Corneal Histopathology in Stevens-Johnson Syndrome: A Case Report and Review of Literature

Stevens-Johnson syndrome is a life-threatening, immune-mediated, acute inflammatory disorder of the mucocutaneous membranes. It affects people of almost any age and has a high mortality and morbidity rate. Therefore, histopathological confirmation of the diagnosis is essential. Ocular involvement occurs in more than 50% of the affected patients. Here, we report a case of Stevens-Johnson syndrome with ocular involvement in a 10-year-old boy suffering from pain, burning, stinging, and decreased vision in both eyes for over 2 years. Histopathological findings were consistent with the changes due to the syndrome. Stevens-Johnson syndrome affects various mucous membranes along with the skin. Ocular involvement may manifest both acutely and chronically and causes morbidities. A careful clinical and histopathologic examination is required in order to give the correct diagnosis.


Introduction
Stevens-Johnson syndrome (SJS) is a life-threatening, immune-mediated, acute inflammatory disorder of the mucocutaneous membranes. Its counterpart, toxic epidermal necrolysis (TEN), is considered the most severe variant, with a high mortality rate of up to 30% [1]. The disease is mostly drug-induced; however, some microbiological agents such as Mycoplasma pneumoniae have proven to be etiological factors. It is frequently seen in adults, and children might also be affected, but they usually have better outcomes [2].
Depending on the severity of the disease, clinical manifestations change, including sepsis, respiratory dysfunction, and multiple organ failures. In addition, ocular involvement occurs in more than 50% of the patients, starting with ocular surface inflammation in the acute phase and moving on to corneal and conjunctival defects as it becomes chronic, which may result in visual impairments [3].
Herein, we report a pediatric case report with a history of ongoing SJS that first manifested with acute ocular complications, did not respond to treatment, and got more severe over the years. We aim to discuss the specific histopathological changes.

Case Report
A 10-year-old boy had been to an outpatient clinic with a high fever, where he had received a prescription for amoxicillin-clavulanate for a diagnosis of upper respiratory tract infection. Two weeks later, cefdinir treatment had been started because of a persistent high fever. On the second day of the treatment, the patient presented with swelling on the lips, redness in the eyes, and bullous eruptions on the body. A skin biopsy was performed with a pre-diagnosis of SJS, and epidermal regeneration, necrotic keratinocytes, and lymphohistiocytic infiltrate in the dermo-epidermal junction were identified. The histopathological findings were consistent with a drug eruption; therefore, a clinicopathological diagnosis of SJS was made. The causative agent of SJS was determined as cefdinir, a third-generation cephalosporin. The patient was then given 2 g/kg intravenous This article is part of the Topical Collection on Medicine * Eylul Gun dreylulgun@gmail.com immunoglobulin. The lesions on the body and the lips subsided after a couple of months. However, ocular complaints persisted. This time he presented with complaints of pain, burning, stinging, and decreased vision in both eyes. Physical examination revealed oral lesions and scars of old skin lesions, including nummular plaques on the face, body, and extremities and occasional hyperpigmented maculae with central scars. His blood tests showed leucocytosis and neutrophilia. The immunoglobulin levels were within normal limits. The ocular examination revealed bilateral conjunctival hyperemia with purulent discharge, eyelid edema, and matting of the eyelashes. He did not benefit from the amniotic membrane graft, and topical treatment with the biological agent bevacizumab and systemic therapy with prednisolone and cyclosporine were started. As the disease progressed over a period of 1 year, ocular complications got more severe. On examination, corneal findings included an epithelial defect on the left cornea and bilateral limbal stem cell destruction evidenced by the loss of the palisades of Vogt with conjunctivalization, opacification, and neovascularization. His visual acuity was 20/160 and bilateral conjunctival hyperemia, symblepharon formation, and trichiasis of the eyelids were seen. Iris, lens, and fundus were not accessible by slit lamp. A corneal biopsy was obtained from the left eye with a pre-diagnosis of conjunctivalization. The microscopic findings revealed epithelial regeneration, necrotic keratinocytes, and perivascular lymphohistiocytic infiltrate (Fig. 1). In addition, there were Goblet cells present in the corneal epithelium (Fig. 2). This finding was confirmed with periodic acid-Schiff stain histochemically (Fig. 3). The histopathologic findings were consistent with the changes due to SJS, and the diagnosis was given as "corneal tissue showing signs of conjunctivalization."

Discussion
SJS is an acute immunological mucocutaneous disorder with a high mortality and morbidity rate that may affect patients at any age. However, children are known to be affected less severely, and the mortality rate is around 7.5%. SJS and TEN are considered two similar entities of the same disease spectrum, differing only in the severity of skin detachment. The distinction is mainly based on the involved body surface area [4].
The most known cause of the disease is the usage of drugs, accounting for approximately 80% of the cases. Even though the pathogenesis of the disease is not fully understood, it is now known that it happens as a result of a cumulative effect of the drug's structure and the patient's genetic predisposition. There are many defined genetic associations between the drugs, human leukocyte antigen (HLA) alleles, cytochrome p450 (CYP) pathways, and various ethnicities [5]. In a study that reviewed the causes of SJS and TEN in children by Ferrandiz-Pulido et al., it was stated that the drugs that cause SJS vary, and the main ones are sulphonamides and anticonvulsants, followed by penicillins and nonsteroidal anti-inflammatory drugs (NSAIDs). Mycoplasma and herpes virus infections are common causes in childhood [2].
The diagnosis of SJS is confirmed by the histopathologic examination of a biopsy of the characteristic skin lesions that are diffuse erythematous macules with purpuric, necrotic centers with blisters. The hypersensitivity reaction results in widespread inflammation of the epidermis, leading to necrosis, blistering, and sloughing of the tissue. In early lesions, scattered necrotic keratinocytes are seen in the epidermis with mild superficial perivascular mixed inflammatory dermal infiltrate, and as the blisters start to form in later stages, full-thickness epidermal necrosis is seen with basal vacuolar change, subepidermal bullae, and mild superficial perivascular mixed inflammatory dermal infiltrate [6,7].
There is an involvement of mucous membranes in approximately 90% of the affected patients, and the lip, oral cavity, conjunctiva, nasal cavity, urethra, vagina, gastrointestinal tract, and/or respiratory tract may be affected as lesions develop. Ophthalmic involvement is common and develops in approximately 50-60% of hospitalized patients [8]. In a retrospective analysis by Chang et al., 60% of the patients with SJS/TEN developed ocular involvement during the acute phase of the disease [9]. Clinically, acute and extensive ocular surface inflammation occurs with the pseudomembranous formation and corneal or conjunctival epithelial defects resulting in dry eye disease, corneal and conjunctival scarring, and symblepharon formation. The most common ocular feature of SJS is the loss of corneal epithelial stem cells located in the limbal area, which is confirmed by the loss of palisades of Vogt. With the loss of the stem cells during the acute phase of the disease, the corneal epithelium stops regenerating, resulting in "conjunctivalization," which can be defined as a conjunctival epithelial invasion into the cornea [3]. This feature can be indicated histopathologically by the presence of Goblet cells in the cornea.
Conjunctiva extends to the limbus that borders the cornea covering the inner eyelids, and Goblet cells are normally present in the conjunctival epithelium on the ocular surface. On the other hand, the cornea has an avascular structure that provides light transmission and vision with the help of the limbus, which prevents vascularization of the cornea. In diseases such as SJS, where the limbus is damaged, the corneal epithelial progenitor cells can no longer maintain the integrity of the corneal epithelium resulting in corneal stem cell deficiency. This allows conjunctival epithelial and Goblet cells to migrate onto the ocular surface, leading to corneal neovascularization and conjunctivalization. As a result, ocular discomfort and reduced vision occur [10].
In a study by Lopez-Garcia et al., histopathologic and cytologic changes were recorded during the acute phase and then 6 months later. They concluded that epithelial cell squamous metaplasia was related to ocular involvement severity in the acute phase and conjunctival cytological samples showed a marked decrease in goblet cell density as the lesions subsided [11].
Corneal involvement then may result in cicatricial, sclerotic changes of the ocular surface and changes such as neovascularization, opacification, keratinization, and even ulceration and perforation. After the acute phase, some of these changes may subside; however, there may be permanent visual impairment and conjunctival inflammation that prolong at the chronic stage [3].
Over the years, studies have shown that the pathogenesis of the SJS/TEN patients who suffer from severe ocular complications (SOC) differed from those who do not. Specific therapeutic agents and genetic predispositions were thought to play a role, given the fact that SOC are very rare in SJS/TEN. Ueta et al. reported that cold medicines such as NSAIDs were among the main causative drugs for the disease, and the genetic analysis performed on these cases revealed that Toll-like receptor 3, the prostaglandin-E receptor 3, and the IKZF1 gene alterations were most likely the reason for the mucocutaneous inflammation of the ocular surface [12]. Moreover, it was reported in an international collaboration regarding genetic predisposition to SOC in different populations that specific HLA types were associated with SOC in SJS/TEN, namely HLA* 02:06 in Japanese and Korean patients and HLA-B * 44:03 in Japanese-, Indian-, and European ancestry Brazilian patients proving the ethnic differences as causes of the disease [13].
Detailed clinical information and histopathological appearance constitute the strengths of our case.
In conclusion, Stevens-Johnson syndrome affects various mucous membranes along with the skin. Therefore, ocular involvement is an essential factor that causes morbidities. A   Fig. 3 Goblet cells in the corneal epithelium (black arrow) are identified with periodic acid-Schiff stain careful clinical and histopathologic examination is required to give the correct diagnosis and start the treatment without further delay.
Author Contribution EG contributed to the literature review and manuscript preparation. EO contributed to the diagnosis, manuscript preparation, and editing.
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Declarations
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Informed Consent to Publication A written informed consent form was obtained from the parents.

Conflict of Interest
The authors declare no competing interests.