Pseudoinflammatory Fundus Dystrophy with Autosomal Recessive Inheritance

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  • PSEUDOINFLAMMATORY FUNDUS DYSTROPHY WITH AUTOSOMALRECESSIVE INHERITANCE

    HENRIK R. FORSIUS, M.D.Oulu, Finland

    ALDUR W. ERIKSSON, M. D.Amsterdam, The Netherlands

    ERKKI A. SUVANTO, M.D.Pori, Finland

    AND

    HANNU I. ALANKO, M.D.Oulu, Finland

    A family in southwest Finland with bilateral hemorrhagic degenera-tion of the retina and choroid was followed up for more than 16 years.The maculas showed subretinal hemorrhages, glial cicatrization of theouter retinal layers, and profound choroidal atrophy, particularly inthe advanced stages of the disease. Fluorescein angiography demon-strated leakage through the pigment layer in the retinal tissue. The ageof onset varied from the second to the fourth decade. The clinicalpattern was similar to Sorsby's pseudoinflammatory dominant fundusdystrophy, except that the disorder appeared earlier in this Finnishfamily, the members of which show secondary dyschromatopsia, manydeep hyaloid bodies in the retina, disturbed dark adaptation (1 to 4 logunits), subnormal Iight-peak/dark-trough ratios, progressive myopia,and a mode of inheritance which is probably autosomal recessive. Theaffected parents are consanguineous in many ways and each of theireight children is affected.

    In 1940 Sorsby' described an apparent-ly autosomal dominant disease with bilat-eral hemorrhages and exudates in the

    Accepted for publication July 23, 1982.From the Department of Ophthalmology, Univer-

    sity of Oulu, Oulu, Finland (Drs. Forsius and Alan-ko), the Institute of Human Genetics, Free Universityof Amsterdam, Amsterdam, The Netherlands (Dr.Eriksson); the Eye Department, Satakunta CentralHospital, Pori, Finland (Dr. Suvanto), and the Popu-lation Genetics Unit, Folkhiilsan Institute of Genet-ics, Helsinki, Finland (Drs. Forsius and Eriksson).This study was supported in part by grants from theFoundation for Medical Research FUNGO, subsi-dized by the Dutch Organization for the Advance-ment of Pure Research (Z.W.O.), The Netherlands,and the Sigrid [uselius Foundation, Helsinki, Fin-land.

    Reprint requests to Henrik R. Forsius, M. D.,Department of Ophthalmology, University of Oulu,Kajaanintie 50, SF-90220 Oulu 22, Finland.

    fundi as the most prominent features.The disease is known as Sorsby's pseudo-inflammatory macular dystrophy, domi-nantly inherited disciform macular dys-trophy," or hereditary hemorrhagicmacular dystrophy.j The disease beginsto appear when the patient is about 40years old and follows a progressivecourse.

    The first symptoms are retinal lesionswith edema, hemorrhages, and exudatesin the macular area. Later, there is con-siderable scarring, with sclerosis in thechoroidal vessels associated with pigmen-tary proliferation which is sometimesmassive. Some months or years later, theother eye develops the same symptoms.The terminal stage, reached after the

    634 AMERICAN JOURNAL OF OPHTHALMOLOGY 94:634--649, 1982

  • VOL. 94, NO. 5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 635

    disease has run its course for about 30years, is a more or less uniform, wide-spread atrophy of the choroid with somepigmentation. In some cases the fundishow glistening colloid bodies around theoptic disk and macula."? Myopia occurs insome members of the affected family, butmost patients are hyperopic or astigmat-ic. There are no symptoms of night blind-ness or constriction of the visual fieldearly in the course, but color vision andvisual acuity are markedly disturbed. 1

    Ashton and Sorsby" made a histologicstudy of the eyes of two elderly sisterswho probably had this disease. The mainpathologic changes can be summarized asfollows: sclerosis and atrophy of the cho-roid with fibrous mural degeneration ofthe remaining vessels; many ruptures ofBruch's membrane in the posterior fun-dus with degeneration of the elastic layerin the same area; newly formed subreti-nal vascular tissue originating from thechoroid and related to the dehiscences inBruch's membrane; disturbance of thepigmentary epithelium; and destructionof the outer layers of the retina with glialreplacement. Babel" found similar chang-es in one eye of a 52-year-old man withthe same disease.

    A number of families with Sorsby'sinflammatory dystrophy with autosomaldominant inheritance have been stud-ied. 3-7,l(}'16

    It has also been suggested that thepseudoinflammatory dystrophy of Sorsbycan be inherited autosomal recessively.One family, first described by Sorsby;!showed autosomal recessive inheritance.Two children, 8 and 12 years old at theonset of the disease, whose parents werefirst cousins, had round, mostly whitemasses of exudate at both maculas. Thisfamily was not included in the later de-scription of inflammatory dystrophy bySorsby, Joll-Mason, and Cardener."

    Francois" reported a pedigree in whichtwo brothers, 41 and 37 years old, had

    the disease, and in which the inheritancewas probably autosomal recessive. Themother still had normal eyes when exam-ined at the age of63 years; the father diedat the age of 32 years. The clinical de-scriptions of affected family memberswere not given in this report, but Fran-cois later described the same brothers.There was an irregular white-yellow areasurrounded by innumerable small yellowpoints in the macula of the older brother.Aplasia of the pigment epithelium waspresent in the periphery, with manysmall pigment points. In the youngerbrother, the periphery was normal butthere was a diffuse disturbance of thepigment layer equatorially and in thecentral parts of the fundus and also yellowpoints combined with a gray-yellow areain the macula, with unclear borders. Theelectroretinogram was subnormal in bothpatients.

    SUBJECTS AND METHODS

    One of us (E.S.) found changes in theposterior part of the fundi in severalmembers of one family in the Pori regionof Finland in 1965 (Fig. 1). The familywas examined by our team in 1966 andhas been closely followed since then. In1966 we found that the parents had pig-mented scars in both fundi and that someof the children had a hemorrhagic diseasein their fundi. The youngest childrenwere at first thought to be unaffected.Our diagnosis was pseudoinflammatorydystrophy of the Sorsby type with domi-nant inheritance. The mother, in whomthe changes were in the central part ofthe fundus, was believed to be the carrierof the disease, and the father, who hadscars throughout the fundus, was thoughtto have had another disease, probablychoroiditis disseminata. During the last15 years all eight children developedchanges in their eyes, and those in thefundus of the mother now closely resem-ble those which the father had at the

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    Fig. 1 (Forsius and associates). Pedigree of a family with probable autosomal recessive pseudoinflammatoryfundus dystrophy. The parents (and their parents) are related in several ways and all the children are affected.So far we have no genealogical evidence that the parents of III -4 and IV-1 have common ancestors, but most oftheir ancestors carne from the same region, which remained a sparsely populated and isolated area until the19th century. Open squares and circles, unexamined males and females; solid squares and circles, affectedmales and females; slash, examined, unaffected; thick vertical line, consaguinity.

    same age. We are now convinced that allthe family members have the same dis-ease but at different stages.

    The father (II-7) and the mother (II-8)are both the youngest of several children(Fig. 1). The father (index case) is theonly one in his sibship known to havedecreased visual acuity. We examinedtwo brothers and two sisters of PatientII-7 and found them to be normal. Fourother siblings died at the ages of 31, 47,58, and 89 years with normal visual acu-ity. All five surviving members have beenexamined in the mother's sibship. Onlyone, Patient II-14, had any degenerativechanges in the fundi. Three brothers diedbetween the ages of 51 and 60 years butwere said to have had good vision. Theparents of Patients II-7 and II-8 had goodvisual acuities until they died (Fig. 1, 1-1,1-2, 1-3, and 1-4).

    Methods-Dark adaptation was studiedwith the Goldmann-Weekers device.

    We studied color vision with a Nagelanomaloscope and Ishihara, AOH-R-R,Bostrom-Kugelberg, and Bostrom pseu-doisochromaticplates. The plates were ex-amined with a daylight illuminator. Weused the same illumination for the Farns-worth panel 0-15 and the Farnsworth-

    Munsell 100-hue tests. In the 100-huetest the upper limit of total error scores isset to 100 for subjects with an averageability to discriminate colors.

    Visual fields were studied with a Gold-mann perimeter and a visual field analyz-er.

    Fundus photographs were taken with aZeiss fundus camera and also with aCanon 60-degree fundus camera (in 1980and 1981).

    We recorded lower eyelid electroretin-ograms with ten flashes (1,500 lux) at15-second intervals after 30 minutes ofdark adaptation and visual-evoked poten-tials with reverse-pattern stimulation(256 reversals, 1 Hz) in three subjects.

    The electro-oculographic tests wereperformed by a semiautomatic method.After a pre-adaptation period of ten min-utes (3,700 lux at the pupillary plane), thestanding potentials were recorded everysecond minute during 12 minutes of darkadaptation. Then, light-adaptation re-cordings were made at 3,700 lux duringthe next 12 minutes. The time constantwas five seconds. The dark-trough andlight-peak amplitudes were measured inmicrovolts, and Arden ratios (light peak-+- dark trough) were calculated for each

  • VOL. 94, NO. 5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 637

    eye. The normal value for our laboratoryis 2.21 0.35.

    CASE REPORTS

    Case 1 (1l-7)-This man, born in 1903, was thefather of the eight affected children. He had beentreated in 1953, when he was 50 years of age, for asudden decrease in the visual acuity of his left eye.There were large and small, partly pigmented, exu-dative, inHammatory colonies in both the macularregion and the periphery of the right eye. Thehospital's journal seven months later also noted oldscars in the choroid of the left eye.

    The patient has been studied by our group for thelast 15 years, during which time the fundus degener-ation progressed (Fig. 2). Between 1965 and 1980 hisvisual acuity decreased from R E.: 20/40 with - 1.50x 150 and L.E.: 20/50 with -1.50 -1.00 x 20 tocounting fingers at 1 m in the right eye and at 30 cmin the left eye.

    At his last examination, scattered atrophy of theretina and choroid in both fundi was observed with aGoldmann three-mirror lens, but there was somenormal-appearing choriocapillaris between the atro-phied areas. There were also changes in the extremeperiphery. In the left eye the optic nerve head wasatrophic and the retinal blood vessels were attenuat-ed. There were many lens opacities in both eyes.Dark adaptation was normal for his age in 1966. Hemade one error on the AOH-RR and Ishihara pseudo-isochromatic plates. On the Farnsworth panel D-15test he arranged the cups in the following order: 1-5,7, 6, 12, 14, 15, 13, 10, 11, 9, 8. The iris wasatrophic, especially in the pupillary region.

    Fig. 2 (Forsius and associates). Patient 11-7. Leftfundus in 1968 at the age of 65 years. There are largeatrophic retinochoroidal areas and the retinal vesselsare attenuated.

    Case 2 (1l-8)-The mother of the affected childrenwas born in 1919. At the age of 33 years she had hadan inflammation in the central fundus in both eyes;when she was 36 years old large pigmented areaswere found in both maculas and her visual acuity was20/60 in both eyes. At 38 years of age her visualacuity was RE.: 201150 with -7.00 and L.E.: 20/60with -6.00. The hospital journal noted central pig-mented areas a little larger than the optic nerve headin both fundi.

    When we first examined her, when she was 46years old, her visual acuity was 20/150 with -7.50 inthe left eye. The optic nerve head was normal andthe retinal arteries appeared to be somewhat attenu-ated. There were large areas of retinal and choroidalatrophy (Fig. 3). There were some large and smallpigment flecks in the periphery. Dark adaptation wasnormal for her age. Defects were observed in thecentral visual fields. In 1980, when she was 60 yearsold, her visual acuity was counting fingers at 20 cm inthe right eye and at 30 em in the left eye. The nervefiber layer was normal. Choroidal atrophy was almosttotal in both eyes.

    Case 3 (IIl-7)-This patient, the oldest child ofPatients 11-7 and 11-8, was born in 1942. We havestudied her since 1965, when her visual acuity wasnormal with RE.: -1.50 -1.50 x 175 and L.E.:-1.25 -1.00 x o.

    When she was 23 years old, the visual acuity in herright eye suddenly decreased to R E.: 20/50 with-2.00 -0.75 x 3 and L.E.: 20/25 with -2.00 -0.75x 167. There was a large pigmented scar surroundedby exudation in the right macular area. A month laterthe exudation had disappeared. In the periphery thepigmentation in both the choroid and retina wasmissing (Fig. 4, top left). In all the other parts of the

    Fig. 3 (Forsius and associates). Patient 11-8. Fundusof the right eye at the age of 47 years shows a largescar with glial formation in the macular area.

  • 638 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1982

    fundus the pigment layer was even. Dark adaptationhad decreased by 2 log units. Color vision testsshowed changes in tritan direction on the Farnsworthpanel D-15 test. The Farnsworth-Munsell loo-huetest showed disturbances without any clear directionand a total error score of 101 with both eyes studiedtogether.

    When she was 26 years old, her visual acuity wasR.E.: counting fingers at 0.5 m and L. E.: 20/20 with-3.50 -0.75 x 165. There was a hemorrhage in thecenter of the scar in the right eye. The central fundusin the left eye still had only small defects in thepigment layer (Fig. 4, top right).

    Ten years later, the visual acuity of her right eyewas hand movements with -5.0. The retina wasdetached with radially formed folds in the maculararea and large pigment clumps in a fibrotic gray area

    Fig. 4 (Forsius and associates). Patient 111-7. Topleft, Retinal periphery of the right eye at the age of26years. There are large pigment defects in the retinaand choroid. Top right, Left fundus at the age of 26years. The retinal pigment layer in the macular areais uneven. Visual acuity is still normal. Bottom left,Left fundus ten years later. An exudative hemorrhag-ic process has developed in the macular region,probably from newly formed subretinal capillaries.

    were noted subretinally. The visual acuity of her lefteye was counting fingers at 2.5 m with -6.50 -1.25x 150. There was a hemorrhagic exudative process inthe macular area, surrounded by a pigment ring(Fig. 4, bottom left). The total error score on theFarnsworth-Munsell loo-hue test had increased to406.

    Photocoagulation of the borders of this area with anargon laser had no effect. The central visual fieldshowed defects in both eyes and a nasal defect in theleft eye.

    One year later the exudation and hemorrhage haddisappeared. The pigment layer of the retina wasuneven throughout the fundus. There were a fewhyaloid bodies deep within the retina in the midpe-riphery between the macular area and the equatorialregion. The retinal pigment layer and choriocapillaris

  • VOL. 94, NO. 5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 639

    were absent in the periphery and the sclera wascovered by only a few large choroidal vessels. In 1968the iris showed atrophy, which is uncommon at theage of 26 years.

    In 1979 the eleetro-oculographic light-peak/dark-trough ratio was abnormal at 1.52 in the right eye andnormal at 2.49 in the left eye. Small electroretino-graphic responses were recorded with 128 Hashes at2 Hz; these were better in the left eye. Visual-evokedpotentials (reverse-pattern stimulation) disclosedlengthened latencies and low amplitudes in botheyes.

    Case 4 (Ill-B)-This patient, the sister of PatientIII-7, was born in 1944. At the age of 15 years hervision and refraction were normal in both eyes.When she was 20 years old, the visual acuity of herleft eye decreased to 20/200 with -0.50 +0.50 x 85.There were two gray-green exudative processes withdistinct borders close to the left macular region.When the edema disappeared, her visual acuityimproved to 20/100.

    Two years later (in 1966), her visual acuity wasRE.: 20/15 with -1.25 -0.50 x 5 and L.E.: 201150with -1.25 -0.50 x 175. The foveola reflex in theright fundus was normal; above this there was a deephemorrhage in the retina. Areas of almost completelyabsent choroidal and retinal pigment layers werefound in the periphery. In the left fundus, beneaththe old scar (Fig. 5, top left), there was an edematousarea about the size of the optic nerve surrounded byhemorrhages in the deep retinal layers.

    Dark-adaptation studies in 1966 and 1979 showednormal cone adaptation, but red adaptation was slowand was 1 log unit above the normal threshold at theend. In 1979 the light-peak/dark-trough ratios wereabnormal in both eyes (1.42 in the right eye and 1.50in the left eye). Color vision studies showed normalanomaloscopic equations, and test with the AOH-R-Rplates showed almost no errors. The Farnsworth-Munsell 100-hue test showed some nonspecific er-rors in 1966, and a total error score of 159 with botheyes studied together. A large error score, 640, wasrecorded as the mean for both eyes in 1979, when thepatient also made major errors on the Farnsworthpanel D-15 test.

    Fluorescein angiography showed a deficient reti-nal pigment layer throughout the fundus in 1979. Awhorl formation was observed near the central area(Fig. 5, top right). The streaks forming the whorlwere clearer than the surrounding areas in the laterphases of the fluorescein angiogram. The streakswere probably sclerosed choroidal vessels. The Gold-mann three-mirror lens showed the whorl to belocated beneath the retinal pigment layer.

    When the patient was last examined in 1980, hervisual acuity was RE.: 20/200 with -8.00 +0.5 x170 and L.E.: counting fingers at 2.5 m with -5.00+0.5 x 90. White spots deep within the retina werenot observed in 1966 but were found in 1968; thesehad disappeared ten years later. The pigment layerhad become thinner and more uneven during theobservation period, and the scars caused by thehemorrhages and exudates had increased in size(Fig. 5, bottom).

    Case5 (III -9)-The third of the eight children wasborn in 1946. When he was 19 years of age, thispatient appeared to have a normal fundus, althoughthe retinal pigment layer was a little uneven in themacular area and the extreme periphery. Dark-adaptation tests, anomaloscopy, and the Farnsworth-Munsell 100-hue test also gave normal results. Hisvisual acuity was normal in both eyes with R E.:-1.25 and L.E.: -0:50 x 90. Three years later hisrefraction was RE.: -1.50 and L.E.: -1.25 -1.00x 60.

    When he was 32 years old his vision was stillnormal in both eyes with R.E.: -7.75 -0.50 X 140and L.E.: -4.75 -1.00 X 50. Fluorescein angiogra-phy showed the retinal pigment layer to be definitelyuneven. The pigment layer in the periphery showedpartial clumping. There were many small white spotsdeep within the retinal layer between the fovea andthe region of the equator. Most of these were round,but some were oval (Fig. 6). The pupillary borders ofthe iris were atrophic, which had not been the case in1966. Some relative defects in the central visual fieldwere found with the visual field analyzer. Smallnonspecific errors occurred in several pseudoisochro-matic plate tests. A total error score of 102 wasrecorded as the mean for both eyes in theFarnsworth-Munsell 100-hue test. Dark adaptationwas reduced by 3 log units. The light-peak/dark.trough ratio was RE.: 1.69 and L.E.: 1.51.

    Case 6 (III-lO)-This patient, who was born in1948, was examined by us for the first time at the ageof 17years. His vision was normal without correction,and the fundi were also normal. The retinal pigmentlayer in the periphery was uneven, but within physi-ologic limits. Dark adaptation was normal. Colorvision tests showed two errors on the Bostrom IIpseudoisochromatic charts and the total error scoreon the Farnsworth-Munsell 100-hue test was 124with both eyes studied together. We believed thatthe patient was unaffected.

    When he was 23 years old, the patient's refrac-tion in both eyes was - 1.0; at the age of 27 yearsit was RE.: -2.75 -0.75 x 160 and L.E.: -2.50-0.50 x O. By the time he was 30 years old, hisrefractive error had increased to -4.5 +0.75 x 90 inthe left eye.

    Fluorescein angiography showed the pigment epi-thelium to be uneven in the macular area. Therewere many small white spots deep within the retinallayers between the fovea and equatorial region thathad not been present at our first examination. Thepigmentation in the periphery was shown to be scantwhen studied with a three-mirror lens. Dark adapta-tion was reduced by 3 log units. The patient madeseveral errors with both eyes on the AOH-R-Rplatesand also on the Farnsworth panel D-15 test. The totalerror score in the Famsworth-Munsell100-hue test,a mean of 146 for both eyes, was at the same level ashis score at the age of 17 years. Subnormal light-peak/dark-trough ratios were recorded in both eyesin 1979: RE.: 1.67 and L.E.: 1.54.

    In January 1980 a break in the retinal pigmentlayer was found in the right eye in the foveal area.The visual field analyzer showed many relative de-

  • 640 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1982

    Fig. 5 (Forsius and associates). Patient III-8. Top left, Fundus of the left eye at the age of 24 years. A large,heavily pigmented fibrotic scar is present. Top right, Fundus of the right eye at the age of 34 years.Fluorescein angiography, 18.4 seconds after injection of the dye, shows a radiating formation (arrows)consisting oflarge atrophied choroidal vessels close to the pigmented central glial scar. Bottom, The left eye atthe age of34 years. There is an edematous hemorrhagic area above the old scar. Pigment clumping is presentin an otherwise pigmentless periphery deep within the retina.

  • VOL. 94, NO.5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 641

    Fig. 6 (Forsius and associates). Patient 111-9. FUndus at the age of32 years. There are many small round oroval spots deep within the retina which were not present ten years earlier. There are atrophic areas in theperiphery.

    fects in the central parts. In November 1980, thepatient's visual acuity suddenly decreased to 20/40 inhis left eye. One week later the retina was slightlythickened in the macular region. Fluorescein angiog-raphy showed the pigment layer in the region be-tween the optic nerve head and the fovea to bedefective, but there were distinct borders. No edemawas present 12 days later and the patient did notundergo photocoagulation.

    Case 7 (III-ll)-This patient's visual acuity de-creased bilaterally within one month (to R E.: 20/200and L.E.: 20/50) when he was 13 years old (in 1963),and he was treated for chorioiditis disseminata. Alarge edematous area was found in the right maculaand there were some pigmented scars or smallexudative flecks in both eyes. One month later, ahemorrhage was observed outside the macular areain the left eye and the visual acuity had decreased to20/150.

    We first examined him when he was 15 years ofage. His visual acuity was RE.: 20/300 and L.E.:20/60 with +0.25 -0.50 x 70. There was a large grayH-shaped pigmented scar deep within the retina inthe macular area of the right fundus and several smallscattered scars were present elsewhere in both eyes.

    An elevated (0.33 mm) gray-black pigmented scarwas present in the fovea of the left eye. The chorio-eapillaris appeared to be normal between the areas inwhich the sclera was bare. The retinal and choroidalpigment was almost absent in the extreme periphery.Dark adaptation was rapid at first and then slower,but only 1 log unit away from normal in the end.During the color vision tests the patient was able tosee only a few of the pseudoisochromatic plates.

    By the time he was 28 years old, his visual acuitywas RE.: counting fingers with -1.0 and L.E.:20/200 with -1.25 -1.00 x O. The optic nerve headsand retinal vessels still appeared to be normal. Therewas a fresh hemorrhage deep within the retina abovethe papilla of the left eye. The fundi were unchangedtwo years later (Fig. 7, top) but the chorioretinaldestruction was more advanced than it had been in1968 (Fig. 7, bottom left). In this case the electroreti-nographic recording could not be used because ofpoor fixation.

    Case 8 (III-12)-This patient was born in 1952.When we first examined her in 1966, her visualacuity was normal with a refraction of +0.25. Thefoveola reflex was normal. The pigmentation in theretinal and choroidal periphery was almost absent,

  • 642 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1982

    the pigment layer was uneven in the central parts,and some pigment clumps were present. Anomalos-copy and other color vision tests gave normal results.Dark adaptation was 1 log unit lower than normal.

    By 1977 the patient's visual acuity was 20/30 inboth eyes with R.E.: -8.25 +0.50 X 160 and L.E.:-8.50 +0.75 x 180. These findings were still the

    Fig. 7 (Forsius and associates). Patient 111-11. Top,FUndus at the age of 2B years. Visual acuity haddecreased by the age of 13 years. There is a largecentral glial sear and atrophic areas throughout thefundus. Only large choroidal vessels, covered byround pigment deposits, are present in the periph-ery. Bottom left, The same fundus ten years earlierwhen the destruction was less advanced.

    same in 1979, when the patient was 26 years old. Thearteries were somewhat attenuated, but the opticnerve heads had a normal color. There were pigmen-tary deposits of various sizes deep in the retina belowthe macular area. Fluorescein angiography showedan uneven retinal pigment layer.

    The visual fields of both eyes had relative defects.

  • VOL. 94, NO. 5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 643

    The AOH-R-R pseudoisochromatic plates and theFarnsworth panel D-15 test still showed normalresults. The Farnsworth-Munselll00-hue test was atthe upper limit of the normal range (mean, 85 forboth eyes). Dark adaptation was reduced by 3 logunits. The light-peak/dark-trough ratio was subnor-mal at 1.58 in the right eye and at 1.56 in the left eye.

    In 1980 the vitreous body and anterior parts of theeye bulb were normal. The nerve fiber layer in theretina appeared to be normal. There were manysmall white spots close to but not in the macularregion deep in the retina. Many of these were abovethe pigment layer, which was partly destroyed. Pig-ment clumps deeper than the retinal vessels werefound in the periphery.

    In March 1981 the vision of her right eye becamehazy. Two weeks later the visual acuity decreased to20/80 and a dark pigment ring the size of the papillawas noted in an exudative area in the fovea (Fig. 8).Some retinal pigment was missing outside and insidethe ring. Her myopia had increased to - 12 dioptersin both eyes. The visual acuity of the left eye was20/25. The area outside the foveola in the left eye wascoagulated with an argon laser. The exudation disap-peared and the visual acuity had improved to 20/60one month later.

    Case 9 (III-13~We first examined this patient in1966 when he was 11 years old. His eyes appeared tobe normal and his visual acuity was 2.0/15 in botheyes. The only suspect findings were in the periph-ery, where the retinal and choroidal pigmentationwas scarce. Dark adaptation and the visual fieldswere normal. The patient had a total error score of145 on the Farnsworth-Munsell l00-hue test withboth eyes studied together.

    When he was 24 years old, his visual acuitysuddenly decreased to 20/40 with -2.00 in the righteye. There was a deep hemorrhage in the macular

    Fig. 8 (Forsius and associates). Patient 111-12.Fluorescein angiography of the right eye at the age of28 years. There is a fresh exudation and pigment ringin the foveal region. The white dots are probablyhyaloid bodies situated deeper in the retina than thenerve fiber layer.

    area and edema in the retina above. The visual acuityof his left eye was 20/15 with -2.00 -0.50 X 90. Twomonths later there was an elevated gray fibrotic scarsurrounded by a pigment border deep within theretina in the edematous area. The retinal vessels hadno contact with the hemorrhage. The periphery waslightly pigmented, with some pigment flecks deepwithin the retina. Dark adaptation was 1 to 1.5 logunits lower than normal in both eyes. The visual fieldanalyzer showed central defects in both visual fields.

    The Farnsworth panel D-15 test showed changes intritan direction, and the Farnsworth-Munsell 100-hue test showed a high error score (550) in the righteye. The results for the left eye were within thenormal range. The electro-oculographic findingswere within normal limits (R.E.: 1.93 and L. E.:1.99).

    We thought that the bleeding had been caused bynewly formed capillaries at the border between thechoriocapillaris and retina, because lI.uorescein angi-ography showed leakage around the area (Fig. 9).Therefore, we coagulated the border of the edema-tous area with an argon laser. The exudation disap-peared within one week and the visual acuity of theright eye increased from 20/80 to 20/25. Nine monthslater, however, it had again decreased to 201150 with-1. 75, and there was a new defect in the pigmentlayer beneath the earlier one, with a hemorrhagebetween it and the old scar. Argon laser coagulationwas repeated, but the visual acuity did not improve.

    Five months later the clinical findings hadchanged, and visual acuity in the right eye wascounting fingers at 0.5 m. The inner retinal layer hadshrunk and become detached and had formed a grayradiated retinoschisis of the same type observed inhis oldest sister (Patient III-7). There was a largewhite fibrotic scar below this elevated layer. Thedeep retinal layers around this area contained manyhyaloid bodies, some of them closely connected to

    Fig. 9 (Forsius and associates). Patient 111-13.Fluorescein angiography at the age of 25 years showsexudative process with deep hemorrhage and leak-age, probably from a newly formed subretinal neo-vascular membrane.

  • 644 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1982

    the pigment layer, but some in retinal tissue clearlyabove the pigment layer. Electroretinographyshowed a slightly lengthened implicit time for theb-waves and a lower amplitude in the right eye,although these findings were within the normal rangefor both eyes.

    Case 10 (I1l-14f-The patient, who was born in1955, was examined by us for the first time in 1966.There were no definitely abnormal findings despitethorough testing, including adaptometry and variouscolor vision tests. Pigmentation was scarce in thefundus, especially in the periphery.

    When the patient was 23 years old his vision wasstill almost normal, but slight myopia had developed(R.E.: -1.00 -0.75 x 85 and L.E.: -1.00 -0.50 x90). Ophthalmoscopically the central region of thefundus appeared to be normal, but there was destruc-tion of the retinal pigment layer in the periphery,which was pale. Dark adaptation was slow at first, butonly 1 log unit lower than normal in the end. Somerelative visual field defects were found. The light-peak/dark-trough ratios were within the normalrange (R.E.: 2.92 and L.E.: 2.80). Fluorescein angi-ography showed the retinal pigment layer outside thefovea to be slightly grainy. The total error score forthe Farnsworth-MunsellIOO-hue test was 152 for theright eye and 102 for the left eye. The electroretino-grams and visual-evoked potentials were normal.

    Case 11 (ll-14)-This woman, the sister of PatientII-8 and the aunt of the eight affected children, wasborn in 1909. When she was last examined, her visualacuity was 20/15 with + 1.25 in both eyes. The fundiwere centrally normal, but there were scattered areasperipherally where the retinal pigment layer haddisappeared. In some places the choriocapillaris wasalso missing and the sclera was covered only by largechoroidal vessels. Dark adaptation was normal for herage.

    Case 12 (IIl-4)-This patient, the nephew of Pa-tient II-7 and the cousin of the eight affected chil-dren, was born in 1931. When he was 36 years ofagethe visual acuity of his left eye decreased to 20/30.Fluorescein angiography disclosed an edematousarea in the macula close to the fovea with a leakagepoint. The diagnosis was chorioretinitis centralisserosa. The leakage point was photocoagulated andthe area dried.

    When we examined him in 1980, his visual acuitywas 20/15 with +0.75 in both eyes. Results of colorvision tests were normal. There were pigment de-fects in parts of the retinal layer in the central area,including the photocoagulated point. Many smallpigmented points and some small and large colloidbodies were present deep within the retina in theextreme periphery. Some of these were surroundedby a pigment ring, but some pigmented rings oc-curred without hyaloid bodies. His mother's familycame from the same region as his father's. Althoughno common ancestors have been found, intermar-riage in earlier generations seems probable.

    Case 13 (IV-If-This patient, a more distant rela-tive of the other 11 (Fig. I), was born in 1945. In

    1979 the visual acuity of her right eye suddenlydecreased to 20/20. That of her left eye was 20/15.There was a dark elevation in the right fundusbetween the papilla and macula and the retinal layerabove and lateral to the elevation was edematous. Adiagnosis of choroidal melanoma was discussed at asecond hospital. The clinical course was unchangedten months later.

    DISCUSSION

    This degenerative disease with pro-gressive changes in the fundus occurredin a family with many interrelationshipswithin the last seven or eight genera-tions. The ancestors can be traced back tothe 17th century in parish registers. De-fects in or beneath the pigment layer inthe retina, but with a somewhat differentclinical pattern, were found in three rela-tives of the immediate family. In two ofthem retinal exudates had formed. Pa-tient II-14 had scars resembling dissemi-nated chorioiditis and we believe she hasa mild form of this disease. Another fami-ly member (IV-8), a 15-year-old girl, hadpigmentation in the periphery that wasscarce but within physiologic limits. Thesymptoms in the immediate family mem-bers varied somewhat, but were compa-rable when the ages of the patients weretaken into account. The youngest affectedsib (III-l4) did not have exudative symp-toms, but the pigment layer showed thesame defects his older sibs had before thedisease developed.

    Myopia-The parents and all eightchildren had myopia that increased rapid-ly in the active phase of the disease. Theother three members of the pedigreewith possible symptoms of the diseasewere all hyperopic. Myopia was not com-mon in other relatives.

    Albinotic periphery of the fundus-Absence or near absence of pigmentationin the periphery of both the choroid andthe retina occurred in all the subjects,even the youngest, and was probably thefirst sign of the disease. Clumping of thepigment in the retinal tissue occurred

  • VOL. 94, NO.5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 645

    peripherally. Some pigmentary depositscovered the retinal vessels in the mother(Patient II-8), but in all the other affectedsubjects the pigment clumps were situat-ed deep within the retina. Peripheralretinal detachment occurred in one child(III-H). We believe this was a secondarydetachment caused by a shrinking vitre-ous hemorrhage. Dry blood cells werealso found in the vitreous body of theother eye. In all the other subjects thevitreous body was normal for the patient'sage.

    The retinal pigment layer-In some ofthe youngest family members the retinalpigment layer showed only peripheralchanges even on fluorescein angiography,whereas it became grainy and thin laterin the course of the disease and breakswith diffuse borders were occasionallyfound (III-7, III-I0, and III-H). In twocases (III-13 and III-7) a whorl formationwas present in the fundus (Fig. 5, topright), probably as a result of a defect inthe pigment layer of choriocapillaris.

    Bleeding and exudates-We found noconnections between the retinal capillar-ies and the hemorrhages. Bleeding oc-curred deep within the retina, resem-bling, at least in the early stages, juvenilehemorrhagic macular degeneration or an-gioid streaks. The skin of our patientsappeared to be normal. Our findings sup-ported the theory of Ashton and Sorsby''that the cause of this pseudoinflammatorydystrophy lies in Bruch's membrane andthe retinal pigment layer.

    White spots-These hyaloid or colloidbodies deep within the retina developedbetween the ages of 24 and 32 years anddisappeared during the follow-up periodof 15 years. In Patient III-8 they ap-peared two years later than the first exu-dative process in the macula and haddisappeared by the next examination tenyears later. In Patients 1II-9, III-I0, and1II-12 they appeared before the exuda-

    tive process. Hyaloid bodies have beendescribed in some members of familieswith the dominant mode of inheritance"?and also in the two brothers in which theheredity was probably autosomal reces-sive. 17 The spots observed in our familywere deep, small, round or oval, andsimilar to those seen in retinitis punctataalbescens'f and also in another distur-bance of this layer, angioid streaks."

    Retinal vessels-The retinal vesselsand retinal nerve layer are usually nor-mal. The father (Patient II-7) was blind inone eye, however, and the retinal vesselswere narrow and the optic nerve headwas pale. Only a few areas of choriocapil-laris were left. Even the large choroidalvessels were atrophied.

    Dark adaptation-These findings vary,and the changes may be pathologic in thelater stages of the disease. Dark adapta-tion in the parents was nevertheless with-in the normal range for their ages.

    Secondary dyschromatopsia-Second-ary dyschromatopsia developed early inthe follow-up period in all cases. This wasshown best by the increasing error scoreon the Farnsworth-Munsell 100-hue testand the number of misread pseudoiso-chromatic plates. Errors occurred onboth the red-green axis and the blue-yellow axis.

    Visual fields-The exudates and hem-orrhages caused defects in the visualfields. Friedmann tests disclosed smallrelative defects in the central area even inthe early stages of the disease, yearsbefore any other clinical signs werenoted.

    Electro-oculography-The mean valuefor the 14 eyes studied here was 1.87 0.51 (Fig. 10). In nine eyes the light-peak/dark-trough ratio was clearly sub-normal; the mean for these nine eyes was1.55 0.08 (range, 1.42 to 1.69). Ourresults indicated either an age-dependentgeneralized dysfunction of the pigment

  • 646

    ,.100

    &DO

    SOO

    AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1982

    400

    300

    200

    100

    Fig. 10 (Forsius and associates).Average electro-oculographic ampli-tudes of 14 affected eyes (opensquares) compared with the meanamplitudes for normal eyes (aster-isks). Solid circles, normal means 2 S.D.

    I " I I I I I10 12 13 15 17 IS 21 23 2i Min

    +lUiHT 01

    epithelium and outer segments of theretina or an electrical shunt effect causedby lesions in the pigment epithelium andBruch's membrane.

    Iris transillumination-The patientsunderwent iris transillumination in1966. 20 Pigmentation in the iris was usual-ly pale and the iris could be transillumi-nated easily, but the findings were withinthe normal range in all the children.Studies using the infrared transillumina-tion technique" were done in 1979. Irisatrophy was present .in the parents, andalso in some of the affected children (Pa-tients III-9 and III-7). Iris atrophy isuncommon in young people, and mayhave been an anterior segment manifesta-tion of the chorioretinal disease.

    Heredity-All eight children and theirparents had a disease in the fundus withmyopia, atrophy of the retinal pigmentlayer, and an albinotic retinal periphery.All those over the age of 30 years had anexudative process in the central parts ofthe retina, often complicated by hemor-rhages, at some stage in the disease. Thefather and mother of the children haddifferent clinical patterns when first ex-amined, but after an observation period

    of more than 15 years, their fundi werealmost identical. Although all the chil-dren and their parents probably had thesame disease, it is more difficult to deter-mine whether the inheritance of this dis-ease was autosomal dominant or reces-sive. The disease described by Sorsby'had an autosomal dominant inheritance.This pattern was unlikely in our family.Each parent had 11 siblings, several ofwhom reached advanced ages, but onlyone of them (11-14) had symptoms thatmight have been caused by pseudoin-flammatory dystrophy. An autosomaldominant heredity with irregular or lowpenetration, like that described by Fran-cois in 1961,11 could explain why so fewaffected individuals were found in ourfamily. This type of transmission couldalso explain why some of the children,being homozygotes, developed the dis-ease early and in a severe form. How-ever, it is difficult to explain why all eightchildren were affected while so few otherfamily members were. The pattern of thisdisease in our family is best explained byassuming that both parents were homozy-gotes to the same recessive disease de-scribed by Francois;'! All the children

  • VOL. 94, NO. 5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 647

    would then be affected, as was the casehere. Recessive inheritance also logicallyexplains the appearance of disease in sofew other members of the family. Thefamily has been living in the same regionfor many centuries, and the parents haveseveral common ancestors within the lasteight generations. The genealogical rec-ords are well-preserved and contain in-formation on myopia and blindness, butwe found only one male described ashaving low vision. The lack of blindnessin earlier generations argues against dom-inant inheritance.

    Differential diagnosis-This family hada disease similar or identical to that firstdescribed by Sorsby' in 1940 and bestknown as pseudoinflammatory dystrophyof the fundus. Our subjects, however,showed earlier manifestations (the young-est subject affected was 13 years old),progressive myopia, peripheral retinaldegeneration, and, in some cases, dis-turbed dark adaptation.

    It is impossible to distinguish individu-al cases of pseudoinflammatory dystrophyfrom bilateral juvenile hemorrhagic de-generation and central choroiditis causedby histoplasmosis or toxoplasmosis. Bothdiseases often occur in both eyes.Gutman22 described two patients withpresumed ocular histoplasmosis in thesame family. Was this actually pseudoin-flammatory dystrophy? It is also uncer-tain whether the case described byPerdriel and associatesf was pseudoin-flammatory dystrophy or presumed ocu-lar histoplasmosis. Histoplasmosis hasnever been found in Finland. Most of theaffected members of our family under-went serologic testing for toxoplasmosis(the complement fixation test) with nega-tive results.

    If studied at a stage when there are nocentral exudates in the fundus but manywhite spots are present in the deep levelsof the retina and dark adaptation is abnor-mal, this disease could easily be diag-

    nosed as retinitis punctata albescens.White dots have also been described inrecessively inherited generalized choroi-dal sclerosis. 24

    Central areolar choroidal sclerosis usu-ally appears in individuals 40 to 50 yearsof age. White-gray dots may occur in andaround the central area and also in theperiphery. Sorsby and Crick,25 describinga family with myopia, found exudativereactions in the macular area ofa 54-year-old woman. Subretinal hemorrhages inthe central fundus may occur in fundusflavimaculatus degenerations, along withan abnormal electroretinogram and de-layed dark adaptation. However, thewhite dots resemble fishtails in this dis-ease.!

    White dots may also appear in patientswith dominant drusen, but they are largeand situated in the central parts of thefundus. According to Carr, Noble, andNasaduke," three of the families de-scribed by Sorsby, Joll-Mason, and Gar-dener'' and the patients reported by Burn"and Rosen and Leighton7 may have haddominant drusen. Fundus albipunctatusis a rare disease that leaves the centralretina unaffected. The white dots mayresemble those seen in pseudoinflam-matory dystrophy.

    Stargardt's disease usually appears bythe age of 10 years and, to the best of ourknowledge, no hemorrhagic complica-tions have been described. In myopia,stretching of the choroid may causebreaks in Bruch's membrane leading tochoroidal neovascularization and hemor-rhages.

    It may be impossible to distinguishSorsby's pseudoinflammatory dystrophyfrom choroiditis disseminata at the termi-nal stage of the disease, and some mem-bers of our family were thought to havethis condition by their ophthalmologists.

    Hoskin, Sehmi, and Bird! suggestedthat accumulated debris (colloid bodies)in the retina is the initial clinical mani-

  • 648 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1982

    festation and an integral part of the dis-ease. However, fluorescein angiographyshowed the pigment layer to be uneveneven before the colloid bodies appeared,and the Goldmann three-mirror lens con-firmed that the pigment layer was unevenat the time the colloid bodies were ob-served. Some pigment flecks had alreadyrisen into the retina. The white dots andpigment never reached the level of thenerve fiber layer.

    Our studies on the children suggestedthat the small changes on the Friedmannvisual field test and the Farnsworth-MunselllOO-hue test were the first signsof the disease, occurring before the slitlamp disclosed any abnormalities.

    The long observation time allowed usto study the retina carefully before thevisual impairment occurred. One patientreported hazy vision but biomicroscopyshowed nothing unusual until some dayslater. Others were studied during theexudative phase, with and without ac-companying bleeding.

    The leakage appears at points wherethe pigment layer is affected. The retinalcapillaries appear to be normal, so thatthere is every reason to believe that thebleeding is caused by ingrowing vesselsmoving from the choriocapillaris throughthe pigment layer and Bruch's mem-brane. The origin seems to be close tothat for angioid streaks.

    Treatment-Antibiotics were used inmany of our cases, but were of courseuseless. The effect of cortisone is alsodubious. In several cases we tried laserphotocoagulation to stop bleeding and tokeep leakage from the capillaries frompenetrating to the retina through thechoriocapillaris. The results were difficultto evaluate. We succeeded in drying upthe exudate in some eyes and vision im-proved, but the disease progressed out-side this area and in one case (III-13)renewed photocoagulation had no effectand the eye became blind. Hoskin,

    Sehmi, and Bird" also tried photocoagula-tion without success.

    We still think, however, that in somecases a laser may stop the capillaries fromleaking, thus preventing secondary de-struction from bleeding and fibrosis. Thesuspected cases are therefore being fol-lowed up closely. A sudden decrease invision without exudations occurred in onepatient (III-IO), however, and gener-alized atrophy of the choroid and retina isprobably unavoidable.

    REFERENCES

    1. Sorsby, A.: The dystrophies of the macula. Br.J. Ophthalmol. 24:469, 1940.

    2. Deutman, A. F.: The Hereditary Dystrophiesof the Posterior Pole of the Eye. Assen, VanGorcum,1971, pp. 400-408.

    3. Carr, R. E., Noble, K. G., and Nasaduke, 1.:Hereditary hemorrhagic macular dystrophy. Am. J.Ophthalmol. 85:318, 1978.

    4. Hoskin, A., Sehmi, K., and Bird, A. C.:Sorsby's pseudoinHammatory macular dystrophy. Br.J. Ophthalmol. 65:859, 1981.

    5. Sorsby, A., [oll-Mason, M. E., and Gardener,N.: A fundus dystrophy with unusual features. Br. J.Ophthalmol. 33:67, 1949.

    6. Bum, R. A.: Further cases of a fundus dystro-phy with unusual features. Br. J. Ophthalmol.34:393, 1950.

    7. Rosen, E. S., and Leighton, D.: Fluoresceinphotography of generalized dominant fundus dystro-phy. Br. J. Ophthalmol. 52:828, 1968.

    8. Ashton, N., and Sorsby, A.: FUndus dystrophywith unusual features. A histological study. Br. J.Ophthalmol. 35:751, 1951.

    9. Babel, M. J.: Le role de lachoriocapillaire dansles affections degeneratives du pole posterieuer.Bull. Soc. Ophtalmol. Fr. 71:389, 1958.

    10. Bedell, A. J.: Progressive bilateral chorioret-initis. Kodachrome record for 18 years. Am. J.Ophthalmol. 52:343, 1961.

    11. Francois, J.: Heredity in Ophthalmology. St.Louis, C. V. Mosby, 1961, p. 475.

    12. Seedorf, H. H.: Hereditary renal glycosuriawith central macular degeneration. Acta Ophthal-mol. 40:91, 1962.

    13. Lefler, W. H., Wadsworth, J. A. C., and Sid-bury, J. B., Jr.: Hereditary macular degenerationand amino-aciduria. Am. J. Ophthalmol. 71:224,1971.

    14. Fraser, H. B., and Wallace, D. C.: Sorsby'sfamilial pseudo-inflammatory macular dystrophy.Am. J. Ophthalmol. 71:1216, 1971.

    15. Kalmus, H., and Seedburgh, D.: Probablecommon origin of a hereditary fundus dystrophy(Sorsby's familial pseudoinHammatory macular dys-

  • VOL. 94, NO. 5 PSEUDOINFLAMMATORY FUNDUS DYSTROPHY 649

    trophy) in an English and Australian family. J. Med.Genet. 13:271, 1976.

    16. Babel, J., Cabernard, E. , Krauchi, H.,Klein, D., Korol, S., and Schafroth, P.: Dystrophiechorioretinienne dominante. Klin. Monatsbl. Augen-heilkd. 176:600, 1980.

    17. Francois, J.: L'electro-retincgraphie dans lesdegenerescences tapeto-retiniennes peripheriques etcentrales. Ann. Oculist. 185:842, 1952.

    18. Forsius, H., and Eriksson, A. W.: Tapeto-retinal degenerations with varying clinical features inAland Islanders. J. Med. Genet. 7:200, 1970.

    19. Liegl, 0.: Pseudoxanthoma elasticum mitDrusen am Augenhintergrund ohne Pigmentstreif-en. Klin. Monatsbl. Augenheilkd. 128:467, 1956.

    20. Waardenburg, P. J., Franceschetti, A., andKlein, D.: Genetics and Ophthalmology. Assen, VanGorcum, 1961, vol. 1, p. 64.

    21. Saari, M., Vuorre, 1., and Nieminen, H.:Infrared transillumination stereophotography of nor-mal iris. Can. J. Ophthalmol. 12:308, 1977.

    22. Gutman, F. A.: The natural course of activechoroidal lesions in the presumed ocular histoplas-mosis syndrome. Trans. Am. Ophthalmol. Soc.77:515, 1979.

    23. Perdriel, G., Bouchat, J., Comand, G., andChevaleraud, J.: A propos d'un cas de degeneres-cence maculaire du type inHammatoire de Sorsby.Bull. Soc. Ophtalmol. Fr. 68:455, 1968.

    24. Guglianetti, L.: Sur la sclerose generalisee desvaisseaux choroidiens d'origine familiale. In XVIConcilium Ophthalmologicum, London, 1950. Lon-don, British Medical Association, 1950, vol. 1, p.493.

    25. Sorsby, A., and Crick, R. P.: Central areolarchoroidal sclerosis. Br. J. Ophthalmol, 37:129, 1953.

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