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]
Workup
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:
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Nonadherence to application of steroid drops
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Increased IOP caused by systemic disease such as high blood pressure, heart disease, hypothyroidism, or diabetes
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Uveitis
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Suture abscess
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Corneal infection
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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.
Treatment
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.
Epidemiology
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.
Etiology
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:
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Preexisting open-angle glaucoma
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Postoperative inflammation
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Viscoelastic substances
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Wound leak with angle closure
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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
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Increased peripheral corneal thickness
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Pupillary block glaucoma
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Preexisting peripheral anterior synechiae
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Penetrating keratoplasty in aphakic eyes secondary to mechanical angle collapse
The causes of elevated IOP in the late postoperative period are as follows:
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Penetrating keratoplasty in aphakic eyes
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Penetrating keratoplasty combined with cataract extraction
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Preexisting primary open-angle glaucoma
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Steroid-induced glaucoma
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Graft rejection with glaucoma
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Ghost cell glaucoma
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Pupillary block
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Malignant glaucoma
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Progressive synechial closure
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Misdirected aqueous or ciliary block (malignant) glaucoma
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Epithelial downgrowth
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Fibrous ingrowth
Pathophysiology
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]
Presentation
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]
Contraindications
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
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]
Tables
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 |
