Journal of

Clinical Medicine

Systematic Review
Corneal Edema after Cataract Surgery
Celeste Briceno-Lopez 1,2, * , Neus Burguera-Giménez 1,2 , M. Carmen García-Domene 1,2 ,
M. Amparo Díez-Ajenjo 1,2 , Cristina Peris-Martínez 3,4 and M. José Luque 1,2

1 Department of Optics and Optometry and Vision Sciences, Faculty of Physics, Universitat de València,
Dr. Moliner 50, E-46100 Burjassot, Spain; neus.burguera@uv.es (N.B.-G.);
m.carmen.garcia-domene@uv.es (M.C.G.-D.); amparo.diez@uv.es (M.A.D.-A.); maria.j.luque@uv.es (M.J.L.)
2 Cátedra Alcon—FOM—UVEG, Universitat de València, Dr. Moliner 50, E-46100 Burjassot, Spain
3 Anterior Segment and Cornea and External Eye Diseases Unit, Fundación de Oftalmología Médica,
Av. Pío Baroja 12, E-46015 Valencia, Spain; cristinaperismartinez0@gmail.com
4 Surgery Department, Faculty of Medicine, Universitat de València, Av. Blasco Ibáñez 15,
E-46010 Valencia, Spain
* Correspondence: celeste.briceno@uv.es; Tel.: +34-962-787-660

Abstract: This systematic review investigates the prevalence and underlying causes of corneal edema
following cataract surgery employing manual phacoemulsification. A comprehensive search encom-
passing databases such as PubMed, Embase, ProQuest, Cochrane Library, and Scopus was conducted,
focusing on variables encompassing cataract surgery and corneal edema. Two independent reviewers
systematically extracted pertinent data from 103 articles, consisting of 62 theoretical studies and
41 clinical trials. These studies delved into various aspects related to corneal edema after cataract
surgery, including endothelial cell loss, pachymetry measurements, visual performance, surgical
techniques, supplies, medications, and assessments of endothelial and epithelial barriers. This review,
encompassing an extensive analysis of 3060 records, revealed significant correlations between corneal
edema and endothelial cell loss during phacoemulsification surgery. Factors such as patient age,
cataract grade, and mechanical stress were identified as contributors to endothelial cell loss. Fur-
thermore, pachymetry and optical coherence tomography emerged as valuable diagnostic tools for
Citation: Briceno-Lopez, C.;
assessing corneal edema. In conclusion, this systematic review underscores the link between corneal
Burguera-Giménez, N.; edema and endothelial cell loss in manual phacoemulsification cataract surgery. It highlights the
García-Domene, M.C.; Díez-Ajenjo, relevance of factors like patient demographics and diagnostic modalities. However, further research
M.A.; Peris-Martínez, C.; Luque, M.J. is essential to unravel the complexities of refractive changes and the underlying mechanisms.
Corneal Edema after Cataract
Surgery. J. Clin. Med. 2023, 12, 6751. Keywords: corneal edema; cataract surgery; visual performance; pachymetry; optical coherence
https://doi.org/10.3390/jcm12216751 tomography; refractive changes
Academic Editors: Giuseppe
Giannaccare, Cristina Bovone and
Massimo Busin
1. Introduction
Received: 6 September 2023
Corneal edema was previously defined as an abnormal swelling of the cornea’s main
Revised: 17 October 2023
layers: the epithelium, stroma, and endothelium [1,2]. However, due to technological
Accepted: 24 October 2023
Published: 25 October 2023
advances, this swelling process has now been reduced to one definition: corneal edema is
an inflammation of the stroma caused by excessive hydration that affects light transmission
above 90%, refraction, transparency, and visual performance [3–9]. These patients have
decreased best-corrected visual acuity (BCVA) and frequency-selective sensitivity loss
Copyright: © 2023 by the authors. (CSF) [3,10].
Licensee MDPI, Basel, Switzerland. Corneal hydration is influenced by five main factors: tear evaporation, the barrier
This article is an open access article function of the epithelium and endothelium, stromal swelling pressure, the endothelial pump,
distributed under the terms and and intraocular pressure [10–13]. The cornea is bounded on the outside by the epithelium
conditions of the Creative Commons and on the inside by the endothelium, which are in contact with the tear film and aqueous
Attribution (CC BY) license (https://
humor, respectively. Both tissues play a role as a barrier and keep the stroma hydrated.
creativecommons.org/licenses/by/
The stroma is composed of collagen fibrils encased in regularly spaced glycosaminoglycans
4.0/).

J. Clin. Med. 2023, 12, 6751. https://doi.org/10.3390/jcm12216751 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2023, 12, 6751 2 of 17

and mucopolysaccharides that tend to absorb fluid and swell [1,5,14–20]. Epithelial and
endothelial cells are intimately involved in regulating the circulation of fluids and electrolytes
in the stroma [1,5,9,11,14,17,21,22]. Therefore, in order to avoid excess hydration by the tear
film or aqueous humor, the epithelial and endothelial layers must act as blockages that can
regulate water exchange in the stroma so that it is properly hydrated [5,14,22–24].
The most common cause of corneal edema is phacoemulsification with intraocular
lens implantation, which happens to be the most commonly performed surgery in the
world for treating cataracts [7,25–28]. Corneal edema can occur due to endothelial damage
during surgery [5,7,15,29,30]. Endothelial decompensation during cataract surgery has
been reported in the literature [20,24,26,30–33]. However, some of the causes of corneal
swelling are classified according to factors directly related to the patient (low endothelial
cell density, cataract grade, shallow anterior chamber depth), to the surgical procedure
(nucleus extraction method, effective power time of ultrasound for lens extraction, type of
viscoelastic used, vitreous loss and rupture of the posterior capsule) [12,26,27,30,32–34], or
to intraocular lens implantation (chronic iritis, secondary glaucoma, peripheral anterior
synechiae, intraocular lens subluxation) [31,32,35].
Finally, it is important to further investigate this corneal disease, as chronic or pro-
longed swelling processes may lead to bullous keratopathy (BK) or pseudophakic cystoid
macular edema (PCME) [15,20,33,35–39]. BK is an incurable disease primarily caused
by endothelial decompensation, typically after surgery, mechanical stress, glaucoma, or
diabetes mellitus, making keratoplasty the only treatment option to restore the patient’s
vision [15,31,35–37,40]. The aim of this analysis is to investigate and understand the cause
and prevalence of the occurrence of corneal edema after manual phacoemulsification in
cataract surgery.

2. Materials and Methods

2.1. Search Databases
The search databases used were PubMed, Embase, ProQuest, Cochrane Library, and
Scopus. The Embase and Medline databases were searched together via the Embase website.
Relevant publications were also carefully reviewed. The search was performed using the
keywords cornea, corneal, edema, oedema, swelling, treatment, surgery, phacoemulsifica-
tion, and causes. In addition, all available reviews on the treatment of corneal edema were
manually reviewed for additional relevant studies. Articles published up to 31 December
2022 were considered. No restrictions or limitations were placed on the search.
The terms used in the search strategy were progressively limited to the keywords
shown in Table 1.

Table 1. Search strategy and keywords. CCT: Central corneal thickness. ECD: Endothelial cell density.

Corneal Edema After Cataract Surgery Variables Measured

“Central corneal thickness”
“Cataract surgery” OR OR “CCT” OR “corneal
“Corneal edema” OR
“after” OR “consequence” “cataract extraction” OR thickness” OR “pachometry”
“corneal oedema” OR
OR “following” OR “phacoemulsification” OR “pachymetry” OR
“edematic cornea” OR
“from” OR “post” OR OR “manual “Endothelial cell density”
AND

AND

AND

“edematous cornea” OR
“pursuant” OR “result” phacoemulsification” OR “ECD” OR “endothelial
“corneal edema
OR “subsequent” OR OR “aphakia” OR cell damage” OR
incidence” OR “corneal
“succeeding” OR “pseudophakic” OR “endothelial cell loss” OR
inflammation” OR
“successive” “manual-incisioned “corneal endothelium” OR
“corneal swelling”
phacoemulsification” “endothelial cells” OR
“specular microscopy”

2.2. Inclusion and Exclusion Criteria

Studies were considered relevant if they described the edema process, its character-
ization, medical treatment, or physiological corneal changes in the presence of corneal
edema. These pairwise meta-analyses followed the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA) method. Studies that were potentially
J. Clin. Med. 2023, 12, 6751 3 of 17

relevant according to the eligibility criteria were selected. The inclusion criteria were
(a) experimental studies on the prevalence and characterization of corneal edema after
cataract surgery, (b) analytical observational studies (control vs. experimental, cohort)
or descriptive studies (transversal), (c) inclusion of comparison groups, and (d) articles
in English, French, Spanish, Catalan, Portuguese, or Italian. The exclusion criteria were
(a) studies with single clinical cases, case series, reviews, or informative articles; (b) studies
that did not specifically investigate the association between corneal edema and phacoemul-
sification; (c) correspondence letters; (d) systematic and literature reviews; and (e) duplicate
studies (repeated in the search databases).
Two independent reviewers (CBL and NBG) reviewed the titles and abstracts of the
retrieved articles in the pre-selection phase of the meta-analysis. The articles selected
for the preparation of this systematic review were read independently by CBL and NBG.
Disagreements regarding the inclusion of studies were resolved through discussion. If
disagreements persisted, third and fourth reviewers (MCGD and MADA) were consulted.

2.3. Data Extraction

Quality assessment and data extraction of the selected studies were performed by two
independent reviewers, CBL and NBG. Data were integrated by CBL using a standardized
data extraction form that focused on the main subject, with no secondary ocular diseases
associated, to ensure feasibility and reliability. The second stage of data extraction involved
the acquirement of relevant data from the included studies in the first stage. Thus, study
characteristics such as study design, sample size, population characteristics, and interven-
tion details were extracted. In addition, outcome data such as primary and secondary
outcomes, measures used to assess outcomes, and study results were also extracted. Dis-
crepancies between data extraction results were reviewed by CBL and NBG and resolved
through discussion. Similarly, third and fourth reviewers were consulted when agreement
could not be reached between the first two reviewers.

3. Results
A total of 3060 records were initially identified through a systematic search of elec-
tronic databases. After using automated tools to remove duplicates and ineligible articles,
3056 articles were screened based on their titles and abstracts. A total of 103 articles met
the eligibility criteria and were considered for full-text review. Finally, 41 clinical trials and
62 theoretical articles on corneal oedema/edema and/or phacoemulsification were deemed
eligible and included in the systematic review. The PRISMA flow diagram (Figure 1) pro-
vides an overview of the study selection process. The included studies were conducted in
different countries and published over a range of years. Study designs varied, and sample
sizes ranged from small pilot studies to large randomized controlled trials. We assessed
the quality of the included studies using the Cochrane Risk-of-Bias Tool (see Table 2) and
the Newcastle–Ottawa Scale. In the case of the Cochrane Risk-of-Bias Tool, the theoretical
articles will not appear since this tool is only for clinical trials.
However, 2939 studies found during the search were excluded due to the presence
of other corneal pathologies associated with the occurrence of corneal edema, such as
keratoplasty (DMEK or DSAEK) and Fuch’s Endothelial Corneal Dystrophy (FECD). In
line with this exclusion, case reports were also excluded. The systematic review allowed
us to include only articles related to uneventful phacoemulsification and the development
of corneal edema to answer our main hypothesis. Thus, the inclusion criteria limited the
sample to healthy patients aged 50 years and older with cataracts in one or both eyes.
J.
J. Clin. Med. 2023,
Clin. Med. 2023, 12,
12, 6751
x FOR PEER REVIEW 4 4of
of 16
17

Previous studies Identification of new studies via databases and registers

Records removed before

Total records identified:
screening:
Identification

(n= 10,939)
Duplicate records removed
Pubmed (n = 838) Records identified from:
(n = 9)
Embase (n= 3234) Databases (n = 5)
Records marked as ineligible
ProQuest (n= 3069) Registers (n = 0)
by automation tools (n = 4)
Scopus (n= 3577)
Records removed for other
Cochrane Library (n= 232) reasons (n = 0)

Records screened Records excluded

(n = 3075) (n = 0)
Screening

Reports sought for retrieval Reports not retrieved

(n = 14) (n = 14)

Reports excluded:
Reports assessed for eligibility Corneal edema related to
(n = 3061) keratoplasty (n = 45)
Missing data (n = 1628)
DMEK/DSAEK (n = 1202)
Case reports (n = 83)

New studies included in review

(n = 0)
Reports of new included studies
Included

(n = 0)

Total studies included in review

(n = 103)
Reports of total included studies
(n = 0)

Figure 1. Study
Figure 1. Study flow
flow diagram.
diagram. DMEK: Descemet’s Membrane
DMEK: Descemet’s Membrane Endothelial
Endothelial Keratoplasty.
Keratoplasty. DSAEK:
DSAEK:
Descemet’s Stripping Automated Endothelial Keratoplasty.
Descemet’s Stripping Automated Endothelial Keratoplasty.

Table 2. Table based on the Cochrane Risk-of-Bias Tool to review the studies’ quality assessment.
Table 2. Table based on the Cochrane Risk-of-Bias Tool to review the studies’ quality assessment.
Studies that were not applicable to a given category are not shown in that category but are included
Studies
in otherthat were not
applicable applicable to a given category are not shown in that category but are included
categories.
in other applicable categories.
RANDOM SEQUENCE GENERATION
Selection
RANDOM Bias (Biased Allocation
SEQUENCE to Interventions) Due to Inadequate Generation of a Randomized Sequence.
GENERATION
Selection Bias (Biased Allocation
References Judgment to Interventions) Due to Inadequate
SupportGeneration of a Randomized Sequence.
for judgment
[7,11,13,18–21,26,28–
References Judgment Referring
Support
Low risk to a for judgment
random number table; minimization
30,32,35,37,39,41–63]
[7,11,13,18–21,26,28–30,32,35,37,39,41–63] Low risk Referring to a random number table; minimization
[3,8,10,12,25,27,31,36,38,
High risk
[3,8,10,12,25,27,31,36,38,40,64–66] High risk Non-random component
Non-random in theinsequence
component generation
the sequence process
generation process
40,64–66]
Insufficient
Insufficient information
information aboutabout the sequence
the sequence generation
generation process to
[67–70]
[67–70] Unclear Unclear
process
permit to permit
judgment judgment
of “Low risk” orof“High
“Lowrisk”.
risk” or “High risk”.
ALLOCATION CONCEALMENT
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
References Judgment Support for judgment
J. Clin. Med. 2023, 12, 6751 5 of 17

Table 2. Cont.

ALLOCATION CONCEALMENT
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.
References Judgment Support for judgment
Central allocation (including telephone, web-based, and
pharmacy-controlled randomization); sequentially
[7,11,13,18–21,26,30,35,37,39,41–47,49,52,56–63] Low risk
numbered drug containers of identical appearance;
sequentially numbered, opaque, sealed envelopes.
Using an open random allocation schedule (e.g., a list of
random numbers); assignment envelopes were used
without appropriate safeguards (e.g., if envelopes were
[3,8,10,12,25,27,31,32,36,38,40,50,53–55,64–66] High risk
unsealed or nonopaque or not sequentially numbered);
alternation or rotation; date of birth; case record number;
any other explicitly unconcealed procedure.
Insufficient information to permit judgment of “Low risk”
or “High risk”. This is usually the case if the method of
concealment is not described or not described in sufficient
[28,29,67–70] Unclear detail to allow a definite judgment—for example, if the use
of assignment envelopes is described, but it remains unclear
whether envelopes were sequentially numbered, opaque,
and sealed.
BLINDING OF PARTICIPANTS AND PERSONNEL
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.
References Judgment Support for judgment
No blinding or incomplete blinding, but the review authors
judge that the outcome is not likely to be influenced by lack
[20,37,44,45,47,48,58,60–62,71–73] Low risk of blinding; blinding of participants and key study
personnel ensured, and unlikely that the blinding could
have been broken.
No blinding or incomplete blinding, and the outcome is
likely to be influenced by lack of blinding; blinding of key
[3,7,8,10–13,18,19,21,25,27,29–32,35,36,38–
High risk study participants and personnel attempted, but likely that
43,46,49–57,59,63–67,69,70,74]
the blinding could have been broken, and the outcome is
likely to be influenced by lack of blinding.
Insufficient information to permit judgment of “Low risk”
[26,28,68] Unclear
or “High risk”; the study did not address this outcome.
BLINDING OF OUTCOME ASSESSMENT
Detection bias due to knowledge of the allocated interventions by outcome assessors.
References Judgment Support for judgment
No blinding of outcome assessment, but the review authors
judge that the outcome measurement is not likely to be
[20,44,45,47,49,51,52,54,56,58,60–62,68,71–85] Low risk influenced by lack of blinding; blinding of outcome
assessment ensured, and unlikely that the blinding could
have been broken.
No blinding of outcome assessment, and the outcome
measurement is likely to be influenced by lack of blinding;
[3,7,8,10–13,18,19,21,25,27,29–32,35–
High risk blinding of outcome assessment, but likely that the blinding
43,46,48,50,53,55,57,59,63–67,69,70,86]
could have been broken, and the outcome measurement is
likely to be influenced by lack of blinding.
Insufficient information to permit judgment of “Low risk”
[26,28] Unclear
or “High risk”; the study did not address this outcome.
J. Clin. Med. 2023, 12, 6751 6 of 17

Table 2. Cont.

INCOMPLETE OUTCOME DATA

Attrition bias due to amount, nature, or handling of incomplete outcome data.
References Judgment Support for judgment
No missing outcome data; reasons for missing outcome data
unlikely to be related to true outcome (for survival data,
censoring unlikely to be introducing bias); missing outcome
data balanced in numbers across intervention groups, with
similar reasons for missing data across groups; for
dichotomous outcome data, the proportion of missing
[3,7,8,10,11,13,18–21,26,28,30,35–47,49–
Low risk outcomes compared with observed event risk not enough to
60,62,63,65–87]
have a clinically relevant impact on the intervention effect
estimate; for continuous outcome data, plausible effect size
(difference in means or standardized difference in means)
among missing outcomes not enough to have a clinically
relevant impact on observed effect size; missing data have
been imputed using appropriate methods.
Reason for missing outcome data likely to be related to true
outcome, with either imbalance in numbers or reasons for
missing data across intervention groups; for dichotomous
outcome data, the proportion of missing outcomes
compared with observed event risk enough to induce
clinically relevant bias in intervention effect estimate; for
[48,61,64] High risk continuous outcome data, plausible effect size (difference in
means or standardized difference in means) among missing
outcomes enough to induce clinically relevant bias in
observed effect size; “As-treated” analysis performed with
substantial departure of the intervention received from that
assigned at randomization; potentially inappropriate
application of simple imputation.
Insufficient reporting of attrition/exclusions to permit
judgment of “Low risk” or “High risk” (e.g., number
[12,25,27,29,31,32] Unclear
randomized not stated, no reasons for missing data
provided); the study did not address this outcome.
SELECTIVE REPORTING
Reporting bias due to selective outcome reporting.
References Judgment Support for judgment
The study protocol is available and all of the study’s
pre-specified (primary and secondary) outcomes that are of
interest in the review have been reported in the
[3,7,8,10–13,18–21,26–30,32,35–87] Low risk pre-specified way; the study protocol is not available, but it
is clear that the published reports include all expected
outcomes, including those that were pre-specified
(convincing text of this nature may be uncommon).
Not all of the study’s pre-specified primary outcomes have
been reported; one or more primary outcomes are reported
using measurements, analysis methods, or subsets of the
data (e.g., subscales) that were not pre-specified; one or
more reported primary outcomes were not pre-specified
[25] High risk (unless clear justification for their reporting is provided,
such as an unexpected adverse effect); one or more
outcomes of interest in the review are reported incompletely,
so they cannot be included in a meta-analysis; the study
report fails to include results for a key outcome that would
be expected to have been reported for such a study.
J. Clin. Med. 2023, 12, 6751 7 of 17

Table 2. Cont.

Insufficient information to permit judgment of “Low risk”

[31] Unclear or “High risk”. It is likely that the majority of studies will
fall into this category.
OTHER BIASES
Bias due to problems not covered elsewhere in the table.
References Judgment Support for judgment
[3,7,8,10–13,18–21,26–30,32,35–37,39–50,52–68,71–
Low risk The study appears to be free of other sources of bias.
87]
Had a potential source of bias related to the specific study
[25,31,38,69,70] High risk design used; has been claimed to have been fraudulent; or
had some other problem.
Insufficient information to assess whether an important risk
Unclear of bias exists or insufficient rationale or evidence that an
identified problem will introduce bias.

4. Discussion
4.1. Endothelial Cell Loss (ECL)
Corneal edema is associated with endothelial cell loss during phacoemulsification,
which is caused by endothelial pump or barrier dysfunction. Endothelial cells contain
specialized Na+/K+-ATPase pumps that use oxygen and energy to keep the cornea clear
and transparent. These pumps move fluid out of the stroma in order to maintain the
water content under 78%, while the endothelial cells’ tight junctions form a barrier that
prevents fluid from flowing into the cornea. Because endothelial cells do not replicate,
after injury, adjacent cells enlarge and spread to cover the affected area, resulting in a
lower cell density (ECD) and hexagonality (HEX) but a higher coefficient of variation
(CV) [39,64]. Based on the literature, a minimum of 500 cells/mm2 is required to maintain
corneal transparency [35,39]. Specular microscopy is used to measure these endothelial
cell parameters, but it is only effective on the central 1 mm2 of the cornea, and it cannot
be used to assess all of the corneal layers in order to determine the degree of corneal
edema [13,41,42,64]. Intraoperative mechanical stress can be caused by stress and thus
trauma to the corneal endothelium. Traumatic edema is when swelling occurs after surgery
due to excessive stress on the corneal tissue or for accidental reasons [5,6,12,17,21,33,37,65].
This stress can be produced by an excess of power in the phacoemulsifier that damages
endothelial cells. Prolonged surgical times can also cause stress, for example, due to
intraoperative difficulties in extracting a dense cataractous lens. Other factors leading to
excessive tissue stress include narrow anterior chamber depths, which increase the risk
of contact with the corneal endothelium, as well as accidental reasons, like poor patient
cooperation or movement. In addition, the resolution of edema depends on the severity
of the trauma. Penetrating damage may be irreversible, as it is caused by the loss of
endothelial cells, which impairs the pumping function of this layer and therefore causes
stromal swelling or bullous keratopathy in severe cases [18,23,31,37–39].
In surgeries such as phacoemulsification, the most common intraocular surgery world-
wide, mechanical stress can be caused by the technique used, the materials used (size
and shape), the density of the nucleus, the intraoperative medications, and the surgeon’s
experience [5,7,10,17,27,30,37–39,43,44,65,67]. Viscoelastic substances are routinely used
in cataract surgeries and anterior segment procedures to avoid complications since they
have a protective effect on the corneal endothelium [12,41,44,66,88]. There are two types of
viscoelastic substances, cohesive and dispersive, with the latter reported to be more effec-
tive in preventing endothelial damage during cataract surgery [41,88]. Because viscoelastic
substances are nontoxic, nonpyrogenic, and noninflammatory and have the same osmo-
lality as the cornea or aqueous fluid (305 and 300 mOsmol/kg, respectively), they should
not interfere with normal intraocular tissue metabolism or intraocular pressure (IOP).
J. Clin. Med. 2023, 12, 6751 8 of 17

Contact with a hypo-osmotic solution causes a breakdown of intercellular junctions and

intracellular edema, resulting in excessive imbibition of fluids into the stroma and corneal
edema [39,41,68]. However, corneal edema may also be due to a disrupted epithelial barrier.
Epithelial edema can occur if excessive local anesthetics or ultrasound vibration is used dur-
ing phacoemulsification. The integrity of both the epithelial and endothelial layers is critical
to keeping corneal deturgescence and a balanced stroma hydration [1,10,21,23,30,45,68,69].
On the other hand, there are factors that contribute to ECL, such as age, nucleus
firmness, and the grade of the cataract [10,12,24,30,44,46,67,69,70,89]. Choi and Han found
that preoperative lens nucleus hardness and postoperative corneal edema were the most
significant predictive factors for endothelial cell loss at 10 years [70]. Eyes with a higher
cataract grade showed an annual endothelial cell loss of 3% or more. While age alone did
not show an independent association, it is likely linked to the cataract grade in elderly
patients. Mechanical stress was also reflected in postoperative corneal edema, which was
associated with accelerated long-term endothelial loss. In addition, they attempted to
measure endothelial cell loss in patients who had undergone cataract surgery using a
mathematical model:

ECL10years = 5.435 + 5.606 × PCEGOCTET + 6.425 × NF,

This model predicts edema with a 10-year time lapse (ECL: endothelial cell loss (in
percentage); PCEG: postoperative corneal edema grade using OCTET classification; NF:
nuclear firmness based on the Emery–Little system).
This mathematical model, developed by Choi and Han, allows for predicting long-
term endothelial cell loss after cataract surgery based on clinically observable factors like
postoperative edema and nucleus hardness [70]. The authors found that their model ac-
counted for 39.7% of the variation in endothelial cell loss at 10 years post-surgery. While
promising, this specific quantitative approach does not yet seem to be widely used, re-
quiring further validation across diverse patient populations. However, it represents an
initial attempt to quantitatively estimate endothelial damage after cataract surgery based
on clinically observable factors. Moreover, based on their model, the authors estimated
that endothelial cell density may decrease by anywhere from 164 to 523 cells/mm2 after
uneventful cataract surgery, depending on crystalline lens firmness. They also claimed
that phacoemulsification causes nearly three times the endothelial cell loss that occurs in
natural aging, with the loss rising to 2.06 ± 1.36% annually in operated eyes compared to
0.6% in non-operated eyes. Other studies estimated that the long-term endothelial cell loss
following cataract surgery may be 0.09 to 2.5% greater than physiological loss related to
aging alone, potentially persisting for at least 10 years [6,44,47,64,67,70].

4.2. Pachymetry
Pachymetry has become the most common means of detecting and diagnosing corneal
edema based on central corneal thickness (CCT) [2,21,27,43,44,65,69,75–77,89], along with
subjective examination with the slit lamp, suggesting that an increase above 10% of the
original pachymetry is an indicator of edema [1,27,48,65,77,90,91]. Hence, for an average
CCT of 550 microns, an increase of 10%, which is 605 microns, after cataract surgery
would be indicative of corneal edema. Some studies suggest that this parameter may
overlook subclinical or mild corneal swelling [74,75,78,92]. Yet, due to the strong correlation
between CCT and endothelial cell loss following cataract surgery that has been documented
in the literature, pachymetry has emerged as the gold standard when corneal edema
occurs [19,38,39,42,69].
Recent study evidence, on the other hand, has shown that optical coherence tomog-
raphy (OCT) is another tool for objectively measuring corneal edema [9,13,37,38,47,78].
Moreover, since its development, OCT has become an indispensable tool in clinical practice,
especially Swept-Source OCT, due to its depth capacity in capturing images and the speed
required by the device to acquire high-resolution images without contact with the patient.
In addition, OCT is able to objectively measure ocular structures and capture architectural
J. Clin. Med. 2023, 12, 6751 9 of 17

features, such as the width, length, thickness, alignment, and gaps of the corneal incision,
which are particularly important in phacoemulsification with manual incision [13,38]. OCT
also allows ophthalmologists to objectively assess the evolution of the corneal incision or
corneal thickness after surgery, among other intraoperative factors, as they have shown
a strong correlation with edema onset [13,38]. In addition, these authors attempted to
classify edema by stromal opacity using the densitometry unit of the device and showed a
strong correlation between optical density, pachymetry, and BCVA, but only for FECD [78].
In contrast, Zéboulon et al. found a good correlation between OCT and Pentacam as an
indicator of edema in normal corneas using pachymetry maps, but these two devices may
perform poorly in thinner or thicker corneas or in subclinical or mild corneal swelling [92].
Another study by Suzuki and colleagues suggests using the corneal volume (CV) measured
by Pentacam to assess corneal endothelial cell damage after phacoemulsification because
endothelial cell density appears to represent only a small portion of the injury inflicted on
this layer and is insufficient to properly represent changes in the entire cornea [42].
In line with these statements, other authors point out that the corneal thickness limit is
650 µm because the device’s algorithms use the refractive index to calculate corneal thick-
ness, and the measurements would otherwise be unreliable [47]. This limit is also disad-
vantageous for severe corneal edema with opacities measured with ultrasound pachymetry
or Pentacam [3].

4.3. Visual Performance

Ishikawa et al. [74] suggested, in contrast to other studies, that the presence of
corneal edema does not affect visual acuity, although visual symptoms may still be
present [1,10,20,37,49,66,74,91,93,94]. In addition, Díez-Ajenjo et al. demonstrated that
despite the absence of changes in corneal radii, refractive changes occur that are not known,
and the underlying mechanisms are unclear [3]. In addition, the authors suggest that
further studies are needed to determine whether the refractive index of the cornea changes
due to increased hydration during the swelling process. They found that even in corneal
edema, the corneal tissues are affected to varying degrees. Furthermore, there is a direct cor-
relation between the refractive index and stromal fluid uptake when the cornea is swollen,
suggesting that corneal edema cannot be explained by changes in corneal thickness only.
On the other hand, Meek et al. found that the refractive index can change due to hydration,
and therefore, it is logical to assume that the corneal refractive index shifts due to corneal
swelling according to Gladstone and Dale’s law [95]. Refractive indices are particularly
important in optical measurements such as pachymetry or automatic refraction because
these devices assume a refractive index that does not necessarily reflect the true refractive
index, especially in the case of swollen corneas [3,95].
Some authors have reported that the quality of vision improves over time as the trans-
parency of the cornea increases as the swelling process recedes [1,7,10,11,20,22,23,39,79].
Corneal edema thus leads to an overall reduction in spatial frequencies, resulting in a
significant loss of sensitivity acuity under mesopic conditions, which could be related
to the loss of transparency and an increase in light scattering in patients with corneal
swelling [3,10,23,80,94,96]. However, De Juan et al. [81] pointed out that significant refrac-
tive changes occur in the first week after cataract surgery and stabilize in the following
weeks. They also revealed that corneal edema causes a hyperopic shift due to corneal
swelling, although this effect diminishes within the first two weeks and changes to myopia
as the edema subsides, ideally approaching emmetropia.

4.4. Mechanical Trauma

Corneal edema is the most common side effect of ocular surgery, with a prevalence,
according to some authors, from 6.2% to 11.3% [36,37], most commonly after phacoemulsifi-
cation or keratoplasty in severe FECD [6,66,82,97]. Preoperative risk factors for phacoemul-
sification include a low endothelial cell density, which should always be greater than 1000
cells/mm2 , and corneal thickness, which should be less than 640 µm [5,20,35,42,47,82].
J. Clin. Med. 2023, 12, 6751 10 of 17

Precautions must be taken during phacoemulsification to avoid corneal edema caused

by trauma phacoemulsifiers, lens hardness, short anterior chamber depths, retained vis-
coelastic fragments of the lens, irrigating solutions and their temperature, phacoemul-
sification time and energy, IOL insertion, and the surgeon’s expertise, which is espe-
cially important in patients with pseudoexfoliation or previous endothelial damage (gut-
tae) [6,9,12,17,34,44,45,47,50,65,98,99].
Traumatic edema is regarded as edema that develops following surgery, in this
case, cataract surgery, as a result of excessive strain on the tissue or for other incidental
reasons [5,6,17,30,45,51,52,79,96,98]. The severity of the trauma determines the resolution
of the edema. Therefore, the loss of endothelial cells can result in penetrating damage
that is irreversible, impairing the pump function of this layer and, in severe cases, causing
stromal swelling or bullous keratopathy [20,31,34,86,96]. The most common intraocular
surgery in the world, phacoemulsification, can cause mechanical stress depending on the
technique used, the material used (size and shape), the use of intraoperative drugs, and the
experience of the surgeon [5,7,12,17,33,45,52–54,67,86].
The phacoemulsification technique, as was already mentioned, is an important point
in the development of corneal edema. According to some authors, microincision cataract
surgery (MICS) results in a smaller corneal incision, which has been shown to reduce wound
misalignment and to carefully preserve the corneal integrity after the cataract removal
procedure [13,46,53,55,56,99,100]. They reported fewer changes in corneal endothelial cell
loss, pachymetric parameters, and corneal edema over the short term, as well as fewer
induced corneal aberrations in the long term [13,55,56,82]. Other authors, on the other
hand, argue that there is no difference in these parameters between MICS and conventional
phacoemulsification [56,67].
Furthermore, it has been reported in the literature that the method of cataract surgery,
as well as the nucleus fracture and extraction techniques, have an effect on the onset of
postoperative corneal edema. Recent research indicates that phacoemulsification and extra-
capsular cataract surgery (ECCE), more specifically manual small-incision cataract surgery
(SICS), are both safe and effective procedures for restoring optimal visual performance in
cataract patients. The primary goal of phacoemulsification extraction techniques (including
pre-chop, stop-and-chop, divide-and-conquer, drill-and-crack, and soft-shell) is to tear
apart the nucleus using mechanical force with the energy released by the needle as it
buries itself inside the lens and to aspirate the cortex debris out of the eye. Some of these
techniques have demonstrated various benefits in terms of ultrasound power (USP) and
effective phacoemulsification time (EPT) in order to cause less endothelial cell loss. As a
result, these methods have been modified for the treatment of dense cataracts, which remain
a challenge in the cataract surgery process [24,28,32,35,38,49,54,100]. Zhao et al. investi-
gated this specifically, comparing reverse-chopper nucleus extraction in dense cataracts
to conventional stop-and-chop under the same conditions. The reverse chopper required
less EPT and USP, resulting in no ultrasonic energy released and thus less endothelial cell
damage with a lower prevalence of corneal edema following cataract surgery [28].
Epithelial edema may develop if topical anesthetics or ultrasonic vibration power
are used excessively during phacoemulsification [29,33,66]. Long-lasting surgery may
cause Descemet’s membrane to detach, which will result in stromal edema [7,83,84,101].
A low endothelial density or shallow anterior chambers have also been noted as risk
factors for postoperative edema development. In every situation, a thorough preoperative
examination is required. Additionally, abrupt changes in IOP may cause an increase in
stromal volume as a result of excessive water intake [17,41]. This hyperhydration causes
a hypertonic state that directly affects the endothelial pump’s ability to function, which
could account for glaucoma patients’ propensity to experience corneal swelling following
phacoemulsification [11].
J. Clin. Med. 2023, 12, 6751 11 of 17

4.5. Treatment
The treatment will vary according to the etiology, aiming to eliminate the underlying
pathology, if possible. The standard treatment for anterior segment inflammation and,
as a result, corneal edema caused by inflammation or infection is topical corticosteroids
[5,51,53,57–62,89,95,102].
During the inflammation process, lymphangiogenesis occurs, which is the inhibition
of lymphatic endothelial cell proliferation. Glucocorticoids inhibit corneal lymphangio-
genesis by suppressing the onset of pro-inflammatory cytokines and macrophage infiltra-
tion, as well as the proliferation of lymphatic endothelial cells [9,57,58,60]. Furthermore,
some research suggests that corticosteroids may activate the endothelial pump function,
thereby preventing corneal edema [53,59,60]. Corticosteroids, such as Dexamethasone,
should be used with caution in patients with high IOP values and low anterior chamber
penetration because they have been shown to raise IOP by 10 mmHg or more in these
patients [53,58,61,63]. Despite this, recent research indicates that Loteprednol, a modern
corticosteroid, is a safe option due to its low impact on IOP, though it is contraindicated in
viral, fungal, or mycobacterial infections. Increased and decreased IOP alters the pressure
in the stroma, leading to increased imbibition, corneal swelling, and increased corneal
thickness, all of which may affect the accuracy of Goldmann Applanation Tonometry (GAT)
measurements [71,85,103]. Sriram and Tai discovered that increased IOP causes fluids to
accumulate intercellularly within the cornea, resulting in epithelial edema [58,103].
Hypotony, on the other hand, only causes stromal swelling; although the mechanism
is unknown, it is thought to be caused by a tautness loss in the tissue. Furthermore, the
ocular tissues’ relaxation could result in folds in Descemet’s and Bowman’s layers [83,103].
The flow and composition of the fluids are altered in chronic hypotony, causing disruptions
in corneal metabolism, a lack of nutrient transport in the tissues, hypoxia, dysfunction of
the blood–aqueous barrier, and eventually, endothelial pump dysfunction [17,45,66,103].
Since a carbonic anhydrase inhibitor lowers pressure, it is prescribed when there is a high
IOP because it prevents corneal edema from developing by lowering IOP. Inhibiting the
carbonic anhydrase pump may have a direct effect on the stroma by decreasing outflow
from this layer to the anterior chamber, resulting in stromal hyperhydration, particularly in
eyes with compromised endothelial function [5,12,39]. Carbonic anhydrase, along with the
Na+/K+-ATPase pump, yields a pH buffer through which a lactate osmotic gradient drives
water out of the stroma and into the aqueous humor [5,12,18,21,37,86,91]. When hypotony
causes edema, it is usually a consequence of an over-filtering trabeculectomy and is less
likely to be chronic. The first case is treatable by resuturing the scleral flap or compressing
the conjunctival autograft once more [74]. The purpose of hypertonic solutions, also known
as hyperosmolar solutions, is to draw fluids out of the cornea, causing dehydration via
the osmotic gradient and increasing tear film tonicity in epithelial corneal edema and
restoring transparency [18,20,41,50,93,96]. To do so, the epithelium must be regular and
functioning properly, as it serves as a semipermeable membrane that allows only water to
pass while keeping the electrolytes in the cornea. As a result, the solutes do not penetrate
the epithelium completely or only partially, attracting diffusible water from the bullae and
preventing stromal hyperhydration.
Crosslinking (CXL) may be used as an alternative to keratoplasty in severe cases of corneal
edema, such as postoperative BK (PBK) and FECD, according to recent research [34,51,76,87]. CXL
is a photopolymerization technique that uses a photosensitizing substance like riboflavin
and UV light to induce additional crosslinks within the matrix of collagen fibers, increasing
corneal stiffness. Some studies suggest that CXL may compact the corneal stroma and
reduce swelling in edematous corneas by improving endothelial pump function or reducing
corneal hydration [51,72,76,87]. For example, Laborante et al. [72] treated six patients
with visually impairing corneal edema using CXL alone or with amniotic membrane
transplantation. They reported improved corneal transparency and visual acuity in all
patients, concluding that CXL could delay the need for keratoplasty. However, the effects
of CXL on corneal edema are not consistent across studies. Coskunseven et al. [73] found
J. Clin. Med. 2023, 12, 6751 12 of 17

no significant improvement in corneal transparency in seven patients with PBK treated

with CXL. Additional randomized controlled trials are warranted to further evaluate
the efficacy of CXL for managing corneal edema before it can be recommended as a
standard therapy.
Additionally, therapeutic contact lenses are typically used to relieve discomfort or
improve vision when there are epithelial irregularities or keratopathies, such as bullous
keratopathy [5,6,72]. Nowadays, either rigid or silicone hydrogel soft contact lenses are
hypoxia-safe, and the prescription varies depending on the case. Despite their comfort,
rigid contact lenses increase oxygen transmissibility and smooth the corneal surface from
higher irregularities. It is sometimes necessary to prescribe therapeutic contact lenses in
conjunction with antibiotics to prevent contact-lens-induced infections, especially when soft
contact lenses are prescribed. Contact lenses should be worn carefully to avoid lens-induced
hypoxia, which can result in excess lactate and protons (stroma), as well as inflammatory
eicosanoids (epithelium), according to some studies [11,18,71,72]. Both protons and lactate
function as osmotic stimulants and change the pH of the stroma directly, which decreases
endothelial pump activity and starts the process of corneal swelling [11,18,22,68,73,91].
In addition to these assertions, due to the importance that oxygen has in achieving
normal corneal metabolic function and visual performance, current research has shown
that postoperative eye patching may cause corneal edema and a slower pace of visual
recovery due to oxygen shortage after successful cataract surgery [11,39].

5. Conclusions
This thorough review of the literature offers a comprehensive exploration of the realm
of corneal edema. Notably, endothelial cells take center stage in maintaining the delicate
balance of corneal transparency and hydration. As confocal microscopy becomes a clinical
standard, endothelial cell density emerges as a predictive factor for post-surgical corneal
swelling. In contrast, changes in pachymetry, alongside subjective observations through
biomicroscopy, stand as significant objective markers for corneal edema progression.
Despite the wealth of knowledge accumulated, a puzzling aspect persists. Corneal
edema significantly impacts visual performance by affecting aspects such as visual acuity
and contrast sensitivity. However, a notable uncertainty looms: What precisely is the
impact of corneal swelling on an individual’s vision? The permanence or transience of
these changes remains a question mark.
Intriguingly, the prevailing classification of edema remains largely subjective, raising a
pertinent concern, particularly in the context of subclinical corneal swelling. This subjective
nature underscores the challenge of achieving a consensus, especially in instances where
subtlety is paramount.
As we navigate this complex landscape, these questions guide us toward a deeper under-
standing of corneal edema’s implications and the quest for standardized assessment methods.

6. Study Limitations
This systematic review avoided time constraints by including a wide range of studies
up to December 2022. On the other hand, bias may have occurred in the language of the
selected articles, although this systematic review included languages other than English.
However, the degree of heterogeneity among the included studies was high, so a possible
publication bias could not be excluded. Finally, a publication bias could also be present,
as the studies included in this work were found using filters such as “pair-reviewed”. In
addition, positive or statistically significant results are more likely to be published than
studies with negative or non-significant results. These limitations highlight the need for
further research in this area.
J. Clin. Med. 2023, 12, 6751 13 of 17

Author Contributions: This study was designed by C.B.-L., N.B.-G., M.A.D.-A., M.C.G.-D., M.J.L.
and C.P.-M. The methodology, software, data curation, and resources were performed by C.B.-L.
and N.B.-G. Writing—original draft preparation, C.B.-L.; writing—review and editing, all authors;
visualization, all authors; supervision, M.A.D.-A., M.C.G.-D., M.J.L. and C.P.-M. All authors have
read and agreed to the published version of the manuscript.
Funding: This study was supported by the following foundations: Alcon-FOM-UVEG Cathedra,
Foundation of Ophthalmology Medicine, and Universitat de València.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The datasets produced and/or analyzed in the course of this study are
accessible upon a justified request to the corresponding author.
Acknowledgments: The authors would like to thank the Cathedra Alcon-FOM-UVEG from the
University of Valencia for their support.
Conflicts of Interest: The funding organizations had no role in the design or conduct of this research.
None of the authors have financial disclosures related to this manuscript.

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