- Email: [email protected]
A Novel Technique for Amniotic Membrane Transplantation in Patients with Acute Stevens-Johnson Syndrome
Accepted Manuscript A Novel Technique for Amniotic Membrane Transplantation in Patients with Acute Stevens-Johnson Syndrome Kelly Ma, MD, MPH, Aristomenis Thanos, MD, James Chodosh, MD, MPH, Ankoor S. Shah, MD,PhD, Iason S. Mantagos, MD PII:
S1542-0124(15)00114-7
DOI:
10.1016/j.jtos.2015.07.002
Reference:
JTOS 144
To appear in:
Ocular Surface
Received Date: 16 June 2015 Revised Date:
12 July 2015
Accepted Date: 14 July 2015
Please cite this article as: Ma K, Thanos A, Chodosh J, Shah AS, Mantagos IS, A Novel Technique for Amniotic Membrane Transplantation in Patients with Acute Stevens-Johnson Syndrome, Ocular Surface (2015), doi: 10.1016/j.jtos.2015.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
SECTION: Innovative Techniques and Technology, Gary N. Foulks, MD, Editor TITLE: A NOVEL TECHNIQUE FOR AMNIOTIC MEMBRANE TRANSPLANTATION IN PATIENTS WITH ACUTE STEVENS-JOHNSON
RI PT
SYNDROME
AUTHORS: Kelly Ma, MD, MPH,1* Aristomenis Thanos, MD,2* James Chodosh, MD, MPH,2 Ankoor S. Shah, MD,PhD,2,3 and Iason S. Mantagos, MD2,3
SC
SHORT TITLE: NOVEL TECHNIQUE FOR AM TRANSPLANTATION FOR ACUTE SJS/Ma et al
M AN U
FOOTNOTES
Accepted for publication August 2015.
From 1Department of Ophthalmology, Boston University Medical Center, Boston University School of Medicine, 2Department of Ophthalmology, Massachusetts Eye and
TE D
Ear Infirmary, Harvard Medical School, 3Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
EP
*Drs. Ma and Thanos contributed equally to this work.
AC C
Financial support: None The authors have no commercial or proprietary interest in any concept or product discussed in this article. Single-copy reprint requests to: Iason S. Mantagos, MD (address below). Corresponding author: Iason S. Mantagos, MD, 300 Longwood Avenue, Fegan 4, Boston, MA 02115. Tel: (617) 355-6401. Fax: (617) 730-0392. E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
ABSTRACT Cryopreserved amniotic membrane (AM) transplantation is an emerging technique that is becoming the gold standard for the management of acute Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis
RI PT
(TEN). We describe a novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring, which facilitates AM placement. Our technique is easy to use and minimizes suturing and manipulation of ocular tissues, leading to decreased
SC
operative time. This technique may be applied in the management of multiple ocular
surface disease processes, including chemical or thermal burns, severe ocular graft versus
M AN U
host disease (GVHD), and other autoimmune diseases.
KEY WORDS amniotic membrane, cryopreserved amniotic membrane, ocular surface, Stevens-Johnson syndrome, transplantation
Introduction
EP
I.
TE D
Outline I. Introduction II. Description of the Technique III. Outcome Data IV. Discussion V. Conclusion
Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal
AC C
necrolysis (TEN) present with widespread exfoliation of the skin and mucous membranes, which can lead to significant ocular involvement and morbidity. If acute ocular surface inflammation is not recognized and treated, cicatrization ensues, leading to photophobia, intractable dry eye, chronic pain, corneal scarring, and vision loss.1 In fact, progressive conjunctival scarring and corneal damage are the most disabling long-term complications
2
ACCEPTED MANUSCRIPT
for SJS and TEN survivors.2,3 The incidence is approximately 2-6 cases per million per year, but can be significantly higher in children, at up to 35.5 cases per million per year.4-6 Cryopreserved amniotic membrane transplantation (AMT) is an emerging
RI PT
technique that is becoming the gold standard in the management of acute SJS/TEN.7,8
Amniotic membrane (AM) arises from the innermost placental membrane and contains a single layer of epithelial cells that are often nonviable in commercially available AM, a
SC
thick basement membrane, and a stroma. The basement membrane supports host epithelial cell migration, adhesion, and differentiation, and it inhibits epithelial cell apoptosis. The
M AN U
stroma is rich in cytokines, growth factors, and protease inhibitors,9,10 providing AM with anti-inflammatory and antiscarring actions. Thus, AM serves as a biological bandage by suppressing inflammation, promoting epithelialization, and thereby preventing sightthreatening sequelae. AM typically dissolves over a period of 1-2 weeks; thus, more than
TE D
one application may be necessary during the acute phase of the disease. It is well understood that early intervention with AM during the acute stage of SJS is beneficial,10 and there are two current methods of applying AM. The first involves
EP
PROKERA® (Bio-Tissue, Doral, FL). This product consists of AM stretched across the lumen of a polycarbonate ring, and it is placed on the eye in a way similar to a contact lens.
AC C
Its advantages include easy bedside insertion without sedation11 and easy replacement if the membrane melts. However, this device only covers the cornea and surrounding bulbar conjunctiva, leaving the rest of the conjunctiva, fornices, and eyelid margins exposed. The second method involves utilizing multiple, pre-cut 3.5 cm or 5 cm square pieces of cryopreserved AM and suturing or gluing these pieces together on the ocular surface and eyelids.8,12 The advantage of this technique is complete coverage of the mucosal surface of
3
ACCEPTED MANUSCRIPT
the eye with AM. The disadvantage is that the technique is time-consuming, requires sedation (especially in children), and allows gaps to form between AM sheets in coverage of the ocular surface.
RI PT
We describe a novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring for AMT in ocular SJS. This technique combines the ease of application provided by PROKERA® and the complete ocular surface coverage
SC
of the multiple AM sheet technique, while minimizing suturing and manipulation of ocular tissues to decrease operative times significantly. Our technique can be applied in the
M AN U
management of multiple ocular surface disease processes, including chemical or thermal burns, severe ocular graft versus host disease (GVHD), and other autoimmune diseases.
II.
Description of the Technique
TE D
Because all the patients in our series were children, the procedure was performed under general anesthesia. First, a custom-made symblepharon ring is fashioned from sterile intravenous (IV) tubing (Ultra™ Small Bore Extension Sets, Reference Number
EP
MX453HL, Smiths Medical, Dublin, OH). The size of the ring is tailored to each patient to ensure proper apposition of the AM to ocular surfaces. The distance between the superior
AC C
and inferior orbital rims is measured, and this distance is used to estimate the diameter of the ring. The length of IV tubing can be adjusted if it is too small or too large, as proper sizing is necessary for expansion of the AM to the fornices while simultaneously allowing for proper eyelid closure. The length of IV tubing is cut with one blunt edge and one oblique edge, and the oblique end is threaded into the other using a clamp (Figure 1A).13
4
ACCEPTED MANUSCRIPT
Next, the patient is prepared for the surgical procedure. The periocular skin is cleansed with either betadine 10% or saline, depending on the degree of periocular skin inflammation. A few drops of 5% betadine solution are placed in each of the fornices. To
RI PT
protect the fragile skin, drapes without adhesive are utilized to create a sterile field in the periocular region. The eyelashes are then trimmed to facilitate membrane contact with the eyelid margins. Erythromycin ointment (or any antibiotic-based ointment) may be smeared
lashes from falling onto the ocular surface.
SC
onto the eyelashes, which facilitates clumping of the lashes, thus preventing individual
M AN U
AMT is initiated with a continuous 5 x 10 cm sheet of cryopreserved AM (Custom Piece, Amniograft, Bio-Tissue, Doral, FL) placed over the entire mucosal ocular surface. This AM is separated from the nitrocellulose paper at one edge and is placed over the upper eyelid with the stromal side facing the skin (Figure 1B). It is anchored to the skin and
TE D
orbicularis, using two, 6-0, polypropylene mattress sutures 2-3 mm superior to the lash line, and styrofoam bolsters from the suture packaging protect the skin (Figure 1C). Alternatively, larger gauge IV tubing cut longitudinally can be used to make the bolsters.
EP
Once anchored superiorly, the AM is completely separated from the nitrocellulose paper. Given that AM is extremely thin and tends to wrap around itself and clump together, the
AC C
sheet is swept from the center to the edges using a blunt, 19-gauge cannula while balanced salt solution is administered to maintain moisture (Figure 1D). With the AM covering the anterior eyelids and ocular surface, an eyelid retractor (i.e., Conway or Demarres) is used to lift the AM-covered upper eyelid off the ocular surface. This lifting motion pulls the AM into the upper fornix, and the custom-made symblepharon ring is inserted into the upper fornix over the AM (Figure 1E), thereby further pushing the membrane into the
5
ACCEPTED MANUSCRIPT
fornix. Next, the lower eyelid is retracted, and the ring-AM complex is inserted into the lower fornix. A muscle hook can also be used to tuck the ring into position. The AM is then brought over the lower eyelid margin and anchored to the skin with 6-0, polypropylene
RI PT
sutures and bolsters (Figure 1F). Excess AM is trimmed with scissors. Antibiotic ointment is applied over the eyelid and ocular surface, and the sterile draping is removed.
Outcome Data
SC
III.
A retrospective chart review of consecutive cases of AMT performed in patients
M AN U
with acute SJS at Boston Children’s Hospital (BCH) was conducted with institutional review board approval. Cases were identified through billing records between 2011 and 2015. Nine cases were identified, each performed by one of the two attending physicians who manage SJS patients at BCH, assisted by second-year ophthalmology residents and/or
TE D
pediatric ophthalmology fellows. The first five cases were performed utilizing two separate 3.5 x 3.5 cm pieces of AM. These pieces were sutured together, with one end anchored along the upper eyelid margin and one end anchored along the lower end with
EP
running sutures. The central portion was then anchored on the ocular surface. The last four cases utilized one large piece of AM with the technique presented here. A summary of
AC C
patient data is given in Table 1.
We compared surgical times of AMT with a single piece of AM as presented here
versus the traditional technique of suturing multiple pieces of AM.12 As shown in Table 1, surgical times were reduced with the single-piece AM technique. On average, surgical duration was reduced by 60% (Figure 2A). AMT with multiple pieces of AM took an
6
ACCEPTED MANUSCRIPT
average of 199.6 ± 35 minutes versus an average of 84 ± 22 minutes (p=.016, MannWhitney U test) for AMT with a single piece of AM. We compared postoperative complications in the two groups and found the
RI PT
formation of symblephara to be less in with our new AMT technique. Temporal
symblephara developed in 3 of 5 patients receiving multiple AM pieces compared with 0 of 4 patients treated with a single large piece of AM, possibly because the single large AM
SC
provided better coverage of the ocular surface. Nearly all patients—regardless of technique used—developed various degrees of meibomian gland dysfunction.
M AN U
Finally, we analyzed the time for AM dissolution in the two groups. The average rate of dissolution using multiple AMT pieces was 7.2 ± 0.83 days compared with 7.5 ± 2.1 days using one single large AMT piece (p=.92, Mann-Whitney U test [Figure 2B]).
Discussion
TE D
IV.
We present a novel technique of AM transplantation utilizing a single 5 x 10 cm piece of AM. We believe this technique has significant advantages over previously
EP
reported methods. First, a single, large piece of AM ensures contiguous coverage of the entire affected ocular surface, including eyelid skin and margins, palpebral, forniceal, and
AC C
bulbar conjunctiva, and the cornea, which is essential in preventing cicatrization of opposing ocular surfaces. Patients receiving AMT with this novel technique had fewer post-syndromic ocular complications. Specifically, more than half of our patients developed temporal symblephara after AM using multiple AM pieces, whereas none of the patients treated with the new technique exhibited such clinical findings, likely attributable to the better AM coverage of the lateral canthal area.
7
ACCEPTED MANUSCRIPT
Surgical time is drastically reduced with the new technique, decreasing exposure to general anesthesia and decreasing cost. We believe this is achieved by decreasing the time spent manipulating sheets of AM and by anchoring the membrane to the upper eyelid at the
RI PT
beginning of the procedure. The anchoring prevents twisting and inversion of the single membrane throughout the rest of the procedure, facilitating orientation of the AM (stromal vs basement membrane side).
SC
The novel technique requires minimal suturing, decreasing tissue manipulation,
intraoperative bleeding, puncture points for bacterial superinfections, and introduction of
M AN U
foreign bodies (i.e., suture material, glue) to an already inflamed ocular surface. This may also contribute to the lower post-syndromic complication rate seen in the single-sheet AMT group.
We believe this technique is customizable to each patient. Given the wide age
TE D
range of patients with SJS and thus globe size, the adjustment of a ring using IV tubing allows proper apposition of the membrane to the ocular surfaces and intraoperative assessment of the applied tension to the eyelids and AM. The latter is very important, as an
EP
inappropriately-sized ring may cause significant postoperative discomfort as well as exposure of the ocular surfaces, affecting the viability of the AM. Other advantages of
AC C
utilizing IV tubing include low cost, availability, ease of use, and the ability to quickly and easily adjust size intraoperatively. One final observation was that the degradation of AM was not affected by our use of IV tubing. V.
Conclusion
This novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring facilitates AM placement. The technique can be applied not
8
ACCEPTED MANUSCRIPT
only in the acute and chronic phases of SJS/TEN, but also in the treatment of other ocular
AC C
EP
TE D
M AN U
SC
RI PT
surface disease processes requiring AMT.
9
ACCEPTED MANUSCRIPT
REFERENCES
De Rojas MV, Dart JKG, Saw VPJ. The natural history of Stevens Johnson syndrome: patterns of chronic ocular disease and the role of systemic immunosuppressive therapy. Br J Ophthalmol 2007;91:1048–53
2.
Morales ME, Purdue GF, Verity SM,et al. Ophthalmic manifestations of StevensJohnson Syndrome and toxic epidermal necrolysis and relation to SCORTEN. Am J Ophthalmol 2010;150:505–10.e1
3.
Tseng SCG. Acute management of Stevens-Johnson syndrome and toxic epidermal necrolysis to minimize ocular sequelae. Am J Ophthalmol 2009;147:949–51
4.
Strom BL, Carson JL, Halpern AC, et al. Using a claims database to investigate drug-induced Stevens-Johnson syndrome. Stat Med 1991;10:565–76
5.
Chan H-L, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990;126:43–7
6.
Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry. J Clin Epidemiol 1996;49:769–73
7.
John T, Foulks GN, John ME, et al. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology 2002;109:351–60
8.
Gregory DG. Treatment of acute Stevens-Johnson syndrome and toxic epidermal necrolysis using amniotic membrane: a review of 10 consecutive cases. Ophthalmology 2011;118:908–14
9.
Dua HS, Gomes JAP, King AJ, Maharajan VS. The amniotic membrane in ophthalmology. Surv Ophthalmol 2004;49:51–77
AC C
EP
TE D
M AN U
SC
RI PT
1.
10.
Shay E, Kheirkhah A, Liang L, et al. Amniotic membrane transplantation as a new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis. Surv Ophthalmol 2009;54:686–96
11.
Shammas MC, Lai EC, Sarkar JS, et al.Management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis utilizing amniotic membrane and topical corticosteroids. Am J Ophthalmol 2010;149:203–13.e2.
12.
Tamhane A, Vajpayee RB, Biswas NR, et al. Evaluation of amniotic membrane transplantation as an adjunct to medical therapy as compared with medical therapy
10
ACCEPTED MANUSCRIPT
alone in acute ocular burns. Ophthalmology 2005;112:1963–9 Rubinate L, Welch MN, Johnson AJ, DeMartelaere SL. New technique for manufacture and placement of enlarged symblepharon ring with amniotic membrane transplantation for ocular surface protection in Stevens-Johnson syndrome and toxic epidermal necrolysis (Abstract, poster presentation). Invest Ophthalmol Vis Sci 2010(13):1135
RI PT
13.
Figure Legends
M AN U
SC
Figure 1. Amniotic membrane (AM) transplantation utilizing a single 5 x10 cm sheet. A. Creation of symblepharon ring with intravenous tubing. B. Placement of AM over upper eyelid. C. Anchoring of AM using 6-0 polypropylene mattress sutures and bolsters. D. Unfolding of AM over the ocular surface. E. Placement of the custommade symblepharon ring in the fornices. The ring is already pushed into the upper fornix and is being gently deposited into the lower fornix. F. Anchoring of AM to lower eyelid.
AC C
EP
TE D
Figure 2. A. Average surgical time for amniotic membrane (AM) transplantation to the ocular surface utilizing multiple versus a single sheet of AM (* p=.016, MannWhitney U test). B. Average rate of dissolution of AM from the ocular surface with either multiple or single sheets transplanted onto the ocular surface (ns not significant based on p=.92, Mann-Whitney U test).
11
ACCEPTED MANUSCRIPT
Table: Cases of amniotic membrane transplantation (AMT) performed at Boston Children’s Hospital using the traditional technique (cases 1-5) of suturing together multiple small pieces of amniotic membrane versus the novel technique of using one large AM
RI PT
segment (cases 6-9).
Case
Age (y)/ Gender
Visual Acuity on presentation (OD - OS)
Visual acuity on last follow up (OD - OS)
1
10/M
20/20 – 20/20-
20/20 – 20/20
Lid edema and erythema, complete lid margin staining, conj epi defects, corneal PEE
2
11M
20/30 – 20/25
20/20-2 – 20/20-3
3
8/F
20/25 – 20/30
20/20 – 20/20
4**
12/F
20/200 – HM with prokera on OS;
20/20 – 20/20
5
18/M
20/20 – 20/25
20/15 – 20/15
Conj epi defects, lid margin ulcerations, conj fornix foreshortening, conj staining, early symblepharon OS nasally Eyelid edema, complete lid margin ulceration, conj staining, bulbar conj ulceration, subconj hemorrhage, corneal PEE Lid edema, pseudomembranes, conj vinjection, sch, conj foreshortening, early symblepharon OD (broken preop with cotton tip), corneal epi defects Eyelid edema, lid margin ulcerations, conj injection, pseudomembrane, bulbar conj epi defects
6
17/F
20/20 – 20/80
20/20 – 20/20
7
10/F
20/20 – 20/20
20/20 – 20/20
8
6/F
20/40* - 20/25
9
11/M
Fix and follow OU (20/40, 20/30 a few months prior to TEN) 20/20 – 20/20
Ocular findings on last follow up
SC
Ocular findings on presentation
Procedure Duration^ (minutes)
Dissolution of AMT (days)
24 mos
207
7
MGD, small symblepharon temporally OD at the canthus
4 mos
199
6
MGD, mild palpebral conj scarring, small symblepharon temporally OS Minimal distichiasis
16 mos
244
8
2 mos
145
7
MGD, meibomitis OU. Small symblepharon temporally OS
10 mos
203
8
Eyelid margin erosions OU , symblepharon OU, conj injection, pseudomembranes, forshortening OU, corneal epithelial defect OS, conj epithelial defects OU
MGD, punctate corneal epithelial erosions (at the area of the original corneal epithelial defect)
13 mos
61
10
Chemosis, conj injection and epi defects, corneal PEE Lid edema, lid margin staining, pseudomembranes, conj epi defects
MGD, eyelash hypotrichosis
7 mos
94
7
MGD
4 mos
71
8
Complete lid margin injection and ulceration, SCH
MGD, posterior lamellar eyelid inflammation
4 mos
110
5
EP
TE D
M AN U
MGD
AC C
20/15 – 20/15
F/U
ACCEPTED MANUSCRIPT
Abbreviations: F/U - follow up; Conj - conjunctival; OD - right eye; OS - left eye; OU - both eyes; MGD - meibomian gland dysfunction; epi - epithelial.
RI PT
* History of anisometropic amblyopia right eye (dx prior to TENS), currently patching OS 2hrs per day ** Trialed prokera for 2 days prior to AMT
^ Procedure duration was defined in all cases as the interval in minutes from the time when the procedure began (e.g. incision) until
AC C
EP
TE D
M AN U
SC
the time when all instrument and sponge counts were completed and verified as correct.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1542-0124(15)00114-7
DOI:
10.1016/j.jtos.2015.07.002
Reference:
JTOS 144
To appear in:
Ocular Surface
Received Date: 16 June 2015 Revised Date:
12 July 2015
Accepted Date: 14 July 2015
Please cite this article as: Ma K, Thanos A, Chodosh J, Shah AS, Mantagos IS, A Novel Technique for Amniotic Membrane Transplantation in Patients with Acute Stevens-Johnson Syndrome, Ocular Surface (2015), doi: 10.1016/j.jtos.2015.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
SECTION: Innovative Techniques and Technology, Gary N. Foulks, MD, Editor TITLE: A NOVEL TECHNIQUE FOR AMNIOTIC MEMBRANE TRANSPLANTATION IN PATIENTS WITH ACUTE STEVENS-JOHNSON
RI PT
SYNDROME
AUTHORS: Kelly Ma, MD, MPH,1* Aristomenis Thanos, MD,2* James Chodosh, MD, MPH,2 Ankoor S. Shah, MD,PhD,2,3 and Iason S. Mantagos, MD2,3
SC
SHORT TITLE: NOVEL TECHNIQUE FOR AM TRANSPLANTATION FOR ACUTE SJS/Ma et al
M AN U
FOOTNOTES
Accepted for publication August 2015.
From 1Department of Ophthalmology, Boston University Medical Center, Boston University School of Medicine, 2Department of Ophthalmology, Massachusetts Eye and
TE D
Ear Infirmary, Harvard Medical School, 3Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
EP
*Drs. Ma and Thanos contributed equally to this work.
AC C
Financial support: None The authors have no commercial or proprietary interest in any concept or product discussed in this article. Single-copy reprint requests to: Iason S. Mantagos, MD (address below). Corresponding author: Iason S. Mantagos, MD, 300 Longwood Avenue, Fegan 4, Boston, MA 02115. Tel: (617) 355-6401. Fax: (617) 730-0392. E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
ABSTRACT Cryopreserved amniotic membrane (AM) transplantation is an emerging technique that is becoming the gold standard for the management of acute Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis
RI PT
(TEN). We describe a novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring, which facilitates AM placement. Our technique is easy to use and minimizes suturing and manipulation of ocular tissues, leading to decreased
SC
operative time. This technique may be applied in the management of multiple ocular
surface disease processes, including chemical or thermal burns, severe ocular graft versus
M AN U
host disease (GVHD), and other autoimmune diseases.
KEY WORDS amniotic membrane, cryopreserved amniotic membrane, ocular surface, Stevens-Johnson syndrome, transplantation
Introduction
EP
I.
TE D
Outline I. Introduction II. Description of the Technique III. Outcome Data IV. Discussion V. Conclusion
Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal
AC C
necrolysis (TEN) present with widespread exfoliation of the skin and mucous membranes, which can lead to significant ocular involvement and morbidity. If acute ocular surface inflammation is not recognized and treated, cicatrization ensues, leading to photophobia, intractable dry eye, chronic pain, corneal scarring, and vision loss.1 In fact, progressive conjunctival scarring and corneal damage are the most disabling long-term complications
2
ACCEPTED MANUSCRIPT
for SJS and TEN survivors.2,3 The incidence is approximately 2-6 cases per million per year, but can be significantly higher in children, at up to 35.5 cases per million per year.4-6 Cryopreserved amniotic membrane transplantation (AMT) is an emerging
RI PT
technique that is becoming the gold standard in the management of acute SJS/TEN.7,8
Amniotic membrane (AM) arises from the innermost placental membrane and contains a single layer of epithelial cells that are often nonviable in commercially available AM, a
SC
thick basement membrane, and a stroma. The basement membrane supports host epithelial cell migration, adhesion, and differentiation, and it inhibits epithelial cell apoptosis. The
M AN U
stroma is rich in cytokines, growth factors, and protease inhibitors,9,10 providing AM with anti-inflammatory and antiscarring actions. Thus, AM serves as a biological bandage by suppressing inflammation, promoting epithelialization, and thereby preventing sightthreatening sequelae. AM typically dissolves over a period of 1-2 weeks; thus, more than
TE D
one application may be necessary during the acute phase of the disease. It is well understood that early intervention with AM during the acute stage of SJS is beneficial,10 and there are two current methods of applying AM. The first involves
EP
PROKERA® (Bio-Tissue, Doral, FL). This product consists of AM stretched across the lumen of a polycarbonate ring, and it is placed on the eye in a way similar to a contact lens.
AC C
Its advantages include easy bedside insertion without sedation11 and easy replacement if the membrane melts. However, this device only covers the cornea and surrounding bulbar conjunctiva, leaving the rest of the conjunctiva, fornices, and eyelid margins exposed. The second method involves utilizing multiple, pre-cut 3.5 cm or 5 cm square pieces of cryopreserved AM and suturing or gluing these pieces together on the ocular surface and eyelids.8,12 The advantage of this technique is complete coverage of the mucosal surface of
3
ACCEPTED MANUSCRIPT
the eye with AM. The disadvantage is that the technique is time-consuming, requires sedation (especially in children), and allows gaps to form between AM sheets in coverage of the ocular surface.
RI PT
We describe a novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring for AMT in ocular SJS. This technique combines the ease of application provided by PROKERA® and the complete ocular surface coverage
SC
of the multiple AM sheet technique, while minimizing suturing and manipulation of ocular tissues to decrease operative times significantly. Our technique can be applied in the
M AN U
management of multiple ocular surface disease processes, including chemical or thermal burns, severe ocular graft versus host disease (GVHD), and other autoimmune diseases.
II.
Description of the Technique
TE D
Because all the patients in our series were children, the procedure was performed under general anesthesia. First, a custom-made symblepharon ring is fashioned from sterile intravenous (IV) tubing (Ultra™ Small Bore Extension Sets, Reference Number
EP
MX453HL, Smiths Medical, Dublin, OH). The size of the ring is tailored to each patient to ensure proper apposition of the AM to ocular surfaces. The distance between the superior
AC C
and inferior orbital rims is measured, and this distance is used to estimate the diameter of the ring. The length of IV tubing can be adjusted if it is too small or too large, as proper sizing is necessary for expansion of the AM to the fornices while simultaneously allowing for proper eyelid closure. The length of IV tubing is cut with one blunt edge and one oblique edge, and the oblique end is threaded into the other using a clamp (Figure 1A).13
4
ACCEPTED MANUSCRIPT
Next, the patient is prepared for the surgical procedure. The periocular skin is cleansed with either betadine 10% or saline, depending on the degree of periocular skin inflammation. A few drops of 5% betadine solution are placed in each of the fornices. To
RI PT
protect the fragile skin, drapes without adhesive are utilized to create a sterile field in the periocular region. The eyelashes are then trimmed to facilitate membrane contact with the eyelid margins. Erythromycin ointment (or any antibiotic-based ointment) may be smeared
lashes from falling onto the ocular surface.
SC
onto the eyelashes, which facilitates clumping of the lashes, thus preventing individual
M AN U
AMT is initiated with a continuous 5 x 10 cm sheet of cryopreserved AM (Custom Piece, Amniograft, Bio-Tissue, Doral, FL) placed over the entire mucosal ocular surface. This AM is separated from the nitrocellulose paper at one edge and is placed over the upper eyelid with the stromal side facing the skin (Figure 1B). It is anchored to the skin and
TE D
orbicularis, using two, 6-0, polypropylene mattress sutures 2-3 mm superior to the lash line, and styrofoam bolsters from the suture packaging protect the skin (Figure 1C). Alternatively, larger gauge IV tubing cut longitudinally can be used to make the bolsters.
EP
Once anchored superiorly, the AM is completely separated from the nitrocellulose paper. Given that AM is extremely thin and tends to wrap around itself and clump together, the
AC C
sheet is swept from the center to the edges using a blunt, 19-gauge cannula while balanced salt solution is administered to maintain moisture (Figure 1D). With the AM covering the anterior eyelids and ocular surface, an eyelid retractor (i.e., Conway or Demarres) is used to lift the AM-covered upper eyelid off the ocular surface. This lifting motion pulls the AM into the upper fornix, and the custom-made symblepharon ring is inserted into the upper fornix over the AM (Figure 1E), thereby further pushing the membrane into the
5
ACCEPTED MANUSCRIPT
fornix. Next, the lower eyelid is retracted, and the ring-AM complex is inserted into the lower fornix. A muscle hook can also be used to tuck the ring into position. The AM is then brought over the lower eyelid margin and anchored to the skin with 6-0, polypropylene
RI PT
sutures and bolsters (Figure 1F). Excess AM is trimmed with scissors. Antibiotic ointment is applied over the eyelid and ocular surface, and the sterile draping is removed.
Outcome Data
SC
III.
A retrospective chart review of consecutive cases of AMT performed in patients
M AN U
with acute SJS at Boston Children’s Hospital (BCH) was conducted with institutional review board approval. Cases were identified through billing records between 2011 and 2015. Nine cases were identified, each performed by one of the two attending physicians who manage SJS patients at BCH, assisted by second-year ophthalmology residents and/or
TE D
pediatric ophthalmology fellows. The first five cases were performed utilizing two separate 3.5 x 3.5 cm pieces of AM. These pieces were sutured together, with one end anchored along the upper eyelid margin and one end anchored along the lower end with
EP
running sutures. The central portion was then anchored on the ocular surface. The last four cases utilized one large piece of AM with the technique presented here. A summary of
AC C
patient data is given in Table 1.
We compared surgical times of AMT with a single piece of AM as presented here
versus the traditional technique of suturing multiple pieces of AM.12 As shown in Table 1, surgical times were reduced with the single-piece AM technique. On average, surgical duration was reduced by 60% (Figure 2A). AMT with multiple pieces of AM took an
6
ACCEPTED MANUSCRIPT
average of 199.6 ± 35 minutes versus an average of 84 ± 22 minutes (p=.016, MannWhitney U test) for AMT with a single piece of AM. We compared postoperative complications in the two groups and found the
RI PT
formation of symblephara to be less in with our new AMT technique. Temporal
symblephara developed in 3 of 5 patients receiving multiple AM pieces compared with 0 of 4 patients treated with a single large piece of AM, possibly because the single large AM
SC
provided better coverage of the ocular surface. Nearly all patients—regardless of technique used—developed various degrees of meibomian gland dysfunction.
M AN U
Finally, we analyzed the time for AM dissolution in the two groups. The average rate of dissolution using multiple AMT pieces was 7.2 ± 0.83 days compared with 7.5 ± 2.1 days using one single large AMT piece (p=.92, Mann-Whitney U test [Figure 2B]).
Discussion
TE D
IV.
We present a novel technique of AM transplantation utilizing a single 5 x 10 cm piece of AM. We believe this technique has significant advantages over previously
EP
reported methods. First, a single, large piece of AM ensures contiguous coverage of the entire affected ocular surface, including eyelid skin and margins, palpebral, forniceal, and
AC C
bulbar conjunctiva, and the cornea, which is essential in preventing cicatrization of opposing ocular surfaces. Patients receiving AMT with this novel technique had fewer post-syndromic ocular complications. Specifically, more than half of our patients developed temporal symblephara after AM using multiple AM pieces, whereas none of the patients treated with the new technique exhibited such clinical findings, likely attributable to the better AM coverage of the lateral canthal area.
7
ACCEPTED MANUSCRIPT
Surgical time is drastically reduced with the new technique, decreasing exposure to general anesthesia and decreasing cost. We believe this is achieved by decreasing the time spent manipulating sheets of AM and by anchoring the membrane to the upper eyelid at the
RI PT
beginning of the procedure. The anchoring prevents twisting and inversion of the single membrane throughout the rest of the procedure, facilitating orientation of the AM (stromal vs basement membrane side).
SC
The novel technique requires minimal suturing, decreasing tissue manipulation,
intraoperative bleeding, puncture points for bacterial superinfections, and introduction of
M AN U
foreign bodies (i.e., suture material, glue) to an already inflamed ocular surface. This may also contribute to the lower post-syndromic complication rate seen in the single-sheet AMT group.
We believe this technique is customizable to each patient. Given the wide age
TE D
range of patients with SJS and thus globe size, the adjustment of a ring using IV tubing allows proper apposition of the membrane to the ocular surfaces and intraoperative assessment of the applied tension to the eyelids and AM. The latter is very important, as an
EP
inappropriately-sized ring may cause significant postoperative discomfort as well as exposure of the ocular surfaces, affecting the viability of the AM. Other advantages of
AC C
utilizing IV tubing include low cost, availability, ease of use, and the ability to quickly and easily adjust size intraoperatively. One final observation was that the degradation of AM was not affected by our use of IV tubing. V.
Conclusion
This novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring facilitates AM placement. The technique can be applied not
8
ACCEPTED MANUSCRIPT
only in the acute and chronic phases of SJS/TEN, but also in the treatment of other ocular
AC C
EP
TE D
M AN U
SC
RI PT
surface disease processes requiring AMT.
9
ACCEPTED MANUSCRIPT
REFERENCES
De Rojas MV, Dart JKG, Saw VPJ. The natural history of Stevens Johnson syndrome: patterns of chronic ocular disease and the role of systemic immunosuppressive therapy. Br J Ophthalmol 2007;91:1048–53
2.
Morales ME, Purdue GF, Verity SM,et al. Ophthalmic manifestations of StevensJohnson Syndrome and toxic epidermal necrolysis and relation to SCORTEN. Am J Ophthalmol 2010;150:505–10.e1
3.
Tseng SCG. Acute management of Stevens-Johnson syndrome and toxic epidermal necrolysis to minimize ocular sequelae. Am J Ophthalmol 2009;147:949–51
4.
Strom BL, Carson JL, Halpern AC, et al. Using a claims database to investigate drug-induced Stevens-Johnson syndrome. Stat Med 1991;10:565–76
5.
Chan H-L, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990;126:43–7
6.
Rzany B, Mockenhaupt M, Baur S, et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry. J Clin Epidemiol 1996;49:769–73
7.
John T, Foulks GN, John ME, et al. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology 2002;109:351–60
8.
Gregory DG. Treatment of acute Stevens-Johnson syndrome and toxic epidermal necrolysis using amniotic membrane: a review of 10 consecutive cases. Ophthalmology 2011;118:908–14
9.
Dua HS, Gomes JAP, King AJ, Maharajan VS. The amniotic membrane in ophthalmology. Surv Ophthalmol 2004;49:51–77
AC C
EP
TE D
M AN U
SC
RI PT
1.
10.
Shay E, Kheirkhah A, Liang L, et al. Amniotic membrane transplantation as a new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis. Surv Ophthalmol 2009;54:686–96
11.
Shammas MC, Lai EC, Sarkar JS, et al.Management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis utilizing amniotic membrane and topical corticosteroids. Am J Ophthalmol 2010;149:203–13.e2.
12.
Tamhane A, Vajpayee RB, Biswas NR, et al. Evaluation of amniotic membrane transplantation as an adjunct to medical therapy as compared with medical therapy
10
ACCEPTED MANUSCRIPT
alone in acute ocular burns. Ophthalmology 2005;112:1963–9 Rubinate L, Welch MN, Johnson AJ, DeMartelaere SL. New technique for manufacture and placement of enlarged symblepharon ring with amniotic membrane transplantation for ocular surface protection in Stevens-Johnson syndrome and toxic epidermal necrolysis (Abstract, poster presentation). Invest Ophthalmol Vis Sci 2010(13):1135
RI PT
13.
Figure Legends
M AN U
SC
Figure 1. Amniotic membrane (AM) transplantation utilizing a single 5 x10 cm sheet. A. Creation of symblepharon ring with intravenous tubing. B. Placement of AM over upper eyelid. C. Anchoring of AM using 6-0 polypropylene mattress sutures and bolsters. D. Unfolding of AM over the ocular surface. E. Placement of the custommade symblepharon ring in the fornices. The ring is already pushed into the upper fornix and is being gently deposited into the lower fornix. F. Anchoring of AM to lower eyelid.
AC C
EP
TE D
Figure 2. A. Average surgical time for amniotic membrane (AM) transplantation to the ocular surface utilizing multiple versus a single sheet of AM (* p=.016, MannWhitney U test). B. Average rate of dissolution of AM from the ocular surface with either multiple or single sheets transplanted onto the ocular surface (ns not significant based on p=.92, Mann-Whitney U test).
11
ACCEPTED MANUSCRIPT
Table: Cases of amniotic membrane transplantation (AMT) performed at Boston Children’s Hospital using the traditional technique (cases 1-5) of suturing together multiple small pieces of amniotic membrane versus the novel technique of using one large AM
RI PT
segment (cases 6-9).
Case
Age (y)/ Gender
Visual Acuity on presentation (OD - OS)
Visual acuity on last follow up (OD - OS)
1
10/M
20/20 – 20/20-
20/20 – 20/20
Lid edema and erythema, complete lid margin staining, conj epi defects, corneal PEE
2
11M
20/30 – 20/25
20/20-2 – 20/20-3
3
8/F
20/25 – 20/30
20/20 – 20/20
4**
12/F
20/200 – HM with prokera on OS;
20/20 – 20/20
5
18/M
20/20 – 20/25
20/15 – 20/15
Conj epi defects, lid margin ulcerations, conj fornix foreshortening, conj staining, early symblepharon OS nasally Eyelid edema, complete lid margin ulceration, conj staining, bulbar conj ulceration, subconj hemorrhage, corneal PEE Lid edema, pseudomembranes, conj vinjection, sch, conj foreshortening, early symblepharon OD (broken preop with cotton tip), corneal epi defects Eyelid edema, lid margin ulcerations, conj injection, pseudomembrane, bulbar conj epi defects
6
17/F
20/20 – 20/80
20/20 – 20/20
7
10/F
20/20 – 20/20
20/20 – 20/20
8
6/F
20/40* - 20/25
9
11/M
Fix and follow OU (20/40, 20/30 a few months prior to TEN) 20/20 – 20/20
Ocular findings on last follow up
SC
Ocular findings on presentation
Procedure Duration^ (minutes)
Dissolution of AMT (days)
24 mos
207
7
MGD, small symblepharon temporally OD at the canthus
4 mos
199
6
MGD, mild palpebral conj scarring, small symblepharon temporally OS Minimal distichiasis
16 mos
244
8
2 mos
145
7
MGD, meibomitis OU. Small symblepharon temporally OS
10 mos
203
8
Eyelid margin erosions OU , symblepharon OU, conj injection, pseudomembranes, forshortening OU, corneal epithelial defect OS, conj epithelial defects OU
MGD, punctate corneal epithelial erosions (at the area of the original corneal epithelial defect)
13 mos
61
10
Chemosis, conj injection and epi defects, corneal PEE Lid edema, lid margin staining, pseudomembranes, conj epi defects
MGD, eyelash hypotrichosis
7 mos
94
7
MGD
4 mos
71
8
Complete lid margin injection and ulceration, SCH
MGD, posterior lamellar eyelid inflammation
4 mos
110
5
EP
TE D
M AN U
MGD
AC C
20/15 – 20/15
F/U
ACCEPTED MANUSCRIPT
Abbreviations: F/U - follow up; Conj - conjunctival; OD - right eye; OS - left eye; OU - both eyes; MGD - meibomian gland dysfunction; epi - epithelial.
RI PT
* History of anisometropic amblyopia right eye (dx prior to TENS), currently patching OS 2hrs per day ** Trialed prokera for 2 days prior to AMT
^ Procedure duration was defined in all cases as the interval in minutes from the time when the procedure began (e.g. incision) until
AC C
EP
TE D
M AN U
SC
the time when all instrument and sponge counts were completed and verified as correct.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT