Central retinal vein obstruction (CRVO) is rarely reported in neonates. Premature infants are at risk of thromboembolic episodes due to deranged hematological parameters. Thus, they can be predisposed to the occurrence of retinal vein occlusion. However, these events go undetected without dilated funduscopy. We report a rare event of CRVO that occurred in a preterm infant during laser therapy for retinopathy of prematurity (ROP).
In November 2012, we treated a 1-month-old female infant for high-risk prethreshold ROP. The antenatal history was normal, except the pregnancy was complicated by maternal type 1 diabetes. She was born of a non-consanguineous marriage at a gestational age of 35 weeks and with a birth weight of 1,600 grams. The neonatal course was eventful with respiratory distress needing oxygen, neonatal jaundice, one seizure episode, and clinical sepsis.
Anterior segment ocular examination was normal with no new iris vessels. Pupils were dilated using 2.5% phenlephrine and 1% tropicamide drops simultaneously three times at 10-minute intervals. Funduscopy revealed stage 3 ROP in posterior zone II with tortuous and dilated vessels in two quadrants. A ridge was present at the junction of the vascular and avascular retina with extraretinal fibrovascular proliferation and early retinal hemorrhage in both eyes (Figure 1).
Fundus in the right eye shows a ridge with neovascularization with hemorrhage (arrows and black dots) suggestive of stage 3 retinopathy of prematurity in zone II posterior high-risk prethreshold disease with pre-plus stage (arteriolar and venular tortuosity in two quadrants [thin arrows]).
After written informed consent was obtained, photocoagulation using an 810-µm diode indirect ophthalmoscope laser was started in the left eye to be followed by the right eye under topical anesthesia as per Institute protocol.1 After treating the avascular retina in the temporal half of the left eye, diffuse, dense, and extensive flame-shaped retinal hemorrhages suddenly appeared all over the fundus, associated with retinal vascular engorgement and a hyperemic disc (Figure 2). Acute onset CRVO was encountered. The etiology of the acute event was uncertain and various possibilities were considered. As first aid, the vital signs of the infant, including pulse rate, respiratory rate, body temperature, and oxygen saturation by pulse oximeter, were checked and found to be normal.
Fundus of the left eye shows hyperemic optic disc, extensive flame-shaped hemorrhages (thin arrows), and fresh laser photocoagulation marks temporally (short arrow).
Excessive globe pressure leading to raised intra-ocular pressure due to indentation while performing laser treatment was considered but ruled out because the pressure is applied intermittently and is no different from hundreds of similar treatments performed previously by the authors. Inadvertent excessive instillation of phenylephrine was ruled out after checking with nursing staff and also because of a normal pulse, respiratory rate, and temperature. Hematological abnormality with a thrombotic tendency was considered and detailed hematological evaluation was ordered. Laser treatment in the right eye was done uneventfully after discussion with the family.
Complete hemogram, bleeding time, clotting time, and renal and liver function tests were within normal range. Thrombophilia screening revealed a protein C deficiency of 22.80% (normal range: 70% to 140%), but negative factor V Leiden mutation. After written informed consent was obtained, intravitreal bevacizumab (0.6 mg in 0.03 mL) was administered to the left eye after 2 days. She was observed closely and 2 weeks after laser treatment the ROP completely regressed in the right eye. The left eye showed regressed ROP with resolving CRVO with foveal hemorrhage and few hemorrhages and skip areas in the temporal retina (Figures 3A–3B). After 1 month, the remaining nasal avascular retina and skip areas in the temporal area of the left eye underwent laser treatment to avoid any recurrence of ROP. At the last follow-up at 6 months, the child had regressed ROP bilaterally and resolved CRVO in the left eye with no retinal sequela noted clinically. Teller acuity at 6 months was normal for age at 20/360. The protein C levels had returned to normal at 90.8%.
(A) Fundus of the left eye shows normal optic disc with resolution of flame-shaped hemorrhages except for small foveal hemorrhage. (B) Fundus of the left eye shows a small blood clot with adjacent skip area devoid of laser marks (arrow) seen temporally.
Intravitreal bevacizumab (anti-vascular endothelial growth factor [VEGF]) therapy was given for acute CRVO with the following rationale: the patient had acute CRVO and, due to difficulty in monitoring this CRVO with adult parameters (eg, random applied polymorphic DNA, angle new vessels, neovascularization of the iris, macular edema, visual acuity and fields), it was decided to give anti-VEGF therapy as an immediate treatment. The anti-VEGF response was quick and substantial and indicates that the effects of secreted VEGF after acute CRVO can be promptly reversed by early anti-VEGF therapy. Although the ROP also regressed, we added more laser treatment later to ensure no recurrences.
Protein C is a vitamin K-dependent coagulation protein that serves a critical role in the regulation of thrombin. Protein C deficiency can be congenital or acquired. Prematurity, sepsis, respiratory distress, and maternal diabetes were all present in our case and are known risk factors for neonatal protein C deficiency.2 Patients with protein C deficiency have a decreased capacity to down-regulate the propagation of thrombin generation by factor Va and VIIIa once they have been activated by the small amounts of thrombin generated in the initiation phase of coagulation activation.2 Protein C deficiency predisposes to systemic thrombosis and is a recognized cause of CRVO in young adults.3 Neonatal protein C deficiencies have been reported to cause systemic thrombosis, especially in the renal and cerebral circulations.4,5 CRVO in a neonate is a rare entity with only a few cases reported.5 It may be going undetected due to lack of symptoms. The deranged thrombophilia profile should be investigated in a neonatal case of retinal vein thrombosis without obvious cause, especially with a history of risk factors. In our case, we believe that acquired protein C deficiency following systemic problems contributed to the acute episode of retinal venous occlusion in our patient.
Acquired protein C deficiency following systemic sepsis may have precipitated acute CRVO during laser therapy in this case. Intravitreal bevacizumab was used successfully to treat CRVO in our patient.
- Jalali S, Azad RV, Trehan HS, Dogra MR, Gopal L, Narendran V. Technical aspects of laser treatment for acute retinopathy of prematurity under topical anesthesia. Ind J Ophthalmol. 2010;58:505–519. doi:10.4103/0301-4738.71689 [CrossRef]
- Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA. Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Paediatr. 1991;119:793–798. doi:10.1016/S0022-3476(05)80305-1 [CrossRef]
- Tekeli O, Gursel E, Buyurgan H. Protein C, protein S and anti-thrombin III deficiencies in retinal vein occlusion. Acta Ophthalmol Scand. 1999;77:628–630. doi:10.1034/j.1600-0420.1999.770604.x [CrossRef]
- Kosch A, Kuwertz-Broking E, Heller C, Kurnik K, Schobess R, Nowak-Gottl U. Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up. Blood. 2004;104:1356–1360. doi:10.1182/blood-2004-01-0229 [CrossRef]
- Chen CY, Tsao PN, Young C, Peng SSF, Tsou KI. Bilateral central retinal vein occlusion with multiple intracerebral hemorrhage in a neonate. Pediatr Neurol. 2003;28:400–402. doi:10.1016/S0887-8994(02)00617-3 [CrossRef]