Grand Rounds at the New England Eye Center

Chinese woman experiences bilateral decreased vision

Exam showed bilateral conjunctival injection, scleral thinning and corneal stromal involvement.

A 55-year-old Chinese woman with no known medical history was transferred to Tufts Medical Center with bilateral decreased vision. She had not seen a physician in 20 years. However, she reported recurrent episodes of redness in both eyes over the last 2 years that seemed to correlate with consuming shellfish. She treated these episodes with artificial tears. About 3 months ago, she started taking Chinese herbal medicine by mouth for “general inflammation.” Around that time, she noticed gradual loss of vision in the left eye; on presentation, she could only see shadows and movement. About 1 week prior, she also started to have loss of vision in the right eye, which prompted her to seek care.

She had no eye pain or light sensitivity with any of the above symptoms. She did not wear glasses or contacts. She had no history of eye trauma or surgery. On general review of systems, she had fatigue but no fevers, night sweats, weight loss, sinus disease, oral or gastrointestinal ulcers, joint pains or skin rash. She had no known family history of eye or systemic disease. She did not smoke cigarettes, drink alcohol or use illicit drugs.

Examination

Slit lamp photos of the right eye
Figure 1. Slit lamp photos of the right eye on initial presentation demonstrating superior stromal thinning and large epithelial defect with stromal haze.

Source: Christine L. Shen, MD, and Helen K. Wu, MD

Slit lamp photos of the left eye
Figure 2. Slit lamp photos of the left eye on initial presentation demonstrating diffuse scleral thinning, corneal neovascularization and corneal stromal thinning with central epithelial defect.

The patient’s visual acuity on initial presentation was light perception in the right eye and hand motion in the left eye. Pupils were symmetric with no afferent pupillary defect. IOP was 16 mm Hg and 20 mm Hg in the right and left eyes, respectively.

On anterior segment exam, the right eye was noted to have diffuse 1+ conjunctival injection and significant superior and inferior scleral thinning. There was a complete corneal epithelial defect with a surrounding white elevated scalloped plaque. Severe corneal stromal thinning extended 1 mm to 2 mm centrally from the limbus from 9 to 2 o’clock. The central cornea was hazy, so there was a poor view of the anterior chamber and iris (Figure 1). Similarly, in the left eye, there was diffuse 1+ conjunctival injection and diffuse scleral thinning (Figure 2). The cornea had diffuse stromal neovascularization and scarring obscuring the view of the anterior chamber. There was a central 2 mm by 3 mm white infiltrate with an overlying epithelial defect. Seidel test was negative bilaterally. On B-scan in both eyes, there was no vitreous cell, and the retina was flat.

On admission, she was noted on physical exam to be volume overloaded and had a serum creatinine level of 18. She was started on hemodialysis for end-stage renal disease (ESRD).

What is your diagnosis?

See answer on next page.

Bilateral decreased vision

Our patient was diagnosed with microscopic polyangiitis (MPA)-related autoimmune peripheral ulcerative keratitis (PUK). The differential for PUK includes autoimmune, infectious, and post-surgical or traumatic etiologies, as well as Mooren’s ulcer and Terrien’s marginal degeneration. In our patient, severe bilateral corneal thinning with overlying epithelial defect, concomitant scleritis and newly diagnosed ESRD made autoimmune PUK the most likely diagnosis. Laboratory studies were negative for rheumatoid arthritis, tuberculosis, syphilis and sarcoidosis. The patient had a mildly positive ANA of 1:80. Anti-PR3-ANCA antibody was not detected. Anti-MPO-ANCA antibody was initially mildly elevated but negative on repeat testing.

Renal biopsy was proposed to obtain pathologic confirmation of the diagnosis. However, due to the kidneys appearing small and fibrotic on ultrasound, it was thought that renal biopsy would be low yield and have high bleeding risk. Conjunctival biopsy was performed on the right superior perilimbal conjunctiva after the patient had received 3 days of intravenous corticosteroids. The result showed only chronic perivascular inflammation and no evidence of vasculitis.

Infectious workup included corneal cultures of both eyes that were negative for bacteria, fungus or Acanthamoeba. Corneal HSV PCR was negative in both eyes. Even so, based on the presence of anti-MPO antibody and severe ocular and renal involvement, the patient was treated for microscopic polyangiitis.

Discussion

Autoimmune PUK is most commonly associated with rheumatoid arthritis, followed by granulomatosis with polyangiitis. However, PUK has been reported in many other vasculitic and autoimmune diseases, including MPA, Churg-Strauss syndrome, polyarteritis nodosa, relapsing polychondritis, systemic lupus erythematosus, sarcoidosis, Sjögren’s syndrome and Behçet’s disease.

PUK develops due to the anatomy of the peripheral cornea and its vascular and lymphatic supply. Limbal vessels and subconjunctival lymphatics extend onto the peripheral cornea where collagen is tightly packed. Inflammation from autoimmune disease leads to chemotaxis of neutrophils to the cornea, where they release collagenases that cause corneal stromal melting. In addition, immune antibody-antigen complexes are deposited in the peripheral cornea, leading to the occlusion of limbal blood vessels. Without adequate blood supply, the peripheral cornea becomes necrotic.

PUK typically presents as a crescent-shaped area of corneal stromal thinning with an overlying epithelial defect along the limbus. The thinning progresses circumferentially and can eventually involve the central cornea, as in our patient. In one study, up to 64% of patients with autoimmune PUK had concomitant episcleritis or scleritis, sometimes with severe scleral thinning or necrosis. Scleral involvement is usually not present in other etiologies of PUK. Mooren’s ulcer can be distinguished from PUK as it is associated with parasitemia and hepatitis C virus, and only involves the cornea, often in the superior one-third. In addition, it is generally painful. Terrien’s marginal degeneration may present as superior corneal thinning, but the epithelium remains intact, in contrast to PUK.

Microscopic polyangiitis is diagnosed first with serum screening tests for anti-MPO antibodies and pANCA. In our patient, there was some diagnostic uncertainty because she had one positive and one negative anti-MPO result. However, one meta-analysis of seven studies showed that the combination of anti-MPO and pANCA testing has a sensitivity of 31.5% and a specificity of 99.4%. Thus, it was likely that the negative result was a false negative. Diagnosis is confirmed with biopsy of involved tissue, often of the skin, kidney or lung. Renal biopsy is invasive and was not an option for our patient. If there is ocular involvement, conjunctival biopsy should be considered early because it can spare the patient a potentially dangerous procedure. A positive biopsy shows immune-mediated vaso-occlusive disease. Surgical recession of the conjunctiva may also improve PUK by removing perilimbal vessels and lymphatics and the source of immune complex deposition.

Empiric treatment is recommended in the setting of severe disease if there is high clinical suspicion and should not be delayed if tissue biopsy cannot be obtained. Topical treatment for PUK includes collagenase inhibitors such as sodium citrate 10%, acetylcysteine 20% and medroxyprogesterone. However, most cases are too advanced for topical therapy alone. Systemic corticosteroids such as those given to our patient acutely treat inflammation. Transition to immunosuppressive therapy can halt the progression of disease. Cyclophosphamide, cyclosporine, methotrexate and rituximab can be used, but attention must be paid to adverse effects of these medications.

Slit lamp photographs of the right eye on follow-up
Figure 3. Slit lamp photographs of the right eye on follow-up at 3 months and 5 months. Visual acuities were 20/70 and 20/50, respectively.

Clinical course continued

Initially, the patient was given fortified topical tobramycin and vancomycin for a possible infectious corneal ulcer. Oral doxycycline was started to prevent further corneal melting. Once autoimmune disease was suspected, the fortified antibiotics were discontinued and switched to ofloxacin. The rheumatology service was consulted, and she was treated with Solu-Medrol (methylprednisolone, Pfizer) 1 g IV every day for 3 days. On discharge, she started prednisone 60 mg by mouth every day, which was tapered slowly. As an outpatient, she received two cycles of rituximab 1 g IV infusion spaced 2 weeks apart.

Slit lamp photographs of the left eye on follow-up
Figure 4. Slit lamp photographs of the left eye on follow-up at 3 months and 5 months. Visual acuities were 20/100 and counting fingers, respectively.

The epithelial defects closed 1 month after initial presentation. At 3 months, visual acuity was 20/70 in the right eye and 20/100 in the left. On exam, the right eye had improved scleral thinning but persistent peripheral corneal thinning 360°, worst superiorly (Figure 3). The left eye had improved scleral thinning as well, with diffuse anterior stromal neovascularization, stromal thinning and central haze (Figure 4). At 5 months, vision in the right eye had improved to 20/50 but remained poor in the left eye at counting fingers. The patient is scheduled to receive additional rituximab infusions. She remains dialysis dependent and has not developed further symptoms of MPA.

A 55-year-old Chinese woman with no known medical history was transferred to Tufts Medical Center with bilateral decreased vision. She had not seen a physician in 20 years. However, she reported recurrent episodes of redness in both eyes over the last 2 years that seemed to correlate with consuming shellfish. She treated these episodes with artificial tears. About 3 months ago, she started taking Chinese herbal medicine by mouth for “general inflammation.” Around that time, she noticed gradual loss of vision in the left eye; on presentation, she could only see shadows and movement. About 1 week prior, she also started to have loss of vision in the right eye, which prompted her to seek care.

She had no eye pain or light sensitivity with any of the above symptoms. She did not wear glasses or contacts. She had no history of eye trauma or surgery. On general review of systems, she had fatigue but no fevers, night sweats, weight loss, sinus disease, oral or gastrointestinal ulcers, joint pains or skin rash. She had no known family history of eye or systemic disease. She did not smoke cigarettes, drink alcohol or use illicit drugs.

Examination

Slit lamp photos of the right eye
Figure 1. Slit lamp photos of the right eye on initial presentation demonstrating superior stromal thinning and large epithelial defect with stromal haze.

Source: Christine L. Shen, MD, and Helen K. Wu, MD

Slit lamp photos of the left eye
Figure 2. Slit lamp photos of the left eye on initial presentation demonstrating diffuse scleral thinning, corneal neovascularization and corneal stromal thinning with central epithelial defect.

The patient’s visual acuity on initial presentation was light perception in the right eye and hand motion in the left eye. Pupils were symmetric with no afferent pupillary defect. IOP was 16 mm Hg and 20 mm Hg in the right and left eyes, respectively.

On anterior segment exam, the right eye was noted to have diffuse 1+ conjunctival injection and significant superior and inferior scleral thinning. There was a complete corneal epithelial defect with a surrounding white elevated scalloped plaque. Severe corneal stromal thinning extended 1 mm to 2 mm centrally from the limbus from 9 to 2 o’clock. The central cornea was hazy, so there was a poor view of the anterior chamber and iris (Figure 1). Similarly, in the left eye, there was diffuse 1+ conjunctival injection and diffuse scleral thinning (Figure 2). The cornea had diffuse stromal neovascularization and scarring obscuring the view of the anterior chamber. There was a central 2 mm by 3 mm white infiltrate with an overlying epithelial defect. Seidel test was negative bilaterally. On B-scan in both eyes, there was no vitreous cell, and the retina was flat.

On admission, she was noted on physical exam to be volume overloaded and had a serum creatinine level of 18. She was started on hemodialysis for end-stage renal disease (ESRD).

What is your diagnosis?

See answer on next page.

PAGE BREAK

Bilateral decreased vision

Our patient was diagnosed with microscopic polyangiitis (MPA)-related autoimmune peripheral ulcerative keratitis (PUK). The differential for PUK includes autoimmune, infectious, and post-surgical or traumatic etiologies, as well as Mooren’s ulcer and Terrien’s marginal degeneration. In our patient, severe bilateral corneal thinning with overlying epithelial defect, concomitant scleritis and newly diagnosed ESRD made autoimmune PUK the most likely diagnosis. Laboratory studies were negative for rheumatoid arthritis, tuberculosis, syphilis and sarcoidosis. The patient had a mildly positive ANA of 1:80. Anti-PR3-ANCA antibody was not detected. Anti-MPO-ANCA antibody was initially mildly elevated but negative on repeat testing.

Renal biopsy was proposed to obtain pathologic confirmation of the diagnosis. However, due to the kidneys appearing small and fibrotic on ultrasound, it was thought that renal biopsy would be low yield and have high bleeding risk. Conjunctival biopsy was performed on the right superior perilimbal conjunctiva after the patient had received 3 days of intravenous corticosteroids. The result showed only chronic perivascular inflammation and no evidence of vasculitis.

Infectious workup included corneal cultures of both eyes that were negative for bacteria, fungus or Acanthamoeba. Corneal HSV PCR was negative in both eyes. Even so, based on the presence of anti-MPO antibody and severe ocular and renal involvement, the patient was treated for microscopic polyangiitis.

Discussion

Autoimmune PUK is most commonly associated with rheumatoid arthritis, followed by granulomatosis with polyangiitis. However, PUK has been reported in many other vasculitic and autoimmune diseases, including MPA, Churg-Strauss syndrome, polyarteritis nodosa, relapsing polychondritis, systemic lupus erythematosus, sarcoidosis, Sjögren’s syndrome and Behçet’s disease.

PUK develops due to the anatomy of the peripheral cornea and its vascular and lymphatic supply. Limbal vessels and subconjunctival lymphatics extend onto the peripheral cornea where collagen is tightly packed. Inflammation from autoimmune disease leads to chemotaxis of neutrophils to the cornea, where they release collagenases that cause corneal stromal melting. In addition, immune antibody-antigen complexes are deposited in the peripheral cornea, leading to the occlusion of limbal blood vessels. Without adequate blood supply, the peripheral cornea becomes necrotic.

PUK typically presents as a crescent-shaped area of corneal stromal thinning with an overlying epithelial defect along the limbus. The thinning progresses circumferentially and can eventually involve the central cornea, as in our patient. In one study, up to 64% of patients with autoimmune PUK had concomitant episcleritis or scleritis, sometimes with severe scleral thinning or necrosis. Scleral involvement is usually not present in other etiologies of PUK. Mooren’s ulcer can be distinguished from PUK as it is associated with parasitemia and hepatitis C virus, and only involves the cornea, often in the superior one-third. In addition, it is generally painful. Terrien’s marginal degeneration may present as superior corneal thinning, but the epithelium remains intact, in contrast to PUK.

PAGE BREAK

Microscopic polyangiitis is diagnosed first with serum screening tests for anti-MPO antibodies and pANCA. In our patient, there was some diagnostic uncertainty because she had one positive and one negative anti-MPO result. However, one meta-analysis of seven studies showed that the combination of anti-MPO and pANCA testing has a sensitivity of 31.5% and a specificity of 99.4%. Thus, it was likely that the negative result was a false negative. Diagnosis is confirmed with biopsy of involved tissue, often of the skin, kidney or lung. Renal biopsy is invasive and was not an option for our patient. If there is ocular involvement, conjunctival biopsy should be considered early because it can spare the patient a potentially dangerous procedure. A positive biopsy shows immune-mediated vaso-occlusive disease. Surgical recession of the conjunctiva may also improve PUK by removing perilimbal vessels and lymphatics and the source of immune complex deposition.

Empiric treatment is recommended in the setting of severe disease if there is high clinical suspicion and should not be delayed if tissue biopsy cannot be obtained. Topical treatment for PUK includes collagenase inhibitors such as sodium citrate 10%, acetylcysteine 20% and medroxyprogesterone. However, most cases are too advanced for topical therapy alone. Systemic corticosteroids such as those given to our patient acutely treat inflammation. Transition to immunosuppressive therapy can halt the progression of disease. Cyclophosphamide, cyclosporine, methotrexate and rituximab can be used, but attention must be paid to adverse effects of these medications.

Slit lamp photographs of the right eye on follow-up
Figure 3. Slit lamp photographs of the right eye on follow-up at 3 months and 5 months. Visual acuities were 20/70 and 20/50, respectively.

Clinical course continued

Initially, the patient was given fortified topical tobramycin and vancomycin for a possible infectious corneal ulcer. Oral doxycycline was started to prevent further corneal melting. Once autoimmune disease was suspected, the fortified antibiotics were discontinued and switched to ofloxacin. The rheumatology service was consulted, and she was treated with Solu-Medrol (methylprednisolone, Pfizer) 1 g IV every day for 3 days. On discharge, she started prednisone 60 mg by mouth every day, which was tapered slowly. As an outpatient, she received two cycles of rituximab 1 g IV infusion spaced 2 weeks apart.

Slit lamp photographs of the left eye on follow-up
Figure 4. Slit lamp photographs of the left eye on follow-up at 3 months and 5 months. Visual acuities were 20/100 and counting fingers, respectively.

The epithelial defects closed 1 month after initial presentation. At 3 months, visual acuity was 20/70 in the right eye and 20/100 in the left. On exam, the right eye had improved scleral thinning but persistent peripheral corneal thinning 360°, worst superiorly (Figure 3). The left eye had improved scleral thinning as well, with diffuse anterior stromal neovascularization, stromal thinning and central haze (Figure 4). At 5 months, vision in the right eye had improved to 20/50 but remained poor in the left eye at counting fingers. The patient is scheduled to receive additional rituximab infusions. She remains dialysis dependent and has not developed further symptoms of MPA.

PAGE BREAK