AMERICAN JOURNAL OF OPHTHALMOLOGY FRANK
W.
NEWELL,
Editor-in-Chief
233 East Ontario St., Chicago, Illinois 60611 EDITORIAL BOARD Mathea R. Allansmith, Boston Douglas R. Anderson, Miami Crowell Beard, San Jose Bernard Becker, St. Louis Benjamin F . Boyd, Panama Charles J. Campbell, New York Ronald E. Carr, New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Fred Ederer, Bethesda
Published
DuPont Guerry III, Richmond G. Richard O'Connor, San Francisco Arnall Patz, Baltimore Paul Henkind, Bronx Robert W. HoIIenhorst, Rochester Steven M. Podos, New York Herbert E. Kaufman, New Orleans Albert M. Potts, Louisville Arthur H. Keeney, Louisville Algernon B. Reese, New York Bertha A. Klien, Tucson Robert D. Reinecke, Albany Carl Kupfer, Bethesda Marvin L. Sears, New Haven James E. Lebensohn, Chicago David Shoch, Chicago Irving H. Leopold, Irvine Bruce E. Spivey, San Francisco A. Edward Maumenee, Baltimore Bradley R. Straatsma, Los Angeles Irene H. Maumenee, Baltimore Gunter K. von Noorden, Houston Edward W. D. Norton, Miami
monthly by the Ophthalmic
Publishing
233 East Ontario St., Chicago, Illinois
Company
60611
Directors: A. E D W A R D M A U M E N E E , President; D A V I D S H O C H , Vice President; F R A N K W. N E W E L L , Secretary and Treasurer; E D W A R D W. D. N O R T O N , B R U C E E. SPIVEY, B R A D L E Y R. STRAATSMA
CLINICAL TRIALS AND RETINITIS PIGMENTOSA It appears to me to be one of the most impor tant desiderata in practical medicine, to ascer tain, in regard to each doubtful disease, how far its cases are really self-limited, and how far they are controllable by any treatment. This question can b e satisfactorily settled only by instituting, in a large number of cases, which are well identified and nearly similar, a fair experimen tal comparison of the different active and expec tant modes of practice, with their varieties in regard to time, order, and degree. This experi ment is vast, considering the number of combi nations which it must involve; and even much more extensive than a corresponding series of pathological observations; yet every honest and intelligent observer may contribute to it his mite. Opportunities for such observations, and especially for monographs of diseases, are found in the practice of most physicians, yet hospitals and other public charities afford the most appropriate field for instituting them upon a large scale. The aggregate of results, success ful and unsuccessful, circumstantially and im partially reported by competent observers, will give us a near approximation to truth, in regard to the diseases of the time and place in which the experiments are instituted. The numerical method employed by Louis in his extensive pathological researches, and now adopted by his most distinguished contemporaries in France, affords the means of as near an ap proach to certainty on this head, as the subject itself admits.
Self-Limited Diseases: A Discourse De livered before the Massachusetts Medical Society, at Their Annual Meeting, May 27, 1835. (As published in Nature in Dis ease, 2nd ed., enlarged. By Jacob Bigelow. Boston, Phillips, Sampson, and Co., 1859) A recent news items and an earlier press release from the embassy of the Union of the Soviet Socialist Republics brought to mind Derrick Vail's 1947 editorial in T H E JOURNAL concerning biogenic stimula tors. The press release told of treatment of "retinitis pigmentosa" by means of a new preparation comprising a nucleotide com plex. It reminded me of the unrealized hope of patients and the indignation of physicians in 1947 when the press de scribed the Russian treatment of retinitis pigmentosa with aloe leaves and placental extract. Derrick Vail's editorial referred to a careful masked clinical study carried out by the late Dan Gordon in which h e indicated that the Filatov method of treat ment of retinitis pigmentosa was useless. In the some 30 years that have elapsed since the rise and fall of the Filatov 720
VOL. 85, NO. 5 treatment, we have learned that Soviet scientists and physicians are as compe tent as any in the world. Thus, it is with much sadness that we find yet another search for patients with a tragic eye disor der by using newspaper publicity instead of the orthodox customary doublemasked studies and reports in medical journals. A portion of the news release states: We began clinical tests of the preparation at the Moscow Helmholtz Eye Diseases Research Institute in 1970. Special attention was paid to avoiding pseudo-positive results due to the psy chological effect of the treatment. It must be said that patients suffering from an incurable illness are sometimes inclined to exaggerate the results of treatment taken because of their strong and quite understandable desire to recu perate. This in turn may beguile doctors into overestimating the effect of a given medicine. To avoid as far as possible such circumstances we have applied a complex of control investiga tions and taken an electroretinogram. The latter makes it possible to objectively determine the action potentials of the retina: in case of a "retinitis pigmentosa" the electroretinogram is either totally absent or substantially lowered. At present, observations of more than 200 patients are available to us, some of them hav ing taken treatment two to seven times. This carefully processed evidence has demonstrated a positive effect in more than 40 percent cases consisting either in improved visual functions (a broader visual field and a higher visual acu ity) or in the stabilization of the disease. Con sidering that the usual course of "retinitis pig mentosa" consists in its steady progression, as a result of which the man becomes an invalid, the retention of even a deprived vision for a number of years should be regarded as a positive result. Dynamic observations of patients who received a systematic treatment (two times a year) for periods ranging from four to seven years have shown the stabilization of the process in ap proximately 60 percent of cases. All physicians dealing with retinitis pigmentosa know the disease course is not steadily progressive but that it is irregular. Soviet physicians must know the failure of all therapeutic regimens, as vividly described by Sir Stewart DukeElder: From what has already been discussed it will be gathered that the treatment of pigmentary dystrophy is most unsatisfactory and indeed may be said not to exist. As usually occurs,
721
EDITORIAL
however, with every progressive disease of un known etiology which is uncurable, innumera ble remedies have been suggested, enthusiasti cally received, tried out, and then discredited. Sometimes with no small psychological and economic loss to the sufferer. Most of these depend upon the views held by their advocates on the etiology of the disease . . . Ballintine, 1 Davis, 2 and Ederer 3 have outlined the clinical trials required to demonstrate whether a new or unproved treatment applied to one group of patients produces results different from those pro duced in an untreated group. There are two essential components: finding a dif ference and demonstrating that an ob served difference is due to the treatment. Certainly the nature of retinitis pigmen tosa and the large number of patients involved makes the double-masked study possible. We hope that rather than trying to attract patients to the Union of Soviet Socialist Republics, Soviet scientists will carry out such trials and publish the re sults in scientific journals. F R A N K W. N E W E L L
REFERENCES 1. Ballintine, E. J.: Objective measurements and the double-masked procedure. Am. J. Ophthalmol. 79:763, 1975. 2. Davis, M. D.: Application of the principles of clinical trials. Am. J. Ophthalmol. 79:779, 1975. 3. Ederer, F.: Why do we need controls? Why do we need to randomize? Am. J. Ophthalmol. 79:758, 1975.
Letters to the Editor must be typed double-spaced on 8V2 x 11-inch bond paper, with 1'/2-inch margins on all four sides, and limited in length to two man uscript pages. CORRESPONDENCE The Uhthoff Phenomenon Editor: At a recent meeting the moderator noted that the physiological explanation of the hot bath test and the Uhthoff phe-
W.
NEWELL,
Editor-in-Chief
233 East Ontario St., Chicago, Illinois 60611 EDITORIAL BOARD Mathea R. Allansmith, Boston Douglas R. Anderson, Miami Crowell Beard, San Jose Bernard Becker, St. Louis Benjamin F . Boyd, Panama Charles J. Campbell, New York Ronald E. Carr, New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Fred Ederer, Bethesda
Published
DuPont Guerry III, Richmond G. Richard O'Connor, San Francisco Arnall Patz, Baltimore Paul Henkind, Bronx Robert W. HoIIenhorst, Rochester Steven M. Podos, New York Herbert E. Kaufman, New Orleans Albert M. Potts, Louisville Arthur H. Keeney, Louisville Algernon B. Reese, New York Bertha A. Klien, Tucson Robert D. Reinecke, Albany Carl Kupfer, Bethesda Marvin L. Sears, New Haven James E. Lebensohn, Chicago David Shoch, Chicago Irving H. Leopold, Irvine Bruce E. Spivey, San Francisco A. Edward Maumenee, Baltimore Bradley R. Straatsma, Los Angeles Irene H. Maumenee, Baltimore Gunter K. von Noorden, Houston Edward W. D. Norton, Miami
monthly by the Ophthalmic
Publishing
233 East Ontario St., Chicago, Illinois
Company
60611
Directors: A. E D W A R D M A U M E N E E , President; D A V I D S H O C H , Vice President; F R A N K W. N E W E L L , Secretary and Treasurer; E D W A R D W. D. N O R T O N , B R U C E E. SPIVEY, B R A D L E Y R. STRAATSMA
CLINICAL TRIALS AND RETINITIS PIGMENTOSA It appears to me to be one of the most impor tant desiderata in practical medicine, to ascer tain, in regard to each doubtful disease, how far its cases are really self-limited, and how far they are controllable by any treatment. This question can b e satisfactorily settled only by instituting, in a large number of cases, which are well identified and nearly similar, a fair experimen tal comparison of the different active and expec tant modes of practice, with their varieties in regard to time, order, and degree. This experi ment is vast, considering the number of combi nations which it must involve; and even much more extensive than a corresponding series of pathological observations; yet every honest and intelligent observer may contribute to it his mite. Opportunities for such observations, and especially for monographs of diseases, are found in the practice of most physicians, yet hospitals and other public charities afford the most appropriate field for instituting them upon a large scale. The aggregate of results, success ful and unsuccessful, circumstantially and im partially reported by competent observers, will give us a near approximation to truth, in regard to the diseases of the time and place in which the experiments are instituted. The numerical method employed by Louis in his extensive pathological researches, and now adopted by his most distinguished contemporaries in France, affords the means of as near an ap proach to certainty on this head, as the subject itself admits.
Self-Limited Diseases: A Discourse De livered before the Massachusetts Medical Society, at Their Annual Meeting, May 27, 1835. (As published in Nature in Dis ease, 2nd ed., enlarged. By Jacob Bigelow. Boston, Phillips, Sampson, and Co., 1859) A recent news items and an earlier press release from the embassy of the Union of the Soviet Socialist Republics brought to mind Derrick Vail's 1947 editorial in T H E JOURNAL concerning biogenic stimula tors. The press release told of treatment of "retinitis pigmentosa" by means of a new preparation comprising a nucleotide com plex. It reminded me of the unrealized hope of patients and the indignation of physicians in 1947 when the press de scribed the Russian treatment of retinitis pigmentosa with aloe leaves and placental extract. Derrick Vail's editorial referred to a careful masked clinical study carried out by the late Dan Gordon in which h e indicated that the Filatov method of treat ment of retinitis pigmentosa was useless. In the some 30 years that have elapsed since the rise and fall of the Filatov 720
VOL. 85, NO. 5 treatment, we have learned that Soviet scientists and physicians are as compe tent as any in the world. Thus, it is with much sadness that we find yet another search for patients with a tragic eye disor der by using newspaper publicity instead of the orthodox customary doublemasked studies and reports in medical journals. A portion of the news release states: We began clinical tests of the preparation at the Moscow Helmholtz Eye Diseases Research Institute in 1970. Special attention was paid to avoiding pseudo-positive results due to the psy chological effect of the treatment. It must be said that patients suffering from an incurable illness are sometimes inclined to exaggerate the results of treatment taken because of their strong and quite understandable desire to recu perate. This in turn may beguile doctors into overestimating the effect of a given medicine. To avoid as far as possible such circumstances we have applied a complex of control investiga tions and taken an electroretinogram. The latter makes it possible to objectively determine the action potentials of the retina: in case of a "retinitis pigmentosa" the electroretinogram is either totally absent or substantially lowered. At present, observations of more than 200 patients are available to us, some of them hav ing taken treatment two to seven times. This carefully processed evidence has demonstrated a positive effect in more than 40 percent cases consisting either in improved visual functions (a broader visual field and a higher visual acu ity) or in the stabilization of the disease. Con sidering that the usual course of "retinitis pig mentosa" consists in its steady progression, as a result of which the man becomes an invalid, the retention of even a deprived vision for a number of years should be regarded as a positive result. Dynamic observations of patients who received a systematic treatment (two times a year) for periods ranging from four to seven years have shown the stabilization of the process in ap proximately 60 percent of cases. All physicians dealing with retinitis pigmentosa know the disease course is not steadily progressive but that it is irregular. Soviet physicians must know the failure of all therapeutic regimens, as vividly described by Sir Stewart DukeElder: From what has already been discussed it will be gathered that the treatment of pigmentary dystrophy is most unsatisfactory and indeed may be said not to exist. As usually occurs,
721
EDITORIAL
however, with every progressive disease of un known etiology which is uncurable, innumera ble remedies have been suggested, enthusiasti cally received, tried out, and then discredited. Sometimes with no small psychological and economic loss to the sufferer. Most of these depend upon the views held by their advocates on the etiology of the disease . . . Ballintine, 1 Davis, 2 and Ederer 3 have outlined the clinical trials required to demonstrate whether a new or unproved treatment applied to one group of patients produces results different from those pro duced in an untreated group. There are two essential components: finding a dif ference and demonstrating that an ob served difference is due to the treatment. Certainly the nature of retinitis pigmen tosa and the large number of patients involved makes the double-masked study possible. We hope that rather than trying to attract patients to the Union of Soviet Socialist Republics, Soviet scientists will carry out such trials and publish the re sults in scientific journals. F R A N K W. N E W E L L
REFERENCES 1. Ballintine, E. J.: Objective measurements and the double-masked procedure. Am. J. Ophthalmol. 79:763, 1975. 2. Davis, M. D.: Application of the principles of clinical trials. Am. J. Ophthalmol. 79:779, 1975. 3. Ederer, F.: Why do we need controls? Why do we need to randomize? Am. J. Ophthalmol. 79:758, 1975.
Letters to the Editor must be typed double-spaced on 8V2 x 11-inch bond paper, with 1'/2-inch margins on all four sides, and limited in length to two man uscript pages. CORRESPONDENCE The Uhthoff Phenomenon Editor: At a recent meeting the moderator noted that the physiological explanation of the hot bath test and the Uhthoff phe-
