Ophthalmologic Presentations of Incontinentia Pigmenti

Abstract

Purpose: To characterize treatments and outcomes in incontinentia pigmenti. Methods: Cases of incontinentia pigmenti were consecutively identified from a retina practice. Inclusion criteria were patients with incontinentia pigmenti with at least 6 months of follow-up. All patients had a full ophthalmic examination, including imaging with widefield fundus photography and widefield fluorescein angiography. Eyes with areas of avascular retina were treated with laser photocoagulation (except for 1 eye with mild changes). Results: Thirty-six eyes of 18 patients with incontinentia pigmenti were included. The median age at presentation was 11 months. On presentation, 7 eyes had a visual acuity (VA) of 20/40 or better and 3 eyes had VA of 20/50 to 20/100. The remaining 26 eyes could fix and follow or had at least light perception (LP) VA given the patients’ young age. Of the 36 eyes, 20 (56%) had retinal involvement. The mean follow-up for treated patients was 6.9 years. Seventy-four percent of treated eyes required 1 laser session only. No eye that received laser treatment subsequently developed a retinal detachment. Of the 26 eyes with initial fix-and-follow or LP VA, 12 had Snellen or Allen VA testing at follow-up. Nine of these eyes had a follow-up VA of 20/40 or better. Of 10 eyes with a Snellen or Allen VA recorded at the initial visit, 9 had a final VA that was the same or improved. Conclusions: Laser photocoagulation was effective in treating patients with retinal manifestations of incontinentia pigmenti. Except for 1 eye, VA remained stable at the final follow-up.

Introduction

Incontinentia pigmenti is an X-linked, dominant disorder that manifests early in life. In most cases, it is caused by a deletion in the NEMO gene on the X chromosome. ¹ Except in rare instances of mosaicism, the vast majority of cases are lethal to males in utero, making it a disease that primarily affects females. ¹ As a result of abnormalities in cell apoptosis and chemotaxis of eosinophils, patients exhibit inflammation and vaso-occlusion of tissue throughout the body, including the skin, brain, retina, and teeth. ² Ocular manifestations have been reported to occur in 35% of patients and include retinal ischemia, neovascularization, retinal detachment (RD), optic nerve abnormalities, strabismus, and cataract. ³ Treatment of retinal ischemia and neovascularization in incontinentia pigmenti consists of peripheral ablative laser photocoagulation to reduce the risk for RD from fibrovascular proliferation ⁴ ; however, there is still controversy about its effectiveness in preventing RD.

Long-term outcomes in treated eyes and untreated eyes are still being characterized in the literature. Such outcomes include the length of disease-free follow-up in eyes without retinal findings on initial presentation and the need for retreatment in eyes with retinal findings. Eye examination guidelines for incontinentia pigmenti have also yet to be fully established, with various groups suggesting different frequencies for screening and follow-up. In the literature, the recommended follow-up frequencies for eyes with retinal involvement range from every 2 weeks for the first 3 months to monthly for the first 3 or 4 months, with less frequent examinations subsequently.^5,6 In young or uncooperative patients who require a detailed fundus examination, an examination under anesthesia (EUA) with widefield fluorescein examination is indicated, although the utility and frequency of EUA and fluorescein angiography (FA) have also been debated.

Further characterization of ocular disease in incontinentia pigmenti, in particular in the pediatric population, as well as the length of follow-up, treatments performed, and long-term visual outcomes may be beneficial in developing such guidelines.

Methods

This study was conducted in accordance with the Declaration of Helsinki. The collection and evaluation of all protected patient health information were performed in a US Health Insurance Portability and Accountability Act–compliant manner. Approval for the study was granted by the Institutional Review Board, Northwell Health (#21-0934), which did not require that informed consent be obtained.

In this consecutive retrospective descriptive case series, cases of incontinentia pigmenti were identified by diagnosis code from a retina subspecialty practice. The diagnosis of incontinentia pigmenti was made by genetic testing in all cases after patients were diagnosed with characteristic skin lesions. Inclusion criteria were patients of any age with incontinentia pigmenti and at least 6 months of follow-up. All patients had a full ophthalmic examination, and all were evaluated with multiple imaging modalities, including widefield fundus photography (Optos [Optos] or RetCam [Natus]) and widefield FA.

Eyes with areas of avascular retina were treated with ablative laser photocoagulation in a typical dense panretinal photocoagulation pattern, with care taken to treat the horizontal meridians less densely and less intensely to protect the long ciliary arteries and nerves. One eye with a mildly affected avascular peripheral retina temporally was observed without laser treatment. Laser photocoagulation for all pediatric patients was performed under general anesthesia; 1 patient who presented at the age of 23 years received laser treatment in the office. The patient age, initial visual acuity (VA), anterior examination findings, dilated fundus examination findings, treatments performed, need for retreatment, follow-up VA, and length of follow-up were recorded.

Results

Thirty-six eyes of 18 patients with incontinentia pigmenti were included in the study (Table 1). Two patients with less than 6 months of follow-up (absent from Table 1) were excluded from the study. Patients presenting to the practice ranged in age from 49 days to 23.6 years (mean, 4.6 years; median, 11 months). Seventeen patients were female, and 1 was male (with documented mosaicism).

Table 1.

Patient Characteristics, Examination Findings, Treatments Performed, Initial and Final Visual Acuity, and Time to Final Follow-up.

Patient	Age at Presentation	Eye	DFE Findings	Treatments Performed	Initial VA	Final VA	Optic Nerve Abnormalities	Strabismus	Time to Follow-up
1	25 mo (2.1 y)	OD	Fibrotic neovascularization elsewhere	PRP	F&F	20/25	None	None	9 mo
		OS	Fibrotic neovascularization elsewhere	PRP	F&F	20/20	None	None
2	2 mo	OD	WNL	None	F&F	F&F	None	None	44 mo
		OS	Noncystic tuft (no retinal involvement of IP)	None	F&F	F&F	None	None
3	47 mo (3.9 y)	OD	WNL	None	20/25	20/20	None	None	29 mo
		OS	Small area of peripheral avascular retina temporally, no NV, no hemorrhage, some round-ended vessels	PRP	20/20	20/20	None	None
4	4 mo	OD	WNL	None	F&F	20/20	None	None	48 mo
		OS	WNL	None	F&F	20/20	None	None
5	3 mo	OD	Fibrotic NV, venous tortuosity, peripheral avascular retina	PRP	F&F	20/70-2 PH 20/60-2	Trace temporal disc pallor	XT	134 mo
		OS	Peripheral avascular retina	PRP	F&F	20/20-1	None	None
6	18 mo (1.5 y)	OD	Peripheral avascular retina	PRP	F&F	F&F	None	None	20 mo
		OS	Peripheral avascular retina	PRP	F&F	F&F	None	None
7	6 mo	OD	WNL	None	F&F	20/20	None	None	187 mo
		OS	WNL	None	F&F	20/20	None	None
8	283 mo (23.6 y)	OD	Temporal NV, peripheral avascular retina, sclerotic vessels, partial PVD, lattice degeneration with atrophic hole	PRP, with barrier laser around lattice/hole	20/50	20/20	None	None	104 mo
		OS	Retinal pigment epithelium changes	None	20/50	20/25	None	None
9	10 mo	OD	Peripheral avascular retina	PRP	F&F	F&F	None	None	10 mo
		OS	Peripheral avascular retina	PRP	F&F	F&F	None	None
10	3 mo	OD	WNL	None	LP	LP	None	None	25 mo
		OS	WNL	None	LP	LP	None	None
11	160 mo (13.3 y)	OD	Peripheral avascular retina	PRP	20/20	20/20	None	None	119 mo
		OS	Peripheral avascular retina	PRP	20/20	20/20	None	None
12	2 mo	OD	WNL	None	F&F	F&F	Temporal rim sloping	None	12 mo
		OS	WNL	None	F&F	F&F	Temporal rim sloping	None
13	12 mo (1.0 y)	OD	Epiretinal membrane, preretinal fibrosis, superior peripheral avascular retina	PRP	F&F	CF 5ʹ	Pallor	XT	187 mo
		OS	Peripheral mild avascular retina temporally	None initially, then PRP later	F&F	20/20	None	None
14	176 mo (14.7 y)	OD	Temporal sclerotic vessels, temporal peripheral avascular retina, PVD	PRP	20/70	20/40	None	None	70 mo
		OS	Temporal sclerotic vessels, temporal peripheral avascular retina	PRP	20/25	20/25	None	None
15	2 mo	OD	WNL	None	F&F	F&F	None	None	29 mo
		OS	WNL	None	F&F	F&F	None	None
16	6 mo	OD	Peripheral avascular retina	PRP	F&F	20/30	None	XT	170 mo
		OS	Decreased foveal reflex, peripheral avascular retina	PRP	F&F	20/400	Pallor	XT
17	211 mo (17.6 y)	OD	Peripheral avascular retina	PRP	20/20	20/20	None	None	54 mo
		OS	Rhegmatogenous retinal detachment, peripheral avascular retina, and preretinal membranes	Vitrectomy, membrane peeling, scleral buckle, endolaser, silicone oil	20/20	20/80 PH 20/40	None	XT
18	18 mo (1.5 y)	OD	WNL	None	F&F	F&F	None	None	6 mo
		OS	WNL	None	F&F	F&F	None	None

Abbreviations: CF, counting fingers; DFE, dilated fundus examination; F&F, fixes and follows; IP, incontinentia pigmenti; LP, light perception; NV, neovascularization; PH, pinhole; PRP, panretinal photocoagulation; PVD, posterior vitreous detachment; VA, visual acuity; WNL, within normal limits; XT, exotropia.

The VA of 10 eyes could be reliably tested with a Snellen VA chart or Allen symbols on the day of presentation. Of these 10 eyes, 7 could be pinholed to 20/40 or better on initial examination and 3 had a VA between 20/50 and 20/100. The remaining 26 eyes could not be assessed with a Snellen chart or Allen symbols because of the young age of the patient. All 26 of these eyes could fix and follow or had at least light perception (LP) VA.

Of the 36 total eyes, 16 (44%) had no retinal involvement of incontinentia pigmenti as determined by a clinical examination and widefield imaging. In the remaining 20 eyes (56%), the most common retinal finding was an avascular peripheral retina with or without neovascularization in the periphery (Figure 1). Eleven of 18 patients had at least 1 eye affected with retinal findings of incontinentia pigmenti. Of these, 9 patients (82%) had bilateral and relatively symmetric presentations. Three eyes had optic disc pallor with a VA at the final follow-up of 20/60 or worse and associated exotropia. One patient, who initially presented as a teenager with no previous laser treatment after being lost to follow-up from another institution, had peripheral ischemia in both eyes and a macula-on combined tractional rhegmatogenous RD in 1 eye. This patient required vitrectomy, a scleral buckle, laser treatment, and silicone oil to repair the RD; the retina remained attached after the silicone oil was removed. The other eye was treated with laser photocoagulation at the time of the vitrectomy and has remained stable.

Figure 1.

Images of Patient 5, who had ischemia and neovascularization in the right eye. (A) Fundus photograph before treatment. (B) Fluorescein angiography before treatment shows area of avascular retina as well as neovascularization leakage.

For 18 (95%) of 19 eyes treated with a laser in the study, the decision to use laser treatment was based on the initial clinical examination and widefield FA. The remaining eye was noted to have a mild temporal peripheral avascular retina at the initial examination and was not treated at that time point. Fifteen months later, the eye was treated with a laser based on a follow-up examination that showed worsening findings.

The mean follow-up of the treated patients was 6.9 years (median, 5.8 years). The mean follow-up of the untreated eyes was 4.0 years (median, 2.4 years). In general, eyes with an avascular retina were treated with 1 laser session (Figure 2); however, 5 of the 19 eyes that were treated required an average of 1.4 additional laser treatments. The repeat laser procedures were principally performed to treat the retina at the posterior junction of previously lasered areas in lightly pigmented eyes, in which it was difficult to identify the junction of vascularized and nonvascularized retina (usually temporally). However, it is possible that additional laser treatment was required because of the progression of retinal ischemia in some cases. No eye that received laser treatment subsequently developed an RD.

Figure 2.

Images of Patient 5. (A) Fundus photograph after treatment. (B) Fluorescein angiography after treatment shows laser scars in the area of avascular retina.

In the 26 eyes with initial fix-and-follow or LP VA, the VA at the follow-up was 20/40 or better in 9 eyes, between 20/50 and 20/100 in 1 eye, and 20/100 or worse in 2 eyes. The VA in 14 eyes remained fix and follow or LP as a result of the patients’ young age (Figure 3). Of the 7 eyes with an initial VA of 20/40 or better, 6 had a VA at follow-up that was the same as or better than that at presentation; the other eye had slightly decreased VA, from an initial 20/20 to a final 20/40. Of the 3 eyes with an initial VA between 20/50 and 20/100, all had a follow-up VA that was better than that at presentation (Table 1).

Figure 3.

Visual outcomes at the final follow-up of patients with initial fix-and-follow (F&F) or light-perception (LP) visual acuity (VA) (n = 26).

Conclusions

Incontinentia pigmenti has a spectrum of retinal manifestations ranging from a normal retina to a severely avascular peripheral retina, neovascularization, and RD. Fifty-six percent of eyes in this series had ocular findings. The increased prevalence of ocular findings compared with a published rate of 35% ³ may be because every patient in our series initially had widefield FA to detect even the most subtle anatomic change from disease. This prevalence is similar to that in a large series from China by Peng et al, ⁷ in which 75 (61%) of 122 eyes of patients referred to a large academic medical center had ocular involvement. In that series, 18% of eyes had preproliferative retinal changes, including ischemia and vascular tortuosity. Another 10% had changes that included neovascularization, epiretinal membranes, and vitreous hemorrhages.

Of the 10 eyes in our series in which vision could be reliably tested at presentation, 7 had a VA of 20/40 or better. Of these 10 eyes, the VA remained stable or was improved at the final follow-up in all but 1 eye, which had a small decrease in vision. Cases of poor VA in patients with incontinentia pigmenti often involve significant abnormalities of the eye, including macular perfusion abnormalities, RD, dragging of the retina, phthisis, and severe myopia. ⁶ In our cohort, eyes with optic disc findings tended to have poorer vision and associated strabismus. All 3 patients in our study with optic disc pallor in 1 eye related to incontinentia pigmenti pathology had exotropia resulting from optic neuropathy and poor vision. Eyes with a measurable Snellen VA worse than 20/40 at the final follow-up tended to be more severely affected by the ocular manifestations of incontinentia pigmenti.

Treatment of the retinal manifestations of incontinentia pigmenti is centered on laser photocoagulation of the avascular peripheral retina, which prevents progression of preproliferative retinopathy into proliferative disease, causes regression of existing fibrovascular abnormalities, and prevents RD. ⁸ Recently, there has been increased use of off-label antivascular endothelial growth factor (anti-VEGF) injections in eyes with incontinentia pigmenti, although to our knowledge no study to date has compared the final visual outcomes of anti-VEGF injections with those of conventional laser therapy. ⁸

One session of laser photocoagulation was sufficient to treat peripheral ischemia in 74% of treated eyes in our study, with no eye requiring further treatment over the follow-up period, which had a mean of almost 7 years. In 95% of treated eyes, the decision to perform laser treatment was based on the initial clinical examination and widefield FA. Of note, laser photocoagulation in all eyes was performed under general anesthesia, with the exception of 1 patient who presented in her 20s. The ability to perform extensive photocoagulation under anesthesia may partially explain why a single session was sufficient for the vast majority of eyes. No eye that received laser treatment subsequently developed RD. The patient whose 1 eye developed an RD initially presented to the practice as a teenager and had no previous laser treatment.

In our study, the overall prevalence of ocular manifestations of incontinentia pigmenti was similar to that in the large series by Peng et al ⁷ ; however, there was an order of magnitude smaller incidence of RD in our patients (2.7% vs 27%). The significantly higher prevalence of RD in Peng et al’s study might have been the result of a lack of timely laser treatment given that 46% of patients with ocular involvement arrived at the study site with a previous misdiagnosis. The authors observed that an avascular retina naturally progressed to neovascularization and RD. In addition, 77% of patients in the Peng study had posterior segment abnormalities on the initial clinical examination, and although all patients were counseled to have FA, only 26% of patients complied. As a result, patients may have had subtle retinal abnormalities that were not detected, which may have contributed to the increased rate of RD.

Our finding that laser-treated eyes did not develop RD is in contrast to results in a longitudinal study with more than 9 years of follow-up by Chen et al, ⁹ in which 11 (22%) of 50 eyes with incontinentia pigmenti developed RD. It is not clear how early these patients were first examined with widefield FA. The current study found that tractional detachments in incontinentia pigmenti tended to occur in young children, and rhegmatogenous detachments tended to occur in adults (presumably as a result of untreated traction). Despite prophylactic laser ablation in 4 eyes of children younger than 2 years, 3 of these eyes subsequently developed tractional RD. Chen et al suggested that laser ablation may lead to contraction of fibrovascular tissue, increasing the risk for tractional detachment. Again, it is not evident how early these 4 patients were evaluated with widefield FA or how densely the laser was placed.

In our experience, similar to that of other groups,^3,4,10–12 laser ablation of an avascular retina causes regression of neovascularization, if present, and protects against subsequent RD. In a case series of 6 eyes of 3 patients with incontinentia pigmenti in Japan, 5 eyes were noted to have an extensively avascular retina without proliferative retinopathy. ⁴ The eye that did not have an extensively avascular retina had only minimal peripheral avascularity and mild foveal hypoplasia (seen on optical coherence tomography). All eyes in this series were evaluated with widefield FA, which confirmed the clinical examination findings and helped detect more subtle retinal changes that required laser treatment. Five eyes were promptly treated with laser photocoagulation. At the final follow-up after laser photocoagulation, none of the treated eyes developed fibrovascular proliferation, despite the severe avascularity at initial presentation. With the stabilization of retinopathy resulting from treatment, none of the eyes developed an RD. ⁴ The authors concluded that early widefield FA is important for guiding laser treatment of preproliferative retinal disease in incontinentia pigmenti and is critical in preventing the fibrovascular proliferation that leads to RD.

In a study of 38 eyes of 19 children with incontinentia pigmenti by Michel et al, ¹² 10 eyes (26%) were found to have retinal disease. If patients had abnormalities on the clinical retinal examination, they had FA, although it is not specified whether the angiography was widefield. In 2 cases, the initial clinical examination was normal, with retinal findings appearing on a subsequent examination. Because patients had FA only if lesions were noted on clinical examination, subtle abnormalities (that may have been picked up on widefield FA) may not have been appreciated on initial examination in these cases. All 10 eyes received 1 or 2 sessions of laser photocoagulation under anesthesia. Similar to our findings, at a median follow-up of 6 years, no eye developed an RD after laser photocoagulation. In Michel et al’s study, the patients were younger at presentation than in our series (median, 19 days vs 11 months). The similarly good outcomes in Michel et al’s study and our study indicate that laser photocoagulation is effective in preventing RD in patients over a wide age range at presentation.

O’Doherty et al ⁵ found retinal abnormalities on clinical examination in 6 eyes of 11 patients with incontinentia pigmenti, including 2 eyes with an RD. The authors treated 2 of these eyes with laser photocoagulation. In 1 eye, FA performed before laser treatment showed areas of severe peripheral ischemia and neovascularization that was not appreciated on indirect ophthalmoscopy alone. This case further illustrates the importance of performing early FA to identify subtle, nonclinically apparent, but potentially important retinal changes.

Our series shows that although eyes with incontinentia pigmenti can have severe retinal abnormalities, many patients can present to the retina specialist with relatively mild or no manifestations and good vision. On the other hand, patients with an untreated avascular retina can present with an RD that requires more serious surgical interventions. Early ablative laser treatment appears to be effective in preventing the most devastating outcome of RD in eyes with a peripheral avascular or neovascular retina. One session of laser treatment under general anesthesia was sufficient to treat the peripheral ischemia in 74% of eyes in this series. No laser-treated eyes required further intervention over a mean follow-up of 7 years, and none progressed to RD. In our experience with patients who have incontinentia pigmenti, vision remains generally stable (or improves) over many years of follow-up, in large part because of the effectiveness of early treatment with laser photoablation.

A strict framework for the ideal frequency of EUA and FA is difficult to establish, although we recommend a general algorithm as follows:

1. An initial EUA with scleral depression should be performed with widefield FA within a short period after presentation. Depending on the severity of disease, the patient can follow up in the office in 3 to 6 months.

2. Repeat widefield FA with an EUA can be performed, if needed, 6 to 12 months after the first EUA. If the retinal findings are stable, an examination can be performed in the office every 6 months, with widefield FA imaging approximately every 1 to 2 years in most cases until later in childhood.

Although oral FA using widefield fundus photography can be done in older children, we prefer performing a standard widefield fluorescein examination in a cooperative older child. If this is not possible, we recommend an EUA with widefield FA and laser treatment as needed. A dilated fundus examination and widefield FA of patients with incontinentia pigmenti is important for an early diagnosis of peripheral ischemia and for early treatment with ablative laser treatment to preserve functional vision into adulthood and minimize the risk for RD.