Stevens-Johnson综合征和中毒性表皮松解症的病理损害、眼部表现及治疗进展

Stevens-Johnson综合征(Stevens-Johnson syndrome,SJS)及中毒性表皮(坏死)松解症(toxic epidermal necrolysis,TEN)这两种药物不良反应能严重威胁到患者的生命安全,其均由机体免疫反应引起,两者临床症状非常相似,且互有交叉.两者均表现出全身不适、高热、皮肤疱疹及斑丘疹,常伴有黏膜损伤以及眼部损伤等.SJS与TEN引起的眼部损伤临床治疗棘手,治疗不及时容易致盲且预后差.主要病理环节为外周血液中角化细胞表面所表达的Fas受体与单个核细胞分泌的可溶性Fas配体之间发生相互作用,使角化细胞迅速凋亡、表皮损伤,临床症状逐渐明显.治疗方法包括一般性治疗(系统支持治疗、皮肤黏膜分泌物或伪膜清理、他克莫司等)和特异性治疗(如糖皮质激素、环磷酰胺等特异性药物)和眼部损伤治疗(视病情给予羊膜移植、结膜瓣覆盖、角膜移植、人工角膜及眼表重建等手术治疗).     

Significant impact of cryopreserved amniotic membrane on acute ocular Stevens-Johnson syndrome and toxic epidermal necrolysis

The ocular surface is covered by an epithelium encompassing an area including the cornea,the limbus and the conjunctiva bordered by the upper and lower lids.The healthy state of the ocular surface epithelium depends on a stable and protective preocular tear film when the eye is open.A stable preocular tear film is governed by sound ocular surface defense that involves effective neuroanatomic integration of compositional and hydrodynamic factors by two neural reflexes (1).     

The ophthalmologist's role in the management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are relatively rare but have high mortality rates. Survivors are frequently afflicted with severe blinding ocular surface diseases. Recent literature in the areas of ophthalmology and dermatology illustrate that the ophthalmologist's role should no longer be considered secondary in the acute management of SJS/TEN. Accurately differentiating SJS or TEN from erythema multiforme majus (EMM) at the onset of the disease is important, because the management approach to these disease entities differs. Systemic cyclosporine and intravenous immunoglobulin have shown some potential as treatments for SJS/TEN, but their efficacies remain controversial. Amniotic membrane transplantation and intravenous corticosteroid pulse therapy at the acute stage have shown promise for preventing late sight-threatening cicatricial complications. An improved staging system for the ocular surface involvement of acute SJS/TEN, as well as better understanding of the underlying destructive pathogenic mechanism, should further improve our ability to predict ocular involvement and develop new therapeutics to abort destructive processes at the acute stage.     

The effects of systemic cyclosporine in acute Stevens-Johnson syndrome/toxic epidermal necrolysis on ocular disease

PurposeTo evaluate the effect of systemic cyclosporine (CsA) on ocular disease in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) patients.MethodsIn this retrospective, comparative cohort study at a single center, patients with a diagnosis of SJS/TEN and with at least 3 months of follow up were divided into two groups: those who received systemic CsA and those who did not receive systemic CsA. Best-corrected visual acuity (BCVA) and chronic ocular surface complications score (COCS) at final follow-up were compared between the two groups.ResultsThe median age and follow-up period of patients was 29 years (range, 1.5–71 years) and 16.8 months (range, 3.67–91.58 months), respectively. BCVA, COCS, meibomian gland dysfunction, limbal stem cell deficiency, and the need for mucous membrane grafting and scleral lenses were not significantly different between patients who received systemic CsA as compared to patients who did not receive systemic CsA.ConclusionsIn this small cohort of patients with SJS/TEN, we could identify no association between the use of systemic CsA as a component of their initial therapy and chronic ocular complications.     

Ocular involvement in Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe reactions of skin and mucous membranes. They are considered as a single disease entity with differing severities and are mainly induced by drugs, less frequently by infections. In 50% of the patients ocular complications occur, which can lead to blindness in the absence of immediate ophthalmological treatment. The acute pattern, the unpredictable course and extreme variations in the manifestation of complications require an interdisciplinary treatment. Early diagnosis and initiation of an intensive lubricating and anti-inflammatory surface care are of utmost importance for the best visual outcome. This article is intended to help ophthalmologists towards a better understanding and interpretation of clinical signs of these conditions with the goal to achieve substantial improvements in visual outcome and of course the patient's quality of life.     

Chronic ocular complications in lamotrigine vs. trimethoprim-sulfamethoxazole induced Stevens-Johnson syndrome/toxic epidermal necrolysis

PurposeThe purpose of this study is to compare the severity of chronic ocular complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by lamotrigine (LT) vs. trimethoprim-sulfamethoxazole (TS).MethodsThis retrospective cross-sectional study evaluated all SJS/TEN patients treated within our hospital network from 2008 to 2018. Inclusion criteria included patients with reactions identified as caused by either LT or TS, and patients with at least one ophthalmology follow up in the chronic phase (≥3 months from disease onset). Primary outcome measures included LogMAR best-corrected VA at most recent visit and the presence or absence of severe ocular complications (SOC). Secondary outcome measures included chronic ocular complication severity scores using a modified Sotozono scoring system.ResultsForty-eight eyes of 24 patients were included in the study. The mean duration of follow-up was 39.50 ± 35.62 vs. 48.17 ± 33.09 months, respectively (p = 0.482). The LT group had worse average VA at the most recent visit (LogMAR VA; 0.508 vs. 0.041, p < 0.0001) and had a higher prevalence of SOCs (66.7% vs. 8.3%, p = 0.0038). The LT group scored worse on Sotozono chronic complications scores for the cornea (1.875 vs. 0.5, p = 0.0018), eyelid margin (5.583 vs.3.083, p = 0.0010), and overall condition (8.500 vs. 4.833, p = 0.0015). Sub-analyses showed that a moderate or severe acute ocular severity score was a significant predictor of chronic outcomes.ConclusionsCompared to patients with TS-induced SJS/TEN, patients with LT-induced SJS/TEN developed worse chronic ocular complications on several parameters. Future prospective studies are warranted to provide additional insight into the drug type as a predictor of chronic ocular complications.     

Long-term outcomes of amniotic membrane treatment in acute Stevens-Johnson syndrome/toxic epidermal necrolysis

PurposeTo report the long-term outcomes of amniotic membrane (AM) use in the form of transplantation (AMT) and self-retained amniotic membrane (ProKera® device, PD) in acute Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).MethodsElectronic records of all patients with a diagnosis of SJS/TEN at Massachusetts Eye and Ear between January 2008 and January 2018 were reviewed. Patients who received AM in acute SJS/TEN were selected. Only patients with follow-up ≥ 3 months after discharge were included.ResultsData of 55 eyes of 29 patients were analyzed. All 55 eyes received the first AM at a median interval of 5 days (inter-quartile range (IQR): 3–7 days) after onset of skin rash. Fifty-six percent of eyes (31/55) received AMT while 44% (24/55) received PD. Forty percent of eyes (22/55) required a repeat AMT or PD. Median follow-up after initial AM was 2.5 years (IQR: 1.2–3.6 years). At last follow-up, the best-corrected visual acuity was ≥20/40 in 87% of eyes (48/55). The most common complications in the chronic phase were meibomian gland disease and dry eye, seen in 78% of eyes (43/55) and 58% of eyes (32/55) respectively.ConclusionsLong-term results show that early use of AM in the acute phase of SJS/TEN may be effective in mitigating severe vision loss after SJS/TEN. However, eyelid-related complications and dry eye remain a common problem even with the use of AM.     

Stevens-Johnson综合征或中毒性表皮坏死松解症24例分析

目的探讨Stevens-Johnson综合征（SJS）或中毒性表皮坏死松解症（TEN）急性期的临床特点、眼部表现及治疗。方法回顾性病例研究。对2012年5月-2014年2月于北京协和医院皮肤科确诊为SJS或TEN的24例患者的病史、眼部表现及治疗进行回顾性分析。结果24例患者均由口服药引起,主要致敏药物为抗生素（7例）、解热镇痛药（6例）和神经精神药（4例）。24例患者中16例出现眼部受累,所有眼部受累患者均为双眼受累,13例出现结膜充血,12例出现结膜渗出,9例累及眼睑,7例出现结膜假膜,7例累及睑缘,3例累及角膜。24例患者均接受全身激素治疗,眼部受累患者联合眼部激素治疗,病情较重者辅以免疫抑制剂,眼部分泌物较多者行人工泪液冲洗,必要时分离睑球粘连。结论SJS或TEN急性期可表现为不同程度的皮肤及黏膜损害,多伴眼部受累,全身和局部足量的糖皮质激素治疗可控制病情发展,减轻眼部损伤。     

Ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with AIDS.

Recent reports suggest that acquired immunodeficiency syndrome (AIDS) patients are at higher risk of developing mucocutaneous reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (SJS). Resultant dry eye may be further exacerbated by human immunodeficiency virus (HIV) related lacrimal gland dysfunction and lead to a chronic keratoconjunctivitis. We report one patient with AIDS and toxic epidermal necrolysis and two patients with AIDS and SJS who developed severe dry eye misdiagnosed as infectious keratoconjunctivitis. Cicatrizing mucocutaneous reactions should be suspected in AIDS patients and the dry eye treated to control symptoms and prevent complications.     

Stevens-Johnson syndrome in India - risk factors, ocular manifestations and management

We conducted a study to analyse the presentation, risk factors, ocular manifestations and ophthalmic management results of Stevens-Johnson syndrome (SJS) in Indian patients. A total of 20 patients with SJS with ocular involvement were studied. Female predominance (70%) was observed. The age ranged from 10 to 30 years (mean +/- SD: 16.85 +/- 5.96). The commonest precipitating risk factor was oral drug intake (80%), sulphonamide (30%; sulphamethoxazole-trimethoprim) being the commonest. One patient had reaction to ciprofloxacin which has not been reported previously. Four patients (20%) had spontaneous onset with no identifiable risk factor. None of the patients had specific infection per se as a risk factor. Conjunctival involvement and its sequelae were the major ocular manifestations. At presentation, the majority of the eyes (68%) had visual acuity less than 3/60. Despite appropriate medical treatment and surgical interventions (11 eyes; 28%) vision continued to deteriorate. In 1 eye, the vision improved after stem cell transplantation. Therapeutic penetrating keratoplasty could preserve ocular integrity in 1 patient.     

Amniotic membrane in the surgical management of acute toxic epidermal necrolysis

OBJECTIVE: To report a new surgical technique to manage severe acute toxic epidermal necrolysis. DESIGN: Two interventional case reports. PARTICIPANTS: Two patients. Case 1: A 6-year-old boy had severe toxic epidermal necrolysis develop after being treated with trimethoprim and sulfamethoxazole for chronic otitis media. Both eyes and eyelids were affected. He underwent bilateral lysis of symblepharon and all adhesions and bilateral amniotic membrane transplantation to the entire ocular surface except the cornea. Loss of eyelid skin required transplantation of amniotic membrane to all four eyelids and strips of amniotic membrane at the eyelid margins. Case 2: An 8-year-old girl with severe toxic epidermal necrolysis associated with mycoplasma pneumonia had bilateral, diffuse keratoconjunctivitis, diffuse corneal epithelial defects, and bilateral symblepharon. Amniotic membrane transplantation was performed bilaterally, using a symblepharon ring in the left eye. INTERVENTION: Amniotic membrane transplantation. MAIN OUTCOME MEASURES: Preservation of normal ocular and eyelid surfaces and prevention of blindness. RESULTS: Case 1: Thirty-six months after bilateral ocular surgery, there is no symblepharon, good ocular surface wetting, and an uncorrected bilateral vision of 20/20. Case 2: Amniotic membrane transplantation protected both ocular surfaces and prevented conjunctival contracture without adhesion of the eyelids to the ocular surface. The central vision was preserved. There was minimal peripheral corneal vascularization and mild conjunctival scarring of the tarsal conjunctival surface 34 months postoperatively. CONCLUSIONS: These are the first cases of acute toxic epidermal necrolysis treated with amniotic membrane transplantation and the first use of the procedure on external eyelid surfaces with good healing of the eyelids. This new treatment for acute toxic epidermal necrolysis preserves normal ocular and eyelid surfaces and may prevent blindness.     

High-dose intravenous immunoglobulin in the treatment of toxic epidermal necrolysis: a study of ocular benefits

PURPOSE: To compare acute ocular complications of toxic epidermal necrolysis (TEN) following treatment with high-dose human intravenous immunoglobulin (IVIG) with a historical cohort not treated with IVIG. METHODS: Retrospective, historically controlled study. In all, 10 consecutive patients with TEN (treatment cohort) presenting between 1 July 2001 and 30 June 2002. Totally, 18 consecutive patients with TEN (historical cohort).SettingTan Tock Seng Hospital, Singapore. The treatment cohort received high-dose IVIG (2 g/kg body weight over 2 days). Patients' records were retrospectively reviewed for their demographic characteristics, causative drug, treatment, ocular involvement (if any, as assessed by an ophthamologist), and its severity. The historical cohort comprised patients coded with a diagnosis of TEN (ICD Code 695.1) between 1 July 1995 and 30 June 2001. RESULTS: Nine (90%) of 10 patients treated with IVIG had ocular involvement. Phenytoin was the implicated drug in three (37.5%) patients. Of the nine patients, 1 died of septic shock. Of the eight survivors, IVIG was initiated immediately upon onset of TEN as all the patients were hospitalized by the time of onset of an exanthema. Acute ocular complications were mild in two (25%) (lid oedema or mild conjunctival injection), moderate in four (50%) (pseudomembranes) and severe in two (25%) (nonhealing epithelial defect with visual loss and symblepharon). In total, 10 (55.6%) of 18 patients in the historical cohort with TEN had acute ocular involvement. Two patients died. Ocular involvement in survivors was mild in five (62.5%) cases and moderate in three (37.5%), with no severe cases. CONCLUSIONS: IVIG did not appear to reduce the severity of visually significant ocular complications. Larger studies are needed to confirm this finding.