CONTENTS
PAGE NO. TITLE
07 From the President’s DESK
08 From the DESK of Chief Editor
09 From the DESK of Managing Editor
10 Guest Editorial
17 Recent Advances in Small Incision Lenticule Extraction
25 Advances in Keratoconus : Imaging, Therapeutics and Beyond
41 Overview of Simple Limbal Epithelial Transplantation for Ocular Surface Reconstruction
47 Recent Advances in Endothelial Keratoplasty : Evolution of Excellence
54 Recent Advances in Pharmacotherapy for Glaucoma
64 Multimodal Imaging in Polypoidal Choroidal Vasculopathy : A Novel Imaging Modality
71 Recent Advances in Retinal Imaging
79 Biologics in the Treatment of Uveitis
86 Energy Based Devices & Their Use in Oculo-Facial Plastic Surgery
89 Recent Advances in Amblyopia Therapy
94 Innovative Ideas in Ophthalmology : Our Needs Our Call
97 Financial Management for Doctors
99 “Boom-Boom” Radiotherapy for Ocular Adnexal lymphoma - How low can we limbo?
102 Intra-lenticular Lens Aspiration in Anteriorly Dislocated Lens in Paediatric Eyes
106 Current Concepts in Refractive Surgery : Comprehensive Guide for Decision Making and Surgical Techniques
107 CM-T Flex Scleral Fixated Intraocular lens
109 Visual Outcomes and Optical Quality after Implantation of Multifocal Intraocular Lens
DOS EXECUTIVE MEMBERS (2021-2023)
DOS Office Bearers
Dr. Pawan Goyal Dr. Jatinder Singh Bhalla Dr. Alkesh Chaudhary
President Secretary Treasurer
Dr. Rajendra Prasad Dr. Sandhya Makhija Prof. Kirti Singh Dr. Jatinder Bali
Vice President Joint Secretary Editor Library Officer
Executive Members
Dr. Om Prakash Anand Dr. Gagan Bhatia Dr. Vivek Gupta Dr. Vivek Kumar Jain
Dr. Prafulla Kumar Maharana Dr. Amar Pujari Dr. Bhupesh Singh Dr. Pankaj Varshney
DOS Representative to AIOS Ex-Officio Members
Prof. Jeewan S. Titiyal Prof. M. Vanathi Prof. Subhash C. Dadeya Prof. Namrata Sharma
www.dosonline.org/dos-times
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DOS Times - Volume 28, Number 1, January-February 2022
Know Your Editor
Dr. Jatinder Singh Bhalla
MS, DNB, MNAMS
Hony. General Secretary
Delhi Ophthalmological Society
DDU Hospital, Hari Nagar
Chief Editor DOS Times
Dr. Prafulla Kumar Maharana, MD
Associate Professor of Ophthalmology
Dr. Rajendra Prasad Centre for Ophthalmic
Sciences, AIIMS, New Delhi
Managing Editor DOS Times
Prof. (Col) Sanjay Kumar Mishra, Dr. Raghav Malik, MS Dr. Deepankur Mahaja
HOD, Dept of Ophthalmology Fellowship Cataract & MBBS, MD (AIIMS), FICO, FAICO
(vitreo retina surgeon), Army Refractive Surgery (Retina and Vitreous)
Hospital (R&R) Associate Consultant Consultant Ophthalmologist and
Dept of Cataract, Cornea & Vitreoretina Specialist, New Delhi
Section Editor - Retina & Uvea Refractive Services, CFS, New Delhi
Section Editors - Retina & Uvea
Section Editor - Retina & Uvea
Dr. Naginder Vashisht
Dr. Rushil Kumar Saxena Dr. Ankur Singh MD, FRCS, FICO
Dept of Vitreoretina Assistant professor Director & Senior Consultant
Dr. Shroff’s Charity Eye Hospital, Dept of Ophthalmology Ophthalmology, Kailash Eye Care,
New Delhi University College of Medical Patel Nagar, New Delhi
Sciences and GTB Hospital, Delhi Senior Consultant Ophthalmology,
Section Editor - Retina & Uvea Artemis Hospitals, Gurugram
Section Editor - Retina & Uvea
Section Editor - Uvea & Ocular
Inflammatory Disorders
Dr. Prateek Kakkar Dr. Aman Kumar Dr. Sameer Kaushal
(Retina Specialist), MD MD, Senior Resident Senior Consultant & Head
Ex-Senior Resident (Vitreo-retina, Vitreo-Retina, Uvea, ROP services (Ophthalmology)
AIIMS, New Delhi) Dr. R P Centre for Ophthalmic Sciences Artemis Hospital and PL Memorial
AIIMS, New Delhi Eye Clinic, Gurgaon
Section Editor - Uvea & Ocular Section Editor - Uvea & Ocular Section Editor - Cornea & External
Inflammatory Disorders Inflammatory Disorders Eye Disease
Dr. Abha Gour Dr. Ritu Nagpal Dr. Parul Jain
Senior Consultant Cornea and MD, Senior Research Associate MBBS, MS, FICO, FAICO, MRCSEd
Anterior Segment Dr. R P Centre for Ophthalmic Sciences, Associate Professor
Dr. Shroffs Charity Eye Hospital, AIIMS, New Delhi GNEC, Maulana Azad Medical College
New Delhi
Section Editor - Cornea & External Section Editor - Cornea & External
Section Editor - Cornea & External Eye Disease Eye Disease
Eye Disease
DOS Times - Volume 28, Number 1, January-February 2022 04 www.dosonline.org/dos-times
Dr. Rajat Jain Dr. Jaya Gupta Dr. Abhishek Dave
MBBS, MS (Gold Medalist), FICO (UK) Consultant Cornea Cataract & Consultant Cornea, Cataract &
Fellow- Cornea and Anterior Refractive Surgery Refractive Surgery - CFS, New Delhi
Segment- LVPEI Hyderabad The Healing Touch Eye Care
Centre, New Delhi Section Editor - Ocular Surface
Section Editor - Ocular Surface
Section Editor - Ocular Surface
Dr. Neeraj Verma Dr. Amrita Joshi Dr. Ritin Goyal
MS (Ophthal) Assistant Professor Director & Cornea, Cataract and
Senior Consultant Department of Ophthalmology LASIK surgeon at Goyal Eye Group
Centre For Eye Care Army Hospital (R&R) of Eye Centers.
Kirti Nagar, New Delhi
Section Editor - Ocular Surface Section Editor - Cataract &
Section Editor - Ocular Surface Comprehensive Ophthalmology
Dr. Amit Mehtani
Dr. Wangchuk Doma MBBS, MS, DNB Dr. Manpreet Kaur
Venu Eye Institute and Research DDU HOSPITAL MD, Assistant Professor
Centre. Cornea, Cataract & Refractive Surgery
Section Editor - Cataract & Services
Section Editor - Cataract & Comprehensive Ophthalmology Dr. R P Centre for Ophthalmic Sciences
Comprehensive Ophthalmology AIIMS, New Delhi
Section Editor - Refractive Surgery
Dr. Pranita Sahay, MD Dr. Rwituja Thomas Grover Dr. Jyoti Batra
(AIIMS), FRCS (Glasgow), Consultant Oculoplastics, Orbit, Consultant, Oculoplasty and
DNB, FICO, FICO (Cornea), Ocular Oncology and Aesthetics Ocular Oncology, ICARE Eye
FAICO (Ref Sx) services, Vision Eye Centres, Hospital and Post graduate
Consultant, CFS, New Delhi New Delhi Institute, Noida
Section Editor - Refractive Surgery Section Editor - Oculoplasty & Asthetics Section Editor - Oculoplasty & Asthetics
Dr. Anuj mehta Dr. Kiran Bhanot Dr. Suneeta Dubey
Consultant and Professor MS, DNB Head - Glaucoma Services
Vardhman Mahavir Medical College Senior Consultant & Hod GGS Medical Superintendent
and Safdarjung Hospital Hospital & Indira Gandhi Hospital, Chairperson - Quality Assurance
Dwarka, New Delhi Dr. Shroff’s Charity Eye Hospital
Section Editor - Oculoplasty & Asthetics New Delhi, India
Section Editor - Glaucoma Section Editor - Glaucoma
Dr. Kanika Jain Dr. Shweta Tripathi Dr. Prathama Sarkar
MBBS, MS, DNB DNB, MNAMS, FMRF Consultant in Eye7
Senior Resident, Dept of Ophthalmology, Senior Consultant Glaucoma Chaudhary Eye Centre
DDU Hospital, Hari Nagar, New Delhi. Services
Indira Gandhi Eye Hospital and Section Editor - Glaucoma
Research Centre, Lucknow
Section Editor - Glaucoma Section Editor - Glaucoma
Dr. Kavita Bhatnagar Dr. Rebika Dhiman Dr. Amar Pujari
Professor & Head, Dept of Assistant Professor Assistant Professor
Ophthalmology, AIIMS, Basani Strabismus and Neuro- Dr. R P Centre for Ophthalmic
Phase-2, Jodhpur Ophthalmology services, Sciences, AIIMS, New Delhi
Dr. R P Centre, AIIMS, New Delhi
Section Editor - Glaucoma Section Editor - Neuro-Ophthalmology
Section Editor - Neuro-Ophthalmology
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DOS Times - Volume 28, Number 1, January-February 2022
Dr. Sumit Monga, Dr. Paromita Dutta Prof. Swati Phuljhale
Senior Consultant. Pediatric, Associate Professor Dr. R P Centre for Ophthalmic
Strabismus and Neuro-Ophthal- Guru Nanak Eye Centre Sciences, AIIMS, New Delhi
mology Services, CFS group of Maharaja Ranjit Singh Marg
Eye Hospitals, Delhi-NCR New Delhi Section Editor - Strabismus
Section Editor - Neuro-Ophthalmology Section Editor - Strabismus Dr. V Rajshekhar
MS, FICO
Dr. Gunjan Saluja Dr. Suraj Singh Senjam Professor & Consultant
Ex SR Strabismus, Oculoplasty and Community Ophthalmology Dept of Ophthalmology
Neuro-ophthalmology services, Dr. R P Centre for Ophthalmic VMMC & Safdarjung Hospital,
Dr. R P Centre, AIIMS, New Delhi Sciences, AIIMS, New Delhi New Delhi
Section Editor - Strabismus Section Editor - Community Ophthalmology Section Editor - Community Ophthalmology
Prof. Bhavna Chawla Dr. Sima Das Dr. Vineet Sehgal
Professor of Ophthalmology Head, Oculoplasty and Ocular MBBS, MD
Dr. R P Centre, AIIMS, New Delhi Oncology Services Fellowship in Glaucoma
Incharge, Medical Education Senior Consultant & Incharge
Section Editor - Ocular Oncology Dr. Shroff’s Charity Eye Hospital Glaucoma Sharp Sight Eye Hospitals
New Delhi
Section Editor - Residents Corner
Section Editor - Ocular Oncology
Dr. Digvijay Singh
Affiliation, Noble Eye Care,
Gurugram
Section Editor - Residents Corner
Congratulations
Dr. Sadhu Ram Gupta (DOS MEMBER) against whose name an Oration has been
started.
The Royal College of Ophthalmologists Examinations department is delighted
to announce the first-ever winner of the Dr. Sadhu Ram Gupta MBE Award for
International (non-UK) Examination Candidates.
DOS Times - Volume 28, Number 1, January-February 2022 06 www.dosonline.org/dos-times
DOS TIMES
From the
President’s DESK
Dr. Pawan Goyal Dear Friends and Colleagues,
We are pleased to send first issue of DOS Times, whose theme is advances &
MBBS, MS innovations.
I would like to congratulate the editorial team and our dynamic Secretary Dr. Jatinder
Singh Bhalla for bringing out this excellent issue on topic of utmost importance. There
are very informative articles written by some eminent Ophthalmologists from all over
the country.
Our Executive have started many innovative academic activities like DOS VT (Video
teaching programme) & DOS Quiz which are organised on Monthly basis.
I would like to invite each one of you to the Mid Term DOS conference which is first
major Ophthalmic conference held physically – PostCovid.
This Executive is starting its tenure & I am fortunate to lead this dynamic team.
Wish each one of you a pleasant reading.
Dr. Pawan Goyal
President, DOS
Chairman Goyal Eye Institute, Delhi
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DOS Times - Volume 28, Number 1, January-February 2022
DOS TIMES
From the DESK of
Chief Editor
If we don’t change, we don’t grow. If we don’t grow, we don’t progress.
Dr. J S Bhalla, NEW TEAM, NEW BEGINNING, NEW HOPE, NEW DREAM
As the new year begins DOS embarks on a new beginning with the freshnew ideas of a dynamic
MS, DNB, MNAMS executive. I’m fortunate to have an energetic team of talented and hard working executive
Secretary members, headed by our president Dr. Pawan Goyal. I shall leave no stone unturned to propel
DOS to glorious heights. I look forward to unmatched enthusiasm, support of all DOS members
Delhi Ophthalmological Society and blessings of the seniors.
The upsurge of COVID cases, difficult COVID times, insecure environment, rising competition
from other societies, uncertainties faced by trade leading to decrease revenue generation has
made the task in hand more challenging but this DOS leadership and executive is competent and
capable of doing its best to tackle the situation head on.
DOS Times, is one of the most popular Ophthalmic magazines. I am humbled to introduce
myself as the new editor in chief of DOS times. DOS times 2021 to 2023 dawns a new refreshing
look. Besides the articles, we are adding some additional features, like DOS quiz, sponsored
article, interesting cases by residents, book review, news and reports from major institutions
and section on Beyond Ophthalmology. This first issue of DOS TIMES 2021-22 is devoted
to compilation of excellent academic topics on the theme of Advances & Innovations from
renowned authors across the country. We welcome suggestions and feedbacks to make DOS
times more informative and useful for all. I hope to bring novel ideas to benefit all sections
of DOS members.
DOS Academic programme has been kick started with video-assisted teaching program by
Prof. J S Titiyal for residents/practitioners on 29/01/22. After starting our Monthly meetings in
Virtual mode at Shroff Charity & RR Hospitals, we shifted to physical meeting at DDU Hospital.
We have added Monthly Quiz & Monthly Video based teaching programne which have become
huge hits.
As a step towards normalcy, we have planned our Mid Term Conference physically & are
pleasantly surprised by the huge enthusiastic response of Delegates & Trade.
Tough times don’t last, tough people do. Efforts will lift DOS up to where we belong.
Where the eagles soar on a mountain high.
Let us drive to reach where we belong.
Far from the world we know,
up where the clear winds blow.
Dr. Jatinder Singh Bhalla, MS, DNB, MNAMS
Chief Editor - DOS Times,
Consultant & Academic Incharge (Ophthalmology)
DDU Hospital, Hari Nagar
DDOOSSTTiimmeess--VVoolluummee2288,,NNuummbbeerr11,,JJaannuuaarryy--FFeebbrruuaarryy22002222 0088 wwwwww..ddoossoonnlliinnee..oorrgg//ddooss--ttiimmeess
DOS TIMES
From the DESK of
Managing Editor
Dr. Prafulla Kumar It’s a great pleasure on my part to bring out this edition of DOS Times. As the medical field
Maharana, MD is gradually coming out of the tentacles of corona virus, we wanted to come out with all the
advances happening around in the field of Ophthalmology. Also, we wanted to highlight
significant contribution by individual researchers in the field of Ophthalmology.
The guest editorial on DMEK with supplementary video will be extremely useful for
the readers to learn the technique of DMEK. Articles on multimodal imaging, diabetic
retinopathy will help the readers to their day to day clinical practice. An update on glaucoma
medications and management, spectacle prescription in myopia, immunomodulator
therapy, and ocular oncology will add on to the knowledge of the readers.
The addition of sections like “Book Review” and “Article Review” will update the readers
about the new developments in the field. Summary of various programs conducted by
DOS in last two months will help the readers to know the ongoing activities of Delhi
Ophthalmological Society.
Change is an essential part of improvement over time. In spite of all our efforts there will
definitely be scope for improvement in future. I would request the readers of this edition to
convey us through whatever possible means their valuable suggestions and help us improve
further.
Dr. Prafulla Kumar Maharana, MD
Managing Editor DOS Times,
Associate Professor of Ophthalmology
Cornea Cataract & Refractive Services
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi
Email : [email protected]
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Guest Editorial
“1000+ DMEK: Lifelong Learning”
Dr. Samar K Basak, Lifelong learning is the ‘ongoing, voluntary, and self-motivated’ pursuit of knowledge for either personal
or professional reasons. It is important for an individual’s competitiveness.
MD, DNB, FRCS Descemet membrane endothelial keratoplasty (DMEK) described by Melles et al in 2006 has
Disha Eye Hospitals, dramatically changed the way we treat endothelial dysfunction for any etiology.[1,2] Every week,
Barrackpore, Kolkata I perform about 6 to 8 DMEK procedures. Some of the cases, it is on the second eye of Fuchs’
dystrophy patients after treating their first eye about a month back. DMEK provides quick unaided
visual recovery, allowing faster sequential bilateral surgery, whereas when penetrating keratoplasty
(PK) was the only option, bilateral transplants were typically spaced over a year or more apart.[3]
First DMEK in Current Series
30 April 2016: I performed my first case of DMEK in this series of 1000+ procedures. She was a
pseudophakic bullous keratopathy (PBK) patient with round pupil with normal anterior chamber
anatomy and the IOL was in-the-bag. A perfect recipient. The Cornisol-preserved donor cornea was
from 70-year-old with cell count of 2650/mm2. 35-minutes surgery went uneventful. Postoperatively,
after 7 days, vision improved from 20/400 to 20/30. That was dramatic!
A Short Flashback
October 2015 to February 2016: I was in 3 different conferences, when I heard many young colleagues
presenting papers and sharing their experiences on DMEK in instruction courses. The fervour with
which these young ophthalmologists talked about the benefits of the techniques inspired me to look
deeper. I was fifty-seven at that time, and I decided if there was a time to master a new surgery, it was
now.
As soon as I was back in Barrackpore, I started following Melles’ lecture series as well as instruction
courses in different international forums. After watching a number of YouTube videos, I began to
practice in Wet Lab by myself. This went on for many weeks. I was also working on S-stamp on DM
side to eliminates iatrogenic primary graft failure owing to upside-down implantation of DMEK
grafts. At that time, Veldman et al published his article on “S-stamp” in Ophthalmology.[4] A kind of
co-incidence. In fact, this S-stamp or F-stamp has made DMEK surgeons’ life easy.
A Long Flashback
To be honest, my first tryst with DMEK was not in 2016. I had performed my first ever DMEK in
2009, but without much understanding of its basics. In fact, that year, I had received the “Best of
Show” and “Best Poster” Award from American Academy of Ophthalmology (AAO) Annual meet-
ing at San Francisco for my DMEK related little works. I did few more procedures and unfortunately,
the failure rate was very high. Disheartened, I had given up. In any case, all the patients were private
paying patients and I was doing excellent Manual DSEK at that time. I thought it would be wise
and practical to stick to what I did best. In 2013, again, I tried to get back into the DMEK game. I
performed 5 cases, again 4 of them failed. Probably, the cause of primary failure was reverse attach-
ment and more manipulation of tissue during unfolding. So, I was again back to manual DSEK and
DSAEK.
But I do not believe in quitting. So, all this while, at the back of my head, I kept introspecting about
my failures after watching all my videos: what exactly was I doing wrong? Was my only option to
enroll in an expensive course abroad and be mentored by someone else? As much as I did not believe
in quitting, I also believe in the power of knowledge and in our individual capacity to learn. Failures
are indeed the pillars of success. Another saying that never gets old: try and try again, and you will
succeed.
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Back to 2016: The Next 6 Months
Otherwise, being a volume EK surgeon, I used to perform 150-180 DSEK procedures in a year. Between April and Oct 2016 – in
six months, I performed only 33 DMEK procedures and 55 DSEK procedures. One primary donor failure and 6 DM detachments
managed by rebubbling, but otherwise happy-happy situation. Many doubts and problems and tried to discuss them with our
colleagues. But I was not comfortable in many cases.
But, then after attending AAO-2016, Chicago, I got the most valuable practical tips from Prof. David Rootman, Toronto, Canada.
That was so nice of him. I spent almost 2 hours with him. And since then, the understanding about DMEK procedure as a whole was
much easier. In Nov-Dec 2016 – in two months - I did perform 39 DMEK procedures! Then I never looked back and never thought
about DMEK failures. Published my first 100 cases in open Ophthalmology journal.[5]
Unlearning is a great part of learning. As much as failure is. I have learnt and unlearnt several things, and I would like to share them
with my fellow DMEK enthusiasts: Please watch the minimally edited DMEK videos. https://youtu.be/i0Zc7BwyyjU
Preparing the DMEK graft
In India, all surgeons prepare their own DMEK graft unlike in the Western world where eye bank prepares the DMEK-graft for the
surgeons. I recommend practicing the graft preparation procedure with relatively healthy cornea (medically contraindicated tissue)
in the Wet lab at least 15 times before you perform in the operating room.
Choose 60-70 year aged donor Tissue: Old is gold. It is thicker, more resistant to tear, DM separates easily and unfolds quickly
and mostly in right orientation.
Create a liftable edge: A variety of methods allow for creation of a liftable edge of DM-Endothelial layer. I find, it is best after
9.5 to 10.0 mm light trephination. Then stain the graft with trypan blue. Using a fine blunt hook (may be Sinsky’s hook) loosen
the inner edge by lifting it all the way 360-degree around reduces the chance of tearing the DM.
Stain the loosened edge: for better visualization.
Strip the tissue: Though SCUBA technique is popular, I prefer trypan blue assisted stripping of the DM with McPherson
forceps by one hand. Fix the cornea with Colibri forceps in other hand if required. Start at 6 ‘o’ clock position by gentle stripping
and mild side-to-side movement to strip up to 90% area with a hinge of 1.5 to 2.0 mm.
Stromal window: Make a 2.5-3.0 mm paracentral stromal window. Float back the DM. Flip the whole donor cornea.
‘S’ stamping: Dry the well and DM surface with PVA sponge. Mark DM-side with S- or F-stamp. Try to create a thinner stamp
by drying the gentian violet ink on the gloves. Flip back the cornea and put a drop of BSS to prevent drying.
Before punching - size it right: Measure the patient’s white-to-white diameter before choosing right donor punch size. A large
donor graft might get stuck in a small eye, and it is difficult to see the edges behind a very dense arcus. Correct sizing and proper
centring is required so that the side ports should not be covered. Also, it is important for air/gas injection, for burping of air
after surgery or for rebubbling is needed.
Punch Eccentrically if possible: We have published our results on Eccentric trephination of DMEK graft and compared it with
central trephination.[6] DMEK-pD is a new concept of using superior peripheral eccentric donor tissue as DMEK-graft. It is to
give more without changing the surgeon’s technique and comfort level. The ECD after 6 months and one year was statistically
significant.
Final stain: for 1-2 minutes are sufficient in most of the cases. In case of very cloudy corneas you need little darker stain.
Shifting in a petri dish and loading in the injector system: It is preferable to shift the graft in a small petri dish so that you
can observe the scroll pattern then load the graft in an injector system which is then ready for transfer into recipient anterior
chamber.
Recipient Preparation: Almost similar to DSEK/DSAEK with some differences:
Speculum: I prefer thinner wire speculum. Heavier speculum may give pressure on eyeball, causing vitreous upthrust which
may create problem during injection and unfolding of the DMEK-graft.
Incisions: I prefer 3.0 mmm posterior limbal main incision and two side-port incisions with 15-degree blade. I mark the side-
ports with gentian violet for better visualization.
Descemetorhexis: As a rule it is 0.5 mm larger than the graft size. It may be best ‘under air’ or cohesive OVD. Remove all the
irregular tags which may be visualized better under air.
Wash and intracameral pilocarpine: Be sure to remove the all viscoelastic by adequate BSS wash before implanting the graft.
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Constrict the pupil with intracameral pilocarpine.
Inferior PI: I prefer to do it by a vitrector. Externally, it can be done via inferior side-port. Check the patency of the inferior PI.
After PI immediate full chamber air injection: This is to stop bleeding from PI site and also to reduce corneal edema.
At this point I prepare tissue: As described above. For first 15-20 cases, prepare donor tissue first before surgery or even before
giving peribulbar block. Later on, at this point graft preparation saves time which usually takes 4-6 minutes.
AC reformation with BSS: Give a repeat through BSS wash before transfer the graft. Look for small blood clots or fibrin thread
at this time which may be sticky at times and may entangle with the the graft and then unfolding will be very difficult or even
the graft may be damaged.
Transferring the DMEK Graft:
Lift the lateral part of speculum with a soaked gauze-piece: This helps in two ways: firstly, it reduces pressure on the globe
and, secondly, if there is accidental expulsion of the graft via main port, it rests on gauze-piece and still you can use that graft.
Otherwise, it may go to drain.
Many ways to transfer the graft: I prefer IOL cartridge and it does not cost anything and every day I use a new one. I make
AC little shallower before insertion of IOL cartridge. I place the cartridge into the incision with the bevel facing downward and
insert the tube all the way into the anterior chamber. If required, I release little BSS via the left paracentesis. You can visualize
the orientation of the S-stamp before injecting it and rotate the cartridge accordingly just before injection. I have made a video
“Scroll-y-tales” and presented in the AAO meeting in 2018.
Stitch the main incision: to prevent expulsion of the graft during the manoeuvre of graft unfolding.
Check the orientation of the graft: If you are sure, then tap to unfold it. If not, then deepen the chamber and recheck the orientation.
Quickly but gently tapping in paracentral area to create small fluid waves within the anterior chamber. As the donor starts to
unscroll, you can see fluttering at the edge.
If the graft is upside down: Give a quick flush of BSS at the iris level so that the donor graft rotates 180-degrees to the correct
orientation.
Unfold the graft:
Universally, I think, the hardest part of DMEK is learning how to unfold or unscroll the graft.
Once inserted, DMEK-graft may present as a double scroll, tight single scroll, or triangle, or it may be opened up at first instance.[7-9]
It’s a series of tapping, intermittent BSS injection and release, corneal manipulations from top or from sides that creates fluid waves
within the eye, affectionately known as the ‘DMEK dance’.
Main principle is “No touch technique”, using intermittent BSS jet, shallowing of the AC via one of the side ports and simultaneous
tapping from top while fixing one edge with a cannula. Work with two cannulas (one cannula fitted with 2 cc BSS-filled syringe),
or one cannula and one iris repositor.
There are all sorts of different techniques and nuances to it. It’s very difficult to explain verbally or by reading from text. It’s probably
best learned by seeing surgeons doing it, and by practicing it several times before attempting it with a live patient.
Centering the graft: I know, I cannot push a DMEK-graft where I want it to place. I have to lead the graft towards centre.
Apply physics: I flatten the cornea to create a straight corridor between the flattened cornea and the iris plane. This facilitates
movement of the graft by creating a smooth-flowing ‘fluid highway’. Then tap from outside limbus, the entire DMEK-graft will move
towards centre.
Fill AC with air: For air injection I use 1 cc syringe. I always check for cannula tightness before air injection. Once the graft is in
position, gently slide the cannula underneath it, go right at the pupillary area and inject a little air bubble. First inject about 1/3rd
air and check for the S- or F-stamp orientation. Once you are sure, inject more air to obtain a complete air fill (not over-fill like
DSEK).[10] SF6 or C3F8 gas is rarely required except in some special situation.
Following surgery: I send the patient to the recovery room and let them be in supine position for 60-90 minutes. Then examine
the patient at the slit lamp to ensure that the graft is perfectly positioned and there is fluid level in the anterior chamber just above
the inferior PI. If not do little burping of air via side-port. Immediately, fluid level is achieved. About 2 mm fluid level from inferior
limbus is mostly desirable.
Post-operative care
I used to send the patient home the same day, 5-6 hours after the surgery and ask the patient to maintain supine position as far
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DOS TIMES
as possible for next 48 hours. I discuss about possibility of rebubbling in 4% eyes. Examine the patient on Day 3 with an ASOCT
cross-image and then on Day 7 and finally at 3rd week for glass prescription. Macular OCT in all cases after 2-3 weeks to detect any
pre-existing CME or newly developed CME. Finally, Clinical specular microscopy at 3, 6 and 12 months and then yearly to analyse
own performance.
Steroid drops: Prednisolone acetate (1%) eye drop 4 times, 3 times and twice - for 2 months each and then once daily till one year.
Then switch to Fluoromethalone (0.1%) or Loteprednol eye drop (0.5%) - once daily for lifelong. Secondary glaucoma in the form
of steroid-induced or due to other causes - to be managed judiciously. It is single most important risk factor for DMEK graft failure.
The Chronology of Learning
Read: Plenty of materials are available. Read specially the ‘Review’ articles and ‘Surgical Techniques’ – articles.
Listen: Listen to master’s instruction courses or lecture series who are performing DMEK regularly.
Watch: Videos: Both edited and unedited. Visit some masters and watch their surgeries live.
Practice: Practice in wet lab. Again practice, practice and practice in wet lab. Take a skill-transfer course if possible.
Ask Questions: Ask yourself first, try to find the answer. Then different online forums are there. Ask questions and participate in
the discussion with your colleagues or experts.
First 15-20 Cases:
In India, most common indication of endothelial keratoplasty (EK) is pseudophakic corneal edema/bullous keratopathy. In our
state, we see more Fuchs’ endothelial corneal dystrophy (FECD) cases (>35% of eyes), than other parts of the country (~15% -
national average). Another interesting point to note, endothelial cell density (ECD) above 60 years is also more in West Bengal. That
is why in our eye bank for any EK, the donor ECD is >2500/mm2.
Once you’re ready to perform your first few DMEK cases,
Patient selection is key to early success:
Mild to moderate corneal edema
Good view of the anterior chamber
A normal lens-iris diaphragm with normal anterior chamber depth
Round normal pupil
IOL preferably in-the-bag
FECD patient with mild corneal edema is also a good choice over PBK patient. You choose to perform DMEK-triple in that case
Avoid
Severe cornea edema patients
Eye with hyper-deep anterior chamber
Patients with high myopia
Any special situation – such as, with trab/tube, iris defects, aphakia, unstable IOL, AC IOL, post PK cases or prior vitrectomy
eyes with or without SF IOLs
Donor selection: Donor age between 60-70 years with cell count >2500/mm2. It may be Cornisol/Optisol or even MK medium
preserved corneas. Always keep stand by good quality tissue from a different donor. Remember, donor preparation and scroll
behaviour are similar with the paired tissues.
You also need a number to start your DMEK surgery. If you are doing 5 EKs/year, then it is a good number. If you follow the
selection criteria, probably 50% of your EK cases are good candidates for DMEK. In that case, you will be performing 25 DMEK/
year, that means 2 in a month. If this is the case, I suggest to club few cases in a row, so that you learn faster. You make mistakes
and rectify them in quick succession. Review the videos, analyse yourself, ask questions and then again go back to new case or may
be few more Wet Labs and then again to your live patient.
Summary and Finally Some Dos and Don’ts in DMEK procedures
After performing 1000+ DMEK procedures, sometimes it seems to many people that it is now more simplified procedure for me.
There are still challenging areas for both less experienced and more experienced DMEK surgeons. Only 70% time, the surgery will
go as you have thought and the tissue will listen to you. Here, I am sharing some Dos and Don’ts during the DMEK procedure.
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DOS Times - Volume 28, Number 1, January-February 2022
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Do’s
Do good wet lab practice before performing your first surgery
Donor preparation first before giving the block to the recipient
Do strip the recipient DM ‘under air’ and remove all DM tags
Do wash thoroughly if you use OVDs, specially from the bag in ‘Triple-DMEK’ cases
Do rinse and stain the graft appropriately before transfer: DMEK-grafts are more difficult to see in eyes with dark brown iris
compared with blue iris
Do check the DM-scroll pattern and its’ behaviour in the petri dish
Do give a good BSS wash and look for clotted blood/fibrin thread before transferring the graft
Do check for double-roll configuration
Do check your syringes and cannula tightness for playing with BSS or air
Do place a suture in the main port
Do inject air from the pupillary area
Do leave the eye at a physiologic pressure at the end of surgery
Do Counselling about re-bubbling
Don’ts
Do not select a case which is difficult to perform
Do not take a donor cornea <50 years of age
Do not use dispersive viscoelastic material during cataract surgery or Descemet stripping
Do not roughened the posterior cornea
Do not overstain the DMEK-graft: Overstaining tends to make the graft more tighter and more difficult to unfold
Do not over-pressurize the eye while injecting the graft into A/C
Do not forget to check the graft orientation before tapping to unfold it
Do not inject too much air bubble at the first instance (use 1 cc syringe) after centering
Do not try to attempt perfect centering if it is not happening easily
Check the orientation of the S-stamp and then increase the size of the bubble
Do not keep the eye at very high pressure after the tamponade
The final Do’s and Don’ts:
Do start with DMEK
Don’t give up
Like any eye surgery, there is a learning curve which may be more steep in DMEK. But if this were your eye, and you were the
patient, this is the surgery that you would want.
References
1. Melles GR, Ong TS, Ververs B, et al. Descemet membrane endothelial keratoplasty (DMEK). Cornea. 2006;25:987–990.
2. Deng SX, Lee WB, Hammersmith KM, et al. Descemet membrane endothelial keratoplasty: Safety and outcomes: A report by the American Academy
of Ophthalmology. Ophthalmol 2018;125:295-310.
3. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s Membrane Endothelial Keratoplasty Prospective Study of 1-Year Visual Outcomes,
Graft Survival, and Endothelial Cell Loss. Ophthalmology 2011;118:2368-73.
4. Veldman PB, Dye PK, Holiman JD et al. The S-stamp in Descemet Membrane Endothelial Keratoplasty Safely Eliminates Upside-down Graft
Implantation. Ophthalmology. 2016123:161-64.
5. Basak SK, Basak S, Pradhan VR. Outcomes of Descemet Membrane Endothelial Keratoplasty (DMEK) using Surgeon’s Prepared Donor DM-Roll
in Consecutive 100 Indian Eyes. Open Ophthalmol J. 2018;12:134–42.
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DOS TIMES
6. Basak SK, Basak S. Clinical Outcomes and Endothelial Cell Density After Descemet Membrane Endothelial Keratoplasty Using Peripherally-
trephinated Donor Tissue (DMEK-pD) in Fuchs Endothelial Corneal Dystrophy. Cornea. 2020;39:437-42.
7. McKee Y, Price MO, Gunderson L, Price FW Jr. Rapid sequential endothelial keratoplasty with and without combined cataract extraction. J Cataract
Refract Surg 2013;39:1372-76.
8. Price MO, Feng MT, Price FW. Endothelial Keratoplasty Update 2020. Cornea. 2021;40:541-547.
9. Hayashi T, Schrittenlocher S, Siebelmann S, et al. Risk factors for endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK).
Sci Rep. 2020;10:11086.
10. Feng MT, Price MO, Miller JM, Price Jr FW. Air reinjection and endothelial cell density in Descemet membrane endothelial keratoplasty: Five-year
follow-up. J Cataract Refract Surg. 2014;40:7:1116-1121.
www.dosonline.org/dos-times 15
DOS Times - Volume 28, Number 1, January-February 2022
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DOS TIMES
Recent Advances in Small Incision Lenticule
Extraction
Sridevi Nair, MD, Manpreet Kaur, MD, Jeewan Singh Titiyal, MD
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi.
Abstract: The field of corneal laser refractive surgery is evolving at a remarkable pace with continual advancement
in visual outcomes, surgical techniques, and ease of surgery. Refractive lenticule extraction is the newest addition
to mainstream refractive surgery and has gained immense popularity during the past decade. While small incision
lenticule extraction (SMILE) has provided consistent results for correction of myopia, the recent advances in treatment
of hyperopia, astigmatism and enhancements are anticipated to further increase its efficacy in these scenarios.
Introduction 2021 as an advancement over the VisuMax 500 kHz laser. It has a
The advent of small incision lenticule extraction (SMILE) more compact design with 2 separate robotic arms for laser and
has heralded a new era in laser vision correction. The microscope respectively. A faster laser pulse repetition rate of
minimally invasive, flapless procedure involves the creation 2MHz allows for a shorter lenticule cut time of <10 seconds and
of an intrastromal lenticule using femtosecond laser, which is an overall reduced suction time. It features an in-built computer-
extracted through a small side incision. The surgery was first assisted cyclotorsion compensation which automatically re-
described by Dr. Walter Sekundo who used two 5mm side cut calculates the laser treatment pattern to counter any cyclotorsion.
incisions to extract the lenticule. Subsequently, single incision In addition, it is equipped with the CentraLign assistant
SMILE surgery was described by Shah et al in 2011.[1] The system, a computer-controlled function that uses pupil center
VisuMax 500 kHz femtosecond laser (Carl Zeiss Meditec, Jena, and corneal vertex position to aid proper centration while
Germany) is United States Food and Drug Administration (FDA) docking.[3]
approved for SMILE to treat myopia of -1 to -10DS and up to 3D The Corneal Lenticule Extraction for Advanced Refractive
cylinder.[2] While SMILE has proven to be a worthy alternative to correction (CLEAR) with Femto LDV Z8 laser (Ziemer
the established technique of laser-assisted in situ keratomileusis Ophthalmic Systems AG, Port, Switzerland) received CE
(LASIK) for treatment of myopia, certain scenarios such as approval in April 2020 and can correct myopia of up to -10DS
hyperopia, high astigmatism and enhancements continue and -5DC. The platform allows the surgeon to recenter and
to remain a challenge. This article focusses on the recent rotate the lenticule after docking to correct the centration and
developments in SMILE including the technological advances compensate for cyclotorsion. The SmartSight procedure with
and its application in these challenging scenarios. Atos femtosecond laser (Schwind eye-tech-solutions, GmbH,
Kleinostheim, Germany) received CE approval in July 2020 and
Newer Platforms for Lenticule Extraction can correct myopia of up to -12.5DS and -6DC. It is equipped
Until recently, VisuMax 500 kHz femtosecond laser was the with features such as automated eye tracking, pupil recognition,
only commercially available platform for performing refractive and cyclotorsion compensation. The lenticule geometry with
lenticule extraction, and till date remains the only FDA approved both these platforms differs from that of VisuMax laser in
device for the procedure. The lack of an inbuilt centration aid, lacking lenticule side-cuts; the SmartSight profile incorporates
eye-tracking and cyclotorsion control are important limitations a refractive progressive transition zone in the periphery to help
of this device. Three new femtosecond laser platforms have been reduce epithelial remodeling and regression.[3] Table 1 details
introducedrecentlyforperformingrefractivelenticule extraction. the features of the various laser platforms that are commercially
The VisuMax 800 femtosecond laser was launched in September available for performing lenticule extraction surgery.
Feature VisuMax 500 (Zeiss) VisuMax 800 (Zeiss) Femto LDV Z8 (Zeimer) ATOS (Schwind)
Source Laser Wavelength 1043 nm 1043 nm 1030 nm 1030 nm
Laser pulse repetition rate 500KHz 2MHz Up to 20 MHz Up to 4 MHz
Energy per pulse 110-150 nJ 110-150 nJ <<100 nJ 75-135 nJ
Laser cut time About 30 seconds About 10 seconds About 30 seconds About 30-40 seconds
Patient Interface Curved Curved Flat Curved
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DOS Times - Volume 28, Number 1, January-February 2022
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Feature VisuMax 500 (Zeiss) VisuMax 800 (Zeiss) Femto LDV Z8 ATOS (Schwind)
(Zeimer)
Inbuilt cyclotorsion No Yes Yes Yes
compensation
Inbuilt centration system No Yes Yes Yes
Lenticule side cut + Lenticule side cut + No lenticule side cut No lenticule side cut
Lenticule geometry
Table 1 : Commercially available femtosecond laser platforms for refractive lenticule extraction.
Hyperopic SMILE lae, all of which may lead to suboptimal refractive outcomes.
Lenticule extraction surgery for treatment of hyperopia has been Difficult lenticule dissection resulting in a retained lenticule or
under investigation for the past decade, and early clinical studies excessive surgical manipulation may also necessitate retreat-
on hyperopic SMILE have reported promising outcomes. Unlike ment after SMILE.[9,11]
the myopic treatment, hyperopic SMILE involves the creation of Management
a larger, doughnut-shaped lenticule that is thinner in the centre Retreatment after SMILE should be typically performed after at
and thicker in the periphery. The initial attempts at refractive least 3 months of the primary surgery once refractive stability
lenticule extraction for hyperopic correction experienced prob- is achieved. Cap thickness should be determined using anterior
lems such as loss of corrected distance visual acuity (CDVA) segment optical coherence tomography (ASOCT) before plan-
and regression, which was attributed to the small optical zone ning retreatment. The various options described for retreatment
(OZ), inadequate transition zone and centration over the pupil. after SMILE include surface ablation, thin flap LASIK, conver-
Modifications in lenticule design to enlarge the optical zone and sion of cap to flap using the CIRCLE pattern of VisuMax laser
include a transition zone of about 2mm, while using a corneal and sub-cap lenticule extraction. (Figure 1) Table 2 describes the
vertex-based centration were suggested to overcome these lim- advantages, disadvantages, and clinical outcomes of each tech-
itations.[4] Theoretically, the larger lenticule diameter and addi- nique. Surgical decision making is determined by factors such
tional transition zone may lead to slightly longer laser cut time as the initial cap thickness, presence of interface haze, residual
as compared to myopic SMILE.[5] Pradhan et al reported that stromal bed thickness (RSBT), patient profile and surgeon’s ex-
53% of eyes undergoing SMILE for hyperopia (up to +7D) were pertise.[11] Figure 2 depicts a flowchart for decision making in
within 0.5D of target at 1 year follow up with 16% of eyes suffer- retreatment after SMILE.
ing one line loss of CDVA.[6] In addition, the functional OZ ob- A) Surface Ablation: Surface ablation is the most straightfor-
tained after SMILE is larger than that obtained with LASIK, with
lesser induction of negative spherical aberrations.[7] Hyperopic ward technique for performing post-SMILE enhancement.
SMILE treatment is not yet available commercially and further Good visual outcomes have been reported with laser-assist-
studies evaluating the long-term outcomes will help establish its ed subepithelial keratectomy (LASEK), epi-off photorefrac-
status in comparison to LASIK, once the software is launched. tive keratectomy (PRK) and transepithelial PRK with mito-
mycin C (MMC) application. While surface ablation retains
Retreatment after SMILE the advantages of a flapless procedure, it has the disadvan-
Enhancement after SMILE is indicated for treating a residual re- tages of slower visual recovery, narrow range of refractive
fractive error due to undercorrection, overcorrection or regres- correction and development of postoperative haze.[12,13]
sion. Retreatment may also be required in cases of retained lent- B) Thin-flap LASIK: Thin-flap LASIK is a retreatment op-
icule fragments or abandoned primary surgery due to difficult tion suitable in cases with an initial cap thickness >130-
lenticule dissection. Regression after SMILE has been found to 140 microns. A 90-100 microns thick LASIK flap, with
be less than that after excimer laser ablative surgery. Blum et al a diameter greater than that of the SMILE cap, and a na-
reported a mean regression of -0.35D over 10 years after myopic sal hinge (to avoid the superior side-cut incision) is
SMILE.[8] The reported rate of retreatment after SMILE ranges created.[10,11] Reinstein et al recommended a safety margin
from 2.1 to 4.4%.[9,10] About 71% of the enhancements are per- of 40 microns between the maximum epithelial thickness
formed within the first year, and retreatment is more likely to be and minimum cap thickness measured on ASOCT to avoid
performed for undercorrection than overcorrection.[9] buttonholing or tissue slivers. Dissection and lifting of the
flap is challenging in these cases as the previous small inci-
Risk Factors sion lies within the flap, which increases the risk of tear at
Preoperative risk factors for enhancement after myopic SMILE the incision site and likelihood of the instrument entering
include older age (>35 years), higher refractive error (>6D) and the original interface. The bimanual inferior pseudo-hinge
greater astigmatism (>3D). Intraoperative suction loss is an im- fulcrum technique that uses a flap lifter and a McPherson
portant risk factor for retreatment. Repeat docking and laser forceps to lift the flap has been described to prevent this
application after suction loss may be associated with improper complication.[14]
centration, inaccurate laser cut and distortion of collagen lamel-
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DOS TIMES
C) CIRCLE Pattern for Retreatment: The CIRCLE software may also be performed to remove a completely retained
on VisuMax platform converts the original SMILE cap into lenticule. The conversion of cap to a flap; however,
a larger diameter flap, which can then be lifted to perform predisposes the patient to flap-related complications with
an excimer laser ablation for retreatment. A lamellar ring potential risk of increased biomechanical weakening in
encircling the original cap cut is created, followed by cases with thicker caps.[11]
a hinged side-cut around the new incision plane and a D) Sub-Cap Lenticule Extraction: Sub-cap lenticule extraction
junction cut that connects the plane of original cap to that is a modified repeat SMILE procedure, which is performed
of the new lamellar ring. The new hinge area should not at the same depth as the first procedure without the upper
overlap with the former side-cut incision. Amongst the cut. The previous interface acts as the superior border of the
four patterns that are provided by the VisuMax platform, new lenticule. The advantages of a flap-less procedure are
pattern D, which creates a lamellar ring at the same depth preserved; however, the surgery may be technically chal-
as the cap, has been shown to produce flaps that are easiest lenging in cases with a thin lenticule. Limited reports have
to dissect and lift, and is therefore preferred by most described outcomes of post SMILE retreatment with this
surgeons.[15,16] The CIRCLE technique avoids multiple technique and further studies are required to establish its
interfaces, has a faster recovery than surface ablation and efficacy and safety.[11,17]
Figure 1 : Techniques of retreatment after SMILE.
Figure 2 : Decision making in retreatment after SMILE. 19
DOS Times - Volume 28, Number 1, January-February 2022
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Procedure Advantages Disadvantages Clinical Outcomes
Surface Ablation (PRK, LASEK) Flapless procedure, better Postoperative haze, delayed visual Good visual outcomes
conservation of corneal recovery Overcorrection with
biomechanical strength Flap related complications, aspherically optimized profile
technically challenging (ASA)
Thin-flap LASIK Stroma between the flap and Good visual outcomes
original interface preserved, no Flap related complications, greater Potential intraoperative
postoperative haze corneal biomechanical weakening, complications include SMILE
especially with thicker caps interface access, interface
CIRCLE pattern of retreatment Avoids multiple dissection planes, Technically Challenging sliver separation and small
Sub-cap lenticule extraction can extract retained lenticule, no incision tear
postoperative haze Good visual outcomes
Retains the benefits of a flapless
procedure Good visual outcomes
(Limited studies reported)
Table 2 : Retreatment after SMILE – Techniques, advantages, limitations, and clinical outcomes.
Astigmatism Correction with SMILE C) Ocular residual astigmatism: Ocular residual astigmatism
(ORA) refers to the vector difference between the
SMILE has demonstrated excellent efficacy and safety in preoperative refractive astigmatism and topographic
treating myopia; however, accurate astigmatic correction re- astigmatism. It is primarily attributed to the posterior
mains a challenge with the procedure. While outcomes of corneal surface and crystalline lens. Higher ORA has been
SMILE in treatment of low to moderate astigmatism is slight- associated with higher postoperative manifest astigmatism
ly less favorable than LASIK, both techniques have been after SMILE.[27]
found to be comparable for correction of high astigmatism
(>3D).[18–21] Studies have reported astigmatic undercorrection D) Other factors: Postural misalignment of the patient during
ranging from 11-16% per diopter of attempted correction with laser treatment can lead to suboptimal astigmatic treatment
greater undercorrection observed with higher degrees of astig- outcomes after SMILE. Lesser undercorrection has been
matism.[22,23] observed in cases with preoperative against-the-rule
Factors affecting astigmatism correction with SMILE: Sub- astigmatism as compared to with-the-rule astigmatism.[28]
optimal astigmatic correction with SMILE has been mainly at-
tributed to improper centration, lack of cyclotorsional adjust- Optimizing Astigmatism Correction with SMILE
ments and postural misalignment. Other factors such as high
ocular residual astigmatism (ORA), preoperative astigmatic Preoperatively, a thorough assessment should be performed to
axis, and method of lenticule extraction may also affect the ac- determine the amount of cylindrical error, ocular residual astig-
curacy of astigmatic correction.[22] matism, and angle kappa. Patients with larger angle kappa and
A) Cyclotorsion: The major cause of cyclotorsion in patients high astigmatism (>3D) should be counselled for the possibility
of undercorrection. Vector planning which integrates topogra-
undergoing refractive surgery is posture-related; other phy parameters into the surgical planning has been recommend-
causative factors include the unmasking of cyclophoria ed in cases with high ORA to improve treatment outcomes.[22]
and rotation of the head under laser. About 20% of Intraoperatively, meticulous patient positioning to avoid head
SMILE patients were reported to have a cyclotorsion of >5 tilting is essential to minimize any misalignment. Cyclotorsion
degrees.[24] Theoretically, a 4° of cyclotorsion can lead to compensation should be considered while performing SMILE
about 14% undercorrection of astigmatism.[25] with VisuMax 500 kHz laser, in cases with significant astigma-
B) Centration of Treatment: Centration of treatment in tism. Preoperative manual marking of the cornea or limbus at 2
SMILE depends on the skill of the surgeon while docking, or 3 points has been suggested, followed by manual adjustment
as well as on the patient who must fixate on the blinking of the cone or patient’s head intraoperatively to align it with the
light. The risk of a decentration is high while using VisuMax markings before cutting the lenticule. Alternatively, cyclotor-
500 laser, especially with novice surgeons due to the absence sion compensation with an image-guided system may also be
of centration aid or eye-tracking. A large angle kappa and performed. Table 3 details the various techniques described for
higher anterior corneal keratometric astigmatism are other cyclotorsion compensation in SMILE.[24,29,30]
potential factors that can lead to decentration of the optical While docking, the patient should be instructed to fixate onto
zone.[26] the green fixating light as the contact glass is placed over the
cornea. The relative positions of visual axis and pupil center (an-
DOS Times - Volume 28, Number 1, January-February 2022 20 www.dosonline.org/dos-times
DOS TIMES
gle kappa) during docking should match the respective positions cornea is in contact with the suction cone to compensate for any
obtained from the preoperative topography. Better visual out- decentration of the optical zone. The newer lenticule extraction
comes have been observed when the lenticule center is closer platforms are equipped with in built cyclotorsion and centration
to the corneal vertex. Fine adjustments can be made when the aids which may provide better astigmatic correction.[22]
Author Technique Advantages/Limitations
Ganesh et al[24] Limbal marks are made at 0 and 180 Advantages: Intraoperative cyclotorsion
Jun et al[29] degrees while patient is sitting upright. compensation achieved. Simple to perform.
Kose et al[30] Intraoperative cyclotorsion compensation Limitations: Potential error in marking/
performed by rotating the cone and aligning aligning the markings, poor visibility of
the limbal marks with the horizontal axis markings, risk of suction loss.
of the reticule of microscope eye piece after
activating the suction.
Triple markings made; 2 at the horizontal Advantages: Intraoperative cyclotorsion
meridian 7mm apart and 1 at inferior compensated.
cornea, bisecting the coaxially sighted Helps achieve better centration
corneal light reflex. Limitations: Potential error in marking, poor
Decentration and cyclotorsion corrected visibility of markings, risk of suction loss
with aid of triple markings during docking.
Sitting position reference axis registered Advantages: May be less prone to error than
with IOLMaster 700 and transferred to the manual marking.
Callisto eye system that is connected to the Limitations: Requires the Callisto eye system
VisuMax microscope. to be connected with VisuMax laser
Cyclotorsion measured by Z-align function
and compensated for by repositioning
the patient’s body or tilting the head till
reference axis from IOLMaster 700 is parallel
to a manually drawn reference axis on the
screen before docking.
Table 3 : Techniques of cyclotorsion compensation in SMILE. dextran-free formulation of riboflavin 5-phosphate solution
(VibeX Xtra, Avedro) for intrastromal application. The UVA
SMILE Xtra energy dose used for SMILE Xtra in published literature ranges
The term “Xtra” has been used to denote corneal collagen cross- from 0.8–3.4 J/cm2; a lower energy has been recommended as
linking (CXL) performed as an adjunct with refractive surgery the indication for CXL in these patients is prophylactic rather
to enhance the corneal biomechanical strength. than therapeutic.[35,36] Lower energy and accelerated protocols
also lead to less keratometric flattening as compared to conven-
Indications tional CXL while reducing the incidence of complications such
At present there are no standardized protocols or patient se- as postoperative haze.[34]
lection criteria for performing SMILE Xtra. Simultaneous Surgical Technique: SMILE Xtra requires the injection of ribo-
CXL with SMILE is indicated in patients at moderate-to-high flavin solution into the stromal pocket for about 45-90 seconds
risk of postoperative ectasia, as determined by the Randle- following the lenticule removal. After soaking the stromal bed
man ectasia risk score.[31] Patients with suspicious corneal with riboflavin the interface is washed off and the central cornea
topography without established keratoconus, high-refrac- is irradiated with UVA light.
tive errors (>6 D), borderline residual stromal bed thick-
ness (250–300 microns), thin corneas (450–520 microns) Outcomes
and increased percentage tissue altered (PTA > 35%) may be The long-term efficacy, predictability, and safety of SMILE Xtra
considered.[32–34] are comparable to that of SMILE. A transient haze observed in
Treatment Protocols the immediate post-operative period may lead to a delayed visual
Different treatment protocols have been described for perform- rehabilitation in SMILE Xtra patients without affecting the long-
ing combined accelerated CXL with SMILE based on the ribofla- term visual outcomes. Liu et al reported a slight overcorrection
vin concentration used, UV irradiation time, UV power, and the after SMILE Xtra that was evident up to 12 months.[32,35–38]
total energy delivered.(Table 4) Most authors have used 0.25%
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DOS Times - Volume 28, Number 1, January-February 2022
DOS TIMES
Author Eyes (n) Riboflavin UVA power UVA radiation Total Energy Clinical
Ganesh et al[36] SMILE Xtra: 40 solution (mW/cm2) time Dose (J/cm2) Outcomes
0.25% Riboflavin 45 75 seconds 3.4
Soaked for 60 Good safety and
seconds efficacy.
Two eyes
Ng et al[35] SMILE Xtra: 21 0.22% riboflavin 18 45 seconds 0.8 developed
Osman et al[32] SMILE: 32 Soaked for 45 18 3 mins 3.2 transient grade 2
seconds haze at 1 month
SMILE: 30 SMILE 0.1% riboflavin which resolved
Xtra: 30 within 3 months.
Liu et al[37] SMILE; 40 0.25% Riboflavin 30 90 seconds 2.7 Slight myopic
SMILE Xtra: 36 Soaked for 90 shifting trend with
seconds SMILE Xtra
Sánchez‐González SMILE Xtra: 48 0.25% Riboflavin 30 90 seconds 2.7 Visual outcomes
et al[38] Soaked for 90 comparable in
seconds both groups.
Higher corneal
resistance factor
and densitometry
with SMILE Xtra
Mild haze with
SMILE Xtra at 1
month; resolved
by 3 months.
Vision recovered
more slowly after
SMILE Xtra
Comparable
predictability;
slight
overcorrection
with SMILE Xtra
3 eyes in the
SMILE Xtra group
had mild corneal
haze at 1 week;
none at 6-months.
Manifest refractive
spherical
equivalent
changed ≥
0.50 D between 3
to 24 months in
8.3% eyes
2 eyes required
enhancement
Table 4 : Treatment protocols and clinical outcomes of SMILE Xtra.
Conclusion the early investigational studies. It is anticipated that the newer
Rapid strides have been made in the field of refractive lenticule laser platforms with in-built cyclotorsion control and centration
extraction with numerous advances in terms of surgical aids will help in achieving more accurate results while treating
techniques, refinements in treatment software and laser astigmatism. With the ongoing advancements SMILE is poised
technology. The much-awaited hyperopic SMILE treatment to become the new benchmark of corneal laser refractive surgery
which is expected to launch soon has shown promising results in that will enable us to further reduce the surgical time, expedite
DOS Times - Volume 28, Number 1, January-February 2022 22 www.dosonline.org/dos-times
DOS TIMES
visual recovery and optimize outcomes in scenarios such as 17. Sedky AN, Wahba SS, Roshdy MM, Ayaad NR. Cap-preserving SMILE
hyperopia, thin corneas and high astigmatism. Enhancement Surgery. BMC Ophthalmol. 2018 Feb 17;18(1):49.
References 18. Khalifa MA, Ghoneim AM, Shaheen MS, Piñero DP. Vector analysis
of astigmatic changes after small-incision lenticule extraction and
1. Shah R, Shah S, Sengupta S. Results of small incision lenticule wavefront-guided laser in situ keratomileusis. J Cataract Refract
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Refract Surg. 2011 Jan;37(1):127–37.
19. Chan TCY, Ng ALK, Cheng GPM, Wang Z, Ye C, Woo VCP, et al.
2. Moshirfar M, Thomson AC, West WB, Hall MN, McCabe SE, Vector analysis of astigmatic correction after small-incision lenticule
Thomson RJ, et al. Initial Single-Site Experience Using SMILE for extraction and femtosecond-assisted LASIK for low to moderate
the Treatment of Astigmatism in Myopic Eyes and Comparison of myopic astigmatism. Br J Ophthalmol. 2016 Apr;100(4):553–9.
Astigmatic Outcomes with Existing Literature. Clin Ophthalmol.
2020 Oct 29;14:3551–62. 20. Taneri S, Kießler S, Rost A, Schultz T, Dick HB. Small-incision
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3. Fuest M, Mehta JS. Advances in refractive corneal lenticule extraction. Cataract Refract Surg. 2019 Jan;45(1):62–71.
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21. Chan TCY, Wang Y, Ng ALK, Zhang J, Yu MCY, Jhanji V, et al.
4. Sekundo W, Messerschmidt-Roth A, Reinstein DZ, Archer TJ, Blum Vector analysis of high (≥3 diopters) astigmatism correction using
M. Femtosecond Lenticule Extraction (FLEx) for Spherocylindrical small-incision lenticule extraction and laser in situ keratomileusis. J
Hyperopia Using New Profiles. J Refract Surg. 2018 Jan 1;34(1):6–10. Cataract Refract Surg. 2018 Jul;44(7):802–10.
5. Moshirfar M, Bruner CD, Skanchy DF, Shah T. Hyperopic small- 22. Chow SSW, Chow LLW, Lee CZ, Chan TCY. Astigmatism Correction
incision lenticule extraction. Curr Opin Ophthalmol. 2019 Using SMILE. Asia Pac J Ophthalmol (Phila). 2019 Oct;8(5):391–6.
Jul;30(4):229–35.
23. Zhong Y, Li M, Han T, Fu D, Zhou X. Four-year outcomes of
6. Pradhan KR, Reinstein DZ, Carp GI, Archer TJ, Dhungana P. Small small incision lenticule extraction (SMILE) to correct high myopic
Incision Lenticule Extraction (SMILE) for Hyperopia: 12-Month astigmatism. Br J Ophthalmol. 2021 Jan;105(1):27–31.
Refractive and Visual Outcomes. J Refract Surg. 2019 Jul 1;35(7):442–
50. 24. Ganesh S, Brar S, Pawar A. Results of Intraoperative Manual
Cyclotorsion Compensation for Myopic Astigmatism in Patients
7. Damgaard IB, Ang M, Mahmoud AM, Farook M, Roberts CJ, Mehta Undergoing Small Incision Lenticule Extraction (SMILE). J Refract
JS. Functional Optical Zone and Centration Following SMILE and Surg. 2017 Aug 1;33(8):506–12.
LASIK: A Prospective, Randomized, Contralateral Eye Study. J
Refract Surg. 2019 Apr 1;35(4):230–7. 25. Alió Del Barrio JL, Vargas V, Al-Shymali O, Alió JL. Small incision
lenticule extraction (SMILE) in the correction of myopic astigmatism:
8. Blum M, Lauer AS, Kunert KS, Sekundo W. 10-Year Results of Small outcomes and limitations - an update. Eye Vis (Lond). 2017;4:26.
Incision Lenticule Extraction. J Refract Surg. 2019 Oct 1;35(10):618–
23. 26. Chan TCY, Wan KH, Kang DSY, Tso THK, Cheng GPM, Wang Y.
Effect of corneal curvature on optical zone decentration and its impact
9. Liu Y-C, Rosman M, Mehta JS. Enhancement after Small-Incision on astigmatism and higher-order aberrations in SMILE and LASIK.
Lenticule Extraction: Incidence, Risk Factors, and Outcomes. Graefes Arch Clin Exp Ophthalmol. 2019 Jan;257(1):233–40.
Ophthalmology. 2017 Jun;124(6):813–21.
27. Chan TCY, Wan KH, Zhang L, Wang Y. Impact of ocular residual
10. Reinstein DZ, Carp GI, Archer TJ, Vida RS. Outcomes of Re-treatment astigmatism on predictability of myopic astigmatism correction after
by LASIK After SMILE. J Refract Surg. 2018 Sep 1;34(9):578–88. small-incision lenticule extraction. J Cataract Refract Surg. 2019
Apr;45(4):525–6.
11. Kaur M, Titiyal JS, Nair S. Retreatment after SMILE. In: Titiyal
JS, Kaur M, Nair S, ed. Current Concepts in Refractive Surgery: 28. Pérez-Izquierdo R, Rodríguez-Vallejo M, Matamoros A, Martínez
Comprehensive Guide for Decision Making & Surgical Techniques. J, Garzón N, Poyales F, et al. Influence of Preoperative Astigmatism
1st ed. New Delhi. Jaypee Brothers; 2022: p. 179–83. Type and Magnitude on the Effectiveness of SMILE Correction. J
Refract Surg. 2019 Jan 1;35(1):40–7.
12. Gab-Alla AA. SmartSurfACE transepithelial photorefractive
keratectomy with mitomycin C enhancement after small incision 29. Jun I, Kang DSY, Reinstein DZ, Arba-Mosquera S, Archer TJ, Seo
lenticule extraction. Eye Vis (Lond). 2021 Sep 1;8(1):28. KY, et al. Clinical Outcomes of SMILE With a Triple Centration
Technique and Corneal Wavefront-Guided Transepithelial PRK in
13. Siedlecki J, Siedlecki M, Luft N, Kook D, Meyer B, Bechmann M, et High Astigmatism. J Refract Surg. 2018 Mar 1;34(3):156–63.
al. Surface Ablation Versus CIRCLE for Myopic Enhancement After
SMILE: A Matched Comparative Study. J Refract Surg. 2019 May 30. Köse B. Detection of and Compensation for Static Cyclotorsion
1;35(5):294–300. With an Image-Guided System in SMILE. J Refract Surg. 2020 Mar
1;36(3):142–9.
14. Reinstein DZ, Carp GI, Archer TJ, Vida RS. Inferior pseudo-hinge
fulcrum technique and intraoperative complications of laser in situ 31. Randleman JB, Trattler WB, Stulting RD. Validation of the Ectasia
keratomileusis retreatment after small-incision lenticule extraction. J Risk Score System for preoperative laser in situ keratomileusis
Cataract Refract Surg. 2018 Nov;44(11):1355–62. screening. Am J Ophthalmol. 2008 May;145(5):813–8.
15. Siedlecki J, Luft N, Mayer WJ, Siedlecki M, Kook D, Meyer B, et al. 32. Osman IM, Helaly HA, Abou Shousha M, AbouSamra A, Ahmed
CIRCLE Enhancement After Myopic SMILE. J Refract Surg. 2018 I. Corneal Safety and Stability in Cases of Small Incision Lenticule
May 1;34(5):304–9. Extraction with Collagen Cross-Linking (SMILE Xtra). J Ophthalmol.
2019;2019:6808062.
16. Siedlecki J, Luft N, Priglinger SG, Dirisamer M. Enhancement
Options After Myopic Small-Incision Lenticule Extraction (SMILE): 33. Ma J, Wang Y, Jhanji V. Corneal refractive surgery combined with
A Review. Asia Pac J Ophthalmol (Phila). 2019 Oct;8(5):406–11. simultaneous corneal cross-linking: Indications, protocols, and clinical
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outcomes-A review. Clin Exp Ophthalmol. 2020 Jan;48(1):78–88. Corresponding Author:
34. Nair S, Selvan H, Kaur M, Titiyal JS. Corneal Collagen Cross-linking Prof. Jeewan Singh Titiyal, MD
and Refractive Surgeries. In: Titiyal JS, Kaur M, Nair S, ed. Current Professor & Chief
Concepts in Refractive Surgery: Comprehensive Guide for Decision Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi.
Making & Surgical Techniques. 1st ed. New Delhi. Jaypee Brothers;
2022. p. 213–20.
35. Ng ALK, Chan TCY, Cheng GPM, Jhanji V, Ye C, Woo VCP, et al.
Comparison of the Early Clinical Outcomes between Combined
Small-Incision Lenticule Extraction and Collagen Cross-Linking
versus SMILE for Myopia. J Ophthalmol. 2016;2016:2672980.
36. Ganesh S, Brar S. Clinical Outcomes of Small Incision Lenticule
Extraction with Accelerated Cross-Linking (ReLEx SMILE Xtra) in
Patients with Thin Corneas and Borderline Topography. J Ophthalmol.
2015;2015:263412.
37. Liu C, Fang X, Wang Z, Zhao X, Zou H, Jhanji V, et al. Comparative
study of small-incision lenticule extraction with and without
prophylactic corneal crosslinking: 1-year outcomes. J Cataract Refract
Surg. 2021 Sep 1;47(9):1196–204.
38. Sánchez-González J-M, Rocha-de-Lossada C, Borroni D, De-Hita-
Cantalejo C, Alonso-Aliste F. Prophylactic corneal crosslinking in
myopic small-incision lenticule extraction - Long-term visual and
refractive outcomes. Indian J Ophthalmol. 2022 Jan;70(1):73–8.
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Advances in Keratoconus : Imaging,
Therapeutics and Beyond
Bhavya Gorimanipalli, MD, Rohit Shetty, FRCS, PhD
Department of Cornea and Refractive Services, Narayana Nethralaya, Bangalore.
Abstract: The management of keratoconus has seen dramatic advances in both diagnostic and therapeutic
areas. We aim to update our readers with these latest advancements. Biomechanical assessment, with newer
combination indices, has become a more clinically applicable diagnostic tool. Polarization sensitive OCT
(PS-OCT) imaging, a functional variant of OCT has the potential to become an integral technology for the diagnosis
and monitoring keratoconus patients due to its inherent capability to image the collagen fibril orientation. Similarly,
hybrid tomographers with ability to perform segmental imaging can help enhance the diagnostic accuracy of ectasia
detection. The newer modifications of collagen crosslinking (CXL) of thin corneas including the latest method of
customized titration of UV-A ‘on’ time are discussed in detail. We further discussed the advancements and clinical
applications of molecular biology, genetics, and artificial intelligence in keratoconus.
Introduction orientation influences the visual acuity and direction dependent
Keratoconus is a progressive ectatic condition with a biomechanics of the cornea across many species.[6,7] The fibrils
multifactorial etiology. The prevalence of keratoco- are oriented orthogonally in the center, and circumferentially
nus in Indian population was reported to be as high as in the periphery. Orthogonal arrangement of collagen
2.3%.[1,2] Being a common ectatic condition, keratoconus has a fibrils result in highest visual acuity and improved corneal
significant impact on visual outcomes and quality of life of the biomechanics.[6] The GAGs and PGs do not directly contribute
patients.[3] Early diagnosis and accurate assessment of progres- to the corneal stiffness but play dominant role in maintaining
sion is crucial in the management of patients with keratoconus. the collagen fibril orientation and the interfibrillar spacing.[7]
With a phenomenal momentum in diagnostic techniques and The clinically applicable techniques of measuring corneal
therapeutic strategies in the field of ectatic corneal conditions, biomechanics have evolved over the years. In this section we
keratoplasty is no longer, the sole therapeutic choice for majority are going to discuss the two machines that are widely used
of patients suffering from keratoconus. In this review, we aim at by the clinicians worldwide - Ocular Response Analyzer and
updating our readers with the lesser known diagnostic advance- Corvis-ST.
ments in the field of ectatic corneal conditions. We further dis-
cuss gene therapy, the role of tear biomarker analysis and artifi- Ocular Response Analyzer (ORA)
cial intelligence in the management of keratoconus. Ocular Response Analyzer (Reichert Ophthalmic Instruments,
Advances in Imaging Buffalo, NY) is a non-contact tonometer which uses a
collimated air puff to indent the central 3-6 mm of the
Corneal Biomechanics cornea.[8] To understand the measurements of the ORA, we need
to understand the process of applanation and measurement
The corneal shape and its response to both external and internal acquisition. The air pulse, when activated, hits the cornea which
forces is influenced by its biomechanical properties. The starts deforming in an inward direction. When the cornea
diagnosis and the prognostication of keratoconus is traditionally reaches the first applanation point, the pressure of air pulse at
done through the topographic (and tomographic) assessment this point is recorded as P1. (Figure 1) The air pulse receives a
of the cornea. But, the concept of ectasia development is that a signal to shut off, once the cornea reaches the first applanation
focal weakening in the cornea initiates a cycle of biomechanical point. But due to inertia in the piston, the pressure continues to
decompensation leading to localized thinning and excessive rise till reaches a peak and then starts dropping, the cornea then
steepening.[4] Since, the biomechanical decompensation starts regaining its original shape, now moving in an outward
precedes the corneal steepening, comprehensive biomechanical direction where the pressure point P2 is recorded when the
assessment helps in early detection of ectasia and in the cornea passes through the second applanation point.[9] The two
assessment of risk of ectasia following refractive surgery.[5] clinically applicable parameters analyzed by the standard ORA
software are corneal hysteresis (CH) and corneal resistance
Understanding Corneal Biomechanics factor (CRF). These parameters are defined as follows
Extracellular matrix (ECM) of corneal stroma is made of Corneal Hysteresis = Difference between P1 and P2
collagens and the ancillary proteins including proteoglycans Corneal Resistance Factor = a [P1–0.7P2] + d
(PGs) and Glycosaminoglycans (GAGs). The collagen fibril
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where a and d are calibration and regression constants mention at this point of discussion. When the air pressure is
applied, the cornea starts to deflect in the backward direction
Figure 1 : Ocular Response Analyzer; P1 is the pressure recorded at but the whole eye also simultaneously begins to move in the
the first applanation moment, P2 is the pressure recorded at the second same backward direction. This antero– posterior movement
applanation moment. increases dramatically when the cornea attains maximum
Corvis ST displacement.[9] The dynamic corneal response (DCR)
The Corvis ST (Oculus, Wetzlar, Germany) is FDA approved parameters compensate for this whole eye motion. Deflection
as a non-contact tonometer and pachymeter. It monitors the parameters exclude the whole eye movement whereas the
corneal response to a collimated air puff using an ultra-high deformation parameters include the whole eye motion into the
speed (UHS) Scheimpflug camera that takes over 4,300 frames calculation.
per second, covering a 8.5 mm width through a single slit over
the recording time of 30ms.[10] Unlike, ORA which takes static Intra-ocular pressure and accuracy of biomechanical
measurements, Corvis ST allows dynamic examination of the assessment
complete corneal deformation process during the non-contact Intraocular pressure directly influences the accuracy of
tonometry. The parameters provided by the Corvis ST include biomechanical calculations. The chamber pressure in
intraocular pressure (IOP), deformation amplitude (DA), experimental corneal models is shown to have significant
DA ratio 1 or 2 mm, integrated inverse radius. The difference impact on the deformation response.[11] Clinically, the standard
between terms “deformation” and “deflection” needs a special Goldman applanation tonometry (GAT) is shown to give
inaccurate measurements in post – refractive surgery eyes.[12]
The biomechanically corrected IOP (bIOP), a Corvis ST index,
is developed to reduce the influence of corneal material
properties on the estimation of IOP.
Corvis ST – New Biomechanical Indices (Table-1)
The initial Corvis ST parameters were found to be a useful
adjunct in keratoconus diagnosis and monitoring but could not
act as a sole discriminators between healthy and keratoconic
eyes.[13] To improve the diagnostic sensitivity and specificity
in detection of ectasia, newer indices were generated from the
Corvis ST measurements.
S. No Biomechanical Index Description and Component measurements Authors
1. Based on the division between corneal thickness at Ambrosio Jr et al (2011)
Ambrosio Relational Thickness thinnest point and Pachymetric Progression Index
2. over the horizontal meridian Vinciguerra R et al (2016)
3. (ARTh) ARTh and Corneal Deformation parameters Ambrosio R Jr et al (2017)
4. Corvis Biomechanical Index Eliasy A et al (2019)
(CBI) Scheimpflug imaging and Corvis-ST parameters
Tomographic Biomechanical
Index (TBI) Based on Finite Element Modelling simulating the
Stress - Strain Index (SSI) effects of IOP and Corvis- ST air puff
Ambrosio Relational Thickness to the horizontal profile intelligence.[16] The authors showed that the cut off of 0.79
(ARTh) is one such parameter which considers the central provided 100% specificity and 100% sensitivity for detecting
corneal thickness (CCT), thinnest point and the pachymetric clinical ectasia in patients with bilateral keratoconus and those
progression index (PPI).[14] The horizontal Scheimpflug with asymmetric ectasia.[16] A cut off of 0.29 provided 90.4%
image of the cornea before the air pulse generation, is used specificity and 96% sensitivity in detecting fellow eyes with
for the computation of the thickness profile. The ARTh was normal topography of patients with asymmetric ectasia. Another
then combined with corneal deformation parameters using a novel stiffness parameter developed from the measurements of
logistic regression model to devise the Corvis Biomechanical Corvis ST is SP-A1 which is the resultant pressure (P1) divided
Index (CBI).[15] (Figure 1) The investigators showed that with by the deflection amplitude at Applanation point 1 (A1).[15]
0.5 as the cut off, CBI showed 98.4% specificity and 100%
sensitivity in separating healthy and keratoconic eyes.[15] The SPA1 = (Adjusted AP1 – bIOP) / A1 deflection amplitude
Tomographic Biomechanical Index was subsequently generated Stress Strain Index(SSI) is developed with the intention to
combining tomographic and biomechanical data using artificial generate a parameter that is independent of CCT and IOP. SSI
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was generated, based on predictions of corneal behavior is warranted.
using finite element (FE) numerical modelling simulating the The newer combination biomechanical indices help differentiate
effects of IOP and Corvis ST air puff.[17] The authors reported a biomechanically normal eye from a keratoconic eye. In the
independence of SSI with both IOP and CCT while maintaining case examples 1 and 2 (Figure 2 and 3), we show the differences
correlation with age in their dataset.[17] Even though, the in biomechanical indices between a normal eye and a
investigators showed the usefulness of SSI as a reliable biomarker keratoconus eye.
for keratoconus progression, validation with larger sample size
Figure 2 : The Vinciguerra Screening Report showing the biomechanically adjusted IOP (bIOP), Ambrósio Relational Thickness over the horizontal
meridian (ARTh) and the Corvis Biomechanical Index (CBI) in a normal eye (Figure 2a) and a keratoconic eye (Figure 2b). The screening report
provides the values of the biomechanical indices with the standard deviation values based on measurements in a healthy population. Note the CBI value
of 0.04 in normal eye and 0.95 in the eye with keratoconus.
Figure 3 : The Ambrósio, Roberts & Vinciguerra (ARV) Display in a normal eye (Figure 3a) and a keratoconic eye (Figure 3b). Note the difference in
Corvis Biomechanical Index (CBI) and Tomographic Biomechanical Index (TBI) values between a normal eye and a keratoconic.
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Figure 4 : The 4 map Refractive display (4a), Belin Ambrosio Enhanced Ectasia Display (4b), The Ambrósio, Roberts & Vinciguerra (ARV) Display
(Figure 4c) and the Vinciguerra Screening Report (Figure 4d) of left eye of a patient screened for refractive surgery shows abnormal Corvis Biomechanical
Index (CBI) (0.86) and Tomographic Biomechanical Index (TBI) (0.84). The refractive surgery was deferred and the patient was kept under observation.
Figure 5 : The Vinciguerra Screening Report (Figure 5a) and The Ambrósio, Roberts & Vinciguerra (ARV) Display (Figure 5b) of right eye of a patient
screened for refractive surgery shows borderline abnormal Corvis Biomechanical Index (CBI) (0.56) but normal Tomographic Biomechanical Index
(TBI) (0.15). Small Incision Lenticule Extraction with prophylactic CXL (SMILE- XTRA) was planned for this patient.
With the case examples 3 and 4 (Figure 4 and 5), we demonstrate With the case example 5 (Figure 6), we demonstrate the
the utility of the biomechanical indices in choosing the correct utility of biomechanical indices in objectively measuring the
refractive surgical technique in patients with borderline tissue stiffening effect of corneal crosslinking in a patient with
topographic features. progressive keratoconus.
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Figure 6 : OD Biomechanical Comparative display of a patient who underwent corneal crosslinking (CXL). The comparative biomechanical indices show
the stiffening effect of CXL.
Polarization Sensitive OCT - Imaging Corneal Collagen is able to provide tissue specific contrast. Birefringence is an
Topography and tomography, are imaging techniques that assess optical property of many fibrous tissues, where a transmitted
only the morphological end effects of steepening and ectasia polarized light is split into two component waves with phase
due to altered collagen fibril orientation in keratoconus eyes. difference based on the intrinsic tissue properties. The corneal
However, an understanding of corneal microstructure is essential birefringence is due to the presence of highly organized col-
to understand the structural pathobiology of keratoconus. In lagen fibrils aggregated into approximately 200 lamellae in the
this section, we describe a unique in-vivo imaging modality, stroma.[19,20] In Keratoconic corneas, the collagen fibril orienta-
polarization sensitive optical coherence tomography (PS-OCT) tion is dramatically altered, resulting in altered birefringence.
which measures corneal birefringence and provides information By measuring the birefringence, PS-OCT indirectly images the
about the collagen fibril orientation in healthy and diseased corneal microstructure and has the potential to diagnose the
corneas. sub-clinical forms of keratoconus before the onset of clinical-
Polarization Sensitive OCT (PS-OCT) - Principles ly significant morphological changes including thinning and
Optical Coherence Tomography(OCT), a well-established im- steepening.
aging modality in the field of ophthalmology, is an intensity Human cornea has a characteristic birefringence pattern
based imaging technique. Even with excellent resolution and (Figure 7a) with central low and homogenous phase
depth penetration capabilities, OCT lacks tissue specific con- retardation that increases approximately radially and
trast and is at times incapable of delineating morphological symmetrically toward the periphery.[20] The keratoconic corneas
changes in the tissues.[18] Polarization sensitive OCT, known display asymmetric or totally irregular retardation patterns
as a functional extension of OCT, acquires the information at the apex with locally increased retardation near the rim of
on the birefringence properties of the biological tissues, and corneal thinning.[21] (Figure 7b)
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Figure 7 : PSOCT images of normal eye (Figure 7a) and Keratoconic eye (Figure 7b). Note the central homogenous and low phase retardation in normal
eye and irregular phase retardation suggesting irregular collagen lamellar arrangement in a keratoconic eye.
Clinical Applications of PS-OCT - (Table-2) disturbance in birefringence is lesser when compared to eyes
As discussed earlier, PS-OCT images show strikingly abnormal with keratoconus, probably suggesting the inherent normal
corneal birefringence in keratoconic corneas. (Figure 7b) Eyes collagen distribution in these eyes with iatrogenic ectasia
with post LASIK ectasia show similar irregular birefringence (unpublished data).
when compared to healthy post LASIK eye (Figure 8), but the
Clinical Applications of Polarization Sensitive OCT in Ectatic Corneal Conditions
Diagnosis of Keratoconus
Diagnosis of sub-clinical forms of Keratoconus including Forme Fruste Keratoconus
Differentiating true progression of Keratoconus from pseudo progression
Assessment of risk of ectasia following refractive surgery
Monitoring of keratoconus eyes post cross-linking
Table 2 : OCT-Optical Coherence Tomography.
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Figure 8 : 8a, 8b, 8c Corneal Topography, pachymetry and PSOCT images of healthy post LASIK eye. Figure 8d, 8e, 8f Corneal Topography, pachymetry
and PSOCT image of an eye with POST–LASIK ectasia. Note the altered central birefringence in post LASIK ectasia eye suggesting disorganized collagen
fibril orientation.
PS-OCT imaging has the potential to be included in the PS-OCT imaging helps with decision making in this scenario,
screening armamentarium prior to refractive surgery. One of by providing information on the collagen fibril orientation.
the biggest dilemmas for refractive surgeons is to whether to In figure 9, we show a thin cornea with essentially similar
perform refractive surgery (or which technique to choose) in an birefringence pattern as a normal cornea, thus making this
eye with thin pachymetry but normal or borderline topography. particular eye suitable for refractive surgery.
Figure 9 : Corneal Topography (9a), pachymetry (9b) and PSOCT image (9c) of an eye with thin pachymetry. (9d) is a PSOCT image of an eye with
normal topography and pachymetry. Note the central homogenous birefringence in the eye with thin pachymetry demonstrating normal collagen
distribution and low risk of ectasia.
Assessment of serial PS-OCT imaging, shows changes in pattern and disorganization in the collagen fibril orientation
birefringence in patients with progressive keratoconus. This suggesting progression of keratoconus.
imaging modality helps provide conclusive diagnosis of The diagnostic technologies of biomechanical assessment,
progressive keratoconus when combined with topographic topography, PS-OCT (corneal birefringence imaging) can be
assessment. In figure 10, we demonstrate a case example of successfully applied together in keratoconus cases to improve
progressive keratoconus imaged serially with PS-OCT, which the diagnostic accuracy.
shows progressive increase in heterogeneity in the birefringence
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Figure 10 : OU serial Corneal Topography and PSOCT images of a patient with unilateral progressive keratoconus in OD(10a). Note that topographic
progression in OD comparative Scheimpflug imaging (10a) and the increased heterogeneity in the central birefringence pattern in right eye (10c).
Compare this appearance with the left (10b and 10c) eye with no progression where serial PSOCT images show similar birefringence pattern. This case
example demonstrates the diagnostic utility of PSOCT in assessing progression of keratoconus.
The figure 11 shows suspicious OD topography (Borderline In figure 12, we discuss the right eye imaging features of
BAD-D) of a 22 year old female. But the Corvis ST biomechan- a 21 year old male (left eye is normal with no features of
ical indices (CBI and TBI) are normal and PS-OCT imaging keratoconus). Corneal topography shows features suspicious of
shows central homogenous birefringence similar to a normal keratoconus. Biomechanical assessment and PS-OCT imaging
eye. Even with suspicious topographic measurements, this par- reveals abnormal CBI and abnormal birefringence respectively.
ticular eye can be treated as an essentially healthy eye. The patient is diagnosed as a keratoconus suspect and is kept
under close observation.
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Figure 11 : OD Pentacam of a 22 year old female showing borderline BAD-D value (11a). But the Corvis ST biomechanical indices (CBI and TBI) are
normal (11b, 11c) and PSOCT imaging shows central homogenous birefringence similar to a normal eye (11d). Thus, even with suspicious topographic
measurements, this particular eye can be treated as an essentially healthy eye.
Figure 12 : OD 4 map refractive display on Pentacam of a 21 year old male showing suspicious topography features (12a, 12b). Corvis ST biomechanical
index - CBI is abnormal implying poor biomechanics (12c) and PSOCT imaging shows increased central phase retardation (more heterogenous
birefringence) when compared to a normal eye (12d). This patient is kept under close observation with frequent follow up visits to monitor for progression.
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Segmental Imaging - Hybrid OCT based Tomographer thickness and stromal elevation over an 8mm diameter along
In this section, we discuss a new anterior segment optical with curvature maps and elevation maps of anterior and
coherence tomographer (ASOCT) combined with Placido disc posterior corneal surfaces.
based topography and high resolution corneal imaging with MS-39 based epithelial and stromal maps in assessing
a 16mm diameter (MS-39, CSO, Florence, Italy). It provides
keratometric indices for anterior and posterior corneal surfaces, keratoconus progression
pachymetric indices, elevation maps, keratoconus summary ASOCT based segmental tomography helps differentiate pseudo
indices, and aberration indices.[22] ASOCT, produces better progression from true keratoconus progression (Figure 13 and
anterior segment images with higher resolution when compared 14). The case example discussed in figure 13 explains how the
to Scheimpflug imaging. The higher resolution has made serial stromal and posterior elevation maps show an increase
it possible to accurately and reliably measure the epithelial with corresponding epithelial hypertrophy around the areas of
thickness.[23] The masking effect of epithelium on stromal thinning. The progression of keratoconus is confirmed in this
irregularities was previously reported.[24,25] Scheimpflug imaging case and crosslinking procedure was planned.
devices due to their intrinsic limitations in terms of resolution In a similar case (figure 14), Scheimpflug imaging shows
cannot obtain epithelial thickness measurements. These devices keratometric steepening between two visits, but the MS-39
cannot reliably distinguish topographic changes due to epithelial shows epithelial remodeling and stable stromal and posterior
remodeling from those due to underlying stromal changes.[24,26] elevation maps, demonstrating that this is a case of pseudo-
MS-39 provides information on epithelial thickness, stromal progression due to epithelial changes.
Figure 13 : (a) OD comparative map on the Pentacam showing progression in right eye (b) OD MS 39 comparative map shows an area of compensatory
hypertrophy around the area of thinning (donut sign) on the epithelial maps and an increase in the stromal elevation map.
Advances in Therapeutics Several authors introduced modifications to Corneal collagen
crosslinking (CXL) by increasing the functional corneal
Crosslinking of Thin Corneas thickness to shallow the CXL effect, by customizing irradiation
Cross-linking a thin cornea, with moderate to advanced of the ectatic tissue, and by reducing the total irradiance energy
keratoconus, is a challenge every treating surgeon likes to take to stay under the endothelial safety threshold of 0.65J/cm2. These
up, despite the significant complications. These are the patients advancements included the use of hypo-osmolar riboflavin,
who show high quantum of benefit, since successful corneal contact lens assisted CXL, lenticule assisted CXL, customized
crosslinking prevents progressive thinning and complications epithelial debridement, and individualized CXL. (Table-3)
like acute hydrops, works as a temporizing measure while these
patients are awaiting a corneal transplant.
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Figure 14 : : (a) OD comparative map on the Pentacam showing progression in the right eye (b) OD MS 39 Comparative epithelial map shows an obvious
epithelial remodelling (b) with no evidence of progression on the stromal or posterior elevation comparative maps.
Technique Authors Sample Size Riboflavin Concentration UV-A irradiation time and
Hypo-osmolar Hafezi et al (2008) 20 patients Iso-osmolar 0.1% riboflavin Dose
riboflavin applied every 3 min x 30 minutes 3mW/cm2 x 30 min – 5.4J/
followed by hypo-0.1% riboflavin cm2
in 0.9% Sodium chloride (NaCl)-
every 20 sec x 5 min/till the
pachymetry becomes 400µ
Contact lens-assisted Jacob et al (2014) 14 eyes Iso-osmolar 0.1% riboflavin 3mW/cm2 x 30 min – 5.4J/
CXL applied every 3 min x 30 minutes, cm2
UV-A barrier free contact lens
(Soflens, B&L) immersed in
iso-osmolar riboflavin x 30 min
placed over the cornea-
Customized / topogra- Seiler et al (2016) 20 eyes 0.1% dextran -free riboflavinx30 Customized UV-A
phy guided CXL min irradiation
Nordstrom et al (2017) 25 eyes 0.1% riboflavin every 2 min x 10 Customized UV-A
min irradiation sparing central
2mm
Customized epithelial Kymionis et al (2009) 4 eyes 0.1% riboflavin every 3 min for 3mW/cm2 x 30 min – 5.4J/
debridement Sachdev et al (2015) 3 patients 15 min cm2
Stromal lenticule Stromal lenticule (6.2mm 3mW/cm2 x 30 min – 5.4J/
assisted CXL diameter) was placed over the cm2
apex of the cone of the cornea,
0.1% riboflavin every 5 min for 30
min followed by every 5 minutes
during UV-A irradiation
Individualized CXL Hafezi et al (2021) 39 eyes 0.1% Hypo-osmolar riboflavin for Irradiation intensity =
20 min 3mW/cm2,
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DOS Times - Volume 28, Number 1, January-February 2022
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Technique Authors Sample Size Riboflavin Concentration UV-A irradiation time and
Dose
duration of treatment
based on intraoperative
pachymetry
Table 3 : CXL- Collagen crosslinking, mW- milliwatts, J/cm2-Joules/centimeter2, min-minutes, mm-millimeter.
NXT (New generation Cross-Linking for Thin Cornea) UV-A absorption co-efficient of riboflavin at different concentrations,
calculator (Figure 15) a specific UV-A ‘on’ time was calculated for the specific thickness
of the treated cornea, post de-epithelialization. The following
A simple but effective way to surpass the conventional barriers equations were used to determine the time:
to cross-linking in thin corneas, is to customize the UV-A ‘on’ T3mW = e(-46.86*[400-MST]*0.0001) (1)
time to the stromal thickness of the treated cornea.[27,28] By using T9mW = e(-93.72*[400-MST]*0.0001) (2)
the Lambert-Beer equation, with the knowledge on the specific
Figure 15 : NXT-UVA calculator screen (https://jscalc.io/calc/VmanUJD6yQ13VQQ6). The clinician can enter the thickness of the cornea, the calculator
gives the time duration for exposure of UV - A irradiation for 3mW/cm2 and 9mW/cm2 and for the riboflavin concentration of 0.1% and 0.2%. The
clinician can follow the UV - A exposure time based on the UV - A irradiation dose and riboflavin concentration.
The equations (1 & 2) are applicable for a UV-A irradiance of VmanUJD6yQ13VQQ6) Since, the total irradiation dose
3mW/cm2 and 9mW/cm2 (for accelerated protocols) with a is within the limits of endothelial toxic exposure, there is
riboflavin concentration of 0.1% (absorption co-efficient- 46.86 no risk of endothelial toxicity or decompensation.[28,29] Any
cm-1) and 0.2% (absorption co-efficient – 93.72 cm-1). ophthalmologist can easily apply the NXT- UVA calculator to
NXT-UVA calculator is currently freely available for the their practice, since this method requires only titration of UV-A
clinicians across worldwide to utilize this technology for “on” time and does not require any additional modifications of
crosslinking eyes with thin corneas. (https://jscalc.io/calc/ CXL procedure. (Figure 16)
Genetics of Keratoconus or genome sequencing and genome wide - association studies
Keratoconus is a heterogenous disorder with multifactorial (GWAS) help explore and identify novel genes and their role
etiology, with a known genetic predisposition with increased in the keratoconus pathobiology. GWAS, which test for single
incidence in families and monozygotic twins. But the disease nucleotide polymorphisms (SNPs) between cases and controls,
does not follow a classic Mendelian inheritance, and involves have revolutionized the search for genetic loci that influence
multiple genes that interact with several environmental and many complex multifactorial diseases. The allelic frequency
systemic factors. Due to the genetic heterogeneity, multiple differs significantly between the cases and controls, and helps
gene loci have been associated with the inheritance of understand the strength of association with a particular disease.
keratoconus in families by linkage analysis. The whole - exome As an example, specific LOX gene polymorphisms are shown
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Figure 16 : OD comparative map on Pentacam of a patient who underwent crosslinking procedure with UV-A irradiation time calculated by NXT-UVA
calculator. Note the preoperative thinnest corneal thickness (TCT) was 390µ. The comparative map shows flattening and stabilization of the cornea, 3
months following the CXL procedure.
to predispose individuals to developing keratoconus.[30] The The testing panel also provides definitive diagnosis of specific
LOX gene encodes lysyl oxidase enzyme which creates covalent corneal dystrophies based on the genetic data from TGFβ gene
crosslinking of fibrils of collagen and elastin.[31] By testing the and its 70 variants.
keratoconus patients for gene loci responsible for sub-optimal Keratoconus and Gene Therapy
responsiveness to collagen crosslinking may help individualize Mashhour et al. successfully transferred the Escherichia coli
the treatment so that only “genotypically suitable individuals” lacZ gene into ocular tissues including corneal endothelial cells
receive the therapy.[30] A recent multi-ethnic GWAS in 4,669 using an adenoviral vector in 1994.[33] Cornea is an excellent
cases and 1,16,547 controls, implicated corneal collagen matrix biological tissue for the gene therapy due to its immune privilege,
integrity pathways in the pathogenesis of keratoconus.[32] The transparency, accessibility and stability. Effective transfer of the
study team reported 36 gene loci strongly associated with IL-10 and tissue plasminogen activator (tPA) and other enzymes
keratoconus, including those near or within genes which code in a sustained concentration into the corneal tissue shows the
for fibrillar collagens (type 1 and 4), microfibrillar (6) and peri- plausibility and the promising clinical applicability of gene
fibrillar (12) structures, implicating impaired cohesion of the transfer into cornea.[34,35] Given the robust evidence of genetic
collagen matrix in the pathogenesis of keratoconus. LOX locus basis of keratoconus pathogenesis,[32] gene therapy is a promising
also showed significant association with one of SNPs associated treatment modality which remains a future prospect for now.
with the transcription of the LOX gene.[32] Future Directions
Genetic Testing - Risk of Inheritance of Keratoconus
A multigene testing panel that assesses the risk of inheriting Tear Biomarkers
keratoconus and corneal dystrophies is being introduced into The knowledge on molecular science enriches and brings
clinical practice. The test gives personalized objective polygenic out excellence in a clinician’s approach to a particular
keratoconus risk score, categorized as low, medium and high. disease management. The field of keratoconus research is
no different. In this particular section, we discuss the key
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molecular biomarkers and their role in the diagnosis and of subclinical keratoconus based on the tomographic parameters
management of keratoconus. Tear biomarkers are molecular derived from Scheimpflug imaging.[43-45] Since, diagnosis of
signatures of disease process in not just the ocular unit but subclinical forms of keratoconus is crucial, particularly in those
the entire human body.[36] In this section, we describe the undergoing refractive surgery, machine learning tools have
various tear biomarkers currently being explored by the potential to be integrated into clinical practice of refractive
scientific community and a novel point of care rapid diagnostic surgeons.
test kit that simultaneously analyses multiple tear biomarkers in AI, is also shown to predict the risk of progression of kerato-
a clinician’s office bringing molecular research to the clinician’s conus with considerable accuracy. Shetty et al developed an AI
door step. model that could differentiate local versus global progression in
keratoconus based on tomographic parameters.[46] Using the AI
Tear specific biomarkers for Keratoconus model, the authors compared the diagnostic decision on pro-
The pathobiology of keratoconus involves tissue degradation, gression based only on increase in steepest keratometry (Kmax)
abnormal extracellular matrix remodeling, collagen (local progression) versus based on concomitant change in mul-
deficiency,[37] and predominance of inflammatory cytokines, tiple tomographic parameters including index of surface vari-
and matrix metalloproteinases.[38] Keratocous eyes showed ance (ISV), index of height asymmetry (IHA), index of vertical
increased tear fluid levels of several inflammatory cytokines asymmetry (IVA), keratoconus index (KI) etc; (global progres-
including interleukins (IL) -4, -5, -6, -8, and tumor necrosis sion). They concluded that AI models assessing progression
factor alpha and beta.[39] Studies also show higher proteolytic based on increase in Kmax and other tomographic parameters
milieu and overexpression of matrix metalloproteinases in tears were in agreement in approximately 60% to 62% of the cases. In
of patients with keratoconus.[40] The assessment of ocular surface the rest 38% to 40% cases, AI models assessing multiple tomo-
biomarkers has significant therapeutic role, Shetty et al showed graphic parameters of ectasia, did not categorize a case as pro-
that treatment with topical cyclosporine 0.05% reduced the gression even though the Kmax showed more than 1D increase
epithelial expression of inflammatory factors (IL-6,TNF-alpha), over serial visits. This study brings out a pertinent concept that
MMP-9 and led to reduction in corneal curvature in patients performing CXL based on progression in just Kmax while ig-
with keratoconus.[41] noring the other valuable tomographic parameters may not be
necessary, and these patients may be kept under observation
Novel Point of Care Diagnostic Test Kit till they show progression in other tomographic parameters as
The knowledge of tear biomarkers can help build a customized well. This hypothesis needs to be tested by prospective interven-
therapeutic approach in the management of keratoconus. tional studies.
However, the need for storage and maintenance of the collected To conclude, the field of keratoconus has seen dramatic advances
tear fluid under rigid temperature conditions, elaborate tear in both diagnostic and therapeutic arms. Biomechanical
profiling process and the need for skilled technicians precludes assessment, with artificial intelligence and machine learning
the application of tear biomarker profiling on a wide scale. A driven newer combination indices, has become a stronger and
point of care tear MMP-9 detection kit was developed for the more clinically applicable diagnostic tool. PS-OCT imaging has
diagnosis and management of dry eye syndrome (DES).[42] the potential to become an integral technology for the diagnosis
We describe a novel office based, state of art, tear biomarker and monitoring keratoconus patients due to its inherent
detection kit. The test kit is an immunoassay based microfluidic capability to image the collagen fibril orientation. Multiple
simple plex cartridge, which is automated and requires authors have introduced modifications to the conventional
approximately 15-30 min of hands on time by the clinician or crosslinking procedure for thin corneas but the titration of
staff. The diagnostic test kit provides tear fluid measurements of UV-A irradiation “on” time could be the most simplistic
the biomarkers in duration of 80 minutes. The test kit currently approach. Molecular biology and genetics are no longer solely
measures the tear, aqueous and vitreous concentrations of an interest of researchers. Clinicians, may soon be able to apply
8 analytes including IL-10, IL-6, IL-17A, IL-1b, TNF-alpha the benefits of decades long basic and translational research to
(Tumor Necrosis Factor-alpha), sICAM-1 (soluble Intercellular their day to day clinical practice, with the availability of point of
Adhesion Molecule), VEGF -A (Vascular Endothelial Growth care diagnostic test kits.
Factor-A) and MMP-9 (Matrix Metalloproteinase-9).
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Overview of Simple Limbal Epithelial
Transplantation for Ocular Surface
Reconstruction
Abha Gour, DOMS, Aastha Singh, MS, Nidhi Gupta, DNB, Virender S. Sangwan, MS
Department of Cornea, Anterior Segment and Uveitis, Dr. Shroff ’s Charity Eye Hospital, New Delhi.
Abstract: Simple limbal epithelial transplant (SLET) as the name suggests is a simple but very effective technique first
described by Sangwan et al in the year 2012[1] and successfully replicated in many parts of the world. The principle
is to harvest a healthy donor limbal tissue and provide it a conducive environment generating limbal cells in the
diseased eye. Even though there is extensive literature available on the procedure and its results, this review aims to
simplify the procedure, for its better understanding and application.
Introduction large tissue is used from the donor eye to cultivated limbal
The most superficial layer of the cornea is formed by non- epithelial transplant (CLET)[4] in which these cells are
keratinised, stratified squamous epithelium which is constantly expanded as a sheet ex vivo adding significantly to the cost of
replaced by differentiation occurring in the limbal stem cells the procedure. Considering both these drawbacks Sangwan
(LSCs). At the limbus, these cells are located in the limbal and co-workers proposed a new technique they named simple
niche.[2] These cells continue to grow and replace the corneal limbal epithelial transplant (SLET) for the treatment of LSCD,
epithelial cells, and hence any damage in the limbal area from which had the advantage of in vivo expansion of the LSCs over
hereditary or acquired causes leads to the limbal stem cell an amniotic membrane which provided a basement membrane
deficiency (LSCD). and also the essential growth factors for these cells to grow and
Multiple modalities have been described for limbal stem replicate. Also, it does not require an expensive set up for ex vivo
cell transplantation from keratolimbal allograft (KLAL), cell expansion hence is gaining popularity in places which do
conjunctival limbal autograft (CLAU)[3] wherein a relatively not have access to such labs. (Figure 1)
Figure 1 : Schematic representation of KLAL,CLAU and CLET. 41 DOS Times - Volume 28, Number 1, January-February 2022
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Role of limbus as a protective barrier
The role of normal functioning LSCs in the maintenance of the
corneal epithelium and wound healing has been documented
with various animal experiments.[5] Along with the stem cells
and progenitor cells the limbal niche also consists of various
supporting cells, a specific extracellular matrix and factors
mediating biochemical and biophysical signals[6], and delicate
interaction between all these factors is important to maintain a
stable ocular surface. Any disturbance in the niche with respect
to trauma or uncontrolled inflammation disturbs this balance
leads to their depletion and hence the ability to maintain a stable
ocular surface. (Figure 2)
Figure 3 : Causes of LSCD in the Indian scenario.
Figure 2 : Anatomy of the limbus and differentiation of the cells. Clinical presentation
LSCD definition and causes Symptoms of LSCD
A limbal stem cell working group recently defined LSCD and In cases of partial LSCD the patient may be asymptomatic or
classified its causes and staging, based on which, limbal stem present with discomfort, irritation, or foreign body sensation
cell deficiency is an ocular surface disease caused by a decrease whereas cases total LSCD present with pain, photophobia,
in the population and/or function of corneal epithelial stem/ tearing, conjunctival redness, decreased vision or blindness
progenitor cells; this decrease leads to the inability to sustain the which can be severely debilitating.
normal homeostasis of the corneal epithelium.[7] This results in Evaluation and formulation of Plan of management
disruption of the limbal barrier and hence conjunctivalization Slit lamp evaluation shows conjunctivalization over the cornea
over the cornea with loss of normal corneal epithelium and also with or without neovascularization and loss of the normal
presence of other signs of epithelial dysfunction like persistent corneal clarity. Fluorescein staining is a very effective technique
epithelial defects, ocular surface inflammation and scarring. to pick up even subtle signs of LSCD most commonly seen in
Partial LSCD is defined as presence of residual functioning the superior limbus at the early stages of the disease. Normally,
LSCs in few quadrants with incomplete conjunctivalization the corneal epithelial cells on the surface are interconnected
of the cornea. Total LSCD is characterised by complete with tight junctions hence preventing the fluorescein dye from
conjunctivalization of the cornea and complete loss of corneal penetrating, but with the loss of the normal corneal epithelial
epithelial phenotype with total destruction of the limbal niche. phenotype, the conjunctival epithelium has loose junctions and
Causes hence the permeability of the dye is significantly more.[9]
Vazirani[8] et al evaluated the causes of limbal stem cell deficiency With the cobalt blue filter the dye allows the detection of abnor-
in a large volume study in the Indian scenario according to mal epithelial cells and highlights their distribution over the cor-
which the causes are (Figure 3) nea. The staining pattern varies with the severity of the disease.
In its early or mild there may be punctate epithelial staining in-
volving either whole or just a quadrant of the cornea. In cases of
advanced LSCD there is complete conjunctivalization over the
cornea, along with neovascularization constituting the fibrovas-
cular pannus and complete loss of the limbal architecture.
Care must be taken to rule out amblyopia in paediatric patients
and surgery must be undertaken only if decent visual prognosis
is anticipated . Etiology and severity of disease governs outcomes
in SLET much like in other techniques of LSCT.[10] Postoperative
outcomes and complications must be clearly communicated to
patients in order to have realistic expectations following surgery.
Detailed history is followed by a diligent clinical evaluation
on slit lamp. Lid abnormalities such as entropion, ectropion,
cicatrisation, trichiasis and MGD is carefully noted. Tear
film status, ocular surface inflammation and status of corneal
innervation is recorded. Extent of LSCD and pannus in clock
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DOS TIMES
hours, areas of corneal thinning and retained lime are observed. anesthesia depending on the patient age and other systemic
While diagnosis is mainly clinical, OCT and conjunctival features, and it’s also recommended preoperatively to use
impression cytology are other diagnostic modalities.[11] brimonidine tartarate 0.15% eye drop two-three times to reduce
Goals of treatment are essentially restoration of epithelisation the intraoperative bleeding.
and limbal health, improvement of visual acuity and improve-
ment in patients symptoms. Adnexal co-morbidities and dry eye Figure 4 : Schematic explanation of procedure of SLET.
must be treated by suitable medical or surgical techniques prior It’s important to preoperatively counsel the patient about the
to undertaking SLET. Similarly control of acute or chronic sur- need for anaesthetizing both eyes in case of an autologous
face inflammation either with topical or systemic immunosup- SLET. Both the eyes are prepped for surgery and first the normal
pressive agents such as steroids is advised prior to performing eye is approached to harvest the limbal biopsy. In patients with
the procedure. Ideal cases for beginners are thus unilateral cases partial limbal stem cell deficiency the biopsy can be harvested
following chemical injury with minimal inflammation and good from a healthy limbal quadrant in the same eye. A 5-6 mm of
tear film status. Patients undergoing allogenic transplant must chord length can be marked, and a limbus based conjunctival
be well prepped with immunosuppressives before surgery as de- flap is raised with the help of a conjunctival scissor till the
scribed in literature.[12] anatomical limbus is reached, after which blunt dissection with
Choice of surgery as per age – adult vs paediatric a 15 number surgical blade on Bard Parker handle is carried out
at least 0.5mm into the clear cornea. (Figure 5) This 5-6 mm
The paediatric population forms a major subset of cases of tissue is then excised near the corneal edge using a vannas
reporting with uniocular LSCD (up to 40%) the most common scissor and is then stored in balanced salt solution till the
cause in our country being chemical injury due to lime (chuna) recipient bed is prepared.
accidentally entering the eye. The inflammatory response to
trauma in paediatric eyes is supposed to be more pronounced Figure 5 : Blunt dissection of the conjunctiva into the clear cornea.
as compared to adults and hence affecting the outcome of the
procedure.[13] Very less literature is available on the outcomes of
SLET in this group but based on the cases included in the larger
outcome studies the outcomes of SLET are satisfactory.
The common problems reported specifically in this subgroup
being loss of the BCL with or without loss of the limbal biopsies
leading to failure of the procedure. This may be because of
epithelial cell growth on the BCL or during instillation of
drops and the patient may need repeated examinations under
anaesthesia to reposition the same. Simple modifications
in the technique have also been reported to prevent this
dislodgement.[14]
Surgical Technique and Pearls (Figure 4)
After a thorough evaluation to rule out persisting surface
inflammation, management of surface keratinization and any
co existing lid abnormalities the patient can be planned for the
procedure.
The most critical steps of the procedure involve
a) harvesting an adequate limbal biopsy from the donor site
and
b) performing an adequate pannus dissection to provide a reg-
ular surface for the LSCs from limbal biopsies to migrate
and repopulate the limbal niche.
In case of related-donor allogenic SLET the biopsies should
be harvested simultaneously or with a minimal time gap in
between the harvesting and implantation of these biopsies. In
cadaveric SLET one can use fresh tissue with a donor age of less
than 60 years harvested less than 48 hours before surgery can be
effectively utilized.
The surgery can be performed under peribulbar or general
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DOS Times - Volume 28, Number 1, January-February 2022
DOS TIMES
For preparation of the recipient bed first, any presence of limbus should also be dissected to leave a smooth transition
symblepharon is noted and released thus leaving the globe zone between the cornea and the limbus to aid in epithelization
freely mobile. Further, a 360-degree conjunctival peritomy of the surface.
is carried out starting 4-5 mm posterior to the limbus. It is The human amniotic membrane is then placed with the epithelial
preferable to start this dissection in the inferonasal quadrant side up on the recipient bed after cauterization of bleeders if
so that the bleeding while dissection does not hamper visibility. any and smoothed out, glued (TISSEEL Kit from Baxter AG,
Also, the surgical assistant can be asked to irrigate the surface Vienna, Austria) and tucked under the conjunctiva. (Figure 6)
being dissected so that a clear plain of dissection is visible. Once The limbal biopsy is then placed on the surface and dissected in
a plain is achieved the pannus can be peeled off keeping the blade 10-12 smaller explants and placed in the circular fashion in the
as parallel to the surface as possible and the underlying surface mid periphery sparing the visual axis, and glued to the amniotic
appears smooth. One must be careful to avoid deep dissection membrane, after which a bandage lens is placed, and the eye is
especially in thinned out areas wherein a preoperative evaluation patched overnight. (Figure 7)
on an ASOCT becomes important. After achieving a relatively
smooth corneal surface any remaining tags of pannus at the
Figure 7 : Explants divided into smaller pieces and arranged onto the
Figure 6 : Amniotic membrane glued to the recipient bed with fibrin glue. amniotic membrane.
Postoperative Period (2%) at around one week. Patients are followed up weekly till
Patients are evaluated on the first post-operative day to inspect one month post operatively followed by 3 monthly intervals
if the bandage contact lens, amniotic membrane, and stem cell thereafter. The explants fade over time and disappear over 6-12
explants are in situ. Post-operative treatment regime comprises months.[15]
of broad-spectrum preservative free antibiotic eyedrop, and Success of SLET has been defined as a completely epithelized,
lubricant eye drops prescribed four times a day in both recipient avascular and stable ocular surface at 6 weeks.[15] Growth of
and donor eyes. Topical prednisolone acetate 1% eye drops are epithelial sheet over amniotic membrane, thinning of explants
prescribed six times a day for a week and tapered gradually in the and variations in sub-membrane space using anterior segment
recipient eye while in the donor eye it is tapered over 4 weeks. OCT have been reported in literature. Additionally, pattern of
Topical corticosteroids are recommended to be maintained in ocular surface epithelialization has been observed to be like
a low dose over months in the recipient eye. Systemic immune CLET.[16] Epithelization has been mostly reported to be between
suppression is only advised in cases of allogenic SLET as per 1-2 weeks and proceeds more rapidly towards the limbus than
regimes described in literature.[12] Systemic corticosteroids are centrally.[17] Failure to epithelize or reappearance of pannus can
the most prescribed therapy followed by shifting to other agents be considered failure of the procedure. Cases of deep alkali burns,
such as cyclosporin, azathioprine and mycophenolate mofetil thermal burns, improper lid closure, severe dry eye fare poorly.
(antimetabolites). Surgical causes of failure include superficial plane of dissection
Close follow-up is advised until the epithelium heals. Fibrin glue during graft harvest, poor handling, and incorrect placement of
disintegrates by the end of the first postoperative week, and the limbal tissue. Early discontinuation of topical steroids or lack of
amniotic membrane disintegrates gradually over 6 weeks. The compliance with systemic immunosuppressive therapy in cases
epithelium is observed to regenerate 10-14 days post-surgery of allogenic SLET leading to rejection are other causes of failure.
however this may vary from case to case.[15] Status of epithelium SLET is a safe procedure and uncommon complications in the
regeneration can be assessed by removing the bandage contact recipient eye include corneal perforation during deep dissection
lens and staining ocular surface with sodium fluorescein dye of recipient bed, dislocation or tearing of amniotic membrane,
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DOS TIMES
hemorrhage under amniotic membrane, post-operative cells to accelerate healing and prevent the formation of pannus
keratitis, and loss of explants. In the donor eye risk of iatrogenic is presently under evaluation.
LSCD is negligible owing to small size of harvested donor tissue. Another factor is the early use of amniotic membrane which
Improper handling of conjunctival tissue can lead to hemorrhage if used in the acute stage makes the ultimate outcome more
or pyogenic granuloma at donor site. favorable. The amniotic membrane may not be easily accessible
Outcomes of SLET and its Limitations to all ophthalmologists in developing countries hence the
availability of a similar synthetic membrane with the necessary
SLET is a widely performed procedure today. Since first reported anti-inflammatory cytokines and growth factors is also a need
in 2010, publications on SLET and its outcomes in various clin- of the hour.
ical scenarios has such as LSCD following chemical injury, ther- Also important is to study the exact mechanism of action of
mal injury, pterygium, ocular surface neoplasia and conjunctival SLET, which is possible by creating an animal model of the
melanoma have been reported.[18-20] disease and evaluating the surface biology at every stage of
Sangwan et al reported successful outcomes in all six of their healing. Though still in the early stages, mesenchymal cells also
patients with an improvement in best corrected visual acuity have a promising role in the outcome of the procedure.
(BCVA) improved from worse than 20/200 before surgery
to 20/40 or better in four (66.6%) eyes.[1] Basu et al in a large Concluding Remarks
series reported success in 76% of the patients with two-line
improvement in visual acuity seen in 75.2% of the patients. In conclusion, SLET is an ingenious, successful, and cost-
Over two thirds of 125 cases in their study attained 20/60 or effective modality for limbal stem cell transplant with results
better vision[21] Another multicenter study comprising of eight comparable to the previously described techniques of CLAU
centers reported outcomes in 83.8% of the patients with 65 % of and CLET. Both the criteria for success that is re-epithelization
patients achieving visual acuity of 20/200 or better.[8] Among of the cornea and improvement in vison are comparable in all
pediatric cases, SLET has shown noteworthy results. Successful the three techniques. There are some areas of improvement
outcomes have been reported in 71.2% and 80% children by which also could be investigated in making this procedure even
Basu et al and Gupta et al respectively.[16,21] SLET has also been more reproducible.
reported to have better outcomes in previously failed CLET.[22]
Anatomical success and graft survival in keratoplasties following References
SLET has been reported to be between 70-85 percent.[23]
Additionally, various modifications of SLET such as G-SLET, 1. Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal
mini-SLET and sandwich technique have reported successful epithelial transplantation (SLET): A novel surgical technique for the
outcomes.[24-26] treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol
Possible limitations of SLET include dependence on human (2012) doi:10.1136/bjophthalmol-2011-301164.
source of amniotic membrane and fibrin glue. Availability, cost,
and proper handling of both can be challenging, especially for 2. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal
a novice surgeon. Tissue engineering based solutions such as epithelium. Surv Ophthalmol. (2000) 44:415–25. doi: 10.1016/
bioengineered or synthetic amniotic membrane can address S0039-6257(00)00109-0.
these limitations in future.[27] Moreover, at the end of the day,
it is a surgical procedure and includes the risks of anesthesia 3. Chen JJ, Tseng SC. Corneal epithelial wound healing in partial limbal
especially in pediatric patients as well as iatrogenic risk factors deficiency. Invest Ophthalmol Vis Sci 1990; 31:1301–1314.
such as perforation during pannus dissection. While the
technique is easily reproducible, nonetheless utmost care is 4. PellegriniG, TraversoCE, FranziAT,etal. Long term restoration
warranted in such aspects.[28] Additionally while gene editing of damaged corneal surfaces with autologous cultivated corneal
can be a possibility in CLET, SLET does not offer such solution epithelium. Lancet 1997; 349:990 – 993.
for inherited disorders.[27]
Future Perspectives 5. Maumenee AE, Scholz RO. The histopathology of the ocular lesions
produced by the sulfur and nitrogen mustard. Bulletin of the Johns
The outcome of the procedure is very encouraging to further Hopkins Hospital. 1948;82:121–147.
focus on the few challenges and improvement in the technique.
SLET can only be undertaken once the surface inflammation 6. Schlotzer-Schrehardt U, Dietrich T, Saito K, et al. Characterization
has resolved hence it’s important to develop modalities of extracellular matrix components in the limbal epithelial stem cell
for faster resolution of inflammation hence hastening the compartment. Exp Eye Res. 2007;85:845–860. [PubMed: 17927980.
intervention, which is of prime importance in the pediatric age
group considering the chances of amblyopia. The idea of using 7. Global consensus on the definition, classification, diagnosis and
amniotic membrane in the acute stage along with mesenchymal staging of limbal stem cell deficiency Sophie X. Deng, Vincent
Borderie, Clara C. Chan, Reza Dana et al Cornea. 2019 March ;
38(3): 364–375. doi:10.1097/ICO.0000000000001820.
8. Vazirani J, Ali MH, Sharma N, et al. Autologous simple limbal
epithelial & transplantation for unilateral limbal stem cell deficiency:
multicentre results. Br J Ophthalmol 2016; 100:1416 – 1420.
9. Huang AJ, Tseng SC, Kenyon KR. Paracellular permeability of corneal
and conjunctival epithelia. Invest Ophthalmol Vis Sci. 1989;30:684–
689.
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10. Basu S, Sureka SP, Shanbhag SS, Kethiri AR, Singh V, Sangwan 22. Basu S, Mohan S, Bhalekar S, Singh V, Sangwan V. Simple limbal
VS. Simple Limbal Epithelial Transplantation: Long-Term Clinical epithelial transplantation (SLET) in failed cultivated limbal
Outcomes in 125 Cases of Unilateral Chronic Ocular Surface epithelial transplantation (CLET) for unilateral chronic ocular
Burns. Ophthalmology. 2016 May;123(5):1000-10. doi: 10.1016/j. burns. Br J Ophthalmol (2018) 102:1640–1645. doi:10.1136/
ophtha.2015.12.042. bjophthalmol-2017-311506.
11. Singh A, Sangwan VS. Mini-Review: Regenerating the Corneal 23. Singh D, Vanathi M, Gupta C, Gupta N, Tandon R. Outcomes of
Epithelium With Simple Limbal Epithelial Transplantation. Front deep anterior lamellar keratoplasty following autologous simple
Med (Lausanne). 2021 May 28;8:673330. limbal epithelial transplant in pediatric unilateral severe chemical
injury. Indian J Ophthalmol (2017) 65:217–222. doi:10.4103/ijo.
12. Serna-Ojeda JC, Basu S, Vazirani J, Garfias Y, Sangwan VS. Systemic IJO_880_16.
Immunosuppression for Limbal Allograft and Allogenic Limbal
Epithelial Cell Transplantation. Med Hypothesis Discov Innov 24. Sati A, Banerjee S, Kumar P, Kaushik J, Khera A. Mini-Simple
Ophthalmol J (2020) 9:23–32. Limbal Epithelial Transplantation Versus Conjunctival Autograft
Fixation With Fibrin Glue After Pterygium Excision: A Randomized
13. Sejpal K, Ali MH, Maddileti S, Basu S, Ramappa M, Kekunnaya R, Controlled Trial. Cornea (2019) 38:1345–1350. doi:10.1097/
et al. Cultivated limbal epithelial transplantation in children with ICO.0000000000002007.
ocular surface burns. JAMA Ophthalmol 2013;131:731-6.
25. Malyugin BE, Gerasimov MY, Borzenok SA. Glueless Simple Limbal
14. Anju Pannu, Alok Sati et al Innovative technique of mini-simple Epithelial Transplantation: The Report of the First 2 Cases. Cornea
limbal epithelial transplantation in pediatric patients, Indian Journal (2020) 39:1588–1591. doi:10.1097/ICO.0000000000002467.
of Ophthalmology Volume 69 Issue 8.
26. Amescua G, Atallah M, Nikpoor N, Galor A, Perez VL. Modified
15. Deng SX, Kruse F, Gomes JAP, Chan CC, Daya S, Dana R, simple limbal epithelial transplantation using cryopreserved amniotic
Figueiredo FC, Kinoshita S, Rama P, Sangwan V, Slomovic AR, membrane for unilateral limbal stem cell deficiency. Am J Ophthalmol
Tan D; and the International Limbal Stem Cell Deficiency Working (2014) 158:469-475.e2. doi:10.1016/j.ajo.2014.06.002.
Group. Global Consensus on the Management of Limbal Stem Cell
Deficiency. Cornea. 2020 Oct;39(10):1291-1302. doi: 10.1097/ 27. Sangwan VS, Gupta N, Singh A, MacNeil S. Cutting corners, or
ICO.0000000000002358. PMID: 32639314. simplifying technology to reach more patients; using the body as
its own incubator for epithelial regeneration. Indian J Ophthalmol
16. Gupta N, Farooqui JH, Patel N, Mathur U. Early Results of Penetrating (2019) 67:1261–1263. doi:10.4103/ijo.IJO_632_19.
Keratoplasty in Patients With Unilateral Chemical Injury After
Simple Limbal Epithelial Transplantation. Cornea (2018) 37:1249– 28. Shanbhag SS, Patel CN, Goyal R, Donthineni PR, Singh V, Basu
1254. doi:10.1097/ICO.0000000000001681. S. Simple limbal epithelial transplantation (SLET): Review of
indications, surgical technique, mechanism, outcomes, limitations,
17. Hernández-Bogantes E, Amescua G, Navas A, Garfias Y, Ramirez- and impact. Indian J Ophthalmol (2019) 67:1265–1277. doi:10.4103/
Miranda A, Lichtinger A, Graue-Hernández EO. Minor ipsilateral ijo.IJO_117_19.
simple limbal epithelial transplantation (mini-SLET) for pterygium
treatment. Br J Ophthalmol (2015) 99:1598–1600. doi:10.1136/ Corresponding Author:
bjophthalmol-2015-306857.
Dr. Virender S. Sangwan, MS
18. Mednick Z, Boutin T, Einan-Lifshitz A, Sorkin N, Slomovic A. Simple Department of Cornea, Anterior Segment and Uveitis
limbal epithelial transplantation for recurrent pterygium: A case Dr. Shroff’s Charity Eye Hospital, New Delhi.
series. Am J Ophthalmol Case Rep (2018) 12:5–8. doi:10.1016/j.
ajoc.2018.07.006.
19. Boutin T, Mednick Z, Zhou TE, Showail M, Einan-Lifshitz A, Sorkin
N, Slomovic AR. Simple limbal epithelial transplantation to treat
recurring kissing pterygium. Can J Ophthalmol J Can Ophtalmol
(2019) 54:e54–e57. doi:10.1016/j.jcjo.2018.06.003.
20. Arya SK, Bhatti A, Raj A, Bamotra RK. Simple Limbal Epithelial
Transplantation in Acid Injury and Severe Dry Eye. J Clin Diagn Res
JCDR (2016) 10:ND06-07. doi:10.7860/JCDR/2016/19306.7997.
21. Basu S, Sureka SP, Shanbhag SS, Kethiri AR, Singh V, Sangwan
VS. Simple Limbal Epithelial Transplantation: Long-Term Clinical
Outcomes in 125 Cases of Unilateral Chronic Ocular Surface
Burns. Ophthalmology. 2016 May;123(5):1000-10. doi: 10.1016/j.
ophtha.2015.12.042.
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Recent Advances in Endothelial
Keratoplasty : Evolution of Excellence
Shikha Pandey[1], MS, Alok Sati[2], MS, Sanjay Mishra[3], MS, Sonali V kumari[4], MS, Sudhanshu Tiwari[5], MD, Brajmohan Chaudhary[6], MS
1. Department of Ophthalmology, Military Hospital, Jaipur.
2. Anterior Segment Surgeon, Department of Ophthalmology Army Hospital(R&R), Delhi.
3. Vitreo-Retinal Surgeon, HOD Department of Ophthalmology Army Hospital(R&R), Delhi.
4. Oculoplasty surgeon, Department of Ophthalmology Army Hospital(R&R), Delhi.
5. Department of Pediatrics, Military Hospital, Jaipur.
6. Department of Ophthalmology, Military Hospital, Jaipur.
Abstract: The fascinating history of Endothelial Keratoplasty can be traced back in 19th century. The concept of
Posterior lamellar keratoplasty was propagated by Barraquer for management corneal dystrophies. We have
come a long way from raising the anterior flap, resecting the recipient posterior corneal lamella to recipient’s
Descemet’s stripping and using air bubble to adhere donor lenticule to recipient’s posterior stroma as introduced
by Melles. The advent of 21st century saw an unprecedented momentum in the advancement of instruments
and surgical techniques that have made Endothelial Keratoplasty (EK) a safer and effective method to manage
multiple posterior corneal pathologies. This article inumerates a few recent advances like, Intra-operative
AS-OCT, air-pump assisted EK, indo-illuminator assisted EK, newer instruments and techniques to unscroll the
graft etc. The evolving horizon of endothelial keratoplasty is making the treatment of corneal blindness more
widely available and more efficacious. We are at the precipice of great innovations in the field of corneal endothelial
rehabilitation and the best is yet to come.
Introduction keratoplasty (ALK) and Posterior Lamellar Keratoplasty
The fascinating history of Endothelial Keratoplasty can be (PLK). ALK is replacement of anterior corneal tissue which
traced back in 19th century when in 1840 von Walther coined retains Descemet’s membrane (DM) and endothelium, but
the term ‘Lamellar keratoplasty’ (LKP) and years later Arthur violates Bowman’s membrane. PLK is replacement of recipient’s
von Hippel invented a mechanical trephine and performed first Descemet’s membrane and endotheium with or without
LKP successfully in human. The concept of Posterior lamellar posterior stroma. A detailed classification of optical PLK is
keratoplasty was propagated by Barraquer for management mentioned in table 1.
corneal dystrophies.[1] We have come a long way from raising the Endothelial Keratoplasty is indicated in pathologies involving
anterior flap, resecting the recipient posterior corneal lamella to Descemets Membrane and corneal endothelium. The host
recipient’s Descemet’s stripping and using air bubble to adhere stroma and epithelium is otherwise healthy. (Table 2) DMEK
donor lenticule to recipient’s posterior stroma as introduced and DMAEK take the idea of thin donor tissue to its maximum
by Melles.[2] The advent of 21st century saw an unprecedented potential Tas it is true anatomic replacement of DM and
momentum in the advancement of instruments and surgical endothelium. These two corneal layers are stripped from
techniques that have made Endothelial Keratoplasty (EK) a the recipient cornea and replaced with a scroll of DM and
safer and effective method to manage multiple posterior corneal endothelium harvested from a donor. When preparing DSAEK
pathologies. We will discuss the basic principles and major tissue, a donor age of approximately 25 years or above may be
breakthroughs in the field of EK in this article. most desirable due to increased corneoscleral rigidity on the
Classification of posterior lamellar keratoplasty other hand, while preparing DMEK tissue, a donor age between
Lamellar Keratoplasty is partial thickness replacement of 50 and 75 years is preferred due to improved ease of unscrolling
diseased corneal tissue. It can be classified as Anterior Lamellar the graft tissue during DMEK surgery.
ALK (John Malbran ALK classification)[3] PLK (John PLK classification)[3]
SALK- Superficial Anterior Lamellar keratoplasty DLEK- Deep Lamellar Endothelial Keratoplasty
<160 microns - F-DLEK: flap associated
- Without flap
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ALK (John Malbran ALK classification)[3] PLK (John PLK classification)[3]
MALK- Mid Anterior Lamellar keratoplasty
160-400 microns DSEK- Descemet’s stripping Endothelial Keratoplasty
- Manual
DALK- Deep Anterior Lamellar keratoplasty - microkeratome assisted or
400-490 microns - femtosecond laser assisted (DSAEK- Descemet’s stripping
Automated Endothelial Keratoplasty)
TALK-Total Anterior Lamellar keratoplasty DMEK- Descemet’s membrane endothelial keratoplasty
Almost 100% stroma DMEK-S with peripheral stromal rim (manual)
Table 1 : Classification of Posterior Lamellar Keratoplasty DMAEK- automated (microkeratome assisted or - femtosecond laser
assisted)
ECT- Endothelial cell Transplantation
ECA- Endothelial cell Activation
Indications Contraindications
Endothelial Dystrophies Stromal opacity/scarring
Congenital Hereditary Endothelial Dystrophy Corneal ectatic diseases
Fuch’s Endothelial Dystrophy
Posterior Polymorphus Dystrophy Keratoconus
Pellucid Marginal degeneration
Bullous Keratopathy Keratoglobus
Pseudophakic Post kerato-refractive surgery ectasia
Aphakic Phthisis bulbi/Hypotony
Post-toxic anterior segment syndrome(TASS)
Endothelial Failure from
Trauma, birth forecep injury
Congenital Glaucoma
Previous surgery
Angle closure
Glaucoma drainage devices
Iridocorneal endothelial (ICE) syndrome
Post-inflammatory and post-infectious
Uveitis
Endotheliitis- HZO, HSV, CMV
Previous Penetrating Keratoplasty with endothelial failure
Table 2 : Indications and contraindications of Endothelial Keratoplasty
DSEK donor tissue cut to an ideal thickness less than 100μm, which
DSAEK It is a method of PLK in which the recipient bed is is achieved by using micro-keratome double pass technique or
prepared by stripping off the recipient’s DM. A 3-5 mm sclero- femto-laser.[4]
corneal tunnel is made with visco-elastic substance filling the Graft insertion is done by using various forceps, like Kelman
anterior chamber, descemetorhexis with removal of host DM as Foreceps, Sheets glide (sheets intraocular lens), Busin glide
a single disk. Descemetorhexis is begun in the distal point (reusable funnel glide) or Insertors/injectors like endosertor,
from the anterior chamber entry site and usually, continued endoglide. (Figure 1) Vajpayee and group from India described
in clockwise fashion. The peripheral stroma is made rough a “hitch suture” technique to unfold the donor lenticule in
using the DSEK scrubber to enhance donor disk attachment to DSAEK to minimize endothelial damage.[5] A “taco fold”
recipient cornea. Ultra-thin DSEK (UT-DSAEK) surgery utilizes technique was also described.[6]
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DOS TIMES
Figure 1 : (A) Busin glide. (B) Sheets glide. (C) EndoGlide. (D) EndoSerter. (E) Neusidl Corneal Inserter. (F) EndoInjector.
DMEK surface which may hinder graft adhesion, or pathologies which
Transplantation of isolated donor endothelium and DM with limit anterior chamber visibility, like history of glaucoma
minimal graft stroma. It involves isolation of donor DM and filtration surgery, vitrectomy, significant corneal edema. For a
endothelium, recipient descematorhexis followed by donor in- novice surgeon, a young pseudophakic patient with minimal
sertion and positioning. Donor DM is can be isolated by several vitreous synersis, average anterior chamber depth and preplaced
techniques broadly grouped as Submerge and strip including. inferior laser peripheral iridotomy is a desirable case.
Submerged cornea using backgrounds away (SCUBA) tech- Recent Advances in Endothelial Keratoplasty
nique, and Punch and stain including Big Bubble technique,
Pneumatic dissection, Muraines punch and sinsky hook assisted Newer Instruments
roll preparation (SHARP). In SCUBA technique, the cornea is Various advances in instruments for anterior segment surgeries
positioned endothelial side up, the endothelium–DM complex is continuously enhancing the ease of operation and pot-
is scored in the periphery with a blunt instrument.[7] Traditional operative results. For example,
DMEK is performed under balanced salt solution (BSS) – the Femtosecond Laser DSAEK
“SCUBA” technique, which has one short-coming that once the The laser uses an infrared wavelength (1053nm) to deliver
detachment has been performed, the graft always rolls up with closely spaced, 3 microns spots that can be focused to a preset
the endothelium to the outside. It makes placement of the graft depth to photodisrupt the tissue within the corneal stroma.[9]
within the anterior chamber much more difficult than if the en- Femtosecond laser is used to create a dissection plane on the
dothelium was on the inside of the roll. Insertion of graft roll donor cornea mounted on artificial anterior chamber. It offers a
is done by glass pipette or IOL cartridge and injector, through potential advantage over microkeratome with regards to better
2.8mm corneal incision. sizing of the posterior lenticule, a smooth surface and precise
stromal cuts ideal for graft apposition.
DSEK vs DMEK
DMEK is vastly considered superior to DSEK in measures of For graft scroll preparation
small incision size, rapid post-operative recovery, lower rejection Reusable artificial anterior chamber land blade microkeratome
rate, and better visual potential due to reduced interface haze. is commonly used to make DSEK graft lenticule and DMEK
DSAEK offers less incidence of graft and less strong host graft scroll. Microkeratomes like Moria, Horizon or Amareus and
apposition at interface allows easier removal of failed/rejected femtosecond lasers can also be used to achieve precise graft
donor lenticule. DSEK leads to an average hyperopic shift of lenticules for Microkeratome assisted or Ultrathin DSAEK.
+1.00DS and higher order aberrations due to negative lens effect Moria Guarded punch is used for partial thickness trephination
of lenticule which are lesser in DMEK.[8] of DM in DMEK. The endothelial side is S stamped and graft is
DMEK is more technically challenging and, hence, deemed lifted from stromal bed by using suture ting forceps after a gentle
relatively contraindicated in eyes with aphakia, aniridia, Balanced salt solution jet. Then graft is stained in trypan blue for
discontinuous iris-lens diaphragm, irregular posterior corneal 3-5 minutes where it looks like “shark” in “ink water”.[10]
www.dosonline.org/dos-times 49
DOS Times - Volume 28, Number 1, January-February 2022
DOS TIMES
For host cornea preparation Use of Pre-cut donor Tissue
A reverse Terry-Sinkey hook is used for descemetorrhexis (to In 2006, eye banks overcame the unfounded inhibition of
score the marked circular area of host descemet’s membrane). preparing pre-cut tissues for DSEK and allowed eye bank non-
In DMEK, the technique of Overstripping, i.e., stripping surgical staff to prepare graft leticules. Now, even DMEK, PDEK
host DM 0.5 mm larger than graft scroll to prevent overlap tissues are also prepared by leading eyebanks and issued in pre-
of host and graft descemt membranes to avoid graft edge loaded form. It has the benefit of examining and preparing the
separation.[11] Sales Paddler stripper and Fogla Seperator is graft under specular microscope and slit lamp, which is not
used to score underlying stroma as rough host stromal bed can possible intra-operatively. Also, one donor tissue can be used
increase risk of graft separation in DMEK. Straiko twin ring to harvest DALk graft, DSEK or DMEK graft. It reduces the
forecep is used to remove stripped DM without engaging stroma. demand and supply gap of corneal tissues.
For scroll insertion Laaser et al has established that Optisol-GS for short term stor-
Fogla DMEK canula is a specialised close ended canula with age at 4 degree and organ culture at 34 degree has comparable
two horizontally oriented orifices on each side which helps to jet post operative BCVA, central corneal thickness and endothelial
the leaflets of a tight scroll to achieve a double leaftlet cell density. Newer storage media like LIFE 4 degree C, Eusol C
configuration.[12] The Straiko Injector, which is a modified Joned and Chen medium are a few latest additions in the list of stor-
tube, helps in controlled entry of scroll by creating a venturi age media. There is further evidence that longer storage time
effect when tissue is aspirated from narrow, high flow orifice of depletes donor T cells and reduces risk of graft rejection. Ex-
injector to its wider, low flow base. It ensures that there is no perimental studies have suggested that Nitric oxide synthase in-
reflux from anterior chamber into the syringe after tip is fully hibitor and fibroblast growth factor-2, when added can further
occluded in the main incision. The Veldman Venn technique improve graft survival.[14]
can be used to check scroll orientation inside the injector. Here,
the ‘V’ which is overlapping edge of scroll is inspected under Modifications in DMEK
operating microscope. Then the syringe is rolled between
the fingers. If the rotation of the V of the scroll is in the same Hemi DMEK
direction, it is right side up. If the V rotates in the opposite It is based on the evidence that entire coverage of denuded host
direction, it is upside down. In this case the bevel is rotated area is not required and and total surface area of untrephined
upside down to get right orientation. half-moon shaped hemi-graft is comparable to trephined
Role of Anterior segment OCT (ASOCT) full graft, hence the endothelial cell count, the post-opertaive
ASOCT has widely accepted role in pre-operative planning, outcomes are also similar. (Diagram 1) Although, there is an
including measurement of central corneal thickness, size of obvious mismatch in graft’s semi-circular shape and a circular
graft lenticule, potential for graft apposition, decision regarding descemetorrhexis of host cornea, it has been observed that
DSEK or DMEK (DSEK is preferred eyes with gross graft host entire host area is covered by endothelial cells post 6 months.[15]
mismatch) and anterior chamber anatomy where corneal edema Descemetorrhexis only (n-DSAEK)) and Descemet
limits visibility. (Figure 2) Membrane Endothelial Transfer (DMET)-
Intra-operative hand-held OCT or OCT device with C arm of Histological evidence of host endothelial cells observed in
operating suite. iOCT has enabled surgeons to visualise graft various full thickness corneal grafts suggest that peripheral stem
apposition, graft orientation, interface fluid in real time.[13] cells of host cornea have the ability to proliferate and migrate
Post-operative OCT imaging has enabled early visualisation of slowly. In Fuch’s endothelial corneal dystrophy, the corneal
graft orientation and apposition which was precluded due to guttae act as a barrier against proliferation of peripheral stem
corneal edema. It also provides excellent insight during graft cells and central migration of endothelial cells, thus, limits
malfunction regarding surgical decision making. corneal ability to heal itself. N-DSEK involves descem (FECD)
etorhexis of central part of host cornea to remove these guttae
Figure 2 : AS-OCT of a DSEK case with clear view of graft lenticule and and allowing migration of peripheral endothelial cells, no graft
interface. is introduced. In DMET, a small donor graft is inserted after
descemetorrhexis which serves to remove guttae of host cornea
through a small incision and is secured at the incision.[16] This
graft is supposed to induce peripheral corneal endothelial cells
to centre of host cornea.
Techniques to prevent donor lenticule detachment
Endo illuminator-assisted DMEK or PDEK
When chandelier illumination is inserted in host anterior
chamber through a corneal side port, it leads to sclerotic scatter
like illumination and provides optimum illiumination to
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