Penetrating Keratoplasty and Glaucoma (PKPG)

Updated: Jan 01, 2021
Author: Shibandri Das, MD; Chief Editor: Inci Irak Dersu, MD, MPH 


Practice Essentials

Corneal transplant is the most frequently performed type of transplantation worldwide.[1]  Corneal transplant is a surgical procedure that involves replacing part of the transparent tissue (cornea) at the front of the eye with healthy donor cornea tissue. Conventional corneal transplant is also called penetrating keratoplasty (PKP). Some other common procedures for corneal transplant include Descemet membrane endothelial keratoplasty and Descemet stripping automated endothelial keratoplasty.

Glaucoma is defined as a longstanding progressive optic neuropathy in which characteristic changes in the optic nerve and retinal nerve fiber layer can be observed in the absence of other eye diseases or birth anomalies.[2]  

Graft rejection and secondary glaucoma development are the 2 leading causes of graft failure after PKP.[3]  Thus, the management of penetrating keratoplasty and glaucoma (PKPG) remains controversial mainly because of the high risk for graft failure associated with the treatment.

This article addresses the history, incidence, etiology, pathophysiology, presentation, diagnosis, and treatment of glaucoma after PKP. Glaucoma after corneal transplantation is a leading cause of eye loss (ocular morbidity).[3]  A history of preexisting glaucoma can further increase the risk for elevated intraocular pressure (IOP) after PKP, which can lead to optic nerve damage and irreversible vision loss. Therefore, managing glaucoma to prevent graft rejection is extremely important because studies have indicated that there is likely only 1 available donor per 70 patients whose vision would benefit from corneal transplantation.[1]  

The risks of developing PKPG are discussed with the patient before PKP is performed. Unfortunately, because the causes and incidence of PKPG are so widely variable, an exact statistical chance of occurrence cannot be provided to patients.

Signs and symptoms

Patients may report worsening or blurry vision accompanied by halos or rainbows and photophobia. Patients may experience systemic symptoms such as headache, nausea, or vomiting.[4]  Corneal sensation is also noted to be decreased in patients with angle-closure glaucoma. Other physical exam characteristics of PKPG include redness of the affected eye and severe pain around the affected eye or both eyes.[4]


The gold standard for IOP measurement is Goldman applanation. Intraocular pressure should be measured during every follow-up visit after PKP.

Various methods can be used to measure IOP in the postoperative period, including digital palpation and applanation tonometry with a Mackay-Marg electronic applanation tonometer, pneumatic applanation tonometer, Tono-Pen, or dynamic contour tonometer.[5, 6, 7]

The differential diagnosis for increased IOP after PKP includes the following:

  • Nonadherence to application of steroid drops
  • Increased IOP caused by systemic disease such as high blood pressure, heart disease, hypothyroidism, or diabetes
  • Uveitis
  • Suture abscess
  • Corneal infection
  • Recurrent disease in the graft (herpetic or corneal dystrophy

The accurate measurement of IOP in patients who have undergone PKP can be difficult. The diagnosis of PKPG is challenging because of the difficulty in measuring IOP in the corneal graft and the possibility of steroid-induced IOP elevations in the postoperative period.[8]  Nonetheless, IOP is the starting point for the diagnosis of PKPG.


The addition of newer classes of individual and combination drugs, novel glaucoma drug delivery systems, laser therapy, surgical procedures, glaucoma drainage devices (GDDs), and minimally invasive glaucoma surgery, have increased the options available to the clinician in the management of PKPG.

Medical management (eg, topical drops, systemic pills) continues to be first-line treatment for PKPG.

Available antiglaucoma medications include β-adrenergic blocking agents (eg, timolol, betaxolol), adrenergic agents (eg, epinephrine, dipivefrin), α2-adrenergic agonists (eg, brimonidine, apraclonidine hydrochloride), miotics (eg, pilocarpine, echothiophate iodide, carbachol), prostaglandin analogues (eg, latanoprost), topical carbonic anhydrase inhibitors (eg, dorzolamide, brinzolamide), and systemic carbonic anhydrase inhibitors (eg, acetazolamide, methazolamide, dichlorphenamide). Two novel glaucoma medications (in newer drug categories) have received US Food and Drug Administration (FDA) approval. These dual action agents include a prostaglandin and nitric oxide analogue (eg, latanoprostene bunod) and a rho kinase and norepinephrine transporter inhibitor (eg, netarsudil).

Surgical treatment may take the form of selective laser trabeculoplasty, glaucoma-filtering procedures such as trabeculectomy and implantation of a GDD, various cyclodestructive procedures, or minimally invasive glaucoma surgery. This article also briefly covers argon laser trabeculoplasty because of its historical significance. 


In 1969, Irvine and Kaufman[9]  were the first to describe the high incidence of increased IOP after PKP. They reported a mean maximum pressure of 24 mm Hg in the first postoperative week, 40 mm Hg in patients with aphakia who had transplants, and 50 mm Hg in patients who had transplants combined with cataract extraction in the immediate postoperative period.[9]  Since then, numerous authors have reported on the incidence and management of PKPG.

The incidence of PKPG is approximately 9 to 50% and ranges from 9 to 13% in the early postoperative period (first few weeks after surgery) and from 18 to 35% in the late postoperative period (several weeks to months after surgery).[5, 10, 11]  This variation in incidence results from the differing definitions of glaucoma across studies. The mean time interval from PKP to diagnosis of PKPG is 24 weeks.[8]  Because the changes in the optic nerve or retinal nerve fiber layer are hard to track consistently across studies, these studies often use a threshold of intraoperative pressure (> 21 mm Hg) to define a diagnosis of glaucoma.[2]  Although the definition of glaucoma according to IOP is practical, we recognize that it is scientifically deficient as reflected by the large range in incidence of PKPG.


Simply put, the important risk factors for glaucoma in patients undergoing PKP include lens status (aphakic, phakic), preexisting glaucoma, and the disease for which PKP was performed.[12]

Penetrating keratoplasty is performed to treat corneal dystrophies and keratoconus, bullous keratopathy, anterior segment trauma, iridocorneal endothelial syndrome, corneal perforations, mesodermal dysgenesis, and adherent leukoma, along with other diseases of smaller incidence. Penetrating keratoplasty may also be performed if previous PKP was unsuccessful or in combination with intracapsular cataract extraction or vitrectomy.[2, 8, 9, 13, 14, 15, 16, 17, 18]  

A 10-year retrospective cohort study of 1657 eyes identified the strongest risk factors for increased IOP requiring therapy after PKP to be preoperative glaucoma (or IOP > 20 mm Hg), postoperative aphakia, and intraocular lens removal or exchange associated with keratoplasty.[19]

When looking at the indication for PKP in particular, bullous keratopathy, trauma, herpes simplex infection, and bacterial corneal ulceration or perforations are associated with higher risk for PKPG than are keratoconus, stromal dystrophies, and Fuchs dystrophy.[5, 20, 21, 22, 23]

The causes of elevated IOP in the early postoperative period are as follows:

  • Preexisting open-angle glaucoma
  • Postoperative inflammation
  • Viscoelastic substances
  • Wound leak with angle closure
  • Operative technique
    • Tight suturing and long bites with compression of the angle
    • Unequal suture bites on either side of the wound
    • Larger recipient bed compared with donor tissue size
    • Thicker recipient corneas
  • Increased peripheral corneal thickness
  • Pupillary block glaucoma
  • Penetrating keratoplasty in aphakic eyes secondary to mechanical angle collapse

The causes of elevated IOP in the late postoperative period are as follows:

  • Penetrating keratoplasty in aphakic eyes
  • Penetrating keratoplasty combined with cataract extraction
  • Preexisting primary open-angle glaucoma
  • Steroid-induced glaucoma
  • Graft rejection with glaucoma
  • Ghost cell glaucoma
  • Pupillary block
  • Malignant glaucoma
  • Progressive synechial closure
  • Misdirected aqueous or ciliary block (malignant) glaucoma
  • Epithelial downgrowth
  • Fibrous ingrowth


The pathophysiology of PKPG has multiple factors; it may be associated with distortion of the angle with collapse of the trabecular meshwork, suturing technique, postoperative inflammation, corticosteroid use, repeat corneal transplant, and/or peripheral anterior synechiae (including history of uveitis). The usual factors that contribute to postoperative glaucoma, such as preexisting glaucoma, postoperative inflammation, use of viscoelastic substances, iatrogenic injury to the angle, and steroid-induced glaucoma, should also be considered.[13]

Specific examples supported by data

Zimmerman and colleagues[24]  demonstrated on eye bank human eye models that the depth of sutures during PKP can disrupt outflow channels of the trabecular meshwork by weakening iridocorneal angle support, particularly in aphakic eyes.

Rumelt and colleagues[11]  reported the incidence of various causes of PKPG as closed-angle glaucoma (59%), corticosteroids (21%), open-angle glaucoma (11%), angle recession (3%), aqueous misdirection (3%), and unknown (3%).

Dada and colleagues[25]  reported ultrasound biomicroscopy findings in 31 eyes with postkeratoplasty glaucoma. The types of synechiae noted on ultrasound biomicroscopy included peripheral anterior synechiae in 96.7% (30/31) of eyes, synechiae at the graft-host junction in 41.93% (13/31) of eyes, both peripheral anterior synechiae and graft-host junction synechiae in 38.7% (12/31) of eyes, central iridocorneal synechiae in 19.3% (6/31) of eyes, and intraocular lens iris synechiae in 9.6% (3/31) of eyes.[25]  The authors concluded that secondary angle closure caused by anterior synechiae formation is one of the important causes of PKPG in eyes with opaque grafts.[25]  

Other factors that are specific to patients who have undergone keratoplasty exist. Olson and Kaufman[26]  used a mathematical model to show that the elevated IOP after keratoplasty in a patient with aphakia might be the result of angle distortion secondary to a roll of excess compressed tissue in the angle. As a result of edema and inflammation, the trabecular meshwork function is compromised. According to Olson and Kaufman,[26]  "F]actors that contribute to angle distortion include tight suturing, long bites (more compressed tissue), larger trephine sizes, smaller recipient corneal diameter, and increased peripheral corneal thickness.”[26]  

Conversely, less tight wounds, smaller trephine sizes, donor corneas larger than recipient corneas, thinner recipient corneas, and larger overall corneal diameter tend to alleviate the angle distortion; therefore, donor corneal size should be kept in the range of 7.5 mm to 8.5 mm with a decentration of 0.5 mm or greater.[27, 28, 29]



In the early postoperative period, the diagnosis of PKPG is made on the basis of IOP measurements. In the late postoperative period, the diagnosis of PKPG is based on IOP, optic disc changes, and progressive visual field changes. Ideally, eyes should be examined for optic disc changes, and exams should be performed at least once per year to monitor progression of glaucomatous optic neuropathy.[30]  Patients with extremely high IOP might present with graft edema and/or failure. A timely diagnosis of PKPG is pivotal to preserve both graft clarity and optic nerve function.[30]

Measurements of IOP can be made by using Goldmann applanation, pneumatic applanation tonometer, a Tono-Pen, Icare rebound tonometry, or a dynamic contour tonometer.[5, 6, 7]  

Relevant Anatomy

The anterior chamber is considered the "front part" of the eye; this is a fluid-filled space. This anterior chamber is filled with a fluid called aqueous humor, which is constantly made by the ciliary body and drained. This fluid provides nutrition and oxygen to the front part of the eye (cornea). An imbalance of this fluid's production and drainage can lead to high pressure within the eye, which can cause optic nerve damage to the back of the eye, defined as glaucoma. Of note, this eye pressure is unrelated to the body's blood pressure, and eye pressure can be normal even if the blood pressure is high (and vice versa).[31]



The main contraindication to PKP is inflammation. Regardless of whether the inflammation is caused by currently present ocular disease (eg, bacterial or viral infection, lesions) or trauma, the operation should be postponed until all signs of inflammation have subsided for at least 6 months; however, in the case of trauma from burns caused by chemicals, flames, or molten metals, it is beneficial to wait up to 1 year or until symptoms of photophobia, blepharospasm, or lacrimation have ceased. Any glaucomatous state in an eye must be treated before PKP is performed because failure to do so can cause worsening of glaucoma and rejection of the graft.[32]


Prognosis after PKP can be divided into 3 main groups as follows:

1. Very favorable: Defined by improvement in vision to be greater than 20/50. This prognosis is seen in patients with central corneal opacities, keratoconus, or interstitial keratitis.

2. Less favorable: Defined by a high likelihood of producing considerable improvement in vision. This prognosis is seen in patients with corneal dystrophies, superficial opacities extending to the entire cornea, tear gas burns, adherent leukomas, descemetoceles, and more extensive cases of interstitial keratitis.

3. Unfavorable: Defined by grafts that become vascularized and subsequently nebulous or opaque. This prognosis is seen in patients with extensive corneal scars, extensive leukomas surrounded by scar tissue, band-shaped opacities, dystrophia adiposogenitalis, deep corneal burns, and extensive corneal opacities, especially in aphakic eyes.[32]



Diagnostic Procedures

When the graft surface is smooth, the epithelium is intact, and the mires are regular, Goldmann applanation tonometry can be used to measure the IOP. Marked corneal astigmatism causes an elliptical fluorescein pattern. To obtain an accurate reading with the Goldmann applanation tonometer, the clinician should rotate the prism so that the red mark on the prism holder is set at the least curved meridian of the cornea (along the negative axis). Alternatively, 2 pressure readings, taken 90 degrees apart, can be averaged. The accuracy of applanation tonometry in general is reduced in certain situations, such as the presence of corneal edema, scars, or bloodstaining or any condition that thickens or alters the cornea. Corneal epithelial edema and stromal edema predispose to inaccurately low readings, and pressure measurements taken over a corneal scar will be falsely high. Thin corneas result in underestimation, and thick corneas result in overestimation.

A meta-analysis comparing the accuracy of various tonometers against the diagnostic standard Goldmann applanation concluded that noncontact tonometers and handheld applanation tonometers appeared to best correlate with Goldmann applanation measurements (66% and 59%, respectively). This is important to keep in mind since measurement of IOP with Goldmann applanation in the early postoperative period is not recommended because the corneal surface is irregular.[33]

The pneumatic tonometer is a better choice for measurement of IOP in a patient with corneal surface irregularities. The pneumatic tonometer has a pressure-sensing device that consists of a gas-filled chamber covered by a Silastic diaphragm. The gas in the chamber escapes through an exhaust vent. As the diaphragm touches the cornea, the gas vent is reduced in size and the pressure in the chamber rises. Because this instrument applanates only a small area of the cornea, it has the advantage of measuring the IOP when corneal surface irregularities such as corneal scars or edema are present or when only a small portion of the cornea is visible (large tarsorrhaphy). In addition, in patients with neurotrophic corneas, this device can be used to measure the IOP with minimal disturbance of the epithelium.

In patients with complete tarsorrhaphy, an attempt must be made to measure the IOP by digital palpation. Measuring the IOP in the normal eye using one of the standard techniques (eg, Goldmann applanation tonometer) is helpful; then digital palpation can be performed on both eyes.

Optic disc imaging

Optic disc changes should be monitored in all patients with elevated IOP. Monitoring can be done either by serial disc photography (where possible) or by serial optic disc diagrams from the same observer. Visual fields may be difficult to perform in patients with corneal grafts, especially in the early postoperative period. In patients with reasonable vision, Humphrey visual field testing or Goldmann visual field testing should be performed.

Ultrasound biomicroscopy

Dada and colleagues[25]  also concluded that ultrasound biomicroscopy is a useful tool for anterior segment evaluation in patients with secondary angle closure caused by anterior synechiae formation and can be useful in determining sites for glaucoma filtering surgeries and drainage devices.

Histologic Findings

Chronic elevations of IOP potentially compromise graft endothelial function, leading to graft failure. Depending on its degree and duration, elevated IOP can result in significant endothelial cell loss. After an acute attack of angle-closure glaucoma, endothelial cell loss of 10 to 33% has been reported, and cell loss of 77% has been reported in eyes with acute angle-closure glaucoma lasting more than 12 days.[34]  Morphologic changes in the endothelial cells, such as vacuolization, loosening of cell junctions, blebbing, disruption of the plasma membrane, exkaryocytosis, and loss of whole cells, have been observed in experimentally induced acute glaucoma.[35]  



Medical Therapy

β-Adrenergic blocking agents are the cornerstone of glaucoma treatment. They act by decreasing aqueous humor production, and they have no effect on the outflow pathways. Lass and Pavan-Langston[36]  demonstrated the efficacy of timolol in the treatment of PKPG, even in the presence of chronic angle-closure glaucoma (a type of glaucoma that results in uveoscleral and trabecular meshwork outflow obstruction). The adverse effects of β-blockers include, but are not limited to, superficial punctate keratopathy, corneal anesthesia, and damage to the ocular surface caused by a decreased aqueous layer production rate or impaired quantity and quality of the mucus layer of the tear film, resulting in a dry eye state. All of these may have an adverse effect on the graft epithelium that might compromise graft function.

Adrenergic agents can help lower the IOP but should be used with caution in patients with aphakia or pseudophakia because they can produce cystoid macular edema. Brimonidine tartrate 0.2%, a relatively selective α2-adrenergic agonist, is better tolerated than apraclonidine hydrochloride and is a safe drug for long-term control of IOP. Apraclonidine 0.5% is a potent anterior segment vasoconstrictor and more useful during the operation to both prevent anterior chamber bleeding and control the pressure spikes resulting from such a bleed.

Miotics, although used for glaucoma, should be used with caution in patients with PKPG. They can be useful in patients with open-angle glaucoma but may have very little effect in the presence of significant angle closure caused by peripheral anterior synechiae. Miotics can induce uveitis by breakdown of the blood-aqueous barrier, and this combined with the resulting inflammatory state can initiate graft rejection. In patients with aphakia, miotics can increase the risk for retinal detachment.

Topical carbonic anhydrase inhibitors (eg, dorzolamide, brinzolamide) have ocular hypotensive efficacy similar to that of betaxolol 0.5% and are not associated with clinically significant electrolyte disturbances or other systemic adverse effects seen with systemic carbonic anhydrase inhibitors. They should be used with caution in patients with PKPG, however. In those with a history of graft rejection, compromised endothelial function, and/or reduced endothelial cell counts, these agents can contribute to an irreversible corneal decompensation.[37, 38]  Systemic carbonic anhydrase inhibitors also decrease IOP by decreasing aqueous humor production. Additionally, systemic carbonic anhydrase inhibitors, such as acetazolamide, are useful in the treatment of pressure spikes in the immediate postoperative period. Their long-term use is limited because 30 to 50% of patients experience adverse effects, such as paresthesias, tinnitus, nausea, gastrointestinal disturbances, fatigue, depression, anorexia, and weight loss.

Prostaglandin analogues, such as latanoprost, appear to decrease IOP by increasing the uveoscleral outflow and can be used in conjunction with β-blockers and carbonic anhydrase inhibitors. This combination helps lower IOP by reducing aqueous humor production and increasing its outflow. During treatment with latanoprost, the most common adverse effects reported include punctate keratitis and ocular hyperemia.[39]  Additionally, latanoprost should be used with caution in patients with a history of herpes simplex keratitis because it has been reported to induce recurrent herpetic infection in humans.[40]  In patients with aphakia and pseudophakia, latanoprost has been reported to cause cystoid macular edema.[41]

No studies have been conducted on the use of latanoprostene bunod and netarsudil in PKPG; however, because of their potency, they will likely be studied specifically for PKPG in the near future and thus are discussed in the following sections.

Latanoprostene bunod (Vyzulta) has dual action as a latanoprost analogue and as butanediol mononitrate, which acts as nitric oxide. Latanoprostene bunod regulates IOP through both the trabecular outflow and uveoscleral outflow tracts.[42]  In a randomized study in which the IOP-lowering effects of latanoprostene bunod 0.024% were compared with those of timolol maleate 0.5%, mean IOP was significantly lower with latanoprostene bunod at all evaluation points within a 3-month period.[43]  This potent medical therapy for glaucoma has also been proven to significantly lower mean IOP in just 24 hours.[39]

Netarsudil acts as a rho kinase inhibitor and as a norepinephrine transporter inhibitor, which decreases IOP through various synergistic physiologic mechanisms. Netarsudil decreases the actin-myosin contraction, reducing the numbers of actin stress fibers and focal adhesions in the trabecular meshwork to improve the outflow of aqueous humor.[42]  Netarsudil has also demonstrated consistent IOP reduction across a range of baseline pressures, particularly in patients with low baseline IOP.[44]  In addition to reducing IOP via increased trabecular outflow and decreased aqueous humor production, netarsudil ophthalmic solution has been shown to decrease episcleral venous pressure, which ultimately enhances aqueous humor outflow and lowers IOP relative to baseline.[45, 46]

Ripasudil, a rho kinase inhibitor only, was found to lower IOP in patients with glaucoma poorly controlled with maximal medical therapy, and is well tolerated at up to 3 months with average IOP reduction from baseline of 2.8 mmHg[47] ; however, long-term use above 2 years does have as great of a safety profile; thus its use is still controversial.[48]

The following table documents the disadvantages of using some of the topical glaucoma medications in patients with PKPG.

Table 1. Physiologic Targets Affecting Aqueous Humor Production or Outflow and Disadvantages of the Various Glaucoma Medications in Patients with PKPG (Open Table in a new window)

Glaucoma medications 

Physiologic targets 

Potential problems in patients with PKPG 


Decrease aqueous humor production 

Superficial punctate keratitis, corneal anesthesia, dry eyes, subconjunctival fibrosis 

α2-Adrenergic agonists 

Decrease aqueous humor production and increase aqueous outflow 

Epithelial toxicity such as superficial punctate keratitis, dry eyes, and allergic reactions. Cystoid macular edema in aphakia and pseudophakia 


Increase aqueous humor outflow through contraction of ciliary muscle 

Inflammation, graft rejection, retinal detachment, subconjunctival fibrosis 

Topical carbonic anhydrase inhibitors 

Decrease aqueous humor production 

Permanent graft failure in eyes with borderline endothelial counts 

Systemic carbonic anhydrase inhibitors 

Decrease aqueous humor production 

Paresthesias, tinnitus, nausea, fatigue, depression, anorexia,  weight loss 

Prostaglandin analogues 

Increase aqueous humor outflow through the uveoscleral tract 

Uveitis, cystoid macular edema in aphakia and pseudophakia, recurrent herpes simplex infection in patients with history of herpes 

Rho kinase inhibitors 

Increase aqueous humor drainage through trabecular meshwork 

Epithelial keratopathy, reticular epithelial edema 

The benefits of pressure reduction with topical glaucoma medications should be weighed against the potential adverse effects. Apart from the specific adverse effects listed previously, topical medical therapy can have the following secondary side effects:

  • Benzalkonium chloride (BAC), the preservative used in most topical glaucoma medications, can cause severe surface toxicity. These effects include cell wall damage and destruction of the corneal epithelial microvilli, leading to increased permeability of the corneal epithelium. [49]
  • The acidic pH of some of the topical drops (eg,  Cosopt, 5.8; dorzolamide, 5.6), in addition to causing a burning sensation, may also be toxic to the corneal epithelium.

In patients who are allergic to the preservatives, preservative-free drugs, such as an Ocudose form of timolol maleate, should be used. Also, pilocarpine powder can be reconstituted with balanced salt solution by the pharmacy without any preservative.

Surgical Therapy

Argon laser trabeculoplasty

Argon laser trabeculoplasty (ALT) is no longer in common use, but it was historically reported to result in a 10 to 40% reduction in IOP in primary open-angle glaucoma in the short term. The efficacy of ALT depends on the clinical characteristics of the patients and the type of glaucoma treated. The IOP-lowering effect tends to diminish between 1.5 and 4 years postoperatively with only a 40 to 50% success rate at 5 years.[50]  Because the beneficial effects appear to decrease over time, ALT may be tried as a short-term measure in patients with open angles and clear grafts with moderately elevated IOP (ie, 20-25 mm Hg) who are receiving glaucoma medications.[51]  Possible complications include pressure spikes and iritis, both of which can trigger graft rejection.

Selective laser trabeculoplasty

Selective laser trabeculoplasty is now more widely used than ALT. It is believed to create less collateral damage while achieving effects comparable to those of ALT. In studies of patients with primary open-angle glaucoma, SLT has been found to lower IOP by 6 to 8 mm Hg, with 70% of patients showing an improvement after the procedure.[52, 53]  Although its use in PKPG has not been specifically studied on a large scale, reports of its effective use in treating PKPG have been noted[54] ; however, similar to ALT, the IOP-lowering effect of selective laser trabeculoplasty tends to decrease over time.[55]


Rates of trabeculectomy success in treating PKPG are highly variable.[56, 57]  Conventional trabeculectomy without antimetabolites (5-fluorouracil [5-FU]) and alkylating agents (mitomycin-C) in patients with PKPG has a high failure rate secondary to limbal conjunctival scarring from previous surgery, extensive peripheral synechiae, aphakia, and extremely shallow anterior chambers.[56]

The introduction of 5-FU and mitomycin-C has increased the success rate of trabeculectomies, especially in patients with complicated glaucoma.[58]  These agents appear to increase the success rate by inhibiting fibroblast proliferation and enhancing the formation of filtering blebs. Apart from the inconvenience of frequent injections, administration of 5-FU is associated with a high rate of corneal epithelial toxicity, corneal ulceration, corneal perforation, and stem cell failure, which could prove to be disastrous to the graft.[59]  Use of 5-FU should be avoided in patients with a damaged epithelium and persistent epithelial defects. Because of corneal toxicity, 5-FU should be used with caution in patients with PKPG.

Intraoperative local application of mitomycin-C has significantly improved the success rate of filtering surgery for glaucoma.[60]  

In addition to the convenience of a single application at the time of surgery, mitomycin-C trabeculectomy has no demonstrable toxicity on the corneal epithelium; however, mitomycin-C trabeculectomy may result in thin cystic bleb formation and an increased risk of bleb-related infection.[61]  The reported success rate in IOP control with mitomycin-C trabeculectomy in patients with PKPG is 67 to 91%, and the rate of graft failure is 12 to 18%.[62, 63]  The bleb failure rate is higher when trabeculectomy is combined with additional surgical procedures, such as cataract surgery and vitrectomy.[64]

Trabeculectomy with mitomycin-C can be attempted in patients with limited or no superior limbal conjunctival scarring, no extensive peripheral anterior synechiae, no aphakia, and extremely shallow anterior chambers. Avoid this procedure in patients who use contact lenses because it can predispose them to bleb infection. Avoid shallow or flat anterior chambers in the postoperative period because this could compromise the graft endothelium.

Patients who have undergone trabeculectomy should be monitored for dellen formation, which can trigger thinning of the adjacent graft cornea, leaking blebs, and bleb-related infections.

Glaucoma drainage devices

Glaucoma drainage devices create an alternate aqueous pathway by channeling aqueous from the anterior chamber through a long tube to an equatorial plate that promotes bleb formation. Kirkness[65]  first reported the use of GDDs in PKPG. Even though GDDs appear to control glaucoma in a high percentage of patients in several published series (71-96% at 1 year, 44-87% at 2 years, and 71-83% at 5 years), it appears to be associated with a high incidence of graft failure in the range of 10 to 51% (with an average of 36.2%).[22, 41, 65, 66, 67, 68]  The etiology of graft failure is probably multifactorial. The presence of underlying chronic inflammation and extensive peripheral synechiae and a history of multiple previous surgeries may compromise the graft. The introduction of a GDD into the anterior chamber may also be associated with increased inflammation and corneal endothelial damage and may further compromise the graft.

Ritterband and the Cornea Glaucoma Implant Study (COGIS) Group[69]  reported on 83 eyes treated with a combination of PKP and implantation of a GDD, with tube placement in the pars plana. Their graft survival rates are among the best reported for this combination of surgeries, with clear grafts in 93% of the treated eyes at 6 months, 87% at 1 year, and 59% at 2 years; however, no grafts remained clear in the small group of patients at 5-year follow-up.

The timing of GDD surgery is another factor that can contribute to graft failure. In the series published by Rapuano and colleagues[66]  and Beebe and colleagues,[67]  a trend toward a higher incidence of graft failure when GDD surgery was performed after PKP was observed. Other studies report no association between timing of GDD implantation relative to PKP and graft survival or IOP control.[70]

With all this inconsistency, the choice of the GDD in the treatment of patients with PKPG depends on the condition of the eye and the surgeon. Four main GDDs are available: the Ahmed, Krupin, Molteno, and Baerveldt implants. The Ahmed implant and the Krupin implant offer resistance to the outflow in the form of a sheet valve and a slit valve, respectively.[41]  The Molteno implant and the Baerveldt implant provide no resistance to the outflow and, thus, may lead to hypotony.[71]  This problem can be overcome with the use of the ripcord technique and/or ligation with a dissolvable suture.

The advantages of the valved implants, especially those of the Ahmed glaucoma valve, appear to be easy insertion after single-quadrant dissection and a low incidence of hypotony in the immediate postoperative phase; however, the Ahmed valve is associated with a high incidence of the hypertensive phase, which may require needling with 5-FU injections.[41]  In a case series of 59 high-risk PKP eyes that underwent Ahmed glaucoma device insertion, Almousa and colleagues[72]  report IOP control success rates of 96% of the eyes at 1 year and 83% at 5 years, but clear corneal graft percentages of 87% at 1 year and 47% at 5 years. 

On the other hand, GDDs with a larger surface area, such as the double-plate Molteno and Baerveldt implants, appear to exhibit a lesser incidence of the hypertensive phase and may achieve slightly lower IOP.71 The overall success rate and the frequency of complications, including corneal decompensation, appear to be similar for all GDD.[41, 66, 68]  Complications of GDD surgery include increased rate of graft rejection and failure (compared with trabeculectomy), conjunctival erosion, prolonged hypotony, tube-endothelial touch, tube obstruction, tube failure, retinal detachment, tube plate extrusion, epithelial downgrowth, and infection.

Cyclodestructive procedures

Cyclodestructive procedures are designed to control IOP by decreasing aqueous humor production by destroying part of the ciliary body. Cyclocryotherapy, transcleral cyclophotocoagulation with Nd:YAG, and semiconductor diode laser are the various cyclodestructive procedures that can be performed on patients with intractable PKPG. The reported success rates, as defined by decrease in IOP, and the complications after any of these procedures appear to be similar.[73, 74, 75]  The individual surgeon must decide which procedure to use, depending on the availability of the instruments and the lasers.

The overall success rate in controlling IOP is 60 to 80%. The major potential complications of any of these procedures are risk for graft rejection (11-65%), loss of vision (22-56%), and phthisis bulbi.[30, 76, 77]

Other complications include persistent hypotony (5-10%), anterior uveitis, epithelial defects, hyphema, hypopyon, intractable pain, sympathetic ophthalmia, scleral thinning, and vitreous hemorrhage.[78]

Minimally invasive glaucoma surgery

Minimally invasive glaucoma surgery can also be considered as a method for lowering IOP. Although there are many methods for minimally invasive glaucoma surgery, 2 prominent modalities include iStent and placement of a CyPass microstent. The iStent is a heparin-coated stent that is inserted into the anterior chamber and penetrates the trabecular meshwork. A CyPass microstent, on the other hand, is a stent inserted into the supraciliary space. Placement of an iStent or CyPass microstent has been commonly performed as an isolated procedure or in combination with cataract extraction.[79]

In a 5-year study of phacoemulsification combined with stent procedures, researchers found a 16% decrease in IOP, with 42% of patients requiring no further medication by the end of the follow-up period.[80]  Although minimally invasive glaucoma surgery has not been systematically studied in conjunction with PKP or other corneal transplantation techniques, these modalities have been demonstrated in preliminary studies to safely lower IOP with fewer complications than with trabeculectomy.[81]  Both the iStent and the CyPass microstent effectively decreased IOP in combination with cataract surgery or when placed as an isolated procedure.  

A study by Mahdavi and colleagues[79]  showed that this IOP-lowering effect is greatest after isolated implantation of CyPass, followed by multiple iStents, and then a single iStent, and lasts up to 2 years.


Uncontrolled IOP after PKP can result in graft failure and vision loss. Intraocular pressure should be monitored regularly after corneal transplantation, and uncontrolled IOP should be treated aggressively. Any patient with preexisting glaucoma must be carefully evaluated before a corneal transplant. Medical management is the first-line treatment, and newly developed drugs are constantly in production.

Patients with uncontrolled IOP or patients with borderline control with 2 or more medications may be treated with either trabeculectomy or GDD surgery before or at the same time as the planned corneal transplant. This recommendation is based on results of multiple studies demonstrating that preoperative glaucoma puts patients at high risk for the development of PKPG and graft failure.[9, 13, 14, 15, 16, 17, 18, 82]  Penetrating keratoplasty and glaucoma unresponsive to medications should be treated surgically. First-time trabeculectomy is the safest operation in terms of both IOP control and graft survival.

The literature favors a combined trabeculectomy with a corneal graft procedure in patients with preexisting glaucoma who need a corneal transplant.[41, 63, 64, 66, 67, 68]  Additional surgical procedures should be avoided, if possible, at the time of the trabeculectomy because they are associated with a higher incidence of trabeculectomy failure.[64]

Glaucoma drainage device surgery is preferred over other surgical options for patients with PKPG who have extensive limbal conjunctival scarring, shallow anterior chambers, or extensive peripheral anterior synechiae and for those in whom trabeculectomy has failed. Glaucoma drainage device surgery appears to be superior to cyclodestructive procedures for patients in whom trabeculectomy has failed or for patients in whom trabeculectomy is contraindicated (ie, individuals who wear contact lenses), but this is still debated.

Akdemir and colleagues[83]  found significant differences in results after trabeculectomy compared with Ahmed glaucoma valve implantation in patients who previously underwent PKP. This study showed a greater mean loss of endothelial cell counts with Ahmed glaucoma valve implantation compared with trabeculectomy but greater decrease in IOP (64.2% vs 46.9%) at 12-month follow-up in the Ahmed valve group. 

A comparison study by Yakin and colleagues[84]  (n = 84) also demonstrated better IOP control with use of a GDD versus trabeculectomy with and without antimetabolites, but with lower graft survival rates by about 8% to 15% in the GDD group. Nassiri and colleagues[85]  showed no significant difference in any outcome measure between trabeculectomy and Ahmed valve implantation in patients for whom previous filtering surgeries failed. This discrepancy over various studies highlights that although GDD surgery is preferred in more complicated cases, more studies are needed to deduce its true advantage over other surgical options for patients with PKPG.

Glaucoma drainage device surgery also has advantages over cyclodestructive procedures. Although GDD surgery and cyclodestructive procedures appear to be the same in terms of graft failure, there appears to be a higher incidence of permanent vision loss and hypotony after cyclodestructive procedures.[77]

It is vital to lower IOP and control PKPG because although a graft can usually be repeated, if the optic nerve is damaged from end-stage glaucoma, useful vision cannot be restored.

Surgical Details

Preexisting glaucoma is frequently more difficult to treat after keratoplasty in both aphakic and pseudophakic eyes.[9]  Preexisting glaucoma has also been determined to be a risk factor for graft failure in multiple studies, including the 10-year Cornea Donor Study.[82, 86]  Reinhard and colleagues[82]  estimated the 3-year graft survival rate in patients with a preoperative history of glaucoma to be 71% in contrast to 89% in patients without such a history. Some studies suggest a higher incidence of graft failure after glaucoma operation performed after PKP.[66]  Hence, in this patient population, it is recommended that the glaucoma operation either precede or be combined with PKP. Clinicians should also be aware that certain indications for transplantation (particularly bullous keratopathy and corneal perforation) are associated with higher risk of developing PKPG.

During penetrating keratoplasty (PKP), measures such as using an oversized donor button (0.5 mm), deep bites, goniosynechialysis in the presence of peripheral anterior synechiae, iridoplasty (iris-tightening procedure) in cases of a floppy iris, removal of viscoelastic material at the end of the operation, and careful wound closure to prevent postoperative wound leaks are useful in reducing the incidence of postoperative glaucoma.

In the postoperative phase, judicious use of steroids controls the inflammation and prevents peripheral anterior synechiae. Cycloplegics (when indicated) keep the pupil mobile and prevent pupillary block glaucoma. 

Outcome and Prognosis

The surgical success rates of the 3 procedures for PKPG (ie, trabeculectomy with mitomycin-C, GDD surgery, cyclodestructive procedure) in controlling the IOP to less than 21 mm Hg are similar (70-75%).

The prognosis for graft survival is not clear. The lowest incidence of graft failure follows trabeculectomy (10-20%), as compared with GDD surgery (10-50%) and cyclodestructive procedures (20-50%); therefore, the long-term prognosis for graft survival appears to be 40 to 60% in patients with PKPG.

More data are needed to determine long-term success and prognosis for graft survival with minimally invasive glaucoma surgery treatment.[81]

Future and Controversies

Controversy still exists as to which surgical procedure is the best initial treatment option in terms of graft survival, as data on prognosis are not clear. In addition, the best timing of the surgery in patients with preexisting glaucoma (ie, whether to perform the surgery before, at the same time as, or after the corneal transplant operation) is still unclear.

Some authors recommend placement of the GDD in the posterior chamber combined with vitrectomy or placement in the ciliary sulcus anterior to the lens and posterior to the iris. These authors believe that placing the tube behind the iris diaphragm decreases the risk for graft failure.

Similarly, diode laser cycloablation is believed to result in less inflammation and more precise ciliary process destruction; however, definitive evidence is still lacking in both situations. Randomized, prospective studies are needed to determine which of the available treatment options should be the treatment of choice for patients with PKPG.

Research on new and alternative therapies is ongoing. In the case of medical treatments, whereas latanoprostene bunod and netarsudil are used for glaucoma, data are needed as to their efficacy and adverse effects in PKPG. Regarding surgical treatments, 2 small studies (n = 10) on the use of trabeculotomy for PKPG showed effective lowering of IOP, with no graft rejection at 72-month follow-up and no acceleration of corneal endothelial cell loss.[87, 88]  The results of these studies suggest that better management of PKPG may prolong the life of the graft.

Borderie and colleagues[19, 89]  conducted studies in which they found that deep anterior lamellar keratoplasty and endothelial keratoplasties had a better long-term outcome in terms of graft survival and endothelial densities than penetrating keratoplasty.[90]



Questions & Answers


What is penetrating keratoplasty and glaucoma (PKPG)?

What are the signs and symptoms of penetrating keratoplasty and glaucoma (PKPG)?

How is IOP measured in the workup for penetrating keratoplasty and glaucoma (PKPG)?

Which conditions are included in the differential diagnoses of penetrating keratoplasty and glaucoma (PKPG)?

How is penetrating keratoplasty and glaucoma (PKPG) treated?

What is the prevalence of penetrating keratoplasty and glaucoma (PKPG)?

What are the risk factors for penetrating keratoplasty and glaucoma (PKPG)?

What causes elevated IOP following penetrating keratoplasty for glaucoma?

What is the pathophysiology of penetrating keratoplasty and glaucoma (PKPG)?

What causes penetrating keratoplasty and glaucoma (PKPG)?

How is penetrating keratoplasty and glaucoma (PKPG) diagnosed?

What anatomy of the eye is relevant to understanding penetrating keratoplasty and glaucoma (PKPG)?

When is penetrating keratoplasty (PKP) contraindicated?

What is the prognosis for penetrating keratoplasty and glaucoma (PKPG)?


What is the role of Goldmann applanation tonometry in the workup of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of optic disc imaging in the workup of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of ultrasound biomicroscopy in the workup of penetrating keratoplasty and glaucoma (PKPG)?

Which histologic findings are characteristic of penetrating keratoplasty and glaucoma (PKPG)?


Which medications are used in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of argon laser trabeculoplasty (ALT) in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of selective laser trabeculoplasty in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of trabeculectomy in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of glaucoma drainage devices in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of cyclodestructive procedures in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of minimally invasive glaucoma surgery in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

What is the role of surgery in the treatment of penetrating keratoplasty and glaucoma (PKPG)?

How does preexisting glaucoma affect the outcomes for penetrating keratoplasty (PKP)?

How is penetrating keratoplasty and glaucoma (PKPG) prevented?

What are the reported outcomes following surgery for penetrating keratoplasty and glaucoma (PKPG)?

What is the best initial treatment option for penetrating keratoplasty and glaucoma (PKPG)?

Which new penetrating keratoplasty and glaucoma (PKPG) treatments are under investigation?