Incontinentia pigmenti (IP), or Block-Sulzberger syndrome, is an X-linked dominant disease caused by a mutation on the IKBKG gene on chromosome Xq28 1. Endothelial cells are affected, which leads to vaso-occlusive phenomena in small and medium caliber vessels.1–5
Vascular occlusions in the central nervous system (CNS) occur in approximately 32% to 50% of the patients appearing from birth to 12 years of age.4 Seizures are the most common CNS manifestation.2,6–11 Retinal vasculature changes, CNS affection, and skin eruption all appear within a similar time frame.10 Retinal vascular occlusions can affect smaller vessels in the far periphery, or larger vessels more centrally.1,2,5,10,12–18
We present a patient with IP and bilateral retinal vascular occlusions detected by fluorescein angiography (FA). There was evidence of revascularization after treatment with anti-vascular endothelial growth factor (VEGF) therapy and angiography-guided laser.
A full-term, 7-week-old female with IP (partial deletion of the IKBKG gene 1) was sent for retinopathy screening by the primary care pediatrician. Mother and maternal grandmother both had a known diagnosis of IP with a history of cerebral infarcts. On examination of the patient, the skin was found to have vesicles as well as hyperpigmented and atrophic lesions. She grimaced to light stimulus in both eyes. An examination under anesthesia (EUA) showed a normal anterior segment in both eyes. Fundus examination showed abnormal vessels in the periphery bilaterally. The FA (RetCam 3; Natus Medical, Pleasanton, CA) exhibited incomplete retinal vascularization in both eyes with vascular leakage from the terminal vessels (Figure 1). Diode angiography-guided prophylactic laser photocoagulation to the avascular periphery was applied in both eyes.
Right eye (A) and left eye (B) color images at 7 weeks of age. Incomplete retinal vascularization on both eyes with vascular leakage on the terminal vessels (C, D).
Twenty-four days after the initial EUA, the patient was admitted to the hospital with enterovirus infection. A clinical diagnosis of a transient ischemic (TIA) event was made. A magnetic resonance imaging (MRI) was obtained 1 week later, suggesting cortical atrophy by prominence of the extra-axial spaces without evidence of an acute hemorrhagic or occlusive event.
Two weeks later (13 weeks old), an FA showed vessels filling only the posterior pole with neovascularization at the optic nerve. In the left eye, a superior temporal branch retinal artery occlusion was seen (Figure 2). Intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) (0.625 mg/0.05 mL) was injected into both eyes.
Thirteen weeks old. Right eye (A) color picture shows mildly visible posterior pole neovascularization and attenuated and occluded vessels. The left eye (B) color image shows same appearance of the vessels at the superior temporal arcade. The fluorescein angiography of the right eye (C) shows absence of vascular filling of both arteries and veins, as well as leakage from neovascularization at the optic nerve. The unfilled vessels on the superior temporal arcade are seen on the FA of the left eye (D). Laser scars are seen in the far periphery of both eyes (A–D).
At 16 weeks old, retinal vessels grew toward the periphery in both eyes (Figure 3). Again, the patient was treated with IVB (0.625 mg/0.05 mL), laser and sub-Tenon's triamcinolone (20 mg/0.1 mL). At 19 weeks old, only IVB (0.625 mg/0.05 mL) and triamcinolone were repeated in both eyes. IVB, angiography-guided laser, and sub-Tenon's triamcinolone (20 mg/0.1 mL) were repeated at 32 and 44 weeks of age in both eyes.
Sixteen weeks old. Leakage at the optic disc disappeared on the right eye (A). No major changes at this moment are observed on the left eye fluorescein angiography (B).
At the final office visit (19 months old), visual acuity was no light perception in the right eye and 6.5 cy/cm (Teller) in the left eye. Optic nerve atrophy appeared to be the cause of low vision of the right eye. The patient maintained normal intraocular pressure. The patient continued to reach normal developmental milestones and did not have any seizures.
To our knowledge, only four cases have been reported using anti-VEGF therapy for retinopathy in IP. One received IVB prior to surgery for a tractional retinal detachment. Two others received IVB to treat active neovascularization. In another case, ranibizumab was used for persistent peripheral neovascularization after laser photocoagulation.16–18
In contrast to these reports, our patient was primarily treated with a combination of IVB and angiography-guided laser for bilateral vascular occlusions. After treatment, revascularization was evidenced by serial FA imaging performed at each EUA. Without FA in our patient, these vascular occlusions would likely have been undiagnosed.
During the revascularization process, evidence of terminal “polyps of growth” in vessels was seen (Figure 4). This is contrary to what is seen in adults with central retinal artery obstruction (CRAO) secondary to an embolus. After CRAO in adults, restoration of the circulation occurs after anastomosis with the cilioretinal capillaries and the central retinal artery. The pattern of revascularization in our patient mimics what is seen in retinopathy of prematurity, where the peripheral retina is revascularized under the effect of anti-VEGF therapy.5,10,14,15,19–23
Nineteen weeks old. “Polyps of growth” and re-vascularization of the right eye are observed in the magnified fluorescein angiography of the right eye (A). Vascular growth of the vessels at the superior temporal arcade and more posterior line of laser are seen on the left eye (B).
The objective of treatment is to diminish the VEGF level by laser, cryotherapy, anti-VEGF and/or surgery. In this case, angiography-guided laser to the peripheral avascular retina and repetitive doses of IVB were used. Sub-Tenon's triamcinolone was attempted to diminish any inflammatory effect after laser.1,12,16–18,25–27
Typically in IP, CNS involvement correlates with the skin and retinal manifestations despite normal neuroimaging tests.2,4,8,10 In our patient, there was a clinical suggestion of a TIA with an MRI scan not showing an infarct. This was within the same time frame as skin and retinal involvement. In our patient, visual impairment likely occurred after the ischemic event to the macula and optic nerve.1,13,14,15
Different guidelines for follow-up are suggested in the literature. Recently Huang et al. reported a review suggesting follow-up guidelines based on a retinopathy grading system.28 Eye screening must be mandatory in every child diagnosed with IP, with or without neurological involvement, soon after birth. If no initial retinal abnormalities are found (grade 0), follow up every 3 to 6 months for 1 year, then semi-annual office visits through age 3 years, then annually for life are suggested. If peripheral avascular retina is found (grade 1) and left untreated, they must be followed up every 2 weeks for 3 months, and then monthly for 6 months. If grade 1 is treated, follow up is advised 6 to 8 weeks later. In both scenarios (treating or not grade 1), it is suggested to repeat FA at 3 months. If retinal neovascularization or retinal hemorrhages are found initially (grade 2), angiography guided treatment must be offered (individualized treatment), then the patient followed up every 6 to 8 weeks with FA. Based on our experience with IP, we recommend screening with FA on every visit for the first 18 months. If, at the moment of diagnosis, a retinal detachment is found (grade 3), surgery should be considered with or without IVB. If treatment yields to stabilization (stages 1 to 3), office examinations every 3 months until age 1 with FA are suggested. Semi-annual office visits until age 5, and annually thereafter, appear to be the best option.3,28,29
A limitation of this report is the relatively short period of follow-up. Prospective studies comparing different modalities of treatment for retinopathy in Incontinentia Pigmenti are needed.
In conclusion, we present a rare case of bilateral retinal vascular occlusions in a patient with genetically confirmed IP. This is the first case of demonstrable revascularization after vascular occlusion in IP using combined therapy with anti-VEGF injection and laser photocoagulation with good functional and anatomical results.
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