Advanced Visualization In Corneal Surgery Evaluation: Intra-operative Optical Coherence Tomography in posterior lamellar keratoplasty

Fuchs endothelial corneal dystrophy (FECD) is a hereditary progressive and
irreversible corneal disease. It is one of the leading corneal visual impairing
diseases in the industrialised world and accounts for 39% of the corneal
transplants worldwide. The disease is characterized by the gradual loss of
corneal endothelial cells, which play a crucial role in the fluid exchange of
the cornea and thus maintaining the clarity of the cornea. The precise etiology
is unknown, but multiple factors play a role in developing the disease. The
main long term therapy is to replace the affected endothelium with healthy
donor endothelium by means of corneal transplant surgery. The current standard
of care is a posterior lamellar keratoplasty. This technique leaves the main
structure and stability of the cornea intact. Currently, two techniques are in
widespread use. The Descemet Stripping Endothelial Keratoplasty (DSEK) and the
Descemet Membrane Endothelial Keratoplasty (DMEK), the latter being considered
superior in terms of visual recovery but less feasible in advanced cases with
marked corneal clouding. Technically, the host endothelium and Descemet*s
membrane are removed after which a folded lamellar graft is inserted in the
eye. With cautious use of air and fluid, this graft is centralized, unfolded,
and adhered to the host cornea. The delicacy of the tissue makes it vulnerable
to endothelial damage through manipulation of the graft. A major complication
is when the graft detaches from the recipient. This complication requires a
second surgery were air is again injected to re-adhere the graft. In some cases
a new transplant is required. Why this complications occurs is presumably
multifactorial. Adherence issues due to fluids between the donor and recipient,
insufficient air/gas pressure, and trauma of the graft have been proposed. To
promote graft adherence several techniques, like venting incisions, corneal
swiping, and post-operative pressurising of the eye have been described. There
is no consensus about the best approach for graft adhesion and the
over-pressurizing the globe has been widely discussed. It is unknown if the use
of overpressure improves graft adherence or only eliminates interface fluid.
Furthermore, manipulation of the graft could damage the graft and lead to
complications. Several studies investigated the use of overpressure to
eliminate interface fluid during DSAEK surgery with iOCT imagery. It was found
that theoretically the period of applied overpressure could be shortened to 1
to 3 minutes if guided by iOCT. However, these were retrospective evaluations
and shortened time was based on the residual interface fluid observed on the
iOCT image. No head-to-head comparison of overpressure has been performed, and
period of applied overpressure varies widely between clinics.

Ocular surgery, including corneal transplant surgery, is routinely performed by
specialists using an operation microscope. A recent development is the addition
of intraoperative optical coherence tomography (iOCT). iOCT enables the surgeon
to visualise the corneal structure in a cross-sectional plane with micrometer
resolution. The tabletop/office configuration of optical coherence tomography
(OCT) is already a widely used ophthalmic imaging technique. It uses the
reflection of infrared light from ocular tissues to form an in-depth image.
Incorporation of OCT during surgery can give the surgeon a better visualisation
of the tissues in a way previously impossible. For instance, the infrared light
is not absorbed by a cloudy cornea. This makes more advanced cases of
endothelial cell dysfunction amenable to lamellar surgery.

Crucial in DMEK surgery is a correct orientation of the graft. If the graft is
adversely oriented upside down (i.e. with the endothelium towards the recipient
stroma) the endothelial cells of the graft are destroyed requiring a new
transplant. The orientation can be determined using the so-called *Moutsouris-
sign*. However, the presence of this sign is not self-evident, especially not
in cloudy corneas, and in some cases requires (extensive) manipulation of the
graft. The use of iOCT gives the surgeon a proper visualisation of the
donor-host interface, which could reduce post-operative graft dislocations and
avoid unnecessary manipulation of the graft. The use of OCT in ocular surgery
is still an upcoming field, though evidence emerges that iOCT is helpful in
surgical decision making: The PIONEER study reported that in 38% of surgeries
the surgeon made a different critical surgical decision based on the iOCT
image. However, it is not self-evident that the iOCT leads to a better surgery
and fewer adverse events. The improved ability to visualize the graft with iOCT
could also lead to more rigorous manipulation.

The availability of iOCT enables a safe investigation of the need of
overpressure, the efficiency of tissue manipulations, and the overall clinical
utility of iOCT in posterior lamellar surgery. This is relevant since a high
intraocular pressure during surgery has several important disadvantages. The
high intraocular pressure temporally reduces the oxygenation of the optic
nerve and retinal tissues. This may cause damage specifically to the optic
nerve head, retinal nerve fibre layer and may aggravate pre-existing glaucoma
Additionally a high ocular pressure is a nauseating and painful experience from
a patients perspective. Refraining from over-pressurizing the eye will also
reduce the net surgical time. In a pilot study we achieved a mean reduction in
surgical time of 25%, which is directly relevant for patients who undergo
complex eye surgery under local anaesthesia.

The access to iOCT technology (LUMERA 700 RESCAN, Carl Zeiss GmbH, Oberkochen,
Germany) at our institution prompted us to investigate an iOCT optimized
surgical protocol and evaluate the clinical value of iOCT for posterior
lamellar surgery in a randomized clinical trial. Currently, iOCT is not
standard of care, and the promise that iOCT improves surgical outcomes is not
yet evaluated in a clinical trial. Will an iOCT optimzed protocol actually lead
to a shortened surgical time without compromising the safety of the procedure?
A decrease of adverse events, less endothelial cell damage, and fewer
manipulations are all factors that can contribute to the survival of a graft,
quality of vision, and patient satisfaction.

Primary Objective:
The aim of this study is to assess the clinical value of intraoperative OCT
(iOCT) for Descemet Membrane Endothelial Keratoplasty (DMEK) by comparing an
iOCT-optimized surgical protocol (iOCT-p) with the current practice (CP-p),
where the eye is over-pressurized for 8 minutes.

The primary research question is;
1. Does the surgical protocol effect the rate of surgical complications;
specifically graft detachments, early graft failures, or induced iatrogenic
acute glaucoma?

The secondary research questions are;
1. Does the iOCT-optimized surgical protocol actually lead to a reduction in
surgical skin-to-skin time compared to current practice?
2. Does refraining from over-pressurizing effect post-operative visual
recovery, and best-corrected visual acuity at 3 and 6 months follow-up.
3. Does refraining from over-pressurizing the eye effect graft endothelial cell
loss measured at 3 and 6 months follow-up, and is the rate of endothelial cell
loss influenced by the surgical protocol?
4. To what extent (amount/duration) are surgical manipulations necessary for a
proper graft positioning and is this influenced by the application of iOCT?
*

The design of the study is a prospective, international, multi-center,
non-inferiority, randomized controlled interventional clinical trial to compare
the outcomes after posterior lamellar surgery with an iOCT optimized surgical
protocol, and current practice, where the eye is over-pressurized for a set
period of time. These groups will be labelled iOCT optimized protocol (iOCT-p)
and current practice protocol (CP-p).

In the iOCT optimized protocol the iOCT will be used to guide manipulation,
such as overpressure and corneal swiping. The classic protocol will be
performed if as no iOCT was present, including overpressure. At the end of
surgery iOCT assessment will be performed and if necessary additional
manipulations will be performed.

Measurements and examinations are performed before and at 3 and 6 months after
the intervention. Some of the measurement are already performed during the
follow-up care, but are taken more frequent. The ophthalmic examinations are
non-invasive, have no side effect and take a few minutes to perform. In
addition patients will be asked to fill in quality-of-life questionnaires and
additional measurements. It is not anticipated that study participation implies
an increased risk for surgical adverse events or poorer clinical outcomes. It
is conceivable that some factors that contribute to graft detachment can be
assed better with the iOCT.The additional measurements will take approximately
45 minutes of additional time.