141Macular vasculopathy & incontinentia pigmenti

Correspondence and reprintrequests to:Morton F. Goldberg, M.D., FAOSThe Wilmer Eye Institute600 North Wolfe StreetBaltimore, MD 21287-9278USA

Acknowledgements: Supported in partby Core Grant No. 5P30EY01765-22from the National Eye Institute,Bethesda, MD; the Guerrieri Fund,Baltimore, MD; an unrestrictedresearch grant from Research toPrevent Blindness, Inc., New York,NY; and the Cara Dunne Fund forResearch and Rehabilitation ofChildhood Eye Diseases, Baltimore,MD.

Presented at the 124th AnnualMeeting of the AmericanOphthalmological Society, TheHomestead, Hot Springs, VA, USA.

Research reports

Ophthalmic Genetics 0167-6784/98/US$ 12.00

Ophthalmic Genetics – 1998, Vol. 19,No. 3, pp. 141-148© Æolus PressBuren (The Netherlands) 1998

Accepted 22 May 1998

Macular vasculopathy and its evolution inincontinentia pigmenti

Morton F. Goldberg

Wilmer Ophthalmological Institute, The Johns HopkinsUniversity School of Medicine and Hospital, Baltimore, MD,

USA

Abstract Purpose: To describe macular vasculopathy in inconti-nentia pigmenti. Methods: Twelve baby girls with incontinentia pig-menti were evaluated under general anesthesia by fluorescein angio-graphy of the macula. Nine eyes of nine patients had sufficient detailto allow evaluation of capillary changes. Angiography was initiated asearly as three months of age, and was repeated in seven eyes at 3-12month intervals. Changes in capillary patterns were identified. Results:Irregularly enlarged or distorted foveal avascular zones were noted inall nine maculas. Sparseness of the perifoveolar capillary bed was acharacteristic finding. Sequential macular angiography demonstratednonprogressive (stable) capillary closure in two eyes; progressive clo-sure was noted in another macula; progressive closure plus addition orreopening of macular capillaries occurred in three eyes; and centralretinal artery occlusion, with cherry red spot formation, was observedin one eye at 12 days of age. In addition, progressive tractional detach-ment of the macula, associated with bleeding pre-retinal neovascular-ization, occurred in two of these eyes, and progressive macular neovas-cularization also occurred in one eye. Conclusions: Macular ischemiais characteristic of incontinentia pigmenti and is often progressive. It isthe initiating event of a typical vasculopathy, characterized by capillaryremodelling and, occasionally, by neovascularization and tractionaldetachment of the retina.

Key words Incontinentia pigmenti; macula; blood vessels; retinaldetachment

Introduction Previous reports have emphasized the visually dis-abling consequences of both macular and peripheral retinal vascularabnormalities in incontinentia pigmenti, but sequential angiographicobservations have been limited to the retinal periphery.1,2 In an attemptto understand both the type and natural course of the macular vasculo-pathy in this disease, 12 baby girls with incontinentia pigmenti wereevaluated by fluorescein angiography. Seven of the girls had sequentialangiography, and the changes in macular capillary patterns are nowreported.

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M.F. Goldberg142

Methods Twelve baby girls had the diagnosis of incontinentia pig-menti established by a combination of positive family history (an un-equivocally affected female in an antecedent generation), characteristiccutaneous findings, and/or results of skin biopsy. Approximately twelveadditional older children and adults were excluded from this study be-cause of presumptive stability in their retinal vascular trees. Because ofthe risk of pre-retinal neovascularization in the fundus periphery1,2 ininfants with incontinentia pigmenti, general anesthesia on one or moreoccasions was utilized to permit performance of fluorescein angiographyand angioscopy of the peripheral retina. At the same time, fluoresceinangiography of the macula was carried out, and analysis of capillaryabnormalities was performed through the use of magnified angiograms.None of the babies was premature. The age range was 3 to 16 monthsat the time of the initial angiogram, and the longest angiographic fol-low-up studies were obtained 24 months thereafter.

Results Nine eyes of nine babies had angiographic detail that wassufficient for evaluation of capillary changes in the macula; three of the12 babies did not and are not included here. Seven of the nine eyes hadfollow-up angiography performed at 3-12 month intervals, and allshowed enough photographic resolution to allow comparative analysisof perfusion patterns at both the start and the end of the observationperiods.

Irregularly enlarged or distorted foveal avascular zones (FAZ) wereangiographically present in all nine eyes; a normal FAZ was observedin none of these eyes (Figs 1-4). Sparseness of the perifoveal capillarybed was a characteristic finding. Enlargement of the FAZ was due toperifoveal closure of capillaries in all instances. In two eyes, the distor-tion was accompanied by vessels traversing the center of the macula,thereby eliminating the normal avascularity of this region. Angiogramsof these two eyes have been reported previously.2

Nonprogressive (i.e., stable for the length of the follow-up period; upto 24 months in duration) closure of perifoveal capillaries was observedin two eyes (Figs 3A,B and 4A-C); while progressive closure of capil-laries over a six-month period was noted in another (Fig. 5A-D).

Progressive closure of perifoveal capillaries, plus addition or re-open-ing (it was impossible to distinguish between these two phenomena) ofother perifoveal capillaries, occurred in three eyes. These different eventsoccurred during the same time interval (Figs 6A,B and 7C-F) and weredetected in the 3-4-month follow-up angiograms. In the early post-occlusion period, cloudy-grey swelling of the macula was seen (Fig.7A,B).

Progressive tractional detachment of the macula occurred in two eyes.These detachments were associated with bleeding pre-retinal neovascu-larization, which led to pre-retinal scar tissue. Progressive macularneovascularization occurred in one eye and central retinal artery occlu-sion, with cherry-red spot formation, was observed in one eye at 12days of age. Some of these findings have been reported previously.1-4

Discussion These results expand upon ophthalmoscopic and an-giographic observations made previously in incontinentia pigmenti.1-4

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143Macular vasculopathy & incontinentia pigmenti

As a result of the follow-up angiography described herein, new obser-vations of abnormal vascular perfusion of the macula can now be re-ported. They include the following: stability of some capillary closures(at least for the observational period of up to 24 months); progressiveclosure of other perifoveal capillaries; and progressive closure pluseither addition or reopening of nearby perifoveal capillaries in the samemacula. In some eyes, the closure of certain capillaries occurred duringthe same time interval when reopening or addition of other capillarieswas occurring in portions of the same macula located a short distanceaway. These progressive changes in the pattern of perfusion can beinterpreted as remodelling of the capillary bed subsequent to the initi-ating ischemic events. They are analogous to similar events followingnonperfusion in the fundus periphery.1 Indeed, peripheral vascular ab-normalities, including nonperfusion, remodelling, or neovascularization,were observed in all eyes having vascular abnormalities in the macula.

Fig. 1. Fluorescein angiogram of leftmacula of 15-month-old girl; earlyA-V phase. Arrows show sparsecapillary bed and incompleteperfusion of innermost ring ofcapillaries around foveal avascularzone (FAZ), resulting in theappearance of an enlarged andirregular FAZ.

Fig. 2. Fluorescein angiogram of leftmacula of 7-month-old girl; early A-Vphase. Arrows show poorly perfusedinnermost capillary ring of FAZ.Several capillaries (e.g., @ 9 and 3o’clock borders of FAZ) appear to benonperfused.

Fig. 3. (A) Fluorescein angiogram ofleft macula of 6½-month-old girldemonstrates passage of perfusedvessels through FAZ. Arrows areplaced similarly in B. (B) Twenty-fourmonths after photo in A, there is nosubstantive change in the perfusionpattern.

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M.F. Goldberg144

Similar pathogeneses probably account for both peripheral and macularvasculopathies in this disease.

The consequences of such vascular remodelling and ischemic atrophyincluded ophthalmoscopically detectable abnormalities or absence ofthe macular light reflex in some eyes (Fig. 4A). Interestingly, ophthal-moscopy of the macula appeared normal in other eyes, despite angio-graphically demonstrable abnormalities of perfusion. Thus, a maculathat appears ophthalmoscopically normal may, in actuality, contain zonesof ischemia with potential loss of visual function. The changes in theophthalmoscopic and angiographic appearances of the macula are verysimilar to those occurring in sickle cell maculopathy,5-9 an ischemicdisease with a presumably different (but possibly similar) pathogenesis(see below). Similar events also occur in ischemic diabetic maculopa-thy. In both sickle cell and diabetic maculopathies, loss of visual acuitydepends on the number and location of closed capillaries as well as onthe area of the induced ischemic macular atrophy. In the cases of incon-tinentia pigmenti reported herein, most babies were too young for ac-curate measurements of visual acuity, but ischemic macular atrophymay well contribute to reduced vision or amblyopia in this disease.2

Other causes of poor vision in incontinentia pigmenti include fovealhemorrhage, vitreous hemorrhage, retinal detachment, persistence ofthe fetal intraocular vasculature, cataract, optic atrophy, and infarctionof the visual pathways within the brain.2-4,10-13

It is interesting to consider the vascular and angiographic similarities

Fig. 4. (A) Fundus photo of leftmacula of 16-month-old girl withabnormal light reflexes (circles) fromleft macula and perimacular regionthat were caused by ischemic atrophy.Initial vascular occlusions were notedat two weeks of age. White markerarrow is placed similarly in B and C.(B) Fluorescein angiogram at 16months of age; early A-V phase. Notethe irregular, sparse, and distortedcapillary pattern around the FAZ.Marker arrow is placed similarly in C.(C) Fluorescein angiogram at 28months of age; early A-V phase. Thevascular pattern is similar to that seenin B.

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145Macular vasculopathy & incontinentia pigmenti

Fig. 5. (A) Fundus photograph ofnormal right macula of 5-month-oldgirl. Note normal circular lightreflexes; cf. B. (B) Fundusphotograph of abnormal left maculaof 5-month-old girl shown in A. Noteabsence of light reflexes caused byischemic atrophy. (C) Fluoresceinangiogram of left macula shown in B;early A-V phase. Note the loss ofperifoveolar capillaries withperfusion of remaining stumps ofsome occluded capillaries. Arrows areplaced similarly in D. (D) Fluoresceinangiogram obtained six months afterthat in C; early A-V phase. Notefurther occlusion of capillary stumpsalong nasal border of deformed FAZ.Addition of new capillaries orreopening of pre-existent capillarieshas not occurred.

Fig. 6. (A) Fluorescein angiogram ofleft macula of 8-month-old girl; earlyA-V phase. Marker arrows are placedsimilarly in B. Note irregularenlargement of FAZ. There is loss ofcapillary perfusion at the superonasalborder of the FAZ from 9 to 12o’clock. Perfusion of capillaries isseen at the temporal border of theFAZ from 2 to 5 o’clock; cf. B. (B)Angiogram of left macula obtainedthree months after that in A; earlyA-V phase. Note new perfusion ofcapillaries at superonasal border ofFAZ and reduced perfusion ofcapillaries at temporal border of FAZ;cf. A; i.e., there has been addition orreopening of capillaries in one portionof the perifoveolar region as well asclosure of capillaries in anotherportion of the perifoveolar regionduring the same period of time.

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M.F. Goldberg146

Fig. 7. (A) Five-month-old girl. Soonafter perimacular infarction OD,cloudy grey swelling can be seen(arrows). Foveola is marked with acircle; cf. B. (B) Normal macularappearance OS; cf. A. (C) Initialfluorescein angiogram of rightmacula at five months of age; earlyA-V phase. Note irregular enlarge-ment of FAZ due to closure ofperifoveolar capillaries. Othercapillaries are nonperfused alonghorizontal raphe located temporal tothe FAZ and throughout perifoveolarregion. Arrows indicate capillaryabnormalities and marker vessels thatcan be observed for comparativepurposes in E and F. (D) Initialangiogram at five months of age; lateA-V phase. Note late leakage offluorescein from incompetentcapillary beds; cf. C. (E) Fluoresceinobtained four months after those in Cand D; early A-V phase. Noteattenuation of capillaries alongtemporal border of FAZ (from 6o’clock to 12 o’clock). Closure ofcapillaries has also occurredinferotemporally to the FAZ (cf.marker arrows in C). During the sameperiod, reopening or addition ofcapillaries has occurred along nasalborder of FAZ (from 2:30 to 4:30o’clock). (F) Fluorescein angiogramobtained six months after that in E (at15 months of age); early A-V phase.No major change has occurred duringthis six-month interval.

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147Macular vasculopathy & incontinentia pigmenti

among incontinentia pigmenti, sickle cell retinopathy, diabetic retinop-athy, and retinopathy of prematurity (ROP). Peripheral retinal ischemiaand secondary neovascularization occur in all these disorders. Macularnonperfusion also characterizes the first three of these diseases, and,although not frequently sought or documented in ROP, may possiblyaccount for some instances of visual loss in this disorder, also.

In earlier reports, the abnormal appearance of the macula was thoughtto represent foveal hypoplasia, a congenital and static malformation1

secondary to abnormal embryogenesis. Additional follow-up now sup-ports the concept that the macular abnormalities begin with perinatal orneonatal vascular occlusions. Some of these occlusions appear to bestable, while others evolve into a pattern of remodelling, characterizedby further occlusions and by reopening or addition of capillaries inpreviously ischemic zones. It is difficult to differentiate reopening ofpre-existent capillaries in this setting from addition of newly formedones, and both processes may account for angiographic evidence ofnewly perfused capillaries in zones of prior ischemia. Fluorescein leak-age across incompetent endothelial barriers characterizes both new ves-sels and recently reopened ones, and thus, the appearance of late leak-age, such as that shown in Figure 7D, does not help distinguish betweenthese two pathogenetic processes. Leakage is also characteristic ofhypoxic vessels. In any event, the foveal distortion appears to be sec-ondary to sequelae of ischemic events, including infarction of tissue,rather than primary intrauterine hypoplasia or dysplasia of the paren-chymal tissue or the vasculature of the macula.

At present, the events that initiate the ischemic vasculopathy of incon-tinentia pigmenti remain obscure, although various speculations havebeen offered.1 It is possible that the well-known eosinophilia (highblood count of eosinophils) that characterizes the newborn infant withincontinentia pigmenti may contribute to increased viscosity within theperifoveal and peripheral retinal capillary beds as well as in the cere-bral blood vessels,10 with resulting vascular closure. If so, the patho-genesis of the ischemic maculopathy in incontinentia pigmenti and thatin sickle cell anemia might well be similar.5-7 Moreover, this mecha-nism for producing ischemia, if valid, could create possibilities forexperimental therapeutic intervention. Presently, there is no known treat-ment for vascular shutdown in such affected babies’ retinas or brains.Because the initial ischemic events appear to occur shortly after birth(and possibly just prior to birth in some instances), neonatal diagnosisand, eventually, therapy in the future should be attempted very early inthe course of this disease; i.e., before irreversible infarction of themacula, peripheral retina, and brain occurs.

References1 Goldberg MF, Custis PH. Retinal and

other manifestation of incontinentiapigmenti (Bloch-Sulzbergersyndrome). Ophthalmology1993;100:1645-1654.

2 Goldberg MF. The blindingmechanisms of incontinentia pigmenti.

Trans Am Ophthalmol Soc1994;92:167-179.

3 Goldberg MF. Retinal and cerebralabnormalities in incontinentiapigmenti. J Jpn Ophthalmol Soc1996;100(Suppl):32.

4 Goldberg MF. Retinal and cerebralabnormalities in incontinentia

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pigmenti. In: Matsui M, editor. TheFirst International Symposium ofOphthalmology (Japan). Kyoto:Japanese Ophthalmological Society,1996; 56-59.

5 Goldberg MF, Galinos S, Lee CB,Stevens T, Woolf MF. Editorial:Macular ischemia and infarction insickling. Invest Ophthalmol 1973;12:633-635.

6 Acacio I, Goldberg MF. Peripapillaryand macular vessel occlusions insickle cell anemia. Am J Ophthalmol1973;75:861-866.

7 Goldberg MF. Retinal vaso-occlusionin sickling hemoglobinopathies. In:Bergsma D, Bron AJ, Cotlier E,editors. The Eye and Inborn Errors ofMetabolism. New York: Alan R. Liss.Birth Defects Orig Artic Ser1976;12(3):475-515.

8 Asdourian GK, Nagpal KC, Busse B,Goldbaum M, Patriankos D, Rabb MF,Goldberg MF. Macular andperimacular vascular remodeling in

sickling hemoglobinopathies. Br JOphthalmol 1976;60:431-452.

9 Goldbaum M. Retinal depression signindicating a small retinal infarct. Am JOphthalmol 1978;86:45-55.

10 Lee AG, Goldberg MF, Gillard JH,Barker PB, Bryan N. Intracranialassessment of incontinentia pigmentiusing magnetic resonance imaging,angiography, and spectroscopicimaging. Arch Pediatr Adolesc Med1995;149:573-580.

11 Fard A, Goldberg MF. Persistence offetal vasculature in eyes of patientswith incontinentia pigmenti. ArchOphthalmol 1998;116:682-684.

12 Fekrat S, Humayun M, Goldberg MF.Spontaneous retinal reattachment inincontinentia pigmenti. Retina1998;18:75-77.

13 Shah GK, Summers CG, Walsh AW,Neely KA. Optic nerve neovascular-ization in incontinentia pigmenti. AmJ Ophthalmol 1997;124:410-412.

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