Thygeson Superficial Punctate Keratitis

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Article initiated by:
Adrián Mauricio Aldrete López, MD
All contributors:
Guillermo Mendoza Adam, MD, Alejandro Rodríguez-García, MD., Adrián Mauricio Aldrete López, MD, Vatinee Y. Bunya, MD, MSCE, Colleen Halfpenny, M.D., Augustine Hong, MD, Benjamin B. Bert, MD, FACS
Assigned editor:
Benjamin B. Bert, MD, FACS
Review:
Assigned status Update Pending
 by Benjamin B. Bert, MD, FACS on April 21, 2025.


Thygeson Superficial Punctate Keratitis
DiseasesDB
31288


Definition

Described in 1950 by Phillips Thygeson in a case report series, Thygeson superficial punctate keratitis (TSPK) is an insidious, chronic, and recurrent disorder, characterized by small and elevated oval corneal intraepithelial, whitish-gray opacities that extend to the entire anterior surface of the cornea of both eyes. Corneal lesions are usually distributed within the central pupillary area, with mild or absent conjunctival inflammation and no association with systemic disease.[1][2] Clinical reports and diagnostic imaging modalities such as in vivo confocal microscopy have shown that TSPK occurs within the anterior stroma and the epithelial layers,[3][4] and can result in anterior stromal scarring.[5]

Epidemiology

There are no specific data on the epidemiology of the disease. TSPK may affect both sexes, but a higher incidence has been reported in women.[1] The onset of the disease occurs between the second and third decades of life (median 29 years), but has been reported in people ranging from 2 1/2 to 70 years of age . It is probable that the prevalence and distribution of the disease is underestimated.

Pathophysiology

The pathophysiology of TSPK remains unknown, though both viral and immunologic mechanisms have been implicated. Adenovirus, herpes simplex virus, and varicella zoster virus have all been studies as possible causes of the disease. While Braley and Alexander said that the hypothesis that a virus may be responsible for TSPK is questionable,[6] in 1974, Lemp et al. isolated varicella zoster virus from the corneal surface of a 10-year-old boy with TSPK.[7] However, more recent studies using polymerase chain reaction testing were not able to detect varicella zoster virus from eyes with TSPK, providing doubts this virus is a causative agent.[8][9]

On the other hand, an immune-based etiology has also been proposed, since the presence of HLA-DR3, a class II major histocompatibility complex molecule associated with immune response genes and multiple autoimmune disorders (e.g., gluten enteropathy, Addison and Sjögren syndromes, systemic lupus erythematosus) has been identified in patients with TSPK. [10]

Clinical Manifestations

Typical TSPK lesion. Image courtesy of Dr. Amir A. Azari, Wills Eye Hospital

The disease is usually bilateral but may also be asymmetric. Patients frequently experience photophobia, tearing, burning, foreign body sensation, and irritation during exacerbations. Pain and blurry vision are also common.[10] Redness of the eyes or mucous secretion may be present. The course of the disease is variable; one episode can last from 1 to 2 months and remission can take as long as 6 weeks to occur.  Some reports suggest that after 4 years, TSPK tends not to recur in most cases without complications.[10] Nevertheless, there are reports of patients who have had TSPK for at least 20 years; in one case, the disease lasted for 41 years.[11]

TSPK shown on fluorescein staining. Image courtesy of Dr. Amir A. Azari, Wills Eye Hospital

The typical TSPK presentation is an elevated or flat round-oval shaped, gray-whitish lesion, occupying the central intraepithelial corneal area with minimal underlying stromal edema or inflammation. The acute lesion may stain minimally with fluorescein and may or may not stain with vital dyes (rose bengal or lissamine green).[12] Occasionally, the lesion is described as starry, and in the late stages, subepithelial fibrosis or an anterior stromal scar can be noticed. Usually, around 20 lesions are present in each eye, but up to 50 lesions have been reported. The lesions tend to disappear without leaving a trace in the course of 4–6 weeks. Corneal sensitivity is usually preserved or slightly diminished. The conjunctiva remains quiet, but in a few cases redness and filament formation may be seen.[12]

Pathology

The histopathology of TSPK is characterized by intra- and intercellular edema at the level of the corneal epithelium[13][4] and involvement of the subepithelial nerve plexus, Bowman’s membrane, and the anterior stroma. These changes are most severe in eyes with a longer TSPK duration.[2][4] Under confocal microscopy, keratocytes show highly reflective nuclei and cell bodies of irregular size, orientation, and shape. One study found that these changes were present under the intraepithelial lesions, and sometimes in other areas where the lesions were not present. In the latter case, the changes were thought to be related to the duration of the disease, as they were not seen in normal controls.[4] There is no evidence of the presence of inflammatory cells in the areas of corneal stroma adjacent to the intraepithelial lesions.[13] Using confocal microscopy, Kobayashi et al. reported 3 findings that were consistently present in all patients with TSPK: aggregates of highly reflective deposits with a starburst-like appearance that might correspond with punctate lesions at the superficial and basal epithelial cell layers; invasion of Langerhans cells at the basal epithelial layer; and anterior stromal haze.[3]

Differential Diagnosis

Based on the clinical course and manifestations of TSPK, particularly the typical corneal lesions, the disease should be easy to diagnose. However, there are several clinical entities that may resemble TSPK and should be considered in the differential diagnosis:

  1. Staphylococcal epithelial keratitis
  2. Pneumococcal conjunctivitis
  3. Seborrheic blepharitis
  4. Keratoconjunctivitis sicca (Sjögren syndrome)
  5. Neurotrophic keratitis
  6. Exposure keratitis
  7. Recurrent corneal erosion syndrome
  8. Map-dot-fingerprint dystrophy
  9. Viral keratitis
  10. Vernal keratoconjunctivitis
  11. Molluscum contagiosum
  12. Trauma

Treatment

Multiple therapeutic strategies have been tried over the years for the management of TSPK. Antibiotics have not shown to be effective so far.[14] Antivirals have shown mixed results; while mild improvements were reported with trifluridine therapy,[15] idoxuridine was found to cause persistent anterior stromal ghost opacities and scarring, and is therefore contraindicated for TSPK.[6][7][16][14]

Topical lubricants are only effective for partially relieving the clinical symptoms of TSPK.[17] However, topical corticosteroids are considered as mainstay treatment for TSPK because they are highly effective in controlling both the clinical signs and symptoms of the disease, although there have been many (unproven) speculations that they may prolong the clinical course of the disease.[12][14] An important point of corticosteroid treatment for TSPK is that in most cases, they must be tapered gradually over several months until an infrequent but regular dose is achieved (i.e., weekly or biweekly). The goal of corticosteroid treatment is to administer the minimum dosage and strength possible to control TSPK symptoms.[11][18]

Due to its therapeutic success and safety profile, topical cyclosporine (CsA) has been proposed as a first-line treatment for TSPK.[15][19][20] However, no controlled clinical trials in TSPK have directly compared CsA with corticosteroids, and one well-recognized inconvenience of topical CsA is stinging at instillation that may compromise therapeutic compliance.[19][20] Topical tacrolimus, given as both drops and ointment, has been used with some success.[21] [22]

Another alternative for severe TSPK is the use of extended-wear therapeutic soft contact lenses, although potential complications such as microbial keratitis may occur.[23] Contact lenses improve symptoms by covering the elevated corneal lesions and nerves, which are constantly in friction with the palpebral conjunctiva during blinking.[14][16]

There have been a few case reports of patients with TSPK being treated with excimer laser phototherapeutic keratectomy. There was only partial improvement of signs and symptoms, but high rates of corneal lesion recurrence were noted; therefore, it is not recommended for disease management.[24][25][26]

Summary

The benign course of TSPK requires the use of lubricant eyedrops and topical surface steroids, at low and infrequent doses for prolonged periods of time with close monitoring of intraocular pressure and cataract formation.[16] Topical CsA or tacrolimus can be used as an alternative treatment to corticosteroids, taking into account the possibility of intolerance, higher costs, and poor compliance issues.[19][20] In severe cases, extended-wear therapeutic contact lenses could be used for the relief of TSPK symptoms, with monitoring for corneal infections and intolerance.[24] After the diagnosis is established, the disease may last for many years with a waxing and waning clinical course, and a tendency to disappear without clinical sequelae.[5]

References

  1. ↑ 1.0 1.1 Thygeson P. Superficial punctate keratitis. JAMA. 1950;144(18):1544-1549.
  2. ↑ 2.0 2.1 Thyeson P. Further observations on superficial punctate keratitis. Arch Ophthalmol. 1962;66:158.
  3. ↑ 3.0 3.1 Kobayashi A, Yokogawa H, Sugiyama K. In vivo laser confocal microscopy findings of Thygeson superficial punctate keratitis. Cornea. 2011;30(6):675-680.
  4. ↑ 4.0 4.1 4.2 4.3 Watson SL, Hollingsworth J, Tullo AB. Confocal microscopy of Thygeson’s superficial punctate keratopathy. Cornea. 2003;22(4):294-299.
  5. ↑ 5.0 5.1 Fintelmann RE, Vastine DW, Bloomer MM, et al. Thygeson superficial punctate keratitis and scarring. Cornea. 2012;31(12):1446-1448.
  6. ↑ 6.0 6.1 Braley AEK, Alexander RC. Superficial punctate keratitis: isolation of a virus. Arch Ophthalmol. 1953;50(2):147-154.
  7. ↑ 7.0 7.1 Lemp MA, Chambers RW Jr, Lundy J. Viral isolation in superficial punctate keratitis. Arch Ophthalmol. 1974;91(1):8-10.
  8. ↑ Reinhard T, Roggendorf M, Fengler I, et al. PCR for varicella zoster virus genome negative in corneal epithelial cells of patients with Thygeson's superficial punctate keratitis. Eye (London). 2004;18(3):304-305.
  9. ↑ Connell PP, O'Reilly J, Coughlan S, et al. The role of common viral ocular pathogens in Thygeson's superficial punctate keratitis. Br J Ophthalmol. 2007;91(8):1038-1041.
  10. ↑ 10.0 10.1 10.2 Darrell RW. Thygeson's superficial punctate keratitis: natural history and association with HLA-DR3. Trans Am Ophthalmol Soc. 1981;79:486-516.
  11. ↑ 11.0 11.1 Tanzer DJ, Smith RE. Superficial punctate keratitis of Thygeson: the longest course on record? Cornea. 1999;18:729-730.
  12. ↑ 12.0 12.1 12.2 Thygeson P. Clinical and laboratory observation on superficial punctate keratitis. Am J Ophthalmol. 1966;61(5 pt 2):1344-1349.
  13. ↑ 13.0 13.1 Cheng L, Young A, Wong A, et al. In vivo confocal microscopy of Thygeson’s superficial punctate keratitis. Clin Exp Ophthalmol. 2004;32(3):325-327.
  14. ↑ 14.0 14.1 14.2 14.3 Tabbara KF, Ostler HB, Dawson C, et al. Thygeson's superficial punctate keratitis. Ophthalmology. 1981;88(1):75-77.
  15. ↑ 15.0 15.1 Nesburn AB, Lowe GH III, Lepoff NJ, et al. Effect of topical trifluridine on Thygeson’s superficial punctate keratitis. Ophthalmology. 1984;91(10):1188-1192.
  16. ↑ 16.0 16.1 16.2 Goldberg DB, Schanzlin DJ, Brown SI. Management of Thygeson's superficial punctate keratitis. Am J Ophthalmol. 1980;89(1):22-24.
  17. ↑ Gock G, Ong K, McClellan K. A classical case of Thygeson’s superficial punctate keratitis. Aust NZ J Ophthalmol. 1995;23(1):76-77.
  18. ↑ Duszak RS. Diagnosis and management of Thygeson’s superficial punctate keratitis. Optometry. 2007;78(7),333-338.
  19. ↑ 19.0 19.1 19.2 Reinhard T, Sundmacher R. Topical cyclosporin A in Thygeson's superficial punctate keratitis. Graefes Arch Clin Exp Ophthalmol. 1999;237(2):109-112.
  20. ↑ 20.0 20.1 20.2 Del Castillo JM, Del Castillo JB, Garcia-Sanchez J. Effect of topical cyclosporin A on Thygeson’s superficial punctate keratitis. Doc Ophthalmol. 1996;93(3):193-198.
  21. ↑ Shoughy SS, Tabbara KF. Topical tacrolimus in Thygeson superficial punctate keratitis. Cornea. 2020;39(6):742-744.
  22. ↑ Marquezan MC, Nascimento H, Vieira LA, et al. Effect of topical tacrolimus in the treatment of Thygeson's superficial punctate keratitis. Am J Ophthalmol. 2015;160(4):663-668.
  23. ↑ Forstot SL, Binder PS. Treatment of Thygeson's superficial punctate keratopathy with soft contact lenses. Am J Ophthalmol. 1979;88(2):186-189.
  24. ↑ 24.0 24.1 Goldstein MH, Feistmann JA, Bhatti MT. PRK-pTK as a treatment for a patient with Thygeson' superficial punctate keratopathy. CLAO J. 2002;28(4):172-173.
  25. ↑ Fite SW, Chodosh J. Photorefractive keratectomy for myopia in the setting of Thygeson's superficial punctate keratitis. Cornea. 2001;20(4):425-426.
  26. ↑ Netto MV, Chalita MR, Krueger RR. Thygeson's superficial punctate keratitis recurrence after laser in situ keratomileusis. Am J Ophthalmol. 2004;138(3):507-508.
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