Beware of the Bleb

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doi:10.62055/63115123Wl

ABSTRACT

Glaucoma is the leading cause of irreversible blindness worldwide. Treatment is focused on lowering the intraocular pressure, the only modifiable risk factor. Methods to reduce intraocular pressure include topical medications, non-invasive laser procedures, minimally invasive glaucoma surgeries (MIGS), and traditional incisional glaucoma surgeries. The incisional glaucoma surgeries- trabeculectomy and tube shunts – are more invasive but provide an important treatment option for patients with advanced disease or who are non-responsive to other methods of lowering intraocular pressure. While effective at lowering intraocular pressure, incisional glaucoma surgeries put patients at risk for infectious sequelae days to years after surgery.

CASE REPORT

A 70-year-old African American man presented to the eye clinic with a complaint of a red eye with associated mild irritation, light sensitivity, and mucous discharge for the past few days. The patient’s ocular history was positive for pseudophakia and open-angle glaucoma, with a filtering bleb post-trabeculectomy in the right eye and diode laser ciliary body ablation to the left eye. The exam was positive for an elevated, white bleb with surrounding bulbar conjunctiva erythema and mucus debris in the tear film. The patient was diagnosed with blebitis and prompt treatment with broad-spectrum topical antibiotics prevented further spread of the infection.

CONCLUSION

Regardless of the length of time since surgery, a bleb-related infection (BRI) should always be considered in patients with a history of bleb-forming glaucoma surgery. Misdiagnosed or undertreated bleb-related infections can lead to endophthalmitis and permanent vision loss. Clinicians should understand the serious nature of BRIs and be knowledgeable about risk factors, treatment, and diagnosis to prevent vision loss in these patients.

Keywords: glaucoma, infection, bleb, blebitis

INTRODUCTION

Glaucoma is a group of progressive optic neuropathies and is the leading cause of irreversible blindness worldwide.¹ The high prevalence and rate of vision loss make glaucoma a public health concern. First-line treatments for glaucoma include topical intraocular pressure (IOP) lowering drops or laser surgery options.² If a patient is non-responsive to these treatments, surgical intervention through MIGS or traditional incisional techniques is warranted.² Surgery is also considered in patients with newly diagnosed advanced glaucoma.³

Although newer glaucoma filtering devices and penetrating glaucoma surgeries have been introduced in the past decade, trabeculectomy remains the procedure of choice for many glaucoma surgeons.^2,4 The art of trabeculectomy has evolved since its inception in 1968.⁴ Early versions of the procedure were associated with poor long-term success and serious complications, including hypotony, hypotonic maculopathy, choroidal detachment, suprachoroidal hemorrhage, bleb-related infections (BRIs), and endophthalmitis.^4,5 Improvements were made to the procedure over time to reduce complications and increase success. The incidence of BRI differs greatly between studies depending on surgical technique, follow-up period, and use of antimetabolite agents but recent retrospective studies have reported the incidence of BRI between 0.5 to 5%.^5–8 While the incidence of BRIs remains low, clinicians must be aware of the risk factors, clinician presentation, and treatment to stop preventable vision loss.

CASE REPORT

A 70-year-old African American male presented to the emergency department with complaints of redness, irritation, and discharge from his right eye (OD) that started two to three days prior. His symptoms were associated with increased blur, light sensitivity, mild pain, and a mild throbbing sensation. His ocular history was significant for keratoconjunctivitis sicca, severe stage open-angle glaucoma, and pseudophakia. His ocular surgery history in the right eye included cataract extraction surgery with insertion of intraocular lens and a separate surgery for trabeculectomy with mitomycin C. His left eye (OS) surgical history included cataract extraction with insertion of an intraocular lens with iStent and a separate procedure for diode cyclophotocoagulation.

The patient’s corrected entrance visual acuity was 20/60 OD, improving with pinhole to 20/40, and no light perception OS. His vision was reduced by two lines OD and stable in the OS compared to his exam findings from the prior week. The patient’s right pupil was round, reactive to light; while the left pupil was fixed with a dense afferent pupillary defect. The extraocular muscles had a full range of motion without pain. The measured IOP OD was 10.8 mmHg and 22.7 mmHg OS with iCare rebound tonometry.

The right upper lid was edematous. There was an elevated, avascular, opaque bleb with negative staining superior-temporal to the cornea OD (Figure 1). The Seidel sign was negative indicating no bleb leak or open ocular wound. The tear film contained a white, ropey discharge. The cornea was clear and the anterior chamber was deep without cells or flare. There were no cells visualized in the anterior vitreous. Biomicroscopy of the left eye was unremarkable. A conjunctival swab to determine microbial sensitivity was not performed as supplies were unavailable in the office.

The differential diagnoses included blebitis, bacterial conjunctivitis, and viral conjunctivitis. The time course and symptoms of the patient’s presentation were consistent with all three disease processes. However, the mucous discharge reported and observed with the patient is more indicative of bacterial etiology than viral. Based on the history of trabeculectomy and clinical findings of a white bleb with surrounding erythema and injection, blebitis was the leading diagnosis. A dilated examination was not performed but is recommended to rule out any anterior chamber reaction or vitritis.

Treatment was initiated with a topical moxifloxacin loading dose, which consisted of one drop every five minutes for twenty-five minutes. The patient was then sent home with instructions to instill moxifloxacin every hour around the clock with a follow-up in one day with the glaucoma specialist on staff.

At the one-day follow-up with a glaucoma specialist, the patient reported the OD felt stable, and maybe a little better. He reported good compliance with glaucoma medications and denied missing any doses of moxifloxacin. The biomicroscopy exam revealed 2+ bulbar conjunctival injection and a cystic bleb with central staining. The lids, lashes, and cornea were unremarkable. The anterior chamber was deep and quiet.

The glaucoma specialist confirmed a leading differential diagnosis of Stage I blebitis. The recommended plan was to continue moxifloxacin use every hour and follow up in another 24 hours. The recommendation was to continue to monitor and treat assertively since the patient was functionally monocular.

At the two-day follow-up, the patient reported that his eye was still red and irritated, but he was no longer experiencing discharge or photophobia. The patient reported good compliance with moxifloxacin every hour. The biomicroscopy exam revealed 1+ bulbar conjunctival injection, a cystic bleb with central negative staining, and negative Seidel sign. The anterior segment examination was otherwise unremarkable. The plan was to continue moxifloxacin every hour around the clock until a follow-up appointment the next day.

At the three-day follow-up, the patient reported continued improvement in symptoms. The biomicroscopy examination revealed a trace injection around the bleb. The bleb appeared cystic with central staining and no leakage. The anterior chamber remained deep and quiet. The glaucoma specialist began an antibiotic drop reduction, lowering the dosing schedule to every two hours while awake with a follow-up appointment in five days with the glaucoma specialist.

At the seven-day follow-up, the patient reported no pain, irritation, or discharge. The visual acuity with habitual spectacle correction was 20/50 OD. On biomicroscopy examination, the conjunctiva was white and quiet with a translucent, cystic bleb OD. The remainder of the examination was unremarkable. The glaucoma specialist further reduced antibiotic therapy to four times a day while awake for an additional seven days. At the next visit, slit lamp examination continued to be stable and antibiotic therapy was discontinued by the glaucoma specialist. The patient was scheduled for a month follow up in the glaucoma clinic and instructed to return sooner with any new pain, redness, irritation, or light sensitivity.

DISCUSSION

The current method of a trabeculectomy involves a partial-thickness flap to make a corneoscleral window for the passage of aqueous humor.⁴ The goal is to create an outflow channel between the anterior chamber and subconjunctival space. Anti-fibrotic agents, such as mitomycin-C (MMC) and 5-fluorouracil (5-FU), are used during surgery to enhance long-term filtration of the bleb.⁵ These agents slow fibroblast proliferation and change the conjunctival vascular endothelium leading to the formation of a thin-walled and avascular bleb.⁶  While improving the success of incisional glaucoma surgeries at lowering intraocular pressure, the use of anti-fibrotic agents has also been linked to an increased risk of bleb-related infection.^5,6,8–11

Anti-fibrotic agents can lead to epithelial breakdown, hypocellularity, and stromal collagen necrosis within the bleb.¹⁰ These changes lead to thin, avascular, leaky blebs that are more susceptible to infection.^6,11–14 It is important to recognize that the same signs of successful filtering surgery – thin walls and avascularity – lead to the greatest risk for developing BRI.^14,15

Other risk factors for developing BRI include an inferiorly located bleb, a conjunctival incision approach, a history of recurrent bleb leaks, younger age, and a history of multiple incisional surgeries.^6,7,8 Less reported risk factors include hypotony, pseudophakia, anti-VEGF injection, blepharoconjunctivitis, contact lens wear, and prophylactic antibiotic use.^6,14

Due to the visually devastating potential of BRI, post-trabeculectomy patients should be monitored for bleb-related complications.^7,8,12 Providers must keep BRI on their differential as it can occur immediately after glaucoma surgery, or more than four decades afterward.^11,12 If infection occurs within the first month of surgery, it is considered short-term, while long-term would be considered after a month.^12,13 Retrospective studies have reported a typically onset time between 20 to 23 months.^5,11 Short-term or early-onset infections tend to be less virulent and carry a better prognosis than long-term infections.¹²

Each patient encounter should include a detailed case history with an inquiry into symptoms and careful examination of bleb tissue for leakage or scar formation. Presenting symptoms of BRI may be nonspecific and mimic bacterial or viral conjunctivitis.⁷ Common initial symptoms include redness, irritation, and/or discharge while blurry vision, pain, and light sensitivity are more common in later stages.

BRIs are classified into stages based on depth of involvement:

• Stage I is a blebitis or localized inflammation of the bleb. It is characterized by a white appearance of the bleb, mucopurulent discharge, and diffuse bulbar erythema.^7,12,15 Stage I will not have anterior chamber or vitreous involvement. It may have an associated bleb leak or conjunctival epithelial defect.⁷  Symptoms at this stage are relatively mild with redness and irritation alongside mild blur and light sensitivity.^12,15 The patient may experience a prodromal brow ache or headache.⁸
• Stage II is characterized by a blebitis with associated cells, flare, or even hypopyon in the anterior chamber.^12,15 The associated symptoms will match those of a blebitis with increased pain and photophobia.^8,12,15
• Stage III will disseminate to the vitreous, causing a vitritis.¹² The later-stage disease will be characterized by worsening visual acuity, ocular pain, and light sensitivity.^7,13

Diagnostic workup should include careful examination of the bleb for a Seidel sign indicating bleb leak, mucopurulent discharge, and cystic appearance. Imaging techniques like laser scanning confocal microscopy may be utilized to view the bleb and corneal findings or B-scan should vitritis prevent a clear view of the retina.⁷ Laboratory studies can be performed on conjunctival swabs or samples of aqueous and vitreous for strain and culture, polymerase chain reaction, and other microbial DNA-identifying methods.^7,12 Ideally, and if available, microbial cultures should be obtained before starting any antimicrobial therapy.

A blebitis can rapidly disseminate to endophthalmitis without early and aggressive treatment.^8,11 In Stage I blebitis, treatment with a broad-spectrum antibiotic, either topical fourth-generation fluoroquinolone or fortified topical aminoglycoside, is recommended every five minutes for three doses as a loading dose and then every hour.^7,8  The follow-up period can range from twice-a-day examination to daily in the first few days to ensure antibiotics are effective and infection is not progressing. Some providers will treat blebitis as an endophthalmitis or later-stage disease, even without signs of anterior chamber reaction or hypopyon.^13,14 Alongside microbial treatment for blebitis, providers should manage any concurrent bleb leak. Non-surgical methods of bleb leak management include aqueous suppressants, pressure patching, oversized contact lenses, and fibrin glue.¹³

In a later-stage BRIs or with no clinical improvement on topical antibiotics, culture studies should be performed on the conjunctiva, aqueous humor, or vitreous samples to ensure that the offending microorganisms are sensitive to antibiotic agents.¹³ In Stage II or III BRI, patients may be hospitalized for treatment with intravitreal or intravenous antibiotics. In addition to antibiotic management, ocular surgery may be indicated. Concurrent bleb leak may be closed with non-surgical methods or methods such as argon laser therapy, autologous blood injections, compression sutures, or conjunctival crosslinking.¹³ Management of an active vitritis often warrants pars plana vitrectomy to reduce microbial load.^7,13

The visual outcome in cases of BRI depends on the virulence of the microorganism, depth of infection and how quickly antibiotic treatment is initiated.⁸ Most patients have a visual acuity of less than 20/400 some studies reporting a final visual acuity of NLP in 25-25% of patients.^7,8,11,13 In these cases with poor visual outcomes, pain or phthisis, evisceration or enucleation may be indicated.^8,13

Early diagnosis and intervention can prevent intraocular microbial progression. Patients and providers must be aware of the necessity of an urgent work up for symptoms of redness, vision changes, and pain in a patient who has had a history of bleb-forming glaucoma surgery. Clinicians must carefully examine these patients for any sign of infection, bleb leak, or intraocular inflammation. With suspicion of any BRI, clinicians should be prepared to perform conjunctival microbial cultures if available, initiate treatment with broad-spectrum antibiotics, address wound leak, and refer to a glaucoma specialist for further management.

CONCLUSION

Clinicians should be vigilant in the assessment of patients with a history of glaucoma surgery. BRIs can occur at any time and are more likely to occur in patients with surgically successful, well-filtering thin blebs. BRIs should always be considered in patients presenting with non-specific symptoms of redness, irritation, and discharge and have a history of bleb-forming glaucoma surgery. Early and assertive treatment with broad-spectrum topical antibiotics and prompt referral for additional management can help prevent devastating vision loss in patients.

REFERENCES

1. Allison K, Patel D, Alabi O. Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future. Cureus. Published online November 24, 2020. doi:10.7759/cureus.11686
2. Al-Haddad C, Abdulaal M, Al-Moujahed A, Ervin AM. Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma. Cochrane Eyes and Vision Group, ed. Cochrane Database of Systematic Reviews. Published online November 25, 2015. doi:10.1002/14651858.CD009380.pub2
3. King AJ, Hudson J, Fernie G, et al. Primary trabeculectomy for advanced glaucoma: pragmatic multicentre randomised controlled trial (TAGS). BMJ. Published online May 12, 2021:n1014. doi:10.1136/bmj.n1014
4. Rao A, Cruz RD. Trabeculectomy: Does It Have a Future? Cureus. Published online August 9, 2022. doi:10.7759/cureus.27834
5. Rai P, Kotecha A, Kaltsos K, et al. Changing trends in the incidence of bleb-related infection in trabeculectomy. Br J Ophthalmol. 2012;96(7):971-975. doi:10.1136/bjophthalmol-2011-300926
6. Poulsen EJ, Allingham RR. Characteristics and Risk Factors of Infections After Glaucoma Filtering Surgery: Journal of Glaucoma. 2000;9(6):438-443. doi:10.1097/00061198-200012000-00004
7. Razeghinejad MR, Havens SJ, Katz LJ. Trabeculectomy bleb-associated infections. Survey of Ophthalmology. 2017;62(5):591-610. doi:10.1016/j.survophthal.2017.01.009
8. Yassin SA. Bleb‐related infection revisited: a literature review. Acta Ophthalmologica. 2016;94(2):122-134. doi:10.1111/aos.12805
9. Anand N, Arora S, Clowes M. Mitomycin C augmented glaucoma surgery: evolution of filtering bleb avascularity, transconjunctival oozing, and leaks. British Journal of Ophthalmology. 2006;90(2):175-180. doi:10.1136/bjo.2005.077800
10. Belyea DA, Dan JA, Stamper RL, Lieberman MF, Spencer WH. Late Onset of Sequential Multifocal Bleb Leaks After Glaucoma Filtration Surgery With 5-Fluorouracil and Mitomycin C. American Journal of Ophthalmology. 1997;124(1):40-45. doi:10.1016/S0002-9394(14)71642-3
11. Luebke J, Neuburger M, Jordan JF, et al. Bleb-related infections and long-term follow-up after trabeculectomy. Int Ophthalmol. 2019;39(3):571-577. doi:10.1007/s10792-018-0851-0
12. Kandarakis SA, Doumazos L, Mitsopoulou D, et al. A Review on Pathogens and Necessary Diagnostic Work for Bleb-Related Infections (BRIs). Diagnostics. 2022;12(9):2075. doi:10.3390/diagnostics12092075
13. Ba’arah B, Smiddy W. Bleb-related endophthalmitis: Clinical presentation, isolates, treatment and visual outcome of culture-proven cases. Middle East Afr J Ophthalmol. 2009;16(1):20. doi:10.4103/0974-9233.48862
14. Mac I, Soltau JB. Glaucoma-filtering bleb infections: Current Opinion in Ophthalmology. 2003;14(2):91-94. doi:10.1097/00055735-200304000-00007
15. Kim EA, Law SK, Coleman AL, et al. Long-Term Bleb-Related Infections After Trabeculectomy: Incidence, Risk Factors, and Influence of Bleb Revision. American Journal of Ophthalmology. 2015;159(6):1082-1091. doi:10.1016/j.ajo.2015.03.001

Aprile Doubt, OD, MS

New Mexico VA Health Care System | Albuquerque, NM

Dr. Doubt graduated from the Ohio State University with a dual degree of Doctorate of Optometry and Masters of Vision Science in 2024. Afterwards, she went on to complete a residency in ocular disease, low vision and specialty contact lenses at Ralph H. Johnson VAMC in Charleston, SC.

William J. Denton, OD, FAAO, FSLS, FORS

Ralph H. Johnson VA Medical Center | Charleston, SC

Dr. Denton desires to be the mentor he felt he never had. He has mentored many and given his time to various optometric organizations through the last couple decades. His career desire is to be a true primary care optometrist who is able to treat any patient that comes in the clinic.

Kelly Singleton, OD, MS

Ralph H. Johnson VA Medical Center | Charleston, SC

Dr. Singleton received her OD and MS degrees from the University of Alabama-Birmingham School of Optometry and completed her residency in Low Vision/Vision Rehabilitation at the University of Houston College of Optometry. She has enjoyed an extensive optometry career including owning her own practice with her husband and serving as the national physician liaison for an eyecare specific EHR company. She currently serves as the Residency Supervisor at the RHJ VA Medical Center in Charleston, SC and is an Assistant Professor at the Medical University of South Carolina. In her free time, she enjoys competitive dragon boating and traveling the world with her husband and four children.