TYPE Review

PUBLISHED 08 May 2024

DOI 10.3389/fopht.2024.1361704

Mechanism and treatment of

OPEN ACCESS secondary glaucoma after
EDITED BY
Shamira Perera,
Singapore National Eye Center, Singapore
corneal transplantation: a review
REVIEWED BY
Riccardo Sacco,
Yumeng Lin 1,2,3†, Qiaoyin Gou 1,2,3†, Ping Yu 1,2,3,
Polytechnic University of Milan, Italy Zhengfang Wu 1,2,3, Liuzhi Zeng 4* and Haoran Chen 5*
Mehmet Cem Sabaner,
Kutahya Evliya Celebi Training and Research 1
Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China, 2 Key Laboratory
Hospital, Türkiye of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with
Traditional Chinese Medicine (TCM) Laboratory, Chengdu, China, 3 Retinal Image Technology and
*CORRESPONDENCE
Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, China,
Liuzhi Zeng 4
Department of Ophthalmology, Chengdu First People’s Hospital, Chengdu, China, 5Science Education
[email protected]
Department, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
Haoran Chen
[email protected]
†
These authors have contributed equally to
this work Corneal transplantation is a common treatment for corneal diseases. Secondary
glaucoma after corneal transplantation is the second leading cause of failure of
RECEIVED 26 December 2023
ACCEPTED 18 April 2024 keratoplasty. This article reviews the mechanism and treatment of secondary
PUBLISHED 08 May 2024 glaucoma after corneal transplantation.
CITATION
Lin Y, Gou Q, Yu P, Wu Z, Zeng L and Chen H
(2024) Mechanism and treatment of
secondary glaucoma after corneal
transplantation: a review. KEYWORDS
Front. Ophthalmol. 4:1361704.
glaucoma, pathogenesis, treatment, corneal transplantation, eye
doi: 10.3389/fopht.2024.1361704

COPYRIGHT
© 2024 Lin, Gou, Yu, Wu, Zeng and Chen. This
is an open-access article distributed under the
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that the Introduction
original publication in this journal is cited, in
accordance with accepted academic
Keratopathy is one of the major blinding eye diseases nowadays and is the second
practice. No use, distribution or reproduction
is permitted which does not comply with leading blinding eye disease after cataract in China. At present, there are about 4 million
these terms. patients with blindness caused by keratopathy in China, and more than 100,000 new cases
are added each year (1). Corneal transplantation is the most effective treatment to restore
vision or control keratopathy in the affected eye.
Common keratoplasty includes lamellar keratoplasty (LK), penetrating keratoplasty
(PK), endothelial keratoplasty (EK), femtosecond laser assisted keratoplasty (FSL), and
keratoprosthesis implantation (KPro). LK includes anterior lamellar keratoplasty (ALK)
and posterior lamellar keratoplasty (PLK). EK includes deep lamellar endothelial
keratoplasty (DLEK), Descemets stripping endothelial keratoplasty (DSEK), and
Descemets membrane endothelial keratoplasty (DMEK).
In China, the indications for keratoplasty are mostly corneal infection and chemical
burns, while in Western countries, the indications for keratoplasty are mainly keratoconus,
bullous keratopathy, and corneal dystrophy. Since the early 20th century, keratoplasty has
been first reported by Eduaed Zirm, and since then a variety of surgical procedures such as
LK, EK, DSEK, DMEK, and DLEK have emerged successively, and keratoplasty has been
widely used in clinical practice and has been greatly developed (2). Corneal transplantation
is transparent tissue without blood vessels and lymphatic vessels, so it is not easily

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recognized by the immune system of the human body and is in the release of prostaglandins, resulting in poor aqueous humor outflow
position of “immune privilege”. Keratoplasty is a relatively high and excessive production, followed by increased intraocular
success rate in all human tissue or organ transplantation surgeries. pressure. It has been reported that postoperative stress response
Common complications after keratoplasty can be divided into and postoperative inflammation may lead to increased corneal
early complications and late complications. Early postoperative thickness, which in turn leads to compression of the trabecular
complications include: 1. Poor postoperative corneal healing; 2. meshwork by anterior chamber angle stenosis interfering with the
Interlamellar effusion and hematocele may occur after LK; 3. Graft drainage of aqueous humor (15, 16). Whether these changes will
detachment after EK; 4. Recurrence of primary infection or combine with PAS to form permanent changes remains to be
postoperative infection; 5. Secondary glaucoma. Late further studied (16).
complications include: 1. Immune rejection; 2. Corneal graft
turbidity. Secondary glaucoma is one of the most serious
complications after keratoplasty and is second only to graft Postoperative glucocorticoid use
rejection leading to corneal graft failure (3).
It has been reported that the incidence of secondary glaucoma The mechanism of glucocorticoid-induced intraocular pressure
varies after different types of keratoplasty, with the incidence of elevation is not clear. Glucocorticoid induced upregulation of
early glaucoma after PK being 9-31%, the incidence of late Myocilin, a gene encoding a 55-kda secretory protein, in
postoperative glaucoma being 18-35%, and 2.8-6.5% after DMEK. trabecular meshwork cells and reorganization of the cytoskeletal
Deep anterior lamellar keratoplasty (DALK) has a low incidence of and cross-linked actin networks, increasing the stiffness of the
glaucoma of 0-4.48% due to small inflammatory response, short trabecular meshwork and inhibiting its contraction. Besides,
duration of steroid eye drops use, and intact Descemet membrane cellular phagocytosis is weakened and extracellular matrix protein
preserving the angle structure (4–9). Glaucoma is a common deposition is increased, leading to trabecular meshwork
complication due to anterior segment dysplasia or postoperative dysfunction, which leads to increased resistance to aqueous
steroid use (5-9%). About half of the eyes of patients with Pitt’s humor outflow (17, 18).
abnormality develop glaucoma before or after surgery (10).
According to Brittany Tsou et al., approximately 15 eyes (88.2%)
of patients treated with Boston type I keratoprosthesis (KPro) Previous history of glaucoma
surgery required recurrent glaucoma surgery (11).
Huber et al. studied 160 patients with secondary glaucoma after
PK surgery, 62 patients (38.7%) had previous history of glaucoma,
Pathogenesis of secondary glaucoma which is the most important risk factor for secondary glaucoma
after corneal transplantation after keratoplasty (13). Some scholars compared the incidence of
PPKG between patients with glaucoma history and those without
The pathogenesis of secondary glaucoma after corneal glaucoma history. The study showed that the incidence of PKGG
transplantation is still unclear, but the possible causes and was 59.4% in patients with preoperative glaucoma history and
mechanisms have been reported in many literatures. 14.6% in patients without glaucoma history (19).

Angle closure Pupillary block

It is mainly caused by trabecular meshwork collapse and Pupillary block is often caused early after DMEK due to
peripheral anterior synechia (PAS).Mechanical collapse of the excessive anterior chamber gas and aqueous circulation disorders
trabecular meshwork is proposed by Zimmerman et al., PK cuts (20). The mechanism of pupillary block is very similar between
off the Descemet’s membrane, so that the trabecular meshwork DMEK and DSEK. However, DMEK grafts without matrix require
loses its anterior support, which in turn leads to poor aqueous longer periods of bubble support and therefore result in a higher
outflow (12). Huber et al. found that patients with preoperative PAS risk of pupillary block compared to DSEK grafts (21, 22).
have a higher proportion of secondary glaucoma after keratoplasty
(13). Kirkness et al. found that repeated PK increases the risk of PAS
formation, which in turn leads to angle closure to post penetrating Lens condition
keratoplasty glaucoma (PPKG) (14).
Aphakic eyes and intraocular lens eyes are important risk
factors for secondary glaucoma after keratoplasty. Aphakic eyes
Surgical factors and intraocular lens eyes have potential mechanical instability. The
removal of lens causes the trabecular meshwork to lose the tension
Improper intraoperative operation can cause damage to the of zonules, weakens the support of ciliary body-lens support system
trabecular meshwork, and the operation itself will also cause the for the trabecular meshwork posteriorly, decreases the aqueous

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humor fluency coefficient, and then causes the increase of In the treatment of intraocular pressure with combined drugs, if
intraocular pressure (8). the conventional combined drugs fail to achieve the expected effect,
oral ocular hypotensive drugs such as methazolamide can be added.
The medication process should be followed up and reexamined to
Immune rejection monitor the patient ‘s intraocular pressure and adjust the medication
regimen in time. For patients with poor compliance and irregular
Onur et al. found that immune rejection caused a greater risk of reexamination, when their intraocular pressure is in a dangerous state
PPKG. Rejection can cause increased prostaglandin secretion, a value, emergency ocular hypotensive regimen should be used, local
large number of inflammatory cell cellulose and iris pigment eye drops combined with oral drugs, and then mannitol 1 mg/kg
blocking the trabecular meshwork and aqueous humor external intravenous drip should be added for treatment.
drainage channels, causing increased intraocular pressure (23). Perry et al. found that switching to 0.5% cyclosporine eye drops
after keratoplasty reduced intraocular pressure and prevented the
occurrence of rejection (42). For steroid-sensitive patients,
Treatment of secondary glaucoma glucocorticoid dosage could be gradually reduced or steroid drugs
after keratoplasty with less efficacy such as fluorometholone could be used instead of
glucocorticoids in clinical practice, which could prevent rejection
The treatment of secondary glaucoma after keratoplasty mainly and reduce the risk of increased intraocular pressure.
includes drug, laser and surgical treatment. The purpose of
treatment is to reduce intraocular pressure and protect the
optic nerve. Laser therapy

Laser peripheral iridotomy

Drug therapy LPI removes a small amount of iris tissue in the periphery of the
iris by laser to allow the posterior chamber aqueous humor to flow
Secondary glaucoma after keratoplasty can be treated with ocular directly into the anterior chamber through this incision and relieve
hypotensive drugs in the early stage. Drug therapy is the first-line the obstruction of the anterior bulge of the peripheral iris and the
treatment for secondary glaucoma after keratoplasty. Local ocular anterior chamber angle due to pupillary block. It is not clear
hypotensive drugs are mostly b-blockers such as timolol eye drops and whether LPI must be performed only in the case of patients
carteolol eye drops, which can effectively treat increased intraocular affected by pupillary block or if it may be adopted as a general
pressure caused by shallow anterior chamber and angle closure after surgical technique to facilitate aqueous humor flow from posterior
KPro surgery, but it may lead to decreased corneal epithelial barrier to anterior chamber. Fu Ronghua et al. reported that intraocular
function, causing superficial punctate corneal epithelial lesions, pressure decreased in one of two patients with pupillary membrane
making dry eye aggravated and corneal sensory loss (24–27). closure after penetrating keratoplasty after YAG laser treatment,
Prostaglandin preparations can be used to treat symptoms of and intraocular pressure was well controlled in the other after
persistent elevated IOP after keratoplasty, but they may lead to trabeculectomy combined with mitomycin C (MMC). The study by
anterior uveal inflammation, cystoid macular edema, increased Yin Wenhui et al. showed that intraocular pressure could be well
rejection, and recurrence of some primary diseases (e.g., herpes controlled in most patients with pupillary block after keratoplasty
simplex keratitis) (28–32). who underwent laser peripheral iridectomy.
The miotic pilocarpine increases the permeability of the blood-
aqueous barrier in patients, thereby increasing the risk of graft Argon laser peripheral iridoplasty
rejection (33, 34). When IOP is poorly controlled, carbonic ALPI uses an argon ion laser to laser irradiate the iris root using a
anhydrase inhibitors such as brinzolamide eye drops can be large spot, low energy, and long exposure time, and the iris matrix
added in combination, but they may lead to graft endothelial contracts at the burned site, which in turn opens the angle by physical
decompensation, cystoid macular edema, or persistent traction. Dada et al. concluded that the main cause of advanced
inflammation (35–38). Oral carbonic anhydrase inhibitors cause PPKG is adhesive angle closure, and the degree of angle closure is
serious hypokalemic side effects. Inhibition of carbonic anhydrase closely related to intraoperative operation, and they concluded that
activity increases the excretion of NaCl and HCO3- in the proximal relaxed and atrophic iris can lead to a higher incidence of PAS
convoluted tubules and increases the exchange of K+ -Na+ in the formation, which can be prevented by iridoplasty (8).
distal nephridium, resulting in low potassium (39, 40).
As an RHO kinase inhibitor, nesudil inhibits Rho kinase to Selective laser trabeculoplasty
dilate the connective tissue proximal to the trabecular meshwork Laser trabeculoplasty acts on the trabecular meshwork through
and reduce superficial scleral venous pressure, thereby increasing YAG laser to realize the remodeling of trabecular meshwork
aqueous outflow. Nesudil is a relatively new drug in the treatment of structure and function, reduce the resistance of trabecular
glaucoma and corneal edema, but studies have shown that it may meshwork aqueous outflow, and finally achieve the reduction of
cause transient vision loss (41). intraocular pressure. Nakakura et al. reported a case of SLT after PK

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surgery, long-term use of latanoprost 6 months after surgery, and anterior chamber after trabeculectomy combined with MMC is as
follow-up intraocular pressure up to 18 mmHg, but its long-term high as 32% (52).
efficacy is poor (43).
Non-perforating deep sclerectomy
Deep sclera was removed, the inner wall of Schlemm ‘s canal
Operative therapy and clinical canal tissue were avulsed, and aqueous humor was
drained from the anterior chamber into the subconjunctival space,
Goniosynechialysis which is the treatment of choice for PPKG without PAS (53). One
GSL increases aqueous humor outflow by separating iris tissue scholar compared the efficacy of NPDS and TRA in the treatment of
adhering to the angle and reopening the angle, thereby reducing PPKG and found that the success rates at 1 and 5 years were 76%
intraocular pressure (44). It has been documented that peripheral and 44% in the NPDS group and 69% and 49% in the
iris adhesions are an important cause of secondary acute angle- trabeculectomy group, respectively (54). NPDS was as effective as
closure glaucoma after Descemet’s stripping automated endothelial trabeculectomy in controlling intraocular pressure, but its long-
keratoplasty (DSAEK). Severe corneal graft edema in patients can term survival rate of the graft after surgery was better (53). Another
lead to unclear vision by physicians, and endoscopic fiberoptic study using NPDS after DSAEK for glaucoma came to the same
fibers and camera probes are mostly used to visualize the attached conclusion (55).
iris tissue in clinical practice. Physicians can gently pull apart the
iris tissue with miniature forceps and successfully complete 270°
Glaucoma drainage devices
synechiolysis to restore trabecular function, and no corneal The GDD consists of a silicone tube that drains aqueous humor
rejection has been found after surgery (45). However, some
from the anterior or posterior chamber to a drainage disc located in
scholars believe that GSL can lead to uveitis, hyphema and the equatorial region of the eyeball. Several weeks after implantation,
iridodialysis and other side effects (46).
a fibrous capsule forms around the drainage disc, and aqueous humor
accumulates in the potential gap between the disc and the peripheral
Peripheral iridotomy capsule. Then it diffuses passively through the capsule wall into
A small amount of iris tissue is removed from the periphery of periocular capillaries and lymphatic vessels, and the fibrous capsule
the iris in patients, and posterior chamber aqueous humor can flow has a major limiting effect on the outflow of aqueous humor in GDD.
directly into the anterior chamber through this incision. Some GDD, also known as an aqueous humor shunt device, is a small
scholars have found through studies that 12.5% of patients have reconstructive surgical device that can be solid or made from a tube
persistent intraocular pressure elevation of more than 30 mmHg fixed to the endplate. A drainage orifice was created surgically and the
after DMEK, but patients do not have any other symptoms, so implant placed correctly on it. All implants were designed to reduce
peripheral iridectomy is recommended in such patients. It should intraocular pressure by increasing intraocular fluid outflow. There are
be noted that peripheral iridectomy may be obstructed by bubbles, many types of GDD, common ones are: Molteno single and double
foreign bodies, or heme (47). The principle of PI is similar to that of plate implants, Baerveldt drainage implants, Schocket implants, Ex-
LPI, but different from LPI, which uses laser to punch the iris tissue, Press R50 implants, Ahmed glaucoma drainage valves(AGD),
PI surgically resects part of the iris tissue. For patients who cannot Krypton implants, And the latest iStent, iStent inject, Hydrus,
be operated by laser for various reasons, such as hard iris tissue, CyPass, XEN and InnFocus (56).GDD is indicated for patients with
surgical resection can be used. significant anterior segment inflammation or severe bulbar
conjunctival scarring. When combined with medical therapy, the
Trabeculectomy success rate of intraocular pressure control ranges from 62% to 96%
TRA is a new aqueous humor drainage channel established at the (57, 58). When combined with medical therapy, the success rate of
limbus to drain aqueous humor from the anterior chamber to the IOP control ranges from 62% to 96% [68, 69]. GDD tends to be more
subconjunctival space, and then absorbed by the surrounding tissues, successful in controlling IOP, but the rate of graft failure is also higher
which is a traditional surgical approach for the treatment of secondary compared with trabeculectomy (59–61). Almousa et al. reported that
glaucoma. TRA combined with mitomycin C (MMC) can successfully the success rate of AGD implantation after secondary glaucoma in 59
reduce intraocular pressure, but there is a certain probability of corneal high-risk keratoplasty patients was 75.8%, the survival rate of patients
transplantation failure and complications. Lin Yongfeng et al. found was 87% after 1 year, and the survival rate of patients decreased to
that TRA combined with MMC can form effective filtering blebs, 47% after 5 years (62). Li Navy et al. showed that AGD implantation
which have a good long-term effect in reducing intraocular pressure reduced the incidence of shallow anterior chamber more than TRA.
and can effectively improve visual acuity. It should be noted that the Studies have demonstrated that GDD can effectively reduce
probability of transplantation failure caused by corneal scars and local intraocular pressure and is an important method for the treatment
tissue fibrosis is 12-18% (48, 49). MMC has not increased the of refractory glaucoma. It should be noted that mechanical corneal
probability of corneal transplantation failure, but MMC has the endothelial injury, reflux of inflammatory cells into the anterior
possibility of causing scleral necrosis and chronic bubble leakage chamber, and drainage valve implantation can affect the blood-eye
(50, 51). Superficial anterior chamber is a common complication of barrier of patients and then change the protein content of aqueous
filtering surgery, and studies have shown that the incidence of shallow humor, resulting in an increased rate of corneal transplantation

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failure in patients (59, 63–66). Some scholars have proposed that stent who reported a 70.5% decrease in mean intraocular pressure
posterior chamber implantation for GDD can reduce the risk of and only one transient intraocular pressure increase at 7 days after
transplantation failure (57). surgery (75).
In conclusion, MIGS may be a new option for the treatment of
Transscleral ciliary photocoagulation glaucoma after keratoplasty. Due to the limited clinical data, its
The principle of TSCPC is that the laser destroys the structure efficacy and safety need to be further studied.
of the ciliary body, thereby reducing aqueous humor production,
and is suitable for patients with poor visual acuity, having
undergone multiple ocular surgeries, and severe conjunctival Conclusion
scarring. Rivier et al. reported 18 Boston Keratoprothesis (B-
KPro) eyes treated with TSCPC for secondary glaucoma, of which Secondary glaucoma after keratoplasty can be treated with
12 eyes had intraocular pressure reduced to less than 20 mmHg, drugs, laser or surgery, and uncontrolled intraocular pressure
suggesting that TSCPC may be particularly suitable for B-KPro eyes elevation will lead to corneal graft and optic nerve damage in
(67). Alejandro et al. reported that the mean preoperative patients. Some scholars have proposed that the transplanted corneal
intraocular pressure in 16 PPKG patients was 31.5 mmHg, which endothelium is more vulnerable to damage than its own corneal
decreased to 17.5 mmHg after the first application of diode laser, endothelium (76). Therefore, early detection, control of intraocular
with an overall reduction of 14.0 mmHg (55.5% reduction) (68). pressure, and timely treatment are essential to promote the survival
Destructive surgery of the ciliary body has a high probability of of grafts and protect vision in patients (77).
complications such as corneal graft failure, hypotony, visual loss, Drugs are the first-line treatment for secondary glaucoma after
and ocular atrophy, so this surgery is a treatment modality after keratoplasty. In the face of patients with different conditions, we
ineffective use of other interventions (3). should individualize the choice of treatment options. Surgical
treatment is suitable for patients whose intraocular pressure
remains uncontrolled after the use of the maximum dose of local
Micropulse transscleral cyclophotocoagulation
anti-glaucoma drugs.
MP-TSCPC is a disruptive surgery that uses continuous diode
The field of glaucoma surgery is undergoing a profound change
laser irradiation of the ciliary body to reduce the generation of
from traditional glaucoma surgery to MIGS surgery. MIGS surgery has
aqueous humor (56). It is commonly used in the treatment of
many advantages such as less tissue destruction, less postoperative
refractory glaucoma. And reduce aqueous humor production by
complications, safety and effectiveness, and is the development trend of
destroying the non-pigmented epithelium of the ciliary body. MP-
glaucoma surgery technology in the future. MIGS provides a new
TSCPC is a form of cyclophotocoagulation in which the transmitted
option in the treatment of secondary glaucoma after keratoplasty.
micropulse wave is set to an alternating cycle of “ON” and “OFF”,
However, there are few literatures on the application of MIGS in the
so that the laser energy acts on the ciliary body not in a continuous
treatment of secondary glaucoma after keratoplasty, so more clinical
manner, but in an intermittent and periodic manner. In a short
data are needed to further study its efficacy and safety.
energy pulse (“ON” period), the laser energy acts on the ciliary
epithelium. In a pause period in which no energy is delivered
(“OFF” period), the adjacent tissue is cooled, thus protecting it from
Author contributions
changes caused by high temperature (69). Therefore, MP-TSCPC
has a satisfactory efficiency of lowering intraocular pressure, while
YL: Writing – original draft. GQ: Writing – original draft.
producing fewer adverse effects (70–74).
PY: Writing – original draft. ZW: Writing – original draft. LZ:
Mihail Zemba et al. observed 29 glaucoma patients treated with
Writing – review & editing. HC: Funding acquisition, Writing –
MP-TSCPC after PK surgery for up to one year and found that the
review & editing.
success rate of MP-TSCPC in lowering intraocular pressure after 12
months was 76%, resulting in corneal graft failure due to severe
postoperative inflammatory response in only one patient (69). MP-
Funding
TSCPC is a safe and effective surgical method for patients after
keratoplasty to achieve ideal intraocular pressure control and
The author(s) declare financial support was received for the
success rate, while minimizing complications and graft failure rate.
research, authorship, and/or publication of this article. The work
was supported by Chengdu Health Commission 2020007.
Minimally invasive glaucoma surgery
Compared with traditional glaucoma surgery, MIGS has the
advantage that its placement device is smaller and avoids damage to Conflict of interest
the corneal endothelium of patients. At present, only a single case
report has described the role of MIGS implant device in glaucoma The authors declare that the research was conducted in the
after keratoplasty. Rahmania et al. reported a patient with absence of any commercial or financial relationships that could be
secondary glaucoma after keratoplasty treated with Xen45 gel construed as a potential conflict of interest.

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Lin et al. 10.3389/fopht.2024.1361704

Publisher’s note organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
All claims expressed in this article are solely those of the claim that may be made by its manufacturer, is not guaranteed or
authors and do not necessarily represent those of their affiliated endorsed by the publisher.

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