From the Department of Ophthalmology (PSR, SS, JZ, MM, IEM), Bronx-Lebanon Hospital Center, Albert Einstein College of Medicine; and the Department of Pathology (PSR), Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
Presented at the New York Ophthalmological Society annual meeting, June 4, 2007, New York, New York.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Pearl S. Rosenbaum, MD, Department of Ophthalmology, Bronx-Lebanon Hospital Center, 1650 Selwyn Avenue, 1C, Bronx, NY 10457. E-mail: email@example.com
Ophthalmologists often initiate the systemic evaluation of vascular occlusive disease when patients present with retinal vascular occlusions. In the case reported herein, a 14-year-old girl presented with a branch retinal artery occlusion and, 1 month later, with acentral retinal vein occlusion involving the same eye. Systemic evaluation led to the diagnosis of hyperhomocystenemia, a treatable hypercoagulable disorder that should be included in the diagnostic evaluation of all patients with retinal vascular occlusive disorders. This case is also clinically unique because it may represent the phenomenon of ischemic preconditioning.
A 14-year-old girl complained of sudden, transient loss of vision in the left eye that started 2 days prior to presentation. The symptoms initially lasted for 5 minutes and resolved spontaneously. Ten minutes later, the visual loss recurred, this time without resolution. Medical and ocular histories, review of systems, and family and social histories were all negative.
Ophthalmologic examination revealed best-corrected visual acuities of 20/20 in the right eye and counting fingers at 5 feet in the left eye. There was an afferent pupillary defect on the left. Slit-lamp examination of the anterior segment was unremarkable and intraocular pressures were normal bilaterally.
Funduscopy and intravenous fluorescein angiography (Fig. 1) revealed an impending central retinal vein occlusion and an inferotemporal branch retinal artery occlusion of the left eye with retinal edema extending to the macula. Optical coherence tomography confirmed the retinal thickening and Humphrey visual field testing (Fig. 2) displayed a corresponding paracentral superior nerve fiber bundle defect. Digital massage was performed in an attempt to dislodge a possible embolus and aspirin therapy was prescribed.
Figure 1. (A) Fundus Photograph of the Left Eye Demonstrates Generalized Arteriolar Narrowing, Marked Venous Dilatation, and Tortuosity, as Well as a Superficial Juxtapapillary Hemorrhage Inferotemporally. There Is also an Inferotemporal Branch Retinal Artery Occlusion (arrow) with Retinal Ischemia and Edema Extending Along the Inferior Macula. (B) Fluorescein Angiography Demonstrates Delayed Arterial Filling Inferotemporally in the Left Eye. The Branch Retinal Artery Is now Reperfused (arrow).
Figure 2. Humphrey Visual Field Testing Demonstrates a Paracentral Superior Nerve Fiber Bundle Defect Consistent with the Patient’s Retinal Vascular Pathology.
Systemic evaluation, including carotid and cardiac echography, were normal. No oral or genital aphthous ulcers were noted. Complete laboratory testing including sickle prep, reactive plasma reagin, anti-nuclear antibodies, anti-neutrophil cytoplasmic antibody (proteinase-3 antibody and myeloperoxidase), anti-cardiolipin antibody, factor V Leiden, protein C and S function, anti-thrombin III, vitamin B12, and folate were all within normal limits. The serum homocysteine level was elevated at 25.4 micromol/L (normal < 10.4 micromol/L). The patient was referred to her primary care physician, who initiated vitamin B6 supplementation.
She was lost to ophthalmologic follow-up until 4 weeks later when she returned without any new symptoms. Funduscopy and intravenous fluorescein angiography showed a non-ischemic central retinal vein occlusion in the same eye (Fig. 3). Best-corrected visual acuity at this time measured 20/50 in the left eye. The patient was subsequently lost to follow-up.
Figure 3. (A) Follow-Up Fundus Photograph 1 Month After Initial Presentation Demonstrates Marked Venous Dilatation and Scattered Flame-Shaped Hemorrhages Along the Vascular Arcades, Consistent with Non-Ischemic Central Retinal Vein Occlusion. (B) Intravenous Fluorescein Angiography of the Left Eye Confirms Generalized Marked Dilatation of the Superior and Inferior Branches of the Central Retinal Vein and Scattered Nerve Fiber Layer Hemorrhages.
Branch retinal artery occlusions occur more commonly in the right eye in approximately 60% of cases, predominantly involving the temporal retina.1 Interestingly, the child described herein developed branch retinal artery occlusion in the left eye inferotemporally.
A review of the literature shows that systemic evaluation of patients with branch retinal artery occlusion must include cardiac and carotid ultrasonography because thromboembolism is the most common cause of branch retinal artery occlusion; carotid artery stenosis is associated with branch retinal artery occlusion in 20% of cases.2 In young individuals (younger than 30 years of age), branch retinal artery occlusion usually occurs in the clinical setting of cardiac valvular disease, atrial myxoma, vasculitis, sickle cell disease, ophthalmic migraine, oral contraceptive use, and hypercoagulable states.3
The child presented herein was found to have elevated serum homocysteine levels. Hyperhomocysteinemia is a known risk factor for retinal vascular occlusive disease. Although an exact mechanism for the relationship between hyperhomocysteinemia and vascular occlusive disease has not been fully elucidated, evidence suggests that homocysteine acts as a weak prothrombotic factor.4 Furthermore, animal model studies have demonstrated that oxidative stress and activation of pro-inflammatory factors may play a role in the pathogenesis of atherosclerosis in the setting of elevated homocysteine levels.5 Hyperhomocysteinemia has been associated with vitamin B12 or folate deficiency, smoking, renal failure, and the use of medications such as thiazide diuretics.6 In this particular case, we attribute both the branch retinal artery and the central retinal vein occlusions to hyperhomocysteinemia.
During protein digestion, amino acids, including methionine, are released. Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals use two different pathways to metabolize homocysteine. One pathway converts homocysteine back to methionine and is dependent on folic acid and vitamin B12. The other pathway converts homocysteine to the amino acid cysteine and requires vitamin B6-dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by at least three vitamins: folic acid, vitamin B12, and vitamin B6.7 Therapeutic strategies for treatment of hyperhomocysteinemia may thus focus on lowering serum homocysteine using folic acid, vitamin B12, and vitamin B6 supplementation.
Treatment of hyperhomocysteinemia with homocysteine-lowering vitamins is associated with a dramatic decrease in the incidence of recurrent venous thromboembolic events.8 Therefore, the clinical exclusion of hyperhomocysteinemia is indicated in patients presenting with retinal vascular occlusions, especially if they are younger than 40 years of age.
It is of particular interest that in this case the visual acuity in the affected eye recovered to at least 20/50 subsequent to branch retinal artery occlusion, as documented when the child returned 4 weeks later with a central retinal vein occlusion. It may be the case that the initial, transient loss of vision sustained 10 minutes prior to more prolonged branch retinal artery occlusion served as an ischemic preconditioning event, which has been shown to protect the retina against ischemic injury by diminishing apoptosis-related gene expression and by altering protein phosphorylation.9,10
To our knowledge, this is the youngest patient reported in the world literature with a branch retinal artery occlusion caused by hyperhomocysteinemia. The ophthalmologist should include measurement of serum homocysteine levels in the diagnostic evaluation of all patients with retinal vascular occlusive disease because the treatment of hyperhomocysteinemia may prevent significant ocular and systemic morbidity.
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- Sharma S, Brown G, Pater S, Creuss AF. Does a visible retinal embolus increase the likelihood of hemodynamically significant carotid artery stenosis in patients with retinal artery occlusion?Arch Ophthalmol. 1998;116:1602–1606.
- Kondamudi V, Reddy R, Kondamudi N, Harvey R, Delarosa M. Sudden painless unilateral vision loss caused by branch retinal artery occlusion: implications for the primary care physician. Am J Med Sci. 2004;327:44–46. doi:10.1097/00000441-200401000-00009 [CrossRef]
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- Oregon State University, Linus Pauling Institute. Vitamin B6. Available at: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB6.
- Sottilotta G, Oriana V, Latella C, et al. Role of hyperhomocysteinemia in retinal vascular occlusive disease. Clin Appl Thromb-Hemost. 2007;13:104–107. doi:10.1177/1076029606296423 [CrossRef]
- Roth S, Li B, Rosenbaum PS, et al. Preconditioning provides complete protection against retinal ischemic injury in rats. Invest Ophthalmol Vis Sci. 1998;39:775–785.
- Zhang C, Rosenbaum DM, Afzhal R, et al. Ischemic preconditioning attenuates apoptotic cell death in the rat retina. Invest Ophthalmol Vis Sci. 2002;43:3059–3066.