[CINE
Minnesota Medicine
Journal of the Minnesota State Medical Association, Southern Minnesota Medical Association, Northern Minnesota Medical Association, Minnesota Academy of Medicine and Minneapolis Surgical Society
Volume 34
December, 1951
Number 12
THE CHANGING MOLE
S. WILLIAM BECKER, M.S., M.D. Chicago, Illinois
HE threshold of suspicion for malignant
disease is probably lower now among Ameri- can physicians and laymen than at any previous time. There is more study and discussion of malignant processes. Much of this zeal springs from the interest and activity of organizations such as the American Cancer Society, which is devoting a great deal of energy in obtaining financial support, to be allocated to worthwhile projects in research institutions. The federally supported National Cancer Institute has for years carried out research in the field of malignancy. Many universities and hospitals have maintained cancer clinics, at which the skill and knowledge of physicians in various fields of medicine are pooled in the interest of the patients with possible malignant disease. There are many smaller or- ganizations dedicated to research and treatment of cancer,
There is most interest in real cancer (carcinoma ), including cancer of the skin, because of its frequency, but malignant neoplasia of other tissues has by no means been neglected. We are interested today in a neoplasm which is less fre- quently seen, namely, melanoma, and, specifically, melanoma originating in the skin. Its infrequency is both fortunate and unfortunate; fortunate for our patients, but unfortunate for physicians, be- cause of limited opportunity for becoming familiar with it, so that, at present, the threshold of suspicion is maintained at too high a level. Miescher found that, at the University of Zurich, Switzerland, cutaneous carcinoma outnumbered
From the Section of Dermatology, Department of Medicine, University of Chicago.
Presented at the annual meeting of the Northern Minnesota Medical Association, Virginia, Minnesota, August 24-25, 1951.
Decemser, 1951
melanoma 20:1. In areas with a high proportion of sunshiny days and a correspondingly greater incidence of cutaneous carcinomas, the ratio would undoubtedly be much higher.
For our purpose today, the word “mole” used in the sense of a pigmented nevus, along
with its non-pigmented relative, the non-pig- mented nevus. By “changing mole” we mean a nevus exhibiting clinical and/or microscopic
alteration leading to malignant melanoma, com- monly known simply as “melanoma.” A_ pig- mented nevus is best considered as a benign tumor of pigment-forming cells, which are known as melanoblasts. Melanoma is a malignant tumor of pigment-forming cells. These cells originate from the neural crest during embryonic life, from which location they wander out to the skin, the eyes and the pia mater about the medulla. Melanoma which has originated in other parts of the body must have arisen from misplaced melanoblasts, or may constitute a misnamed tumor, such as “melanoma” of the adrenal gland, which most authorities believe is not a true melanoma. Melanoma resembles nervous tumors of a malignant nature in its resistance to roentgen and radium irradiation, in contrast to cancer of the skin, which is relatively radiosensitive.
Pigmented Nevi
Pigmented nevi are among the most common of benign tumors. Pack** found that each adult per- son has an average of twenty such lesions. They are located more frequently on the face, neck, trunk and upper extremities, infrequently on the genitalia and feet, and are almost unknown on mucous surfaces. Melanoma, on the other hand, is most frequent on the face, genitalia and feet,
1153
THE CHANGING
and does occur, but less often, on mucous surfaces. This contrast between the sites of predilection for nevi and melanoma makes one wonder whether such malignancy does originate most frequently in nevi, as has been stated by so many authors.
Pigmented nevi vary from smooth brown macules through elevated papular tumors to large hairy lesions covering much of the body (bathing trunk nevus). The mole which becomes malig- nant is usually the smooth brown lesion. Elevated nevi, with or without hairs are not common offenders. However, extensive moles have be- come malignant, even before puberty. They also are often associated with melanosis of the pia mater about the medulla, which may result in benign or malignant tumor of the area, with symptoms of brain tumor.
Microscopically, according to Lund and Stobbe’? a young nevus consists of nevus cells, containing a varying amount of melanin, in close apposition to the epidermis, with or without unpigmented cells deeper in the dermis. In the older nevi, all cells may be deep in the skin. This variety of nevus is the one most frequently seen, and is the common mole of Traub and Keil.2* The nevus cells may be fusiform or oval, and resemble melanoblasts rather than epidermal cells. Nevi in which there is active multiplication of nevus cells at the epidermo-dermal junction are known as active nevi. The designation “junction type nevus,” frequently seen nowadays, includes quiescent nevi with nevus cells at the epidermo- dermal junction, active nevi with cells in the same location, and lentigo maligna; hence, both benign and malignant growths. Therefore it cannot be an accepted term. Some non-pigmented nevi re- semble neurofibromas.
Treatment of Nevi
The consensus is that moles at sites of irritation should be removed, preferably before puberty. Surgical excision is satisfactory, and is always indicated for nevi that are enlarging or becoming darker. My own preference* is for snipping off the superficial portion of an elevated quiescent nevus and cauterizing the base for a good cosmetic result. The removed portion is always biopsied, so that any malignant change can be determined. All excised tumors should be sent to the laboratory for biopsy.
1154
MOLE—BECKER
Acquired Nevi
Acquired nevi are those which appear after early childhood. A good illustration is the remark- able case of Ebert,® as follows:
Case 1—A boy, aged twelve, presented several hundred papules, first noted eight months previously on the covered parts of the body and the backs of the hands, with a predilection for the extensor surfaces of the arms, the buttocks and the posterior surfaces of the thighs. They were increasing in number and varied in color from flesh color to brown. Over a period of two years one of the lesions on the buttock became coal black and many others became black and assumed the appearance of ordinary pigmented nevi. Four years after first being seen, no new lesions were appearing. Some of the
original ones were brownish red and some were coal black.
Microscopic examination showed the tumors to be composed of cells having the appearance of young nevus cells, some of which were still in close association with the epidermis and others were in masses in the dermis. They were all strongly dopa positive, although very little melanin had formed as yet.
Mongolian Spot and Blue Nevus
Mongolian spots (sacral spots) and blue nevi are bluish macular or slightly elevated lesions con- taining pigmented melanoblasts in the dermis. Mongolian spots are present at birth in a large percentage of children of the dark races and tend to fade out over a few years. Blue nevi are smaller and darker and may appear at any time during early life. I have never seen melanoma develop in a blue nevus, and the reported cases of such development are not very convincing. Treatment of blue nevus is excision.
Precipitating Factors in Melanoma
The cause of melanoma is that of malignant disease in general, many etiologic factors of which are only imperfectly understood. Family history is almost unknown. The unusual reports of family incidence suggest that occurrence in more than one member is probably coincidental. Sun- light does not seem to be prominent as a pre- cipitating factor, although the common appearance on the face has been advanced in its support. Irritation appears to play a definite role. Daland and Holmes® reported the influence of trauma in seventy of 174 cases, Amadon* in eleven of twenty-seven cases. Herold*' reported the pro- minent role of trauma in African Negroes, in whom most melanomas originate on the soles,
MINNESOTA MEDICINE
an ba of re an
m pu pt re
sh
eS
unt ich ry
ore in- og nce
THE CHANGING MOLE—BECKER
— a ee ~
(H&E stain, high power).
following injury from sharp objects, such as thorns.
According to Scharnagel and Pack,’* puberty and pregnancy are periods of altered hormone balance which stimulates the formation and spread of melanoma. Spitz?’ called attention to the relative benignity of melanomas before puberty, and for this reason separated them from ordinary melanomas under the designation “juvenile melanomas.” The possible stimulating effect of puberty and the probable stimulation during pregnancy are illustrated in the following case
report (Ref. 4, Case 2):
Case 2.—A girl, aged sixteen, had always had a small pigmented nevus on her right shoulder. It had occasionally become tender because of irritation by a shoulder strap, had bled on occasions, and had been slowly enlarging. She presented a slightly elevated papule, brown in color, 3.0 by 5.0 mm. in size. The lesion was completely removed locally. Microscopic examination showed a superficial nevus, the center of which was composed of a solid mass of cells which was encroaching on both the epidermis and dermis. Diagnosis was made of early melanoma and the area was excised surgically. Seven years later, during pregnancy, a tumor was noted on
Decemser, 1951
- Sid ei ~*~ ? : tra te es ed oo ¥:
Fig. 1. Melanoma arising in nevus. Melanoma cells and lymphocytes are superficial and nevus cells are deep.
; tm er a ak oe re ae ae ae ee Lo
the opposite side of the thorax in the region of a lower rib. It was removed surgically and was found to be a partially pigmented melanoma, In order to avoid further stimulating effect of pregnancy, cesarean section was performed at the eighth month and a normal baby was delivered. During a subsequent period of over one year, no further signs of melanoma have been observed. However, to avoid stimulation of any possible remaining melanoma cells, she has been advised to avoid further pregnancy.
Melanoma from Nevus
Determination of the actual percentage of melanomas that originate in pigmented nevi is difficult. If accurate history reveals that a pig- mented lesion has been present since birth or early childhood, it must be assumed that a nevus existed. If both nevus cells and melanoma cells are found on section (Fig. 1), it is certain that a nevus has been present. Microscopic sections are not always adequate, because diagnosis is usually made on only a few sections, which may not show nevus cells if the melanoma has out- grown the nevus. Serial sections would be more informative.
1155
THE CHANGING MOLE—BECKER
Careful study has shown that melanoma can be proven to have originated in a pre-existing nevus in not over 25 per cent of instances. And even so, the actual malignant cells have their origin in normal melanoblasts at the epidermo- dermal junction rather than in nevus cells them- selves. Pathologic theory states that malignant cells do not arise directly from benign neoplastic cells. Daland and Holmes*® found that only 18 per cent of melanomas originated in pigmented
nevi. In specimens examined in the Dermato- -
logical Laboratory of the University of Chicago, about 23 per cent can be seen to originate from nevi. Miescher, at the University of Zurich, Switzerland, found such origin in 25 per cent of cases.
Lentigo Maligna
Clinically, melanoma originates in the other 75 per cent of cases as a brown macule, at first smooth and non-elevated, which was originally described by Johnathan Hutchinson as a “malignant freckle.” Dubreuilh translated this designation into French as “lentigo malign,” which in English is “lentigo maligna.” “Lentigo” means an acquired brown spot, and “maligna” denotes its malignant nature. Lentigo maligna appears after puberty, enlarges slowly and un- evenly, and shows various degrees of light and dark brown color. After a few months or years, serum exudes and, eventually, bleeding occurs. Later, a tumor forms, which may be pigmented or non-pigmented melanoma. The following case report is illustrative:
Case 3—A housewife, aged forty-nine, had developed a small dark brown spot on the lateral surface of the right ankle about four or five years previously. It
enlarged irregularly, and she had been referred by her -
family physician to a dermatologist one and one half years before being seen. He had advised observation. Three or four months ago serum oozed from the lesion and it later bled. She consulted a second dermatologist, who removed a specimen for biopsy. Microscopic examination (Fig. 2) showed pronounced round cell infiltrate in the superficial dermis. At the epidermo- dermal junction were large numbers of large, succulent, partly pigmented cells, which were working their way to the epidermal surface and also penetrating into the dermis. This is typical for lentigo maligna. When seen, she presented a geographic lesion 2.0 by 3.0 cm. in size, very slightly elevated, with a color varying in different parts from light to dark brown. The area was widely removed surgically and the defect was skin-grafted.
1156
Of course, it must be remembered that pig- mented nevi also enlarge as the person becomes older, become slightly darker and, if injured sufficiently, will bleed. A nevus in which melanoma has developed enlarges more rapidly, becomes more deeply brown or black, and tends to bleed on slighter trauma. Pigmented melanoma can only be diagnosed clinically in 50 per cent of cases. Biopsy is essential.
Non-pigmented Melanoma
Non-pigmented melanoma appears in a variety of forms. Some of them simulate verruca vul- garis, especially one that has been irritated or infected. The most common picture is that of a reddish, soft tumor which bleeds on trauma, and closely simulates granuloma pyogenicum. The following case report is illustrative :
Case 4.—A woman, aged forty-three, a farmer’s wife, had had a mole on her calf all her life. It had grown in the past two years and had bled after having been pecked by a chicken on two occasions. Clinical diagnosis was made of granuloma pyogenicum. The tumor was excised. Microscopic examination showed non-pigmented melanoma. Diagnosis of non-pigmented melanoma can only be made by biopsy.
How has the misconception arisen that most melanomas have originated in pigmented nevi. Several reasons seem apparent:
1. Lack of careful history. With the exception of the acquired variety, which is rare, nevi appear early in life.
2. Lack of careful clinical examination. Quiescent nevi can usually be differentiated from the more rapidly growing lentigo maligna or melanoma.
3. Failure to biopsy all tumors. This procedure is now considered a sine qua non for accurate diagnosis of melanoma. Biopsy is safe if adequate treatment is carried out as soon as microscopic diagnosis is made.
Clinical Course of Melanoma
The clinical course of melanoma is inclined to be regular. There is first of all relatively rapid local growth. There is at times local lymphatic extension appearing in the form of satellite lesions, ordinarily along the lymphatics draining the area. The regional lymph nodes will eventually become enlarged. Only biopsy will reveal the presence of melanoma cells in such nodes.
MINNESOTA MEDICINE
rei
dr; no of of
ap no
cu Si mi
Dr
ty il-
SiS vas ted can
ost Vi.
ion ear
on. om or
ure ‘ate late ypic
1 to pid atic llite ling ally
the des.
CINE
THE CHANGING MOLE—BECKER
: * “4 += B ; ’ ‘ :
~
Fig. 2. Lentigo maligna. Melanoma cells and lymphocytes are superficial. No nevus cells are present. (H&E
stain, high power).
Systemic dissemination will subsequently follow, with tumor cells appearing in practically any tissue of the body. The urine may become darkened (melanuria), and the entire body may become practically black (systemic melanosis). Ackerman! stated that 10 per cent of melanomas are first noted as metastatic growths in the regional lymph nodes. Further search ordinarily reveals a primary lesion or a history is obtained that a “mole” had been removed in the area of drainage. Selig’® reported removal of a metastatic non-pigmented melanomatous mass from the groin of a forty-seven-year-old woman. Careful search of the lower limb revealed no primary growth. Four and one-quarter years later, a painless ulcer appeared on the right heel, which also showed non-pigmented melanoma on biopsy.
Mucosal Melanoma
Melanoma may appear on any of the muco- cutaneous junctions or adjacent mucous surfaces. Since pigmented nevi are almost never seen on mucosal surfaces, the origin is from a blackish
DECEMBER, 1951
oo" fs ~~. ~~ a te Ree oie é eis /
macule corresponding to the cutaneous lentigo maligna. Spread to regional lymph nodes seems to appear somewhat sooner than from the cutaneous surface, possibly because of greater vascularity of the regions.
Treatment of Melanoma
Treatment of melanoma consists of removal. Various other therapeutic measures, such as roentgen and radium irradiation, administration of Coley’s fluid, colloidal lead, and various radio- active isotopes have been unsatisfactory. Soon after Willy Meyer and Halsted’ independently, in 1894, introduced the principle of dissection in continuity, i.e., removal of the breast, lymphatic channels and lymph nodes in one piece, the method was applied by Pringle’ to treatment of melanoma :
A girl, aged seventeen, presented a melanoma on the left forearm of two years’ duration. There had been no pre-existing mole. In 1898, a strip of tissue 2 inches in width was excised and the axillary lymph nodes were removed. They were found to contain metastatic tumor growth. She was again presented’? thirty-eight years
1157
THE CHANGING MOLE—BECKER
after operation, during which time she had had no recurrence. A second patient, a man, aged thirty, presented a melanoma, 3.0 by 4.0 cm. in size, of two years’ duration, on the left thigh, originating in a mole that had been present since birth. The primary growth was removed, along with a strip of tissue up to and including the lymph nodes as far as the bifurcation of the common iliac artery. Metastatic melanoma was found in the lower iliac but not in the upper iliac nodes. The patient was redemonstrated thirty years later,!? during which time he had had no recurrence.
The same principle of dissection in continuity was applied to malignancy of the rectum by Sir Ernest Miles** and to the vulva by Bassett.* It is useful for melanoma occurring in these regions. Pack, Scharnagel and Morfit’® stated that applica- tion of this method to treatment of melanoma requires considerable ingenuity, because the malignant melanomas are so variable in their location and drain into so many groups of regional lymph nodes. Pack’* has recommended an even more radical operation in some instances of ad- vanced melanoma of the extremities, namely, disarticulation at the hip or amputation of the arm and shoulder girdle, as the case may be. Many surgeons hesitate to perform such a radical opera- tion, even though they would not hesitate to amputate for sarcoma of the bone.
Prognosis of Melanoma
Prognosis of melanoma was formerly prac- tically hopeless, Boulay® in 1888 collected 191 cases from the literature, of which 152 had been operated on. From the clinical descriptions, the process was usually already far advanced and hopeless, but, even so, there were a few survivors following radical surgical operation. Following radical surgical treatment, Pack,"* in 1948, stated that in the past fifteen years, their percentage of patients who have survived five years without recurrence, that is to say, the incidence of so- called definitive cures, had increased 600 per cent, surely an improvement far greater than that ob- tained with almost any other common variety of cancer. Still, Pack’s percentage of five-year survivals without metastases to lymph nodes is only 18 per cent, and for melanoma metastatic to regional lymph nodes and treated by surgical means is only 15 per cent. Five-year survival is not as significant in melanoma as in some other malignant tumors because of the tendency to late recurrence. Wilbur and Hartman** found local
1158
recurrence as late as nine years and nodal metastasis as late as thirteen years. However, with early diagnosis and radical surgical treat- ment, the prognosis should improve greatly. Many lives can be saved by prompt and adequate diagnosis and treatment. Capra and Ewing’ recently stated: “Serious as is the outlook for the patient with a malignant melanoma, heroic re- section will often salvage what appears to be the most hopeless case.”
Summary
1. Melanoma arises in a pigmented mole in not over 25 per cent of cases; it usually originates in normal skin in the form of lentigo maligna.
2. All suspected lesions must be biopsied.
3. Post-pubertal melanoma is more serious than the prepubertal variety.
4. Treatment of melanoma is surgical, and must be radical.
5. Prognosis is greatly improved by earlier diagnosis and more radical surgical procedures.
References
1. Ackerman, L. V.: Malignant melanoma of the skin. Am. J. Clin. Path., 18:602 (Aug.) 1948.
2. Amadon, P. D.: Malignant melanoma. J. Michigan M. Soc., 29:713 (Oct.) 1930.
3. Bassett, A.: Traitement chirurgical operatoire de lepithelioma primitiv du clitoris, Rev. de chir., Paris, 46:546, 1912.
4. Becker, S. W.: Diagnosis and treatment of pig-
mented nevi. Arch. Dermat. & Syph., 60:44 (July)
1949,
Becker, S. W., and Obermayer, M. E.: Modern
Dermatology and Syphilology. 2nd ed. Philadelphia:
J. B. Lippincott Company, 1947.
Boulay, M.: Di pronostic des tumeurs melaniques.
Arch. gen. de med., 22:157 (July) 1888.
Capra, L. G., and Ewing, M. A.: Malignant tumors
of the skin. Med. Illus., 4:65, 1950.
Daland, E. M., and Holmes, J. A.: Malignant
melanoma. New England J. Med., 220:651, 1939.
. Ebert, M. H.: Multiple pigmented nevi: a study of the origin of the nevus cell. Arch. Dermat & Syph., 37:1 (Jan.) 1938.
10. Halstead, W. S.: Results of operation for cure of cancer of breast performed at Johns Hopkins Hospital from June, 1889, to January, 1894. Ann. Surg., 20:497, 1894.
11. Herold, R. E.: Malignant melanotic tumors in the negro. New York State J. Med., 36:1418, 1936.
12. Lund, H. Z., and Stobbe, G. D.: The natural history of the pigmented nevus: factors of age and anatomic location. Am. J. Path., 25:1117, 1949.
13. Miles, W. E.: A method of performing abdomino- perineal excision for carcinoma of the rectum and of the terminal portion of the pelvic colon. Lancet, 2:1812 (Dec. 19) 1908.
14. Pack, G. T.: A Clinical Study of Pigmented Nevi and Melanomas, in The Biology of Melanomas, New York: New York Academy of Sciences, 1948.
(Continued on Page 1188)
uw
oe ND
MINNESOTA MEDICINE
10}
O D
ry nic 10- nd ‘et,
evi ew
NE
CONGENITAL OBSTRUCTION OF THE ALIMENTARY CANAL IN THE NEWBORN
DAVID P. ANDERSON, M.D., and ROBERT R. WRIGHT, M.D. Austin, Minnesota
“Dryretergtinigee obstruction of the alimentary canal has received increasing consideration during the past few years since it has been dem- onstrated that the various types of such obstruc- tion are amenable to surgical treatment. It is now evident that these lesions are much more common than previous reports would indicate, and in all probability many congenital obstructions of the alimentary canal are still being overlooked. Evans' in an exhaustive study of atresia of the gastrointestinal tract, including the esophagus and ano-rectal region, estimates that this particular anomaly occurs in approximately one in every 1,500 births. He believes “it is less considered and more unheeded, than uncommon.”
The authors wish to report the incidence and cases of congenital obstruction of the alimentary canal among the 4,374 live births in the St. Olaf Hospital, Austin, Minnesota, during the five-year- period ending December 31, 1950. It is our opin- ion that these congenital anomalies may be more easily overlooked in a predominantly rural area, such as ours, where a special academic interest in such matters may be lacking. It is particularly important that general physicians, who supervise the care of the majority of newborn infants, be especially alerted to the problem.
A review of the 4,374 live-births in the St. Olaf Hospital for the five-year period ending December 31, 1950, was undertaken by one of us (R.R.W.). There were seventy-four neonatal deaths, an incidence of 16.91 per 1,000 live births. This compares very favorably with the reported incidence of neonatal deaths per live births from other surveys. A careful review was made of each neonatal death. Only one of these neonatal deaths could be attributed to congenital obstruc- tion of the alimentary canal. This case is re- ported below. ;
There were three newborn infants with com- plete congenital obstruction of the alimentary can- al who survived. A brief report of each patient is given below. Fourteen infants with congenital pyloric stenosis, all treated successfully by opera- tion, were seen by the authors during the five- year period of this survey. These cases are not
DECEMBER, 1951
specifically included in this report, nor does the number of cases of this disease necessarily rep- resent its true incidence in relation to the number of live births.
Case Reports
Case 1—R. D. Birth weight, 7 pounds. Girl.
The diagnosis of complete atresia of the third portion of the duodenum was established by the family phy- sician, Dr. C. L. Sheedy. Duodenojejunostomy was performed when the infant was fifty-eight hours old. Recovery was uneventful. The infant was discharged on her eighth postoperative day. This patient is now a healthy, normal child, three and one half years of age.
Case 2—F. F. Birth weight, 5 pounds 10% ounces. Boy.
The diagnosis of congenital atresia of the esophagus with a tracheoesophageal fistula was made within forty- eight hours of birth by Dr. F. H. Rosenthal. The infant had episodes of cyanosis and choking due to excessive thick mucus in the pharynx. An end-to-end esophageal anastomosis with closure of the tracheo- esophageal fistula, without an associated gastrostomy, was performed four days after birth. The infant was discharged on the eleventh postoperative day. Several esophageal dilatations with a Philip’s urethral bougie were performed as office procedures. An ano-rectal stenosis also required several dilatations. This patient is now a healthy child, ten months of age.
Case 3—B. N. Birth weight, 6 pounds, 13 ounces. Girl.
Symptoms of partial intestinal obstruction dated from birth, but the diagnosis of complete obstruction was not made until the eighth day. Operation revealed a duode- nal obstruction, partial, due to incomplete rotation of the cecum and an associated volvulus of the midgut. The operation described by Ladd and Gross? was performed. The infant was discharged on the tenth postoperative day. She is now a healthy infant, seven months of age.
Case 4—B. H. Birth weight, 5 pounds 10 ounces. Girl.
The diagnosis of congenital atresia of the esophagus with tracheoesophageal fistula was not established until forty-eight hours after birth. The infant had excessive mucus, cyanosis and difficulty in breathing the day of birth and died three days after birth. Operation was not performed because of the patient’s poor condi- tion. An autopsy was not obtained.
(Continued on Page 1176) 1159
THE USE OF ADRENOCORTICOTROPHIC HORMONE IN THE TREATMENT OF MYASTHENIA GRAVIS
S. K. SHAPIRO, M.D. Minneapolis, Minnesota
“I have now a prudent and honest woman in cure, who for many years has been obnoxious to this kind of bastard palsy, not only in her limbs but likewise in her tongue. This person for some time speaks freely and readily enough, but after long, hasty or laborious speaking presently she becomes mute as a fish, and can- not bring forth a word. Nay, and does not recover the use of her voice until after many minutes.”
HUS, in 1685, Willis' in somewhat graphic
terminology recorded the first description of a patient with myasthenia gravis. Basic contribu- tions to the knowledge of this condition have subsequently been made, but not until 1934 was there any significant advance in the treatment of this “bastard palsy.” Walker®*® in that year made her classical report on the use of eserine and then subsequently prostigmine in the treat- ment of the symptoms of myasthenia gravis. Other therapies have been used which give addi- tional aid to some patients with myasthenia gra- vis; none of these, however, has supplanted prostigmine. With the advent of ACTH it was hoped that a new therapeutic era might be opened to patients with myasthenia gravis.
Although less than thirty reported cases have received this therapy to date, it has become ap- parent that ACTH is not the panacea for patients with myasthenia gravis. Its use is not without danger but nevertheless some patients have been reported to have obtained definite improvement. A backlog of experience will be necessary before the final role of ACTH in the treatment of myasthenia gravis can be delineated. We have recently treated three patients with myasthenia gravis with ACTH, and it is felt that a report of our experience with these patients plus a review of the literature on this subject might prove of interest.
Review of the Literature
In 1948 Soffer et al> reported that the ad- ministration of 400 milligrams of ACTH to a patient with myasthenia gravis, with a thymic tumor, resulted in a marked decrease in the size
From the Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota.
1160
of the tumor, a marked improvement in the clinical symptoms, and elimination of the daily necessity for prostigmine. In 1949 Torda and Wolff* administered a course of 400 milligrams of ACTH to each of five patients moderately to severely ill with myasthenia gravis. These pa- tients during the three years before their study began had experienced minor transient fluctua- tions but no long-lasting nor significant changes in their clinical states. During the period of ad- ministration the patients experienced an increase in disability. The second day after completion of the series of injections the patients experi- enced changes suggesting the beginnings of an incomplete remission of the disorder. This con- sisted of marked improvement of muscle function while on appreciably reduced neostigmine bro- mide. Subsequently Torda and Wolff"* reported further on their experiences with ACTH in myasthenia gravis. In their last report they re- viewed the effect of ACTH on fifteen patients with this condition. Five patients received two courses of ACTH and two patients received three courses of ACTH. Ten patients exhibited a sig- nificant partial remission, and for four the results were inconclusive. One of the patients with so- called bulbar manifestations died on the third day of administration of ACTH. A new series of ACTH induced further remission in all patients to whom it was administered. Millikan and Eaton? administered ACTH and cortisone to five patients with myasthenia gravis. There was a history of long-term myasthenia without re- mission in every instance, and in two of them the disease was gradually becoming more severe. Two of the patients received three and two courses of ACTH ranging in dosage from 800 milligrams to 1,500 milligrams per course. Three of the pa- tients received cortisone therapy in total doses ranging from 1,300 to 1,500 milligrams. One patient who received cortisone needed respirator care and tracheotomy three days after the com- pletion of the course and subsequently succumbed eight days later. In three of the patients transi- tory improvement was observed. Shy et al* treated one myasthenic with cortisone. This patient was
MINNESOTA MEDICINE
dey she an mil pre pre mo Gri anc day 194 acti to. was infe dur min 194 epis the pro: thre pro pro: sary H in § resp hos} was all inte: of t was diap oral sequ com metl (1 < this intr clear cessi adm: plain the mint breat rator came chan color sulfa more ordey
Dect
_S>=_
w
vO
[NE
MYASTHENIA GRAVIS—SHAPIRO
made worse by cortisone but returned to his previous status on the discontinuance of treat- ment.
Case Reports
Case 1—The onset of myasthenia gravis in this white woman, born in 1922, was in January, 1944, when she developed ptosis of the right upper lid. Subsequently, she developed dysarthria, dysphagia, easy fatigability, and difficulty with mastication. Her myasthenia remained mild and was controlled on 30 to 75 milligrams of prostigmine hydrobromide per day. During her second pregnancy, commencing in October, 1946, and for four months after delivery, she required no prostigmine. Gradually her myasthenia gravis increased in severity and 345 milligrams of prostigmine hydrobromide per day were required to control her symptoms. In April, 1949, it was necessary to impose some limitation of her activities and in spite of this the patient commenced to lose weight. An acute exacerbation of her condition was precipitated in April, 1949, by an upper respiratory infection, and hospitalization was necessary at this time, during which the patient received intramuscular prostig- mine. The patient was again hospitalized on June 16, 1949, for regulation of her medication following an episode of diarrhea and vomiting. On discharge from the hospital the patient was receiving 270 milligrams of prostigmine per day plus % of a grain of ephedrine three times a day. During the month of September her prostigmine requirements increased to 375 milligrams of prostigmine hydrobromide per day, and it was neces- sary to markedly restrict her activities.
Her third admission to the University Hospitals was in September, 1949, and this was precipitated by an upper respiratory infection. Examination on admission to the hospita! at this time revealed an acutely ill patient. There was a marked bilateral ptosis, a marked dysarthria, and all the ocular muscles were weak, especially the right internal rectus and the right inferior rectus. A weakness of the palate and tongue could be demonstrated. There was a weakness of all the facial muscles, and a slight diaphragmatic weakness was present. Intramuscular and oral prostigmine failed to control her symptoms and con- sequently intravenous administration of prostigmine was commenced on her second hospital day. The prostigmine methylsulfate was dripped in at the rate of .5 mg. (1 ampoule) per hour. The patient felt comfortable in this regime. About two hours after the onset of the intravenous administration the patient choked while cleaning her teeth, and following this there was an ex- cessive outpouring of mucus. The rate of intravenous administration was increased, and as the patient com- plained of flushing, headache, and intestinal discomfort, the intravenous was temporarily discontinued. Four minutes later the patient experienced great difficulty in breathing, and while being placed in a mechanical respi- rator, her respiration stopped completely and she _ be- came comatose. Seconds after the institution of me- chanical respiration she regained consciousness and her color improved. One milligram of prostigmine methyl- sulfate was given intramuscularly, and the patient once more became comfortable. A nasal tube was passed in order to aid in the nutrition of the patient. During
Decemper, 1951
the next twelve-hour period her prostigmine require- ments were .5 mg. of prostigmine intramuscularly every hour, and three doses of gr. 1/100 atropine were in- jected to control the side effects of the prostigmine.
On the evening of September 19, the patient’s con- dition continued to deteriorate. Her dysarthria and dysphagia were marked and frequent suctioning was necessary as the secretions continued to be a problem. The patient was able to breathe only for short periods without the respirator and her prostigmine requirements became .5 mg. per hour via the intravenous drip and .5 mg. intramuscularly per hour. On the morning of her third hospital day the patient had a sudden outpouring of secretions, became unable to breathe, and lapsed into coma. Within a matter of a minute and a half the patient was intubated and oxygen administered, and the patient regained consciousness. A tracheotomy was then performed, and this was followed by bronchoscopy, by means of which considerable mucus was removed from the left lower bronchus. On the afternoon of the third hospital day ACTH administration was commenced at six-hour intervals and a total of 100 milligrams was given during the next thirty-hour period. As the pa- tient’s immediate course did not appear to be benefited, the ACTH was discontinued at the end of the thirty hours.
The patient’s condition continued to deteriorate. She became increasingly restless, and on the evening of the fourth hospital day her prostigmirie requirements had reached .6 mg. per hour via the intravenous route and .5 mg. of prostigmine per hour intramuscularly. After several hours of this increased rate of prostigmine administration the patient’s restlessness increased and she became psychotic. She complained of claustrophobia and developed auditory and visual hallucinations. She ripped out her intravenous needle and was without intra- venous prostigmine for a period of two and one-half hours. Ten minutes following an injection of .5 mg. of prostigmine intramuscularly, muscular twitchings de- veloped, the patient became comatose and failed to respond to painful stimuli. The prostigmine require- ments were adjusted to one-half ampoule every half hour and the patient regained consciousness. Her psychotic behavior continued, and after consultation with Dr. I. M. Eaton it was decided that the patient had become pro- stigmine-fast and that she was now developing toxic symptoms from the prostigmine. The prostigmine therapy was discontinued and for the next twelve days the patient received only ephedrine, 20 milligrams, three times daily.
The patient in the respirator received the same type of care as is administered to patients with bul- bar poliomyelitis which has been described in a pre- vious publication. One gram of potassium chloride was added to her intravenous feedings daily. The pa- tient’s condition gradually improved and she was able to stay out of the respirator for longer periods. Her degree of oxygenation was followed by means of the oxymeter. On the sixteenth hospital day oxygen therapy was discontinued. On the eighteenth hospital day the patient was removed from the respirator and prostigmine therapy was recommenced. Her dosage was adjusted and it was possible to keep her comfortable on 90 milligrams
1161
MYASTHENIA GRAVIS—SHAPIRO
of prostigmine hydrobromide per day and she was dis- charged from the hospital.
At home the patient was maintained as a bed pa- tient. She remained comfortable and gained weight. This partial remission persisted until December, 1950, when her prostigmine requirements once more commenced to climb, and it was felt that the patient once more was going into an exacerbation of her disease. She was admitted March 22, 1950, to the University Hospitals for an elective course of ACTH therapy. At the time of her admission she was taking 255 mg. of prostigmine per day and three tablets of ephedrine, grains %, daily.
ACTH therapy was commenced at 20 milligrams ev- ery six hours. Concommitant with the ACTH adminis- tration the patient became restless and developed in- somnia. On the third day of ACTH administration the dosage was reduced to 20 milligrams twice a day. On the fourth day of ACTH therapy one-half hour after an injection of ACTH the patient complained of shortness of breath, difficulty in breathing, and pool- ing of secretions. Her condition continued to deterio- rate and on the fifth day of ACTH therapy it was necessary to place the patient in a respirator and the ACTH was discontinued. A total dosage of 280 milli- grams was administered. Coincident with the worsen- ing of her clinical condition her prostigmine require- ments increased. Following the discontinuance of the ACTH the patient commenced to improve and she went into an amazing partial remission and at the time of her discharge on March 30, 1950, her prostigmine re- quirements had dropped to 195 mg. per day with a defi- nite improvement in her strength and general condition. The patient continued to improve, and when seen in April, 1951, her prostigmine requirements had dropped to between 80 and 120 mg. of prostigmine hydrobromide per day. At this dosage she was able to carry on normal activities and compared her condition to the way she had felt during the remissions associated with her second and third pregnancies. On neurological ex- amination the only abnormalities which could be demon- strated were bilateral paresis of the orbicularis oculi and slight paresis in the left upper extremity.
Comment.—This patient demonstrates the diffi- culties in handling an acute exacerbation of my- asthenia gravis. The administration of ACTH during an acute phase of her disease appeared to cause a worsening of her condition. Subsequent- ly a partial remission developed. Following a second course of ACTH there was a definite improvement of the patient’s condition, and she entered an amazing remission of her disease which has persisted for a one-year period.
Case 2.—This white woman, aged twenty-seven, had the diagnosis of myasthenia gravis established in 1948 following th