Central retinal artery occlusion (CRAO) is an ocular ischemic stroke that can result in profound vision loss. It has an average age of onset of 61 years, mainly due to risk factors that increase with age, such as obesity, hyperlipidemia, and carotid artery stenosis, which can increase the risk of thrombotic events.
Our case highlights a presentation of CRAO in a 15-year-old patient who had risk factors such as iron deficiency anemia, obstructive sleep apnea, a family history of thrombotic events, and a heterozygous mutation in the MTHFR (methylenetetrahydrofolate reductase) gene, which in combination possibly led to an early onset presentation.
Figure 1. Fundus photo, taken with a Phelcom Eyer portable fundus camera, of a 15-year-old male patient. The left eye (OS) shows retinal whitening, tortuous vessels, and a cherry red spot at the time of presentation, while the right eye (OD) depicts mild tortuosity of retinal vessels at the time of presentation.
Case Report
A 15-year-old male with a medical history of pancreatitis and mild, intermittent asthma presented for vision loss of the left eye. He began to experience darkening of his vision for 30- to 45-minute episodes 3 months prior to admission but did not come to the hospital due to transient improvement. Three days prior to admission, he noticed intermittent darkening of vision for 10- to 15-minute-long episodes occurring around 15 times per day. The morning of admission, he woke up with no vision in his left eye.
His family history was notable for his maternal grandmother having a stroke in her 30s and his mother having a history of recurrent deep vein thromboses. He does not have a family history of sickle cell disease. On initial exam, his best-corrected visual acuity was 20/20 in the right eye and light perception in the left eye. His slit lamp exam was otherwise unremarkable. On fundus examination, the left eye revealed a slightly pale optic disc, diffuse macular whitening with a cherry red spot, scattered sclerotic vessels with boxcarring, sluggish blood flow, arteriolar narrowing, and flat, scattered sclerotic vessels without evident atrophy. The right eye demonstrated mild vascular tortuosity and arteriolar narrowing (Figure 1). His symptoms and physical exam findings were consistent with CRAO.
An extensive workup for infectious, inflammatory, and hypercoagulable etiologies was largely unremarkable, including negative screenings for vasculitis, celiac disease, and common thrombophilia. Key findings were significant for anemia (hemoglobin level of 7.4 g/dL), marked thrombocytosis (platelet count of 933×10³/µL), and hyperhomocysteinemia (homocysteine level of 20.6 µmol/L). Genetic testing, performed due to the patient’s early presentation of CRAO, revealed 2 heterozygous variants in the MTHFR gene (C677T and A1298C).
The patient was started on brimonidine and timolol in the left eye. He was also started on aspirin due to initial concern for hypercoagulability and IV iron supplementation. The next day, the exam showed stable intraocular pressure (IOP), minimally reactive pupillary constriction, and a relative afferent pupillary defect (RAPD) in the left eye. He was discharged 2 days later.
One week later, he presented to the emergency department due to new flashes and floaters in his central vision. Fundus exam and scleral depressed exam was unremarkable for retinal tears or detachments. The left eye exam revealed a pale disc and macula, findings thought to be dot blot hemorrhages, retinal arterial macroaneurysms, or Roth spots temporally to the macula, with great pallor along the inferotemporal arcades extending to the macula. He was discharged after his symptoms resolved spontaneously. A repeat exam during his follow up appointment the next day showed a persistent RAPD and hand motion vision in the left eye (Figure 2).
Figure 2. Ocular coherence tomography (OCT) images of the left eye approximately 1 week after presentation demonstrate thinning and disorganization of retinal layers with minimal subretinal fluid, suggestive of progressive retinal atrophy from a vascular insult.
Discussion
Central retinal artery occlusion is an extremely rare condition in pediatric populations. CRAO is most strongly associated with ipsilateral carotid artery stenosis. Other etiologies include embolization from the heart, the aortic arch, or the great vessels. Risk factors include obesity, hypertension, tobacco use, hypercholesterolemia, and diabetes. Many of these risk factors are associated with progressive cardiovascular disease that manifests in adulthood. The mean age for admission due to CRAO is 66.8 years, with males being more affected than females.1 In pediatric patients, etiologies are more likely to be trauma, inherited thrombophilia, cardiac defects, or systemic illness.2-5
The MTHFR gene encodes an enzyme that is responsible for catalyzing the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is used in methionine synthase to generate methionine from homocysteine. Mutations in this gene can lead to the abnormal accumulation of homocysteine, resulting in homocysteinemia, which varies in severity depending on the extent of the mutation. The most common mutations are the C677T (p.Ala222Val) and A1298C (p.Glu429Ala).6 The patient had both of these heterozygous mutations, potentially leading to his elevated homocysteine level. The C677T polymorphism has specifically been linked to an increased risk of cardiovascular disease, and hyperhomocysteinemia is associated with hypercoagulability.6 Mechanisms driving increased thrombotic risk from elevated homocysteine include increased tissue factor expression, vascular injury from oxidative stress, and endothelial dysfunction, among other factors.7
CRAO has been linked to hyperhomocysteinemia in other cases. One case described a 7-week-old infant with CRAO who had a homozygous pathogenic variant in the CD320 gene, which encodes the transcobalamin receptor (TCblR). In this case, consanguinity likely contributed to the patient’s increased genetic risk profile.8 This mutation leads to impaired B12 uptake, reducing the cofactor needed for the conversion of homocysteine to methionine, ultimately causing hyperhomocysteinemia. Another case report identified a homozygous mutation in MTHFR, leading to elevated homocysteine levels.9 Cases also report the onset of symptoms after exercise in patients with genetic risk factors, although the relationship has not been explored. Other conditions associated with pediatric CRAO cases include elevated lipoprotein(a), IgA vasculitis, and disseminated intravascular coagulation.8,9
Management of Pediatric CRAO
Upon initial presentation, the workup should include a comprehensive ophthalmologic examination and a neurological examination. A thrombophilia workup is indicated if there is a high suspicion of hypercoagulability. In patients presenting with symptoms of giant cell arteritis, such as jaw claudication, inflammatory markers including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should also be ordered. If the patient is presenting within 4.5 hours of symptom onset, intravenous tissue plasminogen activator (tPA) can be considered to optimize vision. Intra-arterial tPA, administered directly to the ophthalmic circulation, can also be considered for delivering more targeted thrombolysis and reducing systemic effects. Conservative treatments include anterior chamber paracentesis, ocular massage, and topical agents that lower IOP. Secondary prevention is important in mitigating risk factors, such as dyslipidemia, obesity, obstructive sleep apnea, and hypertension.1
Conclusion
This case highlights a rare presentation of CRAO in a 15-year-old patient, substantially younger than the typical age at onset. The patient had multiple potential risk factors, including a family history of thrombosis, heterozygous MTHFR genevariants (C677T and A1298C) associated with hyperhomocysteinemia, obstructive sleep apnea, and iron deficiency anemia with reactive thrombocytosis. Together, these factors may have contributed to the development of CRAO at an unusually young age. This case underscores the importance of a comprehensive evaluation for underlying systemic and hypercoagulable conditions, with consideration of genetic testing in selected pediatric patients with CRAO. RP
References
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