You are here

  • Home
  • Archive
  • Volume 99, Issue 2
  • Severity of acute ocular involvement is independently associated with time to resolution of ocular disease in toxic epidermal necrolysis patients

Article Text

Article menu

Download PDFPDF

Clinical science
Severity of acute ocular involvement is independently associated with time to resolution of ocular disease in toxic epidermal necrolysis patients
  1. Jacob S Heng1,2,3,
  2. Nabeel Malik3,
  3. Naresh Joshi3,
  4. Michelle Hayes1,
  5. Isabel Jones4,
  6. L Claire Fuller5,
  7. Marcela P Vizcaychipi1,2
  1. 1Department of Anaesthesia, Chelsea and Westminster Hospital, London, UK
  2. 2Faculty of Medicine, Imperial College, London, UK
  3. 3Department of Ophthalmology, Chelsea and Westminster Hospital, London, UK
  4. 4Burns Service, Chelsea and Westminster Hospital, London, UK
  5. 5Department of Dermatology, Chelsea and Westminster Hospital, London, UK
  1. Correspondence to Dr Marcela P Vizcaychipi, Chelsea and Westminster Hospital, Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, 369 Fulham Road, London SW10 9NH, UK; m.vizcaychipi{at}imperial.ac.uk

Abstract

Purpose Toxic epidermal necrolysis (TEN) is a severe, life-threatening mucocutaneous disorder that frequently involves the ocular surface. This study aims to investigate the natural history and resolution of acute ocular involvement in patients with TEN admitted to the intensive care unit (ICU).

Methods Case notes of patients admitted to ICU with TEN at a tertiary referral centre in a 9-year period were retrospectively reviewed. Patients’ characteristics, severity of ocular involvement, SCORTEN systemic severity score and treatment were correlated with resolution of ocular involvement and time to resolution.

Results Nine out of 10 (90%) patients had ocular involvement with 4 graded as mild, 2 as moderate and 3 as severe. All had bilateral ocular disease. The median length of hospital stay was 28 days and the median time to resolution of ocular involvement was 19 days. Four out of 9 (44%) patients still had active ocular disease at the time of discharge. Only older age (p=0.032) and a milder grade of ocular disease (p=0.001) were significantly associated with resolution of ocular disease. In a multivariable Cox-regression model, only a milder grade of ocular disease remained independently associated with time to resolution of ocular disease (p=0.006).

Conclusions Grading of acute ocular disease severity does not reflect systemic disease severity and is significantly associated with resolution and time to resolution of ocular involvement in TEN. The high rate of ocular involvement in patients with TEN and relatively large proportion of patients with active disease on discharge reiterates the need for constant ophthalmological monitoring of these patients.

  • Ocular surface
  • Immunology
  • Inflammation
  • Conjunctiva
  • Cornea

https://doi.org/10.1136/bjophthalmol-2014-305506

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Toxic epidermal necrolysis (TEN) is a severe necrotising and de-epithelialising condition of the skin with associated mucositis in multiple sites, often accompanied by systemic compromise.1 TEN is generally considered the most severe manifestation of a spectrum of disorders including TEN and Stevens–Johnson Syndrome (SJS). These disorders are predominantly drug induced.2 ,3 TEN is characterised by epidermal detachment exceeding 30% of total body surface area (TBSA) while SJS involves epidermal detachment of only <10% TBSA.3

    Ocular involvement is more frequent but not necessarily more severe in TEN compared with SJS4–6 and possibly even more frequent in SJS/TEN overlap.4 ,5 Ocular disease affects the eyelids, conjunctiva and cornea. These may arise prior to, in conjunction with or after the skin manifestations of TEN. Ocular disease can be severe in the acute phase and may progress to chronic eye disease such as entropion, trichiasis and/or a severe dry eye syndrome7 even after the skin and systemic illness have resolved, resulting in blinding ocular disease.

    Due to the relatively rare occurrence of TEN, there is a paucity of data on the natural history of ocular involvement in the acute phase of the disease. This study aims to examine the natural history and the factors associated with resolution of acute ocular involvement in patients with TEN admitted to a Burns Intensive Care Unit (BICU).

    Methods

    Case notes of all patients with TEN confirmed on skin biopsy admitted to the Chelsea and Westminster Hospital BICU in a 9-year period were retrospectively reviewed. The Chelsea and Westminster Hospital Burns Unit and BICU are collectively a tertiary referral centre covering the whole of Greater London and the South East of England. The study was conducted in accordance with the UK Good Clinical Practice code, Clinical Governance Reference number 994.

    Patients’ demographic characteristics including age, gender and ethnicity were recorded. The presumed precipitant(s) for each patient's TEN episode was also noted. Acute ocular involvement was graded into mild, moderate or severe for each eye based on the system proposed by Power et al8 (table 1). Severity of involvement of each eye was further categorised into a ‘mild’ group or a ‘moderate/severe’ group for statistical analyses. The extent and severity of patients’ TEN illness were recorded as percentage of TBSA (%TBSA) affected, number of mucosal surfaces involved and SCORTEN systemic severity score.9 Other clinical parameters including days of mechanical ventilation, length of hospital stay and mortality were also noted. Topical ocular treatment modalities including eye drops, bandage contact lenses and amniotic membrane transplantation were recorded. Systemic therapy modalities were also recorded.

    View this table:
    Table 1

    Grading of acute ocular involvement in patients with toxic epidermal necrolysis

    The date of onset of ocular involvement was taken as the onset of ocular symptoms from the patients’ histories as documented in their case notes. The date of resolution of ocular involvement was determined by earliest documentation of ocular disease resolution on examination by an ophthalmologist. Based on these two dates, the number of days to resolution of ocular involvement was calculated for each patient. If a patient did not achieve resolution of ocular disease prior to hospital discharge, ‘ocular non-resolution’ was noted and the number of days to date of discharge was calculated instead.

    Statistical analyses were carried out using SPSS V.21.0 for Windows (IBM Corp, 2012). Demographic and clinical characteristics were compared for patients with and without resolution of ocular disease. In addition, the severity of acute ocular disease was also correlated with measures of systemic disease such as the %TBSA involved, number of mucosal surfaces involved and SCORTEN severity score. Continuous variables were compared using the Mann–Whitney U tests. Categorical variables were compared using Fisher's exact test for 2×2 tables and χ2 test for more than two categories. Univariable survival analyses were conducted for the time to ocular disease resolution using Kaplan–Meier survival analysis, and the log-rank test was used to compare time to ocular disease resolution between patients grouped according to each factor. Statistically significant factors on univariable survival analyses were fitted into a multivariable Cox-regression model to ascertain whether a particular factor was independently associated with time to resolution of ocular disease. A p value of <0.05 was considered significant.

    Results

    Ten patients with TEN proven on skin biopsy were admitted to the Chelsea and Westminster BICU in a 9-year period. Skin biopsies typically showed full thickness epidermal necrosis with a predominantly lymphocytic infiltrate at the dermal–epidermis junction and superficial perivascular dermal regions.

    There were nine females and one male with a median age of 41 years. Nine cases were drug-related while the precipitant was not identified in one case. The drugs implicated were phenobarbitone, hydroxychloroquine, carbamazepine, oseltamivir, lamotrigine, lansoprazole, allopurinol and vemurafenib. The median percentage of body surface area affected was 85% (range 50%–95%) and the median SCORTEN score was 2 (range 1–6). Eight patients were mechanically ventilated with a median duration of 20 days. The median length of stay in BICU is 17 days (range 1–58 days) and the median length of hospital stay is 28 days (range 11–59 days). One patient died on BICU.

    All patients were seen by an ophthalmologist prior to transfer or within 48 h of admission. Patients were reviewed daily or every 2 days as required by an ophthalmologist. Eighteen eyes of nine patients (90% of total eyes and patients) had disease involvement with 8 eyes being graded as mild, 4 as moderate and 6 as severe. Although specific disease features differed slightly between both eyes of each patient, there was complete correlation of disease grading between both eyes of the same patient (ie, the graded severity of ocular disease in one eye is identical to the other eye for each patient in the entire cohort). Conjunctival inflammation was present in 18 eyes of 9 patients, conjunctival membranes in 6 eyes of 3 patients, symblepharon in 6 eyes of 3 patients, ankyloblepharon in 5 eyes of 3 patients, forniceal foreshortening in 3 eyes of 2 patients, corneal epitheliopathy in 9 eyes of 5 patients, lagophthalmos in 4 eyes of 2 patients, ectropion in 1 eye of 1 patient, entropion and trichiasis in 2 eyes of 1 patient as well as severe dry eyes in 8 eyes of 4 patients (table 2).

    View this table:
    Table 2

    Ocular complications in patients with toxic epidermal necrolysis

    Topical therapy included topical lubricants in 18 eyes, topical antibiotics in 18 eyes, topical steroids in 16 eyes and topical immunosuppressants in 6 eyes. Bandage contact lenses were used in 4 eyes of 2 patients and amniotic membranes in 2 eyes of 1 patient. Systemic therapy included intravenous immunoglobulin in 9 patients, corticosteroids in 4 patients, immunosuppressants in 5 patients, G-CSF in 4 patients. Median time to resolution of ocular disease was 19 days. Eight eyes of four patients (44% of total 18 eyes of nine patients) still had active disease at the time of discharge.

    When comparing demographic and clinical characteristics between patients with and without resolution of ocular disease (tables 3 and 4), only older age (p=0.032) and a milder grade of ocular disease (p=0.001) were associated with resolution of ocular disease. The association of ‘ocular non-resolution’ with the use of bandage contact lenses (p=0.023) was due to the usage of bandage contact lenses in severe ocular disease (p=0.006). Patients with mild ocular disease (median age=51.6 years) were significantly older (p=0.034) compared with those with moderate/severe ocular disease (median age=34.2 years). Mild ocular disease was also associated with a higher SCORTEN score (p=0.001), smaller number of mucosal surfaces (p=0.012) but not %TBSA involved (p=0.762).

    View this table:
    Table 3

    Comparison of characteristics of patients with and without resolution of ocular symptoms

    View this table:
    Table 4

    Comparison of ocular characteristics with and without resolution of ocular symptoms

    On univariable survival analyses, a milder grade of ocular disease (p=0.001, figure 1) and more severe systemic disease as indicated by SCORTEN score of 2 and above (p=0.017) were associated with a shorter time to resolution of ocular disease, while the use of topical corticosteroids (p<0.001) and bandage contact lenses (p=0.024) was associated with a longer time to resolution of ocular disease. In a multivariable Cox-regression model, only a milder grade of ocular disease remained independently associated with time to resolution of ocular disease (p=0.006).

    Figure 1
    Figure 1

    Kaplan–Meier survival analysis of persistence of disease in eyes with toxic epidermal necrolysis with mild ocular disease (broken line) and eyes with moderate/severe ocular disease (bold line). There was a difference in the duration of persistence of ocular disease between the two groups on the log-rank test (p=0.001).

    Discussion

    Our study included patients with TEN with high TBSA involvement (median 85%) who required long periods of hospitalisation (median 28 days) with the advantage of continuous close monitoring. We found 90% of patients with TEN with bilateral ocular involvement, which is consistent with previous studies where ocular involvement occurred in between 66.7% and 100% of patients with TEN.4 ,6 ,8 ,10 The high rate of ocular involvement in patients with TEN makes it imperative to include the ophthalmologist as an indispensible member of the multidisciplinary team for the management of patients with TEN.

    In our cohort of patients, resolution of ocular disease was associated with the severity of ocular surface disease, but not greater extent or severity of systemic disease as measured by the %TBSA involved or the SCORTEN score for disease severity in TEN. Paradoxically, patients with more severe ocular involvement had lower SCORTEN scores indicating lower disease severity. This latter finding is more likely to be due to the severity of ocular involvement in TEN being largely dissociated from systemic disease severity. This is consistent with a previous study demonstrating that the severity of ocular involvement was not related to SCORTEN scores,4 ,11 area of skin involvement or aetiology.11 The reasons for this phenomenon remain unclear, but may be due to fundamentally distinct cytopathological processes occurring in the conjunctival mucosa compared with the skin in TEN. It has been suggested from animal models that ocular disease in SJS/TEN is primarily a result of disordered innate immunity on the ocular surface, possibly due to distinct cellular pathways involved.12 In human subjects, an elevation of neutrophils but not lymphocytes is seen in the conjunctiva within days of onset of SJS/TEN13 and remain elevated at 12 months’ follow-up13 as well as during disease remission.14 This is in contrast to the predominantly lymphocytic infiltrate seen in skin biopsies of patients with SJS/TEN. Interestingly, in our cohort, a greater severity of ocular disease is associated with an increased number of mucosal surfaces involved, suggesting that the pathological processes in the conjunctiva may be similar to those in other mucosal surfaces, and it is the extent of mucositis, rather than cutaneous involvement, that may be associated with the severity of ocular involvement.

    The finding of younger patients with more severe ocular involvement could not be adequately explained, although this finding mirrored the results of a recent study of 51 Korean patients, which showed that paediatric patients with SJS/TEN below 18 years of age had poorer ocular outcomes than adult patients.15

    We also showed that milder ocular disease severity was associated with a shorter time to resolution of ocular disease, with a median duration of 9 days to ocular resolution for patients with mild ocular involvement. All patients with mild ocular disease achieved resolution before discharge, whereas only one out of five patients with moderate/severe ocular involvement achieved resolution on discharge. This observation was first reported by Power et al8 in their original paper detailing the grading of ocular disease in SJS/TEN, although no timescale was detailed in their original findings.

    Severe ocular disease in TEN is postulated to start off as a membranous conjunctivitis,16 which evolves into symblepharon and/or ankyloblepharon due to scar tissue formation from wound healing processes.17 The acute phase was thought to last between 2 and 6 weeks.8 ,18 This cicatrisation of the conjunctiva subsequently results in chronic complications such as entropion, trichiasis and lagophthalmos. Severe dry eyes are common and may be a result of the above lid changes and/or damage to the tear production apparatus such as meibomian glands19 or Goblet cells on the ocular surface.20 ,21 There is no consensus on the exact definition of ‘acute’ and ‘chronic’ ocular involvement in SJS/TEN. Various authors have defined chronic ocular complications as occurring 3,10 66 and 12 months20 after the onset of disease. These chronic changes were observed in our patients with severe ocular involvement within 2 months of symptom onset and some within 20 days, suggesting that the transition between ‘acute’ and ‘chronic’ ocular disease in TEN may represent a continuum rather than distinct episodes. Indeed, chronic ocular sequelae in TEN/SJS were found to correlate with the severity of acute ocular involvement in previous studies.5 ,11

    The association of the use of topical corticosteroids and bandage contact lenses with a longer time to ocular resolution as well as the association of bandage contact lenses with lack of resolution of ocular disease were most likely due to patients with more severe ocular disease warranting treatment with these modalities, rather than any detrimental effect of topical corticosteroids or bandage contact lenses per se. Accordingly, these did not prove to be significant on multivariable Cox-regression analysis. Otherwise, our study did not show any association between topical and systemic treatment modalities with resolution of ocular disease and time to resolution of ocular disease. This, however, needs to be interpreted with caution due to the small study size. Controlled studies of promising therapeutic modalities such as the ProKera device22 and novel multimodal therapeutic approaches, such as the ‘Triple-TEN’,23 may yield robust evidence for therapeutic approaches in TEN.

    In conclusion, we have shown that grading of ocular disease severity is significantly associated with resolution and time to resolution of ocular involvement in TEN. The severity of acute ocular involvement is not associated with the severity of systemic disease measured by TBSA affected or SCORTEN severity scores. However, there was an association with greater severity of acute ocular involvement with a greater number of mucosal surfaces involved, suggesting that the severity of ocular disease may reflect the extent of mucosal disease in general. The high rate of ocular involvement in patients with TEN and relatively high proportion of patients with moderate to severe ocular disease with ongoing disease on discharge reiterates the need for constant ophthalmological input in these patients.

    References

    1. ↵
      1. Schwartz RA,
      2. McDonough PH,
      3. Lee BW
      . Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013;69:173.e1–13; quiz 185-6.
      OpenUrlCrossRef
    2. ↵
      1. Mockenhaupt M
      . The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803–13; quiz 814-5.
      OpenUrlCrossRefPubMed
    3. ↵
      1. Schwartz RA,
      2. McDonough PH,
      3. Lee BW
      . Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol 2013;69:187.e1–16; quiz 203–4.
      OpenUrlCrossRef
    4. ↵
      1. Morales ME,
      2. Purdue GF,
      3. Verity SM,
      4. et al
      . Ophthalmic manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis and relation to SCORTEN. Am J Ophthalmol 2010;150:505–10.e1.
      OpenUrlCrossRefPubMed
    5. ↵
      1. Gueudry J,
      2. Roujeau JC,
      3. Binaghi M,
      4. et al
      . Risk factors for the development of ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2009;145:157–62.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Yip LW,
      2. Thong BY,
      3. Lim J,
      4. et al
      . Ocular manifestations and complications of stevens-johnson syndrome and toxic epidermal necrolysis: An asian series. Allergy 2007;62:527–31.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Iyer G,
      2. Srinivasan B,
      3. Agarwal S,
      4. et al
      . Comprehensive approach to ocular consequences of Stevens Johnson syndrome—the aftermath of a systemic condition. Graefes Arch Clin Exp Ophthalmol 2014;252:457–67.
      OpenUrlCrossRefPubMed
    8. ↵
      1. Power WJ,
      2. Ghoraishi M,
      3. Merayo-Lloves J,
      4. 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.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Bastuji-Garin S,
      2. Fouchard N,
      3. Bertocchi M,
      4. et al
      . SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149–53.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Chang YS,
      2. Huang FC,
      3. Tseng SH,
      4. et al
      . Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: Acute ocular manifestations, causes, and management. Cornea 2007;26:123–9.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. López-García JS,
      2. Rivas Jara L,
      3. García-Lozano CI,
      4. et al
      . Ocular features and histopathologic changes during follow-up of toxic epidermal necrolysis. Ophthalmology 2011;118:265–71.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Ueta M,
      2. Kinoshita S
      . Ocular surface inflammation is regulated by innate immunity. Prog Retin Eye Res 2012;31:551–75.
      OpenUrlCrossRefPubMed
    13. ↵
      1. Williams GP,
      2. Tomlins PJ,
      3. Denniston AK,
      4. et al
      . Elevation of conjunctival epithelial cd45intcd11b+CD16+CD14− neutrophils in ocular Stevens-Johnson syndrome and toxic epidermal necrolysis. Invest Ophthalmol Vis Sci 2013;54:4578–85.
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Arafat SN,
      2. Suelves AM,
      3. Spurr-Michaud S,
      4. et al
      . Neutrophil collagenase, gelatinase, and myeloperoxidase in tears of patients with Stevens-Johnson syndrome and ocular cicatricial pemphigoid. Ophthalmology 2014;121:79–87.
      OpenUrlCrossRefPubMed
    15. ↵
      1. Kim KH,
      2. Park SW,
      3. Kim MK,
      4. et al
      . Effect of age and early intervention with a systemic steroid, intravenous immunoglobulin or amniotic membrane transplantation on the ocular outcomes of patients with Stevens-Johnson syndrome. Korean J Ophthalmol 2013;27:331–40.
      OpenUrlCrossRefPubMed
    16. ↵
      1. Prendiville JS,
      2. Hebert AA,
      3. Greenwald MJ,
      4. et al
      . Management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Pediatr 1989;115:881–7.
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Mondino BJ
      . Cicatricial pemphigoid and erythema multiforme. Ophthalmology 1990;97:939–52.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. PATZ A
      . Ocular involvement in erythema multiforme. Arch Ophthal 1950;43:244–56.
      OpenUrlCrossRefPubMed
    19. ↵
      1. Sotozono C,
      2. Ang LP,
      3. Koizumi N,
      4. et al
      . New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. Ophthalmology 2007;114:1294–302.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Sotozono C,
      2. Ueta M,
      3. Kinoshita S
      . The management of severe ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2009;145:1336–7; author reply 1337-8.
      OpenUrlCrossRefPubMed
    21. ↵
      1. Ohji M,
      2. Ohmi G,
      3. Kiritoshi A,
      4. et al
      . Goblet cell density in thermal and chemical injuries. Arch Ophthalmol 1987;105:1686–8.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Ciralsky JB,
      2. Sippel KC,
      3. Gregory DG
      . Current ophthalmologic treatment strategies for acute and chronic Stevens-Johnson syndrome and toxic epidermal necrolysis. Curr Opin Ophthalmol 2013;24:321–8.
      OpenUrlCrossRefPubMed
    23. ↵
      1. Tomlins PJ,
      2. Parulekar MV,
      3. Rauz S
      . ‘Triple-TEN’ in the treatment of acute ocular complications from toxic epidermal necrolysis. Cornea 2013;32:365–9.
      OpenUrlCrossRefPubMed

    Footnotes

    • Correction notice This article has been corrected since it was published Online First. The x-axis in Figure 1 has been corrected to ‘% of eyes with persisting disease’.

    • Contributors JSH performed the data collection and statistical analyses. JSH and NM contributed to the drafting the manuscript. NJ, MH, IJ, LCF and MPV contributed to subsequent revision, proofreading and editing of the manuscript.

    • Funding Chelsea & Westminster Healthcare charity (Fund 556).

    • Competing interests None.

    • Ethics approval Local clinical governance review board (ref no. 994).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement This material was presented as a poster in the 2014 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting in Orlando, Florida, USA.

    Linked Articles

    • At a glance
      Highlights from this issue
      Keith Barton James Chodosh Jost Jonas
      British Journal of Ophthalmology 2015; 99 i-i Published Online First: 20 Jan 2015. doi: 10.1136/bjophthalmol-2015-306627