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Neuronal Necrosis and Hyperoxemia in Premature Infants: Reply
96
July, 1987
AMERICAN JOURNAL OF OPHTHALMOLOGY
Neuronal Necrosis and Hyperoxemia in Premature Infants
Changing Patterns of Uveitis EDITOR:
In the article, "Changing patterns of uveitis" by D. E. Henderly, A. J. Genstler, R. E. Smith, and N. A. Rao (Am. J. Ophthalmol. 103:131, February 1987), the authors point out that the commonest etiologic diagnosis in most studies is idiopathic uveitis. Some of these cases may fall into new clinical entities such as birdshot choroidopathy, acute multifocal placoid pigment epitheliopathy, serpiginous choroidopathy, and retinal necrosis. A study of uveitis in Bantu-speaking blacks 1 showed that certain patterns of uveitis existed that differed from the local white population and also from patterns in other black patients with uveitis. Notable differences were the low incidence of sarcoidosis, toxoplasmosis, and ankylosing spondylitis. Patterns in uveitis seem to be dependent on racial and geographic factors and it would be interesting to learn if racial factors were significant in the study by Henderly and associates, particularly in reference to the new clinical entities of birdshot choroidopathy, acute multifocal placoid pigment epitheliopathy, and serpiginous choroidopathy. JEFFREY FREEDMAN, M.B., PH.D.
Brooklyn, New York
Reference 1. Freedman, J.: A clinical approach to the etiology of uveitis in Bantu adults. Br. J. Ophthalmol. 60:64, 1976.
Reply EDITOR:
Dr. Freedman is correct in pointing out the possibility for different diagnoses among various racial groups or among groups from different geographic locations. Most patients (about 90%) in our study were white. We are therefore unable to make any significant observations related to the issues raised by Dr. Freedman. DALE E. HENDERLY, ARLA J. GENSTLER, RONALD E. SMITH, NARSING A. RAO,
M.D. M.D. M.D. M.D.
Los Angeles, California
Reply EDITOR:
We thank H. H. Brown, B. J. Glasgow, and R. Y. Foos for their correspondence (Am. J. Ophthalmol. 103:726, May 1987) sharing the results of their study, which was triggered by our article, "Neuronal necrosis and hyperoxemia in premature infants" (Am. J. Ophthalmol. 102:423, October 1986). One must question, however, if the neonatal populations studied are similar. Our study involved a single large neonatal intensive care unit and we are uncertain of the derivation of the UCLA sample recorded by Brown, Glasgow, and Foos. This is especially important in premature infants born in outlying hospitals where face-mask oxygen is given in the delivery room or during transport to tertiary centers and blood gas levels are not recorded. Blood gas measurements were recorded in only five of 21 neonates studied by Brown, Glasgow, and Foos, which speaks to that point and we think it is hazardous to draw conclusions about oxygen toxicity in such a sample. Similarly, it is difficult to correlate karyorrhexis with length of survival if the time of hyperoxic insult is not known. The occasional occurrence of karyorrhexis in the eyes of stillborn infants is interesting, but does not negate the mechanism of oxygen toxicity in the neonate. Although hyperoxia, in the absence of well-developed antioxidant defense mechanisms, is the main cause of cellular karyorrhexis reflecting lipid peroxidation of cell membranes, toxic oxygen-free radicals may occur in the fetus in utero when triggered by high levels of prostaglandins and arachidonic acid, such as with prostaglandininduced abortion, or with chorioamnionitis and sepsis. We remain convinced that the ganglion cell is the cell type in the retina that is most sensitive in expressing hyperoxemic neuronal necrosis via its karyorrhectic appearance. In the brain, pontosubicular necrosis has been retained as a term of convenience for designating hyperoxemic neuronal necrosis as these are the areas that are the earliest and most severely involved. Lesions are, however, not strictly limited to those two sites as the hip-
Correspondence
Vol. 104, No. 1
pocampus, thalamus, caudate nucleus, cerebellum, and inferior olivary nuclei are also frequently involved. 1 Similarly, in the retina we occasionally saw karyorrhexis peripherally or in the inner nuclear layer, but most karyorrhectic cells are where ganglion cells are most numerous, that is, in the macula and not the periphery. Experimental evidence favors the hypothesis that those cases in which infants survive longer following a period of severe hyperoxeinia may trigger and maintain the continuous production of oxygen-free radicals and persistence of karyorrhexis. 2 This could explain some cases of peripheral retinal involvement. One should be cautious in accepting what is cytologically a karyorrhectic cell. Nuclear autolytic change, mitoses, and polymorphonuclear leukocytes can all be confused with karyorrhexis. In particular, karyorrhexis "within" retinal capillaries should be better defined. Mitotic activity of proliferating vascular endothelial cells is often impressive and is seen with frequency in premature infants and in newborn rats subjected to experimental hyperoxia. Karyorrhexis has been mistaken for neutrophils in the older neuropathologic literature. MAMDOUHA AHDAB-BARMADA, M.D. BRUCE L. JOHNSON, M.D.
Pittsburgh, Pennsylvania
References 1. Ahdab-Barmada, M , Moossy, j . , and Painter, M.: Pontosubicular necrosis and hyperoxemia. Pediatrics 66:840, 1980. 2. Ahdab-Barmada, M., Moossy, ]., Nemoto, E. M., and Lin, M. R.: Hyperoxia produces neuronal necrosis in the rat. J. Neuropathol. Exp. Neurol. 45:233, 1986.
Adverse Respiratory and Cardiovascular Events Attributed to Timolol Ophthalmic Solution, 1978-1985 Reply EDITOR:
On behalf of my coauthors, I thank Dr. Vogel for his comments (Am. J. Ophthalmol. 103:844, June 1987) on our article, "Adverse
97
respiratory and cardiovascular events attributed to timolol ophthalmic solution, 19781985" (Am. J. Ophthalmol. 102:606, November 1986), by W. L. Nelson, F. T. Fraunfelder, J. M. Sills, J. B. Arrowsmith, and J. N. Kuritsky. I would like to clarify our use of the word "attribute" in the context of spontaneous reporting of adverse drug experiences. In order for an adverse drug experience to be reported to the Food and Drug Administration Spontaneous Reporting System 1 or the National Registry of Drug-Induced Ocular Side Effects,2 the reporter must first recognize that an adverse event has occurred and associate this with a drug. This initial assessment may be prompted by a number of factors, such as a close temporal relationship between the drug exposure and the event, an apparent absence of other risk factors for the event, or an awareness of similar events previously described in association with the drug. In some instances more than one drug may be associated with an event. When the adverse drug experience is reported, the reporter designates one or more drugs as "suspect," and any other drugs that the patient may be taking as "concomitant medications." The reporter thus attributes (in the sense of ascribes) the adverse event to a particular drug. All the adverse event reports summarized in our article were reports for which timolol was designated the sole suspect drug by the reporter. The 32 deaths described in our article were reported by 28 physicians, two pharmacists, one paramedic, and one family member. As we indicated in our article, one must exercise caution when interpreting spontaneous reports of adverse drug reactions. Spontaneous reports are useful for generating signals of problems with drug use. In the case of timolol, the finding that at least 85% of the 32 patients who died had underlying cardiovascular or respiratory disease suggested to us that physicians were prescribing timolol for patients who were probably at risk for adverse reactions to beta blockers. We agree with Dr. Vogel that physicians should carefully review the medical history of patients being considered for beta-blocker therapy. The Office of Epidemiology and Biostatistics at the Food and Drug Administration is presently monitoring adverse drug experience reports for the three beta blockers approved for treating glaucoma: timolol, betaxolol, and levobunolol. Physicians are encouraged to submit adverse drug reaction reports to the
July, 1987
AMERICAN JOURNAL OF OPHTHALMOLOGY
Neuronal Necrosis and Hyperoxemia in Premature Infants
Changing Patterns of Uveitis EDITOR:
In the article, "Changing patterns of uveitis" by D. E. Henderly, A. J. Genstler, R. E. Smith, and N. A. Rao (Am. J. Ophthalmol. 103:131, February 1987), the authors point out that the commonest etiologic diagnosis in most studies is idiopathic uveitis. Some of these cases may fall into new clinical entities such as birdshot choroidopathy, acute multifocal placoid pigment epitheliopathy, serpiginous choroidopathy, and retinal necrosis. A study of uveitis in Bantu-speaking blacks 1 showed that certain patterns of uveitis existed that differed from the local white population and also from patterns in other black patients with uveitis. Notable differences were the low incidence of sarcoidosis, toxoplasmosis, and ankylosing spondylitis. Patterns in uveitis seem to be dependent on racial and geographic factors and it would be interesting to learn if racial factors were significant in the study by Henderly and associates, particularly in reference to the new clinical entities of birdshot choroidopathy, acute multifocal placoid pigment epitheliopathy, and serpiginous choroidopathy. JEFFREY FREEDMAN, M.B., PH.D.
Brooklyn, New York
Reference 1. Freedman, J.: A clinical approach to the etiology of uveitis in Bantu adults. Br. J. Ophthalmol. 60:64, 1976.
Reply EDITOR:
Dr. Freedman is correct in pointing out the possibility for different diagnoses among various racial groups or among groups from different geographic locations. Most patients (about 90%) in our study were white. We are therefore unable to make any significant observations related to the issues raised by Dr. Freedman. DALE E. HENDERLY, ARLA J. GENSTLER, RONALD E. SMITH, NARSING A. RAO,
M.D. M.D. M.D. M.D.
Los Angeles, California
Reply EDITOR:
We thank H. H. Brown, B. J. Glasgow, and R. Y. Foos for their correspondence (Am. J. Ophthalmol. 103:726, May 1987) sharing the results of their study, which was triggered by our article, "Neuronal necrosis and hyperoxemia in premature infants" (Am. J. Ophthalmol. 102:423, October 1986). One must question, however, if the neonatal populations studied are similar. Our study involved a single large neonatal intensive care unit and we are uncertain of the derivation of the UCLA sample recorded by Brown, Glasgow, and Foos. This is especially important in premature infants born in outlying hospitals where face-mask oxygen is given in the delivery room or during transport to tertiary centers and blood gas levels are not recorded. Blood gas measurements were recorded in only five of 21 neonates studied by Brown, Glasgow, and Foos, which speaks to that point and we think it is hazardous to draw conclusions about oxygen toxicity in such a sample. Similarly, it is difficult to correlate karyorrhexis with length of survival if the time of hyperoxic insult is not known. The occasional occurrence of karyorrhexis in the eyes of stillborn infants is interesting, but does not negate the mechanism of oxygen toxicity in the neonate. Although hyperoxia, in the absence of well-developed antioxidant defense mechanisms, is the main cause of cellular karyorrhexis reflecting lipid peroxidation of cell membranes, toxic oxygen-free radicals may occur in the fetus in utero when triggered by high levels of prostaglandins and arachidonic acid, such as with prostaglandininduced abortion, or with chorioamnionitis and sepsis. We remain convinced that the ganglion cell is the cell type in the retina that is most sensitive in expressing hyperoxemic neuronal necrosis via its karyorrhectic appearance. In the brain, pontosubicular necrosis has been retained as a term of convenience for designating hyperoxemic neuronal necrosis as these are the areas that are the earliest and most severely involved. Lesions are, however, not strictly limited to those two sites as the hip-
Correspondence
Vol. 104, No. 1
pocampus, thalamus, caudate nucleus, cerebellum, and inferior olivary nuclei are also frequently involved. 1 Similarly, in the retina we occasionally saw karyorrhexis peripherally or in the inner nuclear layer, but most karyorrhectic cells are where ganglion cells are most numerous, that is, in the macula and not the periphery. Experimental evidence favors the hypothesis that those cases in which infants survive longer following a period of severe hyperoxeinia may trigger and maintain the continuous production of oxygen-free radicals and persistence of karyorrhexis. 2 This could explain some cases of peripheral retinal involvement. One should be cautious in accepting what is cytologically a karyorrhectic cell. Nuclear autolytic change, mitoses, and polymorphonuclear leukocytes can all be confused with karyorrhexis. In particular, karyorrhexis "within" retinal capillaries should be better defined. Mitotic activity of proliferating vascular endothelial cells is often impressive and is seen with frequency in premature infants and in newborn rats subjected to experimental hyperoxia. Karyorrhexis has been mistaken for neutrophils in the older neuropathologic literature. MAMDOUHA AHDAB-BARMADA, M.D. BRUCE L. JOHNSON, M.D.
Pittsburgh, Pennsylvania
References 1. Ahdab-Barmada, M , Moossy, j . , and Painter, M.: Pontosubicular necrosis and hyperoxemia. Pediatrics 66:840, 1980. 2. Ahdab-Barmada, M., Moossy, ]., Nemoto, E. M., and Lin, M. R.: Hyperoxia produces neuronal necrosis in the rat. J. Neuropathol. Exp. Neurol. 45:233, 1986.
Adverse Respiratory and Cardiovascular Events Attributed to Timolol Ophthalmic Solution, 1978-1985 Reply EDITOR:
On behalf of my coauthors, I thank Dr. Vogel for his comments (Am. J. Ophthalmol. 103:844, June 1987) on our article, "Adverse
97
respiratory and cardiovascular events attributed to timolol ophthalmic solution, 19781985" (Am. J. Ophthalmol. 102:606, November 1986), by W. L. Nelson, F. T. Fraunfelder, J. M. Sills, J. B. Arrowsmith, and J. N. Kuritsky. I would like to clarify our use of the word "attribute" in the context of spontaneous reporting of adverse drug experiences. In order for an adverse drug experience to be reported to the Food and Drug Administration Spontaneous Reporting System 1 or the National Registry of Drug-Induced Ocular Side Effects,2 the reporter must first recognize that an adverse event has occurred and associate this with a drug. This initial assessment may be prompted by a number of factors, such as a close temporal relationship between the drug exposure and the event, an apparent absence of other risk factors for the event, or an awareness of similar events previously described in association with the drug. In some instances more than one drug may be associated with an event. When the adverse drug experience is reported, the reporter designates one or more drugs as "suspect," and any other drugs that the patient may be taking as "concomitant medications." The reporter thus attributes (in the sense of ascribes) the adverse event to a particular drug. All the adverse event reports summarized in our article were reports for which timolol was designated the sole suspect drug by the reporter. The 32 deaths described in our article were reported by 28 physicians, two pharmacists, one paramedic, and one family member. As we indicated in our article, one must exercise caution when interpreting spontaneous reports of adverse drug reactions. Spontaneous reports are useful for generating signals of problems with drug use. In the case of timolol, the finding that at least 85% of the 32 patients who died had underlying cardiovascular or respiratory disease suggested to us that physicians were prescribing timolol for patients who were probably at risk for adverse reactions to beta blockers. We agree with Dr. Vogel that physicians should carefully review the medical history of patients being considered for beta-blocker therapy. The Office of Epidemiology and Biostatistics at the Food and Drug Administration is presently monitoring adverse drug experience reports for the three beta blockers approved for treating glaucoma: timolol, betaxolol, and levobunolol. Physicians are encouraged to submit adverse drug reaction reports to the