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Preop LASIK exam reveals intraepithelial infiltrates
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A 23-year-old Hispanic man presented for a refractive surgery consultation. His medical and family histories were unremarkable and he was not taking medication.
The patient’s ocular history was positive for compound myopic astigmatism and occasional burning and foreign body sensation when he wore his soft contact lenses on a daily wear schedule. He changed his lenses every month and denied overwear. Unaided visual acuities were 20/counting fingers in each eye. Best-corrected acuity measured 20/20 in each eye. Refraction was -5.50 D -0.75 D x 120 OD and -5.75 D -0.50 D x 120 OS. Central cornea thickness measured 604 microns in the right eye and 621 microns in the left.
Goldmann tonometry revealed intraocular pressures of 17 mm Hg OD and 16 mm Hg OS. Pupil examination was negative for afferent defect, extraocular muscle motility was full and smooth, and his visual field was full to finger counting in both eyes. Slit lamp examination revealed normal lids and conjunctiva bilaterally.
The cornea revealed small, multiple, white-gray, intraepithelial infiltrates that minimally stained with fluorescein in both eyes. The anterior chamber was deep and quiet, and the iris was without defect in either eye. The dilated fundus examination was unremarkable.
The photograph demonstrates stellate, intraepithelial corneal infiltrates with minimal fluorescein staining. While small, coarse, superficial infiltrates without stromal involvement in a white and quiet eye is most indicative of Thygeson’s superficial punctate keratitis, alternative diagnoses include contact lens-related infiltrative keratitis, adenovirus and herpes simplex keratitis, herpes zoster nummular keratitis, keratitis sicca, topical drug toxicity and filamentary keratitis. However, what most aptly characterizes Thygeson’s superficial punctate keratitis is the intraepithelial location of the infiltrate with a slightly elevated appearance and associated superficial staining.
The cornea revealed small, multiple, white-gray, intraepithelial infiltrates that minimally stained with fluorescein in both eyes.
Images: DelGiodice M
Clinical characteristics
In 1950, Phillips Thygeson published case reports on a type of superficial punctate keratitis that he described as a transient, bilateral disease, having coarse corneal epithelial opacities and no associated stromal involvement. In 1961, Thygeson stated the five diagnostic features that he believed to be sufficient to differentiate this type of keratitis from all other types: the chronic bilateral nature of the keratitis, the long duration with remissions and exacerbations, the eventual healing without scars, the lack of response to antibiotics and the striking symptomatic response to corticosteroids (Darrell).
Today, this condition is known as Thygeson’s superficial punctate keratitis (TSPK). While all ages can be affected, TSPK usually occurs in the second to third decade of life. It has a chronic course with exacerbations and remissions over years to decades. Clinical characteristics include bilateral, multiple, whitish gray, intraepithelial corneal lesions with occasional anterior stromal edema and minimal to no conjunctival involvement. These lesions tend to accumulate centrally in the cornea, minimally stain with fluorescein and can be associated with symptoms of burning, irritation, foreign body sensation, tearing and photophobia. The visual acuity is typically good and infrequently causes transient moderate to severe vision loss. Corneal sensitivity testing is typically normal or may be slightly decreased but is never completely absent as in herpes simplex keratitis (Tabbara et al.).
Pathophysiology
While the exact etiology of TSPK is unclear, associations with viral infections such as adenovirus, herpes simplex virus (HSV), varicella zoster virus (VZV) and Epstein-Barr virus have been suggested by the morphology of the corneal lesions, the protracted course and the mononuclear cell infiltrate (Darrell, Lemp et al., Braley et al.). To date, Lemp and colleagues are the only investigators to recover VZV from lesions of a patient with TSPK.
Recently, studies using advanced DNA analysis with polymerase chain reaction (PCR) in patients with active TSPK revealed no association with HSV, VZV or adenovirus (Reinhard et al., Connell et al.). In addition, in vivo imaging of eyes affected by TSPK via confocal microscopy revealed both highly reflective microdots and refractive bodies below the cornea epithelium, in Bowman’s layer and in the anterior stroma, along with an increase in number and density of mature Langerhans cells (LCs). While LCs have been shown to invade the basal cell layer of the corneal epithelium in eyes infected with HSV, following contact lens wear and in healthy corneas, the cells found in TSPK were mature cells, capable of rapid response to pathogens and trauma of the cornea epithelium or stroma (Kobayashi et al.). These observations suggest that TSPK represents an immune response to an unknown inciting agent.
In addition, HLA-DR3, an antigen associated with immune response genes and multiple autoimmune disorders, has been linked to TSPK. It has been proposed that this antigen may alter the immune response of individuals with the disease, yielding the characteristic prolonged course. HLA-DR-associated diseases have no known causes, but a viral agent is strongly suggested (Darrell).
Medical management
Because of its availability and efficacy in managing both clinical signs and symptoms of the disease, topical corticosteroids remain the mainstay of treatment. More specifically, Nagra et al. have suggested initial management with fluorometholone 0.1% or a similar low-dose steroid, followed by the use of stronger steroids, and then extended-wear contact lenses or topical cyclosporine A in a stepwise approach. In these cases, steroids must be gradually tapered over the course of weeks to months, with some cases requiring weekly or biweekly administration.
Attefa Sultani
It is important to note that while corticosteroids have been shown to be effective, they are also known to be associated with high-risk complications including cataractogenesis and glaucoma. Furthermore, there is speculation that the natural course of the disease may be prolonged secondary to the introduction of these medications (Tanzer et al.). Therefore, in cases that are refractory to traditional therapy or those that require prolonged treatment, topical cyclosporine A should be considered a first-line therapy, with the advantage of fewer adverse effects compared with corticosteroids (Reinhard et al., Del Castillo et al., Hasanreisoglu et al.).
Soft contact lenses used on an extended-wear basis can be therapeutic. While potential complications of extended wear may exist, contact lenses improve symptoms by covering the elevated corneal lesions and nerves (Forstot et al., Goldberg et al.).
Nesburn et al. showed a positive outcome in the treatment of TSPK with topical antivirals. More specifically, trifluridine 1% was effective at favorably reducing the symptoms and signs of the disease, albeit more slowly than observed following corticosteroids. Thus, because trifluridine showed positive effects in treating TSPK, ganciclovir may have similar effects.
On the contrary, Connell et al. has shown that HSV, VZV and adenovirus are not present in the epithelium of patients with TSPK. Consequently, treating with topical antivirals is controversial.
Surgical management
Patients who are refractory to traditional therapy or wish to undergo correction of a refractive error may benefit from photorefractive keratectomy or phototherapeutic keratectomy (PRK) as opposed to LASIK (Goldstein et al., Netto et al.).
Michael DelGiodice
Lastly, while there are reports of both remission and recurrence after laser refractive surgery, there is no consensus with regard to alleviating the course of inflammation, including attempts of superficial keratectomy (Seo et al., Netto et al., Fite et al.).
TSPK represents an immune-mediated superficial corneal inflammation in response to an unknown inciting agent. Management is aimed at correct diagnosis followed by initial judicious use of corticosteroids. Because of the potential deleterious effects of chronic use of topical corticosteroids, other forms of therapy including extended-wear soft contact lenses and topical cyclosporine A should be considered as both adjunct and first-line treatment. While there is no consensus as to whether laser refractive surgery has an influence on the long-term nature of the disease, it is certainly not a contraindication to treatment and perhaps may be a barrier to recurrence.
This patient’s management
The patient in the above case responded well to a 3-week course of fluorometholone 0.1% with complete resolution in each eye. In light of anecdotal reports demonstrating resolution of the disease with PRK, all risks, benefits and options were discussed during the consultation, and the patient elected to proceed with this treatment.
At the 1-week follow-up, the bandage contact lenses were removed, and no evidence of reactivation was observed. The patient was advised to slowly taper the steroid over the course of 2 months. Regular monthly follow-up visits were recommended to measure IOP and observe for reactivation. .