Ocular--hypertensive Response to Topical Steroids in Children

Transcription

1 Ocular--hypertensive Response to Topical Steroids in Children Alvin K. H. Kwok, FRCS, Dennis S. C. Lam, FRCS, FRCOphth/ Joan S. K. Ng, FRCS, Dorothy S. P. Fan, MBChB, Sek~Jin Chew, MD, PhD, 2 Mark O. M. Tso, MOl Objective: The purpose of the study is to investigate the rate and degree of ocularhypertensive response to topical steroids in Chinese children. Design: The study design was an institutional, randomized, clinical trial. Participants: A total of 9 consecutive patients were studied. Intervention: Topical steroids were administered to Chinese children younger than 0 years of age who underwent bilateral strabismus surgery. One eye was randomized to receive topical 0.% dexamethasone (OMS), whereas the fellow eye received 0.% fluorometholone (FML) six times per day for up to 4 weeks. Intraocular pressure (lop) was measured on the day before operation and at postoperative days, 3, 6, 0, 3, and 27, then every 2 weeks thereafter until the lop fell to preoperative levels. Topical steroids would be stopped if lop was mmhg or greater. Main Outcome Measures: Peak lop and maximal change of lop from baseline were measured and categorized into low, intermediate, and high levels. Time to peak lop also was studied. Results: A total of 6 patients were included. The peak lop for OMS-treated eyes was ::+::: 8.35 mmhg (range, mmhg), whereas that in FML-treated eyes was significantly lower at ::+::: 6.03 mmhg (range, mmhg) (P = 0.00). The maximal change in lop ranged from to mmhg in OMS-treated eyes (mean, 5.48 ::+::: 8.7 mmhg), almost double that of FML-treated eyes (range, +.00 to mmhg; mean, 5.83 ::+::: 4.96 mmhg) (P = 0.00). When the ocularhypertensive responses of both OMS and FML groups were categorized into three levels of severity, significant differences were found between the two treatment groups (P = 0.00). In the OMS group, nine patients (56.25%) were high responders and six patients (37.5%) were intermediate responders. In the FML group, only one patient (6.25%) was a high responder. Conclusions: The ocular-hypertensive response to topical OMS in children occurs more frequently, more severely, and more rapidly than that reported in adults. A total of 56% of the studied children, all younger than 0 years of age, were high responders to topical OMS. Of these, 89% attained their peak lop within 8 days. Its use in children should best be avoided if possible. It would be desirable to monitor the lop when it is being used. Conversely, FML produced a much less ocular-hypertensive effect and therefore poses an acceptable risk of clinically significant pressure elevation. Ophthalmology 997; 04:22-26 Originally received: October 28, 996. Revision accepted: May 27, 997. I Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. 2 Singapore Eye Research Institute, Singapore. Presented in part as a paper at the American Academy of Ophthalmology Annual Meeting, Chicago, October 996. The authors have no proprietary interest in any of the materials used in this study. Reprint requests to Dennis S. C. Lam, FRCS, FRCOphth, Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. 22

2 Kwok et al. Ocular-hypertensive Response to Steroids Table. Ocular-hypertensive Response to Topical Corticosteroids Characteristic Armalyll Becker3 Frequency of administration Duration of administration Parameter for classification Classification system Low responder Intermediate responder High responder 3 times daily 4 wks Change in intraocular pressure tllop < 6 mmhg tllop 6-5 mmhg tllop > 5 mmhg 4 times daily 6 wks Final intraocular pressure lop < 20 mmhg lop 20-3 mmhg lop > 3 mmhg ~IOP = change in intraocular pressure measured by applanation measurement; lop = final intraocular pressure by applanation measurement. Corticosteroids are commonly used as an anti-inflammatory agent in the treatment of various systemic as well as ocular diseases. The more common ocular side effects are cataract and ocular hypertension. The ocular-hypertensive response in adults to orav intravenous,2 topical dermatologic,3 topical ocular,4-6 and periocular 7,8 corticosteroids is well established. Even inhalation and nasal corticosteroids 9 were reported to be associated with ocular hypertension in susceptible adults. In contrast, literature describing this phenomenon in children is scarce. We have submitted a correspondence describing a child in whom severe intraocular pressure (lop) rise developed after receiving topical dexamethasone (DMS) for a few days. Ohji et al 0 also reported similar responses in children younger than 0 years of age who underwent strabismus surgery. Among the children, 9 (82%) were high or intermediate responders according to the system by Armaly.l However, in that study, lop of children younger than 6 years of age was measured by noncontact tonometry only and the time of lop measurement was not specified. In addition, there was no mention of family history of glaucoma or high myopia as exclusion criterion. Biedner et al 2 reported opposite results in children who received topical steroid treatment for vernal conjunctivitis. Of the 44 children, 39 (89%) were low responders. However, the age of children ranged from 4 to 9 years, reflecting the fact that the group was more heterogeneous and skewed tow(jid the adolescent population. Topical steroids commonly are used after various operations in children, such as for cataract, glaucoma, and strabismus surgery. The duration of use varies but sometimes can last for weeks. Because lop is less likely to be assessed routinely in children compared with that of adults, there is a need to better characterize the risk of steroid response in children. We conducted a prospecti ve study to evaluate the degree and time course of elevation in lop after the use of topical DMS in children. We also determined the relative benefits of using another topical steroid fluorometholone (FML), which may have a lower ocular-hypertensive effect in the same children. Materials and Methods Patients who underwent bilateral recession surgery for strabismus at Prince of Wales Hospital, Shatin, Hong Kong, between June 995 and July 996 were recruited. Inclusion criteria included age younger than 0, preoperative lop of 2.00 mmhg or less with a cup-disc ratio of 0.3 or less, and the absence of systemic disease and ocular disease (apart from strabismus) in both eyes. Exclusion criteria included a history of steroid usage in the past year, family history of glaucoma, and a failure to comply with lop measurements or the follow-up schedule. Institutional review board approval, as well as informed consent from parents, was obtained. All patients were operated on by two of us (JSKN or DSCL) while they were under general anesthesia. At the end of operation, no subconjunctival steroid was given. The eyes were treated with chloramphenicol ointment. As bilateral operation was done, one eye was randomized to receive topical 0. % dexamethasone (Maxidex; Alcon Laboratories, Ft Worth, TX) six times per day plus topical 0.5% chloramphenicol four times per day, whereas the other eye received topical 0. % fluorometholone (Flucon, Alcon Laboratories) six times per day plus topical 0.5% chloramphenicol four times per day. Topical treatment was commenced on the day of operation and continued for up to 4 weeks. The topical steroid assigned to that particular eye would be stopped before 4 weeks if the lop reached or exceeded mmhg. Topical chloramphenicol would, however, be continued at the same frequency. Ocular hypotensives would be started and closer follow-up instituted when necessary. The lop measurements were done in an assigned room that was quiet and comfortable. All children were accompanied by their parents and were taken care of by ophthalmic personnel experienced in dealing with children. Before measurements were taken, "demonstration" measurements from their parents were shown to the children. In addition, for noncontact tonometry, air puff was directed to children's hands or faces before actual measurement taken on their eyes. Similarly, spare applanation tonometer was used to touch their faces or hands before actual measurements. The lop was measured on the day before surgery and on postoperative days,3,6, 0, 3, 20, and 27. This was continued at two weekly intervals until lop normalized to preoperative levels. Three reliable measurements were obtained from each eye and the mean was taken. The lop measurements were taken within the same 2-hour period 23

3 Ophthalmology Volume 04, Number 2, December 997 Table 2. Types of Recession Surgery for Strabismus No. of Patients Nature of Strabismus Operations Bilateral lateral rectus recession Bilateral medial rectus recession Bilateral lateral rectus recession plus inferior oblique recession Bilateral inferior oblique recession of the day in each patient. Goldman applanation tonometry was performed if the lop measured by noncontact tonometry exceeded 2.00 mmhg. The investigator measuring the lop was blinded from the nature of the topical steroids being used. The two-tailed paired sample t tests were used to compare clinical characteristics between the DMS and FML groups. Ocular-hypertensive response was classified into three levels according to the Armaly II and the Becker l3 system, respectively (Table ). Chi-square tests were used in analyzing categories of response between different population groups. A P value of 0.05 was used as the level of significance. Results During the study period, 9 consecutive patients were recruited. Their ages ranged from 2.75 to 9.92 years (mean, 6.0 :±: 0.56 years). Among these patients, 37.5% were male. We excluded three patients from the study because of their poor cooperation with applanation tonometry. Of the three patients, two had lop of mmhg in the DMS-treated eye at days 3 and 20, respectively. The other child refused any postoperative lop measurement. Table 2 listed the types of recession surgery performed. No significant differences in the refractive error or preoperative lop were found between the eyes randomized to either of the two treatments (Table 3). After treatment, the peak lop was higher in the DMS-treated eyes (mean, :±: 8.35 mmhg; range, mmhg) than for the FML-treated eyes (mean, :±: 6.03 mmhg; range, mmhg; P = 0.00). There was no significant gender difference in peak lop in both treatment groups. The maximal change in lop was similarly greater in the DMS-treated eyes (mean, 5.48 :±: 8.7 mmhg; range, mmhg) than for the FML-treated eyes (mean, 5.83 :±: 4.96 mmhg; range, mmhg; P = 0.00). However, there was no significant difference in maximal change of lop between boys and girls caused by DMS and FML, respectively (P = and P = 0.426, respectively). The mean duration for the peak lop to be attained was similar in both treatment groups. In the DMS-treated eyes, the time to achieve peak lop ranged from 3 to 3 days (mean, 5.56 :±: 8.29 days), whereas in the FML-treated eyes, the duration ranged from to 35 days (mean, 4.94 :±:.04 days). The difference was not statistically significant (P = 0.880). Tables 4 and 5 Jist the three levels of ocular-hypertensive response of both DMS- and FML-treated groups according to the classification system proposed by Armalyll and Becker,3 respectively. Results were very similar between the two classification systems. There were statistically significant differences in various levels of ocularhypertensive response between the DMS- and FMLtreated groups using both systems (P = 0.00 and P = 0.004, respectively). Table 3. Comparison of Clinical Characteristics among Patients on Dexamethasone and Fluoromethalone Variable Dexamethasone Fuoromethalone Spherical equivalent (D) Mean:±: SD :±: ±.28 Range (-2.75)-(.75) (-2.75)-( ) Preoperative lop (mmhg) Mean:±: SD 5.8 ± ± 3.25 Range Maximal lop change (mmhg) Mean ± SD 5.48 ± ± 4.96 Range (-2.60)-( +3.00) (+.00)-( ) Peak lop (mmhg) Mean:±: SD ± ± 6.03 Range Time to peak lop (days) Mean:±: SD 5.56 ± ±.04 Range Paired t Test (P) * 0.00 * SD = standard deviation; D = diopter; lop = intraocular pressure. * Statistically significant at 95% confidence interval. 24

4 Kwok et al. Ocular-hypertensive Response to Steroids Table 4. Categorization of Ocular-hypertensive Response to Steroids by the Armaly System,* Response Drug Low Intermediate High Dexamethasone Fluoromethalone * Chi-square test: P = Discussion 0 In 954, Francois 4 first reported elevated lop, visual field loss, optic nerve cupping, and atrophy in patients using long-term steroid eyedrops. Since then, our clinical practice has become increasingly attuned to this complication, which accompanies various routes of administration of steroids, to prevent steroid-induced glaucoma. However, most of the studies on this problem have been on adults. We lack a clear understanding of any differences that may exist in the pediatric population. A case report describing a child in whom a rapid onset of severe lop elevation developed after strabismus surgery and topical steroids usage has just been accepted for publication in the British Journal of Ophthalmology, The need for information on the natural history of this therapeutic problem is accentuated by prevalent postoperative steroid use in the pediatric age group and the increased risk of steroid responders in myopes,4 especially in the face of increasing prevalence and severity of myopia in children. 5 Part of the reluctance to address this issue may be due because of difficulty in measuring lop repetitively and accurately in young patients. In our study, 3 (6%) of 9 children could not complete the study because of poor cooperation with applanation tonometry. Children were more amenable to noncontact tonometry than to applanation tonometry. Comparative studies of the two methods by Shields 6 have shown that noncontact tonometry is reliable for measuring lop within the normal range but has poorer correlation with Goldmann tonometry in the higher pressure ranges. The cause of lop elevation after steroid use and surgery can be multifactorial. Our study was designed to reduce confounding variables that also may contribute to Table 5. Categorization of Ocular-hypertensive Response to Steroids by the Becker System 3,* 6 5 Response Drug Low Intermediate High Dexamethasone Fluoromethalone * Chi-square test: P = elevated postoperative lop. We excluded patients with primary open-angle glaucoma,7 first-degree relatives of these patients/ 3 and patients with diabetes 8 who are at a greater risk of having raised lop develop when treated with corticosteroids. Because myopic individuals carry a higher risk of ocular hypertension and glaucoma,4 we have ensured that this is not a factor in our study as the mean refraction of the eyes was hyperopic. Additionally, there was no significant correlation between the spherical equivalent and the maximal rise of lop in either group. To address the concern that muscle resection during the strabismus surgery may lead to an lop rise, the strabismus operations selected involved only muscle recession. The possibility of having surgical damage occur to veins that drain aqueous and then causing elevation of lop was remote because only one or two muscles were operated on in each eye. Postoperative inflammation can lead to a postoperative rise of lop. Squint surgery, however, carries a far lower risk of this problem than intraocular operations. To support this contention, we found no significant differences in lop between the preoperative level and that on the first postoperative day (P = 0.79). We thus ascribe the changes in lop after strabismus surgery and steroid usage primarily to the latter. The classifications of steroid responses in adults as proposed by Armali and Becker 3 when applied to the children in our study suggest a high prevalence of steroid responsiveness. The Armaly system was based on the change of lop, whereas the Becker system depended on the absolute value of lop. The former is used in the analysis of results in this study for several reasons. First, the Armaly system is not dependent on the initial baseline lop. In the Becker system, those with baseline lop close to 20 mmhg would be very easily biased to become intermediate or even high responders. Second, the lop of each patient was measured within 2 hours of the same time of day at each visit, but different patients might have different time of lop measurement. We selected the Armaly system for analyzing our results to avoid the problem of individual diurnal variations in lop. The choice of topical steroid clearly affects the risk of ocular hypertension. As in adults, our study showed that DMS is associated with a more severe elevation of lop than FML. 9,20 Nonetheless, FML usage was associated with a high response in 6,25% (one case) and an intermediate response in 3.25% (five cases) of subjects, However, in this study, we cannot exclude the possibility that these effects might be influenced by the systemic absorption of DMS treatment or by inadvertent spillover of DMS eyedrops from the fellow eye, Moreover, the mean peak lop attained in the FML group was ± 6.03 mmhg, which was relatively and reasonably safe. Hence, it appears that even without lop monitoring, FML poses an acceptable risk of clinically significant pressure elevation in children who received short-term FML treatment. The role of topical nonsteroidal anti-inflammatory drug in the postoperative treatment of children may be a good alternative but needs further investigations, The greater and more rapid onset of ocular-hypertensive response to topical DMS in children compared with 25

5 Ophthalmology Volume 04, Number 2, December 997 that of adults reiterates the importance of discretion in prescribing topical steroids to children. This is further highlighted by the fact that symptoms and signs of ocular hypertension in children may be inconspicuous. We noted that most of our children with high or intermediate steroid responses were largely asymptomatic with minimal ciliary congestion, despite lop as high as mmhg. Why should children have such markedly greater ocular-hypertensive response to topical OMS than the adult population? In the study by Becker,3 topical steroid was given four times a day for 6 weeks, whereas steroid was given six times a day for, at most, 4 weeks in our study. Hence, the total amount of steroid given in our study actually was less. This suggests that the initial steroid "loading" dose may be more crucial than the length of treatment in steroid-induced glaucoma. Further studies are already underway to investigate this hypothesis. Another possible contributing factor is the degree of maturity of the drainage angle. Reme and d'epinay2 reported that chamber angle structures were immature at birth, and it took 8 years for the whole chamber angle to become as mature as that of the adult. Knepper et al 22 showed agedependent, steroid-induced glaucoma in a rabbit model. The young rabbits were steroid responders, whereas none of the older rabbits showed any lop rise. Because of the small sample size of our study, we cannot find any correlation between age and degree of lop rise. Further study is warranted to confirm or refute this proposition. Although our study showed that ocular-hypertensive response to topical OMS in children is common, severe, and rapid in onset, its clinical significance in the non Chinese patients has to be evaluated further because there are great racial differences in ocular-hypertensive response to topical steroids. Nevertheless, use in children still is cautioned, and monitoring of lop, especially during the early instillation period, is recommended. Conversely, because FML produced a much less ocular-hypertensive effect, its use is preferred to that of OMS. References. Covell LL. Glaucoma induced by systemic steroid therapy [case report]. Am J Ophthalmol 958;45 : Alfano JE. Changes in the intraocular pressure associated with systemic steroid therapy. Am J Ophthalmol 963; 56: Cubey RB. Glaucoma following the application of corticosteroid to the skin of the eyelids. Br J Dermatol 976; 95: Francois J. Cortisone et tension oculaire. Ann Ocul 954; 87: Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics.. The effect of dexamethasone in the normal eye. Arch Ophthalmol 963;70: Becker B, Hahn KA. Topical corticosteroids and heredity in primary open-angle glaucoma. Am J Ophthalmol 964; 57: Herschler J. Intractable intraocular hypertension induced by repository triamcinolone acetonide. Am J Ophthalmol 972;74: Kalina RE. Increased intraocular pressure following subconjunctival corticosteroid administration. Arch Ophthalmol 969;8: Opatowsky I, Feldman RM, Gross R, Feldman ST. Intraocular pressure elevation associated with inhalation and nasal corticosteroids. Ophthalmology 995; 02: Ohji M, Kinoshita S, Ohmi E, Kuwayama Y. Marked intraocular pressure response to instillation of corticosteroids in children. Am J Ophthalmol 99; 2: II. Armaly MF. Statistical attributes ofthe steroid hypertensive response in the clinically normal eye. I. The demonstration of three levels of response. Invest Ophthalmol 965;4: Biedner BZ, David R, Grudsky A, Sachs U. Intraocular pressure response to corticosteroids in children. Br J Ophthalmol 980; 64: Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 965;4: Podos SM, Becker B, Morton WR. High myopia and primary open-angle glaucoma. Am J Ophthalmol 966; 62: Lin LL, Chen CJ, Hung PT, Ko LS. Nation-wide survey of myopia among schoolchildren in Taiwan, 986. Acta Ophthalmol Suppl 988; 85: Shields MB. The non-contact tonometer. Its value and limitation. Surv Ophthalmol 980;24: Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics. II. The effect of dexamethasone in the glaucomatous eye. Arch Ophthalmol 963; 70: Becker B. Diabetes mellitus and primary open-angle glaucoma. The XXVII Edward Jackson Memorial Lecture. Am J Ophthalmol 97; 77: Morrison E, Archer DB. Effect of fluorometholone (FML) on the intraocular pressure of corticosteroid responders. Br J Ophthalmol 984;68: Akingbehin AO. Comparative study of the intraocular pressure effects of fluorometholone 0. % versus dexamethasone 0.%. Br J Ophthalmol 983;67: Reme C, d'epinay SL. Periods of development of the normal human chamber angle. Doc OphthalmoI98;5: Knepper PA, Breen M, Weinstein HG, Blacik JL. Intraocular pressure and gjycosaminogjycan distribution in the rabbit eye: effect of age and dexamethasone. Exp Eye Res 978;27: