SPECIAL ARTICLE

Glaucoma After Corneal Trauma or Surgery—A Rapid,

Inflammatory, IOP-Independent Pathway
Claes H. Dohlman, MD, PhD, Chengxin Zhou, PhD, Fengyang Lei, MD, PhD, Fabiano Cade, MD, PhD,

Caio V. Regatieri, MD, PhD, Alja Crnej, MD, Jan G. Dohlman, MD, Lucy Q. Shen, MD, and
Eleftherios I. Paschalis, PhD

Conclusions: A rapidly initiated, inflammatory (TNF-a mediated),

Purpose: To review clinical aspects and cellular and molecular IOP-independent pathway to glaucoma, resulting from acute anterior
steps in the development of long-term glaucoma after corneal segment trauma or surgery, has been identified in laboratory studies.
surgery or acute trauma—especially the pivotal role of tumor Prompt prophylactic treatment with antiinflammatory agents has
necrosis factor alpha (TNF-a), the rapidity of the secondary damage been shown to be markedly neuroprotective of retinal ganglion cells,
to the retinal ganglion cells, and the clinical promise of early presumably capable of reducing the risk of late glaucoma.
antiinflammatory intervention.
Key Words: corneal trauma, surgery, inflammation, glaucoma
Methods: A series of laboratory studies on post-injury and post-
surgery glaucoma have been compared to clinical outcome studies on (Cornea 2019;38:1589–1594)
the subject, focusing particularly on the vulnerability of the retinal
ganglion cells. Alkali burn to the cornea of mice and rabbits served as
the main experimental model. TNF-a titer, ganglion cell apoptosis,
and depletion of optic nerve axons have been examined. Anti-TNF-a G laucoma is a frequent and often severe long-term
complication after corneal surgery, infection, or trauma
—well documented in an extensive literature. Almost
antibodies or corticosteroids have been used to protect the retinal
ganglion cells. Intraocular pressure (IOP) postburn was recorded by
invariably, postevent elevated intraocular pressure (IOP) has
been considered the cause. However, in many instances, the
manometric methods.
IOP is poorly documented in the articles or is registered as
Results: In animals with alkali burn to the cornea, damage to the quite modest in magnitude. In a number of cases, IOP has
retina can occur within 24 to 72 hours. This is not because of a direct been normal or low, still resulting in progressive visual
pH change posteriorly—the alkali is effectively buffered at the field loss and blindness. Beyond lowering the IOP in any
iris–lens level. Rather, TNF-a (and other inflammatory cytokines), type of glaucoma, there is clearly a need for additional
generated anteriorly, rapidly diffuses posteriorly to cause apoptosis neuroprotection.1
of the ganglion cells. During this time, the IOP remains much lower We have been confronted with the complication of
than the reported values required to cause ganglion cell damage. The glaucoma because of our interest in artificial corneas.2–4 After
TNF-a antibody infliximab or corticosteroids, if administered marked improvements in postoperative management and also
promptly, are markedly protective of the ganglion cells. in design during the past 2 decades, such devices can give
great vision in the short and intermediate terms, if the rest of
Received for publication April 12, 2019; revision received June 25, 2019; the eye allows, but severe glaucoma can still in the long run
accepted June 25, 2019. Published online ahead of print August 23, 2019. be the most significant complication5–15 (Fig. 1). In addition,
From the Cornea Service, Glaucoma Service and Boston Keratoprosthesis most eyes undergoing keratoprosthesis (KPro) surgery do
Laboratory, Massachusetts Eye and Ear and Schepens Eye Research
Institute, Harvard Medical School, Boston, MA.
already have glaucoma—undoubtedly reflecting the inflam-
Supported by the Boston Keratoprosthesis Fund, Massachusetts Eye and Ear, matory or surgical history of these eyes. This fact has been
Boston, MA. illustrated in a study on 106 consecutive Boston KPro patients

C. H. Dohlman, C. Zhou, F. Lei, F. Cade, C. V. Regatieri, A. Crnej, L. Q. with various severe corneal etiologies10 (Fig. 2). Cup-to-disc
Shen, and E. I. Paschalis have been full-time employed by Massachusetts
Eye and Ear, the manufacturer of the Boston keratoprosthesis. The
ratios were recorded, and the analysis showed that about two-
remaining author has no conflicts of interest to disclose. thirds of these patients had glaucoma already preoperatively,
For this review, no new human or animal studies were performed requiring and many progressed after the KPro surgery. In addition,
further ethical approval. glaucoma de novo was not uncommon. Less than 10% of the
Correspondence: Claes H. Dohlman, MD, PhD, Massachusetts Eye and Ear,
243 Charles St, Boston, MA 02114 (e-mail: claes_dohlman@meei.
eyes remained free of glaucoma after 4 years. Based on the
harvard.edu). original etiology of corneal opacification, patients with
Copyright
2019 The Author(s). Published by Wolters Kluwer Health, Inc. chemical burn had the worst glaucoma outcome. However,
This is an open-access article distributed under the terms of the Creative lowering the IOP by using a valve drainage device usually
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the proved effective in slowing the process.10
work provided it is properly cited. The work cannot be changed in any These clinical findings inspired a series of laboratory
way or used commercially without permission from the journal. studies on mice and rabbits,16–23 where alkali burn of the

Cornea  Volume 38, Number 12, December 2019 www.corneajrnl.com | 1589

Dohlman et al Cornea  Volume 38, Number 12, December 2019

FIGURE 1. An example of kerato-

prosthesis as a rescue procedure
after multiple keratoplasty failures.
A, Status after 4 failed grafts for
keratoconus, the last one was com-
plicated by fungal keratitis/endoph-
thalmitis and glaucoma. B,
Keratoprosthesis, with a follow-up of
17 years. Vision is still 20/20—but
with advanced glaucoma.

cornea was used as a model. Not only did the expected cornea was demonstrated to occur not only in burns but also after
damage occur but also rapid subclinical injury to the ocular hypertension and cornea surgical trauma, indicating
retina16–23(Fig. 3). With TUNEL stain, substantial apoptosis the role of inflammation and TNF-a in long-term retinal
of the ganglion cells (the hallmark of glaucoma) was health.22,23
demonstrated within 24 to 72 hours. In addition, the depletion How do we know that TNF-a is a mediator in the
of the number of optic nerve axons was recorded after process of ganglion cell apoptosis? We showed that inflix-
3 months. These studies helped to understand the importance imab (antibody to TNF-a), infused over 60 minutes starting
of inflammation, and its rapid onset, in this glaucomatous 15 minutes after the burn, had a strong protective effect
neurodegeneration. against the apoptosis16–19 (Fig. 4) and ameliorated the process
Thus, insult to the cornea can result in a very rapid and of neuroglia remodeling.23 These findings may open new
widespread damage to the retina (Figs. 3 and 4). In chemical prophylactic treatment possibilities.26
burns, the retina injury does not result from a direct pH affect Thus (in animals), the TNF-a can promptly destroy
—alkali is effectively buffered at the iris–lens level, as a substantial portion of the retinal ganglion cells. Is that enough
measured with pH probes.16,19 Rather, the inflammatory to cause functional loss in patients? It likely is, because it is
cytokine tumor necrosis factor alpha (TNF-a) is generated already well-established that in humans and primates, a 20% to
in the anterior segment and rapidly (within hours) diffuses 40% ganglion cell loss results in visual field defects.24,25
posteriorly to cause the ganglion cell apoptosis16–21—pre- These results from the laboratory, combined with
sumably capable of resulting in later glaucoma. TNF-a was clinical experience, prompted a reevaluation of the treatment
shown to cause permanent changes in the immune function of of our patients with chemical burns.26 It is well known that
the retina, termed “permanent neuroglia remodeling,” which penetrating keratoplasty (PK) after severe burns have
continued to cause neuronal degeneration even long after the a virtually hopeless visual prognosis,27 whereas KPros
noxious stimuli were removed and the TNF-a production in usually do well surgically.7,28 Late glaucoma is the problem.
the anterior segment had subsided. This immunological shift Therefore, because the above-cited experience from animals

FIGURE 2. Glaucoma prevalence in eyes with kera-

toprosthesis, preoperative and postoperative status.
A cohort of 106 consecutive patient eyes with severe
corneal damage which had keratoprosthesis im-
planted was analyzed for cup-to-disc (C/D) ratio of
the optic nerve head. Seventy eyes had a pre-
operative diagnosis of glaucoma at the time of sur-
gery (green line), and as a group, they worsened
despite treatment. Twenty-seven eyes, with normal
optic nerve appearance immediately after surgery,
developed cupping with time (blue line). Only in 9
eyes did the optic nerve remain totally normal—with
4 years of follow-up (red line). However, a valved
drainage device proved effective in retarding glau-
coma. Reprinted with permission from Crnej,  Pa-
schalis, Salvador-Culla, Tauber, et al., Cornea 201410.

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2019 The Author(s). Published by Wolters Kluwer Health, Inc.
Cornea  Volume 38, Number 12, December 2019 Glaucoma After Corneal Trauma or Surgery

FIGURE 3. Injury to the cornea can

rapidly result in damage to the ret-
ina (sometimes patchy), including
the ganglion cells. After alkali burn
to the cornea of mice or rabbits, the
retinas were subjected to TUNEL
stain for cellular apoptosis. The left
panel shows the retinal stain in rab-
bits 72 hours after exposure, without
(A) and with (B) infliximab adminis-
tration promptly postburn—while
the IOP remained essentially normal.
The right panel shows a normal
optic nerve (C) compared with
a nerve 3 months after a corneal
burn (D), indicating permanent loss
of the axons. Original earlier ex-
periments in mice had given similar
results. Reprinted from Zhou, Rob-
ert, Kapoulea, et al., Invest Oph-
thalmol Vis Sci 2017.21 ª The
Author(s). This work is licensed
under a Creative Commons Attribu-
tion-NonCommercial-NoDerivatives
4.0 International License, under
which the material may be copied
and redistributed in any medium or
format.

points to a very rapid (hours or days) destruction of ganglion when the intraocular inflammation has subsided, a KPro is
cells after a burn, it seems logical to start strong antiin- usually indicated.30
flammatory prophylaxis in patients promptly after the If a major ocular trauma such as a chemical burn to the
accident.26,30 Both corticosteroids and antibodies to TNF- cornea can have immediate dire consequences for the retinal
a show rapid and effective neuroprotection of ganglion cells ganglion cells—with expected glaucomatous optic neurop-
in animals,19 but biologics are well documented to be athy as a consequence—is there a need of prophylactic
considerably safer in long-term treatment (eg, in rheumatol- treatment even after standard corneal surgery such as PK,
ogy) and are used successfully in uveitis.29 A modified where glaucoma is also very common postoperatively?31–34
treatment paradigm for patients with chemical burn might Close to 200,000 PKs are presently being performed
start promptly in the emergency department (in addition to annually worldwide, and a reduction of the incidence of
standard treatment such as lavage, etc.) with the local postoperative glaucoma could result in a major improvement
administration of triamcinolone (Kenalog), injected sub- of ocular public health. To investigate this question further
Tenon or subconjunctivally. The initial choice of a cortico- in the laboratory, mice were implanted with miniature
steroid allows a tuberculosis test to be performed, and the corneal grafts or with miniature KPros into their previously
results returned before considering biologics—which pres- untouched, normal corneas.18 As was suspected, also such
ently can take 24 hours. When tuberculosis has been proven a penetrating surgery triggers rapid upregulation of TNF-a
absent in the patient, a biologic such as adalimumab in the retina, as well as ganglion cell apoptosis, although of
(Humira) subcutaneously, or infliximab (Remicade) intrave- less magnitude than in the alkali burn model used earlier
nously, might be a logical drug for long-term continuation.30 (Fig. 5). Even a short penetrating injury in a mouse cornea
Doses, routes of administration, duration of treatment, and can release potentially injurious levels of inflammatory
the effect of recently introduced new cytokine inhibitors are cytokines.35 The fact that glaucoma is such a long-term
presently under investigation. problem postoperatively after PK and after KPro, in patients,
In the burn patients, prophylaxis against later IOP- speaks for likely future routine local administration of
associated glaucoma from outflow obstruction—often starting a powerful antiinflammatory drug (steroid or biologic) at
in the healing and scarring phase—should be considered as the end of any surgical procedure—similar to what is
well. Thus, prompt institution of a carbonic anhydrase recommended after chemical burns. The route of local
inhibitor (drops can be unreliable, irritating, after burn) is administration can be subconjunctival, sub-Tenon or, less
recommended to bring the IOP to the lowest safe level and likely, intravitreal. Postoperative antiinflammatory drops to
maintain it there for months. Finally, after 3 to 6 months, the surface of the eye, or released from a subconjunctival

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2019 The Author(s). Published by Wolters Kluwer Health, Inc. www.corneajrnl.com | 1591
Dohlman et al Cornea  Volume 38, Number 12, December 2019

ganglion cell damage during the first few days after the
traumatic event? In our animal experiments, the IOP
remained normal before burn and 24 hours later (Fig. 6),
but what about the possibility of a severe peak between the 2
time points? Some additional experiments were therefore
performed in mice and rabbits (unpublished, but with
approved protocols). An IOP spike was indeed recorded in
rabbits with a fleeting maximum of 45 mm Hg, and
remained above 30 mm Hg for a total of only 45 minutes.
Afterward, the IOP fell to normal values. In mice, the
pressures were normal after 1 and 4 hours. This pattern
should be compared with what is known in the literature
about the levels of IOP required to cause ganglion cell
damage. Thus, in one study, a continuous pressure of 45 mm
Hg for at least 7 hours daily, for several days, was necessary
to initiate ganglion cell attrition.37 Therefore, it seems
extremely unlikely that the IOP during the first few
postevent days in our animals—when retinal apoptosis
occurs–will have played any pathophysiological role.
The clinical literature correlated with the laboratory
studies cited in this brief review seems to indicate the
existence of a rapid, inflammatory, IOP-independent path-
way to glaucoma—susceptible to effective inhibition by
FIGURE 4. Further experiments on mice with alkali-burned antibodies (Fig. 7). TNF-a has already been shown exper-
corneas showed that other retinal layers can be affected by imentally to be a mediator between high IOP and ganglion
apoptosis and that infliximab can have a profound protective cell apoptosis.38,39 However, in our animal experiments,
effect on them as well. This graph illustrates the situation 24 ganglion cell attrition was clearly triggered by the postburn
hours postburn, indicating the percentage of apoptosis. Black inflammation, not by the IOP—the latter remaining in
bar: untreated mice. Gray bar: treated with the anti-TNF-a a harmless range within 1 to 3 days after the exposure
antibody infliximab. GCL, ganglion cell layer; IPL, inner plex- (depending on the animal) when severe damage to the
iform layer; INL, inner nuclear layer; OPL, outer plexiform ganglion cells had already occurred19 (Fig. 6). In addition,
layer; ONL, outer nuclear layer. ª Wolters Kluwer Health
2017. Reproduced with permission from Wolters Kluwer
Health from Paschalis, Zhou, Lei, et al., Am J Pathol 201710.

drug-eluting device,20 or from a contact lens (Ciolino,

unpublished), may have some effect also at the retinal level,
but the necessary dosing is not yet known, nor the tradeoffs
regarding complications from the steroids.
Because inflammation-induced ganglion cell apoptosis
is triggered very rapidly after corneal surgery or trauma,
most likely within hours, and seems to result in glaucoma
manifestation often long afterward, how long should antiin-
flammatory prophylaxis be continued? A recent study on
KPro patients revealed that systemic TNF-a/TNF-receptor 2
levels in blood can remain elevated for years after the
surgery.36 The full relevance of this finding is not yet
known, but it suggests ongoing chronic low-grade inflam- FIGURE 5. TNF-a in the retina of mice 8 weeks after PK
mation in eyes with a KPro. One might be able to use TNF-a or miniature Boston keratoprosthesis (KPro), using allogeneic
in blood as an inflammatory marker and indication for (Allo) or syngeneic (Syn) carrier corneal grafts implanted into
treatment. Possibly, a locally or systemically administered normal corneas. The IOP, measured by direct manometry, was
biologic will be proven necessary for a long time after the normal at the time of euthanasia. TNF-a is expressed as copies
surgery or after any major traumatic event to the eye. per 106 copies of glyceraldehyde 3-phosphate dehydroge-
nase. A significant increase was seen in the Syn KPro and Allo
Unfortunately, the high cost of these biologics is presently 
KPro groups. *P = 0.05; **P , 0.05. Reproduced from Crnej,
a barrier to extensive human application. Less expensive Omoto, Dohlman, et al. Invest Ophthalmol Vis Sci. 201618.
immunomodulators such as methotrexate or azathioprine are ª The Author(s). This work is licensed under a Creative
yet to be tested. Commons Attribution-NonCommercial-NoDerivatives 4.0
From a more global perspective of the pathophysiol- International License, under which the material may be copied
ogy of glaucoma, can we exclude the IOP as a link to the and redistributed in any medium or format.

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2019 The Author(s). Published by Wolters Kluwer Health, Inc.
Cornea  Volume 38, Number 12, December 2019 Glaucoma After Corneal Trauma or Surgery

ganglion cells can show substantial apoptosis. A high

percentage of the cells can become affected in
our models.
4. During that time (up to 72 hours), IOP remains normal
or fleetingly elevated and is expected to be harmless.
5. Antibodies to TNF-a, administered shortly after an
alkali burn, are strongly neuroprotective, corroborating
that TNF-a can be a prominent mediator in the
destruction of the ganglion cells.
6. Finally, these results should be interpreted against the
FIGURE 6. Intraocular pressure measured manometrically,
background that already a modest attrition of approx-
before and 24 hours after alkali burn in mice (n = 17) and imately 30% of ganglion cells results in visual field loss
rabbits (n = 3). No significant changes were recorded. To —well documented in humans (Fig. 7).
exclude possible pressure spikes between the 2 end points in Thus, an acute traumatic event to the eye (corneal
time, recent additional experiments with frequent recordings
showed a brief peak immediately after burn, too insignificant
surgery, accidental trauma, etc.) seems to be able to, through
to be expected to cause glaucomatous damage. ª Wolters an inflammatory pathway, very rapidly cause irreversible
Kluwer Health 2017. Reprinted with permission from Wolters damage to retinal ganglion cells and most likely later result in
Kluwer Health from Paschalis, Zhou, Lei, et al., Am J Pathol glaucoma, while the IOP is still essentially normal. Later,
201719. when the injured eye begins to heal with inflammation,
scarring, and trabecular meshwork damage, with frequent
chronic IOP elevation as a result, the molecular mechanisms
autoimmune inflammation has lately been shown to affect involved in the glaucomatous damage may be different and
the optic nerve and result in neuropathy.40 Thus, arguments more difficult to control. Likewise, whether our models will
for an IOP-independent pathway to glaucoma can be be able to elucidate the mechanism of chronic normal-tension
formulated as follows: glaucoma is uncertain. In practical terms, however, these new
1. In patients, it is well known and documented that insights point to needed changes in the management after
corneal surgery or trauma is often later complicated corneal surgery or trauma. Substantially more antiinflamma-
by glaucoma. tory medication is warranted, immediately as well as
2. In animals, an alkali burn to the cornea triggers rapid sustained, as prophylaxis against long-term glaucoma. The
(within hours) upregulation of TNF-a in the balance between biologics, other immunomodulators, and
anterior segment. corticosteroids for such treatment will have to be defined and
3. Within 24 to 72 hours, in mice or rabbits, the TNF-a calibrated further.
level becomes elevated in the retina as well and the

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