SURVEY OF O P H T H A L M O L O G Y VOLUME 40. NUMBER 6. MAY-JUNE 1996 AFTER IMAG ES, JONATHAN WIRTSCHAFTER, EDITOR Ocular Ischemic Syndrome in a Child With Moyamoya Disease and Neurofibromatosis JANET L. BARRALL, MD, 1 AND C. GAIL SUMMERS, MD 1'2 Departments of 1Ophthalmology and 2Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA Abstract. Ocular ischemic syndrome is extremely rare in childhood. Patients with moyamoya disease may be particularly susceptible to the development of ocular ischemia due to the associated carotid occlusion. A 19-month-old boy presented with neurofibromatosis and signs of ocular ischemia. At 29 months of age, he developed dense right vitreous hemorrhage and eventually lost vision in that eye due to phthisis. At almost six years of age, he developed an acute hemiplegia and was then diagnosed with moyamoya disease. This rare instance of childhood ocular ischemia in conjunction with moyamoya disease and neurofibromatosis demonstrates the serious ocular and systemic sequelae of occlusive vascular disease. (Surv Ophthalmol 40:500-504, 1996) Key words, angiography • magnetic resonance imaging neurofibromatosis • ° moyamoya disease • ocular ischemic syndrome axillary freckling, was r e f e r r e d to o u r institution for o p h t h a l m o l o g i c examination in 1987. T h e r e was no history o f strabismus or r e d u c e d vision. Family history was negative for the findings o f neurofibromatosis. The left eye was normal. Neither eye h a d lens opacities or Lisch nodules o f the iris. The right eye c o n t a i n e d a c o m b i n e d h a m a r t o m a of the retina a n d retinal p i g m e n t epithelium, involving the macula. Neovascularization o f the optic disk was noted, in addition to arteriovenous communications, m a r k e d venous dilatation, venous beading, a n d severe arteriolar attenuation (Fig. 1). The retinal p e r i p h e r y was incompletely vascularized and new vessels e x t e n d e d into the vitreous. A small a m o u n t of vitreous h e m o r r h a g e was present inferiorly. The etiology of the retinal changes was unknown. C o m p u t e d t o m o g r a p h y (CT) a n d magnetic resonance imaging (MRI) were notable for non-visualization o f the right internal carotid artery (Fig. 2). T h e right carotid artery was pres u m e d to be absent. T h e optic nerves were also slightly enlarged a n d have r e m a i n e d u n c h a n g e d without treatment. Ocular ischemic syndrome (OIS) usually occurs in elderly patients with carotid obstruction a n d significant systemic illness, most frequently hypertension, diabetes mellitus, or cardiac disease. 18 Ocular ischemic s y n d r o m e is unusual in childhood, presumably because carotid obstruction rarely occurs in y o u n g patients. Moyamoya disease, an idiopathic vascular disorder of the central nervous system in children a n d y o u n g adults, can o c c u r following carotid obstruction. Neurofibromatosis has b e e n r e p o r t e d in association with m o y a m o y a disease. We present the unusual case o f a child with neurofibromatosis who developed b o t h m o y a m o y a disease and ocular ischemia. The o c c u r r e n c e o f ocular ischemic synd r o m e in a child is u n e x p e c t e d , and therefore may go u n r e c o g n i z e d . ease Report A 19-month-old boy with a p r e s u m e d diagnosis of neurofibromatosis type 1, based o n seven carean-lair spots greater than 1.5 cm in diameter, 13 cafe-auqait spots less than 1.5 cm in diameter, a n d 500 © 1996. Surveyof OphthMmology. (7 Kent Street, Brookline, MA 02146. Tel: 61%566-2138. Fax: 617-566-4019) O C U L A R ISCHEMIC S Y N D R O M E Fig. 1. Photograph of mid-peripheral retina shows venous dilation, venous caliber irregularity, severe arteriolar narrowing and arteriovenous communication (ar- 501 Fig. 2. Magnetic resonance imaging shows nonvisualization of the right internal carotid artery and a patent left internal carotid artery (arrow). FOW). At 29 m o n t h s , grating visual acuity was 2 0 / 1 0 0 in the right eye a n d 2 0 / 8 0 in the left. Due to the potential for a m b l y o p i a related to the right macular h a m a r t o m a , the left eye h a d b e e n p a t c h e d for three h o u r s each day with g o o d c o m p l i a n c e . A right esotropia was first n o t e d at 34 m o n t h s of age. T h e patient, who h a d previously c o o p e r a t e d with patching, n o w objected strongly to occlusion of the left eye, a n d t h e r e was no central fixation with the right eye. Dense vitreous h e m o r r h a g e was present, a n d the retina was a t t a c h e d by B-scan ultrasonography. A vitrectomy was p e r f o r m e d d u e to the potential for a m b l y o p i a f r o m the h e m o r r h a g e . Additionally, cryotherapy, air-fluid gas e x c h a n g e , a n d scleral buckling were used to treat a p e r i p h e r a l inferior retinal b r e a k that was n o t e d intraoperatively. Best postoperative vision was light p e r c e p t i o n . A cyclitic m e m b r a n e with h y p o t o n y rapidly developed, followed by retinal d e t a c h m e n t , a n d phthi- sis. T h e child is now nine years old, a n d the left eye has r e m a i n e d n o r m a l . At almost six years o f age, the p a t i e n t suffered an acute left hemiplegia. A diagnosis o f m o y a m o y a disease was m a d e w h e n a n g i o g r a p h y d e m o n s t r a t e d r i g h t c a r o t i d o c c l u s i o n a n d m o y a m o y a vessels (Figs. 3 a n d 4). Review o f the CT scan p e r f o r m e d at 19 m o n t h s showed a right carotid f o r a m e n (Fig. 5), suggesting that the carotid artery h a d develo p e d , b u t was occluded. 16 A right m y o d u r a l synangiosis was p e r f o r m e d in an a t t e m p t to re-establish p e r f u s i o n o f the right cerebral h e m i s p h e r e . Six m o n t h s later, cerebral a n g i o g r a p h y disclosed a patent bypass f r o m the right external carotid a r t e r y into the right middle cerebral artery. T h r e e years later, the patients' strength in his left extremities h a d i m p r o v e d by 50%. Gait r e m a i n e d a b n o r m a l due to a left f o o t drop. Fig. 3. Carotid angiography demonstrates extremely attenuated proximal right internal carotid occlusion (arrow) and absence of distal perfusion. Fig. 4. Carotid angiography demonstrates a patent left internal carotid artery and the smaller abnormal moyamoya vessels on the right (arrow). 502 Surv Ophthalmol 40 (6) May-June 1996 Fig. 5. Computed tomography shows the development of bilateral carotid foramina (arrows). Discussion In 1963 Kearns a n d H o l l e n h o r s t r e p o r t e d a series of patients with " v e n o u s stasis r e t i n o p a t h y " associated with carotid stenosis. 9 In the same year, H e d g e s also described retinal venous changes associated with carotid occlusion. 7 K n o x r e p o r t e d cases o f "ischemic ocular i n f l a m m a t i o n " in conj u n c t i o n with carotid disease; 1° m a n y of these patients also exhibited the retinal features described by Kearns a n d H o l l e n h o r s t . Smith h a d already described the o c c u r r e n c e o f neovascular g l a u c o m a in the setting of carotid occlusive disease. 21 Today, the t e r m " o c u l a r ischemic s y n d r o m e " is used to encompass these m a n y manifestations that result f r o m chronic insufficiency o f carotid or ophthalmic artery flow. P a n o c u l a r ischemia can cause pain a n d decreased vision, a n d myriad clinical signs. 8,22,24 Anterior s e g m e n t signs include episcleral venous congestion, corneal e d e m a , uveitis, a b n o r m a l l y low int r a o c u l a r p r e s s u r e , r u b e o s i s iridis, n e o v a s c u l a r glaucoma, a n d cataract. Pupils may be dilated, sluggish, or nonreactive. Posterior s e g m e n t signs include n a r r o w e d arterioles, dilated a n d irregular veins, neovascularization o f the disk a n d / o r retina, arteriovenous c o m m u n i c a t i o n s (anastomoses), retinal h e m o r r h a g e s , cotton-wool spots, s p o n t a n e o u s retinal arterial pulsations, a n d vitreous h e m o r rhage, presumably from neovascularization. O p h t h a l m o d y n a m o m e t r y frequently reveals abnormally low central retinal artery p e r f u s i o n pressure. Fluorescein a n g i o g r a p h y shows delayed a n d patchy choroidal filling, a n d an increase in arteriovenous transit time. 2 Retinal b l o o d vessels m a y stain, a n d the optic disk m a y also show late staining. Areas o f BARRAIJ., SUMMERS retinal capillary n o n p e r f u s i o n can frequently be identified. OIS typically occurs in o l d e r patients. In a series o f 43 patients, age at p r e s e n t a t i o n r a n g e d f r o m 5 0 86 years, with a m e a n o f 64.5 years. 2 A m a l e pred o m i n a n c e was r e p o r t e d , with a m a l e to female ratio of 2:1. Associated systemic diseases, in decreasing o r d e r of frequency, i n c l u d e d systemic arterial hypertension, diabetes mellitus, ischemic h e a r t disease, cerebrovascular accident, a n d peripheral vascular disease, all o f which are diseases associated with atherosclerosis. 19 T h e ocular ischemic s y n d r o m e is t h o u g h t to be a rare ocular m a n ifestation o f carotid atherosclerosis that usually occurs in elderly individuals who also have generalized atherosclerosis affecting o t h e r m a j o r organs. A significant increase in five-year mortality has b e e n d e m o n s t r a t e d , with cardiac disease accounting for a p p r o x i m a t e l y half the deaths. 19 A l t h o u g h the g r e a t majority o f cases o f OIS occurs in elderly patients with atherosclerosis, cases have rarely b e e n r e p o r t e d in o t h e r settings. D u k e r r e p o r t e d a case o f OIS s e c o n d a r y to s p o n t a n e o u s carotid dissection in a 64-year-old male. 15 To o u r knowledge, ocular ischemia has n o t b e e n previously r e p o r t e d in a child as y o u n g as 19 m o n t h s or in a p a t i e n t with m o y a m o y a disease. Patients with OIS have n o t only significantly increased mortality, b u t also a p o o r visual prognosis. In the series by Sivalingam et al, 43% o f patients h a d 2 0 / 5 0 or b e t t e r acuity on initial p r e s e n t a t i o n ) s However, 58% of their patients h a d c o u n t fingers or worse vision o n e year after presentation, despite m a x i m a l t r e a t m e n t that i n c l u d e d p a n r e t i n a l p h o tocoagulation with carotid e n d a r t e r e c t o m y or superficial t e m p o r a l artery-middle cerebral artery bypass. Visual prognosis was worse for eyes with rubeosis iridis o n initial presentation. Eighty-two percent of eyes with rubeosis at or within three m o n t h s of p r e s e n t a t i o n h a d no b e t t e r t h a n c o u n t fingers vision at one-year follow up. Carotid occlusion can be associated with moyam o y a disease, a central n e r v o u s system vasculopathy that occurs in all ethnic groups, b u t has b e e n m o s t frequently r e p o r t e d in the J a p a n e s e population. M o y a m o y a disease can o c c u r at any age, b u t is m o s t c o m m o n in children. 1 Females m a y be m o r e susceptible. Either unilateral or bilateral carotid stenosis with d e v e l o p m e n t of collateral vessels ( " m o y a m o y a vessels") is characteristic. Patients m a y be asymptomatic, or there m a y be severe neurological deficits. While adults m o r e c o m m o n l y have h e m o r r h a g i c events, children t e n d to p r e s e n t with ischemic events resulting in stroke. M o y a m o y a disease, a f r e q u e n t cause of stroke in children, may be p r e s e n t for s o m e time b e f o r e s y m p t o m s occur. OCULAR ISCHEMIC SYNDROME In a review of 86 children with onset o f acute hemiplegia, S o l o m o n et al described three patients with stenosis of the origin o f the internal carotid artery ( G r o u p III in their series of patients with occlusive vascular disease) with acute hemiplegia; two also h a d a history o f r e c u r r e n t generalized seizures. 2° A minority o f the 122 patients with acute hemiparesis, r e p o r t e d by Aicardi et al did n o t have seizures at the time of their neurological presentation, a n d eight of the 24 angiograms showed arterial occlusion, c o m p a r e d to no a n g i o g r a p h i c abnormalities in the g r o u p with associated seizures. I Diagnosis is c o n f i r m e d with a n g i o g r a p h y or MRI that shows carotid stenosis or occlusion, a n d the typical a b n o r m a l vascular collaterals. 3 Histopathologic examination o f affected cases has shown thickening of the carotid intima, with a distinct lack o f i n f l a m m a t i o n ? 1 T h e n o m e n c l a t u r e o f m o y a m o y a disease is inconsistent in the literature. It has b e e n r e p o r t e d to o c c u r in association with a variety o f diseases, 6,n including neurofibromatosis. 15m T h e term "moyamoya p h e n o m e n o n " has b e e n suggested for those cases that o c c u r in association with a n o t h e r disease. These cases are frequently unilateral a n d are sometimes called "atypical m o y a m o y a . " Given the m a n y ocular signs associated with carotid occlusion a n d the f r e q u e n t o c c u r r e n c e o f carotid occlusion in m o y a m o y a disease, o n e m i g h t expect that patients with m o y a m o y a would be particularly susceptible to the d e v e l o p m e n t o f ocular ischemia. Surprisingly, there are few reports o f ocular abnormalities in m o y a m o y a disease. N o d a et al studied f o u r patients with m o y a m o y a disease a n d r e p o r t e d visual field defects ( h o m o n y m o u s hemianopsia). 14 T h e r e were few a b n o r m a l intraocular findings with only o n e patient having cortical lens opacities a n d a n o t h e r showing t e m p o r a l disk pallor. Visual disturbances resulting f r o m central nervous system p a t h o l o g y are m o r e c o m m o n . Miyam o t o r e p o r t e d visual disturbances in 43 o f 178 patients with m o y a m o y a disease? 2 As o u r case r e p o r t demonstrates, patients can have carotid occlusion or OIS for several years before neurological signs develop. Various vascular lesions have b e e n r e p o r t e d in n u m e r o u s sites (including the central nervous system) in patients with neurofibromatosis. These lesions are t h o u g h t to result f r o m Schwann cell proliferation within arteries. 17 Retinal astrocytic a n d c o m b i n e d h a m a r t o m a s o f the retina a n d retinal p i g m e n t epithelium have b e e n r e p o r t e d in association with b o t h type 1 a n d type 2 n e u r o f i b r o m a tosis, b u t are unusual. 4 To o u r knowledge, there are n o previous reports o f carotid occlusion resuiting in b o t h m o y a m o y a disease a n d ocular isch- 503 emia in a patient with neurofibromatosis. Moadel et al recently r e p o r t e d a similar case o f unilateral retinal ischemia in a child with n e u r o f i b r o m a t o sis. 13 However, their case differs f r o m o u r case rep o r t in several i m p o r t a n t respects. A l t h o u g h cerebral a n g i o g r a p h y was n o t p e r f o r m e d , there was no evidence of carotid stenosis by D o p p l e r flow studies in their patient. Nonetheless, color D o p p l e r imaging did d e m o n s t r a t e r e d u c e d central retinal artery flow. A l t h o u g h n o t specified in this report, flow away f r o m the p r o b e would indicate retrograde filling f r o m a collateral of the external carotid artery, a n d flow toward the p r o b e would indicate filling f r o m the internal carotid artery or a collateral in the proximal orbit. In addition, there was no evidence o f m o y a m o y a disease in their report. It remains u n c l e a r w h e t h e r a single process leads to the neurofibromatosis associated ocular vasculopathy in the patient r e p o r t e d by Moadel a n d the patient r e p o r t e d herein. Clearly ocular ischemia in association with neurofibromatosis can o c c u r b o t h with a n d without m o y a m o y a disease. O u r case is unusual in that ocular ischemia was present in a y o u n g child. In addition, this child also h a d neurofibromatosis that is known to be associated with b o t h vasculopathy in general, a n d m o y a m o y a disease in particular. F u r t h e r studies may lead to a better u n d e r s t a n d i n g of the vascular changes in neurofibromatosis a n d m o y a m o y a disease a n d any shared pathogenesis. Cases of OIS in children may be overlooked, as the index of suspicion for ocular changes is low in children with either neurofibromatosis or m o y a m o y a disease. We suggest that the possibility of ocular ischemia be suspected in patients with neurofibromatosis or m o y a m o y a disease. This is particularly i m p o r t a n t in children who are unlikely to r e p o r t visual loss due to their y o u n g age. OIS, while best known as a disease o f the elderly who have significant vascular disease, can also o c c u r in patients with neurofibromatosis, and intracranial vaso-occlusive disease, regardless of age. Recognition of the vascular abnormalities in children can alert the clinician to the potential for b o t h ocular a n d life-threatening consequences. References 1. Aicardi J, Amsili J, Chevrie ~J: Acute hemiplegia in infancy and childhood. Develop Med Chil Neurol 11:162-173, 1969 2. Brown, GC, Magargal LE: The ocular ischemic syndrome: clinical, fluorescein angiographic and carotid angiographic features. Int Ophthlamol 11:239-251, 1988 3. 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Sivalingam A, Brown GC, Magaral LE: The ocular ischemic syndrome III: Visual prognosis and the effect of treatment. Int Ophthalmol 15:15-20, 1991 19. Sivalingam A, Brown GC, Magargal LE, Menduke H: The ocular ischemic syndrome II: mortality and systemic morbidity. Int Ophthalmol 13:187-191, 1989 20. Solomon GE, Hilal SK, Gold AP, Carter S: Natural history of acute hemiplegia of childhood. Brain 93:107-120, 1970 21. Smith JL: Unilateral glaucoma in carotid occlusive disease. JAMA 182:683-684, 1962 22. Sturrock GD, Mueller HR: Chronic ocular ischemia. Br J Ophthalmol 68:716-723, 1984 23. Tomsick BA, Lukin RR, Chambers AA, Benton C: Neurofibromatosis and intracranial arterial occlusive disease. Neuroradiology 11:229-234 24. Young LHY, Appen RE: Ischemic oculopathy: a manifestation of carotid artery disease. Arch Neurology 38:358-361, 1981 Supported by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. and the Minnesota Lions and Lioness Clubs. Presented, in part, at the 20th annual meeting of the American Association for Pediatric Ophthalmology and Strabismus, Vancouver, British Columbia. Canada, June 20, 1994. Dr. Barrall is now in Seattle, Washington. Reprint Address: C. Gail Summers, MD, University of Minnesota, Department of Ophthalmology, Box 423, 490 Delaware St. SE, Minneapolis, MN 55455-0501