ORIGINAL STUDY
Change in Intraocular Pressure in the Fellow Eye After Glaucoma Surgery in 1 Eye Sushmita Kaushik, MD, Aniruddha Agarwal, MD, Savleen Kaur, MD, Neiwete Lomi, MD, Srishti Raj, MD, and Surinder S. Pandav, MD
Purpose: To measure the change in intraocular pressure (IOP) of the fellow eye after glaucoma surgery in 1 eye. Patients and Methods: In this prospective interventional study, 71 patients with primary and secondary glaucoma, undergoing glaucoma surgery in 1 eye were included. The IOP in the fellow eye following glaucoma surgery in 1 eye from the first postoperative week till 6 months following surgery was studied. Both normal and glaucomatous fellow eyes were included. IOP change from preoperative IOP levels in the fellow eye was analyzed. Patients treated with acetazolamide preoperatively were analyzed separately. Results: The mean baseline IOP of the operated and fellow eyes was 28.14 ± 9.4 and 16.5 ± 6.1 mm Hg, respectively. IOP of fellow eyes significantly increased compared with baseline at all timepoints (P < 0.001), with a maximum rise 6 weeks postoperatively (4.8 ± 3.3 mm Hg). There was no significant difference in the consensual rise between glaucomatous and nonglaucomatous fellow eyes, or between patients treated with or without acetazolamide before surgery. Regression analysis showed no baseline factor associated with the rise in IOP. By the sixth postoperative month, 24 patients required surgery or needed an increase in medications in the fellow eye for IOP control. Conclusions: Glaucoma surgery in eye is associated with a rise in IOP of the fellow eye, regardless of whether the fellow eye is normal or glaucomatous, or had been previously treated with acetazolamide. Fellow eyes of all patients scheduled for glaucoma surgery require careful monitoring of the IOP. Key Words: contralateral intraocular pressure, glaucoma surgery, trabeculectomy, ophthalmic consensual reaction, other eye IOP
(J Glaucoma 2016;25:324–329)
n 1924 Weekers1 sscoined the term “consensual ophthalmotonic reaction” to describe the corresponding pressure change in the contralateral eye after alteration of the intraocular pressure (IOP) in 1 eye. Postulated mechanisms suggest involvement of neuronal, hormonal, and cytokine regulation of aqueous flow dynamics, but the exact mechanism is yet to be elucidated.2,3 A consensual response to antiglaucoma therapy has been shown in normal and glaucomatous subjects,4–9 following uniocular tomography10 and a small decrease has also been reported in the untreated fellow eye after laser
I
Received for publication April 22, 2014; accepted November 27, 2014. From the Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Disclosure: The authors declare no conflict of interest. Reprints: Sushmita Kaushik, MD, Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000217
trabeculoplasty.11–13 Gibbens14 reported that the consensual ophthalmotonic reaction appears to occur in man regardless of the drug used to lower IOP in the treated eye. This was, however, later refuted by Newman et al15 who reported reduction in contralateral untreated eyes only with timolol and not prostaglandins or carbonic anhydrase inhibitors. The response of the fellow eye IOP to trabeculectomy in 1 eye is even more uncertain. Reports in literature are conflicting,16–18 and it is difficult to draw concrete conclusions chiefly because of the variability and inconsistent methodology of the studies. The fellow eyes reported were normal and glaucomatous, unoperated and operated, and on treatment and without treatment. The aim of the present study was to see the behavior of the IOP in the unoperated normal and glaucomatous fellow eye when 1 eye underwent glaucoma surgery, to see if the presence of glaucoma in the fellow eye altered the response in anyway.
METHODS This study was undertaken at a tertiary care referral institute. Patients who required surgical reduction of IOP and presented between August 2012 and January 2013were prospectively enrolled. The Institute Ethics Committee approval was obtained (NK/562/Res/2327) and the study adhered to the tenets of the declaration of Helsinki. Informed consent was obtained from all recruited patients. Patients scheduled for trabeculectomy or glaucoma drainage device implantation [Ahmed Glaucoma Valve, Model FP7; New World Medical Inc., CA or Aurolab Aqueous Drainage Implant (AADI); Aurolab, Madurai, India] in 1 eye, were included. They all had inadequate IOP control on maximally tolerated medical therapy. Patients with both primary and secondary glaucoma were included, where the other eye was glaucomatous or normal, respectively. Fellow eyes with a history of laser treatment for glaucoma such as laser iridotomy or trabeculoplasty or any intraocular surgery were excluded. Only glaucomatous fellow eyes on medical treatment were included in the study. Patients with concurrent ocular or systemic disease (apart from glaucoma) in either eye such as uveitis and/or previous surgery requiring steroids; diabetes, hypertension (those receiving systemic b-blockers); or vascular occlusions were excluded. Details of topical and systemic antiglaucoma medications prescribed were recorded. All eligible patients underwent a comprehensive ophthalmologic examination of both eyes including best-corrected visual acuity in LogMAR units, IOP measured by Goldmann Applanation Tonometry, slit-lamp biomicroscopy, gonioscopy, and stereoscopic fundus evaluation on the slit-lamp using a 90.0 D lens. An average of 3 IOP
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measurements was computed for analysis; if they differed by >2.0 mm Hg, a fourth reading was taken and the average of the 3 closest values was used for analysis. Color stereoscopic optic disc photographs and red-free nerve fiber layer photographs were taken on the Zeiss Fundus camera FF 450 with VISUPAC System 451 (Carl Zeiss Ophthalmic Systems, Jena, GmBH, Germany). The subjects underwent baseline Standard Automated Perimetry on the Humphrey’s Field Analyzer HFA 750 II (Carl Zeiss-Humphrey Systems, Dublin, CA) using the 24-2 testing protocol by SITAStandard strategy. The same surgical technique was used in all patients undergoing trabeculectomy including creation of 4 4 mm partial-thickness scleral flap followed by application of mitomycin C (MMC) 0.02% for 2 minutes in the subconjunctival space before entry into the eye. Standardized technique was used for implantation of the glaucoma drainage device which included insertion of the device into a quadrant free from conjunctival scarring, suturing the plate at least 10.0 mm from the limbus and insertion of the tube in the anterior chamber or ciliary sulcus in pseudophakic or aphakic patients. Postsurgery follow-up visits were variable according to the requirement of trabeculectomy bleb management. However, for the purpose of this study, all patients underwent IOP measurement in both eyes using Goldmann Applanation Tonometry at day 1, day 7, 3 weeks, 6 weeks, 3 months, and 6 months after surgery. The time of IOP measurement was kept within 2 hours of measurement at each visit. IOP rise was defined as clinically significant if it was >4.0 mm Hg from that recorded at baseline. IOP was measured by the same examiner who had measured the baseline IOP, at all timepoints after surgery. Patients who required added intervention for IOP control (whether in the form of additional medications or surgery) in the fellow eye following glaucoma surgery in the first eye, were subsequently excluded from analysis. The final analysis included only those eyes which were on no additional IOP control during the follow-up period. We did not remove these patients from the analysis completely, so that we could have more numbers of patients in the period in which they were not prescribed any medications for IOP control.
Change in IOP in the Fellow Eye
TABLE 1. Diagnosis of the Operated and Fellow Eyes
Diagnosis POAG PACG SOAG SACG JOAG Nonglaucomatous (only fellow eye) Total
Age (Mean ± SD) (y)
Operated Eye (n)
Fellow Eye (n)
24 8 23 5 11 0
24 8 3 0 11 25
51.03 ± 19.2 56.9 ± 9.7 42.8 ± 19.2 53.6 ± 19.1 25.4 ± 15.6
71
71
45.3 ± 19.9
JOAG indicates juvenile open-angle glaucoma; PACG, primary angleclosure glaucoma; POAG, primary open-angle glaucoma; SACG, secondary angle-closure glaucoma; SOAG, secondary open-angle glaucoma.
and 17 females) completed all follow-up visits and their data were analyzed. The mean age was 45.3 ± 19.9 years (range, 15 to 80 y). There was no difference in age between men and women (P = 0.124). Diagnosis of the operated eye and fellow eye are summarized in Table 1. Primary openangle glaucoma (POAG), primary angle-closure glaucoma (PACG), and juvenile open-angle glaucoma (JOAG) were all bilateral. Three of the 7 steroid-induced secondary openangle glaucoma were bilateral, whereas the rest were unilateral traumatic glaucoma (11) and postsurgical glaucoma (5). Of the 5 secondary angle-closure glaucoma, 4 were neovascular glaucoma and 1 was secondary to iridocorneal endothelial syndrome, and they all had uniocular presentation. Twenty-five fellow eyes were normal. Baseline characteristics of the operated and fellow eyes are detailed in Table 2. The mean baseline IOP of the eyes undergoing surgery was 28.1 ± 9.4 mm Hg on maximum tolerated therapy and the fellow unoperated eyes was 16.5 ± 6.1 mm Hg (P < 0.001). Mean number of topical antiglaucoma drugs (including b-blockers, prostaglandins, topical carbonic anhydrase inhibitors, pilocarpine, and a-agonists) in the eyes undergoing surgery was 2.9 ± 1.2 and 49 patients (69.01%) required additional systemic acetazolamide therapy. The mean number of drugs being used in the fellow glaucomatous eyes was
Statistical Analysis Data analysis was performed using the IBM SPSS Statistics, version 20.0 (SPSS Inc., Chicago, IL). Descriptive statistics were computed for all the variables measured. Wilcoxon signed-rank test was used to compute the preoperative and postoperative IOP in both eyes in all patients. Mann-Whitney U test was used to compare the change in IOP between glaucomatous and nonglaucomatous fellow eyes, and in fellow eyes of patients who were and were not on systemic acetazolamide preoperatively. Results were considered significant at P < 0.05. Linear regression analysis was done to analyze the effect of age, sex, glaucoma diagnosis, baseline IOP, magnitude of fall in IOP in the first eye, treatment with acetazolamide, and number of topical antiglaucoma drugs, on the rise of IOP in the consensual eye.
RESULTS Seventy-four patients met the inclusion criteria and were included in the study. Seventy-one of them (54 males Copyright
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TABLE 2. Baseline Data of Operated and Fellow Eyes
Mean ± SD Operated Eyes (N = 71)
Parameters BCVA (LogMAR) Mean IOP (mm Hg) Mean CDR Mean CCT (mm) No. topical medications at baseline No. patients on oral acetazolamide before surgery [n (%)]
Fellow Eyes (N = 71)
P*
0.45 ± 0.33 0.38 ± 0.31 0.191 28.1 ± 9.4 16.5 ± 6.1 < 0.001 0.67 ± 0.2 0.60 ± 0.2 0.117 526.6 ± 37.4 530.7 ± 37.6 0.495 2.9 ± 1.2 1.73 ± 1.7 0.910 49 (69.01)
BCVA indicates best-corrected visual acuity for distance; CCT, central corneal thickness; CDR, vertical cup-disc ratio; IOP, intraocular pressure. *Mann-Whitney U test.
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Volume 25, Number 3, March 2016
TABLE 3. Intraocular Pressure at Each Timepoint in All Fellow Eyes
Change From Baseline (mm Hg) 95% Confidence Intervals Time Interval From Surgery Baseline intraocular pressure (n = 71) Day 1 (n = 71) Day 7 (n = 71) Week 3 (n = 71) Week 6 (n = 65) Month 3 (n = 61) Month 6 (n = 47)
Mean ± SD (mm Hg) (Mean ± SD)
Lower Bound
Upper Bound
P*
3.1 2.8 3.5 3.9 3.8 2.2
3.9 4.2 4.8 5.6 5.5 4.4
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Z4 mm Hg Intraocular Pressure Rise From Baseline n (%)
16.5 ± 6.1 20.1 ± 6.1 20.1 ± 6.6 20.6 ± 6.3 19.98 ± 5.5 19.3 ± 5.2 17.5 ± 3.2
3.5 ± 1.8 3.5 ± 2.7 4.1 ± 2.8 4.7 ± 3.3 4.3 ± 3.5 3.3 ± 3.6
40 37 43 42 39 33
(56.3) (52.1) (60.5) (64.6) (63.9) (70.2)
*Wilcoxon signed-rank test.
1.73 ± 1.7. None of the eyes had undergone previous glaucoma surgery or cyclodestruction procedure. The type of surgery was decided based on the type of glaucoma, associated ocular findings, and discussion with the patient. Fifty-five eyes (77.5%) underwent trabeculectomy with MMC, whereas a glaucoma drainage device was implanted in 16 eyes (22.5%) that included Ahmed Glaucoma Valve in 9 eyes (12.7%) and AADI (Baerveldt prototype) in 7 eyes (9.9%). At the sixth postoperative month, of the 71 operated eyes, 52 (73.2%) had complete success requiring no medication to achieve target IOP, 14 patients (19.7%) had a qualified success and required 1 or 2 medications to control IOP, and 5 patients (7%) required 3 or more medications for IOP control and constituted failure. The respective average number of topical medications required at baseline and follow-up in these 3 groups was as follows: patients with complete success were on 2.9 ± 1.26 topical drugs at baseline and had adequate IOP control without medications following surgery. Those with qualified success were on 2.57 ± 1.28 drugs at baseline which reduced to 1.42 ± 0.5 drugs at 6-month follow-up (P = 0.006), whereas those classified as failures required 3.4 ± 0.54 drugs preoperatively which remained at 3.2 ± 0.45 drugs 6 months after surgery (P = 0.55). At each postoperative visit, the IOP of the fellow eye significantly increased compared with baseline (P < 0.001) (Table 3). The rise was observed from the first postoperative day itself and it was maximum at the sixth postoperative week, when it stayed elevated till the sixth postoperative month. By week 6, 6 patients required additional antiglaucoma drugs or surgery for their IOP rising beyond acceptable limits, and analysis was completed for the remaining 65 patients. By the third month this number rose to 4 more patients, and analysis of the third month was done for the remaining 61 patients. By the sixth month, 47 patients remained in the analysis as additional drugs or surgery was required in the fellow eyes of 14 more patients. Clinically significant rise (>4.0 mm Hg) in IOP was observed in fellow eyes of 40 patients (56.3%) on the first postoperative day and persisted in 33 of 47 (70.2%) patients analyzed at the sixth postoperative month. Baseline data of patients with and without significant rise in IOP at each timepoint was analyzed. There was no significant difference in any parameter between the 2 groups at the third and sixth month after surgery.
Trabeculectomy was performed in the fellow eyes in 3 patients by the sixth week, 2 patients by the third month, and 9 patients between the third and sixth month following surgery in the first eye. Of these 14 patients, surgery was planned in the fellow eye at the time of the first eye surgery itself in 9 patients (whose IOP rose significantly nevertheless), and was required in 5 more patients, where maximum medication could no longer control the IOP which significantly rose after the first surgery. The IOP rise in the fellow eye was compared in glaucomatous versus nonglaucomatous fellow eyes, and in patients who were on systemic acetazolamide and those who were not (Table 4). There was no statistically significant difference in the IOP in glaucomatous fellow eyes compared with nonglaucomatous fellow eyes. However, even those eyes which were nonglaucomatous to start with, required antiglaucoma medications in an increasing number of patients from the third postoperative month onwards resulting in 8 patients by 6 months. They were 4 fellow eyes of steroid-induced glaucoma, 2 fellow eyes of neovascular glaucoma, and 2 fellow eyes of traumatic glaucoma. These patients were subsequently excluded from further analysis. Systemic acetazolamide was withdrawn postoperatively in those who had been prescribed the drug. To study whether this withdrawal was responsible for the rise in IOP of the fellow eye, patients with and without preoperative acetazolamide were separately analyzed (Table 4). There was no significant difference in the mean IOP rise between the 2 groups, although there was a greater rise in IOP measured in patients who were on preoperative acetazolamide between 6 and 12 weeks following surgery, after which it stabilized. Regression analysis showed no relationship to the magnitude of the consensual rise in IOP as regards the age or sex of the patient, baseline IOP, diagnosis of glaucoma, type of surgery, or the magnitude of IOP fall in the first eye. The mean IOP rise was also analyzed at each point in patients with different diagnoses of glaucoma. PACG eyes showed the maximum rise at all timepoints, but the differences from other diagnoses did not reach statistical significance. The factor of increased steroid responsiveness in glaucoma patients was kept in mind, and the pattern of postoperative steroid use was analyzed. Systemic steroids was prescribed postoperatively in a total of 5 patients—2 patients with steroid-induced glaucoma, 1 patient with
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Change in IOP in the Fellow Eye
TABLE 4. Mean Change in IOP in Normal and Glaucomatous Fellow Eyes, and Those Treated With and Without Acetazolamide
Baseline to first postoperative day (n = 71) (mm Hg) Baseline to postoperative day 7 (n = 71) (mm Hg) Baseline to third postoperative week (n = 71) (mm Hg) Baseline to sixth postoperative week (n = 65) (mm Hg) Baseline to third postoperative month (n = 61) (mm Hg) Baseline to sixth postoperative month (n = 47) (mm Hg)
Glaucomatous Fellow Eye
Nonglaucomatous Fellow Eye
3.7 ± 1.9 (n = 46) 3.8 ± 2.7 (n = 46) 3.9 ± 2.8 (n = 46) 4.6 ± 3.4 (n = 42) 4.9 ± 3.7 (n = 39) 4.3 ± 2.4 (n = 30)
3.2 ± 1.7 (n = 25) 3.0 ± 2.6 (n = 25) 4.5 ± 2.7 (n = 25) 5.0 ± 3.3 (n = 23) 4.1 ± 2.7 (n = 22) 4.6 ± 2.4 (n = 17)
Fellow Eyes of Patients on Acetazolamide P* Before Surgery 0.38 0.26 0.46 0.66 0.54 0.66
Fellow Eyes of Patients Without Acetazolamide
3.6 ± 1.8 (n = 49) 3.3 ± 2.8 (n = 49) 4.0 ± 2.8 (n = 49) 5.1 ± 3.2 (n = 43) 5.2 ± 3.7 (n = 41) 4.6 ± 2.4 (n = 29)
3.5 ± 1.8 (n = 22) 4.0 ± 2.5 (n = 22) 4.4 ± 2.7 (n = 22) 4.2 ± 3.4 (n = 22) 3.4 ± 2.4 (n = 20) 4.2 ± 2.7 (n = 18)
P* 0.82 0.26 0.61 0.23 0.10 0.67
IOP indicates intraocular pressure. *Mann-Whitney U test.
POAG, 1 with JOAG, and 1 case with neovascular glaucoma. Of these 5, 2 patients had significant rise of IOP in the fellow eye. The medication regime of the unoperated eye was carefully checked as antiglaucoma medication was withdrawn in the operated eye. The patient and their attendants were counseled thoroughly before discharge from the operating room. At the postoperative follow-up visits, we checked for compliance by directly asking the patient.
DISCUSSION Most reports of change in IOP in the fellow eye following IOP reduction in 1 eye by drugs,4–9 ocular compression,10 or laser trabeculoplasty11–13 have reported a decrease in IOP. The response of the fellow eye to surgical reduction of IOP is not as certain. Wilmer19 in 1927 reported in experimental animals a fall in IOP in 1 eye after a fistulisation operation on the other eye. In contrast, Al-Ghadyan et al20 in 1956 reported a consensual increase in IOP in the contralateral eye in rabbits after paracentesis in 1 eye and postulated the role of increased prostaglandin release as a response to trauma as a possible explanation. In human eyes, reports are conflicting. Yarangu¨meli et al16 reported a rise in IOP in the fellow eye following trabeculectomy in 1 eye. All their patients had POAG, pseudoexfoliation glaucoma, or angle-closure glaucoma. Fellow eyes were medically controlled. Those not on medications had pseudoexfoliation or had had laser iridotomy for narrow angles. Thus no patient was normal. This was followed by a report by Vysniauskiene et al17 who, in contrast, reported a decrease in IOP following surgical reduction in 1 eye. Of note, among the 24 fellow eyes in the study, 12 of them had undergone trabeculectomy with MMC and 11 (45.8%) were on topical ocular hypotensive therapy. It could be possible that the presumed “ophthalmotonic consensual reaction” may be modified in an unknown way by the topical medications or surgery, thereby affecting the interpretation of their results. As trabeculectomy is usually planned when the IOP is high on the variation curve, the decreased IOP in the fellow eye could be the result of the “regression to the mean” effect. Copyright
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A post hoc analysis of data of the Collaborative Initial Glaucoma Treatment Study by Radcliffe et al21 demonstrated no substantial effect of trabeculectomy on the fellow eye, although contrary to our findings, there was a decreasing trend of IOP in the fellow eye at all timepoints. Their analysis included only primary glaucoma, so all their fellow eyes were glaucomatous. More recently, Detorakiset al18 studied the change in IOP of fellow eyes following trabeculectomy in 1 eye, and reported a decrease on the fourth postoperative day, but by 3 months they found no change in IOP in the fellow eye. In the backdrop of this inconsistency, we attempted to study the IOP response in both normal and glaucomatous fellow eyes following glaucoma surgery. We found a uniform increase in the fellow eye IOP across all categories of patients, including those with glaucomatous or nonglaucomatous fellow eyes, or those who had received systemic acetazolamide or had not. Various theories have been postulated that may explain this finding. Diestelhorst and Krieglstein3 studied the effect of trabeculectomy on the aqueous humor flow of the unoperated fellow eye, using computerized anterior chamber fluorophotometry. Aqueous humor flow was measured before surgery and on the fifth day after trabeculectomy. The average postoperative flow in the fellow eye significantly increased from 2.56 to 2.9 mL/min. They postulated that filtration surgery in 1 eye triggers a central nervous system–mediated reflective increase in aqueous flow to maintain physiological stability in the anterior chamber of the surgically treated eye. As this central nervous system reflex on aqueous humor dynamics affects both eyes, it might explain the increase in IOP we observed in the unoperated fellow eye. Another explanation is the possible existence of an ophthalmotonic consensual reaction as postulated by Weekers.1 In this phenomenon, alteration of the IOP in 1 eye is accompanied by a corresponding pressure change in the contralateral eye. It has also been suggested that glaucoma surgery leads to activation of nervous mechanisms leading to increase in fellow eye aqueous production.22 A possible supraoptic controlling pathway has been described in an animal experiment showing rise in IOP in response to water drinking after unilateral optic nerve sections.23
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It is interesting that in our study, the magnitude of consensual IOP rise was significant to the extent that of the 71 patients enrolled, by the sixth postoperative month, fellow eyes of only 47 patients did not need enhancement of antiglaucoma treatment after glaucoma surgery in 1 eye. Five patients who were not planned for glaucoma surgery in the fellow eye required it for inadequate IOP control by medications. In fact the magnitude of IOP rise at later timepoints is actually underestimated, as we excluded those patients whose raised IOP required additional medications or surgery in the fellow eye. The results were a little surprising, especially in those with normal fellow eyes, because we expected a normal trabeculum to have sufficient compensatory outflow mechanism to account for the postulated “ophthalmotonic consensual reaction” of increased aqueous secretion in both eyes in response to reduced IOP in the operated eye. There might have been a possibility of consensual IOP rise due to withdrawal of antiglaucoma medications in the first eye, and this was one of the possibilities for the consensual rise in IOP that we kept in mind. Medications in 1 eye, especially timolol are known to decrease IOP in the fellow eye. Overall, the contralateral eye effect is reported to be smaller in normotensive eyes than in hypertensive eyes; however, there is great variability of results in both the groups. The largest study to look at this effect in hypertensive eyes came from the OHTS study, which reported a mean 1.5 mm Hg reduction in IOP in the contralateral untreated eye,4 which was comparable to the mean 2.1 mm Hg reduction described by Wilson et al24 in 76 glaucomatous subjects and the 2.2 mm Hg reduction in 15 subjects randomized to receive timolol by Zimmerman and Kaufman.5 Martin and Rabineau7 found no significant decrease in IOP in contralateral eyes when normal volunteers were tested. In our study, those patients who had received preoperative acetazolamide showed a higher rise in IOP from the sixth week onwards, indicating that the high IOP was probably “masked” preoperatively. However, we also found a significant consensual rise of IOP in those patients who were not treated with acetazolamide, so it is difficult to draw definitive conclusions at present. The magnitude of mean IOP rise in glaucomatous and nonglaucomatous fellow eyes was similar. This rise is more than what would be expected by just a reversal of the effect of antiglaucoma medication in the treated eye, especially if we consider that all glaucomatous eyes were on medical treatment as well. Further, a lot of our patients were on prostaglandins alone, and not timolol, which is the drug that has been most commonly known to be associated with contralateral eye decrease in IOP. We also looked at the rise in IOP in different diagnostic groups. The PACG subset showed the maximum rise but the number of patients were probably too less to draw meaningful conclusions (8 eyes to start with and 5 after 6-mo follow-up). We also thought of increased steroid responsiveness in glaucoma patients and reviewed our postoperative steroid prescription. In our usual surgical protocol, we do not use systemic steroids routinely. It is prescribed in cases which have postoperative choroidal effusion either due to or as a consequence of hypotony. In this study, on reviewing our data, we found that we had prescribed systemic steroids in a total of 5 patients, of which 2 patients had significant rise of IOP in the fellow eye. It is likely that mechanisms other than steroid responsiveness played a role in the IOP response that we saw.
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The inconsistency in literature may be explained by the spectrum of changes that can occur in the fellow eye following glaucoma surgery. A complex set of mechanisms controlling the IOP may be involved, including neuronal, hormonal, cytokine, and systemic drug effect. The predominance of 1 mechanism resulting due to a particular intervention may guide the IOP changes in the fellow eye. However, a mixture of all these mechanisms acting together following glaucoma surgery may result in a trend toward either an increase or decrease in IOP. The clinical importance of this study is to recognize these changes in IOP possible after glaucoma surgery due to multitude of factors coming in play. A relevant message is that the fellow eye needs to be carefully monitored after glaucoma surgery in 1 eye. In many instances, the fellow eye is often the one with useful vision. Failure to recognize and monitor IOP changes carefully may unnecessarily delay treatment and appropriate management of these eyes. In addition, fellow eyes already damaged by glaucomatous processes may be at significant risk of glaucoma progression due to higher IOP levels in the postoperative period. In addition, this study reiterates that in studies of 1OP responses to a particular treatment the fellow eye should not be used as a control. Limitations of our study include a small patient cohort with few numbers in each subgroup to enable a detailed analysis of the IOP rise in primary compared with secondary glaucoma. However, a consistent demonstration of rise of IOP validates the data. Compliance of medications in the other eye is another possible limitation but it is believed that there is heightened sensitivity among patients for antiglaucoma drugs following lasers or surgery, so this factor is likely to result in decreased IOP after surgery rather than increase. It is standard practice for us to check for compliance by directly asking the patient and checking their drugs, and the patients were compliant with the medications prescribed in the unoperated eye. Like previous studies, the present study is not able to conclusively demonstrate the possible mechanism responsible for changes in IOP. Although the evidence for existence of ophthalmotonic consensual reaction is strengthened, larger studies with more patients in each glaucoma category may shed light on its exact biological role. REFERENCES 1. Weekers L. Modification expe´rimentales de l’ophtalmotonous. Reaction ophtalmotonique consenuelle. Arch Opthalmol (Paris). 1924;41:641–658. 2. Feher J. Glaucoma: Pathophysiology of the Eye. Budapest: Acade´miai Kiado´ Publications; 1998. 3. Diestelhorst M, Krieglstein G. The effect of trabeculectomy on the aqueous humor flow of the unoperated fellow eye. Graefes Arch Clin Exp Ophthalmol. 1991;229:274 – 276. 4. Piltz J, Gross R, Shin DH, et al. Contralateral effect of topical beta-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2000;130:441–453. 5. Zimmerman TJ, Kaufman HE. Timolol: a beta-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol. 1977;95:601–604. 6. Kwitko GM, Shin DH, Ahn BH, et al. Bilateral effects of longterm monocular timolol therapy. Am J Ophthalmol. 1987;104: 591–594. 7. Martin XD, Rabineau PA. Intraocular pressure effects of timolol after unilateral instillation. Ophthalmology. 1988;95: 1620–1623.
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8. Howell SC. Action of epinephrine on the normal human eye. Arch Ophthalmol. 1934;12:833–841. 9. Willetts GS. Autonomic effector drugs and the normal eye. Am J Ophthalmol. 1969;68:216–223. 10. Stocker FW. On changes in intraocular pressure after application of the tonometer. Am J Ophthalmol. 1958;45:192–196. 11. Schwartz AL, Whitten ME, Bleiman B, et al. Argon lasertrabecular surgery in uncontrolled phakic open-angle glaucoma. Ophthalmology. 1981;88:203–212. 12. Latina MA, Sibayan SA, Shin DH, et al. Q-switched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology. 1998;105: 2082 –2088. 13. Rhodes KM, Weinstein R, Saltzmann RM, et al. Intraocular pressure reduction in the untreated fellow eye after selective laser trabeculoplasty. Curr Med Res Opin. 2009;25:787 – 796. 14. Gibbens MV. The consensual ophthalmotonic reaction. Br J Ophthalmol. 1988;72:746–749. 15. Newman H, Kurtz S, David R. Intraocular pressure changes in the contralateral eye after topical treatment: does an “ophthalmotonic consensual reaction” exist? Isr Med Assoc J. 2010;12:568–571. 16. Yarangu¨meli A, Ko¨z OG, Kural G. The effect of trabeculectomy on the intraocular pressure of the unoperated fellow eye. J Glaucoma. 2003;12:108–113.
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17. Vysniauskiene I, Shaarawy T, Flammer J, et al. Intraocular pressure changes in the contralateral eye after trabeculectomy with mitomycin C. Br J Ophthalmol. 2005;89:809–811. 18. Detorakis ET, Tsiklis N, Pallikaris IG, et al. Changes in the intraocular pressure of fellow untreated eyes following uncomplicated trabeculectomy. Ophthalmic Surg Lasers Imaging. 2011;42:138–143. 19. Wilmer WE. Discussion on the results of operative treatment of glaucoma. Trans Ophthalmol Soc UK. 1927;47:230–233. 20. Al-Ghadyan A, Mead A, Sears M. Increased pressure after paracentesis of the rabbit eye is completely accounted for by prostaglandin synthesis and release plus pupillary block. Invest Ophthalmol Vis Sci. 1979;18:361–365. 21. Radcliffe NM, Musch DC, Niziol LM, et al. The effect of trabeculectomy on intraocular pressure of the untreated fellow eye in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 2010;117:2055–2060. 22. Ten Tusscher MP, Beckers HJ, Vrensen GF, et al. Peripheral neural circuits regulating IOP? A review of its anatomical backbone. Doc Ophthalmol. 1994;87:291–313. 23. Cox CE, Fitzgerald CR, King RL. A preliminary report on the supraoptic nucleus and control of intraocular pressure. Invest Ophthalmol. 1975;14:26–28. 24. Wilson RP, Kanal N, Spaeth GL. Timolol: its effectiveness in different types of glaucoma. Ophthalmology. 1979;86:43–50.
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Change in Intraocular Pressure in the Fellow Eye After Glaucoma Surgery in 1 Eye Sushmita Kaushik, MD, Aniruddha Agarwal, MD, Savleen Kaur, MD, Neiwete Lomi, MD, Srishti Raj, MD, and Surinder S. Pandav, MD
Purpose: To measure the change in intraocular pressure (IOP) of the fellow eye after glaucoma surgery in 1 eye. Patients and Methods: In this prospective interventional study, 71 patients with primary and secondary glaucoma, undergoing glaucoma surgery in 1 eye were included. The IOP in the fellow eye following glaucoma surgery in 1 eye from the first postoperative week till 6 months following surgery was studied. Both normal and glaucomatous fellow eyes were included. IOP change from preoperative IOP levels in the fellow eye was analyzed. Patients treated with acetazolamide preoperatively were analyzed separately. Results: The mean baseline IOP of the operated and fellow eyes was 28.14 ± 9.4 and 16.5 ± 6.1 mm Hg, respectively. IOP of fellow eyes significantly increased compared with baseline at all timepoints (P < 0.001), with a maximum rise 6 weeks postoperatively (4.8 ± 3.3 mm Hg). There was no significant difference in the consensual rise between glaucomatous and nonglaucomatous fellow eyes, or between patients treated with or without acetazolamide before surgery. Regression analysis showed no baseline factor associated with the rise in IOP. By the sixth postoperative month, 24 patients required surgery or needed an increase in medications in the fellow eye for IOP control. Conclusions: Glaucoma surgery in eye is associated with a rise in IOP of the fellow eye, regardless of whether the fellow eye is normal or glaucomatous, or had been previously treated with acetazolamide. Fellow eyes of all patients scheduled for glaucoma surgery require careful monitoring of the IOP. Key Words: contralateral intraocular pressure, glaucoma surgery, trabeculectomy, ophthalmic consensual reaction, other eye IOP
(J Glaucoma 2016;25:324–329)
n 1924 Weekers1 sscoined the term “consensual ophthalmotonic reaction” to describe the corresponding pressure change in the contralateral eye after alteration of the intraocular pressure (IOP) in 1 eye. Postulated mechanisms suggest involvement of neuronal, hormonal, and cytokine regulation of aqueous flow dynamics, but the exact mechanism is yet to be elucidated.2,3 A consensual response to antiglaucoma therapy has been shown in normal and glaucomatous subjects,4–9 following uniocular tomography10 and a small decrease has also been reported in the untreated fellow eye after laser
I
Received for publication April 22, 2014; accepted November 27, 2014. From the Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Disclosure: The authors declare no conflict of interest. Reprints: Sushmita Kaushik, MD, Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000217
trabeculoplasty.11–13 Gibbens14 reported that the consensual ophthalmotonic reaction appears to occur in man regardless of the drug used to lower IOP in the treated eye. This was, however, later refuted by Newman et al15 who reported reduction in contralateral untreated eyes only with timolol and not prostaglandins or carbonic anhydrase inhibitors. The response of the fellow eye IOP to trabeculectomy in 1 eye is even more uncertain. Reports in literature are conflicting,16–18 and it is difficult to draw concrete conclusions chiefly because of the variability and inconsistent methodology of the studies. The fellow eyes reported were normal and glaucomatous, unoperated and operated, and on treatment and without treatment. The aim of the present study was to see the behavior of the IOP in the unoperated normal and glaucomatous fellow eye when 1 eye underwent glaucoma surgery, to see if the presence of glaucoma in the fellow eye altered the response in anyway.
METHODS This study was undertaken at a tertiary care referral institute. Patients who required surgical reduction of IOP and presented between August 2012 and January 2013were prospectively enrolled. The Institute Ethics Committee approval was obtained (NK/562/Res/2327) and the study adhered to the tenets of the declaration of Helsinki. Informed consent was obtained from all recruited patients. Patients scheduled for trabeculectomy or glaucoma drainage device implantation [Ahmed Glaucoma Valve, Model FP7; New World Medical Inc., CA or Aurolab Aqueous Drainage Implant (AADI); Aurolab, Madurai, India] in 1 eye, were included. They all had inadequate IOP control on maximally tolerated medical therapy. Patients with both primary and secondary glaucoma were included, where the other eye was glaucomatous or normal, respectively. Fellow eyes with a history of laser treatment for glaucoma such as laser iridotomy or trabeculoplasty or any intraocular surgery were excluded. Only glaucomatous fellow eyes on medical treatment were included in the study. Patients with concurrent ocular or systemic disease (apart from glaucoma) in either eye such as uveitis and/or previous surgery requiring steroids; diabetes, hypertension (those receiving systemic b-blockers); or vascular occlusions were excluded. Details of topical and systemic antiglaucoma medications prescribed were recorded. All eligible patients underwent a comprehensive ophthalmologic examination of both eyes including best-corrected visual acuity in LogMAR units, IOP measured by Goldmann Applanation Tonometry, slit-lamp biomicroscopy, gonioscopy, and stereoscopic fundus evaluation on the slit-lamp using a 90.0 D lens. An average of 3 IOP
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J Glaucoma
Volume 25, Number 3, March 2016
measurements was computed for analysis; if they differed by >2.0 mm Hg, a fourth reading was taken and the average of the 3 closest values was used for analysis. Color stereoscopic optic disc photographs and red-free nerve fiber layer photographs were taken on the Zeiss Fundus camera FF 450 with VISUPAC System 451 (Carl Zeiss Ophthalmic Systems, Jena, GmBH, Germany). The subjects underwent baseline Standard Automated Perimetry on the Humphrey’s Field Analyzer HFA 750 II (Carl Zeiss-Humphrey Systems, Dublin, CA) using the 24-2 testing protocol by SITAStandard strategy. The same surgical technique was used in all patients undergoing trabeculectomy including creation of 4 4 mm partial-thickness scleral flap followed by application of mitomycin C (MMC) 0.02% for 2 minutes in the subconjunctival space before entry into the eye. Standardized technique was used for implantation of the glaucoma drainage device which included insertion of the device into a quadrant free from conjunctival scarring, suturing the plate at least 10.0 mm from the limbus and insertion of the tube in the anterior chamber or ciliary sulcus in pseudophakic or aphakic patients. Postsurgery follow-up visits were variable according to the requirement of trabeculectomy bleb management. However, for the purpose of this study, all patients underwent IOP measurement in both eyes using Goldmann Applanation Tonometry at day 1, day 7, 3 weeks, 6 weeks, 3 months, and 6 months after surgery. The time of IOP measurement was kept within 2 hours of measurement at each visit. IOP rise was defined as clinically significant if it was >4.0 mm Hg from that recorded at baseline. IOP was measured by the same examiner who had measured the baseline IOP, at all timepoints after surgery. Patients who required added intervention for IOP control (whether in the form of additional medications or surgery) in the fellow eye following glaucoma surgery in the first eye, were subsequently excluded from analysis. The final analysis included only those eyes which were on no additional IOP control during the follow-up period. We did not remove these patients from the analysis completely, so that we could have more numbers of patients in the period in which they were not prescribed any medications for IOP control.
Change in IOP in the Fellow Eye
TABLE 1. Diagnosis of the Operated and Fellow Eyes
Diagnosis POAG PACG SOAG SACG JOAG Nonglaucomatous (only fellow eye) Total
Age (Mean ± SD) (y)
Operated Eye (n)
Fellow Eye (n)
24 8 23 5 11 0
24 8 3 0 11 25
51.03 ± 19.2 56.9 ± 9.7 42.8 ± 19.2 53.6 ± 19.1 25.4 ± 15.6
71
71
45.3 ± 19.9
JOAG indicates juvenile open-angle glaucoma; PACG, primary angleclosure glaucoma; POAG, primary open-angle glaucoma; SACG, secondary angle-closure glaucoma; SOAG, secondary open-angle glaucoma.
and 17 females) completed all follow-up visits and their data were analyzed. The mean age was 45.3 ± 19.9 years (range, 15 to 80 y). There was no difference in age between men and women (P = 0.124). Diagnosis of the operated eye and fellow eye are summarized in Table 1. Primary openangle glaucoma (POAG), primary angle-closure glaucoma (PACG), and juvenile open-angle glaucoma (JOAG) were all bilateral. Three of the 7 steroid-induced secondary openangle glaucoma were bilateral, whereas the rest were unilateral traumatic glaucoma (11) and postsurgical glaucoma (5). Of the 5 secondary angle-closure glaucoma, 4 were neovascular glaucoma and 1 was secondary to iridocorneal endothelial syndrome, and they all had uniocular presentation. Twenty-five fellow eyes were normal. Baseline characteristics of the operated and fellow eyes are detailed in Table 2. The mean baseline IOP of the eyes undergoing surgery was 28.1 ± 9.4 mm Hg on maximum tolerated therapy and the fellow unoperated eyes was 16.5 ± 6.1 mm Hg (P < 0.001). Mean number of topical antiglaucoma drugs (including b-blockers, prostaglandins, topical carbonic anhydrase inhibitors, pilocarpine, and a-agonists) in the eyes undergoing surgery was 2.9 ± 1.2 and 49 patients (69.01%) required additional systemic acetazolamide therapy. The mean number of drugs being used in the fellow glaucomatous eyes was
Statistical Analysis Data analysis was performed using the IBM SPSS Statistics, version 20.0 (SPSS Inc., Chicago, IL). Descriptive statistics were computed for all the variables measured. Wilcoxon signed-rank test was used to compute the preoperative and postoperative IOP in both eyes in all patients. Mann-Whitney U test was used to compare the change in IOP between glaucomatous and nonglaucomatous fellow eyes, and in fellow eyes of patients who were and were not on systemic acetazolamide preoperatively. Results were considered significant at P < 0.05. Linear regression analysis was done to analyze the effect of age, sex, glaucoma diagnosis, baseline IOP, magnitude of fall in IOP in the first eye, treatment with acetazolamide, and number of topical antiglaucoma drugs, on the rise of IOP in the consensual eye.
RESULTS Seventy-four patients met the inclusion criteria and were included in the study. Seventy-one of them (54 males Copyright
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TABLE 2. Baseline Data of Operated and Fellow Eyes
Mean ± SD Operated Eyes (N = 71)
Parameters BCVA (LogMAR) Mean IOP (mm Hg) Mean CDR Mean CCT (mm) No. topical medications at baseline No. patients on oral acetazolamide before surgery [n (%)]
Fellow Eyes (N = 71)
P*
0.45 ± 0.33 0.38 ± 0.31 0.191 28.1 ± 9.4 16.5 ± 6.1 < 0.001 0.67 ± 0.2 0.60 ± 0.2 0.117 526.6 ± 37.4 530.7 ± 37.6 0.495 2.9 ± 1.2 1.73 ± 1.7 0.910 49 (69.01)
BCVA indicates best-corrected visual acuity for distance; CCT, central corneal thickness; CDR, vertical cup-disc ratio; IOP, intraocular pressure. *Mann-Whitney U test.
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Volume 25, Number 3, March 2016
TABLE 3. Intraocular Pressure at Each Timepoint in All Fellow Eyes
Change From Baseline (mm Hg) 95% Confidence Intervals Time Interval From Surgery Baseline intraocular pressure (n = 71) Day 1 (n = 71) Day 7 (n = 71) Week 3 (n = 71) Week 6 (n = 65) Month 3 (n = 61) Month 6 (n = 47)
Mean ± SD (mm Hg) (Mean ± SD)
Lower Bound
Upper Bound
P*
3.1 2.8 3.5 3.9 3.8 2.2
3.9 4.2 4.8 5.6 5.5 4.4
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Z4 mm Hg Intraocular Pressure Rise From Baseline n (%)
16.5 ± 6.1 20.1 ± 6.1 20.1 ± 6.6 20.6 ± 6.3 19.98 ± 5.5 19.3 ± 5.2 17.5 ± 3.2
3.5 ± 1.8 3.5 ± 2.7 4.1 ± 2.8 4.7 ± 3.3 4.3 ± 3.5 3.3 ± 3.6
40 37 43 42 39 33
(56.3) (52.1) (60.5) (64.6) (63.9) (70.2)
*Wilcoxon signed-rank test.
1.73 ± 1.7. None of the eyes had undergone previous glaucoma surgery or cyclodestruction procedure. The type of surgery was decided based on the type of glaucoma, associated ocular findings, and discussion with the patient. Fifty-five eyes (77.5%) underwent trabeculectomy with MMC, whereas a glaucoma drainage device was implanted in 16 eyes (22.5%) that included Ahmed Glaucoma Valve in 9 eyes (12.7%) and AADI (Baerveldt prototype) in 7 eyes (9.9%). At the sixth postoperative month, of the 71 operated eyes, 52 (73.2%) had complete success requiring no medication to achieve target IOP, 14 patients (19.7%) had a qualified success and required 1 or 2 medications to control IOP, and 5 patients (7%) required 3 or more medications for IOP control and constituted failure. The respective average number of topical medications required at baseline and follow-up in these 3 groups was as follows: patients with complete success were on 2.9 ± 1.26 topical drugs at baseline and had adequate IOP control without medications following surgery. Those with qualified success were on 2.57 ± 1.28 drugs at baseline which reduced to 1.42 ± 0.5 drugs at 6-month follow-up (P = 0.006), whereas those classified as failures required 3.4 ± 0.54 drugs preoperatively which remained at 3.2 ± 0.45 drugs 6 months after surgery (P = 0.55). At each postoperative visit, the IOP of the fellow eye significantly increased compared with baseline (P < 0.001) (Table 3). The rise was observed from the first postoperative day itself and it was maximum at the sixth postoperative week, when it stayed elevated till the sixth postoperative month. By week 6, 6 patients required additional antiglaucoma drugs or surgery for their IOP rising beyond acceptable limits, and analysis was completed for the remaining 65 patients. By the third month this number rose to 4 more patients, and analysis of the third month was done for the remaining 61 patients. By the sixth month, 47 patients remained in the analysis as additional drugs or surgery was required in the fellow eyes of 14 more patients. Clinically significant rise (>4.0 mm Hg) in IOP was observed in fellow eyes of 40 patients (56.3%) on the first postoperative day and persisted in 33 of 47 (70.2%) patients analyzed at the sixth postoperative month. Baseline data of patients with and without significant rise in IOP at each timepoint was analyzed. There was no significant difference in any parameter between the 2 groups at the third and sixth month after surgery.
Trabeculectomy was performed in the fellow eyes in 3 patients by the sixth week, 2 patients by the third month, and 9 patients between the third and sixth month following surgery in the first eye. Of these 14 patients, surgery was planned in the fellow eye at the time of the first eye surgery itself in 9 patients (whose IOP rose significantly nevertheless), and was required in 5 more patients, where maximum medication could no longer control the IOP which significantly rose after the first surgery. The IOP rise in the fellow eye was compared in glaucomatous versus nonglaucomatous fellow eyes, and in patients who were on systemic acetazolamide and those who were not (Table 4). There was no statistically significant difference in the IOP in glaucomatous fellow eyes compared with nonglaucomatous fellow eyes. However, even those eyes which were nonglaucomatous to start with, required antiglaucoma medications in an increasing number of patients from the third postoperative month onwards resulting in 8 patients by 6 months. They were 4 fellow eyes of steroid-induced glaucoma, 2 fellow eyes of neovascular glaucoma, and 2 fellow eyes of traumatic glaucoma. These patients were subsequently excluded from further analysis. Systemic acetazolamide was withdrawn postoperatively in those who had been prescribed the drug. To study whether this withdrawal was responsible for the rise in IOP of the fellow eye, patients with and without preoperative acetazolamide were separately analyzed (Table 4). There was no significant difference in the mean IOP rise between the 2 groups, although there was a greater rise in IOP measured in patients who were on preoperative acetazolamide between 6 and 12 weeks following surgery, after which it stabilized. Regression analysis showed no relationship to the magnitude of the consensual rise in IOP as regards the age or sex of the patient, baseline IOP, diagnosis of glaucoma, type of surgery, or the magnitude of IOP fall in the first eye. The mean IOP rise was also analyzed at each point in patients with different diagnoses of glaucoma. PACG eyes showed the maximum rise at all timepoints, but the differences from other diagnoses did not reach statistical significance. The factor of increased steroid responsiveness in glaucoma patients was kept in mind, and the pattern of postoperative steroid use was analyzed. Systemic steroids was prescribed postoperatively in a total of 5 patients—2 patients with steroid-induced glaucoma, 1 patient with
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Change in IOP in the Fellow Eye
TABLE 4. Mean Change in IOP in Normal and Glaucomatous Fellow Eyes, and Those Treated With and Without Acetazolamide
Baseline to first postoperative day (n = 71) (mm Hg) Baseline to postoperative day 7 (n = 71) (mm Hg) Baseline to third postoperative week (n = 71) (mm Hg) Baseline to sixth postoperative week (n = 65) (mm Hg) Baseline to third postoperative month (n = 61) (mm Hg) Baseline to sixth postoperative month (n = 47) (mm Hg)
Glaucomatous Fellow Eye
Nonglaucomatous Fellow Eye
3.7 ± 1.9 (n = 46) 3.8 ± 2.7 (n = 46) 3.9 ± 2.8 (n = 46) 4.6 ± 3.4 (n = 42) 4.9 ± 3.7 (n = 39) 4.3 ± 2.4 (n = 30)
3.2 ± 1.7 (n = 25) 3.0 ± 2.6 (n = 25) 4.5 ± 2.7 (n = 25) 5.0 ± 3.3 (n = 23) 4.1 ± 2.7 (n = 22) 4.6 ± 2.4 (n = 17)
Fellow Eyes of Patients on Acetazolamide P* Before Surgery 0.38 0.26 0.46 0.66 0.54 0.66
Fellow Eyes of Patients Without Acetazolamide
3.6 ± 1.8 (n = 49) 3.3 ± 2.8 (n = 49) 4.0 ± 2.8 (n = 49) 5.1 ± 3.2 (n = 43) 5.2 ± 3.7 (n = 41) 4.6 ± 2.4 (n = 29)
3.5 ± 1.8 (n = 22) 4.0 ± 2.5 (n = 22) 4.4 ± 2.7 (n = 22) 4.2 ± 3.4 (n = 22) 3.4 ± 2.4 (n = 20) 4.2 ± 2.7 (n = 18)
P* 0.82 0.26 0.61 0.23 0.10 0.67
IOP indicates intraocular pressure. *Mann-Whitney U test.
POAG, 1 with JOAG, and 1 case with neovascular glaucoma. Of these 5, 2 patients had significant rise of IOP in the fellow eye. The medication regime of the unoperated eye was carefully checked as antiglaucoma medication was withdrawn in the operated eye. The patient and their attendants were counseled thoroughly before discharge from the operating room. At the postoperative follow-up visits, we checked for compliance by directly asking the patient.
DISCUSSION Most reports of change in IOP in the fellow eye following IOP reduction in 1 eye by drugs,4–9 ocular compression,10 or laser trabeculoplasty11–13 have reported a decrease in IOP. The response of the fellow eye to surgical reduction of IOP is not as certain. Wilmer19 in 1927 reported in experimental animals a fall in IOP in 1 eye after a fistulisation operation on the other eye. In contrast, Al-Ghadyan et al20 in 1956 reported a consensual increase in IOP in the contralateral eye in rabbits after paracentesis in 1 eye and postulated the role of increased prostaglandin release as a response to trauma as a possible explanation. In human eyes, reports are conflicting. Yarangu¨meli et al16 reported a rise in IOP in the fellow eye following trabeculectomy in 1 eye. All their patients had POAG, pseudoexfoliation glaucoma, or angle-closure glaucoma. Fellow eyes were medically controlled. Those not on medications had pseudoexfoliation or had had laser iridotomy for narrow angles. Thus no patient was normal. This was followed by a report by Vysniauskiene et al17 who, in contrast, reported a decrease in IOP following surgical reduction in 1 eye. Of note, among the 24 fellow eyes in the study, 12 of them had undergone trabeculectomy with MMC and 11 (45.8%) were on topical ocular hypotensive therapy. It could be possible that the presumed “ophthalmotonic consensual reaction” may be modified in an unknown way by the topical medications or surgery, thereby affecting the interpretation of their results. As trabeculectomy is usually planned when the IOP is high on the variation curve, the decreased IOP in the fellow eye could be the result of the “regression to the mean” effect. Copyright
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A post hoc analysis of data of the Collaborative Initial Glaucoma Treatment Study by Radcliffe et al21 demonstrated no substantial effect of trabeculectomy on the fellow eye, although contrary to our findings, there was a decreasing trend of IOP in the fellow eye at all timepoints. Their analysis included only primary glaucoma, so all their fellow eyes were glaucomatous. More recently, Detorakiset al18 studied the change in IOP of fellow eyes following trabeculectomy in 1 eye, and reported a decrease on the fourth postoperative day, but by 3 months they found no change in IOP in the fellow eye. In the backdrop of this inconsistency, we attempted to study the IOP response in both normal and glaucomatous fellow eyes following glaucoma surgery. We found a uniform increase in the fellow eye IOP across all categories of patients, including those with glaucomatous or nonglaucomatous fellow eyes, or those who had received systemic acetazolamide or had not. Various theories have been postulated that may explain this finding. Diestelhorst and Krieglstein3 studied the effect of trabeculectomy on the aqueous humor flow of the unoperated fellow eye, using computerized anterior chamber fluorophotometry. Aqueous humor flow was measured before surgery and on the fifth day after trabeculectomy. The average postoperative flow in the fellow eye significantly increased from 2.56 to 2.9 mL/min. They postulated that filtration surgery in 1 eye triggers a central nervous system–mediated reflective increase in aqueous flow to maintain physiological stability in the anterior chamber of the surgically treated eye. As this central nervous system reflex on aqueous humor dynamics affects both eyes, it might explain the increase in IOP we observed in the unoperated fellow eye. Another explanation is the possible existence of an ophthalmotonic consensual reaction as postulated by Weekers.1 In this phenomenon, alteration of the IOP in 1 eye is accompanied by a corresponding pressure change in the contralateral eye. It has also been suggested that glaucoma surgery leads to activation of nervous mechanisms leading to increase in fellow eye aqueous production.22 A possible supraoptic controlling pathway has been described in an animal experiment showing rise in IOP in response to water drinking after unilateral optic nerve sections.23
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It is interesting that in our study, the magnitude of consensual IOP rise was significant to the extent that of the 71 patients enrolled, by the sixth postoperative month, fellow eyes of only 47 patients did not need enhancement of antiglaucoma treatment after glaucoma surgery in 1 eye. Five patients who were not planned for glaucoma surgery in the fellow eye required it for inadequate IOP control by medications. In fact the magnitude of IOP rise at later timepoints is actually underestimated, as we excluded those patients whose raised IOP required additional medications or surgery in the fellow eye. The results were a little surprising, especially in those with normal fellow eyes, because we expected a normal trabeculum to have sufficient compensatory outflow mechanism to account for the postulated “ophthalmotonic consensual reaction” of increased aqueous secretion in both eyes in response to reduced IOP in the operated eye. There might have been a possibility of consensual IOP rise due to withdrawal of antiglaucoma medications in the first eye, and this was one of the possibilities for the consensual rise in IOP that we kept in mind. Medications in 1 eye, especially timolol are known to decrease IOP in the fellow eye. Overall, the contralateral eye effect is reported to be smaller in normotensive eyes than in hypertensive eyes; however, there is great variability of results in both the groups. The largest study to look at this effect in hypertensive eyes came from the OHTS study, which reported a mean 1.5 mm Hg reduction in IOP in the contralateral untreated eye,4 which was comparable to the mean 2.1 mm Hg reduction described by Wilson et al24 in 76 glaucomatous subjects and the 2.2 mm Hg reduction in 15 subjects randomized to receive timolol by Zimmerman and Kaufman.5 Martin and Rabineau7 found no significant decrease in IOP in contralateral eyes when normal volunteers were tested. In our study, those patients who had received preoperative acetazolamide showed a higher rise in IOP from the sixth week onwards, indicating that the high IOP was probably “masked” preoperatively. However, we also found a significant consensual rise of IOP in those patients who were not treated with acetazolamide, so it is difficult to draw definitive conclusions at present. The magnitude of mean IOP rise in glaucomatous and nonglaucomatous fellow eyes was similar. This rise is more than what would be expected by just a reversal of the effect of antiglaucoma medication in the treated eye, especially if we consider that all glaucomatous eyes were on medical treatment as well. Further, a lot of our patients were on prostaglandins alone, and not timolol, which is the drug that has been most commonly known to be associated with contralateral eye decrease in IOP. We also looked at the rise in IOP in different diagnostic groups. The PACG subset showed the maximum rise but the number of patients were probably too less to draw meaningful conclusions (8 eyes to start with and 5 after 6-mo follow-up). We also thought of increased steroid responsiveness in glaucoma patients and reviewed our postoperative steroid prescription. In our usual surgical protocol, we do not use systemic steroids routinely. It is prescribed in cases which have postoperative choroidal effusion either due to or as a consequence of hypotony. In this study, on reviewing our data, we found that we had prescribed systemic steroids in a total of 5 patients, of which 2 patients had significant rise of IOP in the fellow eye. It is likely that mechanisms other than steroid responsiveness played a role in the IOP response that we saw.
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Volume 25, Number 3, March 2016
The inconsistency in literature may be explained by the spectrum of changes that can occur in the fellow eye following glaucoma surgery. A complex set of mechanisms controlling the IOP may be involved, including neuronal, hormonal, cytokine, and systemic drug effect. The predominance of 1 mechanism resulting due to a particular intervention may guide the IOP changes in the fellow eye. However, a mixture of all these mechanisms acting together following glaucoma surgery may result in a trend toward either an increase or decrease in IOP. The clinical importance of this study is to recognize these changes in IOP possible after glaucoma surgery due to multitude of factors coming in play. A relevant message is that the fellow eye needs to be carefully monitored after glaucoma surgery in 1 eye. In many instances, the fellow eye is often the one with useful vision. Failure to recognize and monitor IOP changes carefully may unnecessarily delay treatment and appropriate management of these eyes. In addition, fellow eyes already damaged by glaucomatous processes may be at significant risk of glaucoma progression due to higher IOP levels in the postoperative period. In addition, this study reiterates that in studies of 1OP responses to a particular treatment the fellow eye should not be used as a control. Limitations of our study include a small patient cohort with few numbers in each subgroup to enable a detailed analysis of the IOP rise in primary compared with secondary glaucoma. However, a consistent demonstration of rise of IOP validates the data. Compliance of medications in the other eye is another possible limitation but it is believed that there is heightened sensitivity among patients for antiglaucoma drugs following lasers or surgery, so this factor is likely to result in decreased IOP after surgery rather than increase. It is standard practice for us to check for compliance by directly asking the patient and checking their drugs, and the patients were compliant with the medications prescribed in the unoperated eye. Like previous studies, the present study is not able to conclusively demonstrate the possible mechanism responsible for changes in IOP. Although the evidence for existence of ophthalmotonic consensual reaction is strengthened, larger studies with more patients in each glaucoma category may shed light on its exact biological role. REFERENCES 1. Weekers L. Modification expe´rimentales de l’ophtalmotonous. Reaction ophtalmotonique consenuelle. Arch Opthalmol (Paris). 1924;41:641–658. 2. Feher J. Glaucoma: Pathophysiology of the Eye. Budapest: Acade´miai Kiado´ Publications; 1998. 3. Diestelhorst M, Krieglstein G. The effect of trabeculectomy on the aqueous humor flow of the unoperated fellow eye. Graefes Arch Clin Exp Ophthalmol. 1991;229:274 – 276. 4. Piltz J, Gross R, Shin DH, et al. Contralateral effect of topical beta-adrenergic antagonists in initial one-eyed trials in the Ocular Hypertension Treatment Study. Am J Ophthalmol. 2000;130:441–453. 5. Zimmerman TJ, Kaufman HE. Timolol: a beta-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol. 1977;95:601–604. 6. Kwitko GM, Shin DH, Ahn BH, et al. Bilateral effects of longterm monocular timolol therapy. Am J Ophthalmol. 1987;104: 591–594. 7. Martin XD, Rabineau PA. Intraocular pressure effects of timolol after unilateral instillation. Ophthalmology. 1988;95: 1620–1623.
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8. Howell SC. Action of epinephrine on the normal human eye. Arch Ophthalmol. 1934;12:833–841. 9. Willetts GS. Autonomic effector drugs and the normal eye. Am J Ophthalmol. 1969;68:216–223. 10. Stocker FW. On changes in intraocular pressure after application of the tonometer. Am J Ophthalmol. 1958;45:192–196. 11. Schwartz AL, Whitten ME, Bleiman B, et al. Argon lasertrabecular surgery in uncontrolled phakic open-angle glaucoma. Ophthalmology. 1981;88:203–212. 12. Latina MA, Sibayan SA, Shin DH, et al. Q-switched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology. 1998;105: 2082 –2088. 13. Rhodes KM, Weinstein R, Saltzmann RM, et al. Intraocular pressure reduction in the untreated fellow eye after selective laser trabeculoplasty. Curr Med Res Opin. 2009;25:787 – 796. 14. Gibbens MV. The consensual ophthalmotonic reaction. Br J Ophthalmol. 1988;72:746–749. 15. Newman H, Kurtz S, David R. Intraocular pressure changes in the contralateral eye after topical treatment: does an “ophthalmotonic consensual reaction” exist? Isr Med Assoc J. 2010;12:568–571. 16. Yarangu¨meli A, Ko¨z OG, Kural G. The effect of trabeculectomy on the intraocular pressure of the unoperated fellow eye. J Glaucoma. 2003;12:108–113.
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17. Vysniauskiene I, Shaarawy T, Flammer J, et al. Intraocular pressure changes in the contralateral eye after trabeculectomy with mitomycin C. Br J Ophthalmol. 2005;89:809–811. 18. Detorakis ET, Tsiklis N, Pallikaris IG, et al. Changes in the intraocular pressure of fellow untreated eyes following uncomplicated trabeculectomy. Ophthalmic Surg Lasers Imaging. 2011;42:138–143. 19. Wilmer WE. Discussion on the results of operative treatment of glaucoma. Trans Ophthalmol Soc UK. 1927;47:230–233. 20. Al-Ghadyan A, Mead A, Sears M. Increased pressure after paracentesis of the rabbit eye is completely accounted for by prostaglandin synthesis and release plus pupillary block. Invest Ophthalmol Vis Sci. 1979;18:361–365. 21. Radcliffe NM, Musch DC, Niziol LM, et al. The effect of trabeculectomy on intraocular pressure of the untreated fellow eye in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 2010;117:2055–2060. 22. Ten Tusscher MP, Beckers HJ, Vrensen GF, et al. Peripheral neural circuits regulating IOP? A review of its anatomical backbone. Doc Ophthalmol. 1994;87:291–313. 23. Cox CE, Fitzgerald CR, King RL. A preliminary report on the supraoptic nucleus and control of intraocular pressure. Invest Ophthalmol. 1975;14:26–28. 24. Wilson RP, Kanal N, Spaeth GL. Timolol: its effectiveness in different types of glaucoma. Ophthalmology. 1979;86:43–50.
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