Electro-oculography in Autosomal Dominant Vitreoretinochoroidopathy Dennis P.

Han, MD,

Michael F.

Lewandowski, RDMS

\s=b\ Thirteen members of a family presumed to be harboring the gene for autosomal dominant vitreoretinochoroidopathy were examined. In four affected members, electro-oculography demonstrated marked reduction of the Arden ratio (range, 1.1 to 1.5; normal, \m=ge\1.8),despite electroretinographic evidence of mildly affected rod function and normal cone function. These findings suggested that a diffuse disturbance of the

photoreceptor-pigment epithelium complex may have been present prior to widespread loss of photoreceptor function in the affected members of this family. As in previously described families, the pattern of inheritance appeared consistent with autosomal dominance. (Arch Ophthalmol. 1992 ;110:1563-1567)

utosomal

dominant

vitreoretino-

-^"*-

choroidopathy (ADVIRC) is a pe¬ ripheral annular pigmentary dystrophy of the ocular fundus that was first described by Kaufman and associates1 in 1982. The condition is characterized

by a coarse, peripheral, pigmentary retinopathy with a discrete posterior border, punctate whitish opacities in the retina, vitreous cells and fibrillar condensation, blood-retinal barrier breakdown, retinal arteriolar narrow¬ ing and occlusion, retinal neovascular¬ ization, choroidal atrophy, and presenile cataracts.2 To date, detailed descrip¬

tions of two families with this disorder have been published.1,2 Histopathologic Accepted

for publication April 2, 1992. From the Department of Ophthalmology, Medical College of Wisconsin, Milwaukee. Reprint requests to Eye Institute, 8700 W Wisconsin Ave, Milwaukee, WI 53226 (Dr Han).

findings have suggested the term "pe¬ ripheral annular pigmentary dystrophy of the retina" as an appropriate mor¬ phologic description of this condition.3 Electroretinography (ERG) in ADVIRC has typically demonstrated normal to moderately reduced rod and cone function. To our knowledge, results of electro-oculography (EOG) have not been reported previously in this condi¬ tion. Described herein are marked re¬ ductions of the EOG in four affected in¬ dividuals in two generations with a pe¬ ripheral annular pigmentary dystrophy characteristic of this condition. As in previously described families, the mode of inheritance appeared consistent with an autosomal dominant pattern. PATIENTS AND METHODS The subjects in this study consisted of 13 members in two generations of a family pre¬ sumed to be harboring the gene for ADVIRC. Four of the family members dem¬ onstrated clinical findings typical for this con¬ dition.1·2 The family was noted to be of mixed northern European/German descent. There was no known history of consanguinity. The pedigree is described schematically in Fig 1. Because most of the individuals in generation I were dead, confirmation of involvement in a third generation could not be obtained. Thirteen members of the affected pedi¬ gree were examined with an ocular and sys¬ temic history. An ophthalmic examination was performed, including visual acuity mea¬ surement, pupillary, motility, external, and slit-lamp examination, dilated direct oph¬ thalmoscopy or indirect biomicroscopy, and peripheral indirect ophthalmoscopy. If ab¬ normalities were noted on the ophthalmic examination, ERG and EOG were per¬ formed. Formal visual field testing was per¬ formed on two of the patients. Electroretinography was performed with

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the patient's eyes fully dilated and initially dark adapted for a period of 30 minutes. Contact lens electrodes (ERG-JET, Lifetech Ine, Houston, Tex) were used binocularly as the active electrodes. Separate, indifferent, and ground electrodes were affixed to the forehead. A photostimulator xenon arc bulb (Grass PS22) mounted in a Ganzfeld inte¬ grating sphere was employed to present a diffuse retinal stimulus. Under scotopic con¬ ditions, a blue filter (Wratten 47, 47a, 47b, Eastman Kodak Co, Rochester, NY) was used to produce a stimulus selectively elicit¬ ing rod-mediated responses. The filters were removed and a stimulus intensity series from white light ranging more than 4.0 log units was obtained. The maximal stimulus inten¬ sity was measured at approximately 4.45 candela (cd)-s/m2. A background luminance of 785 cd/m2 (250 asb) within the integrating sphere was then used to adapt the patient photopically. Following a 5-minute period of light adaptation, cone-mediated responses were obtained from a single maximal inten¬ sity unfiltered stimulus of 4.45 cd-s/m2. A 30-Hz stimulus of the same intensity was also presented to elicit a cone response. Electro-oculography was performed by af¬ fixing recording electrodes near the inner and outer canthi and a ground electrode on the forehead. Pupils were not pharmacologically dilated for this test. Under conditions of dark adaptation, fixation was alternated horizon¬ tally between red and green fixation lights that subtended a saccadic angle of 35° within the Ganzfeld sphere and was repeated at 1-minute intervals for 15 minutes. This proce¬ dure was then repeated under background light-adapted (785 cd/m2) conditions provided by the Ganzfeld sphere. The Arden ratio was calculated by dividing the light peak ampli¬ tude by the dark trough amplitude. REPORT OF CASES

Case histories are presented on three of the four affected individuals. Patient II-2.—A 52-year-old white man

were

present bilaterally. There were no vit¬

cells. The anterior chamber angles judged to be narrow but nonoccludable by gonioscopy. Fundus examination re¬ vealed cup-to-disc ratios of 0.2 and slight disc pallor bilaterally. Peripapillary hypopigmen¬ tation of the retinal pigment epithelium (RPE) was present at the temporal disc margin in both eyes. Mild nonspecific pig¬ mentary macular changes were seen in the right eye (Fig 2). Generalized narrowing of the retinal vasculature, primarily arterial, was noted in both eyes. In the periphery, marked pigment clumping and hypopigmen¬ tation that extended from just posterior to reous were

the equator to the ora serrata were present for 360° in both eyes. The region of involve¬ ment was sharply demarcated at its poste¬ rior margin (Fig 3). A few pigmentary "bone spicules" and white, sclerotic-appearing ves¬ sels were present in the area of pigmentary disturbance. Preretinal white dots were not visualized. The vortex vein ampullae could not be visualized in either eye, presumably due to the marked overlying pigmentary

changes. Electrophysiologic findings

Fig 1.—Pedigree

of affected

family members.

Fig 2.—Patient 11-2. Arteriovenous phase fluorescein angiogram of proband (right eye) dem¬ onstrating nonspecific pigmentary macular changes and mild vascular attenuation. reported some decrease in night vision of unspecified duration, but he denied any dif¬ ficulties with peripheral vision. His ocular history was significant for narrow angle glaucoma, bilateral surgical peripheral iridectomies in 1975, extracapsular cataract extraction with posterior chamber lens im¬ plantation in the right eye in October 1985 and in the left eye in July 1987, and YAG la¬ ser capsulotomy in both eyes in March 1989. Static perimetry obtained in December 1989 revealed moderately constricted visual fields in both eyes. No mention of fundus abnor¬ malities was noted in his previous records

(obtained elsewhere) until his examination at the Medical College of Wisconsin, Milwau¬ kee, in March 1990. Medical history was sig¬ nificant for systemic hypertension, cardiac arrhythmias, and elevated serum triglycér¬ ide levels. Best corrected visual acuity was 20/30 OD and 20/20 OS. Results of pupillary, motility, and external examinations were normal. In¬ traocular pressures were 27 mm Hg in both eyes. Peripheral iridectomies, posterior chamber lenses, and patent central posterior

capsulotomies

were

present bilaterally.

Fibrillar anterior vitreous condensations

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are shown in Table 1. The ERG revealed the photopic re¬ sponses to be within normal limits in ampli¬ tude and in implicit time. The 30-Hz flicker response was also normal. The dark-adapted, maximal white flash ERG was mildly sub¬ normal in amplitude (a-wave, 140/160 mV OD/OS; normal, 190 to 540 mV; b-wave, 300/ 360 mv OD/OS; normal, 321 to 914 mV). The dark-adapted, blue flash ERG showed a 50% reduction of b-wave amplitude from the lower limit of normal (56/66 mV OD/OS vs normal 128 to 365 mV) and a normal implicit time. The EOG revealed abnormal Arden ratios (light peak/dark trough) of 1.2 in both eyes (normal 1.8 or greater). Patient III-2.—A 24-year-old woman had no visual complaints and denied a history of decreased visual acuity, poor night vision, or peripheral visual field decrease. Her visual acuity was 20/25 OU. Intraocular pressures were 16 mm Hg in the right eye and 17 mm Hg in the left eye. Results of pupillary, mo¬ tility, and slit-lamp examinations were nor¬ mal, except for subtle bilateral posterior subcapsular/cortical spoking of the lenses and mild anterior vitreous cells in both eyes. Goldmann kinetic perimetry demonstrated slightly enlarged blind spots and moderate, generalized, visual field constriction with bi¬ lateral loss of V4e sensitivity at 60° from fix¬ ation nasally and 40° from fixation tempo¬ rally. The I2e sensitivity remained intact within the central 15° to 20° in both eyes. Fundus examination showed slight disc pal¬ lor and generalized vascular attenuation in both eyes. A well-demarcated annulus of RPE atrophy and pigmentary degeneration extended from the postequatorial region out to the ora serrata for 360°. At the posterior demarcation between the area of degenera¬ tion and more normal retina, a narrow bor¬ der of RPE hypopigmentation was noted. Electrophysiologic findings are shown in Table 1 and in Fig 4. The cone-mediated re¬ sponses were normal. The dark-adapted blue-flash ERG was mildly subnormal. The EOG Arden ratios were 1.1 in the right eye and 1.2 in the left eye.

Table 1.—Electrophysiologic Findings in Four Patients Affected With ADVIRC* Cone 30-Hz Flicker ERG Cone ERG

Eye

Amplitude (Normal, 75-216 µ )

OD OS OD OS OD OS OD OS

80 80 120 110 100 110 90 100

Patient No.

III 2

Implicit Time (Normal, 21-32 ms)

Light-Adapted White Flash

b-Wave White Flash

(Normal, 321-914 µ |) 300 (mildly subnormal)

(Normal, 128-365 µ 56 (reduced)

360 240 250 370 350 300 230

(subnormal)

66 110 100

(mildly subnormal)

(normal)

117

(mildly subnormal)

(mildly subnormal)

100 140 160

(normal)

100 110 120 140 120 116 100 100

27

31

Findings

Visual

Age, y/Sex

Acuity

Lens

OD OS OD OS OD OS 20/20 OD 20/20 OS

Extracapsular cataract extraction, posterior chamber lens implant OU Posterior cortical opacities OU

I-2/24/F

I-3/25/M

subcapsular opacities OU_ Posterior subcapsular opacity OD Posterior cortical and

*ADVIRC indicates autosomal dominant

1.2 1.2 1.3 1.3 1.1 1.2 1.5 1.5

in Four Patients Affected With ADVIRC*

Patient No./

-1/19/M

Arden Ratio

(Normal a1.8)

to 65 years.

Table 2.—Clinical

20/30 20/20 20/20 20/15 20/25 20/25

b-Wave Blue Flash

vitreoretinochoroidopathy; ERG, electroretinogram.

fThe ERG values for normal population aged 18

I-2/52/M

Rod ERG

Dark-Adapted

(Normal, 94-267 µ )

28 28 26 26 26 28

"ADVIRC indicates autosomal dominant

Response ERG Dark-Adapted

Maximal

Vitreous Fibrillar condensations OU

Visual Fields Moderate generalized constriction OU (static perimetry) Normal (confrontation)

Normal Vitreous cells OU

Moderate generalized constriction OU (kinetic perimetry)

Normal

Moderate superior constriction OU (confrontation)

vitreoretinochoroidopathy. blue-flash ERG was normal. Arden ratios 1.5 in both eyes.

were

RESULTS

The age, sex, visual acuities, lenticu¬ lar findings, visual fields, if measured, and results of the ERG and EOG are described in Tables 1 and 2. All patients were asymptomatic except for patient II-2, who reported a slight decrease in night vision (see case history). The four affected family members all showed a typical appearance of a well-demar¬ cated annulus of pigmentary degenera¬ tion extending from the equatorial re¬ gion to the ora serrata for 360°, associ¬ ated with varying degrees of retinal vascular attenuation. Fundus photo¬ graphs for the proband and one of his sons, including fluorescein angiography for the latter, are shown in Figs 2, 3, 5, and 6 The fundus abnormalities shown were representative of those observed in other affected family members. None of the affected family members demon¬ strated hyperextensibility of the joints, joint enlargement, or cleft palate. .

Fig 3.—Patient 11-2. Fundus photograph of proband (right eye) demonstrating a sharply delin¬ eated area of peripheral pigmentary disturbance inferiorly. Annulus of pigmentary change ex¬

tended for 360° and

as

far anterior

as

the

ora

Patient III-3.—A 25-year-old man was asymptomatic, but he failed the peripheral vision screening test on his driver's license examination. His visual acuity was 20/20 OU. Intraocular pressure was 16 mm Hg in both eyes. Results of pupillary and motility ex¬

amination were normal. Slit-lamp examina¬ tion revealed a trace posterior subcapsular cataract in the right eye. The vitreous was clear. Visual fields to confrontation showed mild superior constriction in both eyes. Fun¬ dus examination revealed slight disc pallor in

serrata.

both eyes and minimal generalized vascular attenuation in both eyes. A sharply demar¬ cated annulus of pigmentary degeneration extended from the equatorial region to the ora serrata. A hypopigmented border was noted at the posterior margin of the degen¬ erated area (Figs 5 and 6). Electrophysiologic findings are shown in Table 1 and in Fig 4. The cone-mediated re¬ sponses were normal. The dark-adapted, maximal white-flash ERG was mildly sub¬ normal in amplitude, and the dark-adapted

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COMMENT

The clinical findings of lenticular and vitreous abnormalities and a sharply demarcated annular zone of pigmentary degeneration are characteristic of those seen in previously described cases of ADVIRC. It is unlikely that the condi¬ tion observed represented one of other

Dark-Adapted High Intensity White Flash

Dark-Adapted

Blue Flash

30-Hz Flicker

111-2

Flash

4-W_

Normal

Patient

Light-Adapted High Intensity White

4—f~\

4-^-x

-µ^—

Patient II1-3

330 mV 30

ms

Fig 4.—Electroretinogram tracings of patients III-2 and III-3. Because of symmetric findings between both eyes, only tracings from the right eye shown. Normal tracings are provided for comparison (top).

are

Fig 5.—Patient III-3. Fundus photograph of 25-year-old son of proband (right eye) showing similar pigmentary disturbance with hypopigmented posterior border in nasal equatorial region. Moderate vascular attenuation, mild disc pallor, and blunted foveal reflexes were seen in both eyes (not shown).

peripheral vitreoretinal degenerations because of the characteristic findings, as discussed previously by Kaufman and associates.1 Because of the high de¬ gree of penetrance demonstrated in previously reported pedigrees, it seems most likely that in this family the dead father of the proband transmitted the gene in an autosomal dominant fashion. Given the high degree of penetrance

previously reported in ADVIRC, we used ophthalmoscopic findings to deter¬

mine the likelihood of each individual carrying the affected gene. We did not perform an EOG or ERG on individuals with normal fundi, with the exception of patient II-l (wife of the proband), who had a normal EOG and ERG. We are unable to comment on the usefulness of the ERG or EOG in phenotypically

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normal carriers of the gene, had they existed in this pedigree. Electroretinograms in ADVIRC have previously been described as nor¬ mal in younger affected individuals and moderately abnormal in older individuals.13 To our knowledge, how¬ ever, reduction of the EOG Arden ratio has not been reported previously in this condition. In all four of our clinically af¬ fected patients, the EOG appeared to be dramatically affected. Although the ERG showed only mild or moderate dysfunction in these patients, there ap¬ peared to be a consistent reduction of the dark-adapted b-wave amplitudes (white and blue flash) to either lownormal or subnormal levels (see Table 1). In our patients, there was no clinical evidence of pigment epithelial disease or family history to suggest other con¬ ditions in which an abnormal EOG is accompanied by a normal or minimally affected ERG. Such conditions would include early Best's vitelliform macular dystrophy,4 advanced cases of fundus flavimaculatus,5 dominant drusen,6 and various forms of pattern dystrophy of the RPE.7,8 Reduction of the Arden ra¬ tio may also be seen in eyes harboring malignant melanomas of the choroid.9 In light of our current understanding of the EOG light rise, findings of re¬ duced Arden ratios in the four affected members suggest a diffuse disturbance of the photoreceptor-pigment epithe¬ lium complex, despite the clinical pic-

Fig 6.—Patient III-3. Arteriovenous phase fluorescein angiogram of 25-year-old son of proband (right eye) demonstrating characteristic transmission hyperiluorescence through hypopigmented posterior border of pigmentary disturbance in temporal equatorial region.

degeneration involving primarily the pre-equatorial fundus. At the cellular level, the EOG light rise begins with a decrease in extracellular potassium concentration associated with absorption of light by the photore¬ ceptors. Hyperpolarization of the apical ture of regional

and basal membranes of the RPE oc¬ curs in response to this decrease in ex¬ tracellular K+. Subsequent slow depo¬ larization of the basal membrane of the pigment epithelium is reflected in the EOG light rise.8,10 Thus, the EOG re¬ sponse is dependent on the response of the RPE to microenvironmental changes brought about by a functioning photoreceptor layer. The light rise can¬ not generally be detected without func¬ tioning rods, with the exception of cer¬ tain forms of congenital stationary

night blindness in which inner retinal dysfunction may be the primary defect that produces the appearance of defec¬ tive rod function.810 Inner retinal layers are also required for the initiation of the EOG light rise.11 Goldberg and associates3 described histopathologic findings in an elderly person with ADVIRC, consisting of discrete, multifocal loss of photorecep¬ tor cells in the equatorial region, thin¬ ning of the inner nuclear layer, sclerosis of the peripheral retinal vasculature, and depigmentation and atrophy of the RPE. Focal loss of photoreceptors was accompanied by degeneration of the underlying RPE, and rarely did one tissue layer show degeneration without concomitant change in the adjacent tis¬ sue.

A marked reduction of the isolated

rod b-wave response was noted in their patient. The histopathologic abnormal¬ ities reported, if extensive enough, might conceivably represent sufficient loss of the photoreceptor-pigment epi¬ thelium complex to also result in a reduced EOG Arden ratio. The ERG remains an important means of differentiating ADVIRC from retini¬ tis pigmentosa and other tapetoretinal degenerations in which the ERG is usu¬ ally severely affected. However, the value of the EOG in differentiating ADVIRC from other tapetoretinal disor¬ ders remains unclear, since the EOG is usually abnormal in diffuse hereditary rod-cone degenerations of the retina.12 In addition, it is possible that atypical cases of retinitis pigmentosa may have only moderate abnormalities of the ERG13 and it is possible that such cases may demonstrate abnormal EOGs as well. Fortunately, from the reported pedi¬ grees to date, the characteristic clinical findings of ADVIRC and its autosomal dominant pattern of inheritance are usu¬ ally sufficient to indicate the diagnosis. From a pathophysiologic standpoint, our findings suggest the existence of a dif¬ fuse disturbance of the photoreceptorpigment epithelium complex that mani¬ fests itself predominantly in the reduc¬ tion of the EOG Arden ratio, prior to severe involvement of the ERG. The con¬ sistency of these findings awaits further confirmation in other individuals af¬ fected with ADVIRC.

This investigation was supported in pail by core grant EY0193M5 from the National Eye Institute, Bethesda, Md, and by an unrestricted grant from Re¬ search to Prevent Blindness Ine, New York, NY. Harry W. Flynn, MD, Leonard M. Parver, MD,

Paul R. Rice, MD, Warren L. Van Kampen, MD, and Gerard L. van Wesep, MD, provided assistance in examining selected individuals in the reported pedi¬ gree.

References

SJ, Goldberg MF, Orth DH, FishGA, Tessler H, Mizuno K. Autosomal domi-

1. Kaufman man

nant vitreoretinochoroidopathy. Arch

Ophthalmol.

1982;100:272-278.

2. Blair NP, Goldberg MF, Fishman GA, Salzano T. Autosomal dominant vitreoretinochoroidopathy (ADVIRC). Br J Ophthalmol. 1984;68:2-9. 3. Goldberg MF, Lee FL, Tso MOM, Fishman GA. Histopathologic study of autosomal dominant vitreoretinochoroidopathy: peripheral annular pigmentary dystrophy of the retina. Ophthalmology.

1989;96:1736-1746. 4. Cross HE, Bard L. Electro-oculography in Best's macular dystrophy. Am J Ophthalmol. 1974; 77:46-50.

5. Klien BA, Krill AE. Fundus flavimaculatus: clinical, functional, and histopathologic observations. Am J Ophthalmol. 1967;64:3-23. 6. Krill AE, Klien BA. Flecked retina syndrome. Arch Ophthalmol. 1965;74:496-508. 7. Deutman AF, van Blommestein JDA, Henekes HE, Waardenburg PJ, Sollveld-van Driest E. Butterfly-shaped pigment dystrophy of the fovea. Arch Ophthalmol. 1970;83:558-569. 8. Weleber RG, Eisner A. Retinal function and physiological studies. In: Newsome DA, ed. Retinal Dystrophies and Degenerations. New York, NY: Raven Press; 1988:44-47. 9. Dawson WW. Malignant melanoma. In: Heckenlively JR, Arden GB, eds. Principles and Prac-

Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/20/2015

tice

of Clinical Electrophysiology of

Vision. St

Louis, Mo: Mosby-Year Book; 1991:643-645. 10. Carr RE, Siegel IM. Visual Electrodiagnostic Testing: A Practical Guide for the Clinician. Baltimore, Md: Williams & Wilkins; 1982:37. 11. Gouras P, Carr RE. Light-induced DC responses of monkey retina before and after central retinal artery interruption. Invest Ophthalmol Vis Sci. 1965;4:310-317. 12. Arden GB, Fojas MR. Electrophysiological abnormalities in pigmentary degenerations of the retina. Arch Ophthalmol. 1962;68:369-389. 13. Weleber RG. Retinitis pigmentosa and allied disorders. In: Ryan SJ, ed. Retina. St Louis, Mo: Mosby-Year Book; 1989:344-363.

Electro-oculography in autosomal dominant vitreoretinochoroidopathy.

Thirteen members of a family presumed to be harboring the gene for autosomal dominant vitreoretinochoroidopathy were examined. In four affected member...
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