Prolonged Neonatal Myasthenia Gravis: Electrophysiological Studies C l i n t o n E. Branch, Jr, MD, Thomas R. Swift,
MD, a n d P a u l R. D y k e n , MD
A female infant with neonatal myasthenia gravis remained w e a k for a n excessively l o n g period compared to t h e usual situation i n this disease process. A t 71 days o f age, electrophysiological studies revealed evidence of a defect in neuromuscular transmission that improved w i t h intravenous Tensilon therapy. Repeat study at 183 days of a g e was normal. T h i s case represents a n unusually l o n g t i m e for an affected infant to have neonatal myasthenia gravis. Electrophysiological studies are of value in t h e diagnosis a n d management of patients w i t h neonatal myasthenia gravis. Branch CE Jr, Swift TR, Dyken PR: Prolonged neonatal myasthenia gravis: electrophysiological studies. Ann Neurol 3:4 16-4 18, 1978
Myasthenia gravis o c c u r s in 12% of n e o n a t e s born t o myasthenic m o t h e r s [5, 6, 8, 141. The disease in the n e o n a t e is usually of short d u r a t i o n and responds rcadily t o anticholinesterasc medications. T h e purposes of this c o m m u n i c a t i o n are t o p r e s e n t a n infant with neonatal myasthenia gravis w h o s e c o u r s e was m o r e prolonged than i n any case previously r e p o r t e d a n d t o d o c u m e n t t h e value of electrophysiological studies i n t h e evaluation of patients w i t h neonatal myasthenia gravis.
Case Report A 3,178 gm infant girl was delivered after an uneventful labor and delivery t o a 27-year-old black woman who had had generalized myasthenia gravis for three years. The mother's illness had begun with diplopia followed by generalized weakness, dysphagia, and respiratory difficulty. A Tensilon test (edrophonium chloride, 10 mg intravenously) was positive, and therapy with pyridostigmine bromide (Mestinon), 60 mg orally every four hours, was instituted with complete resolution of her symptoms except for occasional diplopia. The mother had one other child, who was born one year after she developed myasthenia gravis. This child had an uneventful delivery and neonatal period. The patient was noted shortly after birth to have increasing problems with secretions, a p o o r suck, and decreased spontaneous movemenrs. A diagnosis of neonatal myasthenia gravis was made, and the infant was started o n pyridostigmine bromide syrup, 6 mg per day, with improvement. At home over the next several weeks the mother noted that the child continued to have feeding problems, poor suck, and decreased movements. O n neurologi-
__
~~
~~
From the Division of Neurology, Firzsimons Army Medical Center, Denver* and the Of Neuro'om and Section Of Pediatric Neurology, Medical College of Georgia. Augusta, GA.
416
cal examination at 71 days of age rhe baby was alert and playful but showed congested upper respiratory passages. Sucking was observed to be strong at first but quickly weakened after a few milliliters of formula was ingested. The baby showed no other objective cranial nerve deficits. Somatic musculature was of normal tone, but cxcessivc fatigability was thought to exist. The baby was in the lowcst third percentile for weight (3,750 gm). Electrophysiological studies performed at 7 1 days of age revealed that on repetitive stimulation of the righr ulnar nerve at 2 per second, a progressive decline in the amplitude of rhe hypothenar muscle action potential occurred (Fig 1). A brief tetanic stimulation initially corrected the defect in ncuromuscular transmission (posttetanic facilitation), which worsened two minutes later (posttetanic exhaustion). Edrophonium chloride, 0.7 mg intravenously, corrected the defect in neuromuscular transmission (Fig 2). These studies showed that the infant continued to have myasthenia gravis and that she was undermedicated. Accordingly, the pyridostigmine bromide dosage was increased to 6 mg every four hours, and she experienced marked clinical improvement as evidenced by the ability to suck the contents of a 240 ml bottle without stopping. The baby showed an increase in spontaneous movements and gained weight, but remained weak. Inadvertently, one dose of medication was not given when the infant was 19 weeks old. Because no symptoms developed, it was decided to rcpeat clectrophysiological studies with repetitive stimulation. This examination was performed in the hospital, aftcr anticholinesterase medication had been withheld for the preceding 24 hours, when the patienr was 183 days old, and i t revealed no evidence of a defect of neuromuscular transmission (Fig 3). When last seen at age 15 months, the child was developing normally and had no clinical evidence of myasthenia gravis.
Accepted for publication Nov 15, 1377.
Address reprint requests to Dr Swift, Department of Neurology, of Georgia, Augusta, G~ 30902, Medical
0364-5134/78/O003-0509$01.25 @ 1978 by Clinton E. Branch, Jr
F i g I. A progressive decline in the hypothenar muscle action potential i.r ceen upon Jtimulating the u l n a r newe a t a rate of 2 per .second. Calibration: I msec, 2 mu.
1’45. LATER
I7’W LATER
F i g 2. The progressive decline i n hypothenar muscle action potential that occurs when the u l n a r nerue i J Jtimulatedat a rate of 2 per second is corrected by Tensilon administration. Calibration: I msec. 2 mu.
F i g 3 . T h e progressir,e decline i n hypothenar muscle action potential ohserued a t 7 l days of age is no longer present at I83 d q s . Calibration: 1 nisec, 2 mu.
Discussion The recognition of a transient form of myasthenia gravis in infants of myasthenic mothers was noted by Viets in 1939 [13] and wasdetailed in 1942 by Strickroot, Schaeffer, and Bergo [ 113. This self-limited disease always occurs in a baby born to a mother with well-developed disease. Another extremely rare, persistent form of the disease, called “congenital” myasthenia gravis, occurs in infants born to normal mothers. This was first described in 1948 by Bowman [21. While uncommon, both forms of myasthenia gravis should be considered in the differential diagnosis of “floppy baby” syndrome. Once found, the two disorders are rarely confused, as the transient form of neonatal myasthenia gravis-besides being seen only in children born of myasthenic mothers-also has its onset within the first three days of life, responds in most cases to anticholinesterase medication, and resolves within a period of days to weeks (mean, 6.4 days; range, 5 to 47 days [S]). O n the other hand,
congenital myasthenia gravis is seen in infants born to normal mothers, has its onset at birth, and, although persistent, is often mild and only slowly progressive. Diagnosis of this form usually is made late and retrospectively. The congenital form is often refractory to therapy [71. T h e patient reported here had a greatly prolonged course for neonatal myasthenia gravis, which raised the possibility of congenital myasthenia gravis in an infant of a myasthenic mother. Indeed, this category of myasthenia gravis was considered more likely until recovery occurred. I t is believed that the usual form of neonatal myasthenia gravis results from passive transfer from mother to infant, via the placenta, of IgG antibody directed against acetylcholine receptor protein [ 1, 4 , 9, 101. Recent studies ofToyka, Drachman, et all121 have shown that passive transfer of the IgG fraction of sera from patients with myasthenia gravis to laboratory mice results in the clinical and electrophysiological picture of myasthenia gravis. Keesey e t a1 [4] have provided proof that the antibody titer against motor end-plate acetylcholine receptor is markedly elevated in the serum of patients with neonatal myasthenia gravis and that in usual cases i t returns to the normal range over a three-month period. In light of these two recent reports, we believe our patient had either an extremely high antibody titer initially o r an unusually slow rate of catabolism. The usefulness of electrophysiological methods i n the diagnosis, management, and follow-up of infants with myasthenia gravis is well illustrated by our patient. Such studies allow the adequacy of anticholinesterase therapy to be objectively assessed and indicate when discontinuation is possible. Indeed, a recent communication by Desmedt and Borenstein [3] reported persistence of a decrement of the evoked muscle action potential in distal muscles at least 30 days after clinical recovery and withdrawal of all anticholinesterase drugs. References I . Bergh N P : Biologic assays in myasthenia gravis for any agents causing a neurornuscular block. Scand J Clin Lab Invest Suppl 5:5-47. 1953 2. Bowman JR: Myasthenia gravis in young children. Pediatrics 1:472-477. 1948 3. Desrnedt JE, Borensrein S: Time course of neonatal myasrhenia gravis and unsuspectedly long duration of neurornuscular block indistal muscles(Ietter). N Engl J Med 296:633, 1977 4 . Keesey J, Lindsrrorn J, Cokely H, et al: Antiacetylcholine receptor antibody in neonatal myasthenia gravis (letter). N Engl J Med 296:55, 1977 5 . Kibrick S: Myasthenia gravis in the newborn. Pediatrics
14:365-386, 1954
6. McNall PG, Jafernia MR: Management of rnyastheniagravis in the obstetrical patient. Am J Obsret Gynecol 92:518-525. 1965
Branch, Swift, and Dyken: Neonatal Myasthenia Gravis
417
7. Millichap J G , Dodge PR: Diagnosis and treatment of myasthenia gravis in infancy, childhood, and aldolexence. Neurology (Minneap) 10:1007-1014, 1960 8. Namba T , Brown SB, G r o b G: Neonatal myasthenia gravis: report of two cases and review of the literature. Pediatrics 45~488-504, 1070 9. Nastuk WL, Strauss AJL Further developments in the search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis, in Viets H R (ed): Myasthenia Gravis. Springfield, IL, Charles C Thomas, 1961, pp 229-237 10. Smith RT, Robbins JB: General physiology: the specific immune response. Developmental aspects of immunity, in Cook RE (ed): T h e Biologic Basis of Pediatric Practice. New York,
418
Annals of Neurology
Vol 3
No 5
May 1978
11.
12.
3. 4.
McGraw-Hill Book Company, 1968, sect 6, pp 495-536, 507-553 Strickroot FL, Schaeffer RL, Bergo HL Myasthenia gravis occurring in an infant born of a myasthenic mother. JAMA 120~1207-1209, 1942 Toyka KV, Drachman DB, Griffin DE, e t al: Myasthenia gravis-study of humoral immune mechanisms by passive transfer to mice. N Engl J Med 206:125-131, 1977 Viers H R , Brown MR: Medical progress: diseases of muscle. N Engl J Med 245:647-653, 1051 Wise G A , McQuillen MP: Transient neonatal myastheniaclinical and electromyographic studies. Arch Neurol 22: 556-565, 1970
MD, a n d P a u l R. D y k e n , MD
A female infant with neonatal myasthenia gravis remained w e a k for a n excessively l o n g period compared to t h e usual situation i n this disease process. A t 71 days o f age, electrophysiological studies revealed evidence of a defect in neuromuscular transmission that improved w i t h intravenous Tensilon therapy. Repeat study at 183 days of a g e was normal. T h i s case represents a n unusually l o n g t i m e for an affected infant to have neonatal myasthenia gravis. Electrophysiological studies are of value in t h e diagnosis a n d management of patients w i t h neonatal myasthenia gravis. Branch CE Jr, Swift TR, Dyken PR: Prolonged neonatal myasthenia gravis: electrophysiological studies. Ann Neurol 3:4 16-4 18, 1978
Myasthenia gravis o c c u r s in 12% of n e o n a t e s born t o myasthenic m o t h e r s [5, 6, 8, 141. The disease in the n e o n a t e is usually of short d u r a t i o n and responds rcadily t o anticholinesterasc medications. T h e purposes of this c o m m u n i c a t i o n are t o p r e s e n t a n infant with neonatal myasthenia gravis w h o s e c o u r s e was m o r e prolonged than i n any case previously r e p o r t e d a n d t o d o c u m e n t t h e value of electrophysiological studies i n t h e evaluation of patients w i t h neonatal myasthenia gravis.
Case Report A 3,178 gm infant girl was delivered after an uneventful labor and delivery t o a 27-year-old black woman who had had generalized myasthenia gravis for three years. The mother's illness had begun with diplopia followed by generalized weakness, dysphagia, and respiratory difficulty. A Tensilon test (edrophonium chloride, 10 mg intravenously) was positive, and therapy with pyridostigmine bromide (Mestinon), 60 mg orally every four hours, was instituted with complete resolution of her symptoms except for occasional diplopia. The mother had one other child, who was born one year after she developed myasthenia gravis. This child had an uneventful delivery and neonatal period. The patient was noted shortly after birth to have increasing problems with secretions, a p o o r suck, and decreased spontaneous movemenrs. A diagnosis of neonatal myasthenia gravis was made, and the infant was started o n pyridostigmine bromide syrup, 6 mg per day, with improvement. At home over the next several weeks the mother noted that the child continued to have feeding problems, poor suck, and decreased movements. O n neurologi-
__
~~
~~
From the Division of Neurology, Firzsimons Army Medical Center, Denver* and the Of Neuro'om and Section Of Pediatric Neurology, Medical College of Georgia. Augusta, GA.
416
cal examination at 71 days of age rhe baby was alert and playful but showed congested upper respiratory passages. Sucking was observed to be strong at first but quickly weakened after a few milliliters of formula was ingested. The baby showed no other objective cranial nerve deficits. Somatic musculature was of normal tone, but cxcessivc fatigability was thought to exist. The baby was in the lowcst third percentile for weight (3,750 gm). Electrophysiological studies performed at 7 1 days of age revealed that on repetitive stimulation of the righr ulnar nerve at 2 per second, a progressive decline in the amplitude of rhe hypothenar muscle action potential occurred (Fig 1). A brief tetanic stimulation initially corrected the defect in ncuromuscular transmission (posttetanic facilitation), which worsened two minutes later (posttetanic exhaustion). Edrophonium chloride, 0.7 mg intravenously, corrected the defect in neuromuscular transmission (Fig 2). These studies showed that the infant continued to have myasthenia gravis and that she was undermedicated. Accordingly, the pyridostigmine bromide dosage was increased to 6 mg every four hours, and she experienced marked clinical improvement as evidenced by the ability to suck the contents of a 240 ml bottle without stopping. The baby showed an increase in spontaneous movements and gained weight, but remained weak. Inadvertently, one dose of medication was not given when the infant was 19 weeks old. Because no symptoms developed, it was decided to rcpeat clectrophysiological studies with repetitive stimulation. This examination was performed in the hospital, aftcr anticholinesterase medication had been withheld for the preceding 24 hours, when the patienr was 183 days old, and i t revealed no evidence of a defect of neuromuscular transmission (Fig 3). When last seen at age 15 months, the child was developing normally and had no clinical evidence of myasthenia gravis.
Accepted for publication Nov 15, 1377.
Address reprint requests to Dr Swift, Department of Neurology, of Georgia, Augusta, G~ 30902, Medical
0364-5134/78/O003-0509$01.25 @ 1978 by Clinton E. Branch, Jr
F i g I. A progressive decline in the hypothenar muscle action potential i.r ceen upon Jtimulating the u l n a r newe a t a rate of 2 per .second. Calibration: I msec, 2 mu.
1’45. LATER
I7’W LATER
F i g 2. The progressive decline i n hypothenar muscle action potential that occurs when the u l n a r nerue i J Jtimulatedat a rate of 2 per second is corrected by Tensilon administration. Calibration: I msec. 2 mu.
F i g 3 . T h e progressir,e decline i n hypothenar muscle action potential ohserued a t 7 l days of age is no longer present at I83 d q s . Calibration: 1 nisec, 2 mu.
Discussion The recognition of a transient form of myasthenia gravis in infants of myasthenic mothers was noted by Viets in 1939 [13] and wasdetailed in 1942 by Strickroot, Schaeffer, and Bergo [ 113. This self-limited disease always occurs in a baby born to a mother with well-developed disease. Another extremely rare, persistent form of the disease, called “congenital” myasthenia gravis, occurs in infants born to normal mothers. This was first described in 1948 by Bowman [21. While uncommon, both forms of myasthenia gravis should be considered in the differential diagnosis of “floppy baby” syndrome. Once found, the two disorders are rarely confused, as the transient form of neonatal myasthenia gravis-besides being seen only in children born of myasthenic mothers-also has its onset within the first three days of life, responds in most cases to anticholinesterase medication, and resolves within a period of days to weeks (mean, 6.4 days; range, 5 to 47 days [S]). O n the other hand,
congenital myasthenia gravis is seen in infants born to normal mothers, has its onset at birth, and, although persistent, is often mild and only slowly progressive. Diagnosis of this form usually is made late and retrospectively. The congenital form is often refractory to therapy [71. T h e patient reported here had a greatly prolonged course for neonatal myasthenia gravis, which raised the possibility of congenital myasthenia gravis in an infant of a myasthenic mother. Indeed, this category of myasthenia gravis was considered more likely until recovery occurred. I t is believed that the usual form of neonatal myasthenia gravis results from passive transfer from mother to infant, via the placenta, of IgG antibody directed against acetylcholine receptor protein [ 1, 4 , 9, 101. Recent studies ofToyka, Drachman, et all121 have shown that passive transfer of the IgG fraction of sera from patients with myasthenia gravis to laboratory mice results in the clinical and electrophysiological picture of myasthenia gravis. Keesey e t a1 [4] have provided proof that the antibody titer against motor end-plate acetylcholine receptor is markedly elevated in the serum of patients with neonatal myasthenia gravis and that in usual cases i t returns to the normal range over a three-month period. In light of these two recent reports, we believe our patient had either an extremely high antibody titer initially o r an unusually slow rate of catabolism. The usefulness of electrophysiological methods i n the diagnosis, management, and follow-up of infants with myasthenia gravis is well illustrated by our patient. Such studies allow the adequacy of anticholinesterase therapy to be objectively assessed and indicate when discontinuation is possible. Indeed, a recent communication by Desmedt and Borenstein [3] reported persistence of a decrement of the evoked muscle action potential in distal muscles at least 30 days after clinical recovery and withdrawal of all anticholinesterase drugs. References I . Bergh N P : Biologic assays in myasthenia gravis for any agents causing a neurornuscular block. Scand J Clin Lab Invest Suppl 5:5-47. 1953 2. Bowman JR: Myasthenia gravis in young children. Pediatrics 1:472-477. 1948 3. Desrnedt JE, Borensrein S: Time course of neonatal myasrhenia gravis and unsuspectedly long duration of neurornuscular block indistal muscles(Ietter). N Engl J Med 296:633, 1977 4 . Keesey J, Lindsrrorn J, Cokely H, et al: Antiacetylcholine receptor antibody in neonatal myasthenia gravis (letter). N Engl J Med 296:55, 1977 5 . Kibrick S: Myasthenia gravis in the newborn. Pediatrics
14:365-386, 1954
6. McNall PG, Jafernia MR: Management of rnyastheniagravis in the obstetrical patient. Am J Obsret Gynecol 92:518-525. 1965
Branch, Swift, and Dyken: Neonatal Myasthenia Gravis
417
7. Millichap J G , Dodge PR: Diagnosis and treatment of myasthenia gravis in infancy, childhood, and aldolexence. Neurology (Minneap) 10:1007-1014, 1960 8. Namba T , Brown SB, G r o b G: Neonatal myasthenia gravis: report of two cases and review of the literature. Pediatrics 45~488-504, 1070 9. Nastuk WL, Strauss AJL Further developments in the search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis, in Viets H R (ed): Myasthenia Gravis. Springfield, IL, Charles C Thomas, 1961, pp 229-237 10. Smith RT, Robbins JB: General physiology: the specific immune response. Developmental aspects of immunity, in Cook RE (ed): T h e Biologic Basis of Pediatric Practice. New York,
418
Annals of Neurology
Vol 3
No 5
May 1978
11.
12.
3. 4.
McGraw-Hill Book Company, 1968, sect 6, pp 495-536, 507-553 Strickroot FL, Schaeffer RL, Bergo HL Myasthenia gravis occurring in an infant born of a myasthenic mother. JAMA 120~1207-1209, 1942 Toyka KV, Drachman DB, Griffin DE, e t al: Myasthenia gravis-study of humoral immune mechanisms by passive transfer to mice. N Engl J Med 206:125-131, 1977 Viers H R , Brown MR: Medical progress: diseases of muscle. N Engl J Med 245:647-653, 1051 Wise G A , McQuillen MP: Transient neonatal myastheniaclinical and electromyographic studies. Arch Neurol 22: 556-565, 1970
