Penetrating Keratoplasty and Glaucoma (PKPG) Treatment & Management

Updated: Dec 30, 2020
  • Author: Shibandri Das, MD; Chief Editor: Inci Irak Dersu, MD, MPH  more...
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Treatment

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 

β-Blockers 

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 

Miotics 

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.

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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]

Trabeculectomy

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.

Summary

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.

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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. 

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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]

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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]

 

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