of lactate infusions in patients with nonmyasthenic neuromuscular diseases. Weakness, decreased vital capacity, and decreased grip strength developed in six of the seven myasthenic patients during the lactate infusion. The weakness was noted 2 to 4 minutes after the start of the lactate infusion, at a time when blood lactates were on the average 22 to 32 mg/100 ml. The weakness involved face, eyelids, voice, and vital capacity, before progressing to involve proximal muscles of the arms and legs. Hence, the muscle groups usually most involved in myasthenia gravis were affected first and most severely by lactate infusion. Some of the myasthenic patients commented that they felt as if they had run a long distance or as they had during their curare test. Two said that the lactate had made them feel weaker than they had ever felt before. None Patten • Mary Walker Phenomenon
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of the eight control patients developed significant weakness during the lactate infusion (31). The average maximum change of vital capacity showed 2 1 % worsening in the myasthenic group and only 3 % worsening in the control group. That difference, using rank-order analysis, was significant ( F = 0.005). The average grip strength declined 15% in the myasthenic patients but was unchanged in the controls, the difference being significant (P = 0.05). The average dose of lactate was 4.2 ml/kg 1 M solution for myasthenic patients and 4.3 ml/kg for the controls. During the lactate infusions, total serum calcium declined in both the myasthenic and control patients, and no change occurred in blood pH (the infusion solutions were pH 7.40) (31). Any decrease in serum calcium in the myasthenic patient, such as occurred during the lactate infusion, would be expected to decrease acetylcholine release (32, 3 3 ) . Because myasthenic patients already have a low safety margin for neuromuscular transmission, a decrease in acetylcholine release, even if mild, would be expected to have an adverse effect on the function of the myasthenic neuromuscular junctions, but it would not be expected to have an adverse effect on the function of normal neuromuscular junctions because they have high safety margins. Thus, reduction of serum calcium might be the mechanism of lactate-induced weakness in myasthenic patients. Any therapy that increases acetylcholine release or effectiveness in myasthenic patients, such as increased serum calcium (32-35), anticholinesterase, or corticosteroid drugs, would be expected to decrease the adverse effect of lactate infusion in the patients. The same should occur during thymectomy-induced remissions or other remissions of the disease. Predictions
On the basis of the analysis of the previously reported data and the theoretical considerations of this paper, it seems appropriate to make the following predictions. 1. Lactate infusion may be a useful adjunctive clinical tool in the diagnosis of myasthenia gravis, but further experience with the lactate infusion test will be needed to evaluate its safety, consistency, and specificity in provoking weakness in the myasthenia gravis patients. 2. Patients with errors of metabolism associated with excessive blood levels of lactate will have weakness and easy fatigability as prominent clinical symptoms. 3. Blood lactate levels will correlate with fatigability in other conditions associated with defective neuromuscular transmission including tick paralysis, botulina intoxication, antibiotic-induced weakness, and the myasthenic syndrome associated with carcinoma (Eaton-Lambert syndrome). Lactate infusions in these patients will produce aggravation of the weakness induced by the disease. 4. The most productive research in myasthenia will be focused on the immunopathic nature of the disease and not the production of a curare-like substance by exercising muscle. A C K N O W L E D G M E N T S : T h e author thanks D r . W . King Engel for reading the manuscript a n d making constructive suggestions and Miss Terry Tomkins for preparation of the references. Received 12 August 1974; revision accepted 8 November 1974. 414
• Address reprint requests to D r . Bernard M . Patten, Department of Neurology, Baylor College of Medicine, 1200 M o u r s u n d Avenue, Houston, T X 77025.
References 1. WALKER M B : Case showing the effect of prostigmin o n myasthenia gravis. Proc R Soc Med 28:759-761, 1935 2. G R O B D , NAMBA T : Corticotropin in generalized myasthenia gravis. Effect of short, intensive courses. JAMA 198:703-707, 1966 3. WARMOLTS J R , E N G E L W K : Benefit from alternate-day prednisone in myasthenia gravis. N Engl J Med 286:17-20, 1972 4. J E N K I N S R B : Treatment of myasthenia gravis with prednisone. Lancet 1:765-767, 1972 5. M E R T E N S
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severe myasthenia gravis with immunosuppressive agents. Eur Neurol 2:321-339, 1969 SCHWARZ H : Curare-like factor in serum of myasthenia gravis patients. Can Med Assoc J 67:238-244, 1952 STRUPPLER A : Vorlaufige Ergebnisse experimenteller Untersuchungen iiber das myasthenische Syndrom. Klin Wochenschr 31:115-118, 1953 GROSSE-BROCKHOFF F , W E L T E E : Uber selten beobachtete E r miidungserscheinungen bei Myasthenia gravis pseudoparalytica; ein klinischer Beitrag zur Frage des V o r k o m m e n s "kurareahnlicher" Stoffe bei M y a s t h e n i c Dtsch Med Wochenschr 75:698700, 1950 BERGH N P : Biologic assays in myasthenia gravis for any agents causing a neuromuscular block. Scand J Clin Lab Invest 5 (suppl 2 ) : 1-47, 1953 W I L S O N A, STONER H B : Myasthenia gravis: consideration of its causation in study of 14 cases. Q J Med 13:1-18, 1944 STRUPPLER A : E x p e r i m e n t e d Untersuchungen zur Pathogenese der M y a s t h e n i c Z Gesamte Exp Med 125:244-273, 1955 N A S T U K W L , STRAUSS AJ, O S S E R M A N K E :
Search for a n e u r o -
muscular blocking agent in the blood of patients with myasthenia gravis. Am J Med 26:394-409, 1959 13.
LAMMERS
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demonstrate paralytic factor in serum of myasthenia gravis patients. Nature (Lond) 173:1192-1193, 1954 14. WALKER M B : Myasthenia gravis: case in which fatigue of forearm muscles could induce paralysis of extraocular muscle. Proc R Soc Med 31:722, 1938 15. LAURENT L P E : Curarizing substance in myasthenia gravis (letter). Br Med J 2:303, 1973 16.
TSUKIYAMA K, NAKAKI A, M I N E R, et a l : M y a s t h e n i c substance
present in the serum of a patient with myasthenia gravis. Med J Osaka Univ 10:159-170, 1959 17.
LORENZ
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sponsive weakness in the dog, similar to myasthenia gravis. J Am Vet Med Assoc 161:795-800, 1972 18. D E S M E D T J E , BORENSTEIN S: T h e testing of neuromuscular transmission, in Handbook of Clinical Neurology, vol. 7, edited by V I N K E N PJ, BRUYN GW. Amsterdam, North-Holland Publishing Company, 1970, pp. 104-115 19. OSSERMAN K E , G E N K I N S G : Critical reappraisal of the use of edrophonium (tensilon) chloride tests in myasthenia gravis a n d significance of clinical classification. Ann N Y Acad Sci 135:312334, 1966 20.
SOFFER
LJ, D A N T E S D A , N E W B U R G E R
R, et a l : M e t a b o l i s m
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sodium d-lactatc I. Utilization of intravenously injected sodium d-lactate by normal persons. Arch Intern Med 60:876-881, 1937 21. H I L L AV, KUPALOV P : Anaerobic and aerobic activity in isolated muscle. Proc R Soc Lond [Biol] 105:313-322, 1929 22. KARLSSON J, SALTIN B : Lactate, A T P , a n d C P in working muscles during exhaustive exercise in m a n . J Appl Physiol 29:596-602, 1970 23.
24. 25.
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K L A U S E N K, K N U T T G E N H G , FORSTER H V :
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ing high blood lactate concentration on maximal exercise performance. Scand J Clin Lab Invest 30:415-419, 1972 SCHMIDT JL, CHASE H F : Effect of muscular activity on curarization in rabbits. Proc Soc Exp Biol Med 65:13-14, 1947 TORDA C, W O L F F H G : Release of curare-like agent from healthy muscle and its bearing in myasthenia gravis. Proc Soc Exp Biol Med 58:242-246, 1945 BREMER F : Sur le mecanisme de la sommation d'influx. C R Soc Biol 97:1179-1184, 1927 BREMER F : Nouvelles recherches sur la sommation d'influx nerveux. C R Soc Biol 102:332-336, 1929 BREMER F : T h e summation of nervous impulses. Am J Physiol 90:297-298, 1929
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29. ROSENBLUETH
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Wedensky inhibition. Am J Physiol 119:236-256, 1937 30. HOFMANN FB: tlber den Einfluss der Reizstarke auf den Tetanusverlauf bei inderekter Reizung. Arch Ges Physiol 95:484532, 1903 31. PATTEN BM, OLIVER K, ENGEL WK: Effect of lactate infusions
on patients with myasthenia gravis. Neurology 24:986-990, 1974 32. DEL CASTILLO J, KATZ B: Quantal components of the end-plate
potential. J Physiol (Lond) 124:560-573, 1954 33. D E L CASTILLO J, KATZ B: The effect
of magnesium on the
activities of motor nerve endings. J Physiol (Lond) 124:553-559, 1954 34. KORNFELD P, SOMLYO A, OSSERMAN KE: Role of calcium in
myasthenia gravis. Arch Neurol 21:466-470, 1969 35. GEORGE WK, HAAN CL: Calcium and magnesium administration
in myasthenia gravis (letter). Lancet 2:561, 1962
The Aged and Sex Taboos Attitudinally, physicians need to understand that aging patients retain their right to sexual expression, if need be in altered form and in altered settings, and that they also retain their right to asking for and receiving professional counsel when they encounter difficulties in their legitimate pursuits for satisfying sexual expression. It is quite clear that many physicians and other health care personnel share with the rest of society a distinct taboo regarding sexual expression on the part of aging individuals. This may relate in part to our own upbringing in a society which, although it has become liberated for all other segments of society in terms of sexual expression still retains certain Victorian standards regarding sexual expression by older persons. In part this taboo is related to feelings which all of us harbor regarding sexual expression in our parent generation, more specifically in our own parents. Our aging patients may remind us to a significant degree of our own parents, and as such we may wish to avoid dealing with the sexuality of elderly people. Nevertheless, however timid and tentative we as professionals may feel about the sexual needs of the elderly, they themselves usually are not at all reluctant to discuss this area of their lives with a professional, and they clearly welcome the physician who is comfortable and capable of dealing with this intimate area of their lives. This is true for an aging population which was born around the turn of the century, which grew up in the 1910's, 1920's or, at the latest, the 1930's. It may be even more strikingly so for future generations of the aging. As people are living longer they are interested in the extension not only of the duration of life but of the quality of life. If sexual expression contributes to the quality of life in the younger and adult years, is it not reasonable to assume that it should continue to do so in the later years? ERIC P F E I F F E R , M.D.
Sexuality in the aging individual. Journal of the American Geriatrics Society 22:481-484, 1974
Patten • Mary Walker Phenomenon
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A Hypothesis to Account for the Mary Walker Phenomenon BERNARD M. PATTEN, M.D., F.A.C.P., Houston, Texas
Certain myasthenic patients show that their skeletal muscles produce a substance during ischemic exercise which, when released into the circulation, increases muscle weakness. This phenomenon has been named after Mary Walker, the physician who popularized its demonstration. It is suggested that ischemic exercise produces lactic acid that binds calcium, reducing ionized and total serum calcium. The decreased calcium has an adverse effect on skeletal muscle function especially in patients with myasthenia gravis, where neuromuscular function is often so precarious it may be interrupted by weak inhibitors.
MYASTHENIA GRAVIS is a disease of unknown origin; its
chief symptoms are weakness and easy fatigability of skeletal muscle. It has been found that patients with myasthenia gravis have defective neuromuscular transmission, which is partially corrected by administration of anticholinesterase drugs (1) or by the administration of ACTH ( 2 ) , corticosteroids (3, 4 ) , or other agents that depress the body's immune response ( 5 ) . Because the clinical condition of the myasthenic patient closely resembles that seen in curare poisoning (6-8), investigators have, for a long time and with variable success, tested the blood of myasthenic patients for curariform substance (9-13). Their efforts were spurred by an experiment that showed that during ischemic exercise, the myasthenic patient may make a substance that, when released into the circulation, causes weakness of a nonexercised muscle (8, 10, 14-16). This experiment was popularized by Mary Walker in the early part of this century (14). The Mary Walker Experiment
When the effect of the patients' neostigmine was just beginning to wear off, although the patients were still strong, the circulation was cut off in both arms by sphygmomanometer armlets at a pressure of 200 mm Hg; the patients then briskly pronated and supinated their forearms until they tired, which took about 1 minute. While the circulation was cut off, no weakness was noted in the rest of the body, not even the eyelids; but W2 minutes after the pressure was released, the eyelids began • From the Neuromuscular Disease Division, Department of Neurology, Baylor College of Medicine, Houston, Texas.
to droop, and after 2 minutes, the patients were about as weak as they had been before their morning injection of neostigmine. As a rule, the weakness always came on IY2 minutes after the pressure was released and always appeared to be equally severe. When only one arm was fatigued by exercise with the circulation cut off and when both arms were exercised in the same way but short of fatigue with the circulation cut off, the ensuing weakness was much less. Cutting off the circulation with the armlets in position for several minutes without exercise caused some weakness, but far less than with exercise. When patients were fully under the influence of neostigmine, pronation and supination of both forearms for about 1 minute with the circulation cut off produced no obvious effect, although the patients thought that they felt a little weaker. In a normal subject, no weakness was apparent after brisk pronation and supination for 1 minute with the circulation cut off. In patients with less severe myasthenia, there was less increase in weakness. Mary Walker interpreted her experiments as showing that increased destruction, defective production, or release of acetylcholine cannot be the immediate cause of myasthenia gravis, but that something produced in the muscles themselves enters the circulation, causing the abnormal fatigability. She reasoned that anything that delays the destruction or facilitates the release of acetylcholine would be antagonistic to this curarizing substance. Since Mary Walker's demonstration, several investigators have refined the experiments and published photographs (15) and movie frames (10) of patients before and after the release of the cuffs that were occluding the circulation. Grosse-Brockhoff and Welte (8) observed development of lid ptosis and weakness in myasthenic patients after release of a tourniquet that had bound the legs while the patient had been instructed to flex and extend his legs. They also suggested that some curare-like substance is liberated in the myasthenic patient when he is fatigued. Struppler (7) noted the same phenomenon and called the effective substance "Ermiidungsstoffe," which was considered to have a curare-like action on neuromuscular transmission because it was inhibited by neostigmine. The most thorough electrophysiologic demonstration of the phenomenon was that of Tsukiyama and colleagues (16), who studied four myasthenic patients using the schema depicted in Figure 1. The right ulnar nerve was stimulated for 5 minutes after blood flow to the upper arm
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Figure 1 . Schema showing Tsukiyama's (1959) method of studying evoked muscle action potentials before and after ischemic work of right forearm muscles. The blood pressure cuff on the right arm is inflated above the systolic blood pressure. Repetitive stimulation of the ulnar nerve for 5 minutes causes the muscles supplied by the ulnar nerve distal to the stimulus to do ischemic work. Meanwhile, the hypothenar electrical activity evoked by stimulating the left ulnar nerve is recorded. One minute after the blood pressure cuff is released, a decrease in amplitude of the hypothenar potentials on the left may be seen in some myasthenic patients.
was shut off by inflating the cuff of the sphygmomanometer above the systolic pressure. Action potentials were recorded from the contralateral hypothenar muscles by means of surface electrodes attached to an amplifier and oscilloscope. After release of the cuff, no changes were observed in the evoked potentials of the hypothenar muscle after ischemic exercise of the contralateral arm in normal subjects. In myasthenic patients, on the other hand, the amplitudes of the evoked muscle action potential began to decrease soon after release of the cuff. The depression of the action potential was prominent 1 to 4 minutes after release of the strangulation, when it reached 50% to 80% of the original amplitude, and recovery was observed in the following 10 to 15 minutes. After administration of anticholinesterase, this depression of the action potential following the "strangle test" was less marked, and recovery occurred sooner. These investigators interpreted their experiments as showing that some neuromuscular blocking agent was produced in the myasthenic patients especially after exercise. Using animal nervemuscle for assay of this substance, Tsukiyama found that previous administration of anticholinesterase had no effect on the production of the myasthenic substance and that the effect of this substance becomes less pronounced in patients or animals pretreated with anticholinesterases (16). His interesting conclusion was that the presence of anticholinesterase can suppress the action of the "myasthenic substance," but cannot inhibit its production. This suggested that anticholinesterase could not be a preventive agent in the treatment of myasthenia gravis. A neuromuscular blocking agent made by muscle may explain some of the well-known clinical phenomena in myasthenia. For instance, myasthenic patients characteristically have weakness and easy fatigability brought on by 412
exercise and relieved by rest. They are worse in the late afternoon and evenings, when such a factor might be expected to have accumulated in the blood, and they are significantly improved in the mornings, when the factor might be expected to be least concentrated in the blood. Myasthenic patients may develop weakness in nonexercised muscles when other muscles are strained, thus explaining the appearance of ptosis after a patient has climbed stairs. The same phenomenon of weakness of nonexercised muscles after exercise has been observed in myasthenic dogs ( 1 7 ) . Desmedt and Borenstein (18) have devised a special method to show subclinical involvement in muscles that present no decrement or exhaustion in the regular tests. The method combines ischemia of the upper limb, produced by a cuff around the upper arm, with stimulation of the ulnar nerve at 3 stimuli per second for 5 to 7 minutes. Usually a myasthenic patient will develop clear decrement to repetitive stimulation after 7 minutes of stimulation while the circulation is still occluded. The decrements are present after release of the cuff but gradually disappear in the ensuing 18 minutes. This method supposedly allows a more critical definition of the concept of subclinical involvement and provides a sensitized method of testing for myasthenia. Naturally, the concept of a muscle-produced "myasthenic factor" would be a suitable explanation of this neurophysiologic phenomenon. The trouble with the concept of a muscle-produced "myasthenic factor" is that it does not explain the autoimmune or thymic involvement in the condition, nor does it fit in with current knowledge of the decreased amount of acetylcholine present in the neuromuscular junctions of myasthenic patients. In other words, the Mary Walker phenomenon is not compatible with current concepts of either the autoimmune or acetylcholine-deficient nature of myasthenia. To resolve this difficulty, it is postulated that muscle that is exercised under hypoxic conditions releases many substances, the principal one of which, lactic acid, has a mildly inhibiting effect on muscle function. In the normal person, the neuromuscular transmission has a large safety margin and hence is not likely to show complete block or even significant impairment when mild inhibitors are present. In the myasthenic patient, however, neuromuscular transmission has little or no safety margin, and, being precarious, it is easily interrupted by weak inhibitors. In short, results of Walker's experiments need not be considered as having fundamental significance with respect to the cause of myasthenia gravis. The Argument for the Lactic Acid Hypothesis
Lactic acid is a normal by-product of muscle metabolism, and its production and release are increased by heavy exercise or impairment of the circulation. Exercise tests done under ischemic conditions show that lactate levels are often increased to three or four times the basal levels in the exercised extremity. Exercising only one arm under ischemic conditions, instead of two, as is required for the Mary Walker test, may result in systemic lactic acidemia, as evidenced by the elevation of blood lactate in serial
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samples drawn from an antecubital vein of the unexercised arm (Table 1). Exercise of both arms under ischemic conditions would be expected to produce approximately twice the amount of lactic acid that is produced by ischemic exercise of one arm. Thus, the procedures of the Mary Walker experiment would be expected to be equivalent to a sudden injection of lactate into the circulation as the tourniquet is released. It should be noted that the time course of initial effect occurring Wi minutes after release closely approximates the circulation time to get from venous drainage of forearm muscles through the right heart, lungs, left heart, and into the arterial circulation to the nonexercised muscles, as is seen, for instance, on intravenous injection of edrophonium chloride (19). Weakness was also seen in some myasthenic patients 2 minutes after the start of an intravenous infusion of lactate. The duration of effect for 18 minutes on the basis of Desmedt's ischemic provocative test for myasthenia corresponds to the known duration of lactacidemia after intravenous infusion of lactate (20). A. V. Hill (21), in his classic experiments, showed that muscle, excited anaerobically, fails to contract when the concentration of lactic acid inside it rises to about 0 . 3 % . In the presence of oxygen, the lactic acid disappears and the muscle recovers. Under conditions in which a thin muscle in oxygen-free Ringer's solution is excited slowly to allow diffusion to remove the lactic acid as it is formed, the muscle was found to liberate two to three times as much energy as it would if diffusion were not permitted. Hill concluded that fatigue of muscle is not ordinarily due to substrate depletion, but rather to lactic accumulation. Since these experiments of Hill and Kupalov (21), it has been a common belief that accumulation of lactic acid in the blood and in the exercising muscles is one cause of fatigue and a lowered performance capacity. Karlsson and Saltin (22) concluded from their experiments that a high lactic acid concentration in the muscle tissue could be the reason for exhaustion; Klausen, Knuttgen and Forster (23) showed that high blood lactate prior to exhaustive exercise can inhibit further lactate production and cause a tendency to reduce endurance capacity and work output. Thus, if high blood lactates may adversely affect normal muscle function, it seems reasonable to assume that lactate would also have an adverse effect on the function of myasthenic muscle. The lactate hypothesis not only explains the Mary Walker phenomenon, Desmedt's ischemic provocative test for myasthenia, and the fatigue post-exercise with relief by rest, but it also might explain in part why patients feel stronger in the morning and get weaker as the day wears on: blood lactate levels are lowest in the morning and then, in general, tend to rise as the day progresses*. The lactate hypothesis is also compatible with Tsukiyama's (16) finding that prior administration of anticholinesterase has no effect on production of the substance that causes the Mary Walker phenomenon but does profoundly decrease its effect on the myasthenic patient. One would not expect anticholinesterase drugs to impair lactate produc* PATTEN BM: Personal observation.
Table 1. Serial Venous Lactate Levels After I sent3mic Exercise of Right Arm* Time
Right Arm
Left Arm
mg/100 ml
mg/100 ml
Before exercise
17.2
15.5
After exercise 1 min 2 min 4 min 6 min 10 min
36.2 44.7 46.6 44.9 43.3
18.7 17.2 21.4 20.7 18.8
* A voiunteer lay still in bed for 1 hour. Baseline blood lactate levels were drawn from indwelling catheters placed in an a ntecubital vein of each arm. A blood pressure cuff around the right arm was then inflated to 200 mm Hg (50 mm Hg above the volunteer's systo lie pressure), and the volunteer exercised his right forearm by opening; and closing his right hand as fast and for as long as he could. Afteir 1 minute and 5 seconds, when the volunteer was unable to move his hand any longer, the blood pressure cuff was deflated, and samples of v enous blood were drawn simultaneously from the catheters at 1, 2, 4, 6 , and 10 minutes after the exercise. The lactate level rose in the unexeircised left arm to a peak 38% greater than the baseline value. The peak of lactate in the unexercised left arm was 46% less than that in the ex ercised right arm, but the peak lactate levels in both arms occurred at the same time, 4 minutes after ischemic exercise.
tion, but one would expect these drugs to alter the myasthenic neuromuscular junction, making it less sensitive to the action of mild inhibitors such as lactate. The lactate hypothesis is supported by the interesting experiments of Schmidt and Chase (24), who found that there was a definite synergism between d-tubocurarine and muscular activity. After only V2 minute of intermittent but strenuous exercise, the dose of d-tubocurarine needed to produce paralysis in the rabbit was reduced by 5 0 % . A prolongation of the period of exertion to 2 minutes measurably augmented the synergism. The results confirm the experiments of Torda and Wolff (25), who showed the presence of a "curare-like" agent in the serum of blood obtained from the hind limbs of anesthetized cats after tetanic stimulation of the sciatic nerve. In this respect it should be noted that fatigued muscles of healthy subjects behave like slightly curarized muscles as far as summation of stimuli (26-28), posttetanic potentiation of single twitches (29), and response to tetanizing currents (29, 30) are concerned. To investigate the possible role of lactate in producing weakness, the effects of intravenous lactate infusions in patients with myasthenia gravis were compared with the effects of lactate infusions in patients with nonmyasthenic neuromuscular diseases. Weakness, decreased vital capacity, and decreased grip strength developed in six of the seven myasthenic patients during the lactate infusion. The weakness was noted 2 to 4 minutes after the start of the lactate infusion, at a time when blood lactates were on the average 22 to 32 mg/100 ml. The weakness involved face, eyelids, voice, and vital capacity, before progressing to involve proximal muscles of the arms and legs. Hence, the muscle groups usually most involved in myasthenia gravis were affected first and most severely by lactate infusion. Some of the myasthenic patients commented that they felt as if they had run a long distance or as they had during their curare test. Two said that the lactate had made them feel weaker than they had ever felt before. None Patten • Mary Walker Phenomenon
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of the eight control patients developed significant weakness during the lactate infusion (31). The average maximum change of vital capacity showed 2 1 % worsening in the myasthenic group and only 3 % worsening in the control group. That difference, using rank-order analysis, was significant ( F = 0.005). The average grip strength declined 15% in the myasthenic patients but was unchanged in the controls, the difference being significant (P = 0.05). The average dose of lactate was 4.2 ml/kg 1 M solution for myasthenic patients and 4.3 ml/kg for the controls. During the lactate infusions, total serum calcium declined in both the myasthenic and control patients, and no change occurred in blood pH (the infusion solutions were pH 7.40) (31). Any decrease in serum calcium in the myasthenic patient, such as occurred during the lactate infusion, would be expected to decrease acetylcholine release (32, 3 3 ) . Because myasthenic patients already have a low safety margin for neuromuscular transmission, a decrease in acetylcholine release, even if mild, would be expected to have an adverse effect on the function of the myasthenic neuromuscular junctions, but it would not be expected to have an adverse effect on the function of normal neuromuscular junctions because they have high safety margins. Thus, reduction of serum calcium might be the mechanism of lactate-induced weakness in myasthenic patients. Any therapy that increases acetylcholine release or effectiveness in myasthenic patients, such as increased serum calcium (32-35), anticholinesterase, or corticosteroid drugs, would be expected to decrease the adverse effect of lactate infusion in the patients. The same should occur during thymectomy-induced remissions or other remissions of the disease. Predictions
On the basis of the analysis of the previously reported data and the theoretical considerations of this paper, it seems appropriate to make the following predictions. 1. Lactate infusion may be a useful adjunctive clinical tool in the diagnosis of myasthenia gravis, but further experience with the lactate infusion test will be needed to evaluate its safety, consistency, and specificity in provoking weakness in the myasthenia gravis patients. 2. Patients with errors of metabolism associated with excessive blood levels of lactate will have weakness and easy fatigability as prominent clinical symptoms. 3. Blood lactate levels will correlate with fatigability in other conditions associated with defective neuromuscular transmission including tick paralysis, botulina intoxication, antibiotic-induced weakness, and the myasthenic syndrome associated with carcinoma (Eaton-Lambert syndrome). Lactate infusions in these patients will produce aggravation of the weakness induced by the disease. 4. The most productive research in myasthenia will be focused on the immunopathic nature of the disease and not the production of a curare-like substance by exercising muscle. A C K N O W L E D G M E N T S : T h e author thanks D r . W . King Engel for reading the manuscript a n d making constructive suggestions and Miss Terry Tomkins for preparation of the references. Received 12 August 1974; revision accepted 8 November 1974. 414
• Address reprint requests to D r . Bernard M . Patten, Department of Neurology, Baylor College of Medicine, 1200 M o u r s u n d Avenue, Houston, T X 77025.
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The Aged and Sex Taboos Attitudinally, physicians need to understand that aging patients retain their right to sexual expression, if need be in altered form and in altered settings, and that they also retain their right to asking for and receiving professional counsel when they encounter difficulties in their legitimate pursuits for satisfying sexual expression. It is quite clear that many physicians and other health care personnel share with the rest of society a distinct taboo regarding sexual expression on the part of aging individuals. This may relate in part to our own upbringing in a society which, although it has become liberated for all other segments of society in terms of sexual expression still retains certain Victorian standards regarding sexual expression by older persons. In part this taboo is related to feelings which all of us harbor regarding sexual expression in our parent generation, more specifically in our own parents. Our aging patients may remind us to a significant degree of our own parents, and as such we may wish to avoid dealing with the sexuality of elderly people. Nevertheless, however timid and tentative we as professionals may feel about the sexual needs of the elderly, they themselves usually are not at all reluctant to discuss this area of their lives with a professional, and they clearly welcome the physician who is comfortable and capable of dealing with this intimate area of their lives. This is true for an aging population which was born around the turn of the century, which grew up in the 1910's, 1920's or, at the latest, the 1930's. It may be even more strikingly so for future generations of the aging. As people are living longer they are interested in the extension not only of the duration of life but of the quality of life. If sexual expression contributes to the quality of life in the younger and adult years, is it not reasonable to assume that it should continue to do so in the later years? ERIC P F E I F F E R , M.D.
Sexuality in the aging individual. Journal of the American Geriatrics Society 22:481-484, 1974
Patten • Mary Walker Phenomenon
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