Autosomal Dominant N eovascular Inflammatory Vitreoretinopathy STEVEN R. BENNETT, MD, 1 JAMES C. FOLK, MD/ ALAN E. KIMURA, MD, 2 STEPHEN R. RUSSELL, MD, 3 EDWIN M. STONE, MD, PhD, 2 E. MIKE RAPHTIS, BGS2

Abstract: Twenty-eight of 61 members of a six-generation family are affected by an autosomal dominant eye disease which has not been described previously. Affected patients are asymptomatic in early adulthood, but have vitreous cells and the selective loss of the b-wave on the electroretinogram. Later, peripheral retinal scarring and pigmentation, peripheral arteriolar closure, and neovascu­ larization of the peripheral retina at the ora serrata or occasionally neovascu­ larization of the optic disc develop. Cystoid macular edema, vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma can cause profound visual loss. Vitrectomy reduces traction on the retina and allows for retinal reat­ tachment. The role of argon laser photocoagulation or cryopexy in reducing the neovascular complications remains uncertain. Ophthalmology 1990; 97:1125-1136

In the last several years, three families were seen at The University of Iowa with a distinct inherited ocular in­ flammatory disease. Features of the disease include prominent anterior and posterior ocular inflammation, vascular dropout in the peripheral retina along with large round spots of hyperpigmentation, neovascularization of the peripheral and posterior retina, vitreous hemorrhage, and tractional retinal detachment. There also was a se­ lective loss of the b-wave on the electroretinogram (ERG) early in the disease and an extinguished ERG late in the disease.

Originally received: November 1, 1989. Revision accepted: April 24, 1990. 1

The Eye Institute, Medical College of Wisconsin, Milwaukee. Department of Ophthalmology, University of Iowa, Iowa City. 3 Bethesda Eye Institute, St. Louis University, St. Louis. 2

Presented at the American Academy of Ophthalmology Annual Meeting, New Orleans, OctjNov 1989 and The Combined Meetings of the Macula and Retina Societies, Boston, Massachusetts, June 25, 1989. Supported in part by an unrestricted grant from Research to Prevent Blind­ ness, Inc, New York, New York, and The Retina Research Fund of The University of Iowa, Iowa City, Iowa. Reprint requests to James C. Folk, MD, Vitreoretinal Service, Department of Ophthalmology, University Hospitals, Iowa City, lA 52242.

Investigations into the pedigree of each of the three families showed that they all shared common ancestors and that the ocular dystrophy was inherited in an auto­ somal dominant fashion. Herein are reported the clinical and electrophysiologic features of this condition and re­ sults of an investigation of this single large family. A study of the underlying genetic defect is ongoing. Be­ cause the specific biochemical cause has not been iden­ tified, the condition is given a descriptive name, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV).

MATERIALS AND METHODS The patients studied are part of a single large pedigree. The family is of Northern European extraction. Sixty-one members of the pedigree have been examined at The University oflowa, 28 ofwhom are affected. Fifty ofthe patients have been personally examined by one or more of the authors, and the rest have complete ophthalmic records. Twenty-one affected patients have been followed at The University of Iowa for extended periods of time with an average follow-up of 12 years (range, 1-44 years). This study has been approved by the Human Subjects Committee at The University oflowa. 1125

OPHTHALMOLOGY



SEPTEMBER 1990



VOLUME 97



NUMBER 9

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The medical records of all affected patients were re­ viewed and pertinent tests were performed in some pa­ tients to rule out systemic conditions that might be as­ sociated with an ocular picture of inflammation or neo­ vascularization. Fifty patients had ERGs. Selected patients also had visual field testing, dark adaptation studies, flu­ orescein angiograms, and fundus photographs. Electroretinography was performed after dilating both pupils. The patients were dark adapted for a minimum of 30 minutes. Electroretinograms were recorded simul­ taneously from both eyes using Burian-Allen bipolar con­ tact lens electrodes inserted under scotopic conditions with dim red light. A Grass photostimulator (PS22, Grass Medical Instruments, Quincy, MA) in a full-sized Ganz­ feld bowl was used to produce the light flashes. The 1-16 intensity setting was used to produce a single, nonatten­ uated white flash of 1.5 X 106 lumen-second/m 2 from a flash of 10 ~ISeconds' duration at the level of the eyes in the dark-adapted eyes. This was followed by light adap­ tation to an ambient illumination of 15 lumens/m 2 and a single white flash. Evoked waveforms, together with a 100-~Im V calibration pulse and a stimulus artifact, were displayed on a special-purpose laboratory computer (Bioengineering, University oflowa 604-C Averager, Iowa City, lA). The waveforms were recorded on Polaroid film after cursors were placed on the digitally stored waveform. The frequency band ranged from DC to 1000 Hz. Most of the ERGs were obtained with the above protocol. The normal b-wave amplitudes using this system were 450 ± 100 II V for the dark-adapted single nonattenuated white flash and 339 ± 85 II V for the light-adapted single non­ attenuated white flash. 1126

Fig l. Pedigree of the family being reported. The double bars between siblings along the top line separate the three major family divisions men­ tioned in the text. A cross­ hatch on a vertical line indi­ cates that the patient has been examined. Circles represent females and squares represent males. Blackened figures represent affected patients. A line through the figure means that the patient is deceased.

Additional data were obtained with the UTAS-E2000 computer-controlled system (LKC Systems, Inc, Gai­ thersburg, MD). An identical dilation, dark adaptation, and contact lens protocol was used. The ground electrode was attached to the wrist. Impedance through the system was verified to be less than 40 Kohms before each stim­ ulus. The stimulus was derived from a Grass PS-11 photo­ stimulator (Grass Medical Instruments, Quincy, MA) in a full-sized Ganzfeld bowl. Low- and high-frequency filters were 0.3 and 500Hz, respectively. The stimulus protocol consisted of a single white flash attenuated 2.4 log units by neutral density filters, followed by a single nonatten­ uated flash of 2.806 candela seconds/m 2 • Patients were then light adapted to a background of 41.76 cd/m2 for 10 minutes facing the Ganzfeld bowl. Next, a single white nonattenuated flash under photopic conditions, and fi­ nally the response to a 30-Hz flicker was recorded. Normal amplitudes using this system have not yet been obtained at The University oflowa.

RESULTS The pedigree of the family (Fig 1) demonstrates the characteristic features ofautosomal dominant inheritance. The condition is present in every generation, there are more than three consecutive generations affected, and there is at least one documented male-to-male transmis­ sion. In those patients at risk for the disease who have been examined, 28 (46%) of 61 have been affected. There was one documented consanguineous marriage in the

BENNETT et al



ADNIV

Table 1. Visual Acuity at Last Examination Visual Acuity (%)

Age of Patient (yrs)

(no. of eyes)

>20/40

20/50-20/100

20/200-5/200

6/200-LP

NLP

,;40 41-59

14

16

12 (75) 2 (14) 1 (4)

1 (6) 4 (29) 1 (4)

3 (19) 4 (29) 7 (27)

0 3 (21) 8 (30)

0 1 (7) 9 (35)

~60

26

LP = light perception; NLP = no light perception.

family, with one affected woman marrying an unaffected first cousin once removed. The fact that one of their two children was affected is consistent with an autosomal dominant pattern of inheritance. This condition cannot be detected reliably in childhood. Nine children at risk who were 14 years ofage or younger have been examined and had electrophysiologic testing. One 6-year-old child had a few vitreous cells, but normal results of an ERG. The remainder had normal exami­ nations. Since each child has a 50% chance of inheriting the condition from an affected parent, it is unlikely that none of them is affected. However, the condition has not developed subsequently in any patient who had had nor­ mal results of examination. The youngest that an affected individual has become symptomatic was at 16 years of age when a vitreous hem­ orrhage occurred from peripheral neovascularization. Most affected patients have been asymptomatic until the third to fourth decade, but older individuals have signif­ icantly decreased vision (Table 1). Other manifestations of the disease also tend to increase with age (Table 2). The disease could be detected in patients by the third decade, but most had only subtle changes at the time. The first fundus manifestation was the closure of the retinal vessels in the far periphery of the temporal retina seen best by indirect ophthalmoscopy with scleral indentation. The vascular closure was associated with small blotches of hyperpigmentation at the level of the retinal pigment epithelium. Although the pigmentation originally was present only in the far peripheral retina, there was not a sharp demarcation between the pigmented and unin­ volved retina (Fig 2). The inner retina had a cystoid ap­ pearance in the area of vascular closure. Invaliably, vit­ reous cells were visible at this point. In two patients who became symptomatic from vitreous hemorrhage in their teens or twenties, no pigmentary changes were noted by the examining ophthalmologist at the time of the hem­ orrhage. In older patients, the pigmentation became more prominent. It formed round patches ofhyperpigmentation at the level of the pigment epithelium reminiscent of pan­ retinal photocoagulation scars (Fig 3). As the disease pro­ gressed, the pigmentary changes spread posteliorly from the peripheral retina toward the posterior pole, but were usually not found within the major vascular arcades (Fig 4). The pigment changes were more prominent in some elderly patients than in others. Vascular closure occurred in the same areas as the pigment change, and may have preceded the pigmentation. The retinal pigment epithe­

Table 2. Prevalence of Various Features of ADNIV No. of Affected Eyes (%) Feature Vitreous cells Peripheral pigmentation Cataracts Traction retinal detachment involving the macula Macular pucker Peripheral neovascularization or fibrotic masses Rubeosis Cystoid macular edema

Age

Autosomal dominant neovascular inflammatory vitreoretinopathy.

Twenty-eight of 61 members of a six-generation family are affected by an autosomal dominant eye disease which has not been described previously. Affec...
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