Progressive Cicatrizing Endotheliitis Associated with Leucocytoclastic Vasculitis and Crohn Disease

Corneal endotheliitis occurs when the innermost layer of the cornea, the endothelium, becomes inflamed.1 It is characterized by corneal inflammation involving the endothelium, a mild anterior chamber reaction, and keratic precipitates (KPs).1 Its etiology is not clear. An autoimmune mechanism was initially thought to be responsible, due to the presence of inflammatory cells, the bilateral nature of the disease, and its response to corticosteroids.1 However, a number of cases were documented in which corneal endotheliitis failed to respond to corticosteroids.1 Multiple studies have demonstrated the presence of diverse viridae in the aqueous humor of affected eyes, including herpes simplex (HSV), cytomegalovirus (CMV), varicella zoster (VZV), and the mumps virus.1,2 DNA has also been isolated from the aqueous humor of affected eyes in patients who were all immunocompetent.1,3 Thus, the pillars of treatment for most cases of endotheliitis now include a combination of systemic antivirals in addition to topical corticosteroids.1

Leucocytoclastic vasculitis (LCV) is a small vessel inflammatory disease, mediated by neutrophil-induced immune complex deposition. It most commonly manifests in the skin as palpable purpura of the lower extremities.4–7 Other features may include abdominal pain, arthralgias, fever, and other constitutional symptoms.6 Many causative agents have been linked to this disease, including medications, infections, malignancy, and several autoimmune diseases, including ulcerative colitis.6 Ocular manifestations of LCV are rare, but documented cases show a link between LCV and peripheral ulcerative keratitis, keratolysis, marginal keratitis, panuveitis, scleritis, and multifocal retinitis.4,5,8

Crohn disease is a type of inflammatory bowel disease (IBD) of unclear etiology, which is both chronic and recurrent in nature.9,10 Ocular manifestations of IBD occur in less than 10% of patients,9,10 and include uveitis, episcleritis, scleritis, keratopathy, and corneal epithelial and stromal inflammation.9,11,12 Corneal disease itself is not as common a manifestation in IBD, but can present as peripheral corneal opacifications and corneal thinning.12 While skin lesions in general are common in IBD, leucocytoclastic vasculitis specifically is a rare complication.13

This case documents an apparently new form of corneal endotheliitis associated with circumferential progression, increased intraocular pressure (IOP), and scarring. In addition, this seems to be the first case in the literature to associate corneal endotheliitis with Crohn disease and/or leucocytoclastic vasculitis. We have termed this bilateral peripheral progressive cicatrizing endotheliitis.

A 43-year-old Caucasian woman presented to our clinic in July 2003 with decreased vision and photophobia in the left eye. She had a previous ocular history of remote optic neuropathy and possible optic neuritis in the left eye, approximately 4 years prior to this visit. There was no history of contact lens use. Her medical history included an 11-year history of Crohn disease and a recent biopsy-proven diagnosis of active cutaneous leucocytoclastic vasculitis. Her LCV had initially been thought to be a reaction to the medication nifedipine, but discontinuation of the drug did not alleviate her rash. She reported a remote history of occasional cold sores.

Uncorrected visual acuity (UCVA) was 20/40 in the right eye and 20/200 in the left eye. IOP was 24 and 32 mmHg for the right and left eye, respectively. Pupillary reactions were normal. On slit-lamp examination, the left eye showed brownish granular keratic precipitates present at the level of the endothelium, affecting the temporal peripheral cornea in an arc from 12 to 7 o'clock. No intraocular inflammation, in the form of cells or flare, was seen. Dilated fundus exam was remarkable only for a pale left optic nerve head as a result of her prior optic neuropathy. Right eye examination was within normal limits.

A diagnosis was made of left corneal endotheliitis associated with elevated intraocular pressure (Figure 1). The patient was started on topical prednisolone acetate 1% hourly, homatropine 2% tid, and timolol maleate 0.5% qAM.

FIGURE 1. Peripheral progressive cicatrizing glaucomatous sclerosing endotheliitis. The lesion is seen advancing circumferentially and centrally.

Six days following the initiation of these drops, on July 16, vision in the left eye had improved substantially to 20/30. Such a substantial improvement in vision was thought to be due to decreased photophobia and pain, which allowed the patient to be more comfortable during testing. Nonetheless, despite the improvement in visual acuity, the area of endotheliitis and granular precipitates had begun to extend circumferentially both superiorly and inferiorly. Corneal sensation was decreased diffusely, thus treatment was altered at this point to cover for HSV as a possible cause of the endotheliitis. On July 18, she was started on oral acyclovir 400 mg 5 times daily. A week later, the endotheliitis temporarily stabilized, though the granular precipitates were starting to coalesce and become white in color, resembling a scar. There was no corneal edema overlying the area of endotheliitis, and pachymetry remained normal. The acyclovir was continued until October 1.

On August 13, systemic tests for syphilis, toxoplasmosis, Lyme disease, rheumatoid factor, ANA, ANCA, and ACE were all negative, and C-reactive protein (CRP) level was normal. Further blood tests on November 24 showed elevated platelet and gamma-glutamyltransferase (GGT) levels. HLA-B27 testing was never performed.

The condition waxed and waned over the next few months, and IOP was difficult to control. By January of 2004, 6 months after initial presentation, the right eye had become involved in the same way, with endotheliitis starting temporally and then extending superiorly and inferiorly. At this point, her condition was termed “bilateral peripheral progressive cicatrizing endotheliitis.” Also at this time, bilateral aqueous humor samples were taken, which were negative for HSV-1 and 2, CMV, Epstein-Barr virus (EBV), and hepatitis C. There were no acid-fast bacilli (AFB) isolates after 8 weeks of growth. The specimens were acellular with no evidence of malignancy. Specular microscopy was not done due to lack of availability.

By February 2004, vision continued to deteriorate to 20/200 in both eyes, with IOP remaining high at 37 mmHg bilaterally. No clear resolution was obtained with increased anti-glaucomatous therapy, or with topical and oral NSAIDs. Having ruled out infectious etiologies, oral prednisone 60 mg daily and azathioprine 150 mg daily were started in conjunction with an internist in March 2004. There had been no previous use of immunosuppression in this patient. One month later, the condition had significantly improved, with visual acuity returning to 20/40 bilaterally, with normal IOP.

Since then, and for the past 8 years, the patient's condition has remained stable on timolol maleate 0.5%, diclofenac ophthalmic and oral azathioprine 75 mg daily, in spite of a flare-up of Crohn disease in 2010. Attempts to taper the medications further have resulted in exacerbation of symptoms, but not progression. As of 2011, best-corrected visual acuity (BCVA) was 20/80 in the right eye and 20/63 in the left eye.

Corneal endotheliitis is characterized by keratic precipitates, corneal edema primarily involving the endothelium, and a mild anterior chamber reaction.1 Four clinical forms of this disease have been classified: linear, diffuse, disciform and sectorial.1 These classifications are based on the distribution of the KPs and the pattern of the overlying corneal stromal and epithelial edema when present.1 In this case, the KPs were granular and circumferential, the endothelium was the primary site involved, the stroma was mildly inflamed, and the epithelium was left intact.

The pattern herein described as bilateral peripheral progressive cicatrizing endotheliitis has not previously been described. This circumferential, progressively advancing cicatrizing process was concerning due to the lack of response to initial measures and the potential for permanent visual impairment if the visual axis became involved. After extensive systemic and intraocular testing ruled out any underlying infectious or malignant etiologies, it became reasonable to proceed with systemic immunosuppression with prednisone and azathioprine, which effectively stopped progression and stabilized the condition. However, the scarring has persisted in the endothelial periphery. The authors believe that it is reasonable to postulate that this type of endotheliitis was autoimmune in nature, and potentially related to either Crohn disease or LCV or both.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.