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Thygeson’s superficial punctate keratitis
Journal of EuCornea 3 (2019) 5–8
Contents lists available at ScienceDirect
Journal of EuCornea journal homepage: www.elsevier.com/locate/xjec
Thygeson’s superficial punctate keratitis a
a
b
b,c
Tommy C.Y. Chan , Hatty H.T. Chau , Amar Krishna Bhat , Ken K. Nischal , Vishal Jhanji a b c
a,b,c,⁎
T
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Centre, Pittsburgh, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: Thygeson’s superficial punctate keratitis Epithelial keratitis Punctate keratitis Diagnosis Treatment
Thygeson's superficial punctate keratitis (TSPK) is a chronic, bilateral epithelial keratitis. Dr Philips Thygeson first reported TSPK in 1950. Although the etiology of TSPK remains unknown, it has been reported to be associated with viral and autoimmune pathologies. The disease course is characterized by exacerbations and remissions. The classical finding on slit lamp examination is the presence of distinctive coarse, raised, oval-shaped corneal epithelium lesions. Patients commonly present with ocular irritation and rarely with reduced visual acuity. Topical corticosteroids are the mainstay of treatment. Other less commonly used treatments included topical cyclosporine, contact lenses and corneal laser.
1. Introduction The term superficial punctate keratitis was first used to describe an epidemic keratoconjunctivitis in 1889 by Dr Ernst Fuchs, that was likely caused by a strain of adenovirus [1]. In 1950, Dr Phillips Thygeson, an ophthalmologist from California, reported 26 cases of distinctive punctate epithelial keratitis, which later came to be known as Thygeson's superficial punctate keratitis (TSPK) [2]. In 1961, Dr Thygeson described another 29 cases and proposed the diagnostic features of TSPK to differentiate TSPK from other forms of epithelial keratopathies [3]. These included, chronic bilateral punctate epithelial keratitis, long duration with remissions and exacerbations, eventual healing without scars, lack of response to antibiotics, and striking response to topical corticosteroids. Jones was the first to suggest in 1963 that superficial punctate keratitis should formally be called Thygeson's superficial punctate keratitis [4]. 2. Epidemiology TSPK affects patients of all age groups. Thygeson reported that the youngest patient was six years of age and the oldest was 62 years old [3]. In another case series of 27 patients, the youngest patient was 9 years old and the oldest was 53 years old [4]. In a 10-year review of 40 cases with TSPK, Nagra et al. reported a mean patient age of 28.7 years [5]. Overall, the onset of disease is likely to be in the second and third decades with a mean age of 29 years and an age range between 2.5 and 70 years [6]. There is no consensus on gender
⁎
predilection. The initial reports by Thygeson reported no sex predilection [3]. Nagra et al. [5] reported female dominance, whereas Tabbara et al. [7] reported a larger proportion of male patients with TSPK. 3. Pathophysiology The underlying etiology of TPSK remains elusive. Thygeson reported scant mononuclear cells on conjunctival scrapings and slightly abnormal epithelial cells with vacuolated cytoplasm, occasional neutrophils, mononuclear cells, degenerating epithelial cells and mucus on corneal scrapings [3]. Normal conjunctival flora was identified in bacterial cultures [8], whereas other studies also revealed no significant ocular pathogen [5,9,10]. Interestingly, TSPK has been associated with viral infection for a long time. Earlier studies suggested presence of virus particles in cases with superficial keratitis [11,12]. Thygeson suggested a viral etiology based on the absence of bacteria or other microorganisms, resistance of disease to sulfonamides and antibiotics, and presence of scanty mononuclear cell exudate on conjunctival scrapings [3]. Later studies, using tissue culture and electron microscopy, demonstrated that viral particles were the present in cornea [5,8,9,13–16]. Jones reported the presence of faint opacification of superficial corneal stroma underlying the epithelial opacities that are characteristic of TSPK [4]. The corneal stroma was transparent or translucent under retro illumination in these eyes suggesting associated corneal edema [4]. Subsequently, Thygeson suggested viral etiology of TSPK and distinguished it from superior limbic keratoconjunctivitis [3]. Later studies by Wakui et al. In 1971 could not identify any viral
Corresponding author at: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. E-mail address: [email protected] (V. Jhanji).
https://doi.org/10.1016/j.xjec.2019.11.001 Received 6 October 2019; Accepted 2 November 2019 Available online 26 November 2019 2452-4034/ © 2019 Published by Elsevier Inc. on behalf of European Society of Cornea & Ocular Surface Disease Specialists. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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particles in corneal epithelia under electron microscopy in eyes with epithelial dystrophies. The electron microscopy revealed cell destruction that was confined to one discrete area, which was different from the typical cell-to cell spread that is observed in herpes simplex keratitis [17]. In 2006, Connell et al. concluded the absence of herpes simplex virus, varicella zoster and adenovirus in epithelium of patient with TSPK using polymerase chain reaction [14]. Schirmer strip impressions were taken from the epithelium of eight patients with TSPK. The samples from patients with TSPK showed no evidence of the presence of herpes simplex virus 1, herpes simplex virus 2, varicella zoster virus or adenovirus. In terms of presentation, there are distinct differences between the clinical features of TSPK and those of herpes simplex virus, herpes zoster virus, adenovirus and Epstein-Barr virus. The corneal epithelial lesions in adenoviral infections can be similar have a subepithelial component and the course of the disease is not prolonged. Epstein-Barr virus can give rise to a punctate keratitis, which is usually self limiting and may have subepithelial involvement. Furthermore, the reports on efficacy of the antiviral treatment are variable. Tabery reported the present of abnormal subsurface cells (about 10 μm in diameter) in the corneal epithelium in TSPK [10]. These cells appeared individually, in small groups, or aggregated in larger lesions, which were identical to the coarse lesions seen under slit lamp, representing areas of cell necrosis [10]. In larger lesions, the surface epithelium contained debris. The morphology was suggestive of an ongoing action of an unknown agent targeted at the deeper epithelial layers [10]. Quere et al. suggested that TSPK was an allergic reaction, but the absence of eosinophils smears and ocular allergic symptoms made this hypothesis unlikely [6,18]. Certain features of TSPK imply an underlying immune mechanism. These include the present of lymphocytes in corneal epithelium, a chronic course with remissions and exacerbations and a marked effect of corticosteroids on the corneal lesions. A literature review by Darrell correlated TSPK with HLA-DR3, a histocompatibility antigen that can alter the immune response to exogenous or endogenous viral infections, yielding the prolonged course characteristic of the disease [8]. HLADR3 antigen is now known to be associated with several autoimmune disorders such as Addison's disease, Grave's disease, insulin-dependent diabetes mellitus and systemic lupus erythematosus.
Fig. 1. Slit lamp photograph showing a case of Thygeson's superficial punctate keratitis.
areas [7]. These opacities often have a raised centre that breaks through the epithelial surface. There may be tiny hair like mucus filaments. Individual lesions, ranging 1–50 in number, tend to accumulate centrally in the cornea. An average of 20 lesions can be observed per flareup [3,7,19]. During an exacerbation, these focal opacities become elevated above the superficial epithelium and stain with fluorescein and Rose Bengal [21]. During remissions, lesions may disappear completely unless there is subepithelial scarring [21]. These inactive, flat, intraepithelial lesions do not stain with fluorescein or Rose Bengal [6].
4. Clinical presentation
5. Diagnosis
Patients suffering from TSPK often have a long history of exacerbation and remission of symptoms. Both eyes are usually affected but the presentation in both eyes can be asymmetrical [5]. The most common clinical presentations include photophobia, blurred vision and ocular irritation [5]. Other symptoms include tearing, burning and foreign body sensation. Although uncommon, there could be trace conjunctival injection and mild corneal hypoesthesia [19]. In 1968, Quere et al. described the chronic course of TSPK in three stages [6]. The onset, lasting 1 to 2 weeks, was characterized by catarrhal inflammation, photophobia, and tearing. The developmental stage can last up to 8 months during which the signs of conjunctival inflammation disappear, leaving characteristic corneal epithelial lesions. The stage of regression lasts up to 3 years, during which the lesions become fewer in number and smaller until they vanish. Most attacks usually persist for 1 to 2 months and resolve spontaneously, followed by recurrence in 6 to 8 weeks [19]. The overall time course of the disease is variable [19]. The longest record of the disease was in a 59-year-old woman with a 40year history of TSPK, reported by Panzer and Smith in 1999 [20]. TSPK is characterized by a focal epithelial keratitis without significant conjunctival or stromal inflammation [3–5,7,8]. The classic corneal lesion in active TSPK is a conglomerate of coarse, oval shaped, slightly raised, whitish gray dotlike opacities, which stains minimally with fluorescein (Fig. 1) [3]. It was shown that the epithelial basement membrane and its hemidesmosomal attachments were intact in these
There is no specific diagnostic test for TSPK. Diagnosis is entirely based on clinical history, slit lamp examination findings, and therapeutic response to topical corticosteroids. The use of laser confocal microscopy in vivo may be helpful in diagnosis of TSPK [6]. Watson et al. reported the presence of irregular nerve fibres and haze in the corneal sub-epithelial nerve plexus in patients with TSPK [22]. Generalized haziness and areas of high reflectivity, microdots and reflective bodies in the anterior stroma, as well as keratocytes with reflective nuclei and cell bodies of irregular size and shape were also observed. The images suggest that wound healing and cell death occurs mainly in the anterior corneal stroma [22]. Another in vivo confocal microscopy study in 16 TSPK patients found that the most characteristic feature of TSPK was presence of highly reflective aggregations with cotton-like appearance in the basal epithelial cell layer and Bowman’s layer, which represents degenerated and necrotic epithelial cell debris [23]. Other isolated reports found clumps of focal desquamating epithelium and intraepithelial hyper-reflective linear lesions, loss of intercellular lesion, and enlargement of cell size in the superficial epithelial cells [11. 13, 24]. A recent study from Japan found an increase in the number of Langerhans cells in the basal cell layer of corneal epithelium and Bowman's layer [25]. The disappearance of Langerhans cells in the affected eyes treated by topical corticosteroid suggested underlying an inflammatory pathogenesis [25]. 6
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6. Differential diagnosis
staining corneal lesions [5].
The differential diagnoses of TSPK include infection conditions such as Staphylococcal blepharitis, Staphylococcal epithelial keratitis, Pneumococcal conjunctivitis, Herpes simplex keratitis and Acanthamoeba keratitis. Non-infective ocular abnormalities can mimic TSPK including vernal keratoconjunctivitis, keratoconjunctivitis sicca, neurotropic keratopathy, exposure keratopathy and epithelial basement membrane dystrophy.
7.4. Topical cyclosporine Cyclosporine is a popular steroid-sparing therapy in patients with TSPK. It has been reported to be effective when used as a first-line treatment for patients with TSPK [16,31]. In a prospective study used topical 2% cyclosporine in 52 eyes (42 adult and 10 children) with TSPK [16]. Cyclosporine eye drops were started 3 drops daily during the first month and was reduced to 1 drop every alternate day within 4 months and stopped after 6 months. Complete suppression of the typical epithelial and subepithelial opacities could be achieved in 71.5% of cases in adults and 40% in children during the course of the therapy. Recurrences were noted during tapering off or shortly after cessation of therapy. Overall, 31% of all adult eyes and 20% of all pediatric eyes seemed to have completely healed during the observation time [16]. In another study, Del Castillo et al. presented long-term results of the use of 2% topical cyclosporin in 8 patients with TSPK [32]. All the patients were treated with 2% cyclosporin four times a day for three months, and two times a day for one month before withdrawing therapy. After cyclosporine treatment, no corneal lesion was observed and the cornea remained clear after the follow-up period (12–25 months) [32]. Recent anecdotal evidence suggests that commercially available cyclosporine 0.05% may be employed instead of compounded cyclosporine eye drops especially in children with TSPK. Although topical cyclosporine has the advantage of fewer adverse effects compare with the use of topical corticosteroids [15,16,33], it has not been compared to corticosteroids in a controlled clinical trial for the treatment of TSPK. Topical cyclosporine is associated stinging at instillation that may compromise therapeutic compliance. Furthermore, the limited availability of topical cyclosporine and its associated cost has resulted in topical corticosteroids remaining the mainstay of therapy for patients with TSPK. Nagra et al. recommended initial management of TSPK with low-dose corticosteroid eye drops followed by use of stronger steroids and then topical cyclosporine in a stepwise approach [5]. The use of steroid-sparing agents may increase the likelihood of being able to complete taper off steroids without the development of a recurrence.
7. Treatment In previous studies, topical antibiotics were found to be ineffective while topical antivirals had inconsistent results in management of TSPK [7]. Topical corticosteroids are now the mainstay of treatment during acute exacerbation. Other topical medications can possibly be effective are cyclosporine and tacrolimus. Non-medical therapies such as contact lenses and excimer laser keratectomy are have also been investigated as alternative treatments for TSPK. 7.1. Topical antivirals Topical antiviral agents have been tried with unsatisfactory results. Nesburn et al. reported mild clinical improvement after application of topical trifluridine 1% eye drops in 5 out of 6 treated eyes [26]. However, the disease resolved more slowly compared with eyes treated with topical corticosteroids alone. Side effects of trifluridine included mild irritation and transient limbal follicular reaction. Some studies also suggested that idoxuridine, another topical anti-viral agent, causes persistent subepithelial ghost opacities and scarring in TSPK patients [7,11,27]. 7.2. Topical lubricants Topical lubricants are generally used for symptomatic relief in mild TSPK [28]. Preservative-free ocular lubricants can be prescribed with or without topical corticosteroid eye drops in all cases of TSPK. 7.3. Topical corticosteroids
7.5. Topical tacrolimus TSPK is known to respond dramatically to topical corticosteroids especially during acute exacerbations [5]. Nagra et al. managed most of their patients with weak topical corticosteroids like fluorometholone 0.1% and loteprednol 0.2% alone [5]. Others recommended using 0.12% prednisone or equivalent 2 to 3 times per day for a few days up to 2 weeks [29]. It was also suggested that acute episodes should be treated aggressively with topical corticosteroids and then tapered and discontinued over a 3 to 4 week interval [30]. The use of corticosteroids is warranted in patients who are disabled by pain or photophobia. Caution should be exercised regarding corticosteroids for an otherwise benign condition such as TSPK since they may prolong the time to resolution [7]. Topical corticosteroids can possibly alter the epithelial lesions and antiviral agents may increase the degree of subepithelial infiltration [7]. It is also important to distinguish TSPK from herpetic keratitis. The former would not respond to anti-virals whereas the latter would become worse with corticosteroid use. Nagra et al. commented that patients who are not treated with corticosteroids might have a shorter disease course although further studies are necessary to confirm this association. Long-term use of corticosteroids may be associated with serious complications such as glaucoma and cataract [5]. However, response to corticosteroids can be variable [31]. Some studies showed that steroid therapy could even prolong the course of the disease [3,7]. Tapering of corticosteroid eye drops is guided by clinical response and should be performed gradually over the course of months, with some patients requiring infrequent, regular use to control symptoms. Steroids may be tapered in asymptomatic patients with non-
Tacrolimus is another steroid-sparing treatment option in patients with TSPK. Similar to cyclosporine, it slower in inducing remission and relief of symptoms when compared to corticosteroid eye drops. In a retrospective case series, Marquezan et al. used 0.03% topical tacrolimus ointment in 14 patients with bilateral TSPK [9]. The ointment was applied twice daily in the lower fornix for the first 2 weeks, followed by nocturnal application. The treatment was effective for controlling TSPK without any local or systemic side effects. However, attempts to withdraw the medication resulted in recurrent disease [9]. Further studies are required to evaluate the role of tacrolimus with or without topical corticosteroid eye drops in long-term management of patients with TSPK. 7.6. Contact lenses Bandage soft contact lenses can be used for temporary symptomatic relief, in patients who are at risk for steroid-related complications or if the relatively slower-acting steroid sparing agents are used as initial therapy. Soft contacts lenses are an alternative to corticosteroid eye drops during acute exacerbation as they provide immediate symptomatic relief. However, they cannot alter the underlying corneal pathology. In 1977, Sundmacher et al. were the first to report the beneficial effect of hydrophilic soft contact lenses in the treatment of TSPK [31]. Three of his 10 patients achieved symptomatic relief from these lenses. Forstot and Binder confirmed the beneficial effect of bandage 7
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References
soft contact lenses for relieving symptoms of TSPK in three of their patients. Since the use of these lenses reduced or eliminated the need for corticosteroids, the authors recommended extended or daily wear soft contact lenses for the treatment of TSPK [33]. Further studies by Goldberg et al. on patients with TSPK confirmed that bandage soft contact lenses improved both visual acuity and symptoms, with resolution of the epithelial lesions despite a small risk of contact lens associated bacterial keratitis [34]. Contact lenses do not have a role in the resolution of corneal lesions per se. In clinical practice, contact lenses can be used in patients during the acute phase for symptomatic relief.
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Soc. 79 (1981) 486–516. [9] M.C. Marquezan, H. Nascimento, L.A. Vieira, M. Serapiao, R.C. Ghanem, R. Belfort Jr., D. Freitas, Effect of topical tacrolimus in the treatment of thygeson's superficial punctate keratitis, Am. J. Ophthalmol. 160 (4) (2015) 663–668. [10] H.M. Tabery, Corneal surface changes in Thygeson's superficial punctate keratitis: a clinical and non-contact photomicrographic in vivo study in the human cornea, Eur. J. Ophthalmol. 14 (2) (2004) 85–93. [11] A.E. Braley, R.C. Alexander, Superficial punctate keratitis; isolation of a virus, AMA Arch. Ophthalmol. 50 (2) (1953) 147–154. [12] M.A. Lemp, R.W. Chambers Jr., J. Lundy, Viral isolate in superficial punctate keratitis, Arch. Ophthalmol. 91 (1) (1974) 8–10. [13] L.L. Cheng, A.L. Young, A.K. Wong, R.W. Law, D.S. Lam, In vivo confocal microscopy of Thygeson's superficial punctate keratitis, Clin. Exp. Ophthalmol. 32 (3) (2004) 325–327. [14] P.P. Connell, J. O'Reilly, S. Coughlan, L.M. Collum, W.J. Power, The role of common viral ocular pathogens in Thygeson's superficial punctate keratitis, Br. J. Ophthalmol. 91 (8) (2007) 1038–1041. [15] M. Hasanreisoglu, R. Avisar, Long-term topical cyclosporin A therapy in Thygeson's superficial punctate keratitis: a case report, Cases J 1 (1) (2008) 415. [16] T. Reinhard, R. Sundmacher, Topical cyclosporin A in Thygeson's superficial punctate keratitis, Graefes Arch. Clin. Exp. Ophthalmol. 237 (2) (1999) 109–112. [17] K. Wakui, S. Komoriya, E. Hayashi, et al., Corneal and epithelial dystrophies, Rinsho Ganka. 25 (1971) 1103–1123. [18] M.A. Quere, J. Diallo, J.P. Rogez, La kératite de Thygeson (à propos de 16 cas de kératite ponctuée superficielle), Bull. Soc. Ophtalmol. Fr. 68 (1968) 276–280. [19] I.R. Schwab, A.C. Vieira, Thygeson's superficial punctate keratitis, Cornea. Mosby (2010;) 1097–1100. [20] D.J. Tanzer, R.E. Smith, Superficial punctate keratitis of thygeson: the longest course on record? Cornea 18 (6) (1999) 729–730. [21] R.L. Abbott, R.K. Forster, Superficial punctate keratitis of Thygeson associated with scarring and Salzmann's nodular degeneration, Am. J. Ophthalmol. 87 (3) (1979) 296–298. [22] S.L. Watson, J. Hollingsworth, A.B. Tullo, Confocal microscopy of Thygeson's superficial punctate keratopathy, Cornea 22 (4) (2003) 294–299. [23] J. Li, J. Qiao, M. Cai, L. Wang, Laser confocal microscopy findings of Thygeson superficial punctate keratitis, Chin. Med. J .(Engl) 127 (3) (2014) 597–598. [24] N.S. Jabbur, T.P. O'Brien, Recurrence of keratitis after excimer laser keratectomy, J. Cataract Refract. Surg. 29 (1) (2003) 198–201. [25] K. Kawamoto, T. Chikama, N. Takahashi, T. Nishida, In vivo observation of Langerhans cells by laser confocal microscopy in Thygeson's superficial punctate keratitis, Mol. Vis. 15 (2009) 1456–1462. [26] A.B. Nesburn, G.H. Lowe 3rd, N.J. Lepoff, E. Maguen, Effect of topical trifluridine on Thygeson's superficial punctate keratitis, Ophthalmology 91 (10) (1984) 1188–1192. [27] R.E. Fintelmann, D.W. Vastine, M.M. Bloomer, T.P. Margolis, Thygeson superficial punctate keratitis and scarring, Cornea 31 (12) (2012) 1446–1448. [28] G. Gock, K. Ong, K. McClellan, A classical case of Thygeson's superficial punctate keratitis, Aust. N. Z. J. Ophthalmol. 23 (1) (1995) 76–77. [29] Thygeson's Superficial Punctate Keratitis, Grayson's Diseases of the Cornea, Mosby, 1997, pp. 323–329. [30] Thygeson's Superficial Punctate Keratitis. In: Leibowitz HM, Waring, G.O. ed, Corneal disorders: clinical diagnosis and management. Saunders, 1998; 460-461. [31] R. Sundmacher, M. Press, D. Neumann-Haefelin, U. Riede, Thygeson's superficial punctate keratitis (author's transl), Klin. Monbl. Augenheilkd. 170 (6) (1977) 908–916. [32] J.M. Del Castillo, J.B. Del Castillo, J. Garcia-Sanchez, Effect of topical cyclosporin A on Thygeson's superficial punctate keratitis, Doc. Ophthalmol. 93 (3) (1996) 193–198. [33] S.L. Forstot, P.S. Binder, Treatment of Thygeson's superficial punctate keratopathy with soft contact lenses, Am. J. Ophthalmol. 88 (2) (1979) 186–189. [34] D.B. Goldberg, D.J. Schanzlin, S.I. Brown, Management of Thygeson's superficial punctate keratitis, Am. J. Ophthalmol. 89 (1) (1980) 22–24. [35] S.W. Fite, J. Chodosh, Photorefractive keratectomy for myopia in the setting of Thygeson's superficial punctate keratitis, Cornea 20 (4) (2001) 425–426. [36] M.H. Goldstein, J.A. Feistmann, M.T. Bhatti, PRK-pTK as a treatment for a patient with Thygeson's superficial punctate keratopathy, CLAO J. 28 (4) (2002) 172–173. [37] M.V. Netto, M.R. Chalita, R.R. Krueger, Thygeson's superficial punctate keratitis recurrence after laser in situ keratomileusis, Am. J. Ophthalmol. 138 (3) (2004) 507–508. [38] K.Y. Seo, J.B. Lee, R.M. Jun, E.K. Kim, Recurrence of Thygeson's superficial punctate keratitis after photorefractive keratectomy, Cornea 21 (7) (2002) 736–737.
7.7. Excimer laser keratectomy There is no definitive role of excimer laser keratectomy in TSPK. Fite and Chodosh reported a case of TSPK treated successfully with rimexolone 1% ophthalmic suspension without exacerbation of corneal lesions [35]. The patient underwent photorefractive keratectomy (PRK) for myopia. A recurrence was noted outside the laser ablation zone. It was suggested that there be an inflammatory signal from the limbus or anterior stroma contributes to the pathogenesis of TSPK following laser refractive surgery [35]. A similar case of a patient diagnosed with TSPK underwent PRK combined with phototherapeutic keratectomy (PTK) without recurrence of symptoms during an eight-month follow-up [36]. Netto et al. reported a case of a patient previously diagnosed with TSPK who underwent PRK in the one eye and LASIK in the contralateral eye [37]. Recurrence was noted after LASIK ten months after ablation with corneal lesions manifesting within the central cornea. Similarly, Jabbur and O’Brien reported a case of recurrent bilateral TSPK in after LASIK [24]. Seo et al. reported a case of TSPK recurrence within the ablation zone of a patient after PRK [38]. 8. Complications Overall, TSPK itself is unlikely to cause significant complications and the visual prognosis is generally excellent regardless of the treatment modality [3,5,7]. However, topical corticosteroid, which is used widely in TSPK, can cause adverse effects such as glaucoma and cataracts. Regular monitoring is recommended during treatment with corticosteroid eye drops. 9. Conclusions Although TSPK has been described in literatures for over 60 years, its etiology remains uncertain and a definite curative treatment is unavailable. It is suggested that further research should be done to elucidate the exact underlying mechanism of the condition so that the most effective therapy can be used to target the disease directly. Identifying the possible triggers of TSPK and investigations on the genetic component can possibly provide a better understanding of the disease. Method of literature research PubMed and MEDLINE were queried with combinations not limited to the following search terms: Thygeson superficial punctate keratitis; epithelial keratitis; keratitis; epidemiology; complications; differential diagnosis; diagnosis; treatment and management. A review of the search results was performed and relevant articles were included. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Contents lists available at ScienceDirect
Journal of EuCornea journal homepage: www.elsevier.com/locate/xjec
Thygeson’s superficial punctate keratitis a
a
b
b,c
Tommy C.Y. Chan , Hatty H.T. Chau , Amar Krishna Bhat , Ken K. Nischal , Vishal Jhanji a b c
a,b,c,⁎
T
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Centre, Pittsburgh, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: Thygeson’s superficial punctate keratitis Epithelial keratitis Punctate keratitis Diagnosis Treatment
Thygeson's superficial punctate keratitis (TSPK) is a chronic, bilateral epithelial keratitis. Dr Philips Thygeson first reported TSPK in 1950. Although the etiology of TSPK remains unknown, it has been reported to be associated with viral and autoimmune pathologies. The disease course is characterized by exacerbations and remissions. The classical finding on slit lamp examination is the presence of distinctive coarse, raised, oval-shaped corneal epithelium lesions. Patients commonly present with ocular irritation and rarely with reduced visual acuity. Topical corticosteroids are the mainstay of treatment. Other less commonly used treatments included topical cyclosporine, contact lenses and corneal laser.
1. Introduction The term superficial punctate keratitis was first used to describe an epidemic keratoconjunctivitis in 1889 by Dr Ernst Fuchs, that was likely caused by a strain of adenovirus [1]. In 1950, Dr Phillips Thygeson, an ophthalmologist from California, reported 26 cases of distinctive punctate epithelial keratitis, which later came to be known as Thygeson's superficial punctate keratitis (TSPK) [2]. In 1961, Dr Thygeson described another 29 cases and proposed the diagnostic features of TSPK to differentiate TSPK from other forms of epithelial keratopathies [3]. These included, chronic bilateral punctate epithelial keratitis, long duration with remissions and exacerbations, eventual healing without scars, lack of response to antibiotics, and striking response to topical corticosteroids. Jones was the first to suggest in 1963 that superficial punctate keratitis should formally be called Thygeson's superficial punctate keratitis [4]. 2. Epidemiology TSPK affects patients of all age groups. Thygeson reported that the youngest patient was six years of age and the oldest was 62 years old [3]. In another case series of 27 patients, the youngest patient was 9 years old and the oldest was 53 years old [4]. In a 10-year review of 40 cases with TSPK, Nagra et al. reported a mean patient age of 28.7 years [5]. Overall, the onset of disease is likely to be in the second and third decades with a mean age of 29 years and an age range between 2.5 and 70 years [6]. There is no consensus on gender
⁎
predilection. The initial reports by Thygeson reported no sex predilection [3]. Nagra et al. [5] reported female dominance, whereas Tabbara et al. [7] reported a larger proportion of male patients with TSPK. 3. Pathophysiology The underlying etiology of TPSK remains elusive. Thygeson reported scant mononuclear cells on conjunctival scrapings and slightly abnormal epithelial cells with vacuolated cytoplasm, occasional neutrophils, mononuclear cells, degenerating epithelial cells and mucus on corneal scrapings [3]. Normal conjunctival flora was identified in bacterial cultures [8], whereas other studies also revealed no significant ocular pathogen [5,9,10]. Interestingly, TSPK has been associated with viral infection for a long time. Earlier studies suggested presence of virus particles in cases with superficial keratitis [11,12]. Thygeson suggested a viral etiology based on the absence of bacteria or other microorganisms, resistance of disease to sulfonamides and antibiotics, and presence of scanty mononuclear cell exudate on conjunctival scrapings [3]. Later studies, using tissue culture and electron microscopy, demonstrated that viral particles were the present in cornea [5,8,9,13–16]. Jones reported the presence of faint opacification of superficial corneal stroma underlying the epithelial opacities that are characteristic of TSPK [4]. The corneal stroma was transparent or translucent under retro illumination in these eyes suggesting associated corneal edema [4]. Subsequently, Thygeson suggested viral etiology of TSPK and distinguished it from superior limbic keratoconjunctivitis [3]. Later studies by Wakui et al. In 1971 could not identify any viral
Corresponding author at: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. E-mail address: [email protected] (V. Jhanji).
https://doi.org/10.1016/j.xjec.2019.11.001 Received 6 October 2019; Accepted 2 November 2019 Available online 26 November 2019 2452-4034/ © 2019 Published by Elsevier Inc. on behalf of European Society of Cornea & Ocular Surface Disease Specialists. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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particles in corneal epithelia under electron microscopy in eyes with epithelial dystrophies. The electron microscopy revealed cell destruction that was confined to one discrete area, which was different from the typical cell-to cell spread that is observed in herpes simplex keratitis [17]. In 2006, Connell et al. concluded the absence of herpes simplex virus, varicella zoster and adenovirus in epithelium of patient with TSPK using polymerase chain reaction [14]. Schirmer strip impressions were taken from the epithelium of eight patients with TSPK. The samples from patients with TSPK showed no evidence of the presence of herpes simplex virus 1, herpes simplex virus 2, varicella zoster virus or adenovirus. In terms of presentation, there are distinct differences between the clinical features of TSPK and those of herpes simplex virus, herpes zoster virus, adenovirus and Epstein-Barr virus. The corneal epithelial lesions in adenoviral infections can be similar have a subepithelial component and the course of the disease is not prolonged. Epstein-Barr virus can give rise to a punctate keratitis, which is usually self limiting and may have subepithelial involvement. Furthermore, the reports on efficacy of the antiviral treatment are variable. Tabery reported the present of abnormal subsurface cells (about 10 μm in diameter) in the corneal epithelium in TSPK [10]. These cells appeared individually, in small groups, or aggregated in larger lesions, which were identical to the coarse lesions seen under slit lamp, representing areas of cell necrosis [10]. In larger lesions, the surface epithelium contained debris. The morphology was suggestive of an ongoing action of an unknown agent targeted at the deeper epithelial layers [10]. Quere et al. suggested that TSPK was an allergic reaction, but the absence of eosinophils smears and ocular allergic symptoms made this hypothesis unlikely [6,18]. Certain features of TSPK imply an underlying immune mechanism. These include the present of lymphocytes in corneal epithelium, a chronic course with remissions and exacerbations and a marked effect of corticosteroids on the corneal lesions. A literature review by Darrell correlated TSPK with HLA-DR3, a histocompatibility antigen that can alter the immune response to exogenous or endogenous viral infections, yielding the prolonged course characteristic of the disease [8]. HLADR3 antigen is now known to be associated with several autoimmune disorders such as Addison's disease, Grave's disease, insulin-dependent diabetes mellitus and systemic lupus erythematosus.
Fig. 1. Slit lamp photograph showing a case of Thygeson's superficial punctate keratitis.
areas [7]. These opacities often have a raised centre that breaks through the epithelial surface. There may be tiny hair like mucus filaments. Individual lesions, ranging 1–50 in number, tend to accumulate centrally in the cornea. An average of 20 lesions can be observed per flareup [3,7,19]. During an exacerbation, these focal opacities become elevated above the superficial epithelium and stain with fluorescein and Rose Bengal [21]. During remissions, lesions may disappear completely unless there is subepithelial scarring [21]. These inactive, flat, intraepithelial lesions do not stain with fluorescein or Rose Bengal [6].
4. Clinical presentation
5. Diagnosis
Patients suffering from TSPK often have a long history of exacerbation and remission of symptoms. Both eyes are usually affected but the presentation in both eyes can be asymmetrical [5]. The most common clinical presentations include photophobia, blurred vision and ocular irritation [5]. Other symptoms include tearing, burning and foreign body sensation. Although uncommon, there could be trace conjunctival injection and mild corneal hypoesthesia [19]. In 1968, Quere et al. described the chronic course of TSPK in three stages [6]. The onset, lasting 1 to 2 weeks, was characterized by catarrhal inflammation, photophobia, and tearing. The developmental stage can last up to 8 months during which the signs of conjunctival inflammation disappear, leaving characteristic corneal epithelial lesions. The stage of regression lasts up to 3 years, during which the lesions become fewer in number and smaller until they vanish. Most attacks usually persist for 1 to 2 months and resolve spontaneously, followed by recurrence in 6 to 8 weeks [19]. The overall time course of the disease is variable [19]. The longest record of the disease was in a 59-year-old woman with a 40year history of TSPK, reported by Panzer and Smith in 1999 [20]. TSPK is characterized by a focal epithelial keratitis without significant conjunctival or stromal inflammation [3–5,7,8]. The classic corneal lesion in active TSPK is a conglomerate of coarse, oval shaped, slightly raised, whitish gray dotlike opacities, which stains minimally with fluorescein (Fig. 1) [3]. It was shown that the epithelial basement membrane and its hemidesmosomal attachments were intact in these
There is no specific diagnostic test for TSPK. Diagnosis is entirely based on clinical history, slit lamp examination findings, and therapeutic response to topical corticosteroids. The use of laser confocal microscopy in vivo may be helpful in diagnosis of TSPK [6]. Watson et al. reported the presence of irregular nerve fibres and haze in the corneal sub-epithelial nerve plexus in patients with TSPK [22]. Generalized haziness and areas of high reflectivity, microdots and reflective bodies in the anterior stroma, as well as keratocytes with reflective nuclei and cell bodies of irregular size and shape were also observed. The images suggest that wound healing and cell death occurs mainly in the anterior corneal stroma [22]. Another in vivo confocal microscopy study in 16 TSPK patients found that the most characteristic feature of TSPK was presence of highly reflective aggregations with cotton-like appearance in the basal epithelial cell layer and Bowman’s layer, which represents degenerated and necrotic epithelial cell debris [23]. Other isolated reports found clumps of focal desquamating epithelium and intraepithelial hyper-reflective linear lesions, loss of intercellular lesion, and enlargement of cell size in the superficial epithelial cells [11. 13, 24]. A recent study from Japan found an increase in the number of Langerhans cells in the basal cell layer of corneal epithelium and Bowman's layer [25]. The disappearance of Langerhans cells in the affected eyes treated by topical corticosteroid suggested underlying an inflammatory pathogenesis [25]. 6
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6. Differential diagnosis
staining corneal lesions [5].
The differential diagnoses of TSPK include infection conditions such as Staphylococcal blepharitis, Staphylococcal epithelial keratitis, Pneumococcal conjunctivitis, Herpes simplex keratitis and Acanthamoeba keratitis. Non-infective ocular abnormalities can mimic TSPK including vernal keratoconjunctivitis, keratoconjunctivitis sicca, neurotropic keratopathy, exposure keratopathy and epithelial basement membrane dystrophy.
7.4. Topical cyclosporine Cyclosporine is a popular steroid-sparing therapy in patients with TSPK. It has been reported to be effective when used as a first-line treatment for patients with TSPK [16,31]. In a prospective study used topical 2% cyclosporine in 52 eyes (42 adult and 10 children) with TSPK [16]. Cyclosporine eye drops were started 3 drops daily during the first month and was reduced to 1 drop every alternate day within 4 months and stopped after 6 months. Complete suppression of the typical epithelial and subepithelial opacities could be achieved in 71.5% of cases in adults and 40% in children during the course of the therapy. Recurrences were noted during tapering off or shortly after cessation of therapy. Overall, 31% of all adult eyes and 20% of all pediatric eyes seemed to have completely healed during the observation time [16]. In another study, Del Castillo et al. presented long-term results of the use of 2% topical cyclosporin in 8 patients with TSPK [32]. All the patients were treated with 2% cyclosporin four times a day for three months, and two times a day for one month before withdrawing therapy. After cyclosporine treatment, no corneal lesion was observed and the cornea remained clear after the follow-up period (12–25 months) [32]. Recent anecdotal evidence suggests that commercially available cyclosporine 0.05% may be employed instead of compounded cyclosporine eye drops especially in children with TSPK. Although topical cyclosporine has the advantage of fewer adverse effects compare with the use of topical corticosteroids [15,16,33], it has not been compared to corticosteroids in a controlled clinical trial for the treatment of TSPK. Topical cyclosporine is associated stinging at instillation that may compromise therapeutic compliance. Furthermore, the limited availability of topical cyclosporine and its associated cost has resulted in topical corticosteroids remaining the mainstay of therapy for patients with TSPK. Nagra et al. recommended initial management of TSPK with low-dose corticosteroid eye drops followed by use of stronger steroids and then topical cyclosporine in a stepwise approach [5]. The use of steroid-sparing agents may increase the likelihood of being able to complete taper off steroids without the development of a recurrence.
7. Treatment In previous studies, topical antibiotics were found to be ineffective while topical antivirals had inconsistent results in management of TSPK [7]. Topical corticosteroids are now the mainstay of treatment during acute exacerbation. Other topical medications can possibly be effective are cyclosporine and tacrolimus. Non-medical therapies such as contact lenses and excimer laser keratectomy are have also been investigated as alternative treatments for TSPK. 7.1. Topical antivirals Topical antiviral agents have been tried with unsatisfactory results. Nesburn et al. reported mild clinical improvement after application of topical trifluridine 1% eye drops in 5 out of 6 treated eyes [26]. However, the disease resolved more slowly compared with eyes treated with topical corticosteroids alone. Side effects of trifluridine included mild irritation and transient limbal follicular reaction. Some studies also suggested that idoxuridine, another topical anti-viral agent, causes persistent subepithelial ghost opacities and scarring in TSPK patients [7,11,27]. 7.2. Topical lubricants Topical lubricants are generally used for symptomatic relief in mild TSPK [28]. Preservative-free ocular lubricants can be prescribed with or without topical corticosteroid eye drops in all cases of TSPK. 7.3. Topical corticosteroids
7.5. Topical tacrolimus TSPK is known to respond dramatically to topical corticosteroids especially during acute exacerbations [5]. Nagra et al. managed most of their patients with weak topical corticosteroids like fluorometholone 0.1% and loteprednol 0.2% alone [5]. Others recommended using 0.12% prednisone or equivalent 2 to 3 times per day for a few days up to 2 weeks [29]. It was also suggested that acute episodes should be treated aggressively with topical corticosteroids and then tapered and discontinued over a 3 to 4 week interval [30]. The use of corticosteroids is warranted in patients who are disabled by pain or photophobia. Caution should be exercised regarding corticosteroids for an otherwise benign condition such as TSPK since they may prolong the time to resolution [7]. Topical corticosteroids can possibly alter the epithelial lesions and antiviral agents may increase the degree of subepithelial infiltration [7]. It is also important to distinguish TSPK from herpetic keratitis. The former would not respond to anti-virals whereas the latter would become worse with corticosteroid use. Nagra et al. commented that patients who are not treated with corticosteroids might have a shorter disease course although further studies are necessary to confirm this association. Long-term use of corticosteroids may be associated with serious complications such as glaucoma and cataract [5]. However, response to corticosteroids can be variable [31]. Some studies showed that steroid therapy could even prolong the course of the disease [3,7]. Tapering of corticosteroid eye drops is guided by clinical response and should be performed gradually over the course of months, with some patients requiring infrequent, regular use to control symptoms. Steroids may be tapered in asymptomatic patients with non-
Tacrolimus is another steroid-sparing treatment option in patients with TSPK. Similar to cyclosporine, it slower in inducing remission and relief of symptoms when compared to corticosteroid eye drops. In a retrospective case series, Marquezan et al. used 0.03% topical tacrolimus ointment in 14 patients with bilateral TSPK [9]. The ointment was applied twice daily in the lower fornix for the first 2 weeks, followed by nocturnal application. The treatment was effective for controlling TSPK without any local or systemic side effects. However, attempts to withdraw the medication resulted in recurrent disease [9]. Further studies are required to evaluate the role of tacrolimus with or without topical corticosteroid eye drops in long-term management of patients with TSPK. 7.6. Contact lenses Bandage soft contact lenses can be used for temporary symptomatic relief, in patients who are at risk for steroid-related complications or if the relatively slower-acting steroid sparing agents are used as initial therapy. Soft contacts lenses are an alternative to corticosteroid eye drops during acute exacerbation as they provide immediate symptomatic relief. However, they cannot alter the underlying corneal pathology. In 1977, Sundmacher et al. were the first to report the beneficial effect of hydrophilic soft contact lenses in the treatment of TSPK [31]. Three of his 10 patients achieved symptomatic relief from these lenses. Forstot and Binder confirmed the beneficial effect of bandage 7
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References
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Binder, Treatment of Thygeson's superficial punctate keratopathy with soft contact lenses, Am. J. Ophthalmol. 88 (2) (1979) 186–189. [34] D.B. Goldberg, D.J. Schanzlin, S.I. Brown, Management of Thygeson's superficial punctate keratitis, Am. J. Ophthalmol. 89 (1) (1980) 22–24. [35] S.W. Fite, J. Chodosh, Photorefractive keratectomy for myopia in the setting of Thygeson's superficial punctate keratitis, Cornea 20 (4) (2001) 425–426. [36] M.H. Goldstein, J.A. Feistmann, M.T. Bhatti, PRK-pTK as a treatment for a patient with Thygeson's superficial punctate keratopathy, CLAO J. 28 (4) (2002) 172–173. [37] M.V. Netto, M.R. Chalita, R.R. Krueger, Thygeson's superficial punctate keratitis recurrence after laser in situ keratomileusis, Am. J. Ophthalmol. 138 (3) (2004) 507–508. [38] K.Y. Seo, J.B. Lee, R.M. Jun, E.K. Kim, Recurrence of Thygeson's superficial punctate keratitis after photorefractive keratectomy, Cornea 21 (7) (2002) 736–737.
7.7. Excimer laser keratectomy There is no definitive role of excimer laser keratectomy in TSPK. Fite and Chodosh reported a case of TSPK treated successfully with rimexolone 1% ophthalmic suspension without exacerbation of corneal lesions [35]. The patient underwent photorefractive keratectomy (PRK) for myopia. A recurrence was noted outside the laser ablation zone. It was suggested that there be an inflammatory signal from the limbus or anterior stroma contributes to the pathogenesis of TSPK following laser refractive surgery [35]. A similar case of a patient diagnosed with TSPK underwent PRK combined with phototherapeutic keratectomy (PTK) without recurrence of symptoms during an eight-month follow-up [36]. Netto et al. reported a case of a patient previously diagnosed with TSPK who underwent PRK in the one eye and LASIK in the contralateral eye [37]. Recurrence was noted after LASIK ten months after ablation with corneal lesions manifesting within the central cornea. Similarly, Jabbur and O’Brien reported a case of recurrent bilateral TSPK in after LASIK [24]. Seo et al. reported a case of TSPK recurrence within the ablation zone of a patient after PRK [38]. 8. Complications Overall, TSPK itself is unlikely to cause significant complications and the visual prognosis is generally excellent regardless of the treatment modality [3,5,7]. However, topical corticosteroid, which is used widely in TSPK, can cause adverse effects such as glaucoma and cataracts. Regular monitoring is recommended during treatment with corticosteroid eye drops. 9. Conclusions Although TSPK has been described in literatures for over 60 years, its etiology remains uncertain and a definite curative treatment is unavailable. It is suggested that further research should be done to elucidate the exact underlying mechanism of the condition so that the most effective therapy can be used to target the disease directly. Identifying the possible triggers of TSPK and investigations on the genetic component can possibly provide a better understanding of the disease. Method of literature research PubMed and MEDLINE were queried with combinations not limited to the following search terms: Thygeson superficial punctate keratitis; epithelial keratitis; keratitis; epidemiology; complications; differential diagnosis; diagnosis; treatment and management. A review of the search results was performed and relevant articles were included. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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