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Controlled Clinical Trials in the Treatment of Macular Disease
1100
AMERICAN JOURNAL OF OPHTHALMOLOGY
syndrome falls within the latter category when compared to cluster headaches (histamine, cephalalgia, Horton's headache). Cluster headaches imply just what their name infers, that is, the pains come in clus ters and are severe. This type of pain gen erally occurs in men and in middle age. In its typical form it is likely to have its onset at night and waken the patient with severe spasms of head pain. The pain can be so severe that it can drive the patient to suicide. It can be an associated Horner's syndrome and usually the eye on the affected side is injected. The patient may also have swelling and mucous secretion from the nasal mem branes on the affected side. This type of headache has responded favorably to medi cation used in the treatment of migraine headache and is also treated with histamine desensitization with some degree of efficacy. These headaches generally occur repeatedly from day to day for a period of time and they disappear for a year or more, only to recur. From the clinical description cluster headaches are apparently different in many ways from the pain associated with Group 2, Raeder's syndrome, as described in our paper and others. While we feel that Raeder's paratrigeminal syndrome is a distinct entity from cluster headaches we agree with Dr. Curran that, in general, patients with the benign type of Raeder's syndrome should not have unneces sary and basic diagnostic procedures. We try to stress the point that the typical benign syndrome should not have invasive pro cedures while certain patients with atypical features of the disease stimulate more inten sive diagnostic examination. Doctor Curran was not correct in stating that surgery was not undertaken in any of the cases described in our paper. One patient (Case 2) underwent a surgical arterial an astomosis between the right superficial tem poral artery and the right middle cerebral artery in an attempt to improve his cerebral circulation. Reading over our case history, however, this was misprinted in the pub lished paper. The conclusion of the case re
DECEMBER, 1975
port on page 1045 should read as follows: "In September 1972, the patient underwent surgical arterial anastomosis between the right superficial temporal artery and right middle cerebral artery." As a further followup in Case 1, one year and nine months after the patient was first seen she still has the same steady pain and the Horner's syndrome persists. DAVID N. COHEN,
M.D.
Z. NICHOLAS ZAKOV,
M.D.
VIRGILIO D. SALANGA,
M.D.
DONALD F. D O H N ,
M.D.
Cleveland, Ohio CONTROLLED CLINICAL TRIALS IN THE TREATMENT OF MACULAR DISEASE
Editor: Professor Jules Frangois, in his response to Dr. Robert Frank's letter (Am. J. Ophthalmol. 80:161, 1975), states that controlled studies are "difficult and hazardous in the treatment of macular diseases, just as they are in diabetic retinopathy, because neither two eyes nor two cases are exactly the same and because the natural course differs from one case to another." If it were possible to predict exactly the prognosis of an eye from the course of a fel low eye, from the status of a matched case, or from a predictable natural history, the need for carefully controlled studies would be obviated. The variable prognosis of chronic medical diseases led Hill 1 and others to develop the controlled clinical trial as a re liable method for evaluating therapy in these diseases. The hallmark of these clinical trials is the random assignment of patients to the treatment or control group. Although no two individuals are exactly comparable, randomi zation helps to assure the comparability of the treated and control groups both in known relevant factors and unknown factors. If the trial is then carried out with these randomly assigned groups and with care to avoid bias, as recently summarized by Ederer, 2 it is pos sible to evaluate treatment modalities in dis eases with a variable natural history. This
VOL. 80, NO. 6
BOOK REVIEWS
evaluation allows us to predict the outcome for a group of patients even though we can not predict the outcome in individuals. I fully agree with Professor Francois that such studies are difficult, but not to undertake them in areas of major importance is hazard ous. As pointed out by Chalmers,3 "It is more ethical to randomize a patient into either standard therapy or a new therapy, than it is to give the patient a new or the standard therapy as if we knew that one or the other was better, when either might actually be more harmful than beneficial." Unfortunately, past experience demonstrates all too clearly that enthusiasm for new treat ment modalities, and patients who are anx ious to get better, make the early subjective evaluations so biased as to be difficult if not impossible to interpret. The personal experiences and subjective observations of individual investigators should lead the major university centers to cooperate in the careful evaluation of the promising treatment modalities so we can merge the art and science of medicine for the maximal benefit of our patients. FREDERICK L. FERRIS III,
M.D.
Baltimore, Maryland REFERENCES
1. Hill, A. B.: The clinical trial. Br. Med. Bull. 7:278-282, 1951. 2. Ederer, F.: Patient bias, investigator bias and the double-masked procedure in clinical trials. Am. J. Med. 58:294-299, 1975. 3. Chalmers, T. C: Ethical aspects of clinical trials. Am. J. Ophthalmol. 79:753-758, 1975. REPLY
Editor: I agree with the comments of Dr. Ferris. Randomization, helping to assure the com parability of treated and control groups both in known relevant factors and unknown fac tors, is a progress in controlled studies. Nevertheless, these remain difficult, as Dr. Ferris agrees. PROFESSOR J. FRANCOIS
Ghent, Belgium
1101 CORRECTIONS
In the article, "Perivascular and intervascular reticular fibers of the retina," by Norman Ashton and Ramesh Tripathi (Am. J. Ophthalmol. 80:337, 1975), Figure 10, center and bottom, were interchanged. In the article, "A new mucolipidosis with psychomotor retardation, corneal clouding, and retinal degeneration," by Frank W. Newell, Reuben Matalon, and Steven Meyer (Am. J. Ophthalmol. 80:446, 1975), Figures 6 and 8 were interchanged.
BOOK REVIEWS THE DEVELOPMENTAL NEUROPSYCHOLOCY OF SENSORY DEPRIVATION. Edited by Aus tin H. Riesen. Academic Press, Inc., 1975. Clothbound, 303 pages, table of contents, index, 40 black and white figures. $16.50
The effect of decreased or abnormally al tered visual input on neural structure and function in visually immature animals has re cently become an area of prime interest for visual scientists. Much information has ac cumulated during the last decade, most of it published in scientific journals not easily ac cessible to the clinically oriented ophthalmol ogist. This is regrettable, inasmuch as this work may eventually have far-reaching im plications with respect to the treatment of strabismus, amblyopia, congenital cataracts, and corneal disease in children. We must be grateful, therefore, to Professor Riesen, and the other contributors to this book who have summarized the current knowledge on this subject. The anatomical, neurophysiological, neurochemical, electrophysiological, and be havioral changes that occur after decreased or enhanced stimulation of the visual sys tem, are reviewed in nine chapters. Because of the nearly overwhelming amount of new data in this area during the past two to three years, an unavoidable shortcoming of a book of this type is that it is no longer current on the day of publication. Some of the authors'
AMERICAN JOURNAL OF OPHTHALMOLOGY
syndrome falls within the latter category when compared to cluster headaches (histamine, cephalalgia, Horton's headache). Cluster headaches imply just what their name infers, that is, the pains come in clus ters and are severe. This type of pain gen erally occurs in men and in middle age. In its typical form it is likely to have its onset at night and waken the patient with severe spasms of head pain. The pain can be so severe that it can drive the patient to suicide. It can be an associated Horner's syndrome and usually the eye on the affected side is injected. The patient may also have swelling and mucous secretion from the nasal mem branes on the affected side. This type of headache has responded favorably to medi cation used in the treatment of migraine headache and is also treated with histamine desensitization with some degree of efficacy. These headaches generally occur repeatedly from day to day for a period of time and they disappear for a year or more, only to recur. From the clinical description cluster headaches are apparently different in many ways from the pain associated with Group 2, Raeder's syndrome, as described in our paper and others. While we feel that Raeder's paratrigeminal syndrome is a distinct entity from cluster headaches we agree with Dr. Curran that, in general, patients with the benign type of Raeder's syndrome should not have unneces sary and basic diagnostic procedures. We try to stress the point that the typical benign syndrome should not have invasive pro cedures while certain patients with atypical features of the disease stimulate more inten sive diagnostic examination. Doctor Curran was not correct in stating that surgery was not undertaken in any of the cases described in our paper. One patient (Case 2) underwent a surgical arterial an astomosis between the right superficial tem poral artery and the right middle cerebral artery in an attempt to improve his cerebral circulation. Reading over our case history, however, this was misprinted in the pub lished paper. The conclusion of the case re
DECEMBER, 1975
port on page 1045 should read as follows: "In September 1972, the patient underwent surgical arterial anastomosis between the right superficial temporal artery and right middle cerebral artery." As a further followup in Case 1, one year and nine months after the patient was first seen she still has the same steady pain and the Horner's syndrome persists. DAVID N. COHEN,
M.D.
Z. NICHOLAS ZAKOV,
M.D.
VIRGILIO D. SALANGA,
M.D.
DONALD F. D O H N ,
M.D.
Cleveland, Ohio CONTROLLED CLINICAL TRIALS IN THE TREATMENT OF MACULAR DISEASE
Editor: Professor Jules Frangois, in his response to Dr. Robert Frank's letter (Am. J. Ophthalmol. 80:161, 1975), states that controlled studies are "difficult and hazardous in the treatment of macular diseases, just as they are in diabetic retinopathy, because neither two eyes nor two cases are exactly the same and because the natural course differs from one case to another." If it were possible to predict exactly the prognosis of an eye from the course of a fel low eye, from the status of a matched case, or from a predictable natural history, the need for carefully controlled studies would be obviated. The variable prognosis of chronic medical diseases led Hill 1 and others to develop the controlled clinical trial as a re liable method for evaluating therapy in these diseases. The hallmark of these clinical trials is the random assignment of patients to the treatment or control group. Although no two individuals are exactly comparable, randomi zation helps to assure the comparability of the treated and control groups both in known relevant factors and unknown factors. If the trial is then carried out with these randomly assigned groups and with care to avoid bias, as recently summarized by Ederer, 2 it is pos sible to evaluate treatment modalities in dis eases with a variable natural history. This
VOL. 80, NO. 6
BOOK REVIEWS
evaluation allows us to predict the outcome for a group of patients even though we can not predict the outcome in individuals. I fully agree with Professor Francois that such studies are difficult, but not to undertake them in areas of major importance is hazard ous. As pointed out by Chalmers,3 "It is more ethical to randomize a patient into either standard therapy or a new therapy, than it is to give the patient a new or the standard therapy as if we knew that one or the other was better, when either might actually be more harmful than beneficial." Unfortunately, past experience demonstrates all too clearly that enthusiasm for new treat ment modalities, and patients who are anx ious to get better, make the early subjective evaluations so biased as to be difficult if not impossible to interpret. The personal experiences and subjective observations of individual investigators should lead the major university centers to cooperate in the careful evaluation of the promising treatment modalities so we can merge the art and science of medicine for the maximal benefit of our patients. FREDERICK L. FERRIS III,
M.D.
Baltimore, Maryland REFERENCES
1. Hill, A. B.: The clinical trial. Br. Med. Bull. 7:278-282, 1951. 2. Ederer, F.: Patient bias, investigator bias and the double-masked procedure in clinical trials. Am. J. Med. 58:294-299, 1975. 3. Chalmers, T. C: Ethical aspects of clinical trials. Am. J. Ophthalmol. 79:753-758, 1975. REPLY
Editor: I agree with the comments of Dr. Ferris. Randomization, helping to assure the com parability of treated and control groups both in known relevant factors and unknown fac tors, is a progress in controlled studies. Nevertheless, these remain difficult, as Dr. Ferris agrees. PROFESSOR J. FRANCOIS
Ghent, Belgium
1101 CORRECTIONS
In the article, "Perivascular and intervascular reticular fibers of the retina," by Norman Ashton and Ramesh Tripathi (Am. J. Ophthalmol. 80:337, 1975), Figure 10, center and bottom, were interchanged. In the article, "A new mucolipidosis with psychomotor retardation, corneal clouding, and retinal degeneration," by Frank W. Newell, Reuben Matalon, and Steven Meyer (Am. J. Ophthalmol. 80:446, 1975), Figures 6 and 8 were interchanged.
BOOK REVIEWS THE DEVELOPMENTAL NEUROPSYCHOLOCY OF SENSORY DEPRIVATION. Edited by Aus tin H. Riesen. Academic Press, Inc., 1975. Clothbound, 303 pages, table of contents, index, 40 black and white figures. $16.50
The effect of decreased or abnormally al tered visual input on neural structure and function in visually immature animals has re cently become an area of prime interest for visual scientists. Much information has ac cumulated during the last decade, most of it published in scientific journals not easily ac cessible to the clinically oriented ophthalmol ogist. This is regrettable, inasmuch as this work may eventually have far-reaching im plications with respect to the treatment of strabismus, amblyopia, congenital cataracts, and corneal disease in children. We must be grateful, therefore, to Professor Riesen, and the other contributors to this book who have summarized the current knowledge on this subject. The anatomical, neurophysiological, neurochemical, electrophysiological, and be havioral changes that occur after decreased or enhanced stimulation of the visual sys tem, are reviewed in nine chapters. Because of the nearly overwhelming amount of new data in this area during the past two to three years, an unavoidable shortcoming of a book of this type is that it is no longer current on the day of publication. Some of the authors'