365
Ped
iutrics
VOLUME 14 OCTOBER 1954 NUMBER 4
SPECIAL
SECTIONS
REVIEW
ARTICLE
MYASTHENIA GRAVIS IN THE NEWBORN
By SIDNEY Krrniicx, M.D., PH.D.#{176}
Boston
T
HIS 1)aI)e1 1)resemits three cases oftran-sitory myasthenia of the newborn, three
probable cases of the same syndrome, and
one case of congenital myasthenia gravis.
The features of these two conditions are
discussed, their etiologies considered, and
all of the previously reported cases are
re-viewed.
Myasthenia gravis is an illness
char-acterized by undue fatigability of
vohun-tary muscles after excercise with partial or
complete recovery following periods of
rest. While this disease may occur at any
age, onset is most common in the third
decade with females more often affected
than males. Muscles innervated by the
cranial nerves are usually the first to show
imivolvement. Ptosis is frequent as an early
sign, and restrictions of ocular movements
as well as disturbances of speech,
mastica-tion, swallowing and respiration may all
occur. Examination reveals no evidence of
From the Department of Pediatrics, Harvard
Medical School, The Children’s Medical Center,
Boston, Mass.. and the North Shore Babies Hospital,
Salem, Mass.
0 Address: 300 Longwood Avenue, Boston 15,
Massachusetts.
central nervous system changes or of
inns-cular atrophy. Despite the apparent muscle
weakness, the tendon reflexes are intact. The
etiology of this condition is still
undeter-mined although a disturbance in the
trans-mission of nerve impulses at the
neuro-muscular junction is believed to be
respon-sible.
The clinical course of myasthenia gravis is characterized by episodes of spontaneous remission and relapse. Relapses are
fre-quently associated with difficulty in swal-lowing and breathing, these symptoms often
occurring suddenly and occasionally
result-ing in fatal termination despite therapy. While the onset of myasthenia gravis is
usually gradual it may occasionally be
ful-minating, with sudden onset and rapid
pro-gression to dysphagia, respiratory distress
and collapse over a one or two day period.1’2
The discovery by Walker3 that
neostig-mine, a cholinesterase inhibitor, was of
value in the treatment of this disease and
the subsequent observation by Viets and Schwab4 that the response to this drug
could be used as a therapeutic test have
greatly simplified the diagnosis of this
also available as aids to diagnosis. In
pa-tients with dysphagia as a symptom of myasthenia the effect of neostigmine in cor-recting the weakness of the pharyngeal
muscles may be observed by fluoroscopy
with the aid of a barium swallow. A char-acteristic response is specific for this
dis-ease.5 The increased sensitivity of these
patients to the action of curariform agents
and the ability of quinine to intensify the myasthenic state have also been employed
for diagnostic purposes.6’7 The use of these compounds is, however, not without risk.
These preparations are of value in
intensify-ing the muscular weaknesses in mild or
un-certain cases, thus enabling a quicker
di-agnosis to be made. The weakness so
in-duced may then be abolished with
neostig-mine, a relatively nontoxic drug the
un-desirable side effects of which can be
in-hibited l)y atropine. Despite the widespread
use of neostigmine in medicine only one
death, and that unexplained, has been
re-ported as due to this drug.8
Prior to neostigmine therapy, myasthenia gravis was usually fatal within a few years
iii the majority of patients, respiratory paralysis amid aspiration pneumonia being
commonly responsible. Since that time,
how-ever, the life expectancy in this condition
has markedly increased.9 Neostigmine is still the drug of choice and is often used in conjunction with ephedrine since this
combination is more effective. Other inhibi-tors of cholinesterase activity have also been
used but with varying success due to their greater toxicity and narrower margins of safety.
Myasthenia gravis is not common in childhood, although it does occur. Levethan
et al.’#{176}in 1941 reviewed the salient features of 34 such cases and Bastedo1 in 1950 noted 44 cases in the literature. The clinical
picture amid course are not unlike those seen
iii the adult and treatment is the same. This
condition may also occur during infancy.
\Tiets and Schwab11 having observed one
case with onset at three months of age.
Occasionally these patients, improperly diagnosed, are first seen in Eye or Plastic
Clinics to which they are referred for im-balance of ocular muscles or for surgical
correction of ptosis.
In 1942 Strickroot et al.12 reported the first case of an infant who developed typical signs of severe myasthenia gravis shortly
after birth. This patient, born of a myas-thenic mother, responded to treatment with oral neostigmine but relapsed when
treat-ment was discontinued after two days and died despite resumption of therapy. As
further cases with signs present at birth or with onset shortly thereafter were noted, it
became apparent that these fell into two groups based on the presence or absence of maternal myasthenia.
Those cases which occurred in newborns
of myasthenic mothers were characterized
by severe signs at birth. They usually
re-quired immediate neostigmine therapy and, when no treatment was given or an
made-quate dose used, occasionally died. Those infants that survived, however, became nor-mal in two to four weeks and showed no signs of myasthenia thereafter, despite
ces-sation of treatment. Such cases have since
been classified as transitory myasthenia of the newborn.
The remaining cases, less common,
oc-curred only in newborns with no maternal
history of myasthenia. They were much less severe, and received no neostigmine during the neonatal period. Their signs persisted
for as long as they were followed and the
majority required neostigmine later
in
childhood. These cases have been desig-nated as congenital myasthenia or as “true”
congenital myasthenia in contradistinction
to the previous group. Each of these syn-dromes will be considered in turn.
TRANSITORY MYASTHENIA OF THE NEWBORN
The many reports in the literature sum-marized by Holt and Hansen13 of normal infants born to myasthenic mothers indicate that this syndrome is not common. It is of interest, however, that only two reports of
this condition, covering three cases, are to
have appeared since that time alone. Three
further cases are added in this paper. In
view of the apparent increase in frequency
and the potentially serious nature of this illness when untreated, this may well be
taken as presumptive evidence that a num-ber of such cases may have escaped
detec-tion or may have died shortly after birth
due to misdiagnosis and improper treat-ment. Since this syndrome responds quickly
to treatment, is self limited, and seems to
leave no residuals, the importance of
recog-nizing and vigorously treating this
condi-tion, which constitutes a true medical
emergency, is obvious. In view of the more
prolonged life expectancy in patients with
myasthenia gravis on present day therapy,
childbirths in these patients may well be expected to become more frequent with
con-sequent further augmentation of the number of newborns with this syndrome.
REPORT OF CASES
CASE 1 (Baby Boy R. A., Probable Transitory
Myasthenia) and CASE 2 (Baby Girl L. A.,
Tran-sitory Myasthenia):
The mother of these patients, Mrs. L. A., was
first seen by the author in June, 1952, at the
age of 24 at which time she had had
myasthe-nia gravis for 23 yrs. Her family history was
non-contributory.
Her 1st and 2nd pregnancies, in 1947 and 1949, terminated in abortions.
In mid-1949 she became pregnant for the 3rd
time, and in January, 1950 when six months
pregnant, began to notice excessive weakness and easy fatigue. Her pregnancy was otherwise
uneventful.
On March 30, 1950, she was delivered of a
fullterm male infant, R. A., by low forceps
fol-lowing a short labor at the Addison Gilbert
Hos-pital, Gloucester, Massachusetts. The fetal
heart, heard 15 mimi. before delivery was
nor-mal. At birth the cord was found to be looped
once tightly around the baby’s mieck and was
immediately clamped and cut. Birth weight was
3.4 kg. On physical examination no apparent
abnormalities were noted although the baby
had a very feeble cry. Over the next few days
the baby appeared to have an excessive amount
of mucus requiring frequent suctioning. He
made attempts to cry but was apparently
un-neck appeared on several occasions and was treated with oxygen. He kept his eyes open. He seemed unable to move his head in any direc-tion although he did move his arms and legs. Two days after birth, feedings were started. The baby did not appear to have the strength to suck and swallowed poorly when Breck feedings were tried. He was started on gavage
feedings supplemented by occasional clyses.
At this time a mild ictenus and a right facial
weakness were noted. By the 5th day, the facial
weakness was less prominent and his cry was
somewhat stronger although he was still unable to suck. Transfer to the Salem Hospital, Salem, Massachusetts, for diagnosis and further care was therefore arranged.
On admission the baby was able to turn his head slightly but the neck muscles seemed weak. No petechiae were noted on the head or neck. A moderate micrognathia was present. He was again placed in oxygen because of
occasional mild cyanosis, particularly on
cx-ertion. Blood counts, urine examination, subdu-ral taps and a lumbar puncture were all within normal limits. A chest film was interpreted as normal. Bottle feedings were again tried but he still appeared unable to suck so Breck feedings were substituted. From the 3rd hospital day
(his 7th day of life) he began to stick on the
Breck feeder during feedings but tired easily. He was tried on bottle feedings on his ninth hospital day and took these without difficulty. The patient was discharged asymptomatic and apparently normal on his 17th day of life, and
in July, 1952, was still well.
The mother at term already had symp-toms of myasthenia gravis for several months
although the true nature of her condition was not then suspected. The history of this
infant is given in detail since both the onset
and course of his illness were consistent with a mild form of transitory myasthenia of the newborn. The final diagnosis in this case re-mains in doubt, however, because of the
complications introduced by the malplaced cord at birth and the micrognathia. To what extent these factors may have been responsi-ble for the clinical picture noted cannot be determined. It should be remembered,
super-such as this, a therapeutic test with
neo-stigmine is indicated as an aid to diagnosis. This drug is specific for the myasthenic state
and relatively innocuous if used with proper precaution. A marked temporary improve-ment in this infant following a test dose of neostigmine would have established the
di-agnosis as myasthenia whereas failure to
re-spond would have ruled this condition out.
Following delivery, the mother’s weakness
increased. She was finally seen at a clinic
where the diagnosis of myasthenia gravis was made, and in September, 1950, 9 mos. after onset of her symptoms and 6 mos. after her
delivery, she was placed on oral neostigmine,
15 mgm. 4 times daily, with improvement. Several months later, because of recurrence of her weakness she sought aid at the Neurologi-cal Clinic of the Massachusetts General
Hospi-tal where she has continued to be followed.
Her weakness became more progressive,
re-quiring gradual increase in neostigmine. By
September, 1951, she was taking 30 mgm.
every 2 hrs. while awake, an average of 9
doses daily, with 0.4 mgm. atropune orally
every 6 hrs. . as needed, to neutralize the
muscarinic effects of this medication.
In September, 1951, she was admitted for a
2 wks. trial of ACTH therapy. She was started
omi ACTH 25 mgm. every 6 hrs., neostigmine
also being continued. While hospitalized, it
was discovered that she had missed her last
menstrual period, due 9 days before admission,
ahd a pregnancy test was ordered. After
receiv-ing 12 days of ACTh therapy, she was found
to be pregnant and this medication was there-fore discontinued. She was discharged at the end of 3 wks. unimproved and on the same dose of neostigmine as before.
She continued under the care of her family
physician with periodic visits to the hospital
clinic tip to the time of her confinement which
was at the same hospital where her previous
child had been born. Her symptoms remained
essentially unchanged during pregnancy and
she continimed on oral neostigmine, 30 mgm.
every 2 hrs. while awake, imp to 2 hrs. prior
to delivery. Fetal movements were apparently
normal during the pregnancy as far as she
could remember.
Neostigmine was resumed following delivery,
30 mgm. every 2 hrs., the first dose being
administered 2 hrs. after the baby’s birth.
After 1 wk., this dosage was reduced and 1 mo. later 30 mgm. 5 times daily was sufficient to control her symptoms. Since that time, how-ever, she has again begun to require larger doses of this medication.
Baby Girl L. A.
The baby, a female, was born May 23, 1952,
by spontaneous frank breech delivery. The
mother received only demerol and a few whiffs of nitrous oxide-oxygen as analgesia. The baby cried weakly at birth. Color was good and no resuscitation was necessary. The head was turned toward the left with the chin pressed against the left shoulder, the result of fetal posture. No other abnormalities were noted. Birth weight was 2.8 kg.
Feedings were started at about 18 hrs. and it was noted that the baby would not suck. Gavage feedings were attempted and the first partly retained but following this she began to regurgitate the major part of each feeding through her nose along with large amounts of mucus. Supplementary fluids were given by
clysis. She required periodic suctioning and
had frequent episodes of cyanosis usually as-sociated with feedings or inability to handle the large amounts of stringy mucus present. She was therefore placed in oxygen.
By the 3rd day of life, her cry was still weak
and sickly and she appeared limp and
apathet-ic. Her eyes tended to remain partly closed with little movement of the lids. Over the next
day her condition remained unchanged. She
continued to lie limply in her crib, her face relatively expressionless and her cry weak. Regurgitation and intermittent cyanosis per. sisted. She had voided daily but had had only 3 stools since birth. On May 27, 4 days after birth, she was transferred to the North Shore Babies Hospital, on the service of Dr. W. Randal Bell, for further treatment.
On admission the patient was extremely limp, having a “flattened out” appearance as she lay in her crib. Her neck and extremities appeared almost toneless. When her body was turned to one side, her head maintained its previous position. She would lie motionless in the posi-hon in which she had been placed. The baby
was apparently unable to move her arms and
legs, even in response to painful stimuli. Her
face was mask-like and she whined weakly
unable to suck. The head was held turned
toward the left as previously described. An
accumulation of clear mucoid secretion was
present in the posterior pharynx.
Respira-tory excursions were bilaterally symmetrical
and adequate. The lungs were clear to
per-cussion and auscultation. The heart and
ab-domen were not remarkable. Deep tendon
re-flexes could not be elicited. The Moro, tonic neck reflex and clonus were absent. A chest
film was interpreted as normal.
Shortly after admission the patient became
quite cyanotic. Much mucus was obtained by
suctiomiimig and she was placed in oxygen with
improvement in her color. She had no evidence
of a gag or cough reflex. A lumbar puncture
amid subdural taps were normal as was the
usual blood cytology. Because of her inability
to handle her secretions she was given
paren-teral fluids and placed on prophylactic
peni-cillin and streptomycin.
Gavage feedings were started on the 2nd
day. Frequent suctioning was still necessary
because of the excessive mucus present, and
regtmrgitation of feeding persisted. In view of the
mother’s history of myasthenia gravis, the
diag-nosis of transitory myasthenia was considered
and plans for a test dose of neostigmine were
made.
About 3 hr. after her evening feeding, the
patient, still in oxygen, was noted to be
cyanot-ic, and her respiratory excursions were feeble.
She was seen within 5 mm. at which time she
was markedly cyanotic and respirations had
apparently ceased. The heart sounds were
distant and the rate was slow. A moderate
amount of mucus was obtained by suction,
artificial respiration was begun, and 1 ml of
caffeine sodium benzoate was given
intra-muscularly with no response. The patient was
then given 0.5 ml of a 1 :4000 solution of
neo-stigmine methyl sulfate subcutaneously. When
no change was observed over the next 3 or 4
mm., artificial respiration still being continued
she was given 1.0 ml caffeine intracardially as
a terminal measure. Shortly thereafter the
heart sounds became stronger and more rapid
and a few minutes later gasping irregular
res-pirations began. These soon became regular
and the baby’s color improved. About 9 mm.
after the neostigmine had been given, the baby
suddenly gave a lusty cry and began to move
her extremities. Her muscle tone was better
than at any time since admission. She now
re-sponded to painful stimuli by withdrawal move-ments accompanied by vigorous crying and her face no longer appeared mask-like. This marked the first time since admission that a vigorous cry or movements of the extremities had been noted.
Six hours after the initial neostigmine in-jection she received a 2nd injection of the same strength which seemed to maintain her im-provement. It was now noted that she could
wrinkle her forehead and was making weak
sucking motions. An attempt at oral feeding,
however, again resulted in regurgitation
al-though the patient now was able to take
sev-eral swallows. A gastric lavage was done amid
a moderate amount of mucus obtained. She was then placed on gavage feedings of sugar solution every 3 hrs. with 3 mgm. neostigmine bromide added to each feeding. The majority
of these feedings were regurgitated in part
with-in to 1 hr. after gavage although her
im-proved activity, cry, and muscle tone were
maintained. Parenteral fluids were given as needed.
The presence of a moderate, though persist-ent, diarrhea associated with the neostigmine
therapy suggested that the continued
regurgi-tation at this point might be due to overdosage
with this drug. Accordingly, on the 4th hospital
day the dosage was reduced to 1 .5 mgm. every
3 hrs. given in an evaporated milk formula by
gavage. When regurgitation persisted, the time
intervals between doses was increased to every other feeding, the total daily dosage being held
at 12 mgm. Since regurgitation seemed more
frequent following neostigmmne, and since the
baby’s activity seemed normal, all neostigmine
was discontinued on May 31, the baby’s 8th
day of life.
Over the miext 14 hrs., the patiemit’s features became more expressionless and her cry be-came weak and whining. Regurgitation, how-ever, was absent. She took and retained 3 gavage feedings well but at the time of the 4th
feeding was found to be limp, with poor color
and a very feeble cry. She was suctioned and
a large amount of mucus was obtained. Shn
was then given 3 mgm. neostigmine bromide by gavage. Over the next 3 hr. her color and
activ-ity improved and her cry again became lusty.
A 2nd 3 mgm. dose was given in 6 hrs. follow-ing which the dosage was reduced to 1.5 mgm.
every 6 hrs. From then on, she continued to do
sub-sided. Breck feedings were started on the 10th
day of life and nipple feedings on the next day
at which time antibiotics were discontinued.
Neostigmine was again discontinued on her
20th day of life. Aside from a slight decrease in
her activity over the next 24 hrs., no further
signs were noted. She was discharged on June
23, her 31st day of life, at which time her
weight was 3.4 kg. and she was apparently normal. Her discharge was somewhat delayed
by a mild cystitis which responded to
chemo-therapy. She has continued to do well at home.
This case presents a number of interesting
features:
1. Although the mother developed sym-toms of myasthenia gravis during her third
pregancy, she showed no progression of her illness until after delivery. She then grew steadily worse until her last pregancy,
dur-ing which her condition again remained un-changed. Following delivery a temporary
improvement was noted.
2. During the seventh and eighth weeks
of her last pregnancy the mother received
100 mgm. ACTH daily for 12 days. There was no apparent ill effect on either fetal de-velopment or on the pregnancy itself as a
result of this treatment.
3. Neostigmine was a life-saving drug for
this patient. This case emphasizes the
dan-ger of delaying the diagnostic test with this
drug. It is also apparent that once the diag-nosis is established, continuous treatment is indicated and cessation should be gradual
since sudden withdrawal of neostigmine
may jeopardize the life of the baby.
4. Despite the initial severity of the
ill-ness, the infant became symptom free in
three weeks and has had no recurrence to date.
CASES 3 and 4 (Baby Girls S. B. and C. B.,
Transitory Myasthenia):
The mother of the 2 infants whose cases are presented below, Mrs. E. B., has been under
the care of Dr. Henry Viets of the
Massachu-sctts General Hospital since 1945. Data on the 1st infant, born in 1944, was obtained from the delivery and post-natal records of the hospital of birth, Pittsfield General Hospital, Pittsfield, Mass. For the remainder of the data
we are indebted to Doctor Viets. Family history was non-contributory.
The mother’s illness began in May, 1942, at the age of 19, with weakness in her legs. This lasted about 2 mos. and was followed by a 3 mos. remission. Her weakness then returned
along with diplopia as a new symptom. In
February, 1943, the diagnosis of myasthenia
gravis was made and the patient was started on oral neostigmine, 15 mgm. 6 times daily. She continued on this dosage throughout both her pregnancies.
In December, 1943, the patient was married and shortly thereafter became pregnant. Thern baby was a breech presentation and since the mother had a small pelvis she was delivered by Caesarian section at the Pittsfield General Hospital in December, 1944.
On admission to the nursery, the baby, S. B.,
a female, seemed drowsy and was whining.
Birth weight was 3.1 kg. Physical examination
was not remarkable aside from a receding jaw.
She was placed in a heated crib and given oxygen. She was listless and never very active.
She never cried or seemed to be hungry. The
infant was unable to nurse and consequently had to be tube fed. At 3 days of age she seemed to have difficulty in swallowing. Later that same day she became very cyanotic. A chest film at this time was not remarkable although the thymus was enlarged. On physical examina-tion the heart and lungs were normal and good aeration was present throughout. Her condi-tion remained about the same until the 20th
day of life when respiration ceased.
A post-mortem examination did not reveal the cause of death. The anatomical diagnosis
was fetal atelectasis with passive congestion
of the lungs, slight hyperplasia of the thymus,
and passive congestion of the liver.
Following her delivery, the mother had a slight temporary memission but her symptoms soon grew worse and she again required the
same daily dosage of neostigmine as before.
In 1945, she became pregnant for a 2nd time and in May, 1946, again gave birth to a full-term female infant, C. B., in the same hospital
as before. This baby showed typical signs of
myasthenia gravis at birth. It was limp, had a
weak cry, and was unable to suck. The diagno-sis was suspected by Doctor Viets and a neo-stigmine test advised. Response to this medica-tion was prompt, all signs of the myasthenic
maintenamice doses of neostigmine and these
were conservatively continued by her family
physician for 3 mos. The infant remained well
when treatment was discontinued. She has been
followed at periodic intervals since that time
and at 5 yrs. was living and well with no
re-currence of any signs of myasthenia.
During this pregnancy the mother showed
ho change in the status of her illness.
Follow-ing delivery her condition also remained
un-changed.
The above two cases present the following
points:
1. The onset of the mother’s myasthenia preceded the birth of both her infants.
2. The first infant presented typical signs of severe myasthenia at birth. Over the fol-lowing weeks, her condition showed little change. The diagnosis was unsuspected, she
received no specific therapy, and died at 20
days. A post-mortem examination revealed
no ascertainable cause of death, a finding
consistent with the diagnosis of transitory
myasthenia of the newborn.
3. The course of the second infant, who presented a similar picture at birth, further strengthens the evidence for this diagnosis
in her sibling. This time the condition was suspected and confirmed by a neostigmine
test. The baby was then placed on
mainte-nance therapy with this drug with continued
improvement. She has remained well for
five years despite cessation of treatment at three months.
4. The mother’s illness was unaffected by her pregnancies aside from a slight
tern-porary remission following the birth of her
first child.
All infants born of myasthenic mothers
should be closely observed for signs of
transitory myasthenia during the first few
day of life. While all of the reported cases
have been relatively severe, many mild cases with spontaneous recovery undoubtedly
occur. It is not unlikely that the signs shown
by many such patients have been attributed
to birth trauma, anoxia, or cerebral damage.
Once recovery occurs, the diagnosis of
tran-sitory myasthenia can no longer be
con-firmed. The presence of a relative
hypo-tonia, a weak cry, or inability to suck in any such infant should be regarded as an in-dication for a neostigmine test before any other diagnosis is considered. The adoption
of this routine should disclose many further cases of this syndrome since the condition
seems to be much more common than the
literature would indicate. The following
history of a myasthenic mother, delivered at the Boston Lying-in Hospital illustrates this
point.
CASES 5 and 6 (Baby Girl H. and Baby Boy H.,
Probable Transitory Myasthenia):
The mother of these infants, Mrs. E. H.,
was well until the age of 21 when she
de-veloped dysphagia, dysarthria and limitation
of eye movements 5 mos. after a miscarriage.
Several months later, in 1932, she was diag-nosed at the Massachussetts General Hospital
as myasthenia gravis and started on ephedrine
therapy. Her family history was
non-contribu-tory. In August, 1932, she again became
preg-nant. About 3 mos. later her symptoms dis-appeared and she remained in remission without treatment for the duration of her
preg-nancy. She was not allowed to go into labor
since her family physician felt she won’4 be unable to deliver normally. Instead, a Ca
smr-ean section was performed at her commumiity
hospital and a female infant, Baby Girl H.,
weighing 1.9 kg. was delivered. Hospital
records on this infant were not available. The
father when questioned in 1941, however,
stated that the baby, who was on artificial
feedings, took these poorly and as a result
re-mained in the hospital for 18 days. For a
month thereafter she had to be slapped and
otherwise stimulated to take feedings. She ate
so poorly that for a while hourly feedings were
necessary. She then began to improve
spon-taneously, developed well and had continued
in good health to that time.
Three months after delivery the mother’s
symptoms returned. In 1936 she was started
on neostigmine requiring 8 to 12 15 mgm.
tab-lets daily.
In April 1940, she became pregnant for the third time. Over the next 3 mos. her myas-thenia grew steadily worse. She required 15 to 18 15 mgm. tablets daily and even on this her
symptoms were not controlled. Toward the 4th
dur-ing the last 3 mos. she went into a partial
re-mission requiring only 1 or 2 tablets daily,
supplemented by ephedrine and potassium
gluconate.
On December 26, 1940, she was admitted to
the Boston Lying-in Hospital for an elective
section. At this time her neostigmine dosage
was increased to 15 mgm. 4 times daily as a
precautiomiary measure. On December 31 she
was delivered of a premature male infant
weighimig 2.2 kg. Followimig delivery the
mother’s condition remained unchanged.
The infant, Baby Boy H., was apparently
normal at birth. He cried immediately, the cry
was good, amid respirations were normal. When
examined by the pediatrician 2 hrs. later, he
was described as dusky in color and somewhat
limp. Much mucus was presemit in the pharynx
but air exchange was good. The baby was
placed imi oxygemi. The next day, the infant
was still limp and dusky and had a whimpering cry. The fomitanelles were not tense. Feedings
were started. At this time the baby’s general
condition was such that the diagnosis of
intra-cranial hemorrhage was suspected. On the 3rd
day of life the cry was still feeble. The baby
was inactive and sucked poorly. He was being
fed by cravage. His color had improved,
how-ever, and oxygen was discontinued. A chest
film showed a moderate atelectasis but was
otl . rwise not remarkable. Over the next few
‘.‘ eeks the infant showed only slight
improve-ment. He vomited more than would be expected
and still seemed unable to take the nipple.
Gay-age feedings were continued and parenteral
flu-ids were given. On the 17th day of life bottle
feeding was again tried but without success.
Two days later, however, the infant appeared
to have developed the ability to suck and took
a bottle well for the first time. He was bottle
fed thereafter without any difficulty. From
then on, he did well showing consistent weight
gain amid good activity. He was discharged on
the 30th day of life, weighing 2.5 kg. and
apparently normal in all respects. No further
data on this patient are available.
Both pregnancies which occurred after the onset of the mother’s myasthenia were marked
by a remission of her symptoms. In the 1st,
remission began after 3 mos. and continued
for 3 mos. after delivery. During the 2nd, a
relapse during the 1st trimester was again
fol-lowed by remission which persisted after term.
These infants are presented as probable cases
of transitory myasthenia although the evidence
for this diagnosis is admittedly inconclusive
in either case, more so in the first because of
the inadequacy of the data. Both infants were
premature and delivered by section. In neither
case could prematurity be eliminated as the
cause, at least in part, of the clinical picture presented. In the 2nd infant the question of intracranial hemorrhage was raised as well.
The neonatal courses of the 2 infants were not
dissimilar and both recovered spontaneously
without treatment, the 2nd within 3 wks. In
neither was the diagnosis of transitory
myas-thenia considered, this condition having not yet been reported at the time. These infants may
well represent unrecognized cases of this
syn-drome similar to others which may have been
overlooked in the past.
The cases which have been presented have many characteristics in common.
1. All were born to mothers suffering from myasthenia gravis during pregnancies.
2. All of the infants had signs of
myas-thenia gravis at birth or within the first few
days of life.
3. In those cases where neostigmine was
given, the response was dramatic. In at least
one this drug was life saving and in another
instance, an infant who did not receive this drug failed to survive.
4. The infants became symptom-free
during the period of neostigmine therapy
and remained so after treatment was dis-continued.
REVIEW OF THE LITERATURE ON TRANSITOR’
MYASTHENIA OF THE NEWBORN
A survey of the literature reveals 17
in-fants who showed signs of myasthenia gravis at birth or shortly thereafter. Of these, 12
were born to myasthenic mothers and re-sembled in their onset and course the cases which are reported here. Cases falling in this group have been variously designated
as neonatal myasthenia, myasthenia
neona-torum, transitory myasthenia of the new-born, myasthenia syndrome of the newborn
and transitory myasthenia neonatonum. This group is considered below. The remaining
represent cases of “true” congenital
myas-themiia and constitute a separate group
whose relation to transitory myasthenia will
also be considered.
The 12 previously reported cases of
transi-tory myasthenia neonatorum together with
the three presented in this paper are
sum-marized in Table I. Three probable or
pre-stmmiiptive cases, also reported here, were
purposely omitted from this table. The
histories of these 15 infants were reviewed
and the results are presented below.
The duration of maternal myasthenia at
the time of the infant’s birth varied from 10
months to 28 years. There was no
correla-tiomi between the severity of the infant’s
symptoms and length of the mother’s illness.
Many normal babies have been born to
myasthenic mothers, as previously noted. In
keeping with this observation, no direct
cor-relation was noted between the severity of
maternal myasthenia during pregnancy and
the baby’s signs at birth. The mother of
Case 6, for example, had only mild
symp-torus during her pregnancy and required
treatment on only two occasions, yet the
infant developed signs of myasthenia shortly
after birth.
Three mothers in this series, Cases 6, 7,
and 8, had had thymectomies prior to
preg-nancy. All three of the infants had signs of
myasthenia at birth. It may, therefore, be
concluded that thymectomy in the mother
appears to have no suppressive influence on
the occurrence of transitory myasthenia in
the infant.
All newborn infants of myasthenic
mothers should be closely followed with this
condition in mind. Three mothers, Cases 2,
9, and 14, again became pregnant after
giv-ing birth to infants with myasthenic signs.
Imi each instance the infant born of the latter
pregnancy also showed evidence of the
same condition. This indicates that this
syndrome is prone to recur. Once this
con-dition has been noted, infants born in
suc-ceeding pregnancies should be particularly
suspected and followed closely at term. A
newborn infant of any myasthenic mother
with a history of a previous pregnancy
re-suiting in a neonatal death of undetermined
etiology should also be more closely
ob-served for signs of this syndrome.
Four of the 15 cases occurred in Negroes. Six of the infants were male, seven female,
and the sex of two was not given. In 10 cases signs were noted the first day of life, in three they appeared within two days
while in one they were not observed until the third day. This delay has been attributed
to the persistence of the effect of maternal medication given immediately prior to
de-livery.
All 15 of the infants were described as
being limp, the limpness usually being generalized. This was one of the earliest
signs noted. The neck muscles in several
cases were described as toneless. One
pa-tient, however, still had fair muscle tone in
his extremities prior to treatment, on the
third day, and a second had shown no ap-parent weakness of his extremities at two
days when neostigmine was instituted.
All of the infants had difficulty with
feeding. This ranged from inability to suck to difficulty in swallowing. Several were described as unable to form their lips for nursing. In two infants, the first sign noted
was an apparent difficulty in taking the
formula, the other features of this syndrome
gradually also becoming prominent. The
majority required varying periods of tube
feeding even after being placed on neostig-mine.
The presence of a weak cry, often from
birth, was noted in 13 of the 15 infants. Two are described as never crying and one as apparently unable to cry before treatment
was instituted.
Regurgitation of feedings was reported as a common sign in 12 infants and the
pres-ence of excessive mucus in eight. These in-fants often had difficulty in handling their secretions and required frequent suctioning to prevent suffocation or aspiration pneu-monia. Several received prophylactic
In 11 cases a mask-like facies was
ob-served. This tended to persist even during painful stimulation. Occasionally the mouth
was held open due to the weakness of the
lower jaw. Several of the infants appeared unable to open their eyes fully, while three were noted as tending to keep their eyes open but with infrequent movements of the
lids.
Recurrent cyanotic episodes, occasionally requiring oxygen, were noted in seven
in-fants. These episodes were associated in
some cases with shallow respiratory
excur-sions, in others with regurgitation and in-ability to handle secretions.
All of the signs noted were effectively controlled when neostigmine therapy in adequate dosage was imistituted.
The thymus has been implicated by num-erous authors in the pathogenesis of my-asthenia gravis. Four of the infants had normal thymus glands by x-ray, one, Case 5,
was suggestively enlarged, and Case 1 and 14, both of whom died, were reported at post-mortem to have mild hypertrophy of
this gland with hyperplasia of the thymic corpuscles. No data were available on the remainder of the patients.
In only three cases, 6, 8, and 13, were data available on fetal activity prior to term. In all of these fetal movements were described as miormal. These mothers,
how-ever, were either in partial remission or on
therapy during this period.
Nine of the 15 cases received adequate
treatment with neostigmine, and all nine
re-covered. Of the remaining six, two cases,
3 and 10, recovered without any specific
treatment and a third, Case 9, who received
only two doses of neostigmine, also
re-covered, all myasthenic signs subsiding over the first few weeks of life. The remaining three received inadequate or no treatment
and died. The first of these, reported by Strickroot et al.,12 had shown a dramatic re-sponse to neostigmine but relapsed when
the drug was discontinued for eight hours following two days of therapy. Treatment was reinstituted with apparent good
re-sponse and the infant took a feeding well but 45 minutes later suddenly became cyanotic and died despite further neo-stigmine given parenterally and other meas-ures. Post-morten showed congestion of various organs, right adrenal hemorrhage, petechial hemorrhages in the brain and
patchy atelectasis. The remaining deaths, Cases 2 and 14, occurred in untreated
in-fants. Post-mortem examinations on these patients revealed no specific cause of death.
In most of the cases reported, the diagno-sis of myasthenia was confirmed by noting
the response to a test dose of neostigmine, given either parenterally or by gavage. Par-enteral dosage ranged from 0.05-0.125.
mgm. neostigmine methyl sulfate given either intramuscularly or subcutaneously while the oral dosage varied from 1.0-3.75 mgm. neostigmine bromide given by
gay-age. A dose of 0.125 mgm. neostigmine
methyl sulfate given subcutaneously is recommended as a test dose in newborns
where the diagnosis of either transitory or
congenital myasthenia is suspected (0.5 ml of the standard 1 : 4000 neostigmine solu-tion). It is important that an adequate test
dose be given for otherwise a detectable re-sponse may not be elicited in all cases. Re-sponse to this drug occurs within 10 minutes when given parenterally, and in about 30
minutes when given by mouth. Since the parenteral route is about 30 times more
effective than the oral route, an oral test dose of 3.75 mgm. is satisfactory. A syringe containing 0.1-0.2 mgm. atropine should be available to counteract any undesirable side reactions due to neostigmine or may be given simultaneously although in none of
the cases reported was any difficulty en-countered with neostigmine alone.
Once the diagnosis is established the in-fant should immediately be placed on maintenance therapy since death may result
unless intensive and adequate treatment is
instituted. The average duration of
after a few doses, two recovered without treatment, and several were treated for one
to four months. As in the adult, the severity of symptoms and response to therapy should
determine the size and frequency of the maintenance dose. The range of oral
main-tenance dosage has varied from 6 to 24 mgm. daily, given in divided doses every three to six hours. This may be given by gavage if necessary or added directly to the
day’s formula. Parenteral therapy has also
been used with dosage ranging from 0.3 to over 1 mgm. neostigmine methyl sulfate
daily, again given in divided doses.
Treatment, once begun, especially in the
more severe cases, should be continuous and terminated only gradually. Abrupt cessa-tion of neostigmine supplies no additional information as to the diagnosis and may jeopardize the life of the patient. In Case 1,
cessation of therapy after two days was fol-lowed by relapse after eight hours. Case 5 relapsed on the ninth and eleventh days
after 12 and 39 hours respectively without neostigmine. Similar relapses were reported in several of the other infants when the drug
was abruptly discontinued prematurely.
Although Geddes and Kidd2#{176} supple-mented neostigmine with ephedrine for the maintenance of their patient, neostigmine
alone, if used in adequate dosage, is satis-factory. The appearance of undesirable
re-actions such as severe diarrhea, vomiting, and bradycardia may be controlled by use
of small amounts of atropine as needed. Other signs associated with neostigmine toxicity include muscle fasciculation,
pro-fuse perspiration, salivation, lacrimation,
nausea, miosis, and loss of accommodation,
all of which are relieved by atropine. Atro-pine does not impair the action of neostig-mine on the skeletal muscle since it blocks
only the muscarinic actions of the drug.
The transitory nature of this syndrome is
shown by the fact that none of the patients
has had any recurrence of myasthenic signs
once they have subsided although several
have been followed for over five years. An
electromyogram, done on the 74th day of
life on Case 8 showed no evidence of myasthenia gravis. A second infant, Case
12, was tested with curare after the method of Bennett and Cash6 on the 67th day of
life and a negative test was obtained. This is the first of the reported infants with this
syndrome so tested and the negative test
further supports the hypothesis that once
recovery in this condition occurs, it is corn-plete. In view of the potential dangers as-sociated with the use of such drugs as
curare or quinine in myasthenia, however,
especially in infancy, such tests do not
ap-pear to be indicated as routine. Continued periodic observation on these patients seems preferable, at least during the first several
years of life.
Myasthenia Gravis and Pregnancy
The course of myasthenia gravis during
pregnancy and following delivery has not
been marked by any consistent pattern. Re-ported cases have shown remissions, regres-sions and no changes both before and after term. In some cases both remission and
re-gression have occurred during the same pregnancy. Kennedy et al.2 reporting on
seven patients during 12 pregnancies noted that there was aggravation of the symptoms during five of the pregnancies although in
four of these improvement occurred after delivery or after weaning of the child. No
change was noted during or after the re-maining seven pregnancies. Laurent25 re-ported a patient in whom the first two preg-nancies were accompanied by remissions
although five subsequent pregnancies, none of which came to term, were associated with relapse. In eight patients representing
nine pregnancies reported by Viets et 2
six showed a complete remission of symp-toms beginning during or shortly after the first trimester with gradual relapse follow-ing delivery. Harris et al.27 reported a pa-tient whose symptoms progressively became so severe that an elective section was done. This patient showed no improvement
376
mother and had shown no symptoms by one
year after delivery.
A review of the cases presented in Table I and of the others considered in this paper
revealed that data were available on the
course of the maternal myasthenia during
17 pregnancies representing 12 mothers.
During seven of the pregnancies the ma-ternal symptoms remained unchanged. Five
pregnancies were associated with
exacerba-tions of varying degrees. Of these, one, Case
4, improved on a new medication after the
fourth month of pregnancy, amid a second,
Case 11, became worse only during the last
four months. In one, Case 13, symptoms of myasthenia were first noted during the sixth
month of pregnancy. The remaining five
pregnancies were marked by remissions of
varying degree.
Data were also available on the course of the maternal myasthenia following
de-livery in eight mothers representing 11
preg-nancies. In six cases no change was noted.
Three were associated with some
improve-nient, although during one of these, Case
11, the improvement was preceded by a
re-lapse of one week’s duration at term.
Dur-ing the remaining two pregnancies, the ma-ternal myasthenia grew worse, one patient, Case 8, dying at home on the 23rd post
partum day.
It is of interest that an exacerbation
dur-ing one pregnancy was not necessarily
indic-ative of a similar course in subsequent
pregnancies.
The data presented confirm the previous
observations that pregnancy exerts no
con-sistent effect on the course of maternal
myasthenia.
CONGENITAL MYASTHENIA GRAvIs
Several cases of myasthenia gravis
oc-curring in relatives or members of the same family have been reported.’5’ 28. 29 The
observations that certain infants born of
myasthenic mothers showed signs of this
ill-ness at birth were at first interpreted as
further evidence for the possible hereditary
nature of this disease. It was soon shown,
however, that this condition was transient,
and that such patients should, therefore, not be designated as having congenital my-asthenia gravis.
Five cases have been reported, however, of infants who showed myasthenic signs at
birth and were born of non-myasthenic mothers (see Table II). The persistence of these signs and the subsequent clinical
course indicated that they all had “true” or non-transitory myasthenia gravis. These
cases have, therefore, been designated
as congenital myasthenia. A probable
sixth case, initially diagnosed as cerebral
palsy, but confirmed as myasthenia by a therapeutic test with neostigmine at three
years has recently been described in the
non-medical literature.32 An additional case
is presented below and the features which
differentiate this group from transitory myasthenia are considered.
CASE G. D., female: Born May 23, 1946. First
seen at the Children’s Medical Center, Boston, at the age of 2 10/12 years.
This patient was the result of the mother’s
2nd pregnancy, the 1st having terminated in a
still birth at 7 mos. following an episode of bleeding. The parents, first cousins, were living and well. Family history was non-contributory although the mother had an allergic history. There was no family history of myasthenia
gravis. The mother stated that fetal activity
began at about 4 to 5 months and that the baby
was very active. The patient was delivered by
Caesarean section following 24 hrs. of
nonpro-gressive labor. The reason for the dystocia is
not known. The baby, a female, weighed 2.7 kg. at birth and was 10 days post mature. At birth, she was noted to have drooping eyelids which made her eyes look small. This persisted, giving the infant an appearance of always being sleepy. The infant ate and gained well and was discharged at the usual time.
At home, she appeared to feed well and her
activities seemed normal. It was noted,
how-ever, that her voice and cry appeared weak.
She was able to lift her head before 1 mo., sat
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when walking, apparentl\’ so she could see
better. The mother then became quite con-cerned about the baby’s drooping lids, and,
prompted by neighbors who said the baby
al-ways looked sleepy, consulted her pediatrician
who reassured her. The mother had also noted
that the baby would open its eyes widely after
awakening in the morning or after a nap but
tlmt after 20 or 30 mm. the eyelids would begin
to droop, remaining that way during the day.
The infant did not appear to have as much
energy as her cousins who were about the same
age although no specific weakness of the
skeletal muscles was observed. There was no
difficulty in eating, chewing, or handling
secre-tions. At 1 yr. she could utter single words and
at 2 yrs. could speak in sentences but her
speech was indistinct and her voice weak thus
makimig it hard to understand her.
At 2 8/12 yrs. (January, 1949) she was
re-ferred to an ophthalmologist because of the
persistence of her ptosis. Myasthenia gravis
was suspected and the patient was given a test
dose of neostigmimie. Shortly after the injection,
her eyes opemied widely, the ptosis
disap-peared, amid she became considerably more
lively, playing and running around in the
office. She was placed omi a maintenance dose
of neostigmine bromide, 3 tablet (7.5 mgm.)
every :3 his. durimig the day for a total of 2
tablets daily alomig with 3 neostigmine
injec-tions weekly (dosage not known) receiving a
total of 12 imijections. She received oral
medi-cation for 1 mos., during which time she was
more lively, her ptosis disappeared and her
general condition seemed much improved. At
this time, however, she was referred to the
Children’s Medical Center at her parents’
re-(luest for comifirmation of the diagnosis.
Neostig-mine was discontinued 1 day prior to
admis-sion.
Examination omi admission, March 10, 1949,
revealed a small well-nourished female in the
10th percentile for length and 3rd percentile
for weight. She had a weak cry and a nasal
voice. Marked bilateral ptosis was present. The
extra-ocular muscles were normal. Generalized
muscular weakness seemed to be present in that
the patient struggled only weakly against the examiners but no weakness of specific skeletal muscles could be ascertained. The remainder
of the examination was negative. Deep tendon
reflexes were normal.
During her hospital stay she showed no
weakness in chewing or swallowing. When
awakened from sleep, she was able to hold her
eyes wide open for about 5 mins. before ptosis
began. A test dose of 0.25 mgm. neostigmine
methyl sulfate was given intramuscularly.
Be-fore the injection she appeared drowsy,
lethar-gic and her eyes were almost entirely closed.
Six minutes after receiving the drug, her eyes
opened widely and she was much more active.
At 15 mm. she began to cry heartily and much
more loudly than at any time since her
ad-missiomi. The neostigmine effect lasted
approxi-mately 3 hrs. as judged by the return of the
ptosis and loss of strength of her voice.
Chest films and fluoroscopy revealed no
ab-normalities. There was mio evidence of thymic
enlargement or of any mediastinal mass. The patient was discharged on neostigmine,
j tablet 3 times daily, her parents planning to
return her to the care of the family physician.
Whemi last heard from, several months after
discharge, she was still doing well on this medi-cation.
In this case the features to be noted in-dude:
1. The absence of myasthenic signs in the
mother.
2. The presence of ptosis at birth and the
weak cry.
3. The gradual appearance of other signs
of myasthenia such as indistinct speech and
easy fatigue.
4. The persistence of this condition into
childhood.
5. The response to neostigmine.
REVIEW OF THE LITERATURE ON
CONGENITAL MYASTHENIA GRAVIS
The five previously reported cases of
con-genital myasthenia gravis along with the case presented in this paper are summarized in Table II. A review of these cases
mdi-cates that all were diagnosed in retrospect, the patients ranging from two months to eight years at the time the diagnoses were made. None of the mothers had any his-tory suggestive of myasthenia gravis. Family histories were also non-contributory, except
with congenital bilateral ptosis, but
un-fortunately neither was available for study.
Levin15 tested the mother of his two patients
with quinine to rule out the possibility of
latent myasthenia. Mackay3#{176} using
tubo-curarine, similarly tested both the parents
and his patient’s binovular twin, also with
negative results. This case is of interest in
that only one of non-identical twins was
affected. Several similar cases involving
only one of binovular twins, but with onset
of symptoms in later life, have been
re-ported’’ 22. but no data are available on the
occurrence of this condition in identical
twins.
In two cases fetal activity was described
as poor, a finding interpreted as indicating a
prenatal inception of this disorder.15 In the
only other case in which data were
avail-able, the author’s, activity was described as normal.
The number of infants reported are too
few to allow any conclusions to be drawn
concerning the sex incidence of congenital
myasthenia.
The course of the reported cases can be
seen to differ markedly from that of transi
tory myasthenia of the newborn. In no
instance was the onset marked by the sever-ity seen in the latter condition or was the necessity for treatment during the neonatal period as urgent. In all of the reported
cases the diagnosis was made only in
retro-spect. Bilateral ptosis was common to all
six of the infants, being present in four
during the neonatal period and appearing
somewhat later in the remaining two. Other
prominent neonatal features included a weak cry in four and poor feeding in three. Two were described as limp or weakly. At
this time, little or no limitation of other
ac-tivity was observed, in contrast to the more
severe generalized involvement seen in
tran-sitory myasthenia during the first few weeks
of life. As these infants grew older, however, various signs of muscular weakness such
as indistinct speech, easy fatigue, inability
to run, and frequent falls gradually also
made their appearance. In all but Case 3, a
gradual progression of the myasthenic signs
was noted. All of these patients were bene-fited by neostigmine and with one exception
required it for continued amelioration of
their disease. The exception, Case 3, showed
spontaneous improvement at six years
with-out treatment, the signs persisting to only
a mild degree. On the basis of the reported
cases, a characteristic feature of congenital
myasthenia which distinguishes it, at least
superficially, from cases with onset in later
life (acquired myasthenia) is the greater tendency toward symmetry in the visible
pattern of muscular weakness. In acquired myasthenia, especially in adults, the in-volvement more often seems to be asym-metric, probably as the result of differences
in the development of various muscle groups involved.
To date, no case of either congenital or acquired myasthenia gravis has been re-ported in any child born of a myasthenic
mother. Conversely, all children with signs of myasthenia at birth and born to mothers with this disease have recovered completely
following neonatal survival, so far as we have been able to determine.
No case of congenital myasthenia with an onset as severe and generalized as that
seen in transitory myasthenia has yet been
reported with the possible exception of Case 5. Since fulminating cases with onset in
childhood have been noted, however, it is not unlikely that similar cases of congeni-tal myasthenia may occur.
Any infant with unexplained limpness, inability to suck, a feeble cry, and especialYy
with evidence of cranial nerve palsies mani-fested by ptosis, ocular paralyses, mask-like facies and inability to handle secretions should be given a test dose of neostigmine parenterally to rule out the diagnosis of
myasthenia gravis, either transitory, con-genital or acquired.
DIscussIoN
According to the present concept of neuromuscular transmission as applied to
skeletal muscles, the arrival of the nerve
im-pulse at the end organ results in liberation
substance then combines with a ‘receptive substance” within the muscle cell, Setting off the chain of reactions which results in
con-traction. An enzyme, cholinesterase, present at the site of acetylcholmne release, rapidly
hydrolyzes the acetylcholmne during the
fractory period of the muscle and thus
limits the duration of its action.
While the etiology of myasthenia gravis is
unknown, several hypotheses have been proposed to account for the weakness of the striated muscles which is the chief char-acteristic of this disorder. Walker, in 1934,
on the basis of the many similarities
be-tween the myasthenic state and partial curarization, was first led to try the effect of physostigmmne3 and later of neostig-mine,3 both curare antagonists, in the treat-ment of this disorder. The marked response
to these drugs suggested to her the presence of some abnormal inhibitory substance with
a curare-like action in this disease. Other
ex-planations, however, have also been pro-posed. The more prominent of these
hy-potheses are considered below.
1. The symptoms of myasthenia gravis
are the result of an abnormally high
con-centration of cholinesterase at the myo-neural junction in striated muscle. This
re-suits in the destruction of the acetylcholine released as the result of nerve impulses be-fore it can initiate sustained muscular
con-traction.
Studies, however, have shown that the
chohinesterase activity of myasthenic muscle is similar to that of normal muscle.’ u, 36
This is true for serum cholinesterase (pseu-do-cholinesterase) as well.1’ ‘ 38 The
evidence, therefore, appears conclusive that the defect in myasthenia gravis is not the result of abnormally high concentrations of chohinesterase with resultant rapid destruc-tion of acetylcholine.
2. A second hypothesis suggests that the
symptoms of this disorder are due to a
decrease in acetylcholmne production at the myoneural junction.
The evidence favoring this hypothesis is
more convincing. Both Torda and Wolff39
and Trethewie and Vright4 found that the
synthesis of acetylcholine by nervous tissue
in vitro was greatly inhibited by addition of serum from myasthenic patients. They concluded that serum from patients with
this disorder provided an unfavorable medium for the synthesis of acetylcholmne and suggested that similar defects in
acetylcholmne synthesis were present in vivo
iii myasthenia gravis.
Neostigmmne is an anticholinesterase and acts by combining with cholinesterase, thus preventing the action of this enzyme on
acetylcholmne. Since cholinesterase activity
appears to be normal in myasthenia, the
re-sponse to neostigmine in these patients is consistent with a deficiency of acetylcholine at the myoneural junction, the neostigmine potentiating the acetylcholine activity to
more normal levels.
Further support of this hypothesis is pre-sented by Harvey and Lilienthal.4’ They point out that acetyicholmne given intra-arterially in low concentrations to normal
subjects has a stimulating effect on skeletal muscle but depresses in high concentration.
Neostigmine when given mntra-arterially to a
normal subject produces a local paresis at-tributed to the accumulation of a depressing
concentration of acetylcholine, since cholin-esterase activity is inhibited. In the my-asthenic patient, however, intra-arterial neo-stigmine results not in paresis but in re-turn of muscle power. This suggests that despite the potentiating action of neostig-mine, insufficient acetylcholine is present to produce a depressant effect.
3. A third hypothesis suggests the
pres-ence of some abnormal inhibitory substance or metabolite with a curare-like action in this disease.
Several workers have presented evi-dence indicating that such a substance exists.’4’ 42 The occurrence of transitory
myasthenia of the newborn is also consistent with the concept of a circulating inhibitory factor in this disorder, this substance
