Herpes stromal keratitis (HSK) is a prevalent and frequently vision-threatening disease associated with herpes simplex virus type 1 (HSV-1) infection. Diseases known to cause interstitial keratitis include: congenital syphilis, herpes simplex, herpes zoster, Epstein-Barr, tuberculosis and leprosy. Anterior segment evaluation of both eyes revealed marked ciliary injection with acute central keratitis, 2×2 mm in size and minimal stromal edema of adjacent cornea. Diagnosis is by slit-lamp examination and serologic tests to determine the cause. Furthermore, chemical burns are capable of damaging the corneal limbus, thereby leading to limbal stem cell deficiency.24 There are numerous potential causes of limbal stem cell deficiency, including inherited (eg, aniridia) and acquired (eg, trauma) etiologies.24,25 Disruption of the corneal limbus leads to corneal damage and provides an avenue for the extension of conjunctival epithelium and blood vessels into the cornea. Tectonic drape patch technique for nontraumatic corneal perforations in which there is tissue loss is a viable temporizing option when cyanoacrylate glue alone fails and when there is no corneal tissue or amniotic membrane available to close the wound. The child had a known history of disseminated varicella infection caused by SCID (fig 1).
On examination it was noted that he had a generalised vesicular rash throughout his body extending to his eyelid margins. The eyes were white with clear corneas and he was alert, fixing and following well with full extraocular eye movements. Both pupils were reactive to light with no afferent pupillary defect. The anterior chambers were unremarkable and the intraocular pressure with the Perkins tonometer was 16 mm Hg bilaterally. Examination of the fundus, including cup to disc ratio was normal. Alternatively, 3% vidarabine ointment (Vira A) may be used 5 times a day. methylprednisolone and cyclophosphamide were given and were followed by oral prednisolone and cyclophosphamide.
He suffered a number of exacerbations of the varicella infection and was treated with systemic aciclovir, foscarnet, and cidofovir. At 12 months of age he underwent allogeneic BMT from a one antigen mismatched unrelated donor following reduced intensity conditioning with fludarabine, melphalan and alemtuzumab. Engraftment was very rapid with neutrophils appearing by day 10. Before BMT the CD3+ CD4+ count was 0.04×109/l but 7 weeks after BMT the CD3+ CD4+ count was 0.47×109/l. Four weeks after BMT his mother noted bilateral corneal haze which was more marked on the left eye. He was reviewed in his isolation cubicle with a hand held slit lamp and Perkins tonometer and was found to have bilateral corneal stromal haze and corneal vascularisation (fig 2). There was no conjunctival injection, and his intraocular pressure was 13 mm Hg in each eye.
Both pupils were reactive to light. The lymphocyte count had recovered at this point to more than 1.0×109/l. An examination under anaesthesia was arranged and a diagnosis of interstitial keratitis without epithelial involvement was made. He was treated with intensive topical prednisolone acetate 1% (one drop every 2 hours) and cyclopentolate 1% twice daily to both eyes. Betaxolol 0.5% twice daily was prescribed prophylactically to prevent raised intraocular pressure which could exacerbate the corneal haze. The child was reviewed regularly and the stromal vascularisation was seen to regress. He was thus gradually weaned off the steroid drops to one drop daily and the cycloplegics were stopped.
Three months after BMT his mother reported a change in pupillary size in the right eye. A definite diagnosis of CS is based upon characteristic involvement of both the eye and inner ear, supported by the histologic abnormalities and exclusion of other conditions. A diagnosis of a right tonic pupil was made. At the most recent review, 6 months following BMT he had clear corneas centrally in both eyes with some persistent peripheral stromal vessels, and a right tonic pupil. Unaided visual acuity was 0.60 logMAR with both eyes using the Cardiff acuity test (Keeler Ltd, Windsor, UK). There was a left fixation preference and amblyopia therapy was commenced with occlusive patches. Currently, the child has an ongoing mild chronic graft versus host disease affecting the skin and intestine which is controlled with low dose systemic steroids.
His systemic medications also include aciclovir 120 mg four times daily. If keratitis develops in association with a childhood viral exanthem it is important to consider a number of possible infectious agents such as HSV, EBV, mumps, syphilis, Lyme disease, or tuberculosis in the differential diagnosis.4 In this setting, other documented complications in association with SCID include bilateral viral endophthalmitis,6 CMV retinitis, and optic neuritis.7 In this case the history and the physical findings were highly suggestive of the diagnosis and were confirmed by PCR testing. As far as we are aware this is the first case of varicella associated interstitial keratitis and a tonic pupil occurring in a child with SCID following BMT. The signs of early interstitial keratitis and a right tonic pupil were noted by the child’s mother about 4 weeks after the allogeneic bone marrow transplant. We believe that an immunological response to pre-existing varicella was responsible for the development of the eye signs. This signifies a positive response from a nascent immune system in the recipient—an example of immune recovery disease. There is experimental evidence to support this as it has been shown that whole lymphocyte and splenocyte transfer leads to herpes simplex keratitis in SCID mice.8 In other words SCID mice reconstituted with T lymphocytes of the CD4 + phenotype developed subsequent corneal lesions in relation to HSV infection.
Conversely Mercadal et al have shown that unreconstituted SCID mice remained lesion free when infected with HSV.8 This suggests that herpes simplex keratitis is a T cell mediated immunopathological reaction to virus in the cornea. In our case the corneal changes occurred following bone marrow reconstitution. Before BMT the CD3+ CD4+ count was 0.04×109/l but 7 weeks following BMT the CD3+ CD4+ count was 0.47×109/l. During the following six months, systemic prednisone was gradually reduced to 30 mg/d, cyclophosphamide was discontinued, and oral methotrexate 20 mg/week was given. We believe that our case illustrates a similar mechanism in the human model in relation to varicella infection. This child did suffer a graft versus host disease-like rash at the time of the development of the keratitis. While it is possible that the keratitis was purely Graft versus host disease this seems unlikely, given that there was no conjunctival involvement and that the graft versus host disease was extremely mild.
Furthermore, in this case the disseminated varicella infection preceded the BMT and formed the basis for identifying a severe immune deficiency in the child. It highlights the importance of frequent ophthalmic follow up in the immediate period following BMT as there is an increased risk of ocular disease.