persistent or recurrent corneal ulcers - thea.be€¦ · after “laucoma” in 2012, “g glaucoma...

w w w. t h e a -t r o p h y. c o m

thea international contest of clinical cases in pathologies of the eye

2013

persistent or recurrent

corneal ulcers

the clinical cases

20142015

tRoPhY 2014-2015 the clinical cases5


preFaceMr. Jean-fRédéRic

chibRet

laboratoires théa is an independent european pharmaceutical company fully specialised in ophthal-mology. for more than 20 years, developing innovative products in all the therapeutical classes in ophthalmology by working closely with the european ophthalmologists has always been a priority. education has also always been a tradition for the chibret family. laboratoires théa supports seve-ral educational activities and in 2012 introduced tRoPhY, ‘théa euRopean contest of clinical cases in Pathologies of the eYe’. tRoPhY is a yearly online contest, designed to encourage residents and fellows in ophthalmology to play an active role by sharing the findings of their case studies and their experience. all information concerning this contest is available on the dedicated website: www.thea-trophy.com originally intended for european young ophthalmologists, it is with great pleasure that we announce that the tRoPhY boundaries will be widening for the next edition. from the fourth edition on, the contest will also open to residents and fellows of Russia, Ukraine, Morocco, algeria and Mexico.

the process remains the same. the contest is organized in two rounds (national and international): a national jury selects the best case from each country and then an international jury designates three winners among the best cases from the first round. the three international winners are invited by laboratoires théa to participate in the aRVo annual meeting in the United states of america and to present their clinical case at laboratoires théa’s symposium.after “glaucoma” in 2012, “glaucoma and ocular surface” in 2013, this year’s topic was “Persistent or recurrent corneal ulcers”.

the topic for the 2015-2016 tRoPhY will be about cornea. a healthy cornea is vital for maintaining the health of the eye and good, clear vision. cornea can be damaged through a wide range of conditions induced by several diseases and invol-ving various process such as inflammation, infection, degeneration, injuries, and inherited dystrophies these conditions can cause disabling symptoms such as ocular irritation and pain and clinical signs (corneal erosions, corneal ulcerations….) leading, if not treated, to significant vision loss. the medical management of corneal diseases requires first, the treatment of underlying diseases and also the control of inflammation and ulceration for the restoration of the normal physiology of ocular surface and tear film. therefore, a wide variety of medical treatments for corneal damages have been developed, from artificial tears to specially formulated eye drops. in this field, almost every patient appears to have a very specific and complicated history and could potentially be a unique and novel clinical case. this is why “Management of corneal diseases” was considered to be a very inspiring topic for tRoPhY 2015-2016.

We look forward to receiving clinical cases from across the world on “Management of corneal di-seases” and wish all the best to the candidates.

m. Jean-Frédéric chibret President of laboratoires théa



preFaceProf. chRistoPhe

baUdoUin

the first edition of the contest of clinical cases in ophthalmology, called tRoPhY, organized by laboratoires théa took place in 2012 and was undoubtfully a success.

this year, the third edition covered a very specific topic: “Persistent or recurrent corneal ulcers”.

not less than eleven european countries participated to the 2014 contest and 42 cases were sub-mitted. after a national selection by acknowledged ophthalmologists in each of these countries, an interna-tional jury of glaucoma experts selected the three best cases.

the first place was awarded to “a troublesome triad: atopic dermatitis, conjunctival intraepithelial neoplasia, and recurrent corneal ulcers”, by dr thabo laPP from geRManY.

the second place went to “neurotrophic keratopathy in type i familial amyloidotic polyneuropathy - a new therapeutic approach” by dr Marta gUeRRa from Portugal.

the third place was attributed to “an unusual cause of persistent corneal ulcers: bilateral mycobac-terium chelonae keratitis” by dr V. swetha Jeganathan from scotland.

the three european winners had the opportunity to present their cases to an international audience at the thea symposium during the 2015 aRVo congress in denver.

besides these three winners, the best national cases selected at the country level are reported in this brochure available on line on the tRoPhY website.

the participation to this contest is easily accessible and submissions are done on line (http://thea-trophy.com/).

i warmly invite the residents and fellows to participate to this contest; the topic for next year is “Management of corneal diseases”, which stays within the scope of corneal disorders.

like the previous editions, the juries made of ophthalmologist experts will appreciate the submitted cases according to their originality, their clarity, their contribution to knowledge in ophthalmology and the quality of the illustrations. isolated case reports but also cases series or innovative clinical research can be submitted.

let’s continue the tRoPhY success story!

prof. christophe baudouin Md, Phd Quinze-Vingts national ophthalmology hospital Vision institute Paris, france



T H É A G I V e s 3 AP P L I C AN T s T H e O P P O R T U N I T Y T O P R e s e N T AN U N P U b L I s H e d C L I N I C AL C A s e T O AN I N T e R NAT I O NAL AU d I e N C e d U R I N G T H e T H É A sY m P O s I U m AT T H e 2 0 1 5 ARVO m e e T I N G.

a national jury of experts in ophthalmology will select the best clinical case among those submitted by contes-tants of their country.the jury will grade the clini-cal cases according to the following criteria: • clarity, • originality, • quality of illustrations, • contribution to ophthalmo-

logical knowledge.

in early december, the best case from each country will be submitted to a european jury of experts that will decide the three winners of the 2014 trophy contest.

the topic oF the 3rd edition oF the contest was "persistent or recurrent corneal ulcers"

the trophy contest takes place in 2 rounds.

RoUnd

n°1RoUnd

n°2

NOVEMBER 2014

NatioNal selectioN

december 2014

EuropEan final

a chance for the three winners of the contest to present their work during théa symposium at the 2015 aRVo meeting in denver, Usa, paid for by théa (registration, travel and accommodation).*

awards

*subject to acceptance by regulatory authorities they depend on.

20152016

the topic oF the 4th edition oF the contest is "management oF corneal disorders".

february 3rd, 2015 – submission openingoctober 31st, 2015 – deadline for submission of cases on www.thea-trophy.comnovember 2015 – round 1: selection of the best national cases december 2015 – round 2: selection of the best three european casesJanuary 2016 - the winners of the 2015-2016 tRoPhY contest announced

milestones

how to enter?

to ensure an independent and fair vote, contestants will remain anonymous until the end of the contest. a contestant number will be given upon submission of the clinical case. this number will be used throughout the entire process.laboratoires théa will not release any information that might help identify the contes-tants. likewise, members of the juries will remain anonymous to the contestants

conFidentiality

submissions can be done on www.thea-trophy.com before october 31th, 2015. all submit-ted clinical cases should be in english and follow the structured format below:

- title- case PResentation With illUstRations and figURes- discUssion - conclUsion

fUll RegistRation PRocess and RUles aRe aVailable on www.thea-trophy.com

trophy becomes international.the contest is now open to all residents or fellows in ophthalmology from the following countries:aUstRia, belgiUM, denMaRk, finland, fRance, geRManY, gReece, iReland, italY, lUxeMbURg, the netheRlands, noRWaY, Poland, PoRtUgal, sPain, sWeden, sWitzeRland, tURkeY, the United kingdoM, RUssia, UkRaine, Mexico, MoRocco, algeRia.

who can participate?

RoUnd

n°1

NatioNal selectioN

noVeMbeR 2015

RoUnd

n°2

INTERNATIONAL fINAL

deceMbeR 2015

top 3clinical cases

trophyedition 2014

“a troublesome triad: atopic dermatitis, conJunctival intraepithelial neoplasia, and recurrent corneal ulcers”dr. thabo laPPUniversitätsklinikum freiburg – germany

“neurotrophic keratopathy in type i Familial amyloidotic polyneuropathy - a new therapeutic approach”dr. Marta gUeRRacentro hospitalar da Universidade de coimbra – portugal

“an unusual cause oF persistent corneal ulcers: bilateral mycobacterium chelonae keratitis”dr. V.swetha Jeganathannhs dUMfRies and galloWaY – scotland

1

2

3

P.14

P.24

P.34



trophy winners at théa arvo symposium in denver on may 5th, 2015.trophy winners at théa arvo symposium in denver on may 5th, 2015.

théa symposium during the aRVo 2015 meeting

théa symposium during the aRVo 2015 meeting in denver


from left to right: henri chibret, Jean-frédéric chibret, christophe baudouin, Marta guerra, swetha Jenagathan, tabo lapp, bernard duchesne

théa trophy 2014-2015 winners




introduction

dr. thabo benjamin laPP was born on January 31st, 1981 in francistown (botswana). he was licensed in medicine from the examination board of the state of saxony-anhalt, halle/saale, germany. he did his clinical internship in ophthalmology at the Meei, harvard Medical school in boston (Usa). he speaks several languages: german (native language), english (fluent), french (basic knowledge), dutch (basic knowledge), and latin.author and co-author of eighteen scientific works (twelve articles and six pos-ters), he has received three awards and two grants. he is a reviewer for four journals (bJo, ioVs, cornea, and immunotherapy). he is also a dog, doP, gMc, and aRVo member.

he is currently a clinical fellow at the cornea and external eye diseases department of the University eye center of freiburg in germany.

resume

1

atopic dermatitis (ad) is a dermatological disease leading to dry and scaly skin. even though the causes for ad are not fully understood, there is strong evidence that muta-tions within the filaggrin gene (flg) strongly increase the risk for developing ad [1 - 2]. Many ad patients suffer from severe, chronic ocular surface disorders, indicating that ad leads to a complex immunolo-gical disturbance of the ocular surface. ocular manifestations of ad can in-volve the lid margin, the conjunctiva, the limbus, and the cornea, resulting in any combination of blepharitis, conjunctivitis, limbal insufficiency and/or kera-titis [3 - 4]. common clinical ocular problems are punctate epithelial keratopa-thy, persistent epithelial defects, shield ulcers, and corne-al vascularization [5 - 7]. additionally, bacterial and viral superinfections [8], as well as malignant tumors of the conjunctiva (e.g. conjunctival intraepithelial neoplasias [9]) can worsen the clinical course. interestingly, apart from the ocular surface disor-ders, ad is also associated with kerato-conus [10].

We present here a patient suffering from a combination of severe surface alte-rations due to ad and additional pre-terminal glaucoma. the ocular surface alterations resulted in limbal insuffi-ciency leading to recurrent therapy-refractory corneal ulcers in the right eye and complete corneal conjunctiva-lisation of the left eye. additionally, a conjunctival intraepithelial neoplasia (cin) in the right eye complicated the clinical course.

Management of ad associated ocular surface alterations is challenging. the increased incidence of ocular surface malignancies [11 - 12], the worse outcome of glaucoma (i.e. due to the increased us-age of topical and systemic steroids as well as due to scaring of the inflamed conjunctiva after fil-trating surgery [13]), and severe corneal defects that are restricted in their curability, require com-plex immunosuppressive and surgical treatments as presented here in this clinical case.

a troublesome triad: atopic dermatitis,

conJunctival intraepithelial neoplasia,

and recurrent corneal ulcers

dr thabo laPP Universitätsklinikum freiburg – germanye-mail [email protected]



a troublesome triad: atopic dermatitis, conJunctival cin,

and recurrent corneal ulcersthabo laPP

case presentation a 53-year old male patient was referred to our hospital for a second opinion in March 2010. Medi-cal history revealed a severe atopic dermatitis and discitis.

Visual acuity in the right eye was 6/60 and defective light perception in the left eye. the patient had cataract surgery in both eyes in 1998 due to a bila-teral steroid-induced lens opacification. both eyes had a long-term history of steroid-induced glaucoma with intraocular pressure in the od up to 55 mmhg and several episodes of ioP exceeding 60 mmhg in the os; the right eye underwent a tra-beculectomy with mitomycin c (MMc) in 2005. because of a progresssive endothelial decompen-sation in the right eye a descemet stripping automated endothelial keratoplasty (dsaek) was performed in January 2009. additionally, a trophic corneal ulcer occurred in the right eye in sep-tember 2009 once. the external ophthalmologists decided not to do any further operations in the left eye besides a removal of a small conjuncti-val cyst in december 2009 because of the absolute glaucoma.

the referral to our clinic was initiated by the patient’s local ophthalmologist after histology of sur-face scrapes of the od revealed atypical conjunctival alterations.

clinical examinationclinical examination revealed anterior and posterior blepharitis in oU. the right eye showed lim-bal stem cell insufficiency, corneal and conjunctival scarring, and a calcified corneal ulcer (fig. 1 and black arrow fig. 2). the bleb of the previous trabeculectomy (blue arrow, fig. 2) was flat and densely vas-cularized. limbal insufficiency involved the whole limbus resulting in conjunc-tival and corneal scaring and increased vascularization (green arrows, fig.2). additionally, the inferior conjunctiva and the inferior cornea were covered with a flat, whitish, gelatinous tissue (fig. 1 – black asterisk, fig. 2, middle and inferior picture). the cornea of the left eye was completely covered with vas-cularized conjunctival tissue (fig. 1).

figure 1 – anterior eye segments of the right and left eye at first presentation. the slit lamp images show a magnification of the deep cen-tral epithelial and stromal defect in the right eye as well as a flat whitish gelatinous tissue involving the inferior cor-neal quadrant and the ad-jacent limbus (*).

figure 2 – further details of the right anterior eye segment. the bleb of the previous trabeculectomy (blue arrow) was flat and densely vascularized; limbal insufficiency involved almost the whole limbus (green arrows). additionally, the inferior conjunctiva and the inferior cornea were covered with a flat whitish gelat-inous tissue (middle and inferior picture and fig. 1).

od (03/2010) os (03/2010)



superficial keratectomy and histologyWe removed the whitish conjunctival und corneal alterations by excising parts of the conjunctiva and performed a superficial keratectomy in the inferior cor-neal quadrant. additionally, we used a 2 minute intraoperative MMc treat-ment and closed the defect with an amniotic membrane.

histology of the excised specimen showed multiple epithelial islets (fig. 3 a and c) above connec-tive tissue (fig. 3 d). the epithelium (fig. 3 b) contained cells with defect maturation in the upper epithelial layers and varying nuclei sizes, indicating the presence of a conjunctival intraepithelial neoplasia (cin – grade i and ii; fig. 3 b, c, and e). the borders of the excised specimen were free of dysplastic epithelium.

We added a topical post-operative MMc treatment (0,02%; three cycles à two weeks with a one week break in-between each cycle) to prevent recurrence of the cin [9].

due to a bacterial-associated discitis in medical history the neurosurgeons and immunologists rec-ommended not to prescribe systemic mycophenolate mofetil or systemic steroids; instead they recommended a trial with systemic cyclosporine a (csa) treatment, keeping in mind the need of regular infec-tious-/immunological controls.

figure 3 – histological details of the cin. histology of the excised specimen showed multiple epithelial islets (3a and 3c) above connective tissue (3d). the epithelium (3b) contained cells with defect maturation in the upper epithelial layers and varying nuclei sizes.

limbal keratoplastythe regime was well tolerated. there were no signs of recurrence of the cin after 24 months. to minimize epithelial toxicity we stopped the topical MMc treatment after three cycles and pre-scribed topical pimecrolimus ointment for the peri-ocular skin (oU) as well as lubricating drops every hour in oU, topical anti-glaucomatous drops (dorzolamide combined with timolol twice daily w/o preservatives; od), and ciclosporine a eye drops (0,1% twice daily, od).

Unfortunately, the patient presented in a&e in november 2011 with a deep corneal ulcer in the right eye, a surrounding corneal epithelial defect, and signs of bacterial keratitis. We prescribed topical antibiotics and immediately performed a steam cautery abrasion [14] [first description by karl Wessely 1912] of the superinfected bacterial plug and injected subconjunctival ste-roids. We covered the deep corneal defect with amniotic membrane (sandwich graft). Within the following twelve weeks there were four more episodes of recurrent epithelial erosions which were handled with a bandage lens (fig. 4) under topical ofloxacin eye drops (5 times daily in the od).

over the next three months the epithelial defect healed but there was a pro-gressive conjunctivalisa-tion of the cornea as seen initially only in the left eye (fig. 1; os) which lead to a progressive de-crease in vision in the right eye.

the conjunctival tissue covering the cornea could not easily be removed wit-hout causing further epithelial erosions due to the fragile epithelium in the right eye. the conjunctivali-sation pro-gressed until the complete cornea was covered, resulting in acuity of hand movements only in both eyes. to regain vision in the right eye we discussed further surgical alternatives. due to the fact that a dsaek had already been performed in the right eye a deep anterior lamellar keratoplasty (dalk) was not possible. Penetrating keratoplasty is known to be a high-risk operation in ad patients; the rejection risk is significantly increased due to the ongoing surface inflammation [15 - 16]. additionally, the limbal insufficiency will promote continuous conjunctival overgrowth. We therefore decided to transplant an hla-matched limbo-cor-neal allograft to minimize long-term postoperative surface problems [17].

figure 4 – the clinical course two years after first presentation. the recurrent epithelial erosions re-quired coverage with contact lenses (▼). furthermore the corneal ulcer led to a progressive thinning of the corneal stroma (*); the borders of the previous dsaek performed in 01/2009 can be detected (white arrows).

*

a troublesome triad: atopic dermatitis, conJunctival cin,




discussion

in our case the patient’s left eye had hand motion vision only, due to steroid-induced terminal glaucomatous optic nerve damage. the right eye showed limbal insufficiency and consecutive cor-neal ulcers as well as a conjunctival intraepithelial neoplasia.

Management of ocular complications resulting from ad is challenging. the right eye showed signs of a severe limbal insufficiency resulting in corneal conjunctivalisation additionally to recurrent epithelial defects and consecutive corneal ulcers. a conjunctival intraepithelial neoplasia – most likely related to the ad associated ocular surface alterations – complicated the clinical course. in the left eye the ad lead to a complete conjunctivalisation of the cornea.

ad leads to a breakdown of the ocular surface immune homeostasis resulting in limbal insuffi-ciency, conjunctival dysplasia (e.g. cin), epithelial defects, and consecutive conjunctivalisation. dysplastic conjunctival tissue requires complete excision and intensified immunomodulating topi-cal treatment – unfortunately these current therapeutic strategies are often toxic to the already (ad associated) pre-damaged limbal stem cells and the corneal epithelium.

to optimize the long term outcome in ad affected eyes limbal keratoplasty combined with sys-temic immunosuppression serves as an alternative to regular perforating keratoplasties. trans-planted donor limbal stem cells provide the basis preventing recurrent corneal ulcers; the intact limbal barrier prohibits corneal conjunctivalisation.

conclusion

• atopic dermatitis (ad) is often associated with various changes of the ocular surface

• ad leads to limbal insufficiency resulting in corneal neovascularisation and conjuncti-valisation as well as in recurrent corneal erosions and ulcers

• additionally, conjunctival neoplasia can complicate the clinical course

• limbal keratoplasty is a surgical alternative to regular penetrating kerato-plasties in eyes with severe ad associated ocular surface alterations

the operation was performed in october 2013. intraoperatively, the conjunc-tival tissue could be completely removed from the underlying corneal tissue. the surgery was uneventful.

Postoperative follow-upso far the follow-up shows a clear graft. the corneal transplant has sufficient endothelial cell count (fig. 5c); visual acuity in the right eye improved to 6/12. opposite of the grafted limbus, the host limbus between 4.00 to 7.00 o’clock is not able to oppress conjunctival overgrowth – nevertheless the grafted lim-bus is able to maintain the corneal clarity of the graft center (fig. 5 a and b).

furthermore, there is early symblepharon formation in the inferior quadrant (fig. 5 b). even though the patient is happy with the surgical outcome we plan to remove the symblepharon to improve the long-term outcome of the graft.

for the past eleven months no corneal erosions or ulcers have occurred. the transplanted limbus shows sufficient required vascularization (fig. 5 a).

figure 5 –limbal corneal transplantation. the limbus (fig. 5 a, arrows) is showing a sufficient vasculariza-tion; the cor-neal graft has a sufficient and stable endothelial cell count (fig. 5 c). besides a symblepharon formation in the inferior quadrant (fig. 5 b), the grafted limbus is able to maintain the corneal clarity of the graft center.

a troublesome triad : atopic dermatitis, conJunctival cin,



literature

[1] a. d. irvine, W. h. i. Mclean, und d. Y. M. leung, „filaggrin mutations associated with skin and aller-gic diseases“, n. engl. J. Med., bd. 365, nr. 14, s. 1315–1327, oct. 2011.

[2] e. Rodríguez, h. baurecht, e. herberich, s. Wagenpfeil, s. J. brown, h. J. cordell, a. d. irvine, und s. Weidinger, „Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease“, J. allergy clin. immunol., bd. 123, nr. 6, s. 1361–1370.e7, June 2009.

[3] s. guglielmetti, J. k. dart, und V. calder, „atopic keratoconjunctivitis and atopic dermatitis“, curr. opin. allergy clin. immunol., bd. 10, nr. 5, s. 478–485, oct. 2010.

[4] t. lapp, c. auw-haedrich, t. Reinhard, R. evans, e. Rodríguez, s. Weidinger, und t. Jakob, „analysis of filaggrin Mutations and expression in corneal specimens from Patients with or without atopic der-matitis“, int. arch. allergy immunol., bd. 163, nr. 1, s. 20–24, nov. 2013.

[5] c. s. foster und M. calonge, „atopic keratoconjunctivitis“, ophthalmology, bd. 97, nr. 8, s. 992–1000, aug. 1990.

[6] s. J. tuft, d. M. kemeny, J. k. dart, und R. J. buckley, „clinical features of atopic keratoconjunctivitis“, ophthalmology, bd. 98, nr. 2, s. 150–158, feb. 1991.

[7] a. s. bacon, s. J. tuft, d. M. Metz, J. i. Mcgill, R. J. buckley, s. baddeley, und s. l. lightman, „the origin of kerato-pathy in chronic allergic eye disease: a histopathological study“, eye lond. engl., bd. 7 (Pt 3 suppl ), s. 21–25, 1993.

[8] d. easty, c. entwistle, a. funk, und J. Witcher, „herpes simplex keratitis and keratoconus in the atopic patient. a clinical and immunological study“, trans. ophthalmol. soc. U. k., bd. 95, nr. 2, s. 267–276, July 1975.

[9] P. eberwein, P. Maier, c. auw-haedrich, und t. Reinhard, „isolated corneal intraepithelial dysplasia“, ophthalmol. z. dtsch. ophthalmol. ges., bd. 106, nr. 10, s. 918–920, oct. 2009.

[10] c. droitcourt, d. touboul, c. ged, k. ezzedine, M. cario-andré, h. de Verneuil, J. colin, und a. taïeb, „a prospective study of filaggrin null mutations in keratoconus patients with or without atopic disorders“, dermatol. basel switz., bd. 222, nr. 4, s. 336–341, 2011.

[11] e. kohl, J. hillenkamp, M. landthaler, und R.-M. szeimies, „skin and eyes“, ophthalmol. z. dtsch. ophthalmol. ges., bd. 107, nr. 3, s. 281–292; quiz 293, March 2010.

[12] c. kallen, t. Reinhard, g. schilgen, o. cartsburg, a. böcking, c. auw-hädrich, und R. sundmacher, „atopic keratoconjunctivitis: probably a risk factor for the development of conjuntival carcinoma“, oph-thalmol. z. dtsch. ophthalmol. ges., bd. 100, nr. 10, s. 808–814, oct. 2003.

[13] J. J. chen, d. s. applebaum, g. s. sun, und s. c. Pflugfelder, „atopic keratoconjunctivitis: a review“, J. am. acad. dermatol., bd. 70, nr. 3, s. 569–575, March 2014.

[14] P. Maier, f. birnbaum, und t. Reinhard, „steam cautery of the cornea in microbial keratitis“, ophthal-mol. z. dtsch. ophthalmol. ges., bd. 105, nr. 1, s. 79–80, Jan. 2008.

[15] t. Reinhard, M. Möller, und R. sundmacher, „Penetrating keratoplasty in patients with atopic dermatitis with and without systemic cyclosporin a“, cornea, bd. 18, nr. 6, s. 645–651, nov. 1999.

[16] J. Y. niederkorn und d. f. P. larkin, „immune privilege of corneal allografts“, ocul. immunol. inflamm., bd. 18, nr. 3, s. 162–171, June 2010.

[17] f. e. kruse und t. Reinhard, „limbus transplantation for reconstruction of the ocular surface“, oph-thalmol. z. dtsch. ophthalmol. ges., bd. 98, nr. 9, s. 818–831, sep. 2001.

thabo laPP



resume

dr. Marta gomes guerra was born on august 27th, 1987. she is currently a resident at the centro Responsabilidade integrado de oftalmologia - centro hospitalar tondela-Viseu and follows a complemen-tarity Medical formation Protocol at the centro hospitalar da Universidade of coimbra, Portugal.she was licensed in medicine in 2011.she attended 26 national and international meetings and is the author and co-author of twenty-one articles, clinical cases and posters.

dr. Marta gUeRRa centro hospitalar da Universidade de coimbra – portugale-mail: [email protected]

introductionfamilial amyloidotic polyneuropathy (faP) is a heterogeneous group of fami-lial diseases characterized by systemic accumulation of amyloid fibrils in the peripheral nerves and other organs, including the eye. knowledge of the bio-chemical nature of the amyloid fibril proteins in these hereditary syndromes is limited. faP is classified in types i-iV, according to the different clinical features and geographic origin. faP type i, firstly described by corino de andrade in 1952[1], is the most frequent type, appearing mainly in Portuguese, Japanese, swedish, and Jewish families. it has its onset in the lower limbs and presents severe autonomic dysfunction affecting the cardiovascular and renal systems[2]. it is an autosomal dominant inherited disease characterized by abnormal production and extracellular deposition of transthyretin (ttR), a carrier protein of thyroxin in the plasma and vitamin a in the retina. More than 90% of this protein is synthesized in the liver, but there is evidence of ocu-lar production by both retinal and ciliary pigment epitheliums[3]. Replacement of valine-30 by methionine in ttR is necessary for the formation of these amy-loid deposits[4].the cornea is one of the most highly innervated tissues of the human body, supplied by the long ciliary nerve, through the ophthalmic branch of the tri-geminal nerve. this assures corneal sensation and provides trophic factors, essential in the maintenance of its structure and function, by regulating epi-thelial integrity, proliferation and wound healing[5,6]. Reduced or absent corneal sensitivity, spontaneous epithelial breakdown and impairment of corneal healing[6] characterize neurotrophic keratopathy (nk), a rare dege-nerative corneal disease, potentially sight threatening. it results from loca-lized or systemic conditions affecting nerve function along its course and is frequently associated to herpes keratitis, chemical burns, long-term use of contact lenses, corneal surgery or ablative procedures for trigeminal neu-ralgia[7]. according to Mackie[8], clinical severity of nk is classified in 3 stages summarized in table 1.

neurotrophic keratopathy in type i Familial amyloidotic

polyneuropathy - a new therapeutic approach

2



table 1 - Mackie's classification{8}

stage clinical findingsi corneal epithelial hyperplasia and irregularity

superficial punctate keratopathy increased viscosity of tear mucus and decreased break-up time

ii Persistent corneal epithelial defect - smooth and rolled edges descemet’s membrane folds and stromal swelling anterior chamber inflammatory reaction with hypopyon (rare)

iii corneal ulcer corneal perforation corneal stromal melting

there are many ocular features associated to faP type i, including, among others, corneal alterations, vitreous opacification, secondary glaucoma, scal-loped pupils, slower pupillary reflexes and anomalous conjunctival vessels. in the cornea, primary amyloid deposits damage the epithelium and stroma. infiltration of the orbital nerves can cause progressive autonomic neuropathy with decreased corneal sensitivity, keratoconjunctivitis sicca and nk. this, together with hyposecretion of tears due to lacrimal gland infiltration, leads to severe dry eye, which contributes to epithelial injury exacerbation, deregu-lated proliferation, and parakeratosis[4,9-12].

once established, both acute and chronic inflammation may sustain progres-sion of the corneal pathology[13].

treatment of these corneal epithelial injuries with vitamins, collagenase inhi-bitors, anti-inflammatory agents, prophylactic topical antibiotic, artificial tears or bandage contact lenses is frequently poor or of transient efficacy. in severe cases, oral doxycycline, autologous serum, amniotic membrane transplantation, tarsorrhaphy or a conjunctival flap are employed alone or in combination[14]. however, successful modulation of the healing response is rarely accomplished.

a new promising topical drop has emerged to revolutionize nk treatment: the matrix Regenerating agent (Rgta, polycarboxymethyl glucose sulfate). it is a biopolymer designed to mimic the heparan sulphates bound to corneal extracellular matrix proteins, protecting them from proteolysis and ena-bling growth factors and cytokines to act on the injured site. Rgta restores the physiological matrix organization and cellular microenvironment, stimu-lating the regeneration process[15]. clinical studies with this new agent were performed in animals[16] and humans[15,17,18], showing encouraging results in the treatment of corneal ulcers and dystrophies of various etiologies. however, no literature using this new agent in nk patients with faP is available.

the aim of this case report is to present three patients with faP type i and nk who were successfully treated with a new matrix-regenerating agent – the Rgta, polycarboxymethyl glucose sulfate.

case presentation

case 1the first patient is a 47-year-old male diagnosed with faP at the age of 20, with predominantly peripheral sensorimotor polyneuropathy, autonomic dysfunc-tion and infiltrative cardiac manifestations, who underwent liver transplanta-tion seven years after the diagnosis. ocular manifestations started ten years later. left eye (le) and right eye (Re) posterior vitrectomy and cataract sur-geries were performed. neurotrophic corneal ulcer grade 2 in Mackie’s clas-sification[8] was diagnosed 2.5 months after cataract surgery, non-responsive to occlusion therapy, or preservative free eye lubricants. total corneal anaesthesia was demonstrated by cotton tip test and corneal ulcer borders were debrided. Rgta eye drops were started, instilled in the morning, once a week. neurotrophic ulcer area was calculated as proportion of the total cor-neal area, assessed by slit lamp photography, using image analysis software (imageJ®, version 1.47, Wayne Rasband Research service branch, national institute of Mental health, bethesda, Md). ophthalmological evaluation with anterior segment photography (figure 1) was performed at days 1, 7, 14, 21 and 28. corneal ulcer area decreased from 8.76% at the 1st day to 3.11% at the 7th day. in day 14, corneal ulcer area was 3.34% followed by 3.11% (21st day) and complete corneal healing was achieved until the 28th day. a total of 5 instillations were applied. after a follow-up period of 7 months, there was no recurrence of corneal ulcer despite no significant improvement in visual acuity (Va).

no systemic or local side effects were noticed and no pain or discomfort during drop instillation was reported.

figure 1 – Patient 1: anterior segment photography at days 1, 7, 14, 21 and 28 with fluorescein eye drop; without fluorescein eye drop at day 28.

neurotrophic keratopathy in type i Familial amyloidotic polyneuropathy -

a new therapeutic approachMarta gUeRRa



case 2a 54-year-old male was diagnosed with faP type i and peripheral sensorimo-tor polyneuropathy, grade iii atrioventricular block (pacemaker carrier) and renal insufficiency. ocular history of central retinal vein occlusion of the Re, with no light perception, was known. liver transplantation was performed at the age of 35. ocular manifestations emerged 13 years after transplantation with le secondary open-angle glaucoma, non-responsive to maximum topical treatment. a trabeculectomy followed by cataract surgery was performed in the le. neurotrophic corneal ulcer grade 2 in Mackie’s classification[8] developed afterwards, non-responsive to occlusion therapy, or preservative free eye lubricants. total corneal anaesthesia was demonstrated by cotton tip test and corneal ulcer borders were debrided. Rgta eye drops were star-ted once a week. ophthalmological evaluation with anterior segment photo-graphy (figure 2) was performed at days 1, 7, 21 and 57. corneal ulcer area decreased from 4.95% at the 1st day to 2.83% at the 7th day. on day 21, corneal ulcer area was 2.67% and two instillations per week were performed thereaf-ter. complete corneal healing was achieved until the 57th day. a total of 10 instillations were applied. after a follow-up period of 4 months, the patient presented no ulcer recurrence. Moderate corneal scarring occurred, with no significant improvement in Va noted. no systemic or local side effects were noticed and no pain or discomfort during drop instillation was reported.

case 3the third patient is a 55-year-old female with faP type i, presenting periphe-ral sensorimotor polyneuropathy and cardiac manifestations. she underwent liver transplantation at the age of 39. ocular manifestations started 8 years after transplantation with posterior capsular amyloid deposition, secon-dary glaucoma, typical iris alterations and vitreous opacities on both eyes. neurotrophic corneal ulcer grade 2 was diagnosed in the Re 6 weeks after cataract surgery. the ulcer was non-responsive to occlusion therapy, or pre-servative free eye lubricants. total corneal anaesthesia was demonstrated by cotton tip test. Rgta eye drops were started, twice a week. ophthalmological evaluation with anterior segment photography (figure 3) was performed at days 1 and 14. corneal ulcer area decreased from 19.10% at the 1st day to complete corneal healing until the 14th day. a total of 5 instillations were applied. after a follow-up period of 2 months, no recurrence was registered, with no significant improvement in Va.

figure 2 – Patient 2: anterior segment photography at days 1, 21 and 57 with fluorescein eye drop; without fluores-cein eye drop at day 57.

figure 3 – Patient 3: anterior segment photography at days 1 and 14 without fluorescein eye drop (left images); with fluorescein eye drop at day 1 and 14 (right images).





discussion

liver transplantation has been widely accepted as an effective therapy to halt systemic amyloid deposition because the liver predominantly synthesizes the precursor protein of amyloid deposits in tissues of faP patients. however, evi-dence of ttR small synthesis in both retinal and ciliary pigmented epithelium and choroid plexus[3] of the brain[19] has been found and cannot be prevented by liver transplantation[20]. despite this surgery, all the 3 presented patients developed not only vitreous opacities, iris alterations and secondary glau-coma, but also decreased corneal sensitivity. these findings are in agreement with previous published reports of patients with faP type-i submitted to liver transplantation[21].

initially, formation of amyloid deposits in the cornea has a cytotoxic effect, damaging corneal sensory nerves, epithelium, and stroma. corneal neu-ropathy associated with an impaired tear film promotes epithelial surface injury and disturbances in hydration and ionic homeostasis. both persistent mechanical damage and cytotoxicity lead to tissue destruction and repeated attempts of wound healing[13].

treating nk is not easy and remains a clinical challenge, particularly in faP patients. in fact, none of the 3 patients responded to current conservative treatment. few cases of nk patients with faP are reported in the literature. nonetheless, all presented severe hypoesthesia and keratoconjunctivitis sicca and culminated in bilateral corneal perforation[13,22], the last stage of nk that should be avoided at all cost.

the introduction of the new topical treatment for nk, the Rgta, polycarboxy-methyl glucose sulphate, is a promising therapy to these patients. it belongs to the polysaccharides’ family, derived from dextran by chemical substitu-tions with carboxymethyl, sulphate and hydrophobic groups[23,24]. this biopo-lymer is engineered to replace the heparan-sulphates destroyed upon tissue injury and to specifically bind extracellular matrix proteins and growth fac-tors, protecting them from proteolysis[23].

Recent clinical studies already showed safety and effectiveness in treating nk in corneal dystrophies, resistant corneal ulcers[15] and after infectious keratitis[18], chemical burns and perforating keratitis[17], with mean wound hea-ling ranging from 4 to 9 weeks.

the series here presented showed encouraging results: total re-epithelia-lization was achieved in all 3 patients within a mean period of 33 days (4.71 weeks) after initiating Rgta once/twice a week with no recurrence registered and a follow up time ranging from 2 to 7 months. these excellent results are reinforced by a larger series observed in the same department: 15 patients with various causes of nk and mean corneal ulcer area before treatment of 16,26%, treated with Rgta agent, showed complete corneal healing within a mean period ranging from 1 to 8 weeks. in these patients, treatment was started with one instillation per week. if no improvement in ulcer area was observed, two instillations were performed until complete corneal healing. due to the limited sites for heparan binding available in the healing tissue, a perfectly well defined posology is not available, only the producer’s recom-mendation of one/two weekly instillations.

conclusion

decreased corneal sensitivity, in patients with faP type i, associated to an impaired tear production, can lead to nk development. the nk in these patients is one of the most challenging ocular surface pathologies. as these three patients were non-responsive to conservative nk topical treatment, a new substance, the Rgta, polycarboxymethyl glucose sulphate, was experi-mented. Rgta is easy to apply, and showed compelling effectiveness in cor-neal wound healing, being well tolerated by all patients.

these are the first cases of nk caused by faP treated with Rgta. true poten-tial of these eye drops was here demonstrated, showing that this approach might be an excellent solution to treat nk, even in this particular type of patients.




reFerences

[1] andrade c. a peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special invol-vement of the peripheral nerves. brain, sep 1952, 75(3), 408-427.

[2] lobato l. classificação das amiloidoses. sinapse. 2006; 6(1), 67-71.

[3] sandgren o. ocular amyloidosis, with special reference to the hereditary forms with vitreous involvement. surv ophthalmol, nov-dec 1995, 40(3), 173-196.

[4] ando e, ando Y, okamura R, Uchino M, ando M, negi a. ocular manifestations of familial amyloidotic polyneuropa-thy type i: long-term follow up. br J ophthalmol, apr 1997, 81(4), 295-298.

[5] holland e, Mannis M, lee Wb. neurotrophic keratopathy. in ocular surface disease: cornea, conjunctiva and tear film. elsevier health sciences, 2013, p. 205-211.

[6] sacchetti M, lambiase a. diagnosis and management of neurotrophic keratitis. clin ophthalmol, 2014, 8, 571-579.

[7] semeraro f, forbice e, Romano V, angi M, Romano MR, filippelli Me, et al. neurotrophic keratitis. ophthalmologica, 2014, 231(4), 191-197.

[8] Mackie ia. neuroparalytic keratitis. in Rf fRaUnfeldeR f, MeYeR sM, editoRs. ed. current ocular therapy. Philadelphia, Pa, Usa: Wb saunders, 1995.

[9] ando e, ando Y, Maruoka s, sakai Y, Watanabe s, Yamashita R, et al. ocular microangiopathy in familial amyloidotic polyneuropathy, type i. graefes arch clin exp ophthalmol, 1992, 230(1), 1-5.

[10] kawaji t, ando Y, nakamura M, Yamashita t, Wakita M, ando e, et al. ocular amyloid angiopathy associated with familial amyloidotic polyneuropathy caused by amyloidogenic transthyretin Y114c. ophthalmology, dec 2005, 112(12), 2212.

[11] Monteiro Jg, Martins af, figueira a, saraiva MJ, costa PP. ocular changes in familial amyloidotic polyneuropathy with dense vitreous opacities. eye (lond), 1991, 5 ( Pt 1), 99-105.

[12] lamkin Jc, Jakobiec fa. amyloidosis and the eye. in the eye and systemic diseases. p. 4517-4533.

[13] dosso aa, Rungger-brandle e. bilateral corneal perforation in familial amyloidotic polyneuropathy. graefes arch clin exp ophthalmol, Mar 2005, 243(3), 273-277.

[14] lambiase a, Rama P, aloe l, bonini s. Management of neurotrophic keratopathy. curr opin ophthalmol, aug 1999, 10(4), 270-276.

[15] chebbi ck, kichenin k, amar n, nourry h, Warnet JM, barritault d, et al. [Pilot study of a new matrix therapy agent (Rgta otR4120) in treatment-resistant corneal ulcers and corneal dystrophy]. J fr ophtalmol, May 2008, 31(5), 465-471.

[16] brignole-baudouin f, Warnet JM, barritault d, baudouin c. Rgta-based matrix therapy in severe experimental corneal lesions: safety and efficacy studies. J fr ophtalmol, nov 2013, 36(9), 740-747.

[17] aifa a, gueudry J, Portmann a, delcampe a, Muraine M. topical treatment with a new matrix therapy agent (Rgta) for the treatment of corneal neurotrophic ulcers. invest ophthalmol Vis sci, dec 2012, 53(13), 8181-8185.

[18] de Monchy i, labbe a, Pogorzalek n, gendron g, M'garrech M, kaswin g, et al. [Management of herpes zoster neurotrophic ulcer using a new matrix therapy agent (Rgta): a case report]. J fr ophtalmol, Mar 2012, 35(3), 187.e181-186.

[19] soprano dR, herbert J, soprano kJ, schon ea, goodman ds. demonstration of transthyretin mRna in the brain and other extrahepatic tissues in the rat. J biol chem, sep 25 1985, 260(21), 11793-11798.

[20] ando e, ando Y, haraoka k. ocular amyloid involvement after liver transplantation for polyneuropathy. ann intern Med, nov 20 2001, 135(10), 931-932.

[21] Rosa a, Quadrado MJ, ferrão J, Marques i, costa e, Murta Jn. Manifestações oculares de polineuropatia amiloidó-tica familiar tipo i em doentes submetidos a transplante hepático. oftalmologia, 2009, 33, 177-183.

[22] frossard Jl, donati g, Reymond JM. Portuguese amyloidosis: a case of spontaneous bilateral corneal perforation. am J Med, nov 1996, 101(5), 562.

[23] Rouet V, Meddahi-Pelle a, Miao hQ, Vlodavsky i, caruelle JP, barritault d. heparin-like synthetic polymers, named Rgtas, mimic biological effects of heparin in vitro. J biomed Mater Res a, sep 15 2006, 78(4), 792-797.

[24] barritault d, caruelle JP. [Regenerating agents (Rgtas): a new therapeutic approach]. ann Pharm fr, Mar 2006, 64(2), 135-144.

Marta gUeRRa



introduction

dr. V.swetha Jeganathan nhs dumfries and galloway – scotlande-mail : [email protected]

she has been a resident at the nhs dumfries and galloway, scotland since september 2014.she attended twenty courses in ophthalmology and surgical and practical skills. she has a teaching experience and is currently a Member of faculty of surgical trainers of scotland at the Royal college of surgeons of edinburgh.author and co-author of thirty-two publications and sixteen posters, she attended thirty five national and international meetings. dr Jeganathan was also awarded fourteen times for her work.she is a member of nine associations like the aao or the Royal college of ophthalmologists in the Uk.

resume

3

an unusual cause oF persistent

corneal ulcers: bilateral

mycobacterium chelonae keratitis

severe microbial keratitis can be accompanied by persistent epithelial defects, infiltrates and progressive corneal melt. the associated inflam-mation causes pain, tissue swelling and hypopyon. in the management of microbial keratitis, it can be challenging to detect and eradicate the causal pathogens. the treatment includes intensive topical agents that are toxic to the ocular surface while the use of systemic drugs can have significant side effects. We present a complex case of Mycobacterium chelonae infection in an elderly contact lens wearer with a protracted clinical course of bilateral non-healing epithelial defects, following poor contact lens hygiene.



case presentation a healthy 75-year-old woman presented to our local ophthalmology depart-ment with discomfort in her right eye, associated with an epithelial defect. she had no previous ocular history, trauma, cold sore or shingles. the patient was initially treated for bacterial infection with ofloxacin drops. oral acyclovir was commenced when a disciform epithelial defect developed. she was later treated with intensive cefuroxime, gentamicin, amikacin and moxifloxacin when her keratitis deteriorated with a hypopyon. two months later, she developed a similar keratitis in her left eye, with subsequent scleral thinning [figure 1].

herpes serology to hsV-1 was positive indicating previous exposure des-pite the fact that never had labial herpes. Multiple corneal scrapes, corneal biopsies and amniotic membrane transplant were all negative, which led to the assumption of a herpetic or fungal keratopathy with persistent epithe-lial defect due to impaired corneal sensation. botox for protective ptosis was injected to allow her epithelial defects to heal.

the patient did not fit the profile of a contact lens wearer, and soft monthly lens use was only revealed upon detailed systematic enquiry. she professed initially washing her contact lenses with domestic tap water, but later chan-ged this practice by using a lens disinfecting solution (sauflon multipurpose solution) [figure 2]. however, inspection of her contact lens solution revealed expiry 3 years earlier.

confocal microscopy confirmed multiple inflammatory cells and a few pos-sible cystic lesions in both eyes. the above contact lens history and confocal microscopy findings suggested a high probability of acanthamoeba keratitis. active treatment against acanthamoeba when instituted, resulted in exacer-bation of her keratitis.

the discovery of heavy contamination of her contact lens solution with Mycobacterium chelonae later led to the inclusion of antimicrobial agents against Mycobacterium as well as agents against acanthamoeba. figure 3 summarises her clinical investigations.

test Resultconjunctival swabs (x4) enterococcus bacillus positive

cornel scrapes (x3){Plated directly onto blood agar, chocolate agar, sabouraud agar, lowensier-Jensen slopes, brain-heart infusion and thioglycolate broths}

1. staphylococcus positive2. no organisms identified3. Wbcs, streptococcus mitis

corneal biopsies (3) no organism identified, no inflammation

sclera biopsies (x1) no organism identified, intense inflammation

amniotic membrane remnants for microbiology

enterococcus feacallis

PcR for hsV-1, hsV-2, VzV, adenovirus negative

PcR for acanthamoeba, Mycobacteria and fungi

negative

confocal microscopy inflammatory cells and cystic lesions suggestive of acanthamoeba

herpes serology hsV-1 positive

anterior chamber fluid sampling for microbiology and pathology (x2)

negative

blood tests :fbc, U&es, lfts, esR, cRP, ena, ana, rheumatoid factor and anca

normal except raised cRP and ggt

contact lens case & solution analysis Mycobacterium chelonae cultured +++

figure 1: Picture of right and left eyes

Figure 1: Picture of right and left eyes

Figure 2: Contaminated contact lens disinfecting solution used by the patient

figure 2: contaminated contact lens disinfecting solution used by the patient

Figure 1: Picture of right and left eyes

Figure 2: Contaminated contact lens disinfecting solution used by the patient

figure 3: summary of the patient’s clinical investigations

an unusual cause oF persistent corneal ulcers : bilateral

mycobacterium chelonae keratitisV.swetha Jeganathan



the patient had several courses of intensive treatment followed by treatment to enhance healing of the epithelial defects. despite being on prednisolone, oral clarithromycin, oral flubiprofen and the following topical medications in both eyes (azithromycin b.d., acetylcysteine 5% six times daily, brolene qds, chlorhexidine 0.02% five times daily, amphotericin 0.5% five times daily, moxifloxacin eight times daily and lacrilube ointment at night), her keratitis failed to improve. there was progressive deterioration of corneal haze with scleritis bilaterally. her visual acuity deteriorated to hand movements in the right eye and counting fingers in her left eye. excessive inflammation caused pain and rapid destruction of ocular tissue which necessitated the titration of anti-inflammatory agents including corticosteroids to limit the effects. eight months after ongoing intensive treatment, it was apparent that local investi-gations were not providing any clues as to the aetiology.

a leading university eye hospital kindly helped to investigate this complex patient using their facilities and specialised laboratories for PcR. the out-comes of all the ocular microbiological investigations however were all negative: corneal and scleral biopsies, showed intense inflammation but no organisms. as the cornea had already been treated with intensive courses of agents against acanthamoeba and Mycobacterium, the only conclusion left was that there must be resistant Mycobacterium present. commencement of treatment with intensive topical amikacin, topical moxifloxacin and topical azithromycin and high dose oral clarithromycin, pleasingly led to resolution. the patient made good progress and later underwent penetrating kerato-plasty in both eyes, with excellent visual prognosis to date (Va 6/6 both eyes). figure 4 shows the summary of events and management of her complex case.

figure 4: summary of the patient’s clinical events and management

Figure 4: Summary of the patient’s clinical events and management





discussion

at presentation with a persistent epithelial defect, the patient was managed as herpetic keratopathy. the diagnosis of contact lens wear as a factor in her keratitis was not considered early in her presentation. subsequently, only on direct interrogation did she admit to poor contact lens hygiene including swimming while wearing lenses, cleaning with tap water and a long expired cleaning solution. the discovery of Mycobacterium chelonae heavily conta-minating the contact lens solution led to the inclusion of antimicrobial agents against Mycobacterium as well as agents against acanthamoeba.

Mycobacterium chelonae, a saphrophyte found in air, soil and water, has been found to colonise antiseptic solutions and cause dacryocystits, canaliculitis, scleritis, and rarely endophthalmitis.(1, 2) surgical trauma (e.g. laser refrac-tive surgery) or breakdown of the corneal epithelium increases the risk of surface infection.(3, 4) in our patient, the most likely source of bilateral kera-titis was from cross contamination of her contact lens solution. the active ingredient in expired lens disinfectants may have become ineffective.(5) in such suboptimal environments, rapidly growing Mycobacteria are virulent enough to cause blindness by forming biofilms that affect antibiotic penetration and potential antimicrobial resistance.(6)

treatment of microbial keratitis has the “sterilisation phase” followed by the “healing phase”. despite treatment to enhance healing of the epithelial defects, there was progressive deterioration of corneal haze with onset of scleritis bilaterally. excessive inflammation and rapid destruction of ocular tissue required titration with corticosteroids.

local investigations were inconclusive. the patient was referred to a centre for excellence eye hospital where all microbiological investigations were negative. as the cornea had already been treated with intensive courses of agents against acanthamoeba and Mycobacterium, the conclusion was that there must be a resistant strain of Mycobacterium. Resolution occurred only following intensive treatment with topical amikacin, moxifloxacin, azithromy-cin and systemic clarithromycin.

conclusion

to our knowledge this is the first reported case of bilateral Mycobacterium chelonae keratitis arising from contaminated contact lens solution. this case illustrates the importance of considering Mycobacterium chelonae in the differential diagnoses when treating non-healing keratitis. it is important to enquire about contact lens wear and hygiene in all keratitis cases, regardless of age. there is a need to create public awareness regarding the potential serious risk of contact lens wear and safe contact lens practice that includes monitoring by eye care professionals.

take home message

• in the presence of corneal inflammation or epithelial pathology, always interrogate the patient regarding contact lens use and hygiene specifics even in the most unlikely cases.

• diagnostic facilities are essential including PcR for acanthamoeba.• beware of Mycobacterium as a potential pathogen.• consider treatment regime against resistant Mycobacterium: topical amika-

cin, moxifloxacin, azithromycin and systemic clarithromycin.

reFerences

[1] lim bon siong R, felipe af. nontuberculous mycobacterial infection after clear corneal phacoemulsification cata-ract surgery: a report of 13 cases. cornea. 2013 May;32(5):625-30.

[2] feder Rs, Rao RR, lissner gs, bryar PJ, szatkowski M. atypical mycobacterial keratitis and canaliculitis in a patient with an indwelling smartPlUg. br J ophthalmol. 2010 Mar;94(3):383-4.

[3] Umapathy t, singh R, dua hs, donald f. non-tuberculous mycobacteria related infectious crystalline keratopathy. br J ophthalmol. 2005 oct;89(10):1374-5.

[4] Yamaguchi t, bissen-Miyajima h, hori-komai Y, Matsumoto Y, ebihara n, takahashi h, et al. infectious kera-titis outbreak after laser in situ keratomileusis at a single laser center in Japan. J cataract Refract surg. 2011 May;37(5):894-900

[5] stapleton f, carnt n. contact lens-related microbial keratitis: how have epidemiology and genetics helped us with pathogenesis and prophylaxis. eye (lond). 2012 feb;26(2):185-93.

[6] ortiz-Perez a, Martin-de-hijas n, alonso-Rodriguez n, Molina-Manso d, fernandez-Roblas R, esteban J. importance of antibiotic penetration in the antimicrobial resistance of biofilm formed by non-pigmented rapidly growing mycobac-teria against amikacin, ciprofloxacin and clarithromycin. enferm infec Microbiol clin. 2011 feb;29(2):79-84.



best national

cases

P.58

“an atypical case oF corneal ulcer in crohn’s disease”dr. eleonora faVUzzaeye clinic, department of surgery and translational Medicine, firenze – italy

P.44

“management oF recurrent neurotrophic epithelial deFects in a patient with a history oF herpetic keratitis and blepharitis”dr. ate altenbURgantwerp University hospital – belgium

P.66

“healing oF corneal persistent ulcers From diFFerent etiologies using a new matrix therapy agent (rgta): illustration oF the dose-dependent relationship explaining the mechanism”dr. aurélie Pison Paris hôtel-dieu hospital – France

P.50“novel matrix therapy success in non-healing persistent sterile melting corneal ulcers due to rheumatoid arthritis and sJogren's syndrome”dr. Monika saRnat-kUchaRczYkUniversity center of ophthalmology and oncology, katowice – poland

P.74

an overview oF noninFectious recurrent corneal erosions and a suggestion For simpliFied clinical practice guidelinesdr. gustav stålhaMMaRstockholm st. erik eye hospital – sweden

P.84

recurrent corneal erosion syndrome : an elusive diagnosis and individualized treatment.dr. elío diez-feiJóo VaRelainstituto clínico Quirúrgico oftalmológico de bilbao – spain

P.88

accelerated pack-cxl (photoactivated chromophore For keratitis- corneal cross-linking) to treat a persistent corneal ulcerdr. david tabibian geneva University hospital – switzerland

P.92

From devastation to restoration: trichosporon asahii can be beatendr. Yasemin aYdin Yazgallipoli state hospital , canakkale – turkey



introduction

dr. david tabibian geneva University hospital – switzerland

corneal blindness and corneal opacities due to infection are part of the priority eye diseases list established by the World health organization1,2. Prevalence fluctuates between countries, but in some african regions infectious keratitis represents the most common cause of monocular blindness3. corneal infec-tious ulceration is also a main concern in developed countries especially since contact lenses are a declared risk factor, and younger patients are using them more frequently on a daily basis4. furthermore the emergence of multi-drug resistant microorganisms is also complicating the cure of persistent corneal ulcerations and alternative treatments are necessary to circumvent this issue.

several organizations already promulgated international guidelines to stan-dardize the treatment of infectious keratitis5. Many of the untreated ulcerations will result in loss of vision through involvement of the central cornea, and can even lead to corneal perforation and endophthalmitis. optimal management of infectious corneal ulceration must be initiated rapidly to avoid any late com-plications. initial standard treatment with broad-spectrum topical antibiotics drops is used until culture and smears of the cornea and conjunctiva determine the causative agent. then, in most cases, a tailored therapy for the specific microorganism can be initiated.

accelerated pack-cxl (photoactivated chromophore For keratitis- corneal cross-linking) to treat a persistent

corneal ulcer

sometimes, the treatment is not sufficient or the pathogen is not identified and a corneal ulceration progresses to perforation despite maximal topical or sys-temic therapy. therapeutic options are limited in these situations. Ultimately, emergency corneal grafting can be performed to reduce the inflammation and infection and to identify the causative agent5. here, we present the case of a young male patient with a persistent corneal ulcer that was progressing under standard treatment despite advanced topi-cal and systemic care, but was halted with an innovative treatment known as photoactivated chromophore for keratitis-corneal cross-linking (Pack-cxl)6,7. cross-linking technology has initially been developed by theo seiler and eberhard spoerl to treat ectatic disorders of the cornea and recently has been successfully introduced to treat corneal ulcerations8,9.

case presentation

a 21 year-old male patient was seen in our department end of May 2014 for a second opinion concerning his right eye. Prior to his visit to us, he had been treated for almost two months abroad for a deep corneal ulcer of his right eye without improvement of his condition. the patient has no other known medical or ocular condition. he never had ocular or general surgery and has no allergies. he has been wearing daily soft contact lenses for eight years.

early april 2014, he developed pain and redness of his right eye within a few days. he consulted an optometrist, received daily topical corticosteroids, and was asked to come back for follow-ups over the next days. he showed sub-sequent deterioration of visual acuity, loss of reading ability, and his right cornea developed a progressing ulcer. after 10 days of steroid treatment, he was referred to a local ophthalmologist. a diagnosis of presumed herpetic keratitis was established, steroid drops were discontinued and the patient was treated with daily antiviral trifluridine drops. the corneal ulcer continued to progress to approximately 3 millimeters, pain and redness increased and the antiviral therapy was maintained for another three weeks, before the patient was referred to the local University hospital. here, a broad antimicrobial treatment was initiated with vancomycine and cephazolin, and later changed to vancomycine, tobramycine and ciprofloxacine drops hourly, and morphine 7.5mg to reduce pain. corneal and conjunctival swabs only revealed coagu-lase negative staphylococcus. treatment was adapted, but the ulcer conti-nued to progress despite further maximum systemic and topical antibiotic, antifungal and antiviral therapy.

accelerated pack-cxl (photoactivated chromophore

For keratitis- corneal cross-linking) to treat a persistent corneal ulcer



When initially examined in our department, he reported worsening of his vision three days prior to his visit with us. his visual acuity was limited to hand movements on his right eye and 1.0 corrected for distance visual acuity (cdVa) with -2.00/-1.25x5° on the left eye. slit lamp examination showed a deep paracentral ulceration of 4x5 millimeters with a residual cornea stro-mal thickness of approximately 250 μm, as measured by our oct (optical coherence tomography) device. We observed signs of active inflammatory melting as well as intraocular inflammatory masses on the corneal endothe-lium and in the pupillary plane. since correct therapy had been protracted for many weeks, and even maximal antimicrobial standard treatment was not able to clinically improve the patient’s ulcer, we opted for a Pack-cxl proce-dure. Prior to Pack-cxl, corneal swabs and smears were taken and sent for analysis.

Pack-cxl was performed as follows: proparacaine hydrochloride 0.5% eye drops containing 0.01% bac (benzalkonium chloride) were administered three times within 10 minutes, followed by instillation of 0.1% hypo-osmo-laric riboflavin solution on the entire cornea every three minutes during 30 minutes. irradiation of the cornea was then performed with a commercially available cross-linking device using 9mW/cm2 for 10 minutes. Riboflavin solu-tion was added once after five minutes. after the procedure, ofloxacin oint-ment was applied and the eye was patched. acetaminophen was administered for analgesia. dexamethasone 0.1% drops t.i.d., moxifloxacine 0.5% s.i.d. and tropicamide 0.5% b.i.d. were pursued after surgery.

two days after the Pack-cxl procedure, the patient reported reduced ocular pain. his visual acuity od was stable (hand movements). slit lamp examina-tion showed a marked reduction of conjunctival hyperemia, reduction of the inflammation and stabilization of the central ulcer in the absence of further progression. signs of infection or melting subsequently disappeared over the following days and scar formation started.

in a second step, and at one week after the Pack-cxl procedure, we per-formed anterior chamber cleansing and revision. during surgery, it became apparent that the intraocular mass in the pupillary plane had penetrated into the lens. We therefore had to remove the remnants of the lens together with the entire capsular bag.

laboratory results form the pre-operative smears revealed fusarium dime-rum, a fungus that is reported to cause corneal ulceration10. since earlier cultures had revealed staphylococcus, a mixed infection might be at the ori-gin of the progressive corneal ulceration. currently, the patient’s cdVa od is 0.2 with +12d. the patient is closely followed-up, and in a few months we will proceed with visual rehabilitation, consisting of secondary iol implan-tation, followed by lamellar or penetrating keratoplasty depending on the final depth of the central scar, and eventually a refractive laser procedure to eliminate residual irregular astigmatism as a last step.

fig 1 : slit-lamp biomicroscopy prior to Pack-cxl fig 2 : corneal oct of the ulcer prior to Pack-cxl

fig 3 : six days (left picture) and two weeks after Pack-cxl (right picture)

fig 4 : corneal oct of the ulcer two weeks after Pack-cxl



david tabibian



discussion corneal cross-linking (cxl) is a treatment that was developed in switzerland and germany a decade ago to treat corneal ectatic disorders such as kera-toconus or post-lasik corneal ectasia.8,11,12 drops of vitamin b2 (riboflavin) penetrate the cornea and, under a specific wavelength, free radicals are crea-ted that generate new covalent bonds between stromal collagen and proteo-glycans in the stroma13,14. this newly created bonds will increase the overall biomechanical stability of the cornea and halt the development of progres-sive ectatic disorder with a high rate of success in the long-term.15,16

now a standard treatment for ectatic disorders, corneal cross-linking has been more recently studied to treat infectious keratitis and renamed for this purpose Pack-cxl9. the presumed mechanism of action of Pack-cxl includes generation of Ros (Reactive oxygen species), thus high levels of oxidative stress that unspecifically kill bacteria, but also fungi. the melting that often occurs in a progressive ulcer can be effectively halted by Pack-cxl, since it changes the three-dimensional conformation of the collagen, and prevents collagenase action through steric hindrance17. there is a small, but rapidly growing body of evidence showing that Pack-cxl might become a valuable tool in treating infectious keratitis9,18-21. a group has only recently shown that Pack-cxl might be an adjuvant therapy even in advanced corneal ulcers although the method might show its greatest benefit when used in early, and yet more shallow ulcers6,22,23.

in the case we presented here, we used an accelerated setting, treating with 9mW/cm2 for 10 minutes. so far, all published data rather used the “classic” settings of 3mW/cm2 for 30 minutes. a recent study was able to show that the antimicrobial efficacy of Pack-cxl remains unchanged, when using the same overall fluence, but delivered with high intensities in shorter time24.

our patient had already been treated unsuccessfully for almost two months by standard topical and systemic therapy and did not responding to treat-ment. further progression of the ulcer might have led to ocular perforation, acute endophtalmitis and even enucleation. Pack-cxl treatment helped to decrease the antimicrobial load, to reduce inflammation and to stabilize the melting process. this way his visual potential was preserved and further treatment will help him recover it.

conclusion Pack-cxl represents a novel and promising alternative to treat infectious keratitis. currently used in cases where conventional treatment fails, it might transition into a first-line treatment, once more clinical evidence is published. this is of particular importance in the light of increasing resistance to avai-lable antibiotics and the risks and dangers associated with it25,26. also, the treatment might reduce the intensity of current antimicrobial treatment, helping to save on socio-economical costs in the future.

reFerences [1] Mariotti sP. global data on visual impairments 2010. geneva: World health organization;2012.

[2] World health organization. Prevention of blindness and Visual impairment - Priority eye diseases. 2014; http://www.who.int/blindness/causes/priority/en/. accessed 08.10.2014, 2014.

[3] Whitcher JP, srinivasan M, Upadhya MP. corneal blindness: a global perspective. geneva: World health organization;2001.

[4] amescua g fau - Miller d, Miller d fau - alfonso ec, alfonso ec. What is causing the corneal ulcer? Management strategies for unresponsive corneal ulceration. 2011(1476-5454 (electronic)).

[5] american academy of ophthalmology cornea/external disease Panel. Preferred Practice Pattern guidelines. bacterial keratitis. 2013.

[6] said dg, elalfy Ms, gatzioufas z, et al. collagen cross-linking with Photoactivated Riboflavin (Pack-cxl) for the treatment of advanced infectious keratitis with corneal Melting. ophthalmology. 2014.

[7] hafezi f, Randleman Jb. Pack-cxl: defining cxl for infectious keratitis. J Refract surg. 2014;30(7):438-439.

[8] Wollensak g, spoerl e, seiler t. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of kera-toconus. am J ophthalmol. 2003;135(5):620-627.

[9] iseli hP, thiel Ma, hafezi f, kampmeier J, seiler t. Ultraviolet a/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. cornea. 2008;27(5):590-594.

[10] Vismer hf, Marasas Wf, Rheeder JP, Joubert JJ. fusarium dimerum as a cause of human eye infections. Medical mycology. 2002;40(4):399-406.

[11] hafezi f, kanellopoulos J, Wiltfang R, seiler t. corneal collagen crosslinking with riboflavin and ultraviolet a to treat induced keratectasia after laser in situ keratomileusis. J cataract Refract surg. 2007;33(12):2035-2040.

[12] Richoz o, Mavrakanas n, Pajic b, hafezi f. corneal collagen cross-linking for ectasia after lasik and Photorefractive keratectomy: long-term Results. ophthalmology. 2013.

[13] Raiskup f fau - spoerl e, spoerl e. corneal crosslinking with riboflavin and ultraviolet a. i. Principles. 2013(1542-0124 (Print)).

[14] zhang Y, conrad ah, conrad gW. effects of ultraviolet-a and riboflavin on the interaction of collagen and proteo-glycans during corneal cross-linking. the Journal of biological chemistry. 2011;286(15):13011-13022.

[15] caporossi a, Mazzotta c, baiocchi s, caporossi t. long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in italy: the siena eye cross study. am J ophthalmol. 2010;149(4):585-593.

[16] Raiskup-Wolf f, hoyer a, spoerl e, Pillunat le. collagen crosslinking with riboflavin and ultraviolet-a light in keratoconus: long-term results. J cataract Refract surg. 2008;34(5):796-801.

[17] spoerl e, Wollensak g, seiler t. increased resistance of crosslinked cornea against enzymatic digestion. curr eye Res. 2004;29(1):35-40.

[18] schnitzler e, sporl e, seiler t. [irradiation of cornea with ultraviolet light and riboflavin administration as a new treatment for erosive corneal processes, preliminary results in four patients]. klin Monbl augenheilkd. 2000;217(3):190-193.

[19] Martins sa, combs Jc, noguera g, et al. antimicrobial efficacy of riboflavin/UVa combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. invest ophthalmol Vis sci. 2008;49(8):3402-3408.

[20] schrier a, greebel g, attia h, trokel s, smith ef. in vitro antimicrobial efficacy of riboflavin and ultraviolet light on staphylococcus aureus, methicillin-resistant staphylococcus aureus, and Pseudomonas aeruginosa. Journal of refractive surgery. 2009;25(9):s799-802.

[21] galperin g, berra M, tau J, boscaro g, zarate J, berra a. treatment of fungal keratitis from fusarium infection by corneal cross-linking. cornea. 2011.

[22] Price Mo, tenkman lR, schrier a, fairchild kM, trokel sl, Price fW, Jr. Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract surg. 2012;28(10):706-713.

[23] Makdoumi k, Mortensen J, sorkhabi o, Malmvall be, crafoord s. UVa-riboflavin photochemical therapy of bacte-rial keratitis: a pilot study. graefes arch clin exp ophthalmol. 2012;250(1):95-102.

[24] Richoz o, kling s, hoogewoud f, et al. antibacterial efficacy of accelerated Pack-cxl (photoactivated chromo-phore for keratitis- corneal cross-linking. J Refract surg. 2014;in press.

[25] World health organization: antimicrobial Resistance, global Report on surveillance. 2014(June 2014).

[26] goldstein Mh, kowalski RP, gordon YJ. emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. ophthalmology. 1999;106(7):1313-1318.



david tabibian



dr. Monika saRnat-kUchaRczYk University center of ophthalmology and oncology, katowice – poland

corneal stromal defects can occur due to acute and chronic factors. chronic defects are usually progressive and resistant to treatment. in this type are distinguished: stromal thinning without ulceration and sterile stromal ulceration1.

corneal ulcers can cause significant vision loss caused by scarring, astigma-tism and perforation. infectious ulcers require antimicrobial therapy, while sterile ulcers can present diagnostic and therapeutic challenges2.

this report presents two patients, male and female, who suffered from per-sistent non-healing corneal ulcers. both of them have rheumatoid arthritis and sjogren's syndrome with severe dry eye, complicated with melting cor-neal ulcers. they were treated in University hospital in outpatients' clinic and in case of exacerbations of the disease referred to ophthalmic ward. because conventional methods of treatment were unsuccessful, a decision was made to start a new matrix therapy agent (Regenerating agent [Rgta], cacicol-20®), mimicking heparan sulfates. Patients were treated with Rgta eye drops instilled at a dosage of one drop once a week for 5 weeks and then it was prolonged for every two weeks. the duration of therapy lasted 10 weeks for patient 1 and 7 weeks for patient 2. in the first case the therapy was applied in both eyes, while in the second patient it was used only in the right eye.

in first patient's right eye because of corneal melting, which led to perfora-tion, segmental keratoplasty was a necessity. this was before the introduc-tion of Rgta. in the left eye corneal melting ulcer was also present but in less advanced stage. he has received Rgta which enhanced healing process and prevented him from undergoing re-keratoplasty in the right eye and kera-toplasty in the left eye.

in second case the female patient underwent cataract surgery and 2 weeks later corneal erosion has occurred, which despite treatment turned into a non-healing corneal ulcer. after single dose of Rtga the size of the ulcer decreased significantly and with the course of therapy it has completely healed.

evolution during the treatment was assessed by best corrected visual acuity (bcVa), slit lamp examination, corneal photography and anterior segment optical coherent tomography casia, tomey (as-oct).

to our knowledge, we report here the first series of this type.

case presentation

case 1Male patient, aged 42, treated in the corneal Unit of University hospital for advanced corneal dry eye syndrome manifested as filamentous keratopathy. the patient suffered from severe depression and therefore received psycho-tropic medication.

23.10.2013 examination revealed bilateral conjunctival hyperemia, filamentary keratitis, and diffuse superficial punctate epithelial defects. Visual acuity Re 0,015 le 0,2, ioP Re 17 mmhg le 16 mmhg. Performed i schirmer test was Re 0mm, le 1mm.

corneal sensitivity as measured with cochet-bonnet esthesiometer was Re 10 mm, le 14 mm. two smears of the conjunctival sac from both eyes were negative for microbials. Patient underwent regular topical treatment for dry eye including preservative-free eye lubricants, gel with dexpanthenol, vita-min a ointment, steroids, cyclosporine, acetylcysteine and also soft contact lenses, punctal occlusion, all without improvement. because of the autoim-mune diseases of the patient, a systemic immunosuppressive therapy such as steroids had been arranged by rheumatologist. it was noted that the dete-rioration of the mental state was associated with ocular disease progres-sion. it could be partly due to patient noncompliance, as less frequent drugs application was observed by his family during cyclical severe depression. this resulted in a vicious circle mechanism, because the progression of corneal

introduction

novel matrix therapy success in non-healing persistent

sterile melting corneal ulcers due to rheumatoid arthritis

and sJogren's syndrome

novel matrix therapy success in non-healing, persistent sterile melting

corneal ulcers due to rheumatoid arthritis and sJogren's syndrome



ulceration also intensified patient's depression.

from the first visit to the clinic visual acuity and eye condition gradually dete-riorated. corneas were prone to opacifications and thinning in the lower parts.

21.02.2014 due to perforating ulcer of right eye the patient was referred to the ophthal-mic ward, where an emergency segmental perforative keratoplasty was per-formed. three weeks after keratoplasty corneal transplant was slightly hazy and tending to thin. to preserve the corneal graft in the right eye (fig. 1,4) and because of progression of corneal ulcer in the left eye (fig. 7,10) patient was administered cacicol® topically every 7 days, which was a new option for epithelial defects and treatment-resistant ulcers at that time.

three weeks after this treatment introduction stabilization of corneal graft in the right eye (fig. 2, 5), thickening of corneal stroma and reduction of corneal haze in the left eye was observed (fig. 8, 11).

bilateral visual acuity improvement (bcVa Re 0,1 le 0,3), stabilization of cor-neal graft in the right eye (fig. 3,6) and healing of corneal ulcer in the left eye (fig. 9,12) was noted after 10 weeks treatment. due to the impaired function of the aqueous component of the tear film the patient had previously been forced to use lubricant drops without preservatives constantly. however, since the introduction of cacicol® the need for artificial tears significantly decreased and mental condition of the patient improved. additionally, advan-cement of filamentary keratopathy has reduced.

fig.1 case 1 - segmental keratoplasty in the right eye before treatment

fig. 2 case 1 - segmental keratoplasty in the right eye 3 weeks after treatment

fig. 3 - case 1 - segmental keratoplasty in the right eye after 10 weeks treatment

fig. 4 case 1 - as-oct of segmental keratoplasty in the right eye before treatment

fig. 5 case 1 - as-oct of segmental keratoplasty in the right eye 3 weeks after treatment

fig. 6 case 1 - as-oct of segmental keratoplasty in the right eye after 10 weeks treatment

fig. 7 case 1 - Melting ulcer in the left eye before treatment

fig. 8 case 1 - the left eye after 3 weeks treatment

fig. 9 case 1 - the left eye after 10 weeks treatment fig. 10 case 1 - as-oct of melting ulcer in the left eye before treatment

fig. 11 case 1 - as-oct of the left eye after 3 weeks treatment

fig. 12 case 1 - as-oct of the left eye after 10 weeks treatment



Monika saRnat-kUchaRczYk



case 2a 67 year old female patient was referred due to severe bilateral dry eye connected with rheumatoid arthritis and sjogren's syndrome.25.05.2014 first visit bcVa was Re 0,1 le 0,1, with normal ioP in both eyes. during slit lamp examination she presented with conjunctival injection, filamentary kera-titis and cataract in both eyes. Patient was treated with topical preservative-free lubricants drops and gels, and in the event of exacerbation she was given systemic steroids.

26.07.2014 during the period of disease alleviation, patient underwent in the right eye uneventful standard cataract surgery. Patient received topical antibiotic, steroid, cycloplegic and non-steroidal anti-inflammatory drugs (nsaids) to prevent cystoid macular edema. next day post-operative slit lamp examina-tion revealed wound closure and filamentary keratitis. two weeks later, des-pite corneal filaments, no alarming symptoms were present.

23.08.2014 Patient presented with severe pain, decreased vision and conjunctival hype-remia of the right eye, with no history of trauma. central corneal erosion was present with adjacent conjunctival injection. smear tests of conjunctival sac appeared to be negative. topical therapy including lubricants, serum eye drops and systemic steroids were unsuccessful. bandage soft contact lenses were not tolerated by the patient. in relatively short course of time corneal erosion progressed into melting ulcer with a surrounding inflammatory infil-trate (fig. 13,16). at that time bcVa Re was 0,02. cohen has reported two cases of sterile corneal ulcer after cataract surgery, which appeared 3 weeks and 1 month post-operatively.

due to lack of response to previous treatment the patient was administe-red cacicol® in the right eye. Within 3 days corneal re-epithelialization had started, the patient's symptoms subsided and with the full course of therapy the corneal ulcer was completely healed after 2 weeks (fig. 14,17). after 6 weeks’ treatment bcVa Re was 0,2 and further corneal stroma regeneration was observed (fig. 15, 18).

discussion

a wide range of factors can cause susceptibility to corneal ulcers and impai-red healing process. these are diabetes, immune deficiencies such as aids, autoimmune diseases and severe microbial inflammations. it is highly impor-tant to find the cause of healing disorders in order to effectively treat the ocular disease. the cause of the corneal ulceration in the presented patients was multifactorial. contributing factors were underlying systemic disease process in rheumatoid arthritis, sjögren's syndrome, and persistent inflam-matory reaction associated with keratoconjunctivitis sicca4.

corneal ulcers associated with sjogren's syndrome, which develop in the pre-sence of rheumatoid arthritis, are known to be resistant to standard therapy5.

despite intensive local treatment, systemic immunosuppressants, as well as surgical procedures, corneal ulcers may progress and as a consequence lead to corneal perforation at the end stage. topical steroids are helpful when the ulceration is secondary to inflammatory mediators. however, they are contraindicated in corneal melts with minimal inflammation.

fig. 13 case 2 - corneal melting ulcer in the right eye before treatment

fig. 14 case 2 - the right eye after 2 weeks treatment

fig. 15 case 2 - the right eye after 7 weeks treatment fig. 16 case 2 - as-oct of corneal melting ulcer in the right eye before treatment

fig. 17 case 2 - as-oct of the right eye after 2 weeks treatment

fig. 18 case 2 - as-oct of the right eye after 7 weeks treatment






in patients with autoimmune diseases, anterior segment surgeries can trig-ger perforating corneal ulcers6. furthermore, it was reported that topical nsaids may cause corneal melting7. topical cyclosporine may be an efficient way in the treatment of some immunological diseases of cornea.

another possible treatment for persistent non-healing corneal ulcers include preparation of autologous serum, but unfortunately, it has short period of use and the preparation procedure is complicated. although amniotic mem-brane transplantation is another good option, is not commonly available in all hospitals8.

tissue-regenerating agents can mimic the action of destroyed heparan-sul-fate molecules9. thanks to this feature they enable healing processes in corneal stroma and epithelium10. Matrix therapy may be a promising option for therapy of chronic corneal ulcers which are resistant to conventional treatment.

conclusions

in the presented two cases corneal ulcers were associated with autoimmune diseases (rheumatoid arthritis, sjögren's syndrome) and have caused a subs-tantial decrease of visual acuity with even a threat of total vision loss. in the first case we assume that poor eye condition was exacerbated by significant alterations of mental state due to severe depression whilst in the second case previous cataract surgery in the right eye has initiated corneal ulceration.

in the above mentioned entities persistent inflammatory processes, wound healing defects, factors such as stress, surgical trauma, infection or drug side effects have caused irreversible damage and decompensation of corneas. corneal stroma regenerant contributes to the healing of persistent corneal ulcers: it promotes epithelialization and supports further reconstruction of the corneal stroma.

these patients displayed significant improvement in corneal thickness and in visual acuity after the novel therapy introduction. furthermore, no systemic or local side effects of the treatment were reported.

Rgta has appeared to be potentially useful, alternative, noninvasive thera-peutic approach in the management of persistent corneal ulcers.

reFerences [1] chapter 5 - a Matrix of Pathologic Responses in the cornea, in cornea, krachmer J, Mannis M, holland e. (eds) elsevier, ltd., 2011, Vol. i,

[2] tuli ss, schultz gs, downer dM. science and strategy for preventing and managing corneal ulceration. ocul surf. 2007 Jan;5(1):23-39.

[3] cohen kl. sterile corneal perforation after cataract surgery in sjögren's syndrome. br J ophthalmol. 1982 Mar;66(3):179-82

[4] augsten R, dawczynski J, Voigt U, oelzner P, schulze e. [corneal ulcers in systemic autoimmunologic diseases]. königsdörffer e klin Monbl augenheilkd. 2011 Jan;228(1):66-9. doi: 10.1055/s-0029-1245122. epub 2010 aug 16.

[5] Pfister RR, Murphy ge. corneal ulceration and perforation associated with sjögren's syndrome. arch ophthalmol. 1980 Jan;98(1):89-94.

[6] Papaconstantinou d, georgopoulos g, kalantzis g, krassas a, georgalas i., Peripheral ulcerative keratitis after tra-beculectomy in a patient with rheumatoid arthritis. cornea. 2009 Jan;28(1):111-3. doi: 10.1097/ico.0b013e318182fc01.

[7] hargrave sl, Jung Jc, fini Me, gelender h, cather c, guidera a, Udell i, fisher s, Jester JV, bowman RW. Muculley JP, cavanagh hd. Possible role of the vitamin e solubilizer in topical diclofenac on matrix metalloproteinase expres-sion in corneal melting: an analysis of postoperative keratolysis. ophthalmology. 2002; 109:343-50.

[8] Rakowska e, zagórski z, kardaszewska a, durakiewicz d. [application of amniotic membrane transplantation in severe corneal diseases]. klin oczna. 1999;101(6):417-21.

[9] Rouet V, Meddahi-Pelle a, Miao hQ, Vlodavsky i, caruelle JP, barritault d. heparin-like synthetic polymers, named Rgtas, mimic biological effects of heparin in vitro. J biomed Mater Res a. 2006;78:792–797.

[10] aifa a, gueudry J, Portman a, delcampe a, Muraine M. topical treatment with new matrix therapy agent (Rgta) for the treatment of corneal neurotrophic ulcers. invest ophthalmol Vis sci. 2012 dec 13;53(13):8181-5. doi: 10.1167/iovs.12-10476.






dr. elío diez-feiJóo VaRela instituto clínico Quirúrgico oftalmológico de bilbao – spain

Recurrent corneal erosion syndrome (Rces) is a relatively common disor-der, which is associated with intense ocular pain and chronic discomfort. this syndrome was first described in 1872 by hansen, who called it intermittent neuralgic vesicular keratitis.1 occasionally it can go unrecognized since the patient can be asymptomatic upon examination. the most frequent symptoms include pain, eye watering and photophobia upon waking, and it is not unusual that the pain wakes the patient during the night.2 symptoms usually decline or even disappear during the day. these patients may present with serious episodes of spontaneous epithelial erosion which cause intense pain and nor-mally require treatment in hospital emergency services. it is not uncommon that these emergency visits are the only care that the patients receive and this leads to a sensation of anxiety and vulnerability, since the patient is unsure if the episode will occur again or what should be done to avoid its recurrence.

case presentation

a 41 year-old businessman presented for the first time at our clinic through the emergency service. the patient was in the city in a business trip and symp-toms had started some hours ago with a sudden onset of intense ocular pain, photophobia and watering of his right eye. the patient referred a recent dia-gnosis of corneal herpes keratitis in his right eye and had been treated with acyclovir ointment 5-times-day and tapered down over the last weeks. at that moment he was using the ointment twice a day. this same episode had occur-red to him often over the last year, apparently has affected both eyes and the episodes have been increasing over the past three months. in this time he has been visiting several emergency units while travelling, getting different treatments and diagnoses. Recently he has being treated with both acyclovir ointment 5-times-day and oral acyclovir to prevent recurrence. he was very anxious with his problem and concerned about the interference of this patho-logy on his everyday work. he is absent from work frequently over the past months due to his eye problem.

on examination at our emergency service, the patient presented a pseudo-dendritic epithelial ulcer with epithelial edema and intense conjunctival hyperemia. diagnosis of a new recurrence of the herpes keratitis was made. treatment was increased to acyclovir ointment 5-times-day and the patient was referred to our cornea unit for follow-up and further examination.

one week after this episode patient was examined at our cornea clinic. at this time the patient presented with signs of bilateral chronic blepharitis (discrete eyelid edema, increased meibomium discharge and conjunctival hyperemia). although the patient symptoms had improved with treatment, black dots were observed under fluorescein staining of the corneal epithelium in both eyes (figure 1). these affected areas of the corneal epithelium were localized in the inferior paracentral cornea of both eyes. examination of the corneal epi-thelium was completed using high resolution corneal oct. epithelium appea-red to be normal on the central cornea and we observed epithelial edema and abnormal hyper-reflection inclusions in the areas detected as abnormal on the slit lamp examination.

introduction

recurrent corneal erosion syndrome: an elusive diagnosis and individualized treatment

figure 1: black dots under fluorescein staining (arrows) observed in both eyes of the patient on his first visit.

recurrent corneal erosion syndrome: an elusive diagnosis and

individualized treatment.



Patient was diagnosed with Rces secondary to a chronic blepharitis and star-ted treatment with oral doxycycline 100 mg every 24 hours plus every day cleaning of the eyelashes. the need of a follow up to complete treatment was also strongly recommended. at this time patient was still confused with so many diagnoses and as he lived in another city preferred to keep the herpes keratitis treatment and be followed up on his city of residence.

three weeks after the first episode the patient presented at the clinic again on the emergency service with a new episode of intense pain on his right eye. complete unattached epithelium was observed with the slit lamp under fluo-rescein staining (figure 2).

this time he had access to a complete treatment and follow up on the clinic. oral and topic acyclovir was suspended. oral doxycycline increased to twice a day, selected debridement of the affected area was performed with a cotton tip and bandaged contact lens applied (figure 3a). treatment was completed with antibiotic drops every 6 hours. follow up was performed four days after and slit lamp images and corneal oct were obtained at every visit (figure 3b).

contact lens was removed after a week with a complete healing of the epithe-lium. doxycycline was maintained once a day for a month. Patient was trained on correct everyday cleaning of his eyelids using an eyelid cleaning lotion. hyaluronic eye drops were also given 4 to 5 times a day. advice was given on the use of computers and air conditioning. night lubricant ointment was applied in both eyes.

figure 2: Unattached epithelium on the acute episode of the Rces in the right eye (a and b). images immediately after selected epithelial debridement (c and d).

figure 3a: oct images obtained immediately after epithelial debridement and bandage contact lens (cl). complete epithelial erosion may be observed under de contact lens.

figure 3b: oct images obtained 3 days after epithelial debridement, epithelial healing and suture may be observed under the contact lens.


individualized treatment.elío diez-feiJóo VaRela



three months after treatment of the right eye he was asymptomatic and really satisfied with the treatment. black dots under fluorescein staining had disappeared from his right eye while persistent on his left eye (figure 4). he was advised to keep lubrication and everyday eyelid hygiene. at these point patient really encouraged us to treat the left eye which he kept feeling every morning upon awaking and after some hours of computer work and during flights. final decision to treat left eye was taken due to persistence of black dots under fluorescein staining and no changes in the oct after three months of treatment of the ocular surface. Persistence of the epithelial lesions obser-ved under fluorescein staining and by the oct images may be seen in figure 5.

treatment was then performed with epithelial debridement of the abnormal epithelium plus anterior stromal micropunctures around the affected area, respecting central cornea (figure 6). a bandage contact lens was placed for a week and antibiotic drops applied every 6 hours. complete recovery of the epithelium was followed up with slit lamp and oct images.

Patient has now completed 6 months since the first treatment and he remains asymptomatic and completely relieved of the anxiety produced by his disease. he maintains everyday lubrication and eyelid hygiene and does not need night-time application of ointment any more.

discussion

it is not uncommon that patients with chronic Rces are only managed on emergency units when they are suffering from an acute episode. Patients are seen by different doctors each time, have different treatments, and often wrong and different diagnoses. these added to the fact that patients don t know when they are going to have to rush again to a hospital increases their anxiety and distress with their pathology: anxiety is commonly observed while interviewing or treating these patients.

correct management and treatment to avoid recurrence should be done during the inter-crisis period. during the acute phase, epithelial erosion and secondary ocular surface inflammation will hide any sign that may help us with a complete diagnose and an individualized treatment. first thing we should say to these patients is “i need to see you when you are not in pain so i can help you”.

figure 4: slit lamp images 3 months after treating the right eye. normal epithelium may be observed on the right eye while black dots remain in the left eye.

figure 5: Upper images (1 and a) were obtained three months before bottom pictures (2 and b) on the left eye. observe persistence of both black spots under fluorescein staining plus abnormal hypereflective epithelium on the oct.

figure 6: Photo and oct images immediately after treating the left eye. epithelial debridement and anterior stromal micropuntures can be observed under the bandage contact lens in the oct (a and b).





diagnosis may also present some troubles. in our patient diagnosis was confused with herpes keratitis by at least to different ophthalmologist due to the pseudo dendritic lesions these patients may present upon examination. these lesions are indeed epithelial sutures caused by recurrent self-limited epithelial breaks or erosions that may be healing at the time of the slit lamp examination. take a look at these other Rces patient treated from an acute episode at the clinic. the corneal image observed three days after starting treatment with antibiotic ointment could be easily confused with herpes kera-titis (figure 7) if it is the first time we see the patient.

diagnosis of Rces should be done based on correct interview of the patient and close examination under the slit lamp.3 the patient should be questio-ned about previous minor trauma of the eye and ocular surgeries. he should describe how often he feels pain or discomfort on his eyes and when in the daytime is more likely to feel symptoms. then, the face, skin, eyelids and blinking may be observed and tested before slit lamp examination. Rces is an ocular surface pathology and a complete ocular surface examination should be done. any abnormal finding of the ocular surface mechanics will affect our treatment of Rces and should be correctly managed.

Under the slit lamp we should look for meibomian gland dysfunction or ble-pharitis as they can be been related to Rces4 and are one of the theories of the physiopathology of these syndrome.5 then, a close look at the corneal epithelium must be completed with and without fluorescein to observe the typical signs associated with Rces. these signs would be: epithelial base-ment membrane dystrophy (ebMd) signs such as map-dot-fingerprint type lesions and black dots under fluorescein staining. ebMd signs will diagnose the case of the Rces, and black dots will show us where the epithelium is not properly attached. suspicious areas of the epithelium may be tested using a cotton tip to observe attachment.

in our patient we did not have ebMd type lesions but we found black dots under fluorescein staining in both eyes in the inferior corneal epithelium. in this particular case we also used corneal oct to analyze these areas finding epithelial edema and abnormal hyper-reflective inclusions in the epithelium. these findings helped us make the decision to treat the patient.

different treatments have been described for Rces. these include both medi-cal and surgical approaches: lubrication, autologous serum, epithelial debri-dement, anterior stromal micro puncture, phototherapeutic keratectomy (PRk) or therapeutic contact lens.3 all of these treatments have the basic principle of trying to increase the adhesion of the epithelium to the underlying stroma but none of them has demonstrated to completely avoid recurrence. success rates are never over 80 % in large series of patients.3

We may increase our success rate combining all of these treatments in an individualized manner. in our case treating blepharitis was the first step nee-ded to improve symptoms plus we decided to use epithelial debridement on the unattached epithelium of the right eye (but only in the affected area of the cornea).

success on the treatment of the right eye plus the persistence of black dots in the left eye with stable lesions followed by the oct took us to a decision to treat the left eye. in these case we made selected epithelial debridement of the abnormal epithelium plus anterior stromal micro punctures around the epithelial debridement.

treatment was applied as showed on the description of the clinical case and symptoms disappeared as well as the black dots under the slit lamp. complete healing of the area was followed up with corneal oct. it is impor-tant to remark on this case the treatment of both the abnormal epithelium plus the blepharitis. treatment of the blepharitis itself may had improved the patient but showed insufficient and the same would probably occurred if we only treat the abnormal epithelium.

conclusion

this case shows how Rces, whilst not a dangerous disease, can be truly inca-pacitating, affecting life of active middle-age patients. diagnosis as well as treatment, has to be done during the inter-crisis period and should be indi-vidualized. oct may help on diagnosis and management of this disease. any ocular surface abnormality should be also treated to increase success when treating these patients.

reFerences [1] hansen e. om den intermitterende keratitis vesicularis neuralgica af traumatisk opindelse. hospitalis-tidende 1872; 51:201-203

[2] hykin Pg, foss ae, Pavesio c et al. the natural history and Management of Recurrent corneal erosion: a Prospective Randomised trial. eye 1994;8:35-40.

[3] das s, seitz b. Recurrent corneal erosion syndrome. surv ophthalmol 2008;53:3-15.

[4] diez-feijóo e, grau ae, abusleme ei, duran Ja. clinical presentation and causes of recurrent corneal erosion sín-drome: review of 100 patients. cornea 2014;33:571-5.

[5] garrana RM, zieske Jd, assouline M, et al. Matrix metalloproteinases in epithelia from human recurrent corneal erosion. invest ophthalmol Vis sci 1999;40:1266-1270.

figure 7: slit lamp images of a patient suffering from Rces and being treated during an acute episode. notice how epithelial suture on the third day may be confused with a dendritic herpes keratitis.





dr. eleonora faVUzza eye clinic, department of surgery and translational Medicine, firenze – italy

crohn’s disease is a chronic inflammatory bowel disease (ibd) that may also involve other organs such as skin, joints, kidneys, central nervous system and the eye. the pathogenesis of the disease, although still not completely understood, is complex and multifactorial, and likely results from an interac-tion between genetic and environmental factors that may trigger an immuno-inflammatory response.1 the incidence is estimated to be 5.6 per 100,000 population per year, even if it is reported an increase over time2. the most frequent age of presentation is early adulthood, and the incidence is similar in both sexes.1

the ocular complications of this disease may occur in a variable portion of cases, between 3.5% and 11.8%, and even though scleritis, episcleritis and uveitis are the most common, every ocular segment can be involved.1,3-5

corneal complications, first described by crohn in 19253, are quite rare (0.5% of patients), and usually consist in small corneal subepithelial peripheral infiltrates that may coalesce leading to corneal opacities, progressive cor-neal thinning and ulceration (Peripheral Ulcerative keratitis, PUk), often associated with adjacent scleritis or episcleritis.1,3-7

in the following report a case of atypical and recalcitrant corneal ulcer rela-ted to crohn’s disease is presented and discussed.

case presentation

a 45 year old male presented in our emergency room reporting a five day his-tory of foreign body sensation and redness in his right eye. he had been visited five days before by his ophthalmologist, who diagnosed a corneal “erosion” and prescribed topical antibiotics (levofloxacin qid), hyaluronic acid lubricant eye drops and gel at bedtime. for the last two days he had noted mild pain and blurred vision.

the patient told us (without showing any clinical report) he was affected by crohn’s disease since 1995, and now well controlled with azatioprine. two surgical ileocecal resections had been performed in 2000 and 2012. neither previous ophthalmological diseases or surgery, nor past or recent history of contact lens wear, trauma, ocular foreign bodies, or infections were reported.the visual acuity was 0.05 in right eye and 1.0 in left eye. While the left eye appeared completely normal, the right eye showed a wide corneal ulcer par-tially involving the center and the 1/3 of the anterior stroma, with diffuse haze and peripheral superior and infero-nasal stromal infiltration; corneal sen-sitivity was reduced. the bulbar conjunctiva was severely hyperemic, with a relevant limbal vessel hyperemia; no symblepharon was present in conjunc-tival fornices. the anterior chamber even though not well visible seemed not inflamed, but the pupil was hyporeactive to light stimuli. the ocular fundus was not explorable but ultrasound imaging was normal. the intraocular pres-sure was digitally normal. there was not mucous or purulent discharge. at the external examination no significant dermatological disorder of face and eyelids was observed, and lid function was normal.

introduction

an atypical case oF corneal ulcer in crohn’s disease

fig 1: anterior segment slit lamp biomicroscopy of right eye at first visit.

an atypical case oF corneal ulcer in crohn’s disease



the negative ophthalmological history, the absence of mucopurulent secre-tions and extended stromal infiltration, the unilaterality of the ulcer, the reduced corneal sensitivity and the absence of significant pain suggested us to consider in the differential diagnosis an herpetic infection in addiction to bacterial infection. so we decided to stop the topical treatment for one day and perform corneal scrubs with an ocular swab for microbiological cultural analysis and PcR (Polymerase chain Reaction) for herpes Virus 1, 2 (hsV) and Varicella zoster Virus (VzV). after performing the swabs we prescribed topical netilmicin (qid), a cycloplegic eye drop (bid) and acyclovir 800 mg 1 tablet five times a day.

after three days the patients came for the scheduled visit, saying to have started therapy with acyclovir only the day before. the first results of the microbiological and cultural testing were negative for bacteria and fungi. he reported worsening of the conjunctival redness and blurring and moderate pain. the slit lamp examination revealed severe limbal vessel hyperemia, an enlargement of the epithelial and stromal defect and of the stromal infil-tration, with 1-mm hypopion in the anterior chamber, without mucopurulent discharge.(fig 2)

the hypopion was considered sterile and the antiviral therapy was confirmed. the patient then returned to our clinic every two days for examinations, and after three days two daily drops of topical dexamethasone were added. in spite of the complete resolution of the hypopion within a week and of the centripetal reduction of the epithelial defect, the corneal stromal infiltrate progressively worsened especially in the infero-nasal area, with a marked 360-degree limbal vascularization and a diffuse haze.(fig 3). the laboratory communicated the PcR results for hsV and VzV as negative.

considering the resistance of the ulcer to antiviral therapy and the negative results of the microbiological tests, a consult with the patient’s gastroente-rologist was asked, in order to inform him regarding the ophthalmological situation. taking into account a recent enteric MR scan revealing a still active ileal disease, not controlled by azatioprine, and considering the severity of the corneal ulcer, in this multidisciplinary consult was decided to switch to syste-mic infliximab (tnf-α inhibitor) 5 mg/kg i.v., that was started two days after. antiviral oral therapy was stopped and topical netilmicin tid, dexamethasone bid, lubricant and cycloplegic eye drops were continued.

after the first infliximab dose we observed a progressive and dramatic reso-lution of the corneal ulcer, the stromal infiltration the bulbar and limbal conjunctival hyperemia. in the anterior chamber signs of chronic inflamma-tion such as posterior synechiae were still evident (fig 4).

fig 3 : slit-lamp examination, right eye, second visit.

fig 2 : slit lamp biomicroscopy examination of the corneal ulcer, two weeks after the first visit.

an atypical case oF corneal ulcer in crohn’s diseaseeleonora faVUzza



one month from the beginning of the biological therapy the cornea was com-pletely epithelizated, the bulbar conjunctiva was normoemic, the limbal ves-sel were completely disappeared except for a small neovascularization in the inferonasal quadrant, the corneal haze was reduced (fig 5). Visual acuity in right eye was 0.1 natural, 0.5 with astigmatic correction.

infliximab 5 mg/kg i.v. was repeated two weeks and 6 weeks after first dosing, and then scheduled every 8 weeks, under strict gastroenterological control. antibiotic topical therapy was stopped after complete epithelization, the topi-cal dexamethasone dosing was gradually reduced in a 3-month course and cycloplegic eye drops was continued until resolution of posterior synechiae. in a four-month follow-up no recurrences were observed.

discussion

this case was a diagnostic challenge because of the atypical presentation of the corneal ulcer.

even if unfortunately an accurate description of the ulcer at the onset was not available, the ulcer had not the typical characteristics and the evolution of the Peripheral Ulcerative keratitis usually associated with crohn’s disease as it is reported in literature1. PUk is described as a crescent-shaped stromal inflammation that involves the juxtalimbal cornea and causes a progressive stromal thinning of the affected area. it is always associated with an overlying epithelial defect (that usually arises after the stromal infiltration), and a contiguous scleritis or episcleritis is often observed.8 When the patient came to our attention the ulceration and the epithelial defect involved the central cornea, with an homogeneous stromal thinning. no scleritis or episcleritis signs were found within the observation period. considering the presentation not suggestive of immunomediated ulcer and the presumed absence of other signs of activity of the disease (as reported by the patient) the patient’s refer-ral to his gastroenterologist for a multidisciplinary consult was delayed.

the initial suspects were of an infectious ulcer: because of the absence of an history of contact lens wearing, trauma or foreign body, the absence of mucous or purulent discharge, the reduced corneal sensitivity, the relatively small infiltration and the wide epithelial defect the herpetic etiology was considered. therefore microbiological testing for bacteria, fungi and PcR for hsV1, hsV2 and VzV were performed, resulting all negative. Unfortunately the patient was already under topical antibiotic treatment when he came to our attention, so the bacterial culture might be have affected by the previous treatment. the hypopion developed few days after first examination was inter-preted as sterile, still lacking clear signs of bacterial infection, and this was confirmed in our opinion by its resolution in few days without the use of sys-temic or fortified antibiotics. Regardless, a topical netilmicin treatment was maintained until the resolution of the epithelial defect for prophylaxis. the herpetic hypothesis was unfortunately not confirmed also by a poor response to oral antiviral therapy.

fig 4 : Right eye, two weeks after the first infliximab dose.

fig 5 : Right eye, one month after first infliximab dose.




only after having excluded infectious causes a consult with his gastroente-rologist was sought, revealing a not optimal control of the disease obtained with oral azatioprine. infliximab therapy was then attempted, following what already reported in literature regarding successful treatment of PUk asso-ciated to crohn’s disease not responding to conventional immunosuppressive treatment. 1,9-10

infliximab is a specific monoclonal antibody against tumor necrosis factor-alpha, (tnf-α), that binding its receptor blocks both the soluble and trans-membrane tnf-α. this proinflammatory cytokine is thought to have a rele-vant role in PUk, stimulating the production of matrix metalloproteinases probably responsible for corneal stromal lysis.8-11

in our case the corneal improvement was immediate and dramatic only few days after the beginning of the treatment, confirming the diagnostic hypothe-sis of immunomediated inflammatory ulcer. at 4-month follow-up no recur-rences were observed.

conclusion

When a corneal ulcer in patients affected by autoimmune or inflammatory diseases is diagnosed, a possible relationship with the systemic disease should be always considered, even in presence of atypical presentations or confoun-ding factors. the multidisciplinary approach is essential for the treatment choice, always considering that ophthalmic complications may occur also in a not active inflammatory bowel disease4. in our case of inflammatory ulcer with an atypical presentation in a crohn’s disease with signs of bowel activity, the systemic treatment with infliximab was effective.

reFerences [1] ghanchi fd, Rembacken bJ. inflammatory bowel disease and the eye. surv ophthalmol 2003; 48(6): 663-676.

[2] shivananda s, lennerd-Jones J, logan R, et al. ec-ibd study group. incidence of inflammatory bowel disease across europe is there a difference between north and south?Results of the european collaborative study on inflam-matorybowel disease (ec-ibd). gut 1996; 39:690–7

[3] crohn bb. ocular lesions complicating ulcerative colitis. amer J Med sci. 1925; 169:260-267.

[4] hopkins dJ, horan e, burton il, et al. ocular disorders in a series of 332 patients with crohn’s disease. br J ophthalmol 1974;58:732-737

[5] knox dl, schachat aP, Mustonen e: Primary, secondary and coincidental ocular complications of crohn’s disease. ophthalmology 1984;91:163–73.

[6] knox dl, snip Rc, stark WJ. the keratopathy of crohn’s disease. am J ophthalmol 1980;90:862–5.

[7] schulman Mf, sugar a: Peripheral corneal infiltrates in inflammatory bowel disease. ann ophthalmol 1981;109–11.

[8] Yagci a. Update on peripheral ulcerative keratitis. clin ophthalmol 2012;6:747-754.

[9] Pham M, chow cc, badawi d, tu eY. Use of infliximab in the treatment of Peripheral Ulcerative keratitis in crohn disease. am J ophthalmol 2011;152:183-188.

[10] angioi k, kaminsky P, Peyrin-biroulet l. infliximab for severe Peripheral Ulcerative keratopathy revealing crohn’s disease. inflamm bowel dis, 2011; 17(3): 866-877.

[11] odorcic s, keystone ec, Ma JJ. infliximab for the treatment of refractory progressive sterile peripheral ulcera-tive keratitis associated with late corneal perforation: 3-year follow-up. cornea 2009;28:89–92.




dr. aurélie Pison Paris hôtel-dieu hospital – France

Persistent corneal ulcers can be linked to different causes, but they are all finally related to neurotrophic keratopathy. a damage to the corneal innerva-tion induces corneal anesthesia (loss of afferent sensory input), which leads to decreased tear secretion, reduced nutritional support, dry ocular surface, and then epithelial breakdown.

the usual treatments are non-preserved artificial tears, fitting of a bandage contact lens, autologous serum (1), amniotic membrane grafting(2)(3)(4), and tar-sorraphy in resistant cases. the feared complication is the globe perforation.

the Rgta® (Regenerating agents) are a new ophthalmic medical device, based on the reconstitution and preservation of the cells environment called “extra-cellular matrix” (ecM)(5).

the ecM is the structural support of the cells and assures tissular homeostasis.

three different components play a role in the ecM: the structural proteins (like collagen, elastin, fibronectin, and laminin), the intercellular com-munication factors (growth factors and cytokins, that allow the tissular

homeostatis), and the glycosaminoglycans (gags) (like heparan-sulfate, that bound the matrix proteins together (6)).

When a lesion occurs, the gags and the matrix proteins are destroyed, and the structural proteins and the intercellular communication factors are not protected anymore, leading to a disorganization of the microenvironment of the cell.

the Rgta® are biopolymers engineered to replace gags (such as heparan-sulfates). they are resistant to matrix enzyme degradation. the heparan-sul-fates bind specifically to matrix proteins and to growth factors, which are des-troyed after a lesion has occurred. the Rgta®-bound proteins are protected from proteolysis. subsequently, the Rgta® enables the restoration of the homeostasis and the proper organization of the ecM.

they first have been developed for chronic skin wound healing (7)(8). in oph-thalmology, experimental studies showed good results (9)(10), decreasing fibroblastic proliferation, and stimulating re-epithelialization. their efficacy in the healing of corneal ulcers has been reported by two clinical uncontrol-led studies (one retrospective(11), and one prospective (12)), by a case report (13), and by a case series (14).

the following case series illustrates the efficacy of this new treatment, and its mechanism, explaining the dose-dependent relationship.

case presentation

case 1a 79 year-old man presented with a chemical burn with a base. Upon examina-tion, he showed a limbal ischemia grade iV (Roper hall classification) on his left eye. he had been treated with a local treatment (rinse, vitamin c, vibra-mycin, steroid and antibiotic drops, artificial tears, β-blocker drops), and then a surgical treatment with 2 membrane amniotic grafts and then a tarsorraphy.

Upon examination, he showed a corneal anesthesia and a large corneal ulcer.

as the usual treatments all failed, we decided to treat him with a Rgta® in a double-blinded protocol. We didn’t know whether he received the Rgta® or only artificial tears. there has been no improvement with the new treat-ment, and a limbal neovascularization appeared. at the end of the protocol, we decided to give him a compassionate treatment with the Rgta®. Within one week, the ulcer receded as its size had been divided by two.

introduction

healing oF corneal persistent ulcers From diFFerent etiologies using a new

matrix therapy agent (rgta): illustration oF the dose-dependent relationship

explaining the mechanism






case 2a 79 year-old woman presented with a corneal ulcer on her right eye, fol-lowing ptosis surgery. her medical history revealed a dermatomyositis trea-ted by corticosteroids and methotrexate, and a breast cancer.

her right eye had been treated surgically with a tarsorraphy.

the evolution was marked by the onset of a corneal ulcer on her left eye, wit-hout any history of surgery.

Upon examination, she showed a bilateral trophic corneal ulcer with a corneal anesthesia.

as the ulcer on her right eye did not disappear after tarsorraphy, we decided to treat her bilaterally with the Rgta®.

Within one month, the ulcers disappeared on both eyes. the treatment was stopped after one month.

she experienced a recurrence of the ulcer on her right eye only, due to the post-surgery lid-lag.

case 3a 61 year-old woman presented with a neurotrophic ulcer on her left eye. her medical history revealed a congenital toxoplasmosis with amblyopia on her left eye. When she presented, she already had tried lubricant eye drops and ciclosporin 0.5% treatments.

We decided to treat her with Rgta®: one drop every two days.

the size of the ulcer decreased progressively and eventually totally disappea-red within one month (figure 3).

the anterior oct (optical coherence tomography) shows the ulcer before treatment, and the re-epithelialization at the end of the treatment.

figure 1: biomicroscopy (slit-lamp examination) and fluoroscopy of the left eye of the patient 1. this figure shows a corneal neurotrophic ulcer that doesn’t heal after one month of double blinded protocol. after only week of Rgta® treatment, the size of the ulcer had been divided by two.

figure 2: biomicroscopy (slit-lamp examination) and fluoroscopy of the two eyes of the patient 2, before and after one month of Rgta® treatment. after one month, the ulcers totally disappeared.

figure 3: biomicroscopy (slit-lamp examination) and fluoroscopy of the left eye of the patient 3, before and after 1, 2 and 3 and 4 weeks of treatment. Within one month, the ulcer totally disappeared.

1 week 2 week 1 month 1 week of RGTA®

OD

1 month

OS

1 month Before treatmentBefore treatment

Before treatment 1 month3 weeks2 weeks1 week




aurélie Pison



case 4a 48 year-old deaf-mute woman presented with a visual loss on left eye that started more than 1 month before, in the context of a neurotrophic ulcer.her ophthalmic history showed that the ulcer was on her monophtalmic eye (amblyopia since childhood on the right eye).her medical history revealed Willebrand disease (autologous serum could not be used).

different treatments had already been tried: topic antibiotics, acetylcystein, valaciclovir, cystin b6, without efficacy.on examination, her vision was limited to counting fingers at 1 meter.the biomicroscopy showed a geographic band of profound stromal fibrosis, with a corneal central and paracentral ulcer of more than 3 mm, involving the anterior third of the stroma.there was a total corneal anesthesia. there were no cells in the anterior chamber.corneal samples had already been analyzed (bacteriology, virology and parasitology were negative).

We decided to treat her left eye neurotrophic central ulcer surgically with an amniotic membrane graft, and with a local treatment (lubricant drops 8 times a day, ointment and palpebral occlusion).as the amniotic membrane graft failed, we decided to treat her with Rgta®, in order to avoid a tarsorraphy that would leave her blind and dependent.after 7 instillations (two weeks of treatment, with 1 drop every two days), the ulcer had almost disappeared, but a small central ulcer remained.the patient incidentally had an appointment with an ophthalmologist who was unaware of the protocol of Rgta® treatment. as the ulcer remained after 3 weeks of treatment, the ophthalmologist decided to double the dose: 1 drop every day.

after one week of treatment, we noticed a recurrence of the ulcer.We rectified the treatment with the initial dosage of one drop every two days, and the ulcer totally disappeared within two weeks.

this case illustrates the dose-effect relationship of this new treatment.

figure 4: anterior spectral-domain oct (optic coherence tomography), vertical scans of the left eye of the patient 3, before treatment, and after 2, 3 and 4 weeks of treatment. before treatment we can see the ulcer, and after treatment, the re-epithelialization.

figure 5: fluoroscopy of the left eye of the patient 4. before treatment, it shows a large ulcer. after 7 instillations, the ulcer almost disappeared. after one week of doubled dose, the ulcer reappared. after two weeks of treatment at one drop every two days, the ulcer had totally disappeared.




aurélie Pison



case 5a 60 year-old woman presented with a neurotrophic ulcer on her right eye, after surgery for acoustic neurinoma one year before.her ophthalmologic history was a bilateral cataract surgery ten years before.

Upon examination, her visual acuity was limited to counting fingers.the biomicroscopy showed a neurotrophic ulcer measuring 3.5 mm on 2.5 mm (with total corneal anesthesia). she had tried artificial tears and ointment.

she has directly been included in a trial with Rgta® treatment (1 drop every two days) and lubricant eye drops.Within one month, the size of the ulcer significantly reduced and almost disappeared.the anterior segment oct images (heidelberg), shows the ulcer before treatment, and the re-epithelialization after treatment.

figure 6: biomicroscopy (slit-lamp examination) and fluoroscopy of the right eye of the patient 5, before and after treatment by Rgta®. the size of the ulcer significantly decreased within one month.

aurélie Pison



discussion

the Rgta® (Regenerating agents) are a new ophthalmic device, based on the reconstitution and preservation of the cells environment called “extra-cellu-lar matrix” (ecM).When a lesion occurs, the gags and the matrix proteins are destroyed, and the structural proteins and the intercellular communication factors are not protected anymore, leading to a disorganization of the microenvironment of the cell.the Rgta® are biopolymers engineered to replace gags (heparan-sulfate mimetic). they bind specifically to matrix proteins and to growth factors, which are destroyed after a lesion has occurred. the proteins that are bound are protected from proteolysis. subsequently, the Rgta® enables the resto-ration of homeostasis and the proper organization of the ecM.

if the dose is increased, the binding sites on the structural proteins get satura-ted. the excess of Rgta® will still bind to the growth factors, but will be elimi-nated in the general circulation .their therapeutic efficacy is thus decreased by a lack of growth factors limiting the tissular homeostasis (6).the right dose would be the one that allows binding of all the available sites on the structural proteins, without any excess.

conclusions

this case series shows a strong effect of the Rgta® in the treatment of resis-tant neurotrophic corneal ulcers, with a great safety. the optimal posology needs to be refined as there is a clear dose-dependent relationship.

reFerences [1] Matsumoto Y, dogru M, goto e, ohashi Y, kojima t, ishida R, et al. autologous serum application in the treatment of neurotrophic keratopathy. ophthalmology. 2004 Jun;111(6):1115–20.

[2] Vasseneix c, toubeau d, brasseur g, Muraine M. [surgical management of nontraumatic corneal perforations: an 8-year retrospective study]. J fr ophtalmol. 2006 sep;29(7):751–62.

[3] chen hJ, Pires Rt, tseng sc. amniotic membrane transplantation for severe neurotrophic corneal ulcers. br J ophthalmol. 2000 aug;84(8):826–33.

[4] nubile M, dua hs, lanzini te-M, carpineto P, ciancaglini M, toto l, et al. amniotic membrane transplantation for the management of corneal epithelial defects: an in vivo confocal microscopic study. br J ophthalmol. 2008 Jan;92(1):54–60.

[5] barritault d, caruelle J-P. [Regenerating agents (Rgtas): a new therapeutic approach]. ann Pharm fr. 2006 Mar;64(2):135–44.

[6] barritault d, garcia-filipe s, zakine g. [basement of matrix therapy in regenerative medicine by Rgta®: from fun-damental to plastic surgery]. ann chir Plast esthét. 2010 oct;55(5):413–20.

[7] groah sl, libin a, spungen M, nguyen k-l, Woods e, nabili M, et al. Regenerating matrix-based therapy for chronic wound healing: a prospective within-subject pilot study. int Wound J. 2011 feb;8(1):85–95.

[8] garcia-filipe s, barbier-chassefiere V, alexakis c, huet e, ledoux d, kerros Me, et al. Rgta otR4120, a heparan sulfate mimetic, is a possible long-term active agent to heal burned skin. J biomed Mater Res a. 2007 Jan;80(1):75–84.

[9] brignole-baudouin f, Warnet JM, barritault d, baudouin c. Rgta-based matrix therapy in severe experimental corneal lesions: safety and efficacy studies. J fr ophtalmol. 2013 aug 16;

[10] cejkova J, olmiere c, cejka c, trosan P, holan V. the healing of alkali-injured cornea is stimulated by a novel matrix regenerating agent (Rgta, cacicol20): a biopolymer mimicking heparan sulfates reducing proteolytic, oxida-tive and nitrosative damage. histol histopathol. 2013 oct 9;

[11] chebbi ck, kichenin k, amar n, nourry h, Warnet JM, barritault d, et al. [Pilot study of a new matrix the-rapy agent (Rgta otR4120) in treatment-resistant corneal ulcers and corneal dystrophy]. J fr ophtalmol. 2008 May;31(5):465–71.

[12] aifa a, gueudry J, Portmann a, delcampe a, Muraine M. topical treatment with a new matrix therapy agent (Rgta) for the treatment of corneal neurotrophic ulcers. invest ophthalmol Vis sci. 2012 dec;53(13):8181–5.

[13] de Monchy i, labbé a, Pogorzalek n, gendron g, M’garrech M, kaswin g, et al. [Management of herpes zoster neurotrophic ulcer using a new matrix therapy agent (Rgta): a case report]. J fr ophtalmol. 2012 Mar;35(3):187.e1–6.

[14] kymionis gd, liakopoulos da, grentzelos Ma, diakonis Vf, klados ne, tsoulnaras ki, et al. combined topical application of a regenerative agent with a bandage contact lens for the treatment of persistent epithelial defects. cornea. 2014 aug;33(8):868–72.

figure 8: schematic representation of the extracellular Matrix (ecM).the structural proteins are fibronectin, elastin, laminin, collagen. they interact with the growth factors and cytokins, and with the glycosaminoglycans like heparin sul-fate to assure tissular homeostasis.




aurélie Pison



dr. Yasemin aYdin Yaz gallipoli state hospital, canakkale – turkey

fungal keratitis is vision threatening corneal disease causing by corneal ulceration; also diagnosis and treatment of the disease is very complicated. fungal keratitis is uncommon infectious keratitis, compared to bacterial kera-titis. in developing countries with tropical, temperate and humid climates, fungal keratitis is seen more frequently. in the Usa fungal keratitis is repre-senting 5-10% of all infectious keratitis cases; however in india and thailand fungal keratitis has been reported in 30-50% of keratitis in different studies (1,2). trauma; particularly with organic and vegetable matter is the most important and common risk factor for fungal keratitis (2,3). the increasing use of broad-spectrum antibiotics, steroids and contact lens wearing has been implicated as major causes for the rising incidence for fungal keratitis (3).

fungal keratitis treatment is difficult due to delayed diagnosis, limited effi-cacy and poor ocular penetrance of the currently available antifungal agents (4). as known in fungal keratitis cases the etiology may be unclear for weeks. often corneal cultures take several weeks to grow and disease is more advanced at the time of diagnosis. therefore, antifungal therapy should be started empirically with a broad-spectrum antifungal in addition to a broad-spectrum antibiotic agent (5). Voriconazole is a safe, broad-spectrum antifun-gal and well penetrated in intraocular tissues, for these reasons a good option for empirical therapy (4,5). also lamellar or penetrating keratoplasty is an alternative treatment for cases that have not respond to antifungal the-rapy (2,3).

filamentous fungi are the most frequent etiologic agents for fungal keratitis. fusarium and aspergillus species have been implicated as main pathogens (3). Whereas other uncommon agents can also cause fungal keratitis in addi-tion to main pathogens. trichosporon is one of the uncommon agent for fun-gal keratitis and there has been reported only one case of fungal keratitis caused by t.asahii in literature (6). trichosporon species are found in the nor-mal ground flora and occasionally in humans; these fungal species can colo-nize in skin, nails, gastrointestinal tract, respiratory tract and vagina. the microorganism can cause superficial skin and hair infections, but at present in immunosuppressed conditions like hematological malignancies, solid organ malignancies and transplantations, trichosporon spp could cause invasive tri-chosporonosis (7).

case presentation

a 79-year-old woman attended with pain and hyperemia in her left eye since 20 days. the patient had undergone phacoemulsification and intraocular lens implantation surgery from her left eye 9 months ago, and after the surgery visual acuity had been reported as 0,8. four months after the surgery bullous keratopathy occurred and was treated with bandage contact lens and topi-cal steroids. she had hypertension and heart failure as systemic disorders. When she was evaluated in our clinic, her visual acuity was light perception in her right eye and slit lamp examination of right eye showed corneal edema and intraocular lens. according to examination findings, the patient was dia-gnosed as pseuodophacic bullous keratopathy, and artificial tears treatment was continued. in the left eye, visual acuity was light perception and slit lamp examination showed in anterior segment a large keratitis area; the central keratitis area was melted, anterior chamber was shallow and hypopyon was present (fig. 1). clinical samples were taken by corneal scraping then direct smear examination and culture had done. Under direct examination hyphae formation was observed (fig. 2).

introduction

From devastation to restoration: trichosporon

asahii can be beaten

figure 1. figure 2.

From devastation to restoration: trichosporon asahii can be beaten



fluconazole 200mg 2x1, cefazolin 50mg/ml gtt per hour, Voriconazole %1 gtt per hour, cyclopentolate %1 3x1, Phenilephrin %2.5 3x1, tropicamide %1 3x1, acetozolamide 250 mg 2x1 treatment were started empirical until the culture and antibiograme were received. after 5 days culture isolated trichosporon asahii (fig. 3,4).

the microorganism was sensitive for voriconazole and fluconazole, resistant for amphotericin b. according to the antibiograme results, systemic flucona-zole and topical voriconazole treatments, which was empirical started before the culture results, were continued. the keratitis area was healed with medi-cal treatment but cornea spontaneously perforated in 15th day of treatment and penetrating keratoplasty was performed immediately (fig. 5, Video 1).

after penetrating keratoplasty visual acuity was reached 0,1 and corneal graft was clear (fig. 6).

Unfortunately the patient had brain stroke one week after the surgery. she was hospitalized in intensive care unit. after her treatment the corneal graft is still clear and recurrence of fungal keratitis has not occur yet. the patient is hemiplegic and aphasic because of stroke and she can communicate with her left eye.

discussion

in the literature there was only one keratitis and two endophthalmitis cases caused by trichosporon spp reported. the first trichosporon asahii keratitis case was occurred with type-1 boston keratoprothesis and contact lens wea-ring, reported in Usa and treated with topical amphotericin b and oral keto-conazole (6).

the patient had risk factors for fungal keratitis as extended contact lens use, local immunosuppression with topical steroids and bullous keratopathy. according to the risk factors and clinical features of the patient, we primarily considered fungal keratitis then topical voriconazole and oral fluconazole treatment had started. Voriconazole was preferred because of deep penetra-tion to intraocular tissues after topical administration (4,5). culture and anti-biograme results were showed trichosporon asahii sensitive for voriconazole and fluconazole. the laboratory results and response to the treatment were evidence for adequate therapy. our patient responded well to therapy, but unfortunately cornea was perforated spontaneously from center of keratitis area and immediately penetrating keratoplasty was performed.

conclusions in conclusion, this is the first case reported as a fungal keratitis caused by t.asahii which was treated successfully with penetrating keratoplasty.

reFerences [1] external disease and cornea american academy of ophthalmology (aao). 2011-2012; section 8:164.

[2] chang hY, chodosh J. diagnostic and therapeutic considerations in fungal keratitis. int ophthalmol clin. 2011;51(4):33-42.

[3] srinivasan M. fungal keratitis. curr opin ophthalmol. 2004 aug;15(4):321-7.

[4] Jurkunas UV, langston dP, colby k. Use of voriconazole in the treatment of fungal keratitis. int ophthalmol clin. 2007 spring;47(2):47-59.

[5] hariprasad sM1, Mieler Wf, lin tk, sponsel We, graybill JR. Voriconazole in the treatment of fungal eye infections: a review of current literature. br J ophthalmol. 2008 Jul;92(7):871-8.

[6] keating a, Pineda R. trichosporon asahii keratitis in a patient with a type i boston keratoprosthesis and contact lens. eye contact lens. 2012 Mar;38(2):130-2.

[7] colombo al, Padovan ac, chaves gM. current knowledge of trichosporon spp. and trichosporonosis. clin Microbiol Rev. 2011 oct;24(4):682-700.

figure 3. figure 4.

figure 5. Vidéo 1.

figure 6.

From devastation to restoration: trichosporon asahii can be beatenYasemin aYdin Yaz



dr. ate altenbURg antwerp University hospital – belgium

a 86 year old man was followed at our department after a recurrence of her-petic keratitis of the right eye. after initial treatment with antiviral medica-tion the patient developed recurrent epithelial erosions.

his ophthalmic history was significant for an episode of herpetic keratitis during the 1980’s which resulted in stromal scarring. he had also attended previously for the management of blepharitis.

case presentation

the patient presented to the ocular emergency services with complaints of redness, decreased vision and ptosis of the right eye, but no sensation of pain or discomfort. slitlamp examination showed mild limbal injection and a cen-tral epithelial defect overlying a stromal scar. there were also two small dendritic-like epithelial lesions superiorly and there was no anterior chamber reaction. Visual acuity was counting fingers at 2m and he displayed corneal sensitivity of the right eye. he was diagnosed with a recurrence of herpetic keratitis and on the basis of this, treatment with ganciclovir 1.5mg/g eyegel 5x/day, ofloxacin 3mg/g eyedrops 4x/day, and systemic acyclovir 800mg 5x/day commenced. after a few days the epithelial defects began to decrease in size slowly. topical fluorometholone 1mg/g 2x/day was added after one week to reduce the inflammatory response and stromal scarring.

at his one-week check-up, the cornea was intact but displayed some epithelial alterations and his visual acuity had increased to 0.1 (snellen decimal best corrected visual acuity). based on the clinical improvement the ganciclovir and ofloxacin treatments were tapered over the following week. his chronic blepharitis showed some increased activity so he was commenced on topical fusidic acid 5mg/g eyegel with a lid hygiene and warm compress protocol. the oral aciclovir was reduced stepwise to 400mg once a day and topical fluoro-metholone tapered.

at his one-month check-up, a small oblong-shaped epithelial defect was seen superonasally. this was thought to be due to minor trauma during his eye drop installation. a thicker ocular lubricant was commenced and two weeks later the defect had healed. two new epithelial defects however, had occurred in the mean time. the defects were mostly inconsistent with a recurrence of the herpetic infection and were attributed to the effect of blepharitis on a neu-rotrophic cornea. systemic treatment with erythromycin 500mg 3x/day was added to augment the treatment regime.

at the next appointment two weeks later, despite a clinical improvement in the blepharitis, he had a new central corneal ulcer, highly suspicious of recurrent herpetic disease. treatment with ganciclovir 5x/day treatment and ofloxa-cin 3x/d was restarted and acyclovir was increased to 800mg 5x/day. after a week of treatment there was no change in the epithelial defect.

at this stage, the recurrent nature of his epithelial defects and the failure to respond the to treatment protocols led us to consider the use of a poly car-boxymethylglucose sulfate (PcMgf) containing agent (cacicol®) to assist in wound healing in this complex neurotrophic cornea. the PcMgs eyedrops were applied by the medical staff twice weekly and progress monitored with corneal photos. treatment with ganciclovir was stopped at the same time and acyclovir was reduced to 3x/day. the ulcer decreased in size after each application of a PcMgs eyedrop (figures) and after treatment with a total of 3 drops the epithelial defect had closed with only some residual epithelial irregularity.

introduction

management oF recurrent neurotrophic epithelial

deFects in a patient with a history oF herpetic keratitis

and blepharitis

management oF recurrent neurotrophic epithelial deFects in a patient with a

history oF herpetic keratitis and blepharitis



slit lamp follow-up cornea photos after treatment with PcMgs eyedrops discussion

in this patient’s case there were multiple corneal pathologies; neutrophic keratopathy, herpetic keratitis and also blepharitis, that impaired the natural wound healing response required to restore his cornea epithelial integrity. his poor responses to the standard therapy provided an opportunity to use an alternative treatment approach to target the corneal extracellular matrix. We hypothesised that the treatment with PcMgs eyedrops would provide additional support to his corneal extracellular matrix and help promote his own corneal regeneration.

in this case, we did see a positive response to the treatment; however it is diffi-cult to attribute his clinical improvement solely to the medication. other fac-tors such as his artificial tear treatments and his antiviral drops were being adjusted to reduce the toxic effects and this may have also played a role. it is also important to note that the duration of treatment was also very short.

aetiologic differential diagnosis of the epithelial defect at different time points also gave difficulties in finding the best treatment regime. the pres-entation made it hard to distinguish between an active herpetic infection and a neurotrophic origin. the fact that not all of the more conventional treatment methods like autologous serum and application of a bandage lens had been used in advance also limits determination of the possible contributing or addi-tive effect of the PcMgs treatment.

although many factors limit interpretation of the exact effect of PcMgs in this specific case, we do think this product may have its use in the treatment of corneal neurotrophic ulcers. further use in our department will hopefully demonstrate this.

conclusion

in this case treatment with PcMgs eyedrops might have had a positive hea-ling effect on the epithelial defects, but unfortunately the exact effect is hard to demonstrate because of many limiting factors in the treatment process. combining this treatment with more conventional treatment methods like artificial tears and contact lenses might be a useful method in the treatment of persistent or recurrent neurotrophic epithelial defects.

reFerences aifa a, gueudry J, Portmann a, delcampe a, Muraine M. topical treatment with a new matrix therapy agent (Rgta) for the treatment of corneal neurotrophic ulcers. invest ophthalmol Vis sci. 2012;53:8181–8185

sacchetti M, lambiase a. diagnosis and management of neurotrophic keratitis. clin ophthalmol. 2014; 9;8:571-579

day 0. before application

day 7. after 2x application



management oF recurrent neurotrophic epithelial deFects in a patient with a

history oF herpetic keratitis and blepharitis

ate altenbURg



dr. gustav stålhaMMaR stockholm st. erik eye hospital – sweden

corneal Ulcers (cU) have a variety of manifestations and causes as wide and complex as any ulceration of an epithelial surface. the common denominator is their environment: the unique biochemical, physiological and anatomical conditions of the cornea exerts a large effect on their healing and resolution, and increases the risk of recurrent disease 1 2 3 4. While the primary lesions are commonly induced by infectious agents, trauma or corneal diseases and dys-trophies, the recurrent lesions are typically relatively spontaneous and at least initially sterile. episodes are characterized by sudden onset of anterior ocular pain, usually at night or upon first awakening, accompanied by redness, photophobia and tearing 1 5.

in this report, a case of Recurrent corneal Ulcers (RcU) evolving into a pro-longed Recurrent corneal erosion (Rce) syndrome in a 38-year-old male is presented along with an overview of the pathogenesis as well as a suggestion for simplified clinical guidelines for primary and recurrent lesions and refer-ral for adjunct therapies such as Photo-therapeutic keratectomy (Ptk) and anterior stromal Puncture (asP).

case presentation

first visita 38-year-old caucasian male working as a forklift driver sought the atten-tion of the emergency ward (eR) at a University eye hospital one afternoon in october 2013 with a complaint of blurry vision, severe eye pain and epiphora since the morning hours. the patient negated any previous trauma, awareness of foreign bodies and use of contact lenses. he medicated with Warfarin after receiving a mechanical aortic valve due to an aortic aneurysm five years ear-lier, but had no known connective tissue disease or earlier ophthalmic medical record.after some probing questions by the attending resident, it was revealed that the patient’s son had accidently scratched his cornea with a fingernail one week earlier. the initial discomfort and tearing on that occasion had however improved promptly and the patient made no association with that incident and the current symptoms.When examined in the slit lamp biomicroscope, the resident found a ciliary injection, and subtle floruescein-absorbing epithelial erosion measuring 2 x 2 mm inferiorly in the cornea (fig 1). there was, however, no sign of an infectious infiltrate, stromal edema or presence of inflammatory cells in the anterior chamber. this led to a diagnosis of traumatic corneal abrasion (classification h16.0 according to icd-10) and the patient was prescribed an ointment with chloramphenicol 6 times a day for 5 consecutive days as a lubricant and prophylaxis for infection. no future clinical controls of the healing process were planned, but the patient was asked to come back in the absence of rapid improvement.

introduction

an overview oF noninFectious recurrent corneal erosions

and a suggestion For simpliFied clinical practice guidelines

fig. 1. slit lamp biomicroscope (10 x) examination with cobalt-blue filter revealing a subtle fluorescein-absorbing erosion of 2 x 2 mm.

an overview oF noninFectious recurrent corneal erosions and a suggestion For simpliFied clinical practice guidelines



and back he cametwo weeks later, the patient was seen a second time at the eR with a complaint of intensified anterior ocular pain. Rather than a gradual improvement of the symptoms, he had experienced a worsened, daily suffering of redness, photo-phobia and tearing since the first examination. his visual acuity had now fallen from – 0,1 to 0,2 (logMaR scale) in the affected eye. he firmly negated any new trauma and added that the pain was most marked in the morning. Upon examination, a non-infected corneal erosion with a discrete stromal edema in addition to the very same characteristics as two weeks earlier was found. also, Meibomian gland dilation and inspissation was noted on the eyelid margins of both eyes (fig 2). this time, the diagnosis of RcU (classification h18.839 according to icd-10) was set, and the patient prescribed a lubricant ointment 5 times a day the first 5 days, followed by 3 months of nightly applications.

this strategy, like the previous antibiotic treatment, proved to be futile. at a great personal discomfort and cost to the healthcare system, the patient continued to receive repeated medical attention and prescriptions of various ointments, drops and antibiotics including chloramphenicol and levofloxacin for quite some time: during the following 6 months, the patient saw the atten-tion of the eR at no less than six additional occasions and the general outpa-tient ward at four occasions, eventually under the diagnosis of Rce. still, he continued to suffer from the very same symptoms that had led him to the eR in the first place, intermittently to an extent that prevented him fulfilling his duties in his job as a forklift driver.

Resolutionin March 2014, the patient was finally referred to the subspecialized anterior segment outpatient ward at the University eye hospital. When examined here, the corneal erosion was temporarily less symptomatic but still as frequently a distress to the patient. in the slit lamp biomicroscope, the boundaries of the lesion was seen being marked by a thin epithelial fluorescein-absorbing opacity, and its centre by ≈ 20 whitish microcysts, indicating the recent distur-bance in epithelial maturation (fig. 3).

this time, the patient was given a soft silicone hydrogel bandage lens wit-hout refractive power. the lens was to be replaced every 2 weeks by an opti-cian at the outpatient ward for a total duration of 10 weeks, and the patient was asked to use rewetting eye drops at his own comfort during this period. a week into the use of the bandage lens, the patient was finally completely free of his pains.

at a follow up at the anterior segment outpatient ward just over a year after the onset of the symptoms, and 3 months after the discontinuation of the ban-dage lens the patient was perfectly happy with the situation and had regained his visual acuity to – 0,1 (logMaR) without any recurrence of symptoms. at this final examination, no sequelae of the Rce could be seen in the slit lamp biomicroscope.

fig. 2. slit lamp biomicroscope (6,3 x) examination revealing Meibomian gland dilation and inspissation in the upper eyelid.

fig. 3. slit lamp biomicroscope (6,3 x) examination revealing microcysts and the boundaries of a recent corneal erosion.


gustav stålhaMMaR



discussion Pathogenesis

Whether the primary ulceration occur spontaneously, following trauma or in association with corneal dystrophies and secondary to certain systemic diseases, the separation of epithelium from the corneal basal lamina induces specific biochemical responses in the subbasal zone that increases the risk of a prolonged state of incomplete healing and resolution 2 6. i.e.: after denuda-tion of the basal cell layer and basal lamina, remnants of the cell-extracel-lular matrix (ecM) adhesion complexes, constituted mainly by hemidesmo-somes formed by laminin, integrin and actin proteins, as well as much of the ecM collagen, is dissolved by a cascade of inflammatory response mediated by enzymes such as metalloproteinase (MMP) 2 and 9, plasmin, tnfα and il-1 7 8. studies have shown that these inflammatory enzymes can be measured in elevated concentrations for up to 6 weeks after an abrasion, a long with a delayed remodeling of the ecM 9 1 2.

the absence of hemidesmosomes and increased amounts of granulomatous debris between the edematous basal layer and basal lamina following the surge in cell and ecM turnover can be clearly visualized in electron micro-graph studies 7 (fig. 4) further, corneal nerve endings are severely affected when exposed and damaged: causing both pain and the sensation of a per-sistent foreign body and a decreased sensory function and growth factor pro-duction 10.

these biochemical and neuronal responses, in addition to the unique anato-mical conditions of the cornea with no rete ridges and poor access to aug-mentations in circulatory supply, interact to increase the risk of delayed hea-ling. this implicates that the new epithelium, quickly proliferating from the undamaged sides of the ulceration 1112, will be loosely anchored to the basal lamina for an extended period of time 3 6. typically in Rce, the recently for-med epithelium tears off in the morning hours when the basal cell layer is at its most edematous state and the superficial keratinocytes dry from the low tear and lubricant production at night 13, each time forcing a setback in the healing process. thus, a majority of patients that once has developed Rce will be symptomatic for years 14.

simplified treatment – suggestionsas a majority of primary lesions heal without progression to Rce 12 despite the risks mentioned above, most publications recommend them being trea-ted with abrasion of loose epithelium residues and extended periods of topi-cal ointments 15 2 10, i.e.: an otc ointment 5 times a day until the erosion is somewhat securely covered by a new layer of epithelium (≈ 5 days) followed by nightly applications for 3 months. the aim of this management is to pro-mote re-epithelialisation and formation of a competent basement membrane complex, by reducing friction and keeping the new epithelium intact for a suf-ficient length of time to allow the reformation of adhesion complexes 12. in the majority of cases there will be a risk of infection (traumatic abrasion by finger-nails, organic and/or dirty material etc), why the initial ≈ 5 day treatment with a otc lubricating ointment should be replaced by topical antibiotics such as an ointment with chloramphenicol 5 times daily or, for patients with contact lenses, an ointment with activity against Pseudomonas aeruginosa such as ciprofloxacin 15. if the pain-relieving effect of the lubrication is insufficient, an oral nsaid such as dexibuprofen can be added. in case of manifest infection in an ulcer, separate guidelines for diagnosis and treatment of infectious kera-titis should be followed.

in the case of sparse recurrences after asymptomatic periods of one or seve-ral weeks, basic further measures should be taken 5 10 16 10. i.e.: Meibomian gland dysfunction is present in almost all cases of Rce 13, and should therefore be considered and treated. other aggravating factors such as punctal plug-requiring dryness, allergies, menopause, sleeping habits, cigarette smoking and use of alcohol should be addressed and discussed with the patient. When these factors are acknowledged and appropriately dealt with, the first line treatment for delayed improvement and sparse recurrences should be new prescriptions of ointments and lubricants with or whiteout antibiotics from primary or secondary centers.

Patients that suffer from absence of improvement or frequent recurrences, but show no sign of predisposing corneal disease and/or ocular conditions such as uveitis, infections, surgical sequelae or corneal dystrophies, dege-nerations and keratopathies, should be offered a soft bandage lens (bl) for 2-3 months. a topical antibiotic drop such as ciprofloxacin or levofloxacin

fig. 4. granulomatous cellular debris (g) between the basal cells and basal membrane (bM). electron micrograph x 10000. note the edematous pallor of the basal layer compared to the suprabasal cells. tripathi et al 1972 7. Reused with license agreement from bMJ Publishing group ltd.


gustav stålhaMMaR



should be administered as a prophylaxis 2 times daily until the integrity of the epithelium is incomplete and the risk of secondary infection decreases. it is important that an optician fits the bl appropriately, and replaces it regu-larly (the producer’s recommendation and fda-approval for length of use for the chosen bl should be followed). experienced users of contact lenses can usually replace the bl themselves. the patient’s expectations are to be adjusted and clear information given about the role of the bl as an attempt at a solution when lubrication has proven futile. in a randomized controlled study 71 % of patients enjoyed complete clinical healing after 3 months with bl, compared to 73 % with lubrication only. the time to relief of symptoms was however significantly shorter with a bl 17.

Patients with 1) recurrent erosions and known corneal disease or 2) no impro-vement with bl, should be referred to a subspecialized outpatient clinic or to a tertiary centre where adjunct therapies can be considered. the details of these therapies are beyond the scope of this report, but include non-invasive medical management such as corticosteroids, oral antibiotics, autologous serum, MMP inhibitors, as well as surgical techniques such as excimer laser Ptk, diamond burr polishing of bowman’s membrane and asP 12 10 2 3 5 16. at this level, efforts should be put into a systemic work up and careful consi-derations into the possibility of cofounding diseases such as Rosacea, sicca, sjögren’s syndrome, rheumatism, epidermolysis bullosa and connective tis-sue diseases, as well as into differentials such as self-inflicted corneal injury, exposure keratitis, diffuse herpes simplex keratitis, neurotropic keratitis and roughening of the tarsal plate12.

as an illustration, the patient described in this case report was rescreened for connective tissue diseases considering his previous aortic aneurysm, but was ultimately deemed to suffer from Rce with no underlying disease. this should illustrate the situation for a majority of patients.

a suggestion for simplified clinical Practice guidelines

taking the pathophysiological background and the practical circumstances illustrated by this case report into consideration, a proposal can be made for an algorithm for simplified clinical Practice guidelines for the treatment of noninfectious primary and recurrent corneal erosions (fig. 5). the intention is to aid the important discussion on stringent and consistent treatments for this large group of patients with a basis that can be altered and updated according to local and future conditions and experience. in conjunction with similar pro-posals by other writers 5 18 19, this algorithm neither can nor is intended to cover all clinical situations or give a complete support for decisions. indeed, all cases must be assessed individually and with careful attention to their individual circumstances.

conclusion

this report presents an overview of RcU and Rce, illustrated by a case report and general pathogenesis. it further suggests a simplified clinical guideline in the format of an algorithm, adapted to representative conditions. no claims can be made to the finality of this and similar algorithms, or to their feasibility to in itself solve the old but very much still relevant problem of noninfectious recurrent erosions. efforts should be concentrated to the development and validation of their managements, equally in the lower end of the spectrum where a majority of patients suffer from transient but fairly severe symp-toms to the top of the pyramid where a few patients need invasive procedures. improvements in these managements should then gradually change imple-mented algorithms to secure an equal and up-to-date treatment for all.

fig. 5. Proposed algorithm for simplified clinical Practice guidelines for the treatment of noninfectious primary and recurrent corneal erosions


gustav stålhaMMaR


reFerences [1] Reidy, J. J., Paulus, M. P. & gona, s. Recurrent erosions of the cornea: epidemiology and treatment. cornea 19, 767-771 (2000).

[2] das, s. & seitz, b. Recurrent corneal erosion syndrome. surv ophthalmol 53, 3-15 (2008).

[3] Reeves, s. W. et al. Recurrent corneal erosion syndrome: a study of 364 episodes. ophthalmic surg lasers imaging 1-2 (2010).

[4] afonso, a. a. et al. tear fluid gelatinase b activity correlates with il-1alpha concentration and fluorescein clea-rance in ocular rosacea. invest ophthalmol Vis sci 40, 2506-2512 (1999).

[5] thakrar, R. et al. treatment of Recurrent corneal erosions. eyenet Magazine 1-3 (2013).

[6] Panda, a., Wadhwani, M. & gupta, Y. k. the demographic patterns and treatment outcomes of patients with recur-rent corneal erosions related to trauma and epithelial and bowman layer disorders. am J ophthalmol 157, 1117-1118 (2014).

[7] tripathi, R. c. & bron, a. J. Ultrastructural study of non-traumatic recurrent corneal erosion. br J ophthalmol 56, 73-85 (1972).

[8] sugioka, k. et al. immunohistochemical localization of urokinase-type plasminogen activator, urokinase-type plas-minogen activator receptor and alpha2-antiplasmin in human corneal perforation: a case report. bMc ophthalmol 12, 60 (2012).

[9] brooks, d. e. inflammatory stromal keratopathies: medical management of stromal keratomalacia, stromal abs-cesses, eosinophilic keratitis, and band keratopathy in the horse. Vet clin north am equine Pract 20, 345-60, vi (2004).

[10] Weiner, g., afshari, n., Mah, f., tu, e. & tuli, s. confronting corneal Ulcers - Pinpointing etiology is crucial for treatment decision Making. eyenet Magazine 44-52 (2012).

[11] zhao, M., song, b., Pu, J., forrester, J. V. & Mccaig, c. d. direct visualization of a stratified epithelium reveals that wounds heal by unified sliding of cell sheets. faseb J 17, 397-406 (2003).

[12] Ramamurthi, s., Rahman, M. Q., dutton, g. n. & Ramaesh, k. Pathogenesis, clinical features and management of recurrent corneal erosions. eye (lond) 20, 635-644 (2006).

[13] hope-Ross, M. W., chell, P. b., kervick, g. n. & Mcdonnell, P. J. Recurrent corneal erosion: clinical features. eye (lond) 8, 373-377 (1994).

[14] heyworth, P., Morlet, n., Rayner, s., hykin, P. & dart, J. natural history of recurrent erosion syndrome--a 4 year review of 117 patients. br J ophthalmol 82, 26-28 (1998).

[15] Willcox, M. d. Management and treatment of contact lens-related Pseudomonas keratitis. clin ophthalmol 6, 919-924 (2012).

[16] stasi, k. & chuck, R. s. Update on phototherapeutic keratectomy. curr opin ophthalmol 20, 272-275 (2009).

[17] ahad, M. a., anandan, M., tah, V., dhingra, s. & leyland, M. Randomized controlled study of ocular lubrication Versus bandage contact lens in the Primary treatment of Recurrent corneal erosion syndrome. cornea (2013).

[18] Wipperman, J. l. & dorsch, J. n. evaluation and management of corneal abrasions. am fam Physician 87, 114-120 (2013)

[19] hykin, P. g., foss, a. e., Pavesio, c. & dart, J. k. the natural history and management of recurrent corneal erosion: a prospective randomised trial. eye (lond) 8, 35-40 (1994).

gustav stålhaMMaR

This brochure is produced under the sole responsibility of the authors, Laboratoires Thea are not involved in the writingof the clinical cases. This brochure may contain MA off-label and/or not validated by health authorities information.

12, rue Louis Blériot Z.I. du Brézet 63017 Clermont-Ferrand CEDEX 2 FRANCETél. +33 4 73 98 14 36 • Fax. +33 4 73 98 14 38

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persistent or recurrent

corneal ulcers

the clinical cases

this bRochURe is PRodUced UndeR the sole ResPonsibilitY of the aUthoRs, laboRatoiRes théa aRe not inVolVed in the WRiting of this docUMent. this bRochURe MaY contain Ma

off-label and/oR not Validated bY health aUthoRities infoRMation.

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