Ocular--hypertensive Response to Topical Steroids in Children

Alvin K. H. Kwok, FRCS,1 Dennis S. C. Lam, FRCS, FRCOphth/ Joan S. K. Ng, FRCS,1 Dorothy S. P. Fan, MBChB,1 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 ocular-hypertensive response to topical steroids in Chinese children.

Design: The study design was an institutional, randomized, clinical trial. Participants: A total of 19 consecutive patients were studied. Intervention: Topical steroids were administered to Chinese children younger than

10 years of age who underwent bilateral strabismus surgery. One eye was randomized to receive topical 0.1% dexamethasone (OMS), whereas the fellow eye received 0.1% 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 1, 3, 6, 10, 13, and 27, then every 2 weeks thereafter until the lOP fell to preoperative levels. Topical steroids would be stopped if lOP was 30.00 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 16 patients were included. The peak lOP for OMS-treated eyes was 30.66 ::+::: 8.35 mmHg (range, 13.00-48.00 mmHg), whereas that in FML-treated eyes was significantly lower at 20.66 ::+::: 6.03 mmHg (range, 11.30-36.30 mmHg) (P = 0.001). The maximal change in lOP ranged from -2.60 to +31 .00 mmHg in OMS-treated eyes (mean, 15.48 ::+::: 8.71 mmHg), almost double that of FML-treated eyes (range, +1.00 to +17.00 mmHg; mean, 5.83 ::+::: 4.96 mmHg) (P = 0.001). 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 = 0.001). 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 10 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 1997; 104:2112-2116

Originally received: October 28, 1996. Revision accepted: May 27, 1997.

Annual Meeting, Chicago, October 1996.

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

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The authors have no proprietary interest in any of the materials used in this study.

Reprint requests to Denni s S. C. Lam, FRCS, FRCOphth , Depart­ment of Ophthalmology & Visual Sciences , The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.

Kwok et al . Ocular-hypertensive Response to Steroids

Table 1. Ocular-hypertensive Response to Topical Corticosteroids

Characteristic Armalyll Becker13

3 times daily 4 wks

4 times daily 6 wks

Frequency of administration Duration of administration Parameter for class ification Classification system

Change in intraocular pressure Final intraocular pressure

Low responder Intermediate responder High responder

tllOP < 6 mmHg tllOP 6-15 mmHg tllOP > 15 mmHg

lOP < 20 mmHg lOP 20-31 mmHg lOP > 3 1 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 periocular7

,8 corticosteroids is well established. Even inhalation and nasal corticoste­roids9 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 10 also reported similar responses in children younger than 10 years of age who underwent strabismus surgery. Among the 11 children, 9 (82%) were high or intermediate responders according to the system by Armaly.1l 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 12 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 19 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 1995 and July 1996 were recruited. Inclusion criteria included age younger than 10, preopera­tive lOP of 21.00 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 0.1 % 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 0.1 % 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 30.00 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 1,3,6, 10, 13, 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

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Ophthalmology Volume 104, Number 12, December 1997

Table 2. Types of Recession Surgery for Strabismus

No. of Patients

10 3 2

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 21.00 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 Beckerl3

system, respectively (Table 1). 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, 19 consecutive patients were recruited. Their ages ranged from 2.75 to 9.92 years (mean, 6.10 :±: 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 30.00 mmHg in the DMS-treated eye at days 13 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, 30.66 :±: 8.35 mmHg; range, 13.00-48.00 mmHg) than for the FML-treated eyes (mean, 20.66 :±: 6.03 mmHg; range, 11.30-36.30 mmHg; P = 0.001). 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, 15.48 :±: 8.71 mmHg; range, -2.60-31.00 mmHg) than for the FML-treated eyes (mean, 5.83 :±: 4.96 mmHg; range, 1.00-17.00 mmHg; P = 0.001). However, there was no significant difference in maximal change of lOP between boys and girls caused by DMS and FML, respectively (P = 0.599 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 31 days (mean, 15.56 :±: 8.29 days) , whereas in the FML-treated eyes, the duration ranged from 1 to 35 days (mean, 14.94 :±: 11.04 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,13 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 = 0.001 and P = 0.004, respectively).

Table 3. Comparison of Clinical Characteristics among Patients on Dexamethasone and Fluoromethalone

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Variable Dexamethasone F1uoromethalone

Spherical equivalent (D) Mean:±: SD +0.23 :±: 1.07 +0.38 ± 1.28 Range (-2.75)-(1.75) (-2.75)-( + 3.00)

Preoperative lOP (mmHg) Mean:±: SD 15.18 ± 2.89 14.83 ± 3.25 Range 11.30-20.70 9.00-19.30

Maximal lOP change (mmHg) Mean ± SD 15.48 ± 8.71 5.83 ± 4.96 Range (-2.60)-( +31.00) (+ 1.00)-( + 17.00)

Peak lOP (mmHg) Mean:±: SD 30.66 ± 8.35 20.66 ± 6.03 Range 13.00-48.00 11 .30- 36.30

Time to peak lOP (days) Mean:±: SD 15.56 ± 8.29 14.94 ± 11.04 Range 3.00-31.00 1.00-35 .00

SD = standard deviation; D = diopter; lOP = intraocular pressure.

* Statistically significant at 95% confidence interval.

Paired t Test (P)

0.314

0.527

0.001 *

0.001 *

0.880

Kwok et al . Ocular-hypertensive Response to Steroids

Table 4. Categorization of Ocular-hypertensive Response to Steroids by the Armaly System11,*

Response

Drug Low Intermediate High

Dexamethasone Fluoromethalone

* Chi-square test: P = 0.001.

Discussion

1 10

6 5

9 1

In 1954, Francois4 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,14 especially in the face of increas­ing prevalence and severity of myopia in children. 15

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 (16%) of 19 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 16 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 System13,*

Response

Drug Low Intermediate High

Dexamethasone Fluoromethalone

* Chi-square test: P = 0.004.

1 8

7 7

8 1

elevated postoperative lOP. We excluded patients with primary open-angle glaucoma,17 first-degree relatives of these patients/3 and patients with diabetes 18 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,14 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 = 0.179). 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 1 and Becker13 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. 19

,20 Nonetheless, FML usage was associated with a high response in 6,25% (one case) and an interme­diate response in 31.25% (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 20.66 ± 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

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Ophthalmology Volume 104, Number 12, December 1997

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 48.00 mmHg.

Why should children have such markedly greater ocu­lar-hypertensive response to topical OMS than the adult population? In the study by Becker,13 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'Epinay21 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 al22 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 non­Chinese 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

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2. Alfano JE. Changes in the intraocular pressure associated with systemic steroid therapy. Am J Ophthalmol 1963; 56:245-7.

3. Cubey RB. Glaucoma following the application of cortico­steroid to the skin of the eyelids. Br J Dermatol 1976; 95:207-8.

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4. Francois J. Cortisone et tension oculaire. Ann Ocul 1954; 187:805-16.

5. Armaly MF. Effect of corticosteroids on intraocular pres­sure and fluid dynamics. 1. The effect of dexamethasone in the normal eye. Arch Ophthalmol 1963;70:482-91.

6. Becker B, Hahn KA. Topical corticosteroids and heredity in primary open-angle glaucoma. Am J Ophthalmol 1964; 57:543-51.

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