Ophthalmic Aspects of Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: A Narrative Review

The acute phase of SJS/TEN develops 4–28 days after the triggering event [34]. SJS/TEN begins with a prodrome of fever, cough, rhinorrhea, anorexia and malaise. This is followed by the acute phase with inflammation and ulcerations of the oral, genital, ocular and anal mucosa 1–3 days later [3, 5]. Acute SJS/TEN can be recognized by the inflammation of at least two mucous membranes [4]. The acute phase takes place within 2 weeks after the appearance of SJS/TEN and is characterized by excessive epidermal and keratinocyte necrosis. Skin lesions appear as erythaematous maculas or atypical targetoid lesions, bullae, erosions and ulcers on the trunk [19].

Differentiation between SJS and TEN is based on the affected total body surface area (BSA): SJS with < 10% BSA, SJS/TEN overlap with 10–30% BSA and TEN with > 30% BSA involvement [35]. The most frequently found ocular symptoms (Fig. 1) are bilateral conjunctivitis and corneal epithelial defects. Widespread eyelid margin necrosis, meibomitis, epithelial loss of the conjunctiva and pseudomembrane/membrane development can lead to symblepharon formation, and corneal erosions may result in corneal ulceration and perforation [36].

The most common ophthalmic complaints of patients with acute SJS/TEN are visual impairment, eye pain and photophobia. The severity of ocular sequelae does not always correspond to the severity of cutaneous lesions or systemic disease [37].

A grading system for ocular manifestations of acute SJS/TEN was developed by Gregory [38] (Table 1). The grading scheme is developed based on the epithelial defects at the eyelid margins, on the conjunctiva, and on the cornea. Ocular surface alterations in acute SJS/TEN result in devastating long-term complications.

Predicted mortality can be calculated with the SCORe of TEN (SCORTEN) [39] and ABCD-10 [40] methodologies. SCORTEN is a mathematical model that uses seven independent risk factors (age, malignancy, heart rate, epidermal detachment, serum urea, serum glucose and serum bicarbonate) to estimate the probability of mortality due to SJS/TEN [39]. ABCD-10 is a newer risk prediction model for predicting the mortality rate from SJS/TEN. The estimation is based on five risk factors: age, serum bicarbonate, cancer, dialysis and 10% body surface area. ABCD-10 uses ‘dialysis before SJS/TEN’ instead of SCORe’s renal dysfunction at mortality prognostication [40]. SCORTEN has been proven to be superior to ABCD-10 in mortality rate estimation for SJS/TEN [41].

The most frequently isolated bacterium in the early acute phase of SJS/TEN is Staphylococcus aureus, while the most commonly isolated microbe that can lead to a prolonged hospital stay in SJS/TEN is Pseudomonas aeruginosa [6].

Chronic ocular sequelae may occur in 35–90% of people with SJS/TEN and may affect the eyelid, conjunctiva and cornea. Chronic SJS/TEN can be considered an aftermath of mechanical and physiological insults of the ocular surface [42]. There is no explicit zero point at which SJS/TEN can be considered chronic, but it generally starts between 3 and 6 months following the acute phase, after stabilization of the ocular surface inflammation [43].

Sotozono et al. [13] evolved a three-category grading scheme for chronic ocular complications of SJS/TEN (Table 2) in 2007, using 13 clinical components based on eyelid, conjunctival and corneal involvement. Sharma et al. [34] developed a modified multi-step grading system for chronic ocular sequelae of SJS/TEN (Table 3) based on the grading scheme of Sotozono et al. in 2019, addressing the more severe cases in greater detail.

Chronic ocular sequelae of SJS/TEN (Fig. 2) are unpredictable and have poor correlation with acute SJS/TEN [27]. However, the severity of acute SJS/TEN is the best predictor for chronic eye complications [44].

Eyelid complications include meibomian gland destruction, lid margin keratinization, entropion or ectropion development, trichiasis, lacrimal punctal occlusion and mucocutaneous junction involvement. It should be emphasized that most corneal sequelae can originate from lid margin keratinization [45].

Conjunctival complications may lead to persistent inflammation, hyperaemia, membrane formation, ulceration, scarring and squamous metaplasia. Obstruction of the ductal openings of the lacrimal gland due to conjunctival scarring and destruction of the goblet cells impair the tear film quality [3, 5]. All components of the tear film can be affected (mucin, aqueous and lipid layers) in chronic SJS/TEN, and their dysfunction may lead to severe dry eye, which is one of the most common ocular complications of the disease. Ocular surface scarring leads to ankyloblepharon and symblepharon formation with inadequate closure of the eyelids and limited ocular motility [37].

Microtraumas through the affected eyelids lead to long-term corneal complications, including loss of the palisades of Vogt, limbal stem cell deficiency, neovascularization, keratinization, conjunctivalization and corneal decompensation. Keratinization of the eyelid margin may lead to persistent or recurrent corneal epithelial defects, ulceration, stromal melting and corneal perforation [14]. The ocular surface in healthy eyes has a high diversity of microbiomes, with Streptococcus and Lactobacillus as the most prevalent bacteria. In contrast, the ocular surface in chronic SJS/TEN shows a lower bacterial diversity with a Staphylococcus predominance, and these bacteria can become easily pathogenic. Accordingly, the incidence of infective keratitis is higher in people with SJS/TEN than in persons with earlier severe ocular burns [46].

The combination of these processes may lead to blindness and loss of the eye. The end stage of chronic ocular SJS/TEN can be characterized by an entirely keratinized and dry ocular surface [4]. In total, 87% of people with chronic SJS/TEN have difficulties with driving at night or reading [47].

SJS/TEN diagnosis must be based on clinical characteristics, but histological confirmation should always be performed. Histologically, SJS/TEN shows partial to full-thickness keratinocyte necrosis and slight lymphohistiocytic inflammation around the vessels [6].

Nevertheless, there are some other vesiculobullous and desquamating skin diseases that may have a similar appearance as SJS/TEN. The most important differential diagnostic entity is erythema multiforme major (EMM). Previously, SJS/TEN and EMM with similar histologic and clinical appearances were considered different presentations of a spectrum disease, but currently, both are considered two separate entities [48]. EMM may recur more often than SJS/TEN and affects only one mucosal surface in most cases; it is caused most commonly by M. pneumoniae and herpes simplex virus (HSV) [49]. EMM concerns mainly the facial and acral skin, while SJS/TEN predominantly involves the trunk [7].

Other differential diagnostic options that should be considered are staphylococcal scalded skin syndrome, acute generalized exanthaematous pustulosis, linear immunoglobulin (Ig)A bullous dermatosis, pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid and acute graft-versus-host disease. Therefore, the most important differential diagnostic step is to visit a dermatologist [50].

The management of acute SJS/TEN is multi-disciplinary and starts with the discontinuation or suppression of the causative factor [51]. Medical history is essential to explore the cause of the disease, as the first symptoms typically appear within 1–8 weeks after starting taking the causative drug [7, 52].

All people with acute SJS/TEN should be managed first in a burn unit or intensive care unit. The most important general aspects of medical attendance are to manage nutritional, electrolyte and fluid imbalances; to maintain respiratory and renal function; and to control infection, as well as to assure analgesia [6]. Dermatological, ophthalmic, gynaecological, urological and nephrological consultation may be necessary in the early phase [53], depending on the patient’s needs. Ophthalmic examination is necessary at admission or within 1–2 days after SJS/TEN diagnosis [54].

Cornerstones of acute ophthalmic care are to inhibit the immune response on the ocular surface and to prevent chronic ocular sequelae. Waiting for skin biopsy results should not delay eye care. Ophthalmic care of acute SJS/TEN should be initiated based on the clinical signs [43]. Daily eye examinations should be performed, as ocular inflammation can evolve rapidly [37].

Eyelid margins should be managed with a combination of antibiotic–steroid ointment (tobramycin 0.3%/dexamethasone 1%) 4–6 times daily [38].

Mild and moderate SJS/TEN cases should be treated with levofloxacin 0.5–1.5% or moxifloxacin 0.5% eye drops three to four times a day, with topical corticosteroid (dexamethasone 1% or prednisolone acetate 1%) eye drops two to six times daily and cyclosporine 0.05–0.09% drops two to four times daily, depending on the severity [4, 14, 43]. The use of preservative-free topical lubricants is also recommended to protect the ocular surface, which should be instilled every hour. Topical lubricants could also be replaced by autologous serum eye drops. The removal of ocular surface membranes and pseudomembranes is recommended with a glass rod in all patients [42]. Healing of smaller corneal epithelial defects can be promoted by fitting soft therapeutic contact lenses [5].

Severe and extremely severe cases should be managed similarly to moderate cases with topical drops and ointment. In addition, all patients must undergo thorough removal of inflammatory debris and amniotic membrane transplantation (AMT) as a patch, combined with conformer, symblepharon ring or ProKera use within the first 10 days. AMT for acute SJS/TEN was first reported by John et al. in 2002 [55]. The amniotic membrane patch must cover the entire ocular surface, the fornix, the tarsal conjunctiva and the eyelid margins [56]. AMT prevents eye surface ruination, inhibits inflammation and hastens re-epithelization. AMT reduces the risk of chronic ophthalmic complications, such as limbal stem cell deficiency, corneal haze, ankyloblepharon, symblepharon or other eyelid sequelae. People with acute SJS/TEN are frequently medically unstable; therefore, AMT in general anaesthesia may be unfeasible. Thus, AMT should be performed bedside with local anaesthesia [42]. The AMT could be fixated to a conformer using 10/0 nylon sutures, and this complex could be inserted under the eyelids. In addition, the suture-less AMT technique with cyanoacrylate glue has been described by Shanbhag et al. [57]. Suture-less AMT is more feasible under local anaesthesia and causes less discomfort. Generally, the amniotic membrane dissolves in several weeks, and topical therapy should be further continued [42]. An eye check-up should occur on the fourth day and then every week following AMT [4]. Complications of AMT in people with SJS/TEN are extremely rare [58].

In the case of extremely severe acute SJS/TEN, the presence of large de-epithelized ocular surface areas and ocular surface inflammation, a repeat AMT should be performed 7–14 days following the first AMT [44].

The effect of systemic anti-inflammatory therapies is still a subject of debate. The published data on adjunctive therapies in acute SJS/TEN are equivocal. To date, there is no available evidence regarding whether systemic corticosteroid, intravenous immunoglobulin (IVIG), plasmapheresis, systemic cyclosporine, tumour necrosis factor (TNF) inhibitors or cyclophosphamide have advantageous effects on visual outcome and chronic eye sequelae in SJS/TEN [59]. Moreover, the use of these systemic therapeutic possibilities includes severe systemic risks [43].

A larger meta-analysis has not found any statistically significant positive effect of systemic corticosteroid monotherapy [60]. Interestingly, people taking systemic corticosteroids for other diseases still develop SJS/TEN [61]. Moreover, corticosteroids seem to be associated with higher rates of mortality and infections [62]. Therefore, many experts advise against the use of systemic corticosteroids as monotherapy for people with acute SJS/TEN [28].

Nevertheless, a 3-day course of high-dose pulsed corticosteroid (1.5 mg/kg/day) appeared to improve the mortality rate and visual outcome [50], with no systemic complications [37].

IVIG is a commonly administered, first-line therapy for acute SJS/TEN. IVIG down-regulates Fas-mediated keratinocyte apoptosis [63]. Nevertheless, in the largest published treatment series, there was no significant mortality benefit compared with the SCORTEN-predicted mortality using IVIG treatment [28]. Other studies have shown that IVIG monotherapy can lead to longer hospital stays [64] and increase mortality [50]. In addition, IVIG does not seem to decrease the severity of chronic ocular sequelae [65], and acute renal failure – which is the most severe complication – may occur [66].

Nevertheless, combining IVIG with high-dose pulsed steroid treatment (500–1000 mg/day for 4 days) has been shown to restrain ocular complications when administered within 4 days of SJS/TEN onset [67].

Plasmapheresis removes non-dialysable pathogenic agents from the plasma. The method is relatively safe. Several case reports and series are available in the literature, reporting controversial results [50]. The only available prospective study, published by Han et al., showed that people with acute SJS/TEN had a lower severity of illness scores in the chronic phase following plasmapheresis [68]. However, there is no evidence that plasmapheresis has any significant effect on mortality or reepithelization [69].

Cyclosporin A has an immunosuppressive effect and can inhibit apoptosis [70]. Cyclosporin A (4 mg/kg/day) may have a mortality benefit compared with the SCORTEN-predicted mortality, and delays the progression of the disease [28]. Nevertheless, it can be associated with severe side effects such as neutropenia, nephropathy, pneumonia and leucoencephalopathy [71].

TNF inhibitors may inhibit keratinocyte apoptosis. Unfortunately, administration of thalidomide in SJS/TEN had to be stopped during the first trial as it increased mortality [72]. In contrast, infliximab and etanercept have promising prospects, as they may hamper progression, induce skin reepithelization and seem to decrease mortality [28, 50].

Cyclophosphamide can facilitate re-epithelization. However, its usage also had to be discontinued in people with acute SJS/TEN due to its higher mortality rate [73].

The management of chronic ocular sequelae of SJS/TEN is based on prevention of ocular surface irritation, treatment of the complications and visual rehabilitation [4]. The first follow-up examination should occur within 4 weeks after release from the hospital and should be performed every 2–4 months repeatedly in the first year and every 6 months thereafter [74].

Ocular surface dryness can be managed from several aspects. Replacement of the aqueous layer with preservative-free artificial tears is frequently a first-line therapy [75]. Autologous serum eye drops contain several ingredients similar to natural tears, such as vitamin A, fibronectin and epidermal growth factor [76]. In addition, topical cyclosporine improves goblet cell density [77]. Meibomian gland dysfunction should be treated with daily eye lid hygiene. Depending on the ocular surface inflammation, topical steroid eye drops and antibiotics can be used [78]. Oral azithromycin or doxycycline may add to the management of inflammation [79].

It is important to avoid any surgical procedures in chronic SJS/TEN, unless it is definitely inevitable. If the lacrimal drainage system is intact, lacrimal punctal occlusion using punctal plugs or cautery may help in controlling ocular surface dryness [43].

In cases of severe dry eye, salivary gland transplantation can be performed either from the submandibular or minor salivary glands. Nevertheless, it has limited popularity as it may often be accompanied by excessive tearing, and this type of surgery has low reproducibility [78]. Epiphora is rarely observed following minor salivary gland transplantation compared with submandibular gland transplantation [80].

Before any surgical procedures for visual rehabilitation, it is essential to manage eyelid abnormalities. To protect the ocular surface, keratin must be removed from the eyelid margins. Ectropion and entropion can be treated with eye lid surgery, trichiasis and distichiasis with epilation, cryotherapy and extirpation [74].

The use of scleral contact lenses protects the corneal surface from micro-traumas caused by keratinized eyelid margins and misdirected eyelashes, and therefore supports the healing of corneal epithelial defects. In addition to scleral contact lenses, the prosthetic replacement of the ocular surface ecosystem (PROSE) device is a promising treatment option in patients with chronic SJS/TEN, and has beneficial features similar to those of scleral lenses. PROSE is a scleral prosthetic device that can be used in people with highly irregular ocular surfaces [37].

Other aims of scleral contact lenses and PROSE are to reduce photophobia and mask corneal irregular astigmatism. Overnight wear of scleral lenses is not recommended as it may enhance the risk of microbial keratitis. Soft and rigid contact lenses are not appropriate as they do not ensure enough fluid-filled space between the posterior surface of the contact lens and the anterior surface of the cornea. However, considerable symblephara may hamper the use of scleral contact lenses [42].

In patients with symblepharon, lid margin keratinization and reconstruction of conjunctival surfaces and lid margins with mucous membrane grafting (MMG) can be a solution. Keratinized tarsal and bulbar conjunctiva can be replaced with autologous buccal or labial mucosa, which can be fixed either with Vicryl sutures or with fibrin glue. MMG has been reported to be sufficient in stabilizing the ocular surface and improving visual function [81]. Moreover, MMG seems to have a beneficial effect on corneal neovascularization, haze formation and corneal reepithelialization [19]. MMG can be combined with AMT for fornix restoration [74]. MMG combined with scleral contact lens use is an optimal treatment method in chronic SJS/TEN.

MMG addresses lid margin-related keratopathy, even overnight, while wearing scleral contact lenses, and PROSE is not recommended. Early use of MMG in conjunction with scleral contact lens use may have synergistic effects, can prevent the development of limbal stem cell deficiency and persistent corneal epitheliopathy, and is effective in preservation and improvement of visual acuity. MMG may also improve the compliance of children in wearing rigid contact lenses and PROSE [42, 82, 83].

Persistent corneal epithelial defects can be treated with AMT [84]. Penetrating keratoplasty (PK) may help in urgent cases, such as corneal perforation, advanced thinning or ulceration [43], but is not suitable for people with SJS/TEN as PK does not facilitate the regeneration of corneal epithelial stem cells. Limbal stem cell transplantation (LSCT) is a general surgical intervention for limbal stem cell deficiency. However, it has been reported that allogenic LSCT has a poorer success rate for people with chronic SJS/TEN than for persons who suffered ocular burn [4, 85]. Graft failure is a frequent complication of LSCT in people with SJS/TEN, as patients with SJS/TEN have severe ocular comorbidities (ocular surface inflammation, serious dry eye, eye lid margin and epithelial abnormalities) preoperatively [36]. Therefore, allogenic LSCT is not the recommended procedure for chronic SJS/TEN, even with immunosuppression. Since SJS/TEN affects both eyes, autologous LSCT is not a possibility [37].

Since 2002, autologous cultivated oral mucosal epithelial transplantation (COMET) has been developed for reconstruction of the corneal surface in people with chronic SJS/TEN as it promotes post-operative corneal re-epithelialization and stabilizes the corneal surface in the long term. Additionally, after COMET patients do not need immunosuppression after surgery [86]. For COMET, autologous mucosal epithelial cells are gathered from the buccal mucosa and seeded on an amniotic membrane, first in vitro [87]. These cultivated cells are later used for ocular surface reconstruction. Sotozono et al. reported that better postoperative visual acuity is achievable in people with chronic SJS/TEN using COMET than with LSCT [88].

Keratoprosthesis is suitable for the replacement of an opaque cornea. Keratoprosthesis implantation is actually regarded as a safe and effective treatment option for patients with severe limbal stem cell deficiency and corneal surface disease, where further PK, LSCT or COMET are deemed likely to fail [89]. Keratoprosthesis implantation is a suitable procedure for visual rehabilitation in special cases of corneal blindness, and it has been proven to be more effective than PK with or without LSCT. Boston type I keratoprosthesis is used in cases of unchanged eyelid function, while xerotic ocular surfaces are only suitable for Boston type II keratoprosthesis and osteo-odonto-keratoprosthesis (OOKP) implantation [90]. Nevertheless, unfortunately, compared with other ocular surface diseases, SJS/TEN is associated with a higher post-operative complication rate of ulceration, corneal melting and endophthalmitis, as well as worse visual prognosis following keratoprosthesis surgery, than other autoimmune-based disorders [43].

It is important to note that referral of patients with severe chronic SJS/TEN to a clinical psychologist may provide great support to the patients [4].