LOUIS S. LEO AND BERNARD LIDMAN
10. Frank, I. : Plasmocytoma of the tonsil. Ann., Otol., Rhin.,& Laryng., 51:21, 1942. 11. Bernier, J. L., and Tiecke, R. W. : Tumors: plasmocytoma. J. Oral. Surg., 8:70, 1950. 12. Maguda, T. A., and Maiden, S. D. : Plasmocytoma of nasal cavity. Arch. Otolaryng., 51:258, 1950. 13. Mattick, W. L. : Plasmocytoma. Arch. Otolaryng., 51:263, 1953. 14. Gordon, J., and Walker, C. : Plasmocytoma of lung. Arch. Path., 37:22, 1944. 15. Hellwig, A. C. : Extramedullary plasma-cell tumors as observed in various locations. Arch. Path., 36:9S, 1943. 16. Stout, A. P., and Kenney, F. R. : Primary plasma-cell tumors of the upper respiratory passages and oral cavity. Cancer, 2 :261, 1949. 17. Marshalko, T. : Ueber die Sogenannten Plasmazellen ein Beitrag zur Kenntniss der Herkunft der entzündlichen Infiltrationzellen. Arch. f. Dermat u. Syph., 30 :241, 1895. Cited by Stout, A. P., and Kenney, F. R. : Primary plasma-cell tumors of the upper respiratory passages and oral cavity. Cancer, 2:261, 1949. 18. Pappenheim, A. : Unsere derzeitigen Anschaug über Natur, Herkunft und Abstammung der Plas mazellen und über die Entwicklung der Plasmazellfrage. Folia haemat., 4 : (suppl.) 206, 1907. Cited by Stout, A. P., and Kenney, F. R. : Primary plasma-cell tumors of the upper respiratory passages and oral cavity. Cancer, 2:261, 1949. 19. Verhoeff, F. H., and Derby, C. S. : Plasmoma of the lacrimal sac. Arch. Ophth., 44:252, 1915. 20. Fuchs, E. : Textbook of Ophthalmology (translated by Duane) Philadelphia, Lippincott, 1919, ed. 8. 21. Friedenwald, J. S., et al. : Ophthalmic Pathology. Philadelphia, Saunders, 1952. 22. Benedict, W. L. : Diseases of the orbit. Tr., Am. Acad. Ophth., 54:26, 1949.
DICUMAROL IN R E T I N I T I S PIGMENTOSA R E S U L T I N G CHANGES I N VISUAL ACUITY AND VISUAL F I E L D S : A L O U I S S. L E O , * M.D.,
AND BERNARD L I D M A N ,
This paper is presented in the hope that it will offer some help in the management of retinitis pigmentosa, a disease which we have heretofore considered hopeless. We cannot at this time answer those ques tions which naturally arise concerning the probable physiologic or physicochemical ef fects of Dicumarol in this disease. It is our hope that the more general use of this drug in the treatment of this disease may result in satisfactory answers to the perplexing problems that confront us at this time. Because this paper is being presented solely to offer a new method of treatment, the prob lems of etiology, pathogenesis, and pathology will not be considered. Suffice it to say that we accept the conclusion that retinitis pig mentosa is primarily a degenerative disease of the retinal neuro-epithelium. Of the many theories advanced about the pathologic pat tern, the one most generally accepted is that the ring scotoma is the end result of early * Deceased.
maturation of the equatorial neuro-epithe lium followed by rapidly advancing prema ture senility with resulting necrosis of the cells. It is generally accepted that there are no known means at the present time which can prevent this disappearance of the neuro-epi thelium. In 1947 it was noted by one of us (L. S. L.) that a patient suffering from vascular disease and who also had retinitis pigmentosa showed a sudden improvement in visual acu ity along with an enlargement of the pe ripheral field after treatment with Dicumarol. Also in 1948, McGuire published a series of nine cases of glaucoma in which he had used Dicumarol with a resulting enlargement of the visual fields. Our interest in Dicumarol was further stimulated by McGuire's work. Since 1948, 37 cases of retinitis pigmen tosa have been treated with Dicumarol. Two of the cases were studied and treated by another physician, under our direction, with the deliberate purpose of having someone else test this form of therapy. Thirty-three of
DICUMAROL IN RETINITIS PIGMENTOSA
these cases showed varying degrees of im provement and four showed no improvement. This finding suggests that the method is worthy of further investigation. These pa tients have been under observation from 1950 to the present time, and all have retained the degree of improvement initially reached, even though in most cases the drug has been dis continued for a long period of time. All patients with retinitis pigmentosa hos pitalized for Dicumarol therapy received a careful medical study prior to use of the drug. None of the patients considered for treatment gave a history of hemorrhagic di athesis, ulcerative lesions of the gastro intestinal tract, or of central nervous-system bleeding. None of the patients had severe hypertension. The patients were carefully studied for evidence of cardiovascular dis ease and for evidence of hepatic and renal dysfunction. All patients also received blood sugar and cholesterol determinations and, where indicated, carbohydrate tolerance tests. The original method of treating these pa tients has been hospitalization for study and for daily prothrombin determinations made by the method of Quick. Dicumarol was then given in doses of 300 mg. daily until the prothrombin time was prolonged to an arbi trary limit of 38 seconds, or two and onehalf to three times the control factor. When the desired prothrombin time was reached, the dosage was then regulated and reduced to a level that would hold the prothrombin time between two and two and a half times the control. After one week of this intensive therapy, the patient was allowed to go home on a sus taining dose of 50 to 75 mg. of Dicumarol daily. Weekly prothrombin-time determina tions were then made to permit adjustment of Dicumarol dosage. After discharge from the hospital it was noted there was usu ally a slow fall in the prothrombin time in spite of continued Dicumarol therapy at home. Therapy was continued for six weeks. In six cases the method of therapy has
been changed, in that the dosage of Dicuma rol has been increased to an average of 350 mg. to 400 mg. daily and kept constant while intravenous injections of vitamin Ki oxide (manufactured by Merck and Company under the trade name Mephyton) in dosage of 50 mg.* were given so that the prolonga tion of the prothrombin time did not occur. This vitamin Ki oxide was given in the belief that the anticoagulant factor in Dicumarol might not be the therapeutic agent, but that another factor in the drug might act directly on the retina. Now all cases are given 400 mg. daily and vitamin Ki oxide intravenously if the prothrombin time exceeds 30 seconds. In this series of 37 cases, hemorrhagic tendencies have occurred in only three pa tients. Two showed microscopic hematuria tt't
Fig. 1 (Leo and Lidman). Mr. R. I. F., aged 52 years, treated by Dr. E. Clarence Kern, Montclair, New Jersey. Field studies were made on April 28, 19S3, and June 25, 1953, before and after treat ment which consisted of two periods of hospitaliza tion, one week on Dicumarol alone and the other week on Dicumarol and 50 mg. of vitamin Ki oxide on alternate days.
LOUIS S. LEO AND BERNARD LIDMAN TABLE
D A T A I N 10 C A S E S OF R E T I N I T I S P I G
Date First Seen
(seconds) 12 Con. 14
* Received mephyton to limit prothrombin prolongation.
DICUMAROL IN RETINITIS PIGMENTOSA
TABLE l—continued MENTOSA T R E A T E D W I T H
Final Vision O.D.
Fingers, 12 Ft.
Fingers, Fingers, 3 Ft. 3 Ft.
Fingers, 2 Ft,
20/40 + 20/50 +
.20/50 + 20/25
LOUIS S. LEO AND BERNARD LIDMAN fn .Uli
by the administration of vitamin K± oxide, but there seems to be some other property of the drug which may act directly on the retina. Improvement is not evidenced if small doses of Dicumarol are given. 2. Visual acuity and visual fields are some times markedly improved and with spectacu lar speed. This speed of recovery casts doubt as to the pathologic process being on a cellu lar degenerative basis but rather suggests a chemical change within the cells. 3. Return of visual fields are mirror images of the fields, as they are lost in the progression of the disease, and the return seems to be on a basis of increased sensi tivity rather than an increase in form. The form follows as the sensitivity of the retinal elements increases.
Fig. 2 (Leo and Lidman). Mr. W. H. F., aged 56 years, brother to Mr. R. I. F., also treated, as outlined, by Dr. Kern. (Above) Before treatment, January 30, 1953. (Below) After treatment, April 13, 1953.
after three or more weeks, but this cleared spontaneously. The third showed petechiae of the ankles after four weeks, but this also cleared when the drug was withheld. This patient was later given Dicumarol without re currence of the hemorrhagic manifestations. The 12 case reports as charted in Table 1 and Figures 1 and 2 are presented as char acteristic of some of the successful cases in this series. Cases 1 and 2 (fig. 1) were treated under the direction of Dr. E. Clarence Kern, of Montclair, New Jersey, using the same rou tine as in the other cases. SUMMARY
1. Dicumarol appears to be helpful in the treatment of retinitis pigmentosa. The anti coagulant action of the drug may or may not be a factor in the treatment, as it is suspended
4. The results appear to be permanent, es pecially in those early cases in which im provement followed discontinuance of treat ment. 5. The only unpleasant reaction to the treatment has been a marked decrease in light tolerance and many patients complain of the discomfort of glare. 6. Dicumarol has given what appears to be encouraging results, possibly more than might be expected from the psychologic ele ment or the frequent fluctuations which oc cur in this disease. This is a preliminary report and is pre sented only in the hope that it will stimulate further investigations with this drug. No suggestions as to the mode of action of the drug can be made at this time. 421 Waimvright Building
* Since using Mephyton in order to increase the dose of Dicumarol and still sustain the prothrombin levels in the near vicinity of the 12- or 13- seconds control we find the results seem to be inhibited. We are now using the Mephyton only to hold the pro thrombin to a safe level or within 40 to 45 seconds as against the normal 12 seconds of the control. We would like to express our appreciation to Merck & Company for supplying the Mephyton that has been used over the period of these treatments.
CARBOMYCIN IN OCULAR INFECTIONS REFERENCES
Duke-Elder, W. S. : Textbook of Ophthalmology. St. Louis, Mosby, 1941, v. 3, p. 2765. Link, K. P. : Hardy Lectures, 29:162, 1943-44. McGuire, W. P. : Am. J. Ophth., 32:1095, 1949. Nettleship : Roy. London Ophth. Hosp. Rep. 17 :1, 151, 333, 1907-08; 19 :123, 1914. Quick : J.A.M.A., 110:1658, 1938. Rodenick, L. L. : J. Am. Vet., 74:314, 1929. Schofield : J. Am. Vet. M. A., 64:5S3, 1924.
CARBOMYCIN IN OCULAR J. A. H A L L I D A Y , M.D.,· AND H .
INFECTIONS* L. O R M S B Y ,
Carbomycin^ a new antibiotic developed by scientists working in the laboratory of Chas. Pfizer and Co., Inc., was first reported in September, 1952, by Tanner and coworkers. 1 It was recovered by the conven tional methods from a strain of the soil actinomyces identified as Streptomyces halstedii. The spectrum of activity of carbomycin has been shown by Tanner, 1 English,2 Welch,3 and their co-workers, to be chiefly against gram-positive and gram-negative cocci. It has little effect against the gramnegative bacilli, with the exception of some strains of Hemophilis influenzae and Hemophilus pertussis. Wong 4 has demonstrated that it is highly effective in ovo and in vivo (mice and guinea pigs) against many of the rickettsiae and large viruses, namely those causing Rocky Mountain spotted fever, epi demic scrub and murine typhus, rickettsial pox, lymphogranuloma venereum, and psit tacosis. English and co-workers 2 in preliminary studies on the development of resistance of Staphylococcus aureus and other test organ isms toward carbomycin, state that such resistance does not develop readily and that, when it does occur, there is a low, steplike gradual rise. Carbomycin appears to offer certain ad vantages in the treatment of ocular infec* From the Department of Ophthalmology, Uni versity of Toronto. + Magnamycin, Chas. Pfizer & Co., Inc.
tions. Not only does it have a good inhibitory effect on streptococci and pneumococci sim ilar to that of penicillin and the broad-spec trum antibiotics, but it has the added advan tage of a lower index of resistance to staphylococcal strains. When given orally, it is less likely to alter the normal intestinal flora. Cross-resistance between carbomycin and penicillin or the broad-spectrum antibiotics has so far not developed in our series of 126 strains of Staphylococcus aureus isolated from ocular sources. Finland, et al.,5 reported that strains of staphylococci which have been made resistant to either carbomycin or erythromycin, simultaneously became resist ant to the homologous antibiotic. This study was undertaken : 1. To compare the in vitro sensitivities of pathogenic staphylococci with carbomycin, erythromycin, penicillin, aureomycin, terramycin, streptomycin, and chloramphenicol. 2. To test the efficacy of ophthalmic oint ments containing carbomycin hydrochloride and carbomycin as the base, in the treatment of external ocular infections. 3. To determine the intraocular penetra tion of carbomycin hydrochloride when ap plied topically. I N VITRO SENSITIVITIES OF STRAINS OF PATHOGENIC STAPHYLOCOCCI
A total of 126 strains of Staphylococcus aureus isolated from ocular sources (in-pa tients and out-patients) were subcultured in