Pseudophakic Bullous Keratopathy

Etiology

The main etiology of PBK is due to endothelial loss post-surgical trauma, especially in older patients. The other main causes are endothelial burns secondary high energy use during phacoemulsification. High irrigation and aspiration can also result in endothelial damage during cataract surgery and manifest as striate keratopathy post-cataract surgery. The other etiologies linked with PBK are all diseases affecting corneal endothelium like:

• Fuchs endothelial dystrophy
• Posterior polymorphous endothelial dystrophy
• Congenital hereditary endothelial dystrophy[4]
• Iridocorneal endothelial (ICE) syndrome-Chandler syndrome
• Essential/progressive iris atrophy
• Iris nevus / Cogan-Reese syndrome[5]
• Herpetic disciform keratitis[6]
• Diabetes mellitus[7]
• Pseudoexfoliation syndrome[8]
• Narrow-angle glaucoma[9]
• Blunt trauma[10][11]
• Endothelitis, uveitis, keratitis[12]
• Surgical trauma during any intraocular surgery[13]
• Toxic anterior segment syndrome (TASS)[14]
• Silicon oil in the anterior chamber[15]
• Implantable collamer lens[16]
• Vitreous touch syndrome[17]
• Vitreous wick syndrome[18]

The intraoperative etiology is linked to closed-loop anterior chamber intraocular lens (ACIOL) > open-loop ACIOL> iris fixated IOL> posterior chamber IOL.[3] Postoperative etiologies include after routine surgery there is usually 10 % endothelial cell loss, 1% endothelial loss/ year naturally, vitreous touch syndrome, vitreous wick syndrome, flat anterior chamber post-surgery Intermittent IOL touch.[19][20]

Epidemiology

Although its difficult to estimate the exact incidence of PBK, but the current reported rate of PBK in the USA is 0.1%. During the years 1978 to 1982, various US FDA-approved studies showed the incidence of 0.06% of PBK after PCIOL implantation, 1.2% after anterior chamber lenses and 1.5% after iris fixated lenses.[21]

The long-term reported incidence of PBK is 15%. The amount of endothelial cell loss during cataract surgery can also be correlated to PBK, which is estimated to be approximately 4.72% after extracapsular cataract extraction (ECCE), 4.21% after small incision cataract surgery (SICS), and 5.41% after phacoemulsification. There is no gender, sex, or racial predilection for PBK. The most common risk factor for PBK is Fuchs dystrophy which is 3 times more common in females. Old age is another important risk factor as the endothelial count reduces with age.[22]

Pathophysiology

The ability of the cornea to remain in a dehydrated state determines its transparency. The epithelium and endothelium act as a barrier to water and electrolytes due to their semipermeable membrane property. The NaKATPase pump located in the lateral cell membrane of the endothelium prevents corneal hydration. The endothelial cells pump the fluid out of the corneal stroma and help in maintaining transparency.

Any damage to endothelial cells will hamper corneal transparency when aqueous entering the cornea cannot be pumped out due to fewer viable endothelial cells. Approximately 700 cells/ mm square are required to maintain transparency. The endothelium lacks mitotic activity. At birth, the endothelial cell count is 7500 cells/mm^2, and it reduces to 2500 to 2700 cells/mm^2 by adulthood. The average cell loss per year is 0.5% after the age of 20. Surgically induced trauma, persistent inflammation, hereditary conditions like Fuch’s, and congenital hereditary endothelial dystrophy can promote this cell loss.

When the cell density reaches around 300-500 cells/ mm^2, it is called critically low cell density, resulting in the development of PBK. It results in increased polymegathism (irregular small and large cells) and pleomorphism (abnormal cell shape, increase non-hexagonality). There is abnormal production of the Descemet membrane; the pump fails and manifests as stromal edema.

The corneal anterior stromal has a high ratio of dermatan to keratan sulfate, making the posterior stroma swell more whenever there is an endothelial failure. This edema can change in response to a change in intraocular pressure (IOP). Imbibition pressure = IOP - swelling pressure. The aqueous can migrate from stroma to epithelium resulting in epithelial edema, blisters, and bullae formation. Early morning edema is seen due to lack of evaporation and hypertonic environment overnight.[23]

Histopathology

The various histopathological features in PBK are loss of corneal endothelial cells, pleomorphism and polymegathism of endothelial cells, reduced stromal keratocytes, thickening of posterior collagen layer of Descemet membrane, lack of adhesive proteins like laminin, fibronectin, and type 4 collagen in the epithelial basement membrane, increased antiadhesive proteins like tenascin C and thrombospondin-1 and increases levels of interleukin 8 (IL-8), interleukin 2 (IL-2), insulin-like growth factor (IGF-1), bone marrow factor-4 (BMP-4), and transforming growth factor (TGF- β).[24]

History and Physical

The clinical diagnosis of PBK is made by detailed history and clinical evaluation.

History

The patient usually gives a history of gradually progressive vision loss after cataract surgery. The patient may also give a history of prolonged surgical time or a history of intraocular complications. The patient also gives a history of early morning blurring due to overnight fluid accumulation and corneal edema.

Symptoms

At presentation, the patient may be asymptomatic. In the early stages, the patient may complain of blurring of vision. In advanced stages, the patient will complain of severe loss of vision. Other symptoms can be pain, redness, excessive photophobia, irritation, foreign body sensation, and halos around light.

Signs

A meticulously performed slit-lamp examination may reveal findings in each layer of the cornea. In the epithelium, there can be an epithelial defect, epithelial edema, microcysts, and bullae. The subepithelial layer may show scarring or haze formation, the stromal layer shows stromal edema, scarring, and haze, the Descemet membrane shows folds and scarring, and the endothelium reveals edema and decompensation.

Other signs to look for are the type of surgical incision (superior scleral incision for SICS and superior or temporal clear corneal for phacoemulsification), corneal neovascularization, shallow anterior chamber, iris chaffing, atrophic patches, iridodialysis, peripheral anterior synechia or posterior synechia, peripheral iridectomy pupil irregularity, pupil peaking, posterior capsular rupture, zonular dialysis, the position of IOL whether anterior, iris fixated, iris-claw, sulcus or posterior chamber IOL, optic capture and any vitreous prolapse in the anterior chamber, vitreous touch syndrome or vitreous wick syndrome. The other eye should also be examined for guttae and to rule out Fuch’s endothelial, congenital hereditary endothelial dystrophy, posterior polymorphous endothelial dystrophy, or any other endothelial pathology. The guttae appear as a golden brown confluent excrescence of Descemet membrane and give endothelium a beaten bronze appearance.[3]

Evaluation

Imaging Studies

Specular Microscopy

It basically means photographic mapping of the corneal endothelium. When light rays fall onto the cornea, the reflected images from the optical interface can be imaged (endothelium or aqueous humor). The endothelial layer is mapped under high magnification, and thus the cell density can be quantified. The normal cell density is 3000 to 3500 cell/mm^2 in young individuals and 2000 to 2500 cell/mm^2 in older adults. A cell density below 1000 cells/ mm^2 is labeled as critical cell density, and individuals with such cell density are at the highest risk of developing corneal decompensation. The various endothelial parameters assessed are polymorphism (variation in cell shape), polymegathism (variation in cell size), the maximum or minimum number of cells, average cells, number of cells showing hexagonality, coefficient of variation, standard deviation, presence or absence of guttae and artifacts. Endothelial cells depicting various sizes and shapes are considered under stress and are abnormal.[25]

Ultrasound Pachymetry

The corneal thickness can be easily assessed using ultrasound and corneal pachymetry. The normal central corneal thickness is 0.55 mm, and it increases to 0.80 in the corneal periphery. In conditions causing cornea thickening and edema, the thickness is usually more than 0.60, indicating corneal edema. The clinical application for pachymetry is to help assess the progression of endothelial diseases like Fuch’s endothelial dystrophy and follow up of corneal graft rejection cases under steroid regimen.[26] 

Optical Pachymetry

This imaging modality helps assess the depth of corneal pathology (e.g., nebular, macular, or leucomatous corneal opacities), especially when full-thickness stroma is not involved, and it becomes necessary to decide for depth before preoperative excimer laser phototherapeutic keratectomy.[27]

Treatment / Management

Medical Management

Hyperosmotic Agents

Topical sodium chloride- 2% drops and 5% ointment. These agents help by forming a hypertonic tear film by imbibing water out of the cornea. The drops are usually prescribed 4 times per day and ointment at bedtime to reduce early morning corneal edema due to accumulation of fluid overnight.[28](A1)

Antiglaucoma Drugs

The drugs commonly employed are beta-blockers and alpha agonists—these work by reducing the intraocular pressure, which reduces corneal edema and thickness in the postoperative period. Miotics and prostaglandins are avoided because they usually aggravate inflammation. Carbonic anhydrase inhibitors are also avoided as they are epitheliotoxic.[29](B3)

Steroids

Steroids are usually employed to reduce acute inflammation or postoperative uveitis immediately after cataract surgery. Before starting steroids, the cornea must always be stained with fluorescein to rule out any epithelial defect or infectious keratitis.[30]

Lubricants

They are used to lubricate the ocular surface and cornea to prevent surface irritation and dryness.[31]

Contact Lens

Extended wear of soft contact lenses plays a huge role in the management of patients with PBK. The various added advantages of contact lens are that they alleviate pain associate with epithelial bullae, protect infectious keratitis again when bullae are ruptured, and there is an epithelial defect, help to improve visual acuity when used in conjunction with hypertonic saline, and also prevents the formation of new bullae due to its barrier effect.[32][33][34](B3)

Surgical Management

Gunderson Conjunctival Flap

In this technique, a thin flap of the conjunctiva, usually from the superior bulbar conjunctiva, is transposed over the cornea with intact nasal and temporal bridges. It meets the metabolic demands of the cornea, increases local blood supply, helps in healing, and replaces the dead and denuded epithelium[35]

Amniotic Membrane Grafting (AMG)

In this technique, first, the loose epithelium is removed with the help of a sponge or a blade. This results in a large epithelial defect, usually sparing the limbus. A required amniotic membrane is cut and placed over the cornea with the stromal side towards the cornea, which is sticky compared to the basement membrane. The AMG is then attached to the cornea with the help of interrupted stay sutures. If needed, a BCL can also be placed.[36]

Bowman’s Membrane Cautery

This procedure helps in pain relief by forming a tight barrier between epithelium and stroma. This prevents fluid migration to the epithelium and prevents bullae formation[37]

Anterior Stromal Puncture

In this technique, multiple stromal punctures are created with the help of a 26G needle sparing the corneal periphery. This helps in pain and symptomatic relief. It results in subepithelial scarring and fibrosis in all cases.[38]

Annular Keratotomy

This technique helps in pain relief in symptomatic patients without visual potential. A partial-thickness trephination of the cornea is performed in an annular fashion. This helps in pain relief by severing the branches corneal ciliary nerve and reduce corneal sensations.[39](B3)

Basement Membrane Polishing

It is done with the help of a diamond burr. After removing the epithelium, a 4.5 to 5 mm diamond burr can be used to gently polish the basement membrane across the area of epithelial debridement.[40](B3)

Phototherapeutic Keratectomy (PTK)

The laser used for PTK is Nidek EC 500 excimer laser. This is of three types:

• Superficial PTK-  Ablation of 8 to 25 um stroma with 62% success rate
• Intermediate PTK- Ablation of 50 to 100 um stroma with 42% success rate
• Deep PTK- Ablation of 25% stroma with 60% success rate[41]

Thoman et al., in their analysis, proposed that superficial PTK is an effective procedure for pain relief and bullae resolution in the majority of the patients. They also highlighted that deep ablation has a better effect in reducing the pain by ablation of the preterminal neural plexus of the cornea located deep to the bowman’s membrane. It also reduces stromal edema by reducing the quantity of mucopolysaccharide and results in increased scarring with improved stability of the epithelium.[42]

Corneal Collagen Crosslinking with Riboflavin (C3R)

C3R is a new treatment tool for the temporary reduction of corneal edema in patients with PBK. The free radical generated by the action of riboflavin with UVA light induces cross-linking of stroma and strengthens the bonds. It has been found useful to reduce edema, thickness, improve corneal transparency and alleviate pain after surgery.[43]

Corneal Transplantation

Penetrating Keratoplasty

This is the gold standard surgery. In this technique, full-thickness host cornea is replaced by a donor cornea which is opposed to the host cornea with interrupted or continuous running sutures. The visual recovery takes some time. The graft size is usually 7 to 7.5 mm to avoid complications of small and large grafts, such as astigmatism and secondary glaucoma.

Descemet Stripping Endothelial Keratoplasty (DSEK) or Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)

DSAEK was first introduced and popularised by Melles and colleagues, which has revolutionized PBK management off late. In this technique, the Descemet membrane is stripped off from the host and replaced with donor Descemet membrane along with some part of the posterior stroma. Then an air bubble is introduced for 20 minutes to ensure a perfect opposition. Before completing the surgery, 10 to 20 percent of the air bubble is removed to prevent postoperative pupillary block glaucoma. If the donor is prepared manually, it is called DSEK, and if the automated anterior chamber is employed, it is called DSAEK.[44]

Descemet Membrane Endothelial Keratoplasty (DMEK)

This technique is a further refinement over DSEK. In this, the Descemet and endothelium of the host are replaced with the endothelium without any stromal tissue. Hence, this technique offers quicker visual recovery, better corrected distant visual acuity, and reduced risk of graft rejection. DMEK has a steep learning curve and requires more skill and expertise to get the desired outcome

Hence, in a nutshell, endothelial keratoplasty offers a lot of advantages over traditional penetrating keratoplasty. The few advantages are reduced risk of graft rejection, being a closed globe procedure, there is minimal chance of expulsive choroidal hemorrhage, the suture related complications are avoided, the corneal contour and topography are preserved, there is less induced astigmatism, there is no need for long term steroid use, and more wound strength due to smaller incision. The various disadvantages are interphase haze, steep learning curve, and graft/ lenticule dislocation, which may require rebubbling.[45][46](B2)

Differential Diagnosis

• Fuch’s endothelial dystrophy
• Congenital hereditary endothelial dystrophy (CHED)
• Posterior polymorphous corneal dystrophy (PPMD)
• Iridocorneal endothelial syndrome (ICE)
• Herpetic stromal keratitis (HSK)
• Recurrent corneal erosion syndrome (RCES)

Prognosis

Timely and meticulously done optical penetrating keratoplasty or Descemet stripping endothelial keratoplasty (DSEK) has a good prognosis in pseudophakic bullous keratopathy cases. However, the medical treatment is for symptomatic relief, and cases treated with medical treatment alone usually have a poor prognosis.

Complications

Medical

• Irreversible corneal edema
• Dry eyes
• Drug toxicity

Surgical

• Graft failure
• Iatrogenic trauma
• Graft infection
• Secondary glaucoma
• Expulsive choroidal hemorrhage
• Vitreous prolapse
• Cystoid macular edema[3]