Acute Treatment of Severe Ocular Inflammation

Overview

Surgical use of amniotic membrane in the acute stage of chemical burns and Stevens-Johnson Syndrome:
Clinical pearls using PROKERA for treatment of chemical burns or Stevens-Johnson syndrome

AMT for Controlling Inflammation and Promoting Healing

To cover both corneal and conjunctival surfaces, secure a large piece of amniotic membrane (AM) (AMNIOGRAFT® size 3.5 x 3.5 cm) to the skin surface of the upper lid margin using a 10-O nylon suture in an interrupted or running manner. Push the AM up into the upper fornix with a muscle hook and use a double-armed 4-O black silk suture in a mattress fashion to secure the AM to the skin surface with a bolster made of butterfly tubing. The remaining AM is spread to cover the upper bulbar conjunctiva and a part of the upper corneal surface.

A second large piece of AM (AMNIOGRAFT® size 3.5 x 3.5 cm) is secured to the lower lid with 10-O nylon sutures in the same manner to cover the lower fornix. The second piece of AM will overlap the first piece of AM on the corneal surface.

A temporary tarsorrhaphy is added to minimize the lid fissure if there is an exposure concern due to large scleral show or infrequent blinking as a result of a neurotrophic state (see Figure- Schematic Drawing/Video).

 

To cover only the corneal surface, AM (AMNIOGRAFT® 2.5 x 2.0 cm size) is secured using a 10-0 nylon suture at 2 to 3 mm from the limbus in a purse-string running fashion for a total of 8 to10 episcleral bites. The AM will cover the corneal surface like a biological bandage lens. Alternatively, PROKERA™ can be inserted following topical anesthetic eye drops and insertion of a lid speculum (see video for insertion and removal).

 

Standard Surgical Supplies Used for AMT

Cryopreserved Amniotic Membrane (AM) grafts

Cryopreserved AM grafts are used to treat corneal defects because while cryopreservation kills allogeneic cells in the AM eliminating the need for immunosuppression, it maintains the integrity of the cytokine-rich extracellular matrix which provides biological actions that help reduce corneal haze and aid in ocular surface wound repair and wound healing.

AMNIOGRAFT®, distributed by Bio-Tissue, Inc. (Miami, FL), is available in 4 sizes. The standard size to cover the cornea is 2.5 x 2.0 cm (Catalog # AG-2520). To cover only part of the cornea, the 2.0 x 1.5 cm (Catalog # AG-2015) can be used and if more than the cornea needs to be covered a 3.5 x 3.5 cm size (Catalog # AG-3535) can be used.

PROKERA™, distributed by Bio-Tissue, Inc., is a device that contains AMNIOGRAFT® clipped into a polycarbonate ring set conformer manufactured so the stromal side of the tissue is in contact with the corneal and limbal surface. This device can be inserted under the patient’s eye lids in the office or in the OR setting without the need for sutures or fibrin glue. There are two different diameters of PROKERA™ available: 15 mm (Catalog # PK-15) and 16 mm (Catalog # PK-16). Most adult patients will tolerate a 16-mm device. After epithelial healing is completed, the membrane is dissolved and the PROKERA™ ring set can be removed.

Fibrin Glue

Tisseel®, distributed by Baxter Biologics, Inc., is recommended over other fibrin glues because of the quick setting time. Tisseel® requires pre-warming in a thermal/stirrer provided without costs by the manufacturer. The recommended size is 2.0 mL (Catalog #: 1501236).

Topical Aesthesia

0.5% proparacaine hydrochloride, 0.5% tetracaine hydrochloride, or 2% xylocaine jelly (AstraZeneca) is used for PROKERA™ insertion and for most of the surgeries described here.

Sutures

AMT is conventionally performed using sutures. If fibrin glue is not used, AMNIOGRAFT® can be secured using several interrupted 10-0 nylon sutures on peri-limbal bulbar conjunctiva and by 8-0 Vicryl sutures in a mattress fashion, parallel to the fornix, with solid episcleral bites to seal the fornix border.

Post Operative Care for Corneal Indications Following AMT

Postoperative care varies depending on the clinical setting in which the AMT has been performed. Medications such as medication usually includes 1% prednisolone acetate four times a day and 0.3% ofloxacin three times a day are typically prescribed.

The corneal epithelialization can be assessed by fluorescein staining and the intraocular pressure can be monitored by Tonopen without removing PROKERA™ or AMNIOGRAFT®.

When used as a temporary graft, the membrane does cut down the light transmission, leading to a blurry vision.

If the membrane dissolves within one week, it usually indicates that there is still unwanted exposure, such as lagophthalmos.

If the membrane stays longer than one week, the healing coincides with the membrane dissolution, e.g., 1-2 weeks in general. Upon complete healing, ProKera™ or AmnioGraft® can be easily removed from the ocular surface under a slit-lamp microscope with forceps.

Ofloxacin is then stopped and prednisolone eye drop is tapered off at a weekly schedule. A high DK contact lens is applied for one to two weeks before 10-O nylon suture holding the permanent graft is removed. Afterwards, one should continue watching for SPK returning to the area. If so, a Night and Day Focus lens or a permanent small tarsorrhphay is needed.

Stevens-Johnson Syndrome (SJS) Treatment

Stevens-Johnson Syndrome (SJS) is an immune-complex–mediated hypersensitivity disorder which typically involves the skin and the mucous membranes.¹ SJS is a serious systemic disorder with the potential for severe morbidity and even death. Significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness.² The severe variant of SJS showed extensive skin involvement resulting in toxic epidermal necrolysis (TEN). Although SJS/TEN is considered one of the most devastating ocular surface diseases which causes corneal damage and threatens vision, management of ocular involvement may be compromised because more attention is directed to maintaining the vital functions during the acute stage. Furthermore, upon bedside eye examination of patients suffering SJS/TEN at the acute stage it is difficult to recognize hidden conjunctival inflammation and ulceration deep in the fornix and tarsus. Inadequate control of ocular surface inflammation and ulceration at the acute stage will set in a vicious circle, leading to the chronic stage of scarring (cicatrix), which then contributes greatly to subsequent corneal complications.^3,4

Although systemic corticosteroids are commonly used and shown to be of some benefit in ameliorating systemic manifestations of the acute phase of SJS and TEN,⁵ its therapeutic effect has never been demonstrated in a controlled trial. Furthermore, retrospective studies demonstrate no benefit of corticosteroids or higher rates of morbidity and mortality in corticosteroid-treated patients.^6,7 Cyclosporin A⁸ and plasmapheresis⁹ have been proposed as alternatives. Recently, IV immunoglobulin has also been advocated for both SJS¹⁰ and TEN.¹¹ Despite these measures, specific attention to suppress ocular surface inflammation and to promote early epithelialization has not been considered. A recent retrospective study verified that the extent of lid margin keratinization and tarsal scar (as a result of cicatricial complications) is highly correlated with sight-threatening corneal complications.¹²

Amniotic membrane transplantation has been used as a temporary graft (or patch) during the acute stage, defined as the first two weeks, of chemical and thermal burns. It can suppress inflammation and prevent subsequent scarring in the later stage.^13-15 Amniotic membrane has also been used as a temporary graft in patients with acute SJS/TEN with^16,17 or without^12,18 corneal involvement in the acute stage to suppress inflammation and facilitate wound healing, resulting in restoration of a normal and healthy ocular surface and sight.

A new medical device recently approved by the FDA, PROKERA® (Bio-Tissue, Miami, FL), can facilitate the early delivery of the needed biological effects of cryopreserved amniotic membrane at the bedside or clinic without sutures. This delivery mechanism for cryopreserved amniotic membrane is an important utility in treating this devastating disease at the acute stage.

In conclusion, transplantation of cryopreserved amniotic membrane performed in the acute phase of SJS/TEN can be highly effective not only in reducing inflammation and preventing scarring in the conjunctival and corneal surfaces and in restoring corneal epithelial integrity in eyes even when the hidden inflammation and ulceration is not detected. As a result, it prevents sight-threatening cicatricial complications at the chronic stage.¹⁷

Frequently Asked Questions (FAQ)

What is Stevens-Johnson Syndrome (SJS) and what are the symptoms?

Stevens-Johnson Syndrome is a serious, potentially life-threatening skin disease. With Stevens-Johnson Syndrome the sufferer can first experience non-specific symptoms, such as headaches, aching body, fever, and cough. Then a rash may develop over the face and trunk, which then spreads to other parts of the body. The rash is patchy and spreads. Blistering can then appear, usually in places such as the eyes, mouth, nose and genital areas, and the mucous membrane becomes inflamed. Because some of the above symptoms can be found in many other diseases, it is important to consider SJS in the differential diagnosis due to its severe morbidity.

What is Toxic Epidermal Necrolysis (TEN)?

Toxic Epidermal Necrolysis is another variation of the disease. With this variation the skin also begins to peel away in large amounts. This leaves the sufferer looking as though the patient has burns. There is signficant risk of infection and fluid profusely leaks out of areas where the skin has come away.^19,20

What are the differences between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)?

SJS and TEN (Toxic epidermal necrolysis) are characterized by identical clinical signs and symptoms, identical treatment approach, and identical prognosis.

Several classification schemes have been reported, the simplest (French, Allergol Int, 2006) breaks the disease down as follows:

• SJS – A “minor form of TEN,” with less than 10% body surface area (BSA) detachment
• Overlapping SJS/TEN – Detachment of 10-30% BSA
• TEN – Detachment of more than 30% BSA

Patients with 90% skin detachment and diagnosed with TEN may have none or only mild ocular involvement with excellent prognosis, and patients with 10% skin detachment may have severe ocular involvement with blinding consequences, and vice versa.²¹

What is the main cause of SJS/TEN?

The most common cause of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis is through an allergic drug reaction. The drugs that are usually responsible for these reactions include: Penicillin family, some non-steroid anti-inflammatory drugs (NSAIDS), Allopurinol, Phenytoin, Carbamazepine, barbiturates, anticonvulsants, and sulfa antibiotics. The onset of symptoms in drug related Stevens-Johnson Syndrome may not appear for one or two weeks after first taking the drug. Reaction to drugs is by far the most common cause of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

What causes SJS/TEN in children?

Medication is usually the cause of the disease of Stevens-Johnson Syndrome in children. However, this condition can stem from other unknown causes. Some of the medications that have been linked to SJS in children include children’s Motrin, Advil, and other ibuprofen based drugs. These drugs have received highly negative publicity on a number of occasions after being identified as the cause in a range of cases where children have become seriously ill with SJS.²²

Who can diagnose SJS/TEN?

A dermatologist is the most likely clinician to establish the diagnosis, with or without biopsy. Severe cases may require the involvement of a burn specialist or plastic surgery specialist. Internal medicine, critical care, or pediatrics consultants direct inpatient care.

A consultation with an ophthalmologist is mandatory when there is ocular involvement. Even if the eye is closed, one cannot assume the eye is not involved. Bedside examination is inadequate to assess ocular involvement because hidden inflammation and ulceration in the fornix and tarsus may not be visible when eyelids are not everted. Due to the severe ocular morbidity of this disease at the chronic stage, it is advised to assume all victims of SJS/TENS have ocular involvement until a thorough ocular examination can be performed.

Are there any laboratory tests for diagnosing SJS/TEN?

Skin biopsy is the only diagnostically helpful laboratory study. Serum levels of tumor necrosis factor-a, soluble interleukin 2-receptor, interleukin 6, and C reactive protein typically are elevated in patients with SJS; however, none of these serologic tests is used routinely in diagnosing and managing SJS.

What is the differential diagnosis of ocular SJS?

Although there are other diseases that may present cicatricial complication such as Chemical burns, Conjunctivitis, Keratoconjunctivitis, Atopic Dermatitis, Trichiasis, Entropion, Ocular Rosacea, Sarcoidosis, Scleritis, Sjogren Syndrome, Squamous Cell Carcinoma and Trachoma, SJS/TEN has a characteristic clinical presentation different from these diseases.

How is SJS treated?

Upon diagnosis of SJS, the doctor will first need to identify the cause of the disorder, as this will determine the treatment and steps required. If the disease has occurred as a reaction to medication, the patient should stop taking the medication immediately. Treatment may take place in the burns unit at the hospital depending on the severity of the symptoms. It is important that anyone with this type of disease is treated in the cleanest environment, as this is a disease that leaves both adults and children open to secondary infections. If you have already contracted an infection on top of the SJS, the doctor may also need to administer antibiotics.

The treatment for a patient with SJS can vary depending on the health of the person and the severity of the disease. Fluid replacement and topical steroids may be needed, and the doctor may also administer oral and eye exams and treatments. For eye problems, it is important to consult ophthalmologists to consider early (within the first two weeks) intervention with amniotic membrane transplantation.

What are the complications of SJS/TEN?

• Ophthalmologic: Corneal ulceration, anterior uveitis, panophthalmitis, blindness
• Gastroenterologic: Esophageal strictures
• Genitourinary: Renal tubular necrosis, renal failure, penile scarring, vaginal stenosis
• Pulmonary: Tracheobronchial shedding with resultant respiratory failure
• Cutaneous: Scarring and cosmetic deformity, recurrences of infection through slow-healing ulcerations

How can SJS/TEN be prevented?

Early recognition and avoidance of possible offending agents may reduce the incidence and/or severity of SJS/TEN.

Referrences

1. Stevens AM, Johnson FC: A new eruptive fever associated with stomatitis and opthalmitis. Report of two cases in children. Am J Dis Child 1922; 526-533.
2. French LE: Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int 2006 Mar; 55(1): 9-16.
3. Belfort R Jr, de Smet M, Whitcup SM, et al. Ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with AIDS. Cornea 1991;10:536–8.
4. Power WJ, Ghoraishi M, Merayo-Lloves J, et al. Analysis of the acute ophthalmic manifestations of the erythema multiforme/ Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology 1995;102:1669 –76.
5. Patterson R, Miller M, Kaplan M, et al. Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 1994;73:27–34.
6. Halebian PH, Corder VJ, Madden MR, et al. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986;204:503–12.
7. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272– 85.
8. Arevalo JM, Lorente JA, Gonzalez-Herranda C, Jimenez-Reyes J. Treatment of toxic epidermal necrolysis with cyclosporin A. J Trauma 2000;48:473– 8.
9. Egan CA, Grant WJ, Morris SE, et al. Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 1999;40:458–61.
10. Prins C, Vittorio C, Padilla RS, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology 2003;207:96 –9.
11. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998;282:490 –3.
12. Di Pascuale MA, Espana EM, Liu DT, et al. Correlation of Corneal Complications with Eyelid Cicatricial Pathologies in Patients with Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis Syndrome. Ophthalmology 2005; 112:904–912.
13. Kim JS, Kim JC, Na BK, et al. Amniotic membrane patching promotes healing and inhibits protease activity on wound healing following acute corneal alkali burn. Exp Eye Res 2000;70:329 –37.
14. Meller D, Pires RT, Mack RJ, et al. Amniotic membrane transplantation for acute chemical or thermal burns. Ophthalmology 2000;107:980–89; discussion 990.
15. Kobayashi A, Shirao Y, Yoshita T, et al. Temporary amniotic membrane patching for acute chemical burns. Eye 2003;17: 149–58.
16. John T, Foulks GN, John ME, Cheng K, Hu D. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology 2002;109:351-320.
17. Kobayashi A, Yoshita T, Sugiyama K, et al. Amniotic Membrane Transplantation in Acute Phase of Toxic Epidermal Necrolysis with Severe Corneal Involvement. Ophthalmology 2006;113:126–132.
18. Roujeau JC: Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997 Nov; 24(11): 726-9
19. Lyell _. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956;68:355– 61.
20. Roujeau JC. The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification. J Invest Dermatol 1994;102:28S–30S.
21. Ball R, Ball LK, Wise RP, et al: Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system. Pediatr Infect Dis J 2001 Feb; 20(2): 219-23.

Documents

Stevens – Johnson Syndrome and Toxic Epidermal Necrolysis

Pubmed.gov list of published papers
Amniotic Membrane for Chemical Burns

Videos

(all youtube videos link where broken)

 

 

If you have additional surgical questions after viewing this information, contact OSREF’s Research Director, Scheffer C.G. Tseng, MD, PhD, by e-mail at [email protected] or by phone at 305-274-1299.

Videos edited by: Scheffer C.G. Tseng, MD, PhD, Hosam Sheha, MD, PhD, Ahmad Kheirkhah, MD, Antonio Elizondo, MD, Victoria Casas, MD

Note: The videos are for peer discussion purposes and the creators are not participating in commercial promotion of any product.

Financial Interest Disclosure: Dr. Tseng and his family are more than 5% shareholders in TissueTech, Inc. and Bio-Tissue, Inc. which currently distributes AMNIOGRAFT® and PROKERA™

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