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Incidence of Late-Onset Bleb-Related Complications Following Trabeculectomy With Mitomycin
Peter W. DeBry, MD;
Todd W. Perkins, MD;
Gregg Heatley, MD;
Paul Kaufman, MD;
Lyndia C. Brumback, PhD
Arch Ophthalmol. 2002;120:297-300.
ABSTRACT
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Objectives To determine the incidence of late-onset bleb-related complications
following trabeculectomy with mitomycin and to report the management and outcome
of bleb leaks following trabeculectomy with mitomycin.
Methods A retrospective medical record review of all patients who underwent
trabeculectomy with mitomycin from June 1, 1991, through April 30, 1998, at
our institution was performed. The Kaplan-Meier survival method was used to
estimate the probability of (1) endophthalmitis, (2) blebitis, (3) a bleb
leak, and (4) the combined outcome (the first occurrence of a bleb leak, blebitis,
or endophthalmitis). This survival analysis included only the first trabeculectomy
in an eye, with at least 3 months of follow-up during the study period. A
separate description of bleb leak management and outcome was performed.
Results Two hundred thirty-nine eyes of 198 patients were included in the survival
analysis. The average follow-up was 2.7 (range, 0.3-7.3) years. Twenty eyes
(8%) from 19 patients experienced a bleb leak; the adjusted incidence was
3.2% per patient-year. Five eyes (2%) had an episode of blebitis. Eight eyes
(3%) experienced an episode of endophthalmitis; the follow-up adjusted incidence
(number of events per patient-year) was 1.3%. Twenty-seven eyes (11%) from
26 patients had at least 1 of the complications of a bleb leak, blebitis,
or endophthalmitis; the adjusted incidence was 4.4% per patient-year. A Kaplan-Meier
analysis estimated the 5-year probability of developing a bleb leak, blebitis,
or endophthalmitis to be 17.9%, 6.3%, and 7.5%, respectively. Two hundred
fifty-eight trabeculectomies in 242 eyes of 198 patients were included in
the description of bleb leak management and outcome. Bleb leaks occurred in
22 eyes (9% of the 258 trabeculectomies). Seventeen eyes were successfully
treated with office-based measures, and 4 ultimately underwent surgical bleb
revision. One eye without infection continued to leak after 11 months of office-based
therapy.
Conclusions There is significant morbidity associated with a trabeculectomy with
mitomycin. The incidence of a bleb leak or an infection continues at a fairly
constant rate over time, such that at 5 years, up to 23% of all patients might
develop one of these complications. An isolated bleb leak seems to be a relatively
benign condition, as three quarters resolve with office-based methods.
INTRODUCTION
TRABECULECTOMY remains the standard of care for patients who have failed
maximal tolerated medical therapy. Risk factors, such as previous surgery,
age, and race, may predispose patients to bleb failure if an antifibrotic
agent is not used with trabeculectomy. The use of intraoperative mitomycin
as an adjunct to standard trabeculectomy has increased the likelihood that
this procedure will maintain low intraocular pressures.1
Because of this greater chance of long-term intraocular pressure control,
mitomycin is used frequently in high-risk cases.
Mitomycin inhibits the postoperative scarring response by cross-linking
the DNA in the conjunctival and episcleral fibroblasts to which it is exposed,
decreasing their ability to proliferate. While this technique produces thinner
blebs that provide enhanced filtration, it also leads to an increased incidence
of postoperative hypotony,2 bleb leak,3 and endophthalmitis.4
Bleb leaks place patients at risk of developing endophthalmitis5
and are, therefore, considered a significant late postoperative complication.
We are not aware of a study that has described the incidence and outcome of
late-onset bleb leaks. We undertook a retrospective review of patients undergoing
trabeculectomy with mitomycin to determine the incidence of late-onset endophthalmitis
and the incidence and outcome of late postoperative bleb leaks.
PATIENTS AND METHODS
Medical records were reviewed for all patients who underwent trabeculectomy
with mitomycin from June 1, 1991, through April 30, 1998, at our institution.
A standard surgical technique using a superior limbal-based incision encompassed
most procedures. Mitomycin, most commonly 0.5 mg/mL, was applied for periods
ranging from 30 seconds to 5 minutes based on the patient's age, race, and
number of prior operations. Data from 285 trabeculectomies performed in 266
eyes of 219 patients were examined. Attempts were made to collect as much
follow-up information as possible from referring physicians who resumed postoperative
care. Minimal acceptable information for each patient included any surgical
interventions during the study period, demographics, visit date, and slitlamp
examination findings indicating the presence of endophthalmitis, blebitis,
or a late bleb leak. Blebitis was defined as localized anterior segment inflammation
with mucopurulent material in or around the bleb, usually with anterior chamber
cells but without a hypopyon. An infection was considered endophthalmitis
when a hypopyon or vitreous inflammation was present. A late bleb leak was
defined as a positive leak by Seidel test result that occurred at least 3
months after the initial surgery. This interval was chosen to avoid inclusion
of bleb leaks that were related to the initial surgery.
The Kaplan-Meier survival method was used to estimate the probability
of a patient developing (1) endophthalmitis, (2) blebitis, (3) a bleb leak,
or (4) the combined outcome (the first occurrence of a bleb leak, blebitis,
or endophthalmitis). The combined outcome was considered because some eyes
experienced more than 1 event type. Data on eyes were removed from further
analysis (censored) at the last examination or additional operation. Confidence
intervals (CIs) were based on log (survival) and transformed back to the original
scale. Only the first trabeculectomy in each eye and only those trabeculectomies
with follow-up longer than 3 months were considered for the survival analysis.
Separate from the survival analysis, the follow-up adjusted incidence was
determined by dividing the number of events (eg, bleb leak or blebitis) by
the total number of eyes that had undergone trabeculectomy with mitomycin,
then dividing this number by patient-years of follow-up.
The description of bleb leak outcomes included the management, duration,
and number of recurrences of the leak. Bleb leaks that occurred after a second
or later trabeculectomy during the study period were included in the description.
Management was divided into office based, which included interventions such
as prophylactic antibiotics, bandage contact lens, mecrylate tissue adhesive,
and autologous blood injection; and surgical, which included surgical revision
in the operating room. Management and duration of recurrences were not assessed.
Bleb function and pressure-lowering medication use were also not considered.
RESULTS
Data from 285 trabeculectomies performed by 1 of 3 different surgeons
(T.W.P., G.H. or P.K.) in 266 eyes of 219 patients were examined. Twenty-seven
operations in 27 eyes of 25 patients were excluded from the study because
either no follow-up information from the referring physicians (8 operations
in 8 eyes of 7 patients) or less than 3 months of postoperative follow-up
information (19 operations in 19 eyes of 18 patients) was available. Nineteen
operations in 18 eyes of 17 patients represented a second or later operation
on a particular eye during the study period. These 19 subsequent operations
were excluded from the survival analysis but were included in the description
of bleb leak management and outcome.
SURVIVAL ANALYSIS
A total of 239 eyes from 198 patients were included in the survival
analysis. Demographics are shown in Table
1. The failure estimates (1 - survival) are shown in Figure 1. The mean postoperative follow-up
was 2.7 years (range, 0.3-7.3 years). Twenty eyes (8%) developed a bleb leak.
The follow-up adjusted incidence was 3.2% per patient-year. The Kaplan-Meier
estimates of developing a bleb leak at 1 and 5 years were 1.5% (95% CI, 0-3.1)
and 17.9% (95% CI, 9.2-25.7), respectively. Five eyes (2%) had an episode
of blebitis. The failure estimates were 0% risk at 1 year and 6.3% risk (95%
CI, 0.4-11.8) at 5 years. Eight eyes (3%) experienced an episode of endophthalmitis.
The follow-up adjusted incidence (number of events per patient-year) was 1.3%.
The Kaplan-Meier estimates of developing endophthalmitis at 1 and 5 years
were 1.0% (95% CI, 0-2.3) and 7.5% (95% CI, 1.9-12.8), respectively. A specific
delineation between blebitis and endophthalmitis can be difficult, and some
overlap between the 2 conditions must be assumed to exist. Finally, 27 eyes
(11%) of 26 patients had at least 1 of the events (a bleb leak, blebitis,
or endophthalmitis). The adjusted incidence was 4.4% per patient-year. The
Kaplan-Meier estimates of the probabilities of developing at least 1 of these
events were 2.4% (95% CI, 0.3-4.5) and 22.8% (95% CI, 13.6-31.0) at 1 and
5 years, respectively (Figure 1).
Plots of the cumulative hazards (cumulative hazard = -log [survival])
vs time appear linear and, thus, suggest that the hazard (or probability of
failure in the next instant) was relatively constant during follow-up.
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Demographic Characteristics*
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Kaplan-Meier estimates of the probability of failure by bleb leak,
blebitis, or endophthalmitis alone or in combination. CI indicates confidence
interval; ellipses, data not applicable.
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MANAGEMENT AND OUTCOME
A total of 258 trabeculectomies in 242 eyes of 198 patients were considered
in the description of bleb leak management and outcome. Twenty-two trabeculectomies
(9%) from 21 patients experienced bleb leaks. Two of these trabeculectomies
were excluded from the survival analysis because they occurred in eyes after
a second operation. Seventeen eyes were successfully treated with conservative
measures, and 4 ultimately underwent surgical bleb revision. One eye without
signs of blebitis or endophthalmitis continued to leak after 11 months of
conservative therapy. Thirteen (59%) of the 22 bleb leaks resolved with antibiotic
prophylaxis alone, with an average leak duration of 55 days (range, 3-230
days). Other therapies included mecrylate tissue adhesive (n = 3), trichloroacetic
acid topical application (n = 4), cryotherapy (n = 1), bandage contact lens
(n = 3), and autologous blood patch (n = 1). In some cases, it was difficult
to determine which therapy contributed to the final resolution of the leak
because a series of treatments was undertaken before the leak resolved. Of
the 22 eyes that experienced a leak, 8 (36%) had 1 or more bleb leak recurrences,
with an average of 0.6 recurrences per eye (range, 0-3 recurrences per eye).
Most bleb leaks were in asymptomatic patients. However, bleb leaks were diagnosed
in 5 patients who were seen with a clinical picture consistent with blebitis,
and 1 had a concurrent leak and endophthalmitis. One patient with a bleb leak
treated with antibiotic prophylaxis for 1 month developed an infection (blebitis
vs early endophthalmitis). Blebitis did not progress to endophthalmitis in
any of the patients treated with topical antibiotics.
COMMENT
Our study demonstrates that there is significant morbidity associated
with a trabeculectomy with mitomycin. Based on the follow-up adjusted incidence,
1 of every 100 patients developed endophthalmitis each year, and 4% of patients
each year developed a bleb-related complication consisting of a bleb leak,
blebitis, or endophthalmitis. This incidence continued at a fairly constant
rate over time, such that at 5 years, 23% of all patients would be predicted
to develop one of these bleb-related complications.
An isolated bleb leak seems to be a relatively benign condition. Early
in the study, bleb leaks were treated more aggressively with measures such
as mecrylate glue, cryotherapy, and contact lenses. Because of the small sample
size, it is difficult to determine whether any of these conservative measures
were superior to the others. However, as it became apparent that leaks often
resolved without these interventions, a less aggressive approach was adopted
and leaks underwent only antibiotic treatment for months. Further management
was only undertaken if there was hypotony with a shallow anterior chamber,
hypotony maculopathy, or other factors that might increase the risk of infection,
such as recurrent bacterial conjunctivitis, severe blepharitis, or dry eye.
Only 1 patient developed endophthalmitis while being followed up regarding
a leaking bleb. Our patients were routinely treated with prophylactic antibiotics
while experiencing a leak, typically with gentamicin sulfate; it was thought
that the conjunctival irritation produced might encourage a healing response.
There is no direct evidence that antibiotics decrease the risk of infection
or speed wound healing, and not all clinicians use them.
Endophthalmitis is typically manifest with significant symptoms that
bring cases to the attention of a physician. Bleb leaks, on the other hand,
are often asymptomatic and, therefore, the true incidence is somewhat difficult
to determine. These data likely underreport the actual incidence of bleb leaks
in functioning filters for 2 reasons. First, we included all eyes that underwent
trabeculectomy with mitomycin, even those that ultimately developed scarred
nonfunctioning blebs with no significant risk of leaking. If only functioning
blebs were considered, the denominator would be smaller and the incidence
of endophthalmitis and bleb leaks would be larger. Second, some bleb leaks
may not have been observed because leaks are frequently asymptomatic and Seidel
testing was not routinely performed on all patients. The clinical indication
for Seidel testing was an ischemic thin bleb with a suspicious appearance
or low pressure. Because some asymptomatic leaks were likely to be missed,
our numerator is expected to be smaller than the number of actual leaks, which
would also lead to an underestimation of the overall incidence.
Several similar studies have reported information on endophthalmitis
and bleb leaks. Greenfield et al4 reported
the incidence of endophthalmitis after superior trabeculectomy with mitomycin
(in 251 eyes) to be 1.6% (4 episodes), with a mean follow-up of approximately
16 months. The adjusted incidence (events per patient-year) was 1.3% after
superior trabeculectomy. We also estimate an adjusted incidence of 1.3% per
patient-year.
Higginbotham et al6 reported on bleb-related
endophthalmitis after mitomycin administration in 229 eyes of 192 patients,
with a mean of 18 months of follow-up. Of 179 eyes that underwent
superior trabeculectomy with mitomycin, 2 developed endophthalmitis, for an
overall rate of 1.1%. Survival curve analysis of the whole patient group,
including the inferior filtering sites (4 of 6 cases of endophthalmitis),
at 2 years after surgery estimated the probability of developing endophthalmitis
to be 4.8%. Our estimate at 2 years was lower, 2.4% (95% CI, 0-4.8),
but included mainly superior filters.
There is less comparable information regarding bleb leaks. A large study
of bleb leak prevalence by Greenfield et al3
found 10 (3.7%) of 273 trabeculectomies with mitomycin to have a leak during
2 months of examinations. A smaller study on a slightly different
category—sequential multifocal bleb leaks—by Belyea et al7 showed sequential multifocal leaks in 2 (1%) of 192
eyes after trabeculectomy with mitomycin, with 20.4 months of follow-up. This
study supports our finding that bleb leaks often recur following resolution
of the initial leak. We observed 22 bleb leaks (9%) of 258 trabeculectomies,
including bleb leaks that occurred after a second operation during the study
period. At 5 years, there is almost a 20% risk of developing a bleb leak.
This information is disturbing, particularly in young patients who may have
40 or 50 years of life remaining after their filtering procedure.
Only 1 patient in our study developed an infection while being followed
up regarding a leaking bleb. A recent article by Soltau et al5
confirmed the clinical impression that a bleb leak is a risk factor for infection.
In a case-control study, a multivariate analysis found the odds of a leak
in a patient in the bleb-related infection group to be 25.8 times the odds
of a leak in a patient in the control group. Variables other than bleb leak
found to be risk factors for infection were younger age, black race, and inferior
bleb location.
The limitations of this study include its retrospective nature and the
lack of complete follow-up on all patients. In addition, all patients did
not undergo Seidel testing of the blebs at each follow-up visit unless clinically
indicated.
Within the limits of this study, it may be concluded that the incidence
of endophthalmitis associated with filtering blebs after mitomycin administration
is approximately 1.3% per year. The risk of developing at least 1 complication
(a bleb leak, blebitis, or endophthalmitis) remains relatively stable during
the first 5 years after surgery, with an annual incidence of approximately
4.4%. There seems to be no period when filtered eyes are more or less vulnerable
to these complications. Bleb leaks seem to be safely managed with conservative
interventions over long periods. In some cases, surgical intervention is necessary.
AUTHOR INFORMATION
Submitted for publication March 2, 2001; final revision received October
3, 2001; accepted November 16, 2001.
This study was supported by grant EY07119 from the National Institutes
of Health, Bethesda, Md (Dr Brumback); and by an unrestricted grant from Research
to Prevent Blindness Inc, New York, NY.
We thank Ronald Gangnon, PhD, for his helpful discussions.
Corresponding author and reprints: Todd W. Perkins, MD, Department
of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, 2870
University Ave, Suite 206, Madison, WI 53705 (e-mail: twperkin{at}facstaff.wisc.edu).
From the Departments of Ophthalmology and Visual Sciences (Drs DeBry,
Perkins, Heatley, and Kaufman), Statistics (Dr Brumback), and Biostatistics
and Medical Informatics (Dr Brumback), University of Wisconsin, Madison. Dr
DeBry is now with the Ophthalmology Department, Sabates Eye Center, Kansas
City, Mo, and Dr Brumback is now with the Division of Allergy and Infectious
Diseases, University of Washington School of Medicine, Seattle.
REFERENCES
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1. Robin AL, Ramakrishnan R, Krishnadas R, et al. A long-term dose-response study of mitomycin in glaucoma filtration
surgery. Arch Ophthalmol. 1997;115:969-974.
ABSTRACT
2. Kupin TH, Juzych MS, Shin DH, et al. Adjunctive mitomycin C in primary trabeculectomy in phakic eyes. Am J Ophthalmol. 1995;119:30-39.
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3. Greenfield DS, Liebmann JM, Jee J, Ritch R. Late-onset bleb leaks after glaucoma filtering surgery. Arch Ophthalmol. 1998;116:443-447.
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4. Greenfield DS, Suner IJ, Miller MP, et al. Endophthalmitis after filtering surgery with mitomycin. Arch Ophthalmol. 1996;114:943-949.
ABSTRACT
5. Soltau JB, Rothman RF, Budenz DL, et al. Risk factors for glaucoma filtering bleb infections. Arch Ophthalmol. 2000;118:338-342.
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6. Higginbotham EJ, Stevens RK, Musch DC, et al. Bleb-related endophthalmitis after trabeculectomy with mitomycin C. Ophthalmology. 1996;103:650-656.
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7. Belyea DA, Dan JA, Stamper RL, Lieberman MF, Spencer WH. Late onset of sequential multifocal bleb leaks after glaucoma filtration
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