Background

Epidermal necrolysis (EN), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a severe and rare drug reaction, the incidence of which has recently been estimated at 6 cases/million/year in France [1]. EN is characterized by necrosis of the epidermis and mucosa. SJS and TEN differ in the percentage of detached-detachable body surface area (SJS < 10% and TEN ≥ 30%)[2]. Twenty to 79% of patients with acute forms of the disease have vision-threatening ocular damage [3]. The main risk factor for ocular sequelae is the severity of the initial ocular damage [4]. In addition, we recently reported that phototypes V and VI were also risk factors for greater severity of ocular sequelae [5].

The most disabling long-term sequelae of EN is ocular damage with severe visual impairment. The incidence is between 35 and 50% depending on the series [6]. After the acute phase of EN, the ocular surface remains subject to chronic inflammation that can lead to limbal stem cell deficiency, keratinization of the palpebral margin, and corneal opacification which may lead to blindness. The aim of EN management in the acute phase is to limit and prevent chronic eye disease and the blindness it can cause [6]. The mechanism of chronic ocular damage is based on a combination of physiological and mechanical aggressions of the ocular surface. Therefore, the objective of management is to limit ocular inflammation and the factors aggravating it as well as the toxicity of the treatments [6].

To date, there is no consensus on the ophthalmologic management of the ocular sequelae of EN, nor is there a standardized consensual ophthalmologic evaluation form, as we proposed in a previous study on the management of ocular involvement in the acute phase [7]. However, patients with ocular sequelae present significant permanent discomfort impacting their quality of life and high ocular morbidity requiring adapted management [8].

We conducted a national audit of ophthalmologic management practices during the chronic phase of EN in the 11 sites of the French reference center for toxic bullous dermatoses and severe drug reactions (TOXIBUL). We then compared our results with the literature. Based on this audit, we were able to propose an evaluation form to facilitate ophthalmic data collection during the chronic phase of EN as well as an algorithm for the ophthalmologic management of ocular sequelae of EN.

Material and methods

First, we surveyed ophthalmologists and dermatologists at the 11 centers of the TOXIBUL reference center. We sent them a standardized questionnaire by email about care practices for the ocular sequelae of EN. The survey focused on the presence of a referent ophthalmologist at the center, the use of topical treatments (artificial tears, corticosteroid eye drops, antibiotic-corticosteroids, antiseptics, vitamin A ointment (VA), cyclosporine, tacrolimus), the management of trichiatic eyelashes, meibomian gland dysfunction, symblepharons, and corneal neovascularization, as well as the contactologic solutions implemented. If a center had more than one referent ophthalmologist, each one could answer independently of the others.

In a second step, we performed a literature review. We searched PubMed for all articles published between 1987 and 2021 dealing with the ophthalmologic management of the chronic phase of SJS/TEN. The bibliography search was guided by four themes: topical treatments, systemic immunosuppressive treatments, eyelid treatments, and adjuvant treatments (amniotic membrane transplantation (AMT), contactology, subconjunctival injection of anti-vascular endothelial growth factor VEGF). We selected the most relevant meta-analyses, cohort studies and retrospective case series according to the research themes for each treatment category. We excluded single case reports and articles on ocular management during the acute phase.

Finally, bringing together the results of the survey and data from the literature, we proposed an evaluation form to facilitate ophthalmic data collection during the chronic phase of EN as well as an algorithm for the ophthalmologic management of ocular sequelae of EN.

Results of the survey

Eleven ophthalmologists and 9 dermatologists from 9 of the 11 centers completed the questionnaire (Table 1). All the dermatologists answered that they had a referent ophthalmologist for this disease at their center (9/9). The majority of ophthalmologists responded that they almost systematically prescribed preservative-free artificial tears (10/11, 91%) and VA (11/11, 100%), and, as needed, antiseptic or antibiotic eye drops (8/11, 73%), or antibiotic-corticosteroids eye drops (7/11, 64%). In the case of chronic inflammation, topical cyclosporine was consistently proposed (11/11, 100%). Tacrolimus eye drops (4/11, 36%) and autologous serum eye drops (6/11, 55%) were also proposed as needed, whereas systemic immunosuppressants were never used (0/11).

Table 1 Audit of ophthalmologic management practices during the chronic phase of epidermal necrolysis: Response from 11 ophthalmologists
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The removal of trichiatic eyelashes was mainly performed by the ophthalmologist (10/11, 91%), rarely by the patient (3/11, 27%). The surgical release of symblepharon (i.e. a cicatricial fusion between the bulbar and tarsal conjunctiva) was not systematic (8/10, 80%), it was reserved in case of difficulty with contactology fitting (SL, 8/10, 80%) or of severe eyelid malposition (9/10, 90%), and was associated with AMT or oral mucosa transplant (OMT) to limit symblepharon recurrence (7/10, 70%).

In case of chronic corneal ulcers, most ophthalmologists recommended AMT (9/11, 82%) and some recommended tectonic keratoplasty (6/11, 55%) in case of large corneal perforation. In case of meibomian gland dysfunction, eyelid hygiene was recommended by all ophthalmologists (11/11, 100%) with specific topical antibiotics if necessary (10/11, 91%). All the centers proposed scleral lenses (SL) in the event of disabling keratoconjunctivitis sicca with functional discomfort and/or visual impairment (9/10, 90%). More than half of the centers used anti-VEGF in case of corneal neovascularization (7/11, 64%).

Literature review

We retrieved 39 articles; 19 are presented in Table 2. The majority of the studies were retrospective and quite small in size. Few studies have assessed visual acuity in EN in the literature [5, 9].

Table 2 Literature review of the ophthalmologic management of ocular sequelae in SJS/TEN
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Local treatments

Artificial tears

Severe dry eye, the most common ocular sequelae, is associated with chronic inflammation of the ocular surface and is explained by tear deficiency, decreased corneal wettability, and increased tear evaporation [8]. The instillation of preservative-free artificial tears is necessary and recommended to increase their volume while preserving the ocular surface [3, 10-12]. Instillation of eye drops containing non-steroidal anti-inflammatory drugs is contraindicated as they are known to worsen corneal damage (ulceration, keratitis) that can lead to corneal perforation [13, 14]. Artificial tears should be used as required.

Vitamin A Ointment

VA ointment maintains the wettability of the ocular surface and limits conjunctival keratinization in patients with SJS/TEN [15] [16]. It should be used as required.

Corticosteroid eye drops

Due to their anti-inflammatory properties, short courses of topical corticosteroids reduce inflammatory ocular symptoms (redness, pain, burning) in patients. However, regular monitoring must be carried out to detect adverse effects such as infectious keratitis and elevation of intraocular pressure responsible for corticosteroid-induced glaucoma, and cataract [3, 10, 17]. These complications explain why long-term use of corticosteroids is not recommended. There is no consensus on the posology of eye drops. It depends on the presence and degree of clinical inflammation.

Cyclosporine eye drops

The beneficial effect of cyclosporine eye drops is recognized in the severe dry eye in EN allowing corticosteroid sparing and long-term instillation [18, 19]. The main problem with cyclosporine ophthalmic solution is its safety. Although one study showed a good safety profile over for 3 years [20], cyclosporine can be poorly tolerated with burning prickling, and foreign body sensation, all of which are reversible on discontinuation of treatment. Cyclosporine 0.05% is usually administered.

Antibiotic eye drops

A significantly higher proportion of various pathogenic microorganisms was found in conjunctival swabs in patients with EN (60% vs 10% in controls, p = 0.001) [21]. The use of local antibiotics must be appropriate, temporary, and discussed on a case-by-case basis as soon an infection is detected by bacteriological samples [8]. Antiseptics can be used for preventive purposes.

Autologous serum eye drops 20%

Autologous serum has the particularity of containing the elements present in the tear film allowing the regeneration and the proliferation of the epithelial cells of the cornea and the conjunctiva. Autologous serum contains essential components for the ocular surface such as vitamin A, fibronectin, epidermal growth factor (EGF), transforming growth factor-β (TGF-β) which allow the renewal of the ocular surface epithelium. Autologous serum also has an anti-inflammatory property through the action of interleukin-1 receptor antagonists, which explains its use in these diseases. Therefore, autologous serum eye drops could be useful in the treatment of ocular surface disease with cell damage. Their effectiveness has been demonstrated in the treatment of dry eye syndrome or in the persistence of corneal epithelial defects [10, 14]. In vitro toxicity tests showed that autologous serum eyedrops reduced toxicity compared to hypromellose, a substance forming the texture of eyedrops, present in preservative-free eye drops [22].

Indeed, the regulations and the manufacturing conditions of autologous serum eye drop require a blood transfusion center, which limits their use in practice. They are produced by centrifugation of the patient’s peripheral blood and then diluted in saline solution or artificial tears. Moreover, a risk of infection by contamination of eye drop bottles is not rare. A series of cases in Thailand evaluated a rate of 6.12% of positive cultures, including fungus, without clinical expression in patients [23]. The period of use varies in the literature from 1 day to 7 months, usually 4 times a day.

Topical tacrolimus

The role of tacrolimus in controlling ocular surface inflammation and reducing the use of local corticosteroids has been demonstrated in the literature[24]. In six patients with EN, the administration of tacrolimus ointment 0,02% in combination with local corticosteroid tapering therapy suppressed the inflammatory relapse. The corticosteroid sparing effect of tacrolimus thus made it possible to reduce corticosteroid-induced intraocular pressure by significantly reducing the need for local corticosteroids (p = 0.004). However, a complete cessation of corticosteroids treatment with topical tacrolimus was impossible because the inflammation of the ocular surface increased after discontinuation. A low dose of topical corticosteroids had to be maintained to avoid this inflammatory relapse[24]. Tacrolimus 0.02% ointment was topically applied 1 to 3 times per day, depending on disease severity, for up to 31 months.

Systemic treatments

Some studies agreed that systemic immunosuppressants (cyclosporine, azathioprine, cyclophosphamide, methotrexate, mycophenolate, dapsone, and infliximab) should not be used except before ocular surgery to control inflammation to prevent inflammatory rebound or in cases of recurrent inflammation or moderate to severe involvement [3, 17]. However, the side effects of systemic immunosuppressants are not insignificant.

Eyelid treatments

Examination of the eyelids is essential to identify eyelid malposition that may aggravate trauma to the ocular surface. The permeability of the lacrimal puncta, the position of the eyelashes, the state of the meibomian glands, the height of the lacrimal meniscus, the quality of the tear film, the depth of the fornices, and the presence of symblepharon(s), as well as the presence or absence of keratinization of the eyelid margin and the ocular surface are all elements to be taken into account [17].

Surgical management of trichiasis is common. Other anatomical abnormalities such as scarring entropion are possible requiring an OMT at the posterior lamella of the eyelid. This transplant provides good functional and aesthetic results as well as long-term stability with a low recurrence rate [25].

Oral mucosa transplant (OMT)

The use of the oral mucosa as a posterior flap transplant (marginoplasty technique) showed good functional and cosmetic results, long-term stability, and a low recurrence rate in the treatment of severe scarring entropion of the upper eyelid [25, 26].

AMT can also be used in combination with OMT or as an alternative for the repair of the fornix following the removal of the symblepharon. However, AMT should never be used instead of OMT when palpebral rigidity is required [27, 28].

Electrolysis treatment of trichiatic eyelashes

Several techniques have been compared in the literature to reduce the delay of eyelash regrowth using epilation, electrolysis, cryotherapy, or thermal ablation with argon laser [29]. In this experimental study comparing four rabbits, Argon laser thermal ablation was found to be an appropriate alternative to electrolysis or cryotherapy in some cases of trichiasis. Cryotherapy could promote the formation of symblepharons.

Adjuvant treatments

Subconjunctival injection of anti-VEGF

Ranibizumab 0.1 ml injected subconjunctivally significantly inhibited corneal neovascularization as early as one-week post-injection in an experimental study comparing two groups of rabbits, one group receiving anti-VEGF and one control group (p = 0.001). No side effects were noted [30].

A prospective study of 12 patients conducted by Gueudry et al. in 2010 also showed regression of corneal neovascularization at day 45 after subconjunctival injections of anti-VEGF (bevacizumab 0.1 ml) (p = 0.0003) without improvement of visual acuity [31]

Scleral lenses

With their high oxygen permeability lens characteristics and non-contact geometry on the corneal surface, SL maintain a tear reservoir between the cornea and the posterior surface of the lens, thereby reducing patient discomfort and improving visual acuity by smoothing out corneal surface irregularities. A recent study demonstrated the therapeutic benefits of SL in the management of disabling ocular sequelae of EN [9]. Another study showed a significant improvement in visual acuity and quality of life after wearing SL [32]. Scleral lenses require a rigorous training of the patient for their daily manipulation. It is important to specify that SL can be difficult to fit in case of symblepharons and a reduced size of the fornix, hence the importance of fitting them in specialized centers [32].

Limbal stem cell transplant (LST)

Patients with limbal epithelial deficiency (such as EN) could be treated with autologous limbal transplantation [33]. However, this is only possible when there is enough limbus left and ocular damage is mostly bilateral in EN. Moreover, the residual limbus must be preserved on the valid eye in order not to cause a deficiency following harvesting since 70 to 80° of the limbal arc must be harvested to be effective.

Therefore, given the constraints and reduced success rate of limbal transplantation, the clinical use of epithelia obtained by ex vivo culture of autologous limbal stem cells could be considered [34].

Since allograft limbal transplants are subject to rejection, if both eyes are affected, the use of epithelial cells from the patient's oral mucosa (by removing the mucosa under local anesthesia) would allow the reconstitution of an epithelial layer in vitro within three weeks. A recent prospective study evaluating this technique of culture and grafting showed favorable results with an improvement of visual acuity at 2 years [26].

Few complications have been described, such as the risk of rejection and infection. The monitoring of postoperative healing is extremely important and requires an experienced team. Therefore, this technique is generally reserved for patients with good quality oral mucosa, which may be rare in EN, and to prepare the cornea for possible keratoplasty [34].

Amniotic membrane transplantation

In addition to its role in the acute phase of EN, AMT is known to be used in the management of chronic ulcers or after the removal of symblepharons, acting as a substrate for epithelial cells. However, the effect of AMT is limited in the severe sequelae of EN [8]. A recent study reported that patients who received acute AMT remained susceptible to chronic ocular damage and required close monitoring in the short, medium, and long term [35].

Keratoplasty

Transplantation, penetrating keratoplasty (PK), is reserved for certain cases of corneal perforation and associates a patch graft with a conjunctival flap. [36]. PK can be considered in EN when there is adequate limbal stem cell reserve and aqueous tear production and minimal or nonexistent eyelid margin and conjunctival keratinization. In the other cases, an osteodontokeratoprosthesis (OOKP) may be proposed. Although described more than 40 years ago, OOKP remains the keratoprosthesis of choice for end-stage corneal blindness that is not amenable to conventional PK. It is particularly resistant to a hostile environment such as the dry and keratinized eye resulting from severe EN.

The principle of this surgery is to use a tooth and its periodontium (periosteum—alveolar bone—alveolar-dental ligament) as biological support known as an "osteo-dental blade" for a synthesis optic of polymethylmethacrylate, thus constituting the OOKP, sutured to the cornea. This OOKP, once sutured to the cornea, is covered by a flap of jugal mucosa ensuring biological coverage of the device. The OOKP thus plays the role of the cornea allowing the light influx to be conducted to the retina.

This surgery requires cooperation with trained multidisciplinary teams (ophthalmologists, ENT or maxillofacial surgeon). Life-long follow-up is provided throughout life to detect and treat complications, which include oral, oculoplastic, glaucomatous, vitreoretinal and device extrusion complications [37]. Glaucomatous complications remain the most frequent postoperative complications inducing a decrease in visual acuity [38].

When surgery is decided a combination of limbal allograft, AMT, and tarsorrhaphy, followed by the use of serum-derived tears, could be proposed for ocular surface reconstruction [39].

Conclusion

Although there are no recommendations for the management of ocular sequelae in SJS-TEN syndromes, a certain uniformity of management in France has been demonstrated. Based on this practice audit and literature review, we propose an evaluation form to facilitate ophthalmic data collection in the chronic phase of EN (Fig. 1). We also propose an algorithm for the ophthalmologic management of ocular sequelae (Fig. 2), guided initially by the management of ocular surface alteration then, in a second step, we focus on visual rehabilitation.

Fig. 1
figure 1

Ophthalmologic evaluation form in the chronic phase of epidermal necrolysis

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Fig. 2
figure 2

Algorithm for the ophthalmologic management of ocular sequelae during the chronic phase of epidermal necrolysis

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