Isabel M. Balderas
An otherwise healthy 23-year-old woman was referred to the retina clinic at New England Medical Center with complaints of decreasing vision for 4 months. When asked to describe her symptoms, she attributed the most trouble to night driving, where contrast sensitivity was sharply reduced. She was told she had some pigment changes in her retina 10 years prior during a routine eye examination, and she had no other known eye problems. She was a college student and denied tobacco or illicit drug use. Her grandmother had macular degeneration; the patient was not aware of any other ocular illnesses in her family. She was taking birth control pills, a daily multivitamin and vitamin C, and she was allergic to penicillin.
At her initial visit, the patient’s Snellen visual acuity was 20/40 in the right eye and 20/50 in the left eye, with no improvement on pinhole or manifest refraction. Both pupils were reactive with no relative afferent pupillary defect. Extraocular movements were full in both eyes. IOP was 16 mm Hg in both eyes. On external examination, the patient’s lids and anterior structures were otherwise normal.
On dilated fundus examination, a few vitreous cells were noted. The optic discs, retinal vessels and retinal periphery were normal. There was some cystoid macular edema evident on exam (not visible in color fundus photos, Figure 1). A fluorescein angiogram was obtained, which was essentially normal in both eyes, with no late leakage of dye in either eye (Figure 2). Optical coherence tomography clearly demonstrated the presence of cystoid macular edema in both eyes (Figure 3).
|Fundus photograph of both eyes (Figures 1a and 1b). Images: Witkin AJ |
|Late fluorescein angiographic images in both eyes. |
|OCT images of the macula in both eyes. Central circle thicknesses were 358 µm in the right eye and 380 µm in the left eye.|
What is your diagnosis?
Cystoid macular edema
The differential diagnosis for cystoid macular edema is extensive and includes postoperative, tractional, vascular, inherited, medication-induced, inflammatory and tumor-related causes.
Commonly reported operative causes include cataract surgery, penetrating keratoplasty and retinal detachment repair. Tractional causes include epiretinal membrane and vitreomacular traction. Vascular causes can include diabetic retinopathy and retinal vein obstructions, among others. Inherited causes include autosomal-dominant CME, X-linked retinoschisis and retinitis pigmentosa (including Goldmann-Favre syndrome). Medication-induced causes include topical epinephrine, oral nicotinic acid and prostaglandin analogues (latanoprost). Inflammatory causes include Eales disease, CMV retinitis, pars planitis, birdshot chorioretinopathy, sarcoidosis, scleritis, toxoplasmosis and Behçet’s disease. Tumor-related causes include choroidal melanoma, choroidal nevus, retinal hemangioma and choroidal hemangioma.
Most causes of CME may be explained by a breakdown of the blood-retina barrier at the level of the retinal vasculature, causing leakage of fluid into extracellular spaces within the retina that accumulates in the loosely arranged outer plexiform layer of Henle as well as the inner nuclear layer. Increased permeability of the retinal vasculature may be caused by a variety of mechanisms, typically involving diffusion of mediators such as prostaglandins, TGF-a, VEGF and IL-1.
In our patient, no late leakage of dye was noted, narrowing the differential diagnosis. Only a few causes of CME may not cause leakage on fluorescein angiogram (FA), and these include some types of retinitis pigmentosa, X-linked retinoschisis, nicotinic acid-induced CME, and some cases of epiretinal membrane and vitreomacular traction syndrome. X-linked retinoschisis may be ruled out because the patient is female. Epiretinal membrane and vitreomacular traction would be visualized on examination, on OCT or both. This leaves retinitis pigmentosa and nicotinic acid toxicity.
Retinitis pigmentosa (RP) includes a group of inherited retinal diseases with typical findings on examination. Key features include “bone-spicule” pigment clumping, thinning and atrophy of the retinal pigment epithelium in the mid- and far-peripheral retina, relative preservation of the macula until later in the disease, waxy pallor of the optic disc and attenuation of the retinal vessels. Typical symptoms of RP include decreased night vision and particularly prolonged dark adaptation times. As the disease progresses, patients may note decreased peripheral vision. Electroretinography (ERG) demonstrates reduced or delayed signal typically starting in childhood. CME secondary to RP may or may not be associated with leakage on FA. It has been hypothesized that in contrast to typical CME (caused by increased permeability of the retinal vasculature), RP may increase vascular permeability and fluid leakage through the retinal pigment epithelium. Carbonic anhydrase inhibitors have been shown to decrease macular edema in some cases of CME secondary to RP and perhaps work by stimulating the pumping mechanism of the retinal pigment epithelium. CME in RP is associated with the high prevalence of antiretinal autoantibodies in patients with RP, suggesting an inflammatory autoimmune-like process, which raises the possibility of treatment with anti-inflammatory agents such as steroids. However, CME in RP is notoriously difficult to treat.
Goldmann-Favre syndrome is an autosomal-recessive illness included in the RP group of diseases and is an example of an RP variant typically associated with CME without leakage on FA. Vitreous changes include liquefaction and fibrillar degeneration. Fundus changes include equatorial chorioretinal atrophy and pigment clumping.
Niacin-induced CME was initially described by Dr. Gass in 1973. Since then, a few case reports and case series have been published describing similar cases of niacin toxicity. In all cases, patients were taking therapeutic doses of niacin for reduction of serum cholesterol levels, ranging from 1.5 g to 6 g of niacin per day. CME secondary to therapeutic niacin typically does not cause leakage on FA and has been reported to occur 1 to 36 months after initiation of niacin therapy. In all cases, CME resolved after discontinuation of oral niacin. Recommended daily amounts of niacin are 14 mg to 18 mg, much lower than the levels of niacin reported to cause CME. The mechanism of CME production is unclear, although prostaglandin-induced Mueller cell cytotoxicity is frequently postulated.
If a patient is taking a medication that may induce CME, initial therapy should include stopping the inciting agent. Otherwise, the initial treatment for CME includes topical steroids and/or topical NSAIDs. If topical treatment fails, a sub-Tenon’s depot steroid injection may be attempted. Intravitreal steroid injection is a more invasive option for treatment of CME, and oral steroids may be used if the benefits are perceived to outweigh the systemic side effects. A steroid- releasing intravitreal implant may be considered if intravitreal steroid injections are shown to temporarily resolve or reduce macular edema. In some cases, particularly in CME secondary to RP, a carbonic anhydrase inhibitor such as acetazolamide may be tried. The use of systemic octreotide for CME has also been described in the literature. For cases in which a component of vitreomacular traction or epiretinal membrane is suspected, vitrectomy may be an option for treatment.
Because RP was included in the differential diagnosis of our patient, an ERG and visual field testing were ordered. Our patient was also initially started on topical prednisolone and Acular (ketorolac tromethamine 0.5%, Allergan) eye drops, each four times per day. The ERG was normal, with normal scotopic, photopic, and 30-hz flicker amplitudes and implicit times. Humphrey 24-2 visual fields were found to be reliable and full in both eyes. The absence of ERG or visual field abnormalities significantly reduced the suspicion of RP in this patient.
She returned 1 month later with no change in visual acuity or OCT thickness. On further questioning, the patient revealed that she had been taking some dietary supplements, including a cranberry supplement, and the possibility of niacin toxicity was considered. The patient was advised to stop all dietary supplements, and topical NSAIDs and prednisolone were stopped. The patient returned to the eye clinic twice over the next 3 months with no change in visual acuity or OCT thickness. Xibrom (bromfenac ophthalmic solution 0.09%, Ista Pharmaceuticals) eye drops were then started twice a day. Over the subsequent 4 months, visual acuity improved to 20/25 in both eyes. Because the patient’s vision improved, she is currently continuing bromfenac eye drops and is scheduled to return in 2 months for follow-up.
Currently, there is no clear cause of CME in this patient, and it may be considered a case of idiopathic CME. Because of the possibility of early RP without ERG findings, the patient should be monitored with dilated fundus examination and periodic ERG testing. Of particular note, our patient described having some pigment changes seen on fundus examination 10 years prior, and difficulty driving at night over the past 4 months, which raises the suspicion of an early inherited retinal disorder. If CME and blurred vision persist despite treatment with topical NSAIDs, sub-Tenon’s steroid injection may be offered. However, the absence of leakage on FA suggests that this case of CME may be caused by a non-inflammatory mechanism. A carbonic anhydrase inhibitor therefore may be a logical alternative for treatment of CME in this patient.
For more information:
- Andre J. Witkin, MD, and Jay S. Duker, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; Web site: www.neec.com.
- Edited by Isabel M. Balderas, MD, and Tom Hsu, MD. Drs. Balderas and Hsu can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; 617-636-4219; fax: 617-636-4866; Web site: www.neec.com. Drs. Balderas and Hsu have no direct financial interest in the products mentioned in this article, nor are they paid consultants for any companies mentioned.
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