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Show Journal of Clinical Neuro~ophthalmology 13(21: 79-97, 1993 Acute Zonal Occult Outer Retinopathy Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992 J. Donald M. Gass, M.D. 'C;, 1993 Raven Press, Ltd" New York Purpose: This report describes 13 patients, predominantly young women, with a syndrome characterized by rapid loss of one or more large zones of outer retinal function, photopsia, minimal funduscopiC changes, and electroretinographic abnormalities affecting one or both eyes. All patients on follow-up examination had persistent visual field defects, and most had chronic photopsia and zones of pigment epithelial atrophy. Evidence is presented that these patients probably represent part of the spectrum of a single disorder that includes the multiple evanescent white-dot syndrome (MEWDS), acute idiopathic blind-spot-enlargement syndrome (AIBSES), acute macular neuroretinopathy (AMN), and the pseudopresumed ocular histoplasmosis syndrome (P-POHS). Methods: The medical records of these 13 patients and 2 additional patients, who developed, in addition to the features of this syndrome, funduscopic changes typical of MEWDS, AMN, and P-POHS, were reviewed and follow-up obtained. Results: These patients had extensive unrewarding medical and neurological investigations because of suspected diagnoses, including central nervous system disorders, cancer-associated retinopathy, retinal vasculitis, diffuse unilateral subacute neuroretinitis, and tapetoretinal degenerations. Although most patients retained good visual acuity, all had permanent visual field loss that in some cases was severe. The cause of the disorder was not determined. No effective treatment was found. Conclusions: Acute visual loss and photopsia in these patients is probably caused by damage to large zones of the outer retina that appears unaffected ophthalmoscopically. Electroretinography is important in early diagnosis. Future investigations probably will reveal further evidence linking this disorder to MEWDS, AIBSES, AMN, and P-POHS. Key Words: Scotomata-Photopsia-Electroretinography. From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida, U.S.A. This investigation was supported in part by Public Health Service Research Grant EY02549 and Core Grant EY02180, Department of Health and Human Services, National Institutes of Health, National Eye Institute, and in part by Research to Pre~ vent Blindness, Inc., New York City. Address correspondence and reprint requests to Dr. J. Donald M. Gass, Bascom Palmer Eye Institute, P.O, Box 016880, Miami, FL 33101, U.S.A. 79 This report concernS a clinical syndrome characterized by (a) acute loss of one or more zones of outer retinal function, involving one or both eyes of predominantly young women, usually associated with photopsia, (b) minimal or no fundus changes initially, (C) electroretinographic abnormalities, and (d) permanent visual field loss that is often associated with late development of fundus changes. These patients were subjected to extensive medical and neurological investigations because of suspected optic neuritis, central nervous system disorders, retinal vasculitis, cancer-associated retinopathy, and tapetoretinal dystrophy. The purpose of this report is to present evidence that these patients represent part of the spectrum of what probably is a single disease, that includes the multiple evanescent white-dot syndrome, acute idiopathic blind-spat-enlargement syndrome, acute macular neuroretinopathy, and the pseudo-presumed ocular histoplasmosis syndrome. Acute zonal occult outer retinopathy is suggested as an appropriate name for this disorder. METHODS AND MATERIALS Since 1986 I have examined 10 patients and followed by mail consultation 3 other patients with the aforementioned syndrome. All patients had complete eye examinations that included fundus photography, fluorescein angiography, and electroretinography. All had medical consultation, and all but one had neurological consultation that included at least the following: magnetic resonance imaging or computed tomography, brain scan, chest radiography, routine blood counts, sedimentation rate, blood chemistries, ANA, rheumatoid factor, RPR, and FTA-ABS. Three had serologic analysis for antibodies to retinal proteins (retinal S antigen, rhodopsin, interreceptor binding protein, 80 f. D. M. GASS CASE REPORTS Case 1 Case 3 On January 14, 1988, a healthy 25-year-old woman developed photopsia and a large central trophoresis, and angiotensin-converting enzyme were negative. HLA B27 assay was positive. One month later, she developed a zone of pigment epithelial depigmentation and focal venous sheathing in the inferotemporal quadrant of the right fundus (Fig. 2). During the subsequent 6 years she was bothered by the photopsia and the field defect, both of which were accentuated by bright light, upper respiratory infections, and fatigue. Although she believed that the scotoma in the right eye had enlarged somewhat, serial visual fields showed no change. At last examination her visual acuity was 20/20 bilaterally, and the fundi were unchanged except for intraretinal migration of pigment within the depigmented zone inferotemporally in the right eye and several focal areas of perivenous sheathing in the retina of the left eye nasally. Color vision (Hardy-Rand-Rittler plates) testing was normal in both eyes. Electroretinography revealed subnormal rod and cone amplitudes in the right eye. Electrooculography showed a reduced response in the right eye (Arden ratio: 1.71 right eye, 2.68 left eye). Case 2 In September 1988, a 13-year-old girl noted a large temporal scotoma in the right eye. Initial examination by her optometrist revealed no explanation for her complaints. She was referred to a retinal specialist in April 1989. Her visual acuity at that time was 20/30 right eye, 20/20 left eye. There was a dense scotoma temporally and inferiorly on Amsler grid testing and to finger-counting in the right eye. Ophthalmoscopic examination of the right eye revealed a large, sharply defined 12 x 15 mm zone of mild depigmentation of the pigment epithelium that involved the juxtapapillary area and extended into the midperiphery nasally. There were 1+ vitreous cells in the right eye. Fluorescein angiography showed the large zone of depigmentation in the right eye. It was normal in the left eye. Electroretinographic examination revealed reduced rod and cone amplitudes and delayed responses in the right eye. Electrooculography showed no light rise in the right eye and was normal in the left eye. In February 1992, her examination was unchanged except for greater prominence of the pigment epithelial atrophy. CASE 3 00 CASE 5 00 i CASE 1 00 ~ , • V .(!J I CASE 8 OS CASE 10 00 CASE 10 OS 0~~ CASE 5 OS CASE 6 OS CASE 8 00 In June 1986, a 29-year-old female nurse noted a large scotoma associated with the acute onset of "a blue light, iridescent flash, and shimmering heat wave" involving the superonasal visual field of the right eye. Examination by several ophthalmologists revealed visual acuity of 20/20 in both eyes, vitreous cells in the right eye, normal fundi, and a dense peripheral superonasal visual field defect in the right eye (Fig. 1). Neurological examination and investigations, including visual evoked response, complement C3, C4, CH 1100, serum elec-and cancer-associated antigen) by Dr. C. E. Thirkill. All patients were followed for 6 to 71 months (mean: 33 months; median: 27 months). No patient meeting the selection criteria was lost to follow-up. To demonstrate the interrelationship between these patients and those previously reported as having the multiple evanescent white-dot syndrome, acute idiopathic blind-spot-enlargement syndrome, acute macular neuroretinopathy, and the pseudo-presumed ocular histoplasmosis syndromes, two additional case reports (Cases 14 and 15) are presented. Details of the early clinical course of one (Case 14) have been previously reported (1). FIG. 1. Diagrams of Goldmann visual fields, 111-4e, and in Case 3, 1-4e. I CI/II NellrtHl/,hI/Ullmol. Vol. 13. No.2. 1993 ZONAL OCCULT OUTER RETINOPATHY 81 A B FIG. 2. Case 1: Right eye. A-B: Inferotemporal zone of depigmentation of pigment epithelium. Arrows indicate focal perivenous sheathing and staining. Continued. and temporal scotoma in the right eye. Examination revealed visual acuity of 20/400 right eye, 20/20 left eye, and a 4 + afferent pupillary defect in the right eye. Visual field examination showed a large dense central and temporal defect (Fig. 1). The fundi were normal. Retrobulbar neuritis was suspected. Neurological examination and laboratory investigations, including visual evoked potential, were normal. One month later the visual acuity was 20/200 right eye and the visual fields were unchanged. Examination of the right fundus and fluorescein angiography revealed two subtle discrete zones of pigment epithelial depigmentation. One zone was at the temporal margin of the macula, and the other large zone surrounded the optic disc and extended to the equator nasally (Fig. 3). In February 1989, an electroretinogram revealed reduced rod and moderately abnormal cone responses in the right eye. In March 1989, the visual function of both eyes was unchanged. There was no evidence of optic atrophy or abnormality in the central macular area of the right eye. Telephone follow-up in May 1992 revealed no change in symptoms. Case 4 In October 1988, a 25-year-old male medical student developed "blips of burgundy and yellow JClill Neuro-ophlhalmol. Vol. 13. No.2. 1993 82 f. D. M. GASS c FIG. 2. Continued. (C): Six years later showing intraretinal migration of pigment epithelium. lights with amoeboid movement" in the superior visual fields of both eyes. This was followed within a few days by a large scotoma involving most of the superior visual field of both eyes. The fundi were normal. Neurological examination and laboratory investigations, including HIV titers, were normal. When examined 1 month later, his visual acuity was 20/15 in both eyes, and the visual fields were unchanged (Fig. 4). There were a few vitreous cells in the left eye. The fundi were normal. Electroretinography revealed reduced cone responses bilaterally, more so in the left eye. Over the subsequent months there was incomplete resolution of the scotomata and photopsia, but both were still present in October 1990. Case 5 In November 1991, a healthy 33-year-old man suddenly noticed "persistent and constantly moving blue and red dots of light" and a scotoma in the inferonasal field of the left eye. Several days later he developed an inferior scotoma in the right eye. One month later his visual acuity was 20/20 bilaterally. Fundus examination and fluorescein angiography were normal. Visual field examination showed slight blind-spot enlargement bilaterally and a dense scotoma inferiorly in the right eye and nasally in the paracentral area in the left eye (Fig. 1). Neurological examination and laboratory studies including visual evoked responses, color vision testing, and Lyme Western blot were normal. In January 1992, a focal electroretinogram was abnor- I Clm Nt'lIro-0l'hthalnwl. Vol. 13, No.2, 1993 mal in the left eye. When examined 6 months after the onset of symptoms, his visual acuity and visual fields were unchanged. There were no vitreous cells. His fundi were normal except for a subtle, 2 x 3 disc-diameter zone of depigmentation of the pigment epithelium temporal to the center of the macula in the left eye (Fig. 5). Case 6 On July 13, 1989, a 63-year-old woman noted the abrupt onset of photopsia and a scotoma temporally in the left eye. Several years previously she had repair of a rhegmatogenous detachment in the right eye. Visual acuity in that eye did not return to normal postoperatively. Examination by her local physician and a retinal specialist failed to find a cause for her complaints. Neuro-ophthalmological and neurological consultations provided no explanation for her large dense temporal visual field defect in the left eye (Fig. 1). Studies, including cerebral arteriography and bronchoscopy, were unrevealing. Examination on July 31, 1989 revealed visual acuity 20/60 right eye and 20/30 left eye, a 1+ left afferent pupillary reaction, and 2+ vitreous cells in the left eye. Her visual fields were unchanged. Both fundi were normal except for evidence of an equatorial scleral buckle in the right eye and mild juxtapapillary pigment epithelial atrophy in both eyes. The latter was evident by fluorescein angiography that was otherwise normal. Electroretinography revealed 20% reduction in the rod and cone amplitudes in the left eye. The pho- ZONAL OCCULT OUTER RETINOPATHY 83 FIG. 3. Case 3: Right eye. Top (left & right): Arrows indicate temporal and juxtapapillary zones of pigment epithelial depigmentation. Bottom (left & right): Angiogram shows two zones of depigmentation neither of which extends into the foveal center of this patient whose visual acuity was 20/200. topsias and the scotoma lessened over the following few months. In August 1991, the visual acuity in the left eye was 20/20, there were fewer vitreous cells, and the visual field defect was smaller. In June 1992, she was still aware of the scotoma but no longer had photopsia. Case 7 On June 8, 1989, a healthy 44-year-old airline stewardess developed a scotoma superotemporally and "an explosion of pink, white, blue, and red lights, like St. Elmo's fire on the control panel of an airliner" in the right eye. The scotoma progressed to involve the nasal field. Examination by her local physician revealed bilateral superior visual field defects and 20/20 visual acuity (Fig. 4). The fundi were normal. Color vision (Hardy-RandRittler plates) and fluorescein angiography were normal. Neurological and medical evaluations were normal except for elevated blood pressure and hypercholesterolemia. When examined here on August 3, 1989, the visual acuity and fundi were normal. Central field examination revealed a biquadrantic superior field defect involving the blind spot in the right eye and a similar but less prominent defect in the left eye. She was asymptomatic in the left eye. Electroretinography revealed low normal amplitudes in both eyes. The cones were more affected than the rods and the right eye was more affected than the left eye. In September 1990, there was slight improvement in the visual fields. Telephone follow-up in May 1992 revealed that the scotoma and photopsia in the J Clin Nt'liro-ophthalmol, Vol, 13, No.2, 1993 84 f. D. M. GASS CASE 4 00 CAse II OS CASE" os CASE 11 (lD CASE 7 00 " -. , CASE 11 OS CASE 7 OS CASE 12 00 CASE 12 os c....se 13 os CASE 13 OD FIG. 4. Diagrams of 3D-degree Humphrey visual fields. Solid black is region ,.;;0 dB and shaded area is ,.;;10 dB, roughly equivalent to 111-4e and 1-4e on Goldmann perimeter. right eye were unchanged. She had no symptoms in the left eye. Case 8 On September 26, 1986 a 24-year-old woman, who was recovering from an upper respiratory infection, awoke to find she had loss of peripheral vision, photopsia, and nyctalopia in both eyes. Several days later, examination by her local ophthalmologist revealed multiple widespread dense scotomata in both eyes and normal fundi (Fig. 6). Visual acuity was 20/200 right eye and 20/20 left eye. Over the subsequent 3 weeks her vision deteriorated further, and the field defects became confluent. Her visual acuity was 20170 right eye and 20/300 left eye. There were a few anterior chamber cells, many vitreous cells, and retinal perivenous cuffing in both eyes. Sarcoidosis was suspected but medical and neurological evaluation were negative. She was treated with oral prednisone and the visual acuity improved. By November 1986, she had developed narrowing of the retinal vessels bilaterally. Her visual evoked potential was abnormal in both eyes. Electroretinography revealed extinguished rod responses and cone responses 10% of normal in both eyes. In March 1987, her visual acuity was 20/30 right eye and 201 40 left eye. In both eyes, there were marked visual field defects (Fig. 1), vitreous cells, retinal vessel narrowing, and attenuation of the retinal pigment epithelium that were not evident in her initial fundus photographs (Fig. 6). She missed 10 of 15 Ishihara plates with the right eye and 15 of 15 with the left eye. Over the following 4 years the pigment epithelial atrophic changes became more prominent and were associated with bone-spicule migration into the retina. Despite minimal changes in her visual fields, the patient continued to lose central vision in her left eye. At the time of last examination in April 1991, the visual acuity was 20/25 right eye and 20/200 left eye. She was still bothered by photopsia and "wormlike movements" in both eyes. Case 9 In January 1989, a 23-year-old woman noted floaters, photopsia, and, within several months, an inferior scotoma that soon extended to involve the superior visual field in the left eye. Around 18 ZONAL OCCULT OUTER RETINOPATHY 85 FIG. 5. Case 5: Left eye. A & B: Arrows indicate zone of pigment epithelial depigmentation and prompt perfusion of underlying choriocapillaris. months previously she had had infectious mononucleosis and chronic fatigue thereafter. In April 1989, a retinal specialist noted mild swelling of the left optic disc and slight narrowing of the retinal arteries. Visual field examination revealed a marked loss of the peripheral field in the left eye (Fig. 4). The visual field was normal in the right eye. Neurological and rheumatological evaluations, including lumbar puncture and complement C3/C4, were normal, except for an ANA of 1:2560. A several weeks course of oral and sub-Tenon's injections of corticosteroids produced no improvement. Examination here in June 1989 revealed visual acuity 20/20 right eye, 20/25 left eye, a 3+ left afferent pupillary defect, and marked constriction of the left visual field to counting fingers. In the left eye there were 1+ vitreous cells, mild blurring of the optic disc margin, some narrowing of the retinal vessels and diffuse hypopigmentation of the pigment epithelium in the mid- and peripheral fundus (Fig. 7). Fluorescein angiography showed evidence of these changes as well as mild diffuse intraretinal staining in the posterior fundus. The right eye was normal. Visual field examination was unchanged. Electroretinography revealed extinguished rod and markedly reduced cone function in the left eye. Responses in the right eye were normal. Her last examination in May 1992 revealed no change in her eye examination and electroretinographic findings. She still complained of photopsia. Case 10 In July 1988, a 36-year-old woman developed allergic bronchitis and conjunctivitis that she attributed to cleaning a dusty attic. One month later she struck the right side of her head on her car door. I (Ii" Nl'lIro·"l'hthalmol. Vol. 13. No.2, 1993 86 J. D. M. GASS FIG. 6. Case 8: Top (left & right): Right eye, September 1986. Bottom (left & right): Right and left eyes, 7 months later. Note narrowing of retinal blood vessels. Several weeks later she became aware of loss of side vision, blurred central vision and "an orange spray of lights" temporally in the right eye. Her local ophthalmologist noted a peripheral round retinal hole, some narrowing of the peripheral retinal vessels, cystoid macular edema, and unexplained loss of the temporal visual field in the right eye. The left eye was normal. In retrospect, the patient recalled that defective temporal vision in the right eye was probably the cause of her head injury. The retinal hole was treated with photocoagulation, and she was referred for medical and neurological evaluations that were negative. Her medical history was positive for an episode of pseudomembranous colitis in 1985, severe gastroenteritis of undetermined cause in 1987, and recurrent episodes of herpetic gingivitis and dermatitis. Over the following few months there was progressive loss of the peripheral visual field and narrowing of the retinal vessels in the right eye. An elec- I CII/I ."Jeuro-ophthai/1/oi, Vol. 13. No.2. 1993 troretinogram in October 1988 revealed marked reduction of the A and B wave amplitudes in both photopic and scotopic conditions in the right eye. The left eye was normal. On examination here in December 1988, her visual acuity was 20/30 right eye and 20/15 left eye. In the right eye she had a 2+ afferent pupillary defect, 1 + vitreous cells, cystoid macular edema, narrowing of the retinal vessels, diffuse slight depigmentation of the retinal pigment epithelium, and marked constriction of the visual field (Fig. 8). The left eye was normal except for a small focal atrophic scar superior to the optic disc (Fig. 8). Fluorescein angiography revealed a large juxtapapillary zone of early hyperfluorescence and no evidence of late staining in the macular area of the right eye (Fig. 8). Frequent visual field examinations showed stabilization of the field loss in the right eye by March 1989 (Fig. 1). During this time the photopsia and the cystoid macular edema diminished. The patient remained ZONAL OCCULT OUTER RETINOPATHY 87 A 8 FIG. 7. Case 9: (A & B): Right and left eyes. Note narrowing of retinal vessels in left eye. Continued. asymptomatic in the left eye until September 1990, when, soon after developing allergic bronchitis and conjunctivitis, she experienced the rapid onset of photopsia and visual field loss in the left eye. It began in the temporal field and spread to involve much of the peripheral field within several weeks. Examination confirmed the visual field loss and revealed trace vitreous cells and a normal fundus of the left eye. One month later visual acuity was 20/25 bilaterally. In the left eye there was narrowing of the retinal vessels. Fluorescein angiography was unchanged in both eyes. Cancer-associated retinopathy was suspected. Medical evaluation including CT scans of the chest and abdomen, mammograms, serum protein electrophoresis, lupus anticoagulant, anticardiolipin, and antithrombin III were within normal limits. Serological titers for Lyme disease, Epstein-Barr virus, Coxsackie virus, herpes simplex virus IgM, herpes zoster IgM, and influenza A and B virus were negative. Herpes zoster virus IgG was positive 1:256. An assay for circulating antibodies to retinal antigens was negative. Despite orally administered prednisone 60 mg/ day for 2 months, the visual field loss progressed and she developed blurred vision and cystoid macular edema. Electroretinography revealed extinguished scotopic and minimal photopic responses in both eyes. Electrooculography revealed an Ardan ratio 1.27 right eye and 1.14 left eye. Progression of the visual field loss in the left eye stopped after 4 months (Fig. 1). By December 1991, the funduscopic and angiographic findings in the left eye were the same as the right eye (Fig. 8). On last examination, in June 1992, her visual acuity was 20/25 right eye and 20/20 left eye. There were 1+ 88 J. D. M. GA55 c o FIG. 7. Continued. (C & D): Left eye. Angiograms show evidence of diffuse pigment epithelial depigmentation and mottled hyperplasia (arrows) and cystoid macular edema (arrowhead). vitreous cells and cystoid macular edema bilaterally. Visual fields were unchanged. Case 11 In July 1991, a 41-year-old woman presented with the history that 2 years previously in Cuba she noted the onset of "firecrackerlike" lights and a scotoma that began temporally and rapidly spread to involve all of the peripheral field of the right eye. She was examined by several ophthalmologists who initially could find no cause for the visual loss. Neurological evaluation was unremarkable. Later diagnoses of posterior uveitis and unilateral retinitis pigmentosa were made. Unsuccessful treatments included oral corticosteroids, vitamin A, plasmapheresis, and "artery transplant" to the temporal wall of the right eye. An electroretinogram in June 1990 was reported as extin-guished in the right eye and subnormal in the left eye. At the time of examination here she complained of chronic photopsia and visual loss in the right eye. Her visual acuity was 20/40 right eye, 20/20 left eye. In the right eye there was a 1+ afferent pupillary defect, 1+ vitreous cells, cystOid macular edema, diffuse depigmentation of the pigment epithelium, and narrowing of the retinal vessels. The left eye was normal except for mild pigment epithelial mottling anterior to the equator. Visual field examination showed marked concentric constriction of the field in the right eye and slight nasal constriction in the left eye (Fig. 4). An electroretinogram revealed extinguished rod function and markedly abnormal cone function in the right eye. Electroretinography was normal in the left eye. Four months later her visual field and other findings were unchanged. ZONAL OCCULT OUTER RETINOPATHY 89 FIG. 8. Case 10: (A & B): Right and left eyes, December 1988. Note narrowing of retinal blood vessels, juxtapapillary pigment epithelial depigmentation, cystoid macular edema (arrow) in the right eye, and a depigmented scar (arrowhead) in the left eye. (C): Angiogram showing juxtapapillary zone of depigmentation and no staining in the area of cystoid macular edema. Continued. , Gin Neuro-opl,thalmol, Vol. 13, No.2. 1993 90 ]. D. M. GASS o FIG.8. Continued. (D): Left eye, December 1991. Note narrowing of retinal vessels. Case 12 In late 1987, a 34-year-old woman noted loss of peripheral vision nasally in the right eye associated ",:ith photopsia and light sensitivity. One year prevlOusly she had had a prolonged illness associated with infectious mononucleosis. Her past medical history was otherwise negative except for an allergic reaction to penicillin. On initial eye examination in August 1988, her visual acuity was 20/25 bilaterally, and the fundi were normal except for a few flecks of pigment temporally in the right eye and mild mottling of the pigment epithelium peripherally bilaterally. Visual field examination revealed an arcuate scotoma that involved most of th~ superior and nasal visual field of the right eye (Fig. 4). There was enlargement of the blind spot in the left eye. Fluorescein angiography, Farnsworth 0-15 color panel and visual evoked potential were normal. Neurological examination that included electroencephalography was within normal limits. IgG and IgM titers for Epstein-Barr virus were positive. Electroretinography showed reduction of the B-wave to 70 microvolts with normal implicit times in the right eye. The left eye was normal. In August 1989, examination here revealed her visual acuity was 20/25 bilaterally. In the right eye there were a 1+ afferent pupillary defect, 1+ vitreous cells, a wedge-shaped area of depigmentation of the pigment epithelium and bone-spicule intraretinal pigmentation nasally from 2 to 3 o'clock. There were several flecks of intraretinal pigment in the midperiphery in the left eye nasally. The retinal vessels posteriorly and optic discs were normal in both eyes. There was narrowing of the peripheral retinal vessels in the right eye. The visual fields were unchanged. Electroretinography revealed re-duced rod and cone amplitudes in the right eye; reduced rod amplitudes and borderline cone amplitudes and timing in the left eye. In May 1990, she returned complaining of further visual loss in the right eye. Visual acuity was 20/50 right eye and 20/20 left eye. The visual field revealed new involvement of the superonasal paracentral field of the rig~t eye. ~o ~ther changes were present. Spinal flUld exammation and serum Lyme titers were negative. Screening for HLA group A, B, C, DR, and DQ antigens was positive for A3, A31(19), B8, B35, Bw6, Cw4, Cw7, DR3, DR4, DQ2, DQ3, DR52, and DR53. The patient received a 2-month course of oral prednisone. 80 mglday at tapering doses, supplemented with several sub-Tenon's injections of prednisolone, followed by a 2-month course of oral acyclovir 800 mg five times daily. Between October 1990 and May 1991, visual field examinations revealed development of a small superior paracentra~ arcuate scoto,:,a in the left eye. Repeat spinal flUld and serologiCal examinations for Lyme disea~ e were negative. Nevertheless, the patient received cephtriaxone intravenously for 13 days before it was discontinued because of diarrhea and f~ver. Orally ~drninisteredvancomycin hydrochlonde 100 ~g-bid was given for 1 month. The patient noted no improvement, and the acuity in the right eye decline~ to 20/400 by November 1991. In May 1992 her visual acuity, visual field and electroretinographic findings were uncha~ged. Case 13 .On June 15, 1990, a 17-year-old male student with a 3-week history of coryza and allergic rhinitis ZONAL OCCULT OUTER RETINOPATHY 91 noted the rapid onset of a scotoma that began temporally but rapidly spread to involve the nasal and paracentral visual field of the left eye. The patient denied photopsia. His medical history was positive for hay fever and allergy to penicillin. Examination by his local ophthalmologist revealed normal visual acuity, ophthalmoscopic, and fluorescein angiographic findings in both eyes. There were multiple zones of visual field loss involving the blind spot, the inferior and superonasal fields (Fig. 4). Medical and neurological investigations, including echocardiogram, electrocardiogram, antiphospholipid antibodies, and antibodies to HIV and Epstein-Barr virus were negative. Screening for HLA-A and -C and HLA-DR antigens were positive for A, A29, B7, B8, DR2, and DRW6. An electroretinogram revealed 75% reduction in cone amplitudes and 25% reduction in rod amplitudes in the left eye. The patient noted progressive visual field loss for 2 months, followed by slow improvement. When examined on February 19, 1991 his visual acuity was 20/20 bilaterally. Amsler grid testing revealed a small central island of vision in the left eye. The fundi were normal. Tangent field examination revealed a 10 x 15 degree enlargement of the blind spot to 18/1000/W test objects and loss of all field beyond the central 10 degrees to 18/10001red and blue test objects in the left eye. The visual field was normal in the right eye. An electroretinogram done 2 weeks later was unchanged. On May 16, 1992 during an exacerbation of hay fever, he developed in the right eye the acute onset of a superior nasal scotoma that spread within 2 days to involve most of the superior and nasal visual field. Visual acuity was 20/20 bilaterally. There were 1+ vitreous cells in the right eye. The fundi of both eyes were normal. Visual field examination revealed extensive temporal and nasal field loss in the right eye (Fig. 4). The visual field in the left eye was slightly improved compared to the fields done 2 years previously. A standard electroretinogram done 4 days after the onset of symptoms was within normal limits, although the rod amplitudes were reduced compared to previous recordings in the right eye. The left eye was unchanged. A focal electroretinogram done 1 week later revealed moderate depression of responses in the right eye. Several weeks later he noted "bursts of light with amoeba-like movement" involving all of the zones of visual loss in the right eye. Fluorescein angiography, serum antiphospholipid, herpes simplex, and retinal antigen titers were negative. EpsteinBarr titers were compatible with past infection (IGG antibody to YCA 1:320). Case 14 In February 1982, a 23-year-old woman developed photopsia and paracentral scotomata that corresponded with multiple reddish-orange outer retinal lesions typical of acute macular neuroretinopathy in the left eye. The lesions and the photopsia gradually disappeared, but some of the paracentral scotomas remained until January 1987, when she noted the acute onset of photopsia, multiple small central scotomas, and a large temporal scotoma in the left eye. She described the photopsia as "multiple dancing spots of light, like bacteria under a microscope" within each of the scotomatous areas. Her visual acuity in the left eye was 20/80. The fundus of the left eye showed multiple grey-white lesions scattered in the peripheral macular and juxtapapillary areas and fluorescein angiographic changes typical for the multiple evanescent white-dot syndrome. There were multiple rings of early pinpoint hyperfluorescence and patchy areas of late staining in the macular and juxtapapillary regions. There was also staining of the optic disc. Amsler grid testing showed multiple small scotomas involving the nasal half of the grid and a large scotoma affecting most of the temporal half of the grid. Electroretinography revealed moderately reduced rod and cone responses in the left eye. The white spots disappeared within several weeks, the visual acuity returned to 20/20 within 2 months. She continued to be bothered by the temporal scotoma and the photopsia, particularly in bright light. By July 1987, there was evidence of slight depigmentation of the pigment epithelium in the juxtapapillary area as well as the temporal periphery in the left eye. A repeat electroretinogram in August 1988 was unchanged. In June 1992, she was still aware of the temporal scotoma and photopsia in the left eye. Her eye findings were unchanged. Goldmann field examination revealed a 20-degree scotoma involving the blind spot of the left eye. Fluorescein angiography revealed a prominent juxtapapillary zone of pigment epithelium depigmentation in the left eye that was not evident in her previous angiogram in January 1987. Case 15 A 48-year-old woman complained of floaters and flashes of light inferiorly in the left eye of 3 months duration. Visual acuity was 20/25 right eye and 20/ 30 left eye. In the left eye there were 2 + vitreous cells and the left optic disc margins were indistinct. In both eyes there were many widely scattered fo- J Clill Nflln>-vp"thalnrol. Vol. 13. No.2. 1993 92 f. D. M. GASS cal atrophic chorioretinal scars that were most prominent in the superior temporal quadrants in the midperiphery. There was no evidence of choroidal neovascularization. The diagnosis was the pseudo-presumed ocular histoplasmosis syndrome. One year later she returned, complaining of recent acute loss of vision, a temporal scotoma, photopsia, and light sensitivity in the left eye. Her visual acuity was 20/20 right eye and 20/80 left eye. There was a 2 + left afferent pupillary reaction. The fundi were unchanged except for slight narrowing of the retinal arteries in the left eye (Fig. 9). She missed all but one of the pseudoisochromatic plates with the left eye. There was marked enlargement of the blind spot and loss of a large segment of the inferior nasal field in the left eye. The diagnosis was retrobulbar neuritis. Laboratory studies, including chest radiograph, FTA-ABS, RPR, and tuberculin and mumps skin tests were normal. Lyme disease index was 1.3 (normal <1) and Lyme disease IgG titer was 1:128 (presumptive evidence of recent infection). Epstein-Barr viral titers were capsid antigen (IGG) 1:40, and nuclear antigen 1:40 (normal 1:10). Angiotensin-converting enzyme level was 15. Electroretinography revealed markedly reduced rod and mixed rod-cone amplitudes and extinguished cone responses in the left eye. The responses in the right eye were normal. Nine months later the eye findings were unchanged. FINDINGS Cases 1-13 Tables 1 and 2 summarize the demographics and the eye findings in these patients at the time of their presentation to the referring physician. Table 3 summarizes their eye findings at the time of my initial examination that occurred between 2.5 weeks and 24 months (mean and median: 5 I Gin Nl"uro-ophthalmol, Vol. 13, No.2, 1993 FIG. 9. Case 15: Left eye. Top & Bottom: Note vitreous haze, blurred optic disc margins, narrowing of retinal arteries, and focal areas of depigmentation in the periphery. ZONAL OCCULT OUTER RETINOPATHY 93 TABLE 1. Patient characteristics (N Characteristic Mean j: SEM 13) Range TABLE 3. Characteristics of eyes at initial examination by the author (J.D.M.G.) (N = 22ya • Data not always available on all 22 eyes. Mean: 20/25 20/1:r20/200 11/21 (52) 9/22 (41) 10/22 (45) 3/12 (25) 17/21 (81) 3'3 (100) 2/11 (18) Age at presentation Weeks to presentation Months of follow-up Female Bilateral Antecedent illness Oral contraceptives or estrogenic medications Major medical evaluation Relative afferent pupillary defect Caucasian 30 j: 3.9 7 j: 3.7 34 j: 5.2 N(%) 10 (77) 9 (69) 5 (38) 1 (8) 12 (92) 6 (46) 13 (100) 7-63 0.6--52 6--71 Characteristic Visual acuity Vitreous cells Normal fundus Zonal atrophy of retinal pigment epithelium Color vision abnormal Electroretinogram abnormal Electrooculogram abnormal Visual evoked response abnormal N(%) Range TABLE 2. Characteristics of eyes at presentation to referring physician (N = 22) months) after the onset of their symptoms. Table 4 summarizes their eye findings at their final examination that occurred between 6 and 71 months (mean: 33 months; median: 27 months). . These pr~dominantly young female (77%) patients expenenced rapid onset of visual field loss that most frequently involved the superior and temporal quadrants, often included the blind spot, and only occasionally caused loss of visual acuity. During the early course of the disease, 18 of 22 affected eyes (82%) had 20/30 or better visual acuity. The scotomas typically increased in size within a matter of days or weeks before stabilizing. In some cases enlargement continued for 2 to 6 months. Several patients complained of progression beyond 6 months, but this could not be documented objectively. In most cases the visual field loss in the two eyes was asymmetric. In all but four patients, depigmentation of the retinal pigment epithelium corresponding with part or all of the zones of visual loss occurred usually within several months (Figs. 2,3,~8). Initially, this change was subtle ophthalmoscopically but was easily detected with fluorescein angiography that demonstrated prompt perfusion of the underlying chorio: apillaris. Narrowing of the retinal vessels oc: urred in the zones of depigmentation, particularly when they were large and involved the peripheral retina. Fluorescein angiography in such cases ;howed evidence of increased retinal circulation Characteristic N(%) Range time in the vessels supplying the affected zones. Later, the depigmentation in these zones became more prominent and, in some cases, there was migration of pigment into the overlying retina (Figs. 2,~8). In some eyes the zones of dense visual field lo~s were larger than the zones of depigmentation (FIg. 3). Other eyes with multiple zones of field loss showed depigmentation in some zones but not i~ others (Fig. 6). In four patients, longstand10g dense scotomas were unassociated with any alterations in the pigment epithelium or retina (Cases 4, 6, 7, and 13). Optic atrophy did not develop, even in eyes with large zones of severe field loss (Figs. 3,6-8). Only 3 patients had symptomatic or documented improvement of the visual field and this occurred within the first 4 months after onset of symptoms. Of the 13 patients, 12 complained of photopsia in at least one of the affected eyes. In 4 patients this occurred within several days or weeks prior to their awareness of a scotoma; in 5 patients it developed simultaneously; and in 3 patients it followed soon after onset of the scotomata. Typically, the photopsia was projected toward the zone of visual loss. The photopsia was often described as multicolored and was associated with micromovements likened to bacteria or amoeba under a microscope. In two patients with ?oth eyes affected, the photopsia was only present 10 one eye. The photopsia and the scotomata in :oost patients we~e accentuated by bright light and I~ some by exerClse, stress, and fatigue. In 10 patients the photopsia was chronic, and was present at the time of last follow-up. TABLE 4. Characteristics of eyes at most recent examination (N = 22) 'isual acuity ~ight eye affected )hotopsia ,ubjective scotoma 'ubjective floaters lormal fundus Mean: 20/30 11 (50) 12 (55) 16 (73) 1(5) 18 (82) 20'1 :r20/200 Characteristic Visual acuity Photopsia Scotoma Normal fundus N(%) Mean: 20/25 13 (59) 14 (64) 8 (36) Range 20/1 :r20/400 I Cli" Nellro-ol",lllalmol, Vol. 13. No.2, 1993 94 J. D. M. GASS Vitreous cells were observed in either one or both of the affected eyes of 11 patients. In 3 with bilateral involvement, cells were present only in the eye with more widespread visual field loss. The vitreous cells were graded as trace to 1+ in 12 eyes and 2 + in 3 eyes. Patients with 2+ cells had large field defects and 2 of them were examined within the first week after onset of symptoms. Two patients developed focal retinal perivenous infiltration or sheathing in the affected eyes (Fig. 2). Mild optic disc swelling was suspected in one patient but failed to change in its appearance several years later. Fluorescein angiography demonstrated some retinal and optic disc vascular leakage in 4 eyes (3 patients), including one with mild cystoid macular edema (Fig. 6). In one patient with bilateral cystoid macular edema, angiography failed to show staining (Fig. 8). Fluorescein angiography was done during the first few weeks after the onset of symptoms in only 5 patients, and was within normal limits in all of them. While all patients had electroretinography, it was done in only 2 patients during the first month of their illness. Most of the affected eyes showed only mild to moderate reduction in rod and cone amplitudes. In a few eyes, the responses were within the lower range of normal but were lower than in the unaffected eye. Even in the most severely affected eyes, the ERG was extinguished in only one patient who later showed ERG evidence of some cone function. In the lesser affected eyes the cone responses generally were affected more than rod responses, whereas the reverse was true in the eyes with severe peripheral field loss. Six patients had evidence of bilateral involvement at the time of presentation. Two of these were asymptomatic in one eye. Three patients had delayed involvement of the fellow eye. In two patients it occurred after an interval of 2 years. In one patient the time of fellow eye involvement that was unassociated with symptoms was unknown. One patient (Case 12) developed a small segmental enlargement of a scotoma in both eyes at 22 and 34 months after the onset of symptoms. This was associated with loss of visual acuity in one eye. Cases 14 and 15 shared several features demonstrated in cases 1-13. The shared features included acute loss of zones of visual field (including blindspot enlargement); absence of fundus findings to explain the field loss; and electroretinographic evidence of outer retinal damage. In Case 14, these features were accompanied by fundus lesions typical of the multiple evanescent white-dot syndrome that occurred 5 years after acute macular neuropathy in the same eye (1). In Case 15 they oc- I Clln Ncuro-ophthalmol. Vol. 13. No.2, 1993 curred in one eye of a patient with evidence of the pseudo-presumed ocular histoplasmosis syndrome in both eyes. DISCUSSION Acute zonal occult outer retinopathy seems an appropriate descriptive name for the syndrome demonstrated by Cases 1-13. All these cases shared the following features: rapid loss of one or more large zones of outer retinal function, minimal fundus changes, electroretinographic abnormalities, and permanent visual field loss that, in most cases, was associated with delayed development of visible atrophic changes in the pigment epithelium and narrowing of the retinal vessels. Both clinical and electrophysiological findings suggest that the retinal photoreceptors and pigment epithelium are the primary loci of disease in this syndrome. Acute dysfunction of these cells is usually accompanied by normal fundus and fluorescein angiographic findings. This dysfunction may be temporary or permanent. When permanent, it is usually associated with the late development of depigmentation of the pigment epithelium in the affected zones in the absence of angiographic evidence of alteration in perfusion of the choriocapillaris. When these zones are large, there may be noticeable narrowing of the retinal vessels, angiographic evidence of increased retinal circulation time, and eventually migration of pigment into the overlying retina in a bone-spicule pattern. These findings suggest severe damage to, and loss of, the receptor cells within these zones of pigment epithelial depigmentation. In some patients the zone of prolonged visual field loss may be associated with no funduscopic or angiographic abnormalities. This implies that in these zones the dysfunctional receptor cells may still be viable and that restoration of function is still possible. There is little evidence that the retinal ganglion cells are affected by this disease. Evidence that suggests the outer retina is primarily affected includes the configuration and density of the visual field defects, the localization of photopsia to the zones of field loss, the accentuation of both in bright light, the electroretinographic abnormalities, the frequent development of zones of pigment epithelial atrophy corresponding with the visual fields loss, and the failure of development of optic atrophy, even in patients with large permanent field defects affecting the macula. The cause of acute outer retinal dysfunction in these patients is unknown. The preservation of retinal transparency and normal color of the pig- ZONAL OCCULT OUTER RETINOPATHY 95 ment epithelium during the acute stage of this disorder suggests that neither severe ischemia nor intense inflammatory cell infiltration of the retina are present. The absence of fundus and fluorescein angiographic abnormalities suggests an acute malfunction of intracellular enzyme systems of the retinal receptor-pigment epithelial cell complex caused by either one or a combination of an immune- mediated injury, intracellular invasion by a toxic substance, or a virus. Interestingly two patients had infectious mononucleosis 2 years prior to the onset of ocular symptoms. However, two other patients who were tested for Epstein-Barr virus (EBV) showed no evidence of recent infection with EBV. Tiedeman (2) found evidence of chronic or persistent EBV infection in 10 patients with multifocal choroiditis and panuveitis. This was not confirmed, however, by Spaide and colleagues (3). The potential for this virus to cause acute damage to an organ is suggested by recently described evidence that latent EBV infection of the lacrimal gland may incite development of Sjogren's syndrome, a disorder predominantly affecting women (4,5). The cause of vitreous inflammatory cellular infiltration that is usually present during the early stages of this disorder is unknown. The predilection for eyes with more vitreous cells and those with biomicroscopic and angiographic evidence of retinal and optic nerve head capillary leakage to have large zones of retinal dysfunction suggests that both may be caused by substances liberated by the acutely damaged outer retina. This damage is similar to that which occurs more diffusely in the retina in patients with cancer-associated retinopathy (CAR), bilateral diffuse uveal melanocytic proliferation, and metastatic cutaneous melanoma (611). Retinal antigens, including the CAR antigen, were not identified in the three patients studied. Unlike some patients with CAR, these patients demonstrate minimal response to systemic corticosteroid therapy. During the early stages of this disease, visual loss is often attributed to retrobulbar neuritis, a pituitary tumor or other intracranial lesion, and CAR. Later, as retinal vessel narrowing and pigment epithelial depigmentation occur, retinal vasculitis, syphilitic chorioretinitis, diffuse unilateral subacute neuroretinitis, and localized or generalized retinal dystrophies are frequent misdiagnoses. The history of acute onset of a scotoma, particularly when it involves the temporal field, and when it is associated with photopsia, should alert the physician to the correct diagnosis. The early detection of unequivocal electroretinographic abnormalities will avoid unnecessary neurological investigations. In some patients, electroretinogram (ERG) amplitudes may be borderline normal, and a focal ERG may be required to detect the abnormality (14). In both instances these minimal ERG findings should be interpreted with caution before excluding other causes for the visual field loss. Only 1 of 6 patients who received orally administered corticosteroids that in 2 cases was supplemented with sub-Tenon's injection of cortisone showed improvement. Two patients were treated with oral acyclovir. One received it 2 weeks after onset of severe field loss in his fellow eye and had no further progression during 1 month of followup. The other received it 2 months after development of a new scotoma that failed to respond to a course of systemic corticosteroid treatment. Although the visual field stabilized, the acuity declined. Because of slight enlargement of her scotoma in the lesser involved fellow eye, 8 months later this same patient received ceftriazone sodium and vancomycin hydrochloride because of suspected Lyme disease. The visual fields were unchanged 1 year later. The visual prognosis for most patients appears to be good. However, longer follow-up is necessary to determine the natural course of this disease. All of the patients reported in this series have retained 20/25 or better visual acuity in at least one eye. One patient is legally blind because of severe loss of peripheral visual field. I believe that Cases 1 through 13 have the same disorder, and that they represent only part of the spectrum of what probably is either one disease or closely related diseases that have been described previously as the multiple evanescent white-dot syndrome, acute idiopathic blind-spot-enlargement syndrome, acute macular neuroretinopathy, and multifocal chorioretinitis resembling the presumed ocular histoplasmosis syndrome. In 1984 ]ampol and colleagues (12) described the multiple evanescent white-dot syndrome (MEWDS) in 10 young women and 1 man with unilateral acute visual loss, multiple rapidly fading white outer retinal lesions, electroretinographic abnormalities, and spontaneous recovery of vision and electrophysiological function within several months. Other findings included vitritis, punctate white or orange foveal flecks, and in approximately 50% of patients, a history of an antecedent viral-like infection. Takeda and colleagues (13) independently reported the same disease in 4 young adults. There was minimal evidence of response to treatment in these patients. In 1988 Fletcher and colleagues (14) reported the acute idiopathic blind-spot-enlargement syndrome J C/il1 NeuTth'l'hlhalmol, Vol. 13, No.2, 1993 96 J. D. M. GASS (AIBSES) in predominantly young women with acute unilateral loss of vision, photopsia, dense scotomas centered around the blind spot, normal fundi, and abnormal electroretinographic findings. Hamed and colleagues (15), Aaberg (16), and Gass and Hamed (1) presented evidence that MEWDS and AIBSES are the same disease. In 1990, Gass and Hamed (1), and more recently Singh and colleagues (17) reported evidence that some patients with MEWDS and AIBSES develop paracentral, reddish-orange outer retinal lesions characteristic of acute macular neuroretinopathy (AMN), a syndrome originally described in 1975 by Bos and Deutman (18). At the January 1991 Macular Society Meeting I presented evidence for the following: 1. Of patients seen at the Bascom Palmer Eye Institute with MEWDS and AIBSES, 25% either had, at the time of presentation or subsequently developed, either one or both, multifocal active and atrophic fundus lesions typical for that seen in patients with the pseudo-presumed ocular histoplasmosis syndrome (P-POHS) (19-21). 2. Patients with AIBSES may present with large zones of peripheral visual field loss, not necessarily continuous with the blind spot, and later develop fundus changes that simulate retinitis pigmentosa and cancer-associated retinopathy. 3. MEWDS, AIBSES, AMN, and P-POHS may have a common cause. Singh and colleagues (17) and Khorram and colleagues (22) recently described acute enlargement of the blind spot in patients with the presumed ocular histoplasmosis syndrome ((POHS and with multifocal choroiditis. Singh and colleagues (17) suggested that POHS is but one of multiple causes of acute blind spot enlargement. Callanan and Gass (23), on the other hand, have recently presented further evidence that MEWDS, AIBSES, and P-POHS may have a common cause. Cases 1-13 share the following features in common with MEWDS, AIBSES, AMN, and P-POHS: acute visual loss in predominantly young women, acute blind-spot enlargement in the absence of fundus changes to explain it, electroretinographic abnormalities, retention of good visual acuity in most cases, and all of these syndromes have been reported since 1975. The literature contains limited information concerning the frequency of blind-spot enlargement in patients with P-POHS and AMN. Results of visual field examination are often not included in reports of these disorders. Of interest in this regard is that the two initial reports of 15 patients with MEWDS described blind-spot enlargement in only 2 patients and photopsia in none, yet both occur in r ClIII Neuro-or,hthalmol. Vol. 13. No.2. 1993 most of these patients (1). Dreyer and Gass (19) in their report of 28 predominantly female patients with P-POHS did not describe visual field findings, yet they did report electroretinographic abnormalities in 11 of 16 patients tested, and in 8 it showed moderately severe to extinguished electroretinographic responses in one or both eyes. Some of these patients probably had enlarged blind spots as well as other large zones of visual field loss similar to Cases 1 to 13 and Case 15. The acute focal lesions of P-POHS may be difficult to distinguish from those of MEWDS. While those of P-POHS are generally more intensely white, sharply circumscribed, often clustered in the macular area, more homogeneously stained with fluorescein, and more likely to cause a focal area of depigmentation of the pigment epithelium similar to POHS, some are indistinguishable in all respects from those of MEWDS. Although the lesions of P-POHS are more likely to be complicated by subretinal neovascularization, those of MEWDS are not immune to this complication (23,24). The lesions of both are located at the retina-choroid interface. The primary difference between the two may be the intensity of the patients immune response to the same insult. The location of active lesions in MEWDS and P-POHS may be partly or completely outside of the zone of dense visual field loss that in MEWDS often includes the blind spot. It is curious that, while the reaction responsible for the focal white lesions and that causing the zonal loss of vision both appear to occur at the same level, one results in a visible change and the other does not. Only 9 patients with AMN have been seen at the Bascom Palmer Eye Institute since the first one presented in 1972. Of these, 2 (including Case 14) have had evidence of both MEWDS and acute blind spot enlargement (1). None of the other 7 patients had a visual field examination other than Amsler grid testing, which showed sharply defined scotomas that precisely correlated with the reddish lesions at the level of the outer retina. The biomicroscopic features of these often subtle lesions, their precise correlation with the scotomas, the absence of fluorescein angiographic evidence of pigment epithelial cell damage, and their frequent association with electroretinographic abnormalities, suggest that they involve primarily the retinal receptor cells and that the retina is affected beyond the confines of the reddish lesions that are never found outside the macular area. Sieving and colleagues have demonstrated reduction of early retinal receptor potential in AMN (25). Future visual field investigations of patients with AMN and ZONAL OCCULT OUTER RETINOPATHY 97 TABLE 5. Classification of acute zonal occult outer retinopathy I. AZOOR without focal fundus lesions II. AZOOR with focal fundus lesions A. Multiple evanescent white-dot syndrome B. Pseudo-presumed ocular histoplasmosis syndrome C. Acute macular neuroretinopathy D. Geographic atrophy of pigment epithelium P-POHS probably will demonstrate the frequent presence of occult zones of outer retinal damage. Acute loss of large zones of outer retinal function in the absence of fundus changes occurring predominantly in women is the common denominator that links Cases 1 to 13 with patients with MEWDS, AIBSES, AMN, and P-POHS. The female predilection suggests the possible role of autoimmunity in the pathogenesis of these disorders. Rather than designating a separate name for these 13 patients, I propose that acute zonal occult outer retinopathy is an appropriate and inclusive name for this group of disorders that may prove to have the same, or closely related, underlying causes (Table 5). REFERENCES 1. Gass IDM, Hamed LM. Acute macular neuroretinopathy and multiple evanescent white dot syndrome occurring in the same patients. Arch Ophthalmol 1989;107:189-93. 2. Tiedeman IS. Epstein-Barr viral antibodies in multifocal choroiditis and panuveitis. 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