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Myotonia congenita
MYOTONIA CONGENITA
DONALI) R. HIRSOH, M.D., JOSEPH I)ANCIS, M.D., AND RICHARD
S. WARD, M.D.
NEW YORK, N. Y.
Y O T O N I A congenita is a h e r e d i t a r y condition in which tile patient is
M unable to relax his muscles quickly after a strong v o l u n t a r y contraction
It is commonly associated with muscular hypertrophy. The condition is usually not disabling and the prognosis for life is good. Tile disease is rare, but is one of great interest to physiologists because of the possibility that an understanding of the mechanisms behind the muscular abnormality will give us an insight into the physiology of normal muscular contraction. l~yotonia congenita was first described b y Bell in 1833. I t received general recognition, however, only after Thomsen described twenty-one cases in his own family in 1876. A related disease, dystrophia myotonia, is more common. This latter eondition has an onset later in life and there are associated findings: muscular a t r o p h y and weakness, cataracts, testieu]ar atrophy, baldness, and a low basal metabolic rate. Most of the studies on myotonia have been carried out on patients with dystrophia myotonia, but so far as we know the muscular abnormality is the same in the two diseases, v a r y i n g in severity. There are several good reports and reviews on this subject in the literature. ~-6, 9, ~0 The justification for an additional report lies in the use of two new approaches to the study of myotonia: (1) a search for a humoral substance in the blood of a patient with myotonia, which would be capable of reproducing myotonia, and (2) observation of the effects of curare on the myotonic reaction. The latter of these techniques has become available for clinical research only in the past few years. CASE REPORT
It. C., a 6-year-old Negro boy (B. tI. 28255-47) was admitted to Bellevue IIospital in June, 1947, with a chief compalint of persistent symmetriea] swellings in the neck region. It was also reported that the child seemed slow and lethargic in play. The child came from a boarding school, and only the father was available to give a history. H e described the patient's birth and neonatal development as normal, except perhaps for the fact that the child's nmseular development had always seemed advanced for his age. Aside from measles, chicken pox, and appendicitis requiring operation, there had been no illnesses. The child had entered the boarding school eight months before the hospital admission and the admitting physician had noted the bilateral neck swellings, which he attributed to cervical lymphadenitis secondary to chronic tonsillitis. I n the school, it was noted that the boy walked slowly and seemed sluggish in play, compared to the other children. He was also seen to have a peculiar staring mannerism, most noticeable in the early morning on awakening. F r o m the D e p a r t m e n t of Pediatrics, ;New ~rork University-Bellevue Medical Center a n d the Children's IVs Service, Bellevue I-Ios!oital. A loreliminary repport of this c o m m u n i c a t i o n w a s presented at the meeting of the Society for Pediatric :Research, May 4, 1948, in Atlantic ,City,
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The f a t h e r and two brothers of the patient were h e a l t h y and free f r o m m u s c u l a r abnormalities. B o t h the m o t h e r and the m a t e r n a l g r a n d m o t h e r , however, were said to show p r o m i n e n t o v e r d e v e l o p m e n t of the muscles of the n e c k and shouIder girdle, a n d to suffer f r o m an inability to move rapidly. The m o t h e r h a d the same s t a r i n g m a n n e r i s m as the child. P h y s i c a l e x a m i n a t i o n on admission showed an alert, intelligent, welldeveloped a n d well-nourished Negro b o y of 6 y e a r s of age. He was not ill. Positive findings were limited to the skeletal muscle system an(] the eyes. The tonsils were large and cryptic, but free of active infection. T h e r e w e r e no signs of h y p o t h y r o i d i s m . Neurologie e x a m i n a t i o n was n e g a t i v e except f o r the muscle findings.
Fig.
1,
iFig. 2.
Fig. l.--Obvious lid lag due to increased tonus of the levator palpebrae. Fig. 2.---The patient has been instructed to close his eyes tightly and then open them as rapidly as possible. The photograph was taken about two seconds after the patient began to open his eyes. The palpebral orifice is still reduced in all diameters despite the maximal effort he is making to open his eyes.
The child's herculean build was striking. The masses in the neck region could be d e m o n s t r a t e d to be h y p e r t r o p h i e d strenocleido mastoid muscle r a t h e r t h a n l y m p h nodes. The muscles of the shoulder girdle stood out clearly. The abnormalities in eye m o v e m e n t s first s u g g e s t e d to us t h a t the p a t i e n t was suffering' f r o m a generalized muscle disturbance. There was severe m y o t o n i a of all the e x t r a o c u l a r muscles. The child h a d g r e a t difficulty in following r a p i d l y m o v i n g objects with his eyes. I f an object were m o v e d v e r t i c a l l y or h o r i z o n t a l l y in f r o n t of him, there would be a short i n t e r v a l before he could m a k e his eyes move in the r e q u i r e d direction. W h e n he closed his eyes t i g h t l y and then tried to open t h e m again, he could not do so f o r
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several seconds, even though he tried hard. He had pronounced lid lag, which we a t t r i b u t e d to myotonia of the levator palpebrae superioris. There was no exophthalmos. These abnormalities of the e x t r a o e u l a r muscles were most m a r k e d in the early morning on awakening. The myotonia disappeared r a p i d l y when the affected muscles were " w a r m e d u p . " Thus a f t e r the child had opened and closed Ms eyes several times in succession, the movements became progressively easier, and lid lag disappeared. Aside from these abnormalities of movement, examination of the eyes revealed nothing. This included slit lamp examination.
Fig. 3.---There
is marked
muscular
hypertrophy.
The
scar is the result of a muscle
biopsy.
lViyotonia was then f o u n d in other muscles, too. A f t e r s t r o n g l y flexing or extending his neck the child had difficulty in straightening it. His gait was abnormally slow and labored. He a p p e a r e d stiff-jointed. H e r e the " w a r m i n g u p " phenomenon could be clearly seen; a f t e r five or six steps his gait was normal. Myotonia r e a p p e a r e d r a p i d l y if tie did not continue to use his nluscles.
The myotonia could also be demonstrated after mechanical stimulation of muscle groups. When the thenar eminence of the hand was tapped with a percussion hammer, contraction was rapid and strong', and relaxation delayed. The braehioradial "reflex" was similarly abnormal. Routine laboratory results were as follows: The routine urinalysis was negative. Blood count showed hemoglobin 14.5 Gin., red blood count 4.27 million, white blood count 5,800, polymorphonuelear leucocytes 28 per cent, lymphoeytes 68 per cent. This lymphocytosis persisted on all the examinations. Mazzini test was negative. X-rays of the skull, long bones, neck, lungs, and heart were negative. Carpal and tarsal ossifications were within normal limits. Serum calcium was ]0.4 mg. per cent and serum phosphorus 4.5 rag. per cent. Mantoux tests were negative up to 1.0 rag.
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Several observations were m a d e on the b e h a v i o r of the m y o t o n i a u n d e r a v a r i e t y of conditions. These e x p e r i m e n t s were repetitions of e x p e r i m e n t s p r e v i o u s l y r e p o r t e d b y others in the literature. No a t t e m p t was m a d e to record results m e c h a n i c a l l y or electrically; the eva]uatiou was entirely clinical. Changes t h a t w e r e observed were unequivocal. 1. Electrical reactions: I n c r e a s e d muscle excitability in m y o t o n i a h a d been found p r e v i o u s l y b y P o a c h e r and W o o d w a r d . ~ I t usually required a galvanic c u r r e n t of ].8 Ma. to p r o d u c e a n m s e u l a r contraction in a normal 6-year-old child. I n this p a t i e n t c u r r e n t s of less t h a n 1.0 Ma. were sufficient. 2. Effeets of chilli~lg: I t is g e n e r a l l y r e p o r t e d t h a t m y o t o n i a is worse in cold weather, a l t h o u g h R a v i n ~, a f o u n d t h a t m y o t o n i a in his patients decreased w h e n the t e m p e r a t u r e of the e n v i r o n m e n t was reduced f r o m 40 ~ C. to 20 ~ C. Our p a t i e n t was placed in a cold b a t h for a b o u t ten minutes. He was t h e n m o v e d out into the open air. A t this time the m y o t o n i a was unchanged, despite the f a c t t h a t he was shivering w i t h cold. 3. E p i n e p h r i n e : I n the l i t e r a t u r e t h e r e are eonflicting reports as to the effect of epinephrine on myotonia. Some i n v e s t i g a t o r s r e p o r t accentuation of s y m p t o m s , ~' ~ a n d others a deereaseY, 3 I n our p a t i e n t r e p e a t e d injections of 0.3 e.e. of I :1000 epinephrine h y d r o c h l o r i d e i n t r a m u s c u l a r l y had no effect on the myotonia. 4. Prostiglnine: There is a u n i f o r m i t y of opinion t h a t p r o s t i g m i n e accentuates m y o t o n i a 2 -7 The injection of 1.0 c.e. of 1:2000 p r o s t i g m i n e hydrochloride i n t r a m u s c u l a r l y e x a g g e r a t e d the m y o t o n i a in out' patient. 5. Quinine: Since 1936, ~, 6, s quinine has been used as a specific medication in this disease. Small doses often cause a complete d i s a p p e a r a n c e of the myotonia. Our p a t i e n t was completely relieved of his s y m p t o m s b y 0.6 Gin. quinine sulfate orally, or 0.5 Gin. quinine dihydrochloride intravenously. The m y o t o n i a r e t u r n e d slowly in six hours. 6. D u a l n a t u r e of the m y o t o n i a contra, ction: This f e a t u r e of m y o t o n i a was commented on by D a n a 9 and Griffith, ~~ and has more recently been inv e s t i g a t e d b y Ravin. 2 The m y o t o n i a c o n t r a c t i o n a p p e a r s to be initiated b y the first strong v o l u n t a r y contractions, but f r o m t h e n on is i n d e p e n d e n t of them, lasting a definite period r e g a r d l e s s of w h e t h e r r e l a x a t i o n is a t t e m p t e d following these first contractions, or w h e t h e r a v o l u n t a r y tetanus is k e p t up. The boy was a s k e d to close his eyes t i g h t l y f o r v a r y i n g lengths of time, a f t e r which he was to open his eyes as quickly and as widely as possible. The length of time it tOok him to open his eyes was recorded. I t was f o u n d t h a t a m i n i m u m period of v o l u n t a r y c o n t r a c t i o n was necessary (two seconds) before m y o t o n i a appeared. B e y o n d t h a t m i n i m a l period, however, the d u r a t i o n of m y o t o n i a was not increased b y h a v i n g the boy squeeze his eyes shut for longer periods. On the c o n t r a r y it t o o k him less time to open his eyes the longer he k e p t t h e m closed. W h e n he k e p t t h e m closed for ten seconds no m y o t o n i a was n o t e d on relaxing. This can be i n t e r p r e t e d as m e a n i n g t h a t the m y o t o n i a r a n its course u n d e r cover of the p r o l o n g e d v o l u n t a r y effect. I n s u m m a r y , a 6-year-old N e g r o boy p r e s e n t e d the classical picture of m y o t o n i a eongenita. I-Ie h a d p r o n o u n c e d h y p e r t r o p h y of m a n y of his skeletal muscles, and an inability to r e l a x a n t a g o n i s t i c muscles rapidly. R a p i d movem e a t s thus could not be accomplished. The m y o t o n i e delay in r e l a x a t i o n disa p p e a r e d a f t e r several " w a r m i n g u p " contractions. The f a m i l y history suggested t h a t both the p a t i e n t ' s m o t h e r a n d the m a t e r n a l g r a n d m o t h e r suffered f r o m t h e disease. Observations of the m y o t o n i e reaction in this boy, u n d e r v a r y i n g conditions, were consistent with similar observations on c~lses previously r e p o r t e d in the literature.
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A. Search for a Humoral Factor.--The drug veratrine can produce myotonia in normal muscle. An isolated strip of muscles, poisoned with veratrinc, behaves remarkably like the muscle of myotonia congenita21 There is a myo,tonic p a t t e r n of response following stimulation of the nerve. I f electromyograms are made from the muscle during the myo,tonic contraction, it is found that a single shock stimulus in the nerve produces a volley of electrical impulses in the muscle. The veratrine reaction disappears :following repeated contraction, or " w a r m i n g u p . " Quinine also abolishes the reaction. I n all these cardinal points tile myotonia of veratrine poisoning resembles that of myotonia congenita. Even in response to curare poisoning the two types of myotonia behave similarly. Curare affects neither (see section B). In view of this, it seemed reasonable to search for a veratrine-like substance in the blood of patients with myotonia. In 1936 Loewi ~2 reported success in finding such a substance in the plasma dialysate of a p a t i e n t with myotonia congenita. His experiment needed to be repeated. Using essentially the same technique, we attempted this with our patient. The procedure was as follows: Blood from the external j u g u l a r vein was used, because of the prominence of eye signs in this patient. Specimens were also taken from the antecubital vein, before and after tourniquets had been applied. The blood was drawn, heparinized, separated, and frozen until ready for testing. Control specimens were obtained u n d e r identical conditions from a normal child. The sartorius muscle of a frog was exposed to (1) the dialysate, and (2) the residue, and was stimulated each time with a galvanic current. The sartorius muscle is usually used for such testing. Characteristic patterns are produced by veratrine in dilutions as high as 1:5,000,000. No veratrine-like substance could be detected in any of these specimens. A normal twitch resulted in each case. ~ An in vivo experiment was also tried with this patient, in the hope of demonstrating a myotonia-indueing substance in the blood. The idea for this experiment was taken from the classical one on myasthenia gravis described by M a r y B. W a l k e r before the Royal Society of Medicine in 1938. ~5 Tourniquets were placed on the child's arms to obstruct venous return. This was to increase the concentration of such a substance locally. The patient was instructed to open and close his eyes r e p e a t e d l y until his eye muscles had " w a r m e d u p , " and all signs of myotonia disappeared. At this point he was asked to open and close his hands several times. Myotonia of the hands was quite evident. TILe tourniquets were then a b r u p t l y removed. It was t h o u g h t that with the release of this venous blood into t h e general circulation a myotonia-inducing substance might cause the myotonia of the eye muscles to reappear. No such effect resulted. W e were not able to demonstrate a humoral f a c t o r by this in vivo experiment. B. Curarization E x p e r i m e n t . l - - I n recent years investigators have come to *We a r e i n d e b t e d to D r . Givlio C a n t o n i f o r p e r f o r m i n g t h e s e e x p e r i m e n t s . SDr. E m m a n u e l P a p p e r s u p e r v i s e d t h e e u r a r i z a t i o n in t h e s e e x p e r i m e n t s .
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tile eon.elusion t h a t the site of the a b n o r m a l i t y in m y o t o n i a is peripheral. However, the exact locus is not known. K e n n e d y and Wolff * demonstrated that spinal anesthesia does not affect myotonia. Schaffer ~3 showed t h a t myotonia persisted w h e n the n e r v e endings in the muscles were p a r a l y z e d by regional anesthesia. B r o w n and H a r v e y ~ showed that section of the motor nerves and d e g e n e r a t i o n of the m o t o r end plate did not a l t e r the a b n o r m a l i t y . This last w o r k was done with myotonie goats---goats with a congenital disease reo sembling h u m a n m y o t o n i a congenita. Curare is a logical d r u g to use in c a r r y i n g this localization f u r t h e r . C u r a r e is said to p a r a l y z e muscle t h r o u g h action on the m y o n e u r a l junction. I n an excellent review of the literature, M e I n t y r e ~4 pointed out t h a t the chief effect of c u r a r i z a t i o n was a d i m i n u t i o n in the end plate potential. A p p a r e n t l y there was also some effect u p o n the muscle fibers themselves, diminishing their sensitivity to aeetyl choline, but this need not concern us. All effects of c u r a r e are either u p o n the m y o n e n r a l j u n c t i o n or on points distal to it. I n 1939 B r o w n and t t a r v e y 7 curarized m y o t o n i c goats and fonnd the m y o t o n i a uninfluenced b y the curare. T h e y r e a s o n e d f r o m this e x p e r i m e n t t h a t the site of the a b n o r m a l i t y in the goats was p e r i p h e r a l to the m y o n e n r a l junction. T h e r e h a v e been no r e p o r t s of this e x p e r i m e n t carried out w i t h a h u m a n ease of myotonia. A e c o r d i n g l y , w i t h our patient, the following procedure was u n d e r t a k e n : The p a t i e n t received n e m b u t a l and scopolamine premedieation, and was anesthetized with v i n y l ether and e t h e r - o x y g e n mixture. The response a f t e r mechanical stimulation of. the extensors of the f o r e a r m (the braehioradial " r e flex"~) was used as an index of myotonia. Motion pictures were taken of all reflexes elicited. A f t e r pictures were taken of the " r e f l e x " before curare, curare was given until d i a p h r a g m a t i c contractions stopped.l A total of 30 units was used. R e s p i r a t i o n s were m a i n t a i n e d b y the anesthetist. Pictures were then t a k e n of the " r e f l e x " u n d e r the influence of_ curare. W e were f o r t u n a t e to be able to m a k e control observations on a n o r m a l child of_ the same age and w e i g h t u n d e r identical conditions of anesthesia. Here, too, motion pictures were t a k e n of the b r a e h i o r a d i a l " r e f l e x " before a n d a f t e r full curarization. ~ e e h a n i c a l stimulation of the extensor muscles of this b o y ' s forea~'m p r o d u c e d (under anesthesia) a s t r o n g c o n t r a c t i o n w i t h a myotonie d e l a y in r e l a x a t i o n ; the h a n d r e m a i n e d up for several seconds, and only fell slowly to its original position. Af.ter complete e u r a r i z a t i o n this response was unchanged. I n the n o r m a l control the n o r m a l b r a c h i o r a d i a l " r e f l e x " was also uninfluenced b y curare. 9 T h e b r a e h i o r e u d i a l " r e f l e x " i s n o t a t r u e r e f l e x in t h e s t r i c t s e n s e o r t h e w o r d . I t d o e s n o t depend upon a reflex ~rc, and is independent of the eentrat nervous system. It is appKrently a direct resl~onse to mechanical stimulation of the muscle fibers themselves. The persistence of the reflex after curarization makes this apparent. We ha.ve been unable to find any comment on t h e m y o t a t i e n a t u r e o f t h i s r e f l e x i n t h e l i t e r a t u r e , a l t h o u g h it a p p e a r s t o b e g e n e r a l l y ' a c c e p t e d by neurologists. tThis degree of eurarization is commonly accepted as complete since the diaphragm is the l a s t m u s c l e to b e D a r a l y z e d .
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In human beings with myotonia eongenita, therefore, as welt as in myotonie goats, curare does not eliminate the myotonic reaction. The abnormality in myotonia must then be peripheral to the site of action of curare. Since, according to our present knowledge, all effects of curare are at the myoneural junction or distal to it, this would put the abnormality in human myotonia somewhere in the muscle fiber itself. SUMMARY
1. The clinical findings in a case of myotonia congenita (Thomsen's disease) are presented. 2. Attempts at demonstrating a myotoniadnducing substance in the blood of the patient are described. These attempts were unsuccessful. 3. The myotonie pattern of response was uninfluenced by complete eurarization of the patient. The significance of this in the localization of the muscular abnormality is discussed. REFERENCES l. Poncher, It. G., and Woodward, It.: Pathogenesls and Treatment of l~[yotonia Congenita, Am. J. Dis. Child. 52: 1065, 1936. 2. Ravin, A.: Studies in Dystrophia ~[yotoniea. III. Experimental Studies in ~[yotonia, Arch. Neuroh & Psych. 43: 649, 1940. 3. Ravin, A.: Myotonia, lVledicine 18: 443, 1939. 4. ~ennedy, F., and Wolff, A.: Experiments With Quinine and Prostigmine in the Treatment of !V[yotonia and Myasthenia, Arch. Neurol. & Psych. 37: 68, 1937. 5. Russell, W. R., and Stedman~ E.: Observations on 1Kyotonia, Lancet 2: 742, 1936. 6. I~2olb~ L. C.~ IIarvey~ A. lVL, and Whitehill, 3/[. R.: A Clinical Study of IV[yotonie Dystrophy a~d 1Kyotonia Congenita, With Special Reference to the Therapeutic Effect of Quinine, Bull. J o h n s / { o p k i n s Hosp. 62: 188, 1938. 7. Brown, G. L., and tIarvey, A. IV[.: Congenital Myotonia in the Goat, Brain 62: 341, 1939. 8. Kolb, L . C . : Congenital lgyotonia in Goats, Bull. Johns Itopkins Kosp. 63: 221, 1938. 9. Dana, C.L.: An Atypical Case of Thomsen's Disease, 3s Ree. 33: 433, 1888. 10. Griffith, T . W . : On 3/[yotonia Congenlta, Quart. J. ~,[ed. 5: 229, 1911. 11. Krayer, O., and Aeheson, G. It.: The Pharmacology of the Veratrum Alkaloids, Physiol. Rev. 26: 383~ 1946. 12. Loewi~ Otto: Personal communication. 13. Schaffer~ It.: Zur Analyze der myotonischen Bewegtmgsstbrung, nebst Bemerkungen fiber die Tonusfunktion des Skeletmuskels~ Deutsche Ztsehr. f. Nervenh. 67" 29.5, 1920; quoted from Adie, W. J., and Greenfield, J . G . : Dystrophia IV[yotoniea, Brain 46" 73, 1923. 14. McIntyre, A. R.: Some Physiological Effects of Curare and Their Application to Clinical 3~[edleine, Physiol. ~Rev. 27: 464, 1947. 1.~. Quoted in Goni, Adalberto R." 3dyasthenia Gravis, Baltimore, 1946~ Williams and Wi]Mns.
DONALI) R. HIRSOH, M.D., JOSEPH I)ANCIS, M.D., AND RICHARD
S. WARD, M.D.
NEW YORK, N. Y.
Y O T O N I A congenita is a h e r e d i t a r y condition in which tile patient is
M unable to relax his muscles quickly after a strong v o l u n t a r y contraction
It is commonly associated with muscular hypertrophy. The condition is usually not disabling and the prognosis for life is good. Tile disease is rare, but is one of great interest to physiologists because of the possibility that an understanding of the mechanisms behind the muscular abnormality will give us an insight into the physiology of normal muscular contraction. l~yotonia congenita was first described b y Bell in 1833. I t received general recognition, however, only after Thomsen described twenty-one cases in his own family in 1876. A related disease, dystrophia myotonia, is more common. This latter eondition has an onset later in life and there are associated findings: muscular a t r o p h y and weakness, cataracts, testieu]ar atrophy, baldness, and a low basal metabolic rate. Most of the studies on myotonia have been carried out on patients with dystrophia myotonia, but so far as we know the muscular abnormality is the same in the two diseases, v a r y i n g in severity. There are several good reports and reviews on this subject in the literature. ~-6, 9, ~0 The justification for an additional report lies in the use of two new approaches to the study of myotonia: (1) a search for a humoral substance in the blood of a patient with myotonia, which would be capable of reproducing myotonia, and (2) observation of the effects of curare on the myotonic reaction. The latter of these techniques has become available for clinical research only in the past few years. CASE REPORT
It. C., a 6-year-old Negro boy (B. tI. 28255-47) was admitted to Bellevue IIospital in June, 1947, with a chief compalint of persistent symmetriea] swellings in the neck region. It was also reported that the child seemed slow and lethargic in play. The child came from a boarding school, and only the father was available to give a history. H e described the patient's birth and neonatal development as normal, except perhaps for the fact that the child's nmseular development had always seemed advanced for his age. Aside from measles, chicken pox, and appendicitis requiring operation, there had been no illnesses. The child had entered the boarding school eight months before the hospital admission and the admitting physician had noted the bilateral neck swellings, which he attributed to cervical lymphadenitis secondary to chronic tonsillitis. I n the school, it was noted that the boy walked slowly and seemed sluggish in play, compared to the other children. He was also seen to have a peculiar staring mannerism, most noticeable in the early morning on awakening. F r o m the D e p a r t m e n t of Pediatrics, ;New ~rork University-Bellevue Medical Center a n d the Children's IVs Service, Bellevue I-Ios!oital. A loreliminary repport of this c o m m u n i c a t i o n w a s presented at the meeting of the Society for Pediatric :Research, May 4, 1948, in Atlantic ,City,
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CONGENITA
The f a t h e r and two brothers of the patient were h e a l t h y and free f r o m m u s c u l a r abnormalities. B o t h the m o t h e r and the m a t e r n a l g r a n d m o t h e r , however, were said to show p r o m i n e n t o v e r d e v e l o p m e n t of the muscles of the n e c k and shouIder girdle, a n d to suffer f r o m an inability to move rapidly. The m o t h e r h a d the same s t a r i n g m a n n e r i s m as the child. P h y s i c a l e x a m i n a t i o n on admission showed an alert, intelligent, welldeveloped a n d well-nourished Negro b o y of 6 y e a r s of age. He was not ill. Positive findings were limited to the skeletal muscle system an(] the eyes. The tonsils were large and cryptic, but free of active infection. T h e r e w e r e no signs of h y p o t h y r o i d i s m . Neurologie e x a m i n a t i o n was n e g a t i v e except f o r the muscle findings.
Fig.
1,
iFig. 2.
Fig. l.--Obvious lid lag due to increased tonus of the levator palpebrae. Fig. 2.---The patient has been instructed to close his eyes tightly and then open them as rapidly as possible. The photograph was taken about two seconds after the patient began to open his eyes. The palpebral orifice is still reduced in all diameters despite the maximal effort he is making to open his eyes.
The child's herculean build was striking. The masses in the neck region could be d e m o n s t r a t e d to be h y p e r t r o p h i e d strenocleido mastoid muscle r a t h e r t h a n l y m p h nodes. The muscles of the shoulder girdle stood out clearly. The abnormalities in eye m o v e m e n t s first s u g g e s t e d to us t h a t the p a t i e n t was suffering' f r o m a generalized muscle disturbance. There was severe m y o t o n i a of all the e x t r a o c u l a r muscles. The child h a d g r e a t difficulty in following r a p i d l y m o v i n g objects with his eyes. I f an object were m o v e d v e r t i c a l l y or h o r i z o n t a l l y in f r o n t of him, there would be a short i n t e r v a l before he could m a k e his eyes move in the r e q u i r e d direction. W h e n he closed his eyes t i g h t l y and then tried to open t h e m again, he could not do so f o r
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several seconds, even though he tried hard. He had pronounced lid lag, which we a t t r i b u t e d to myotonia of the levator palpebrae superioris. There was no exophthalmos. These abnormalities of the e x t r a o e u l a r muscles were most m a r k e d in the early morning on awakening. The myotonia disappeared r a p i d l y when the affected muscles were " w a r m e d u p . " Thus a f t e r the child had opened and closed Ms eyes several times in succession, the movements became progressively easier, and lid lag disappeared. Aside from these abnormalities of movement, examination of the eyes revealed nothing. This included slit lamp examination.
Fig. 3.---There
is marked
muscular
hypertrophy.
The
scar is the result of a muscle
biopsy.
lViyotonia was then f o u n d in other muscles, too. A f t e r s t r o n g l y flexing or extending his neck the child had difficulty in straightening it. His gait was abnormally slow and labored. He a p p e a r e d stiff-jointed. H e r e the " w a r m i n g u p " phenomenon could be clearly seen; a f t e r five or six steps his gait was normal. Myotonia r e a p p e a r e d r a p i d l y if tie did not continue to use his nluscles.
The myotonia could also be demonstrated after mechanical stimulation of muscle groups. When the thenar eminence of the hand was tapped with a percussion hammer, contraction was rapid and strong', and relaxation delayed. The braehioradial "reflex" was similarly abnormal. Routine laboratory results were as follows: The routine urinalysis was negative. Blood count showed hemoglobin 14.5 Gin., red blood count 4.27 million, white blood count 5,800, polymorphonuelear leucocytes 28 per cent, lymphoeytes 68 per cent. This lymphocytosis persisted on all the examinations. Mazzini test was negative. X-rays of the skull, long bones, neck, lungs, and heart were negative. Carpal and tarsal ossifications were within normal limits. Serum calcium was ]0.4 mg. per cent and serum phosphorus 4.5 rag. per cent. Mantoux tests were negative up to 1.0 rag.
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Several observations were m a d e on the b e h a v i o r of the m y o t o n i a u n d e r a v a r i e t y of conditions. These e x p e r i m e n t s were repetitions of e x p e r i m e n t s p r e v i o u s l y r e p o r t e d b y others in the literature. No a t t e m p t was m a d e to record results m e c h a n i c a l l y or electrically; the eva]uatiou was entirely clinical. Changes t h a t w e r e observed were unequivocal. 1. Electrical reactions: I n c r e a s e d muscle excitability in m y o t o n i a h a d been found p r e v i o u s l y b y P o a c h e r and W o o d w a r d . ~ I t usually required a galvanic c u r r e n t of ].8 Ma. to p r o d u c e a n m s e u l a r contraction in a normal 6-year-old child. I n this p a t i e n t c u r r e n t s of less t h a n 1.0 Ma. were sufficient. 2. Effeets of chilli~lg: I t is g e n e r a l l y r e p o r t e d t h a t m y o t o n i a is worse in cold weather, a l t h o u g h R a v i n ~, a f o u n d t h a t m y o t o n i a in his patients decreased w h e n the t e m p e r a t u r e of the e n v i r o n m e n t was reduced f r o m 40 ~ C. to 20 ~ C. Our p a t i e n t was placed in a cold b a t h for a b o u t ten minutes. He was t h e n m o v e d out into the open air. A t this time the m y o t o n i a was unchanged, despite the f a c t t h a t he was shivering w i t h cold. 3. E p i n e p h r i n e : I n the l i t e r a t u r e t h e r e are eonflicting reports as to the effect of epinephrine on myotonia. Some i n v e s t i g a t o r s r e p o r t accentuation of s y m p t o m s , ~' ~ a n d others a deereaseY, 3 I n our p a t i e n t r e p e a t e d injections of 0.3 e.e. of I :1000 epinephrine h y d r o c h l o r i d e i n t r a m u s c u l a r l y had no effect on the myotonia. 4. Prostiglnine: There is a u n i f o r m i t y of opinion t h a t p r o s t i g m i n e accentuates m y o t o n i a 2 -7 The injection of 1.0 c.e. of 1:2000 p r o s t i g m i n e hydrochloride i n t r a m u s c u l a r l y e x a g g e r a t e d the m y o t o n i a in out' patient. 5. Quinine: Since 1936, ~, 6, s quinine has been used as a specific medication in this disease. Small doses often cause a complete d i s a p p e a r a n c e of the myotonia. Our p a t i e n t was completely relieved of his s y m p t o m s b y 0.6 Gin. quinine sulfate orally, or 0.5 Gin. quinine dihydrochloride intravenously. The m y o t o n i a r e t u r n e d slowly in six hours. 6. D u a l n a t u r e of the m y o t o n i a contra, ction: This f e a t u r e of m y o t o n i a was commented on by D a n a 9 and Griffith, ~~ and has more recently been inv e s t i g a t e d b y Ravin. 2 The m y o t o n i a c o n t r a c t i o n a p p e a r s to be initiated b y the first strong v o l u n t a r y contractions, but f r o m t h e n on is i n d e p e n d e n t of them, lasting a definite period r e g a r d l e s s of w h e t h e r r e l a x a t i o n is a t t e m p t e d following these first contractions, or w h e t h e r a v o l u n t a r y tetanus is k e p t up. The boy was a s k e d to close his eyes t i g h t l y f o r v a r y i n g lengths of time, a f t e r which he was to open his eyes as quickly and as widely as possible. The length of time it tOok him to open his eyes was recorded. I t was f o u n d t h a t a m i n i m u m period of v o l u n t a r y c o n t r a c t i o n was necessary (two seconds) before m y o t o n i a appeared. B e y o n d t h a t m i n i m a l period, however, the d u r a t i o n of m y o t o n i a was not increased b y h a v i n g the boy squeeze his eyes shut for longer periods. On the c o n t r a r y it t o o k him less time to open his eyes the longer he k e p t t h e m closed. W h e n he k e p t t h e m closed for ten seconds no m y o t o n i a was n o t e d on relaxing. This can be i n t e r p r e t e d as m e a n i n g t h a t the m y o t o n i a r a n its course u n d e r cover of the p r o l o n g e d v o l u n t a r y effect. I n s u m m a r y , a 6-year-old N e g r o boy p r e s e n t e d the classical picture of m y o t o n i a eongenita. I-Ie h a d p r o n o u n c e d h y p e r t r o p h y of m a n y of his skeletal muscles, and an inability to r e l a x a n t a g o n i s t i c muscles rapidly. R a p i d movem e a t s thus could not be accomplished. The m y o t o n i e delay in r e l a x a t i o n disa p p e a r e d a f t e r several " w a r m i n g u p " contractions. The f a m i l y history suggested t h a t both the p a t i e n t ' s m o t h e r a n d the m a t e r n a l g r a n d m o t h e r suffered f r o m t h e disease. Observations of the m y o t o n i e reaction in this boy, u n d e r v a r y i n g conditions, were consistent with similar observations on c~lses previously r e p o r t e d in the literature.
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SPECIAL STUDIES
A. Search for a Humoral Factor.--The drug veratrine can produce myotonia in normal muscle. An isolated strip of muscles, poisoned with veratrinc, behaves remarkably like the muscle of myotonia congenita21 There is a myo,tonic p a t t e r n of response following stimulation of the nerve. I f electromyograms are made from the muscle during the myo,tonic contraction, it is found that a single shock stimulus in the nerve produces a volley of electrical impulses in the muscle. The veratrine reaction disappears :following repeated contraction, or " w a r m i n g u p . " Quinine also abolishes the reaction. I n all these cardinal points tile myotonia of veratrine poisoning resembles that of myotonia congenita. Even in response to curare poisoning the two types of myotonia behave similarly. Curare affects neither (see section B). In view of this, it seemed reasonable to search for a veratrine-like substance in the blood of patients with myotonia. In 1936 Loewi ~2 reported success in finding such a substance in the plasma dialysate of a p a t i e n t with myotonia congenita. His experiment needed to be repeated. Using essentially the same technique, we attempted this with our patient. The procedure was as follows: Blood from the external j u g u l a r vein was used, because of the prominence of eye signs in this patient. Specimens were also taken from the antecubital vein, before and after tourniquets had been applied. The blood was drawn, heparinized, separated, and frozen until ready for testing. Control specimens were obtained u n d e r identical conditions from a normal child. The sartorius muscle of a frog was exposed to (1) the dialysate, and (2) the residue, and was stimulated each time with a galvanic current. The sartorius muscle is usually used for such testing. Characteristic patterns are produced by veratrine in dilutions as high as 1:5,000,000. No veratrine-like substance could be detected in any of these specimens. A normal twitch resulted in each case. ~ An in vivo experiment was also tried with this patient, in the hope of demonstrating a myotonia-indueing substance in the blood. The idea for this experiment was taken from the classical one on myasthenia gravis described by M a r y B. W a l k e r before the Royal Society of Medicine in 1938. ~5 Tourniquets were placed on the child's arms to obstruct venous return. This was to increase the concentration of such a substance locally. The patient was instructed to open and close his eyes r e p e a t e d l y until his eye muscles had " w a r m e d u p , " and all signs of myotonia disappeared. At this point he was asked to open and close his hands several times. Myotonia of the hands was quite evident. TILe tourniquets were then a b r u p t l y removed. It was t h o u g h t that with the release of this venous blood into t h e general circulation a myotonia-inducing substance might cause the myotonia of the eye muscles to reappear. No such effect resulted. W e were not able to demonstrate a humoral f a c t o r by this in vivo experiment. B. Curarization E x p e r i m e n t . l - - I n recent years investigators have come to *We a r e i n d e b t e d to D r . Givlio C a n t o n i f o r p e r f o r m i n g t h e s e e x p e r i m e n t s . SDr. E m m a n u e l P a p p e r s u p e r v i s e d t h e e u r a r i z a t i o n in t h e s e e x p e r i m e n t s .
ttIRSCtt
ET
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CONGENITA
765
tile eon.elusion t h a t the site of the a b n o r m a l i t y in m y o t o n i a is peripheral. However, the exact locus is not known. K e n n e d y and Wolff * demonstrated that spinal anesthesia does not affect myotonia. Schaffer ~3 showed t h a t myotonia persisted w h e n the n e r v e endings in the muscles were p a r a l y z e d by regional anesthesia. B r o w n and H a r v e y ~ showed that section of the motor nerves and d e g e n e r a t i o n of the m o t o r end plate did not a l t e r the a b n o r m a l i t y . This last w o r k was done with myotonie goats---goats with a congenital disease reo sembling h u m a n m y o t o n i a congenita. Curare is a logical d r u g to use in c a r r y i n g this localization f u r t h e r . C u r a r e is said to p a r a l y z e muscle t h r o u g h action on the m y o n e u r a l junction. I n an excellent review of the literature, M e I n t y r e ~4 pointed out t h a t the chief effect of c u r a r i z a t i o n was a d i m i n u t i o n in the end plate potential. A p p a r e n t l y there was also some effect u p o n the muscle fibers themselves, diminishing their sensitivity to aeetyl choline, but this need not concern us. All effects of c u r a r e are either u p o n the m y o n e n r a l j u n c t i o n or on points distal to it. I n 1939 B r o w n and t t a r v e y 7 curarized m y o t o n i c goats and fonnd the m y o t o n i a uninfluenced b y the curare. T h e y r e a s o n e d f r o m this e x p e r i m e n t t h a t the site of the a b n o r m a l i t y in the goats was p e r i p h e r a l to the m y o n e n r a l junction. T h e r e h a v e been no r e p o r t s of this e x p e r i m e n t carried out w i t h a h u m a n ease of myotonia. A e c o r d i n g l y , w i t h our patient, the following procedure was u n d e r t a k e n : The p a t i e n t received n e m b u t a l and scopolamine premedieation, and was anesthetized with v i n y l ether and e t h e r - o x y g e n mixture. The response a f t e r mechanical stimulation of. the extensors of the f o r e a r m (the braehioradial " r e flex"~) was used as an index of myotonia. Motion pictures were taken of all reflexes elicited. A f t e r pictures were taken of the " r e f l e x " before curare, curare was given until d i a p h r a g m a t i c contractions stopped.l A total of 30 units was used. R e s p i r a t i o n s were m a i n t a i n e d b y the anesthetist. Pictures were then t a k e n of the " r e f l e x " u n d e r the influence of_ curare. W e were f o r t u n a t e to be able to m a k e control observations on a n o r m a l child of_ the same age and w e i g h t u n d e r identical conditions of anesthesia. Here, too, motion pictures were t a k e n of the b r a e h i o r a d i a l " r e f l e x " before a n d a f t e r full curarization. ~ e e h a n i c a l stimulation of the extensor muscles of this b o y ' s forea~'m p r o d u c e d (under anesthesia) a s t r o n g c o n t r a c t i o n w i t h a myotonie d e l a y in r e l a x a t i o n ; the h a n d r e m a i n e d up for several seconds, and only fell slowly to its original position. Af.ter complete e u r a r i z a t i o n this response was unchanged. I n the n o r m a l control the n o r m a l b r a c h i o r a d i a l " r e f l e x " was also uninfluenced b y curare. 9 T h e b r a e h i o r e u d i a l " r e f l e x " i s n o t a t r u e r e f l e x in t h e s t r i c t s e n s e o r t h e w o r d . I t d o e s n o t depend upon a reflex ~rc, and is independent of the eentrat nervous system. It is appKrently a direct resl~onse to mechanical stimulation of the muscle fibers themselves. The persistence of the reflex after curarization makes this apparent. We ha.ve been unable to find any comment on t h e m y o t a t i e n a t u r e o f t h i s r e f l e x i n t h e l i t e r a t u r e , a l t h o u g h it a p p e a r s t o b e g e n e r a l l y ' a c c e p t e d by neurologists. tThis degree of eurarization is commonly accepted as complete since the diaphragm is the l a s t m u s c l e to b e D a r a l y z e d .
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THE JOURNAL OF PEDIATRICS
In human beings with myotonia eongenita, therefore, as welt as in myotonie goats, curare does not eliminate the myotonic reaction. The abnormality in myotonia must then be peripheral to the site of action of curare. Since, according to our present knowledge, all effects of curare are at the myoneural junction or distal to it, this would put the abnormality in human myotonia somewhere in the muscle fiber itself. SUMMARY
1. The clinical findings in a case of myotonia congenita (Thomsen's disease) are presented. 2. Attempts at demonstrating a myotoniadnducing substance in the blood of the patient are described. These attempts were unsuccessful. 3. The myotonie pattern of response was uninfluenced by complete eurarization of the patient. The significance of this in the localization of the muscular abnormality is discussed. REFERENCES l. Poncher, It. G., and Woodward, It.: Pathogenesls and Treatment of l~[yotonia Congenita, Am. J. Dis. Child. 52: 1065, 1936. 2. Ravin, A.: Studies in Dystrophia ~[yotoniea. III. Experimental Studies in ~[yotonia, Arch. Neuroh & Psych. 43: 649, 1940. 3. Ravin, A.: Myotonia, lVledicine 18: 443, 1939. 4. ~ennedy, F., and Wolff, A.: Experiments With Quinine and Prostigmine in the Treatment of !V[yotonia and Myasthenia, Arch. Neurol. & Psych. 37: 68, 1937. 5. Russell, W. R., and Stedman~ E.: Observations on 1Kyotonia, Lancet 2: 742, 1936. 6. I~2olb~ L. C.~ IIarvey~ A. lVL, and Whitehill, 3/[. R.: A Clinical Study of IV[yotonie Dystrophy a~d 1Kyotonia Congenita, With Special Reference to the Therapeutic Effect of Quinine, Bull. J o h n s / { o p k i n s Hosp. 62: 188, 1938. 7. Brown, G. L., and tIarvey, A. IV[.: Congenital Myotonia in the Goat, Brain 62: 341, 1939. 8. Kolb, L . C . : Congenital lgyotonia in Goats, Bull. Johns Itopkins Kosp. 63: 221, 1938. 9. Dana, C.L.: An Atypical Case of Thomsen's Disease, 3s Ree. 33: 433, 1888. 10. Griffith, T . W . : On 3/[yotonia Congenlta, Quart. J. ~,[ed. 5: 229, 1911. 11. Krayer, O., and Aeheson, G. It.: The Pharmacology of the Veratrum Alkaloids, Physiol. Rev. 26: 383~ 1946. 12. Loewi~ Otto: Personal communication. 13. Schaffer~ It.: Zur Analyze der myotonischen Bewegtmgsstbrung, nebst Bemerkungen fiber die Tonusfunktion des Skeletmuskels~ Deutsche Ztsehr. f. Nervenh. 67" 29.5, 1920; quoted from Adie, W. J., and Greenfield, J . G . : Dystrophia IV[yotoniea, Brain 46" 73, 1923. 14. McIntyre, A. R.: Some Physiological Effects of Curare and Their Application to Clinical 3~[edleine, Physiol. ~Rev. 27: 464, 1947. 1.~. Quoted in Goni, Adalberto R." 3dyasthenia Gravis, Baltimore, 1946~ Williams and Wi]Mns.