Bleb-related endophthalmitis
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Synonyms and keywords: Bleb-associated endophthalmitis; BAE; BRE

# Overview
Bleb-related endophthalmitis (BRE) is the second most frequent type of postoperative endophthalmitis. Bleb-related endophthalmitis is a complication of trabeculectomy. The exact pathogenesis of bleb-related endopthalmitis following trabeculectomy is not fully understood. It is thought that bleb-related endophthalmitis is the result of bleb leakage, which allows bacterial entry from the tear film and the periocular structures into the anterior chamber or the vitreous humor.
Based on latency of onset, bleb-related endophthalmitis (BRE) may be classified into early onset and late onset. Common causes of bleb-related endophthalmitis include Streptococcus spp., Staphylococcus spp., and Haemophilus influenzae. Common risk factors for the development of bleb-related endophthalmitis include bleb leakage, inappropriate use of  antifibrotic agents such as 5-fluorouracil (5-FU) and mitomycin C, inferior and nasal placement of bleb, and prior history of blebitis. Bleb-related endophthalmitis is a medical emergency. If left untreated, it may lead to corneal infiltration, retinal toxicity, corneal perforation, retinal detachment, and panophthalmitis that may require enucleation.
Bleb-related endophthalmitis presents as an accelerated prodromal syndrome, which can progress rapidly over several hours. It is usually characterized by severe visual loss and marked pain.
Endophthalmitis is a clinical diagnosis supported by culture and polymerase chain reaction (PCR) of intra-ocular fluids.
Patients with bleb-related endophthalmitis need urgent examination by an expert ophthalmologist and/or vitreo-retinal specialist. Intravitreal injection of antibiotics, topical fortified antibiotics, and surgical repair are necessary in the management of bleb related endophthalmitis. However, the benefit of vitrectomy in the management of bleb related endophthalmitis remains unclear. Assessment of bleb leakage following trabeculectomy surgery in every visit seems to be the most effective measure for the primary prevention of bleb-related endophthalmitis.

# Historical Perspective
- Since the introduction of trabeculectomy in 1968, the first phenomenon of bleb related infections was documented.
- Since the use of anti-metabolite agents such as mitomycin C (MMC) and 5-fluorouracil (5-FU) after 1984, the second phenomenon of bleb related endophthalmitis was reported.

# Classification
Based on latency of onset, bleb-related endophthalmitis (BRE) can be classified into:
- Early onset (Less than 6 weeks since surgery)
- Late onset (more than 6 weeks since surgery)

# Pathophysiology
Bleb-related endophthalmitis is a complication of trabeculectomy.
The exact pathogenesis of bleb-related endopthalmitis following trabeculectomy is not fully understood. It is thought that bleb-related endophthalmitis is the result of bleb leakage, which allows bacteria from the tear film and the periocular structures access into the anterior chamber or the vitreous humor.
Trabeculectomy is performed to achieve low intraocular pressure (IOP) in glaucoma that has failed medical management. A filtering bleb is a surgically created defect in the sclera which allows excess aqueous humor to leak out of the anterior chamber and be absorbed into the systemic circulation.
There is a serious concern for bleb-related endophthalmitis (BRE) even after successful trabeculectomy.
Early onset bleb leakage is commonly caused by either wound dehiscence or incomplete conjunctival closure. Late onset bleb leakage is caused by the use of adjunctive anti-metabolites such as mitomycin C (MMC) and 5-fluorouracil (5-FU), which are usually used to prevent fibrosis and scarring of the scleral flap and bleb.
Anti-metabolites may result in bleb leakage by the following mechanism:
- Reduced mucin production (secondary to loss of goblet cell)
- General conjunctival thinning
- Reduced cellularity
- Avascular bleb
Even in the absence of a leak, it is also thought that more virulant organisms, such as streptococcus spp, can penetrate an intact bleb into the anterior chamber and vitreous humor.

# Causes
Common causes of bleb-related endophthalmitis include:
- Early onset BRE
Staphylococcus epidermidis
- Staphylococcus epidermidis
- Late onset BRE
Streptococcus spp. (31%)
Staphylococcus spp. (7%-22%)
Haemophilus influenzae( 23%)
Enterococcus
Pseudomonas
Moraxella
- Streptococcus spp. (31%)
- Staphylococcus spp. (7%-22%)
- Haemophilus influenzae( 23%)
- Enterococcus
- Pseudomonas
- Moraxella

# Differentiating Bleb-related Endophthalmitis from Other Diseases
Bleb-related endophthalmitis must be differentiated from:
- Blebitis (bleb-related endophthalmitis is characterized by severe loss of vision, marked pain, and presence of vitritis)
- Anterior uveitis
- Uveitis-glaucoma-hyphema syndrome

# Epidemiology and Demographics

## Incidence
- The incidence of bleb-related endophthalmitis is approximately range from 170 to 1,300 per 100,000 individuals with trabeculectomy surgery.
- The incidence of bleb-related endophthalmitis is approximately 3,000 per 100,000 individuals with the use of antiproliferative agent.
- The incidence of bleb-related endophthalmitis is approximately 9,000 per 100,000 individuals with inferior placement of bleb.

## Age
The incidence of  bleb-related endophthalmitis decreases with age.
Many studies have shown a higher prevalence of blebitis in younger patients (younger than 40 years old).

## Gender
Males are more commonly affected with bleb-related endophthalmitis than females.

## Race
African-Americans are more commonly affected with bleb-related endophthalmitis than other races.

## Developed countries
In the United States, the incidence of bleb-related endophthalmitis is approximately range from 450 to 1,300 per 100,000 individuals with trabeculectomy after up to 5 years follow up.

# Risk Factors
Common risk factors in the development of bleb-related endophthalmitis include:
- Bleb-related risk factors
Bleb leakage (increase the risk of bleb infection 26 fold)
Inappropriate use of  of The antifibrotic agents (such as 5-fluorouracil (5-FU) and mitomycin C (MMC))
Inferior and nasal placement of bleb
Prior history of blebitis
Bleb manipulation/trauma
Bleb revision surgery
- Bleb leakage (increase the risk of bleb infection 26 fold)
- Inappropriate use of  of The antifibrotic agents (such as 5-fluorouracil (5-FU) and mitomycin C (MMC))
- Inferior and nasal placement of bleb
- Prior history of blebitis
- Bleb manipulation/trauma
- Bleb revision surgery
- Ocular risk factors
Conjunctivitis
Blepharitis
Nasolacrimal duct obstruction
Contact lens wear
Abnormal lid position
- Conjunctivitis
- Blepharitis
- Nasolacrimal duct obstruction
- Contact lens wear
- Abnormal lid position
- Systemic risk factors
Diabetes
Chronic antibiotic use
Juvenile glaucoma
Male
Age under 60 years
Black race
Upper respiratory infection (URI)
Malnutrition
- Diabetes
- Chronic antibiotic use
- Juvenile glaucoma
- Male
- Age under 60 years
- Black race
- Upper respiratory infection (URI)
- Malnutrition

# Screening
Screening for bleb-related endophthalmitis is not recommended following trabeculactomy surgery.
However, screening for bleb leakage by ophthalmologist following each visit is recommended among patients with trabeculactomy surgery.

# Natural History, Complications, and Prognosis

## Natural History
Bleb-related endophthalmitis is a medical emergency. If left untreated, It may lead to corneal infiltration, retinal toxicity, corneal perforation, retinal detachment, and panophthalmits that may require enucleation.

## Complications
Complications to bleb resalted endophthalmitis include:
- Corneal perforation
- Corneal edema
- Persistence intraocular inflammation
- Cataract
- Hypotony
- Residdual vitreous opacity

## Prognosis
Despite intensive topical, systemic, and intravitreal antibiotics in combination with vitrectomy. Bleb-related endophthalmitis is associated with a poor visual outcome. Bleb-related endophthalmitis caused by moraxella and coagulase negative staphylococcus is associated with more favorable outcomes compared with those caused by streptococcus.

# Diagnosis
Endophthalmitis is a clinical diagnosis, supported by culture and polymerase chain reaction (PCR) of intra-ocular fluids.

## History
Specific areas of focus when obtaining a history from the patient with bleb-related endophthalmitis include:
- Prior history of trabeculectomy
- History of blebitis
- Use of adjunctive anti-metabolites, such as mitomycin C(MMC) and 5-fluorouracil (5-FU)

## Symptoms
Patients with bleb-related endophthalmitis present with accelerated prodromal syndrome, which can progress rapidly over several hours.
Symptoms of bleb-related endophthalmitis may include the following:
- Ocular pain and  discomfort
- Redness
- Blurred vision
- Eye Discharge
- Loss of vision
- Eyebrow ache
- Headache
- External ocular inflammation

## Physical Examination
A thorough physical and eye examination from the patient is necessary. Common ophthalmoscopic examination findings of bleb-related endophthalmitis include:
- Ocular pain
- Redness
- Decreased vision
- Conjunctival injection
- Chemosis
- Hyperemic conjunctiva, opacified bleb with purulent adherent material, hypopyon, and fibrinous AC reaction.
- White-on-red appearance of acute blebitis
- Thin walled, transparent, tense, avascular bleb

## Laboratory Findings
Laboratory studies consistent with the diagnosis of bleb-related endophthalmitis include: 
- Culture and gram stain of aqueous humor as well as the vitreous humor
- Polymerase chain reaction (PCR) of aqueous humor as well as the vitreous humor
- Conjunctival and eyelid cultures

## Imaging Findings

### X Ray
There are no diagnostic x ray findings associated with bleb-related endophthalmitis.

### CT
There are no diagnostic CT scan findings associated with bleb-related endophthalmitis.

### MRI
There are no diagnostic MRI findings associated with bleb-related endophthalmitis.

### Ultrasound
B scan ultrasonography may be helpful in diagnosis of coexisting posterior segment problem, such as vitreous changes or retinal detachment, in patient with bleb-related endophthalmitis.

### Other Imaging Findings
There are no other Imaging Findings associated with bleb-related endophthalmitis.

## Other Diagnostic Studies

### Slit lamp examination
- A mucopurulent infiltrate
- Anterior chamber and vitreous inflammation
- Hypopyon
- Inflamed bleb
- Bleb leak

# Treatment
The patient needs urgent examination by an expert ophthalmologist and/or vitreo-retina specialist who will usually decide for urgent intervention to provide intravitreal injection of potent antibiotics. Enucleation may be required to remove a blind and painful eye.
- Bacterial and fungal cultures from vitreous samples are necessary in the management of bleb related endophthalmitis
- Surgical repair may be considered in the presence of poor bleb morphology
- Topical fortified antibiotics should be considered
- The benefit of vitrectomy in the management of bleb related endophthalmitis remains unclear

## Medical Therapy

### Antimicrobial Regimens
- Infectious endophthalmitis
- 1. Causative pathogens
- Staphylococci
- Streptococci
- Enterococci
- Pseudomonas aeruginosa
- Haemophilus influenzae
- 2.Empiric antimicrobial therapy
- Preferred regimen: Vancomycin 1 mg per 0.1 mL normal saline intravitreal injection, single dose AND Vancomycin 1 g IV bid for 2 weeks AND Ceftazidime 2.25 mg per 0.1 mL normal saline intravitreal injection, single dose AND Ceftazidime 1 g IV bid for 2 weeks AND Clindamycin 600-1200 mg IV bid to qid for 2 weeks
- Note (1): Re-injection should be considered if the infection does not improve beyond 48 hours of the first injection. Re-injection significantly increases the risk of retinal toxicity.
- Note (2): In addition to intravitreal and systemic antibiotic therapy, vitrectomy is usually necessary
- 3. Pathogen-directed antimicrobial therapy
- 3.1 Bacillus spp.
- Preferred regimen: Vancomycin 1 mg per 0.1 mL normal saline intravitreal injection, single dose AND Vancomycin 1 g IV bid for 2 weeks AND Clindamycin 600-1200 mg IV bid to qid for 2 weeks
- Note: In addition to antimicrobial therapy, vitrectomy is usually necessary
- 3.2 Non-Bacillus gram-positive bacteria
- Preferred regimen: Vancomycin 1 mg per 0.1 mL normal saline intravitreal injection, single dose AND Vancomycin 1 g IV bid for 2 weeks
- Note: In addition to antimicrobial therapy, vitrectomy is usually necessary
- 3.3 Gram-negative bacteria
- Preferred regimen: Ceftazidime 2.25 mg per 0.1 mL normal saline intravitreal injection, single dose AND Ceftazidime 1 g IV bid for 2 weeks
- Note: In addition to antimicrobial therapy, vitrectomy is usually necessary
- 3.4 Candida spp.
- Preferred regimen: (Fluconazole 400-800 mg IV/PO qd for 6-12 weeks OR Voriconazole 400 mg IV/PO bid for 2 doses followed by 200-300 mg IV/PO bid for 6-12 weeks OR Amphotericin B 0.7-1.0 mg/kg IV qd for 6-12 weeks) AND Amphotericin B 5-10 microgram in 0.1 mL in normal saline intravitreal injection, single dose
- Note (1): In addition to antimicrobial therapy, vitrectomy is usually necessary
- 3.5 Aspergillus spp.
- Preferred regimen: Amphotericin B 5-10 microgram in 0.1 mL normal saline intravitreal injection, single dose AND Dexamethasone 400 microgram intravitreal injection, single dose
- Note (1): In addition to antimicrobial therapy, vitrectomy is usually necessary
- Note (2): Repeat antimicrobial regimen in 2 days post-vitrectomy

## Surgery

### Vitrectomy
- The benefit of vitrectomy in the management of bleb related endophthalmitis remains unclear.

## Prevention

### Primary Prevention
Effective measures for the primary prevention of bleb-related endophthalmitis include:
- Assessment of bleb leakage following tabeculectomy surgery in every visit
- Aggressive treatment of blebitis
- Bleb revision with conjunctival advancement to manage avascular leaking blebs (100% success rate)
- Amiotic membrane grafting as a possible alternative to conjunctival advancement (45% success rate)
- Surgical repair in the presence of poor bleb morphology without an apparent leak

### Secondary prevention
There are no secondary preventive measures available for bleb-related endophthalmitis.