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Enlarged Blind Spots in Chonoretinal Inflammatory Disorders
Enlarged Blind Spots in Chorioretinal Inflammatory Disorders Chittaranjan V. Reddy, MD, Jeremiah Brown, Jr., MD, James C. Folk, MD, Alan E. Kimura, MD, Sunil Gupta, MD, Jonathan Walker, MD Purpose: This study was undertaken to better characterize patients with multifocal choroiditis and panuveitis (MCP), punctate inner choroidopathy (PIC), multiple evanescent white dot syndrome (MEWDS), and diffuse subretinal fibrosis syndrome. The specific aim was to determine whether these disorders were different entities or part of a spectrum of diseases with similar features. Methods: Seventy-nine patients were included in the study. Most of the patients have been followed up prospectively since July 1980 with some found retrospectively. Results: Forty-one patients had MCP, 16 had PIC, 6 had diffuse subretinal fibrosis syndrome, and 16 had MEWDS. Patients with MCP had visual loss and visual field defects caused directly by visible lesions or recurrent inflammation around old lesions. In particular, clustering of lesions around the optic nerve and nasal periphery was seen in patients with MCP and appeared to be related to visual field loss. Patients with PIC also had enlarged blind spots and other field defects explained by fundus lesions. Patients with PIC and MCP did not have recurrent lesions on extended follow-up. Patients with diffuse subretinal fibrosis syndrome represented a subset of patients characterized with lesions in the posterior pole, severe scarring, and visual loss. Patients with MEWDS had the least inflammation with symmetrically distributed lesions. Minimal permanent chorioretinal scarring was seen in patients with MEWDS. Visual field defects improved in most patients with MEWDS and PIC, whereas most patients with MCP and diffuse subretinal fibrosis syndrome did not improve. Conclusions: Although enlarged blind spots are a feature of all four disorders, other clinical, angiographic, and electroretinographic evidence suggest that these are different entities. Ophthalmology 1996;103:606-617
Enlarged blind spots are a well-recognized occurrence in patients with multiple evanescent white dot syndrome (MEWDS).1-3 In fact, patients initially described with the acute idiopathic enlarged blind spot syndrome likely represent those patients with MEWDS in whom the white fundus lesions have faded. 4 ,5 More recently, Khorram et Originally received: October 30, 1994. Revision accepted: January 3, 1996. From the Department of Ophthalmology, The University oflowa Hospitals and Clinics, Iowa City. Presented at the American Academy of Ophthalmology Annual Meeting, San Francisco, November 1994. Correspondence to Chittaranjan V. Reddy, MD, Retina Consultants of Central Illinois, 5016 N. University St, Peoria, IL 616144763.
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al 6 described three patients with multifocal choroiditis and Singh et al? described one patient with presumed ocular histoplasmosis and one with acute macular neuroretinopathy having associated enlarged blind spots. It has been proposed that many of these disorders are closely related and may, in fact, have the same etiologic basis. 8 The rationale for this has been that these disorders, namely multifocal choroiditis and panuveitis (MCP), MEWDS, acute macular neuroretinopathy, as well as acute idiopathic enlarged blind spot syndrome, typically occur in young women in their 30s and 40s and have overlapping features. 8 ,9 The present study describes the clinical, visual field, and electroretinographic findings in a series of patients with MEWDS, MCP, punctate inner choroidopathy (PIC), 10,11 and the diffuse subretinal fibrosis syndrome.
Reddy et al . Chorioretinal Inflammatory Disorders The findings in these disorders were compared to determine whether they are separate entities or different manifestations along a spectrum of a single disorder.
Methods and Patients Patients for the study were recruited prospectively beginning in July 1980 with the remainder of the patients being found through review of the photographic files at The University of Iowa Hospitals and Clinics. These patients had the diagnosis of nonspecific multifocal choroiditis. Patients with MCp I2 were included only if there were any sign of active vitritis, anterior chamber inflammation, or active chorioretinallesions at any time during the clinical course. In particular, any patient who could not be clearly differentiated from the presumed ocular histoplasmosis syndrome was excluded. Patients with sarcoidosis, inflammatory bowel disease, lymphoma, tuberculosis, or any other identifiable cause for the choroiditis were excluded as well. Patients with PIC were seen by either of two observers (JCF or CVR). Patients were considered to have PIC if they had symptoms attributable to the typical small chorioretinal lesions, which evolved into scars on follow-up. These patients also had no sign of vitreous or anterior chamber cells during the clinical course or any new fundus lesions on follow-up. 10,1 1 Patients with MEWDS were included only if white dots could be seen at the time of examination or if photographs clearly showing the white fundus lesions were available from the referring physicians. Most of these latter patients had the characteristic orange granularity around the fovea. Patients with enlarged blind spots and no fundus lesions were not included. Patients with the diffuse subretinal fibrosis syndrome presented with numerous small, yellow lesions in the posterior pole along with variable vitreous inflammation. Often, the lesions coalesced into subretinal pigment epithelial or subretinal lumps followed by rapid subretinal scarring. 11,13, 14 All patients in the study had best corrected visual acuity measurements, slit-lamp examinations of the anterior segment and vitreous, and detailed fundus examinations. Patients were evaluated with either the Goldmann perimeter or Humphrey 30-2 or both. An enlarged blind spot was defined as being at least 15 0 to 20 0 in diameter with features of an absolute scotoma and steep margins. Electroretinography (ERG) was performed using a protocol established by the International Standardization Committee l5 on aUT AS E2000 instrument (LKC Technologies, Gaithersburg, MD). Responses were recorded with a bipolar Burian-Allen contact lens (Hansen Ophthalmic Development Lab, Iowa City, IA). Dark adaptometry was performed with a Goldmann-Weekers dark adaptometer (Haag Streit, Bern, Switzerland). Focal ERG was performed using a MaculoScope (Doran Instruments, Littleton, MA). Fluorescein angiography was obtained on all consenting patients. Many of the patients in the study were brought back for the different clinical evaluations.
All photographic files were reviewed. The number of lesions within the temporal arcades, in the nasal, temporal, superior, and inferior periphery were quantitated for each eye. The severity of disease in each eye was graded as follows: mild involvement (1 to 20 lesions), moderate involvement (21 to 50 lesions), and severe involvement (more than 50 lesions). Additionally, each area with 10 or more lesions was noted. The pigmentation of the lesions, the presence of swelling around the lesions, disc edema, peripapillary scarring or fibrosis, choroidal neovascularization, and cystoid macular edema were noted as well. All serial photographs, including the angiograms, were scrutinized for the presence of new chorioretinal lesions. Initial and final visual acuity data for each of the different groups were analyzed. The average was determined using the 10gMAR scale. 16
Results A total of 182 patients were reviewed and 79 were found to meet the entry criteria of the study. Of these, 41 patients had MCP, 16 had PIC, 6 had diffuse subretinal fibrosis syndrome, and 16 had MEWDS. Multifocal Choroiditis Sixty-eight eyes of 41 patients with MCP were involved. The patients' average age at onset, gender, and race are listed in Table 1. Presenting complaints included decreased vision, scotomata, photopsia, and floaters. Of note, many patients complained of temporal photopsia and scotomata, which persisted for several weeks to months. Few patients complained of pain or photophobia. Initial vision was relatively good with most patients having visual acuity of20/50 or better. All patients had varying amounts of either anterior chamber or vitreous cells or both. Fifty-one of the 68 (75%) affected eyes underwent visual field testing during the clinical course of the disease. As listed in Table 1, enlarged blind spots and full fields were the two most frequent findings. The enlarged blind spot was seen as a manifestation of the initial episode of inflammation in approximately 40% of eyes with this visual field defect, whereas the other eyes developed enlarged blind spots as a consequence of recurrent inflammation. The enlarged blind spots ranged from 25 0 in size to those extending to the far temporal periphery. All patients had discrete chorioretinallesions in the areas of involvement. Smaller lesions and diffuse intervening areas of involvement were more apparent with fluorescein angiography (Fig 1). Twenty three (34%) eyes had disc edema or staining with fluorescein angiography. However, this did not appear to be sufficient to account for the visual field defect. Additionally, most central and paracentral scotomata were directly related to chorioretinal lesions, choroidal neovascular membranes, or cystoid macular edema. A review of fundus photographic files of patients with multifocal choroiditis showed a large preponderance of lesions clustered around the optic nerve and in the nasal midperiphery and periphery (Fig 2). This was seen not
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Table 1. Multifocal Choroiditis N = 41 patients, 68 eyes Age at onset Average: 35.5 yrs Range: 13-63 yrs Sex: 32 females (78%) Race: 40 white, 1 black Bilateral involvement: 27 (66%) Presenting symptom Blurred vision/scotomata: 27 patients Photopsias: 15 patients Floaters: 9 patients Visual acuity· Initial average: 20/45 Range: 20/15 to counting fingers Final average: 20/33 Range: 20/15 to counting fingers Refractive error (spherical equivalent) Average: -2.19 diopter Range: -9.00 to +2.50 diopters Recurrent infiammation:t 86% Anterior chamber cells: 22 eyes (32%) Vitreous cells: 52 eyes (76%) Choroidal neovascularization: 17 eyes (25%) Disc edema/hyperemia: 23 eyes (34%) Visual field defectst Enlarged blind spot: 24 eyes (47%) Central/paracentral: 13 eyes (25%) Cecocentral: 2 eyes (4%) Peripheral: 4 eyes (8%) Full: 22 eyes (43%) Distribution of lesions§ Macular: 23 eyes Nasal: 28 eyes Temporal: 2 eyes Superior: 3 eyes Inferior: 3 eyes Diffuse: 4 eyes ERG findings II Mild: normal ERG Moderate: rod dysfunction and poor OPs Severe: rod and cone dysfunction; poor OPs ERG
= electroretinogram; OP = oscillatory potential.
• Patients with a minimum of 6 months' follow-up (N months; range, 6-234 months).
=
25; average, 64.9
t Patients with a minimum of 1 year follow-up (N = 21) to ensure recurrent and not persistent inflammation. t
Fifty-one (75%) of the 68 affected eyes underwent visual field testing.
§ Eyes with a minimum of 10 lesions in each of the involved areas.
II Ten (27%) patients tested; severity of fundus lesions compared with ERG findings.
only in the patients with enlarged blind spots but also in those with full visual fields. Identifying 10 or more lesions in the other peripheral areas (outside the temporal arcades) was relatively less common. The review of photographic files probably underestimated the frequency of nasal clustering compared with macular lesions, because there were
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frequently better photographs of the latter. Nineteen photographic files with fundus photographs or angiograms or both and a minimum follow-up of 6 months were available for review. The mean period of follow-up for these photographic files was 64 months, with a median of 50 months. In all involved eyes, no new inflammatory chorioretinallesions were noted. Although the lesions became larger and more pigmented with time, they could be directly traced to previous lesions seen on color photographs or fluorescein angiograms. These findings were made independently by two observers (JCF and CVR). This was surprising because 86% of eyes (n = 21) observed clinically for 1 year or longer had recurrent inflammation characterized by new symptoms, along with either anterior chamber or vitreous cells. These patients had swelling around old lesions on ophthalmoscopy, and fluorescein angiography showed leakage around pre-existing scars. Some patients had new symptoms without any visible change ophthalmoscopically or angiographically. Electroretinography was performed on 10 patients during the course of their disease. Two patients with mild disease (20 lesions or fewer/eye) had essentially normal ERG responses. Five patients had moderate disease (21 to 50 lesions) and 3 had severe disease (>50 lesions). The patients with moderate disease had abnormal ERG responses characterized by rod dysfunction, prolonged cone B-wave-implicit times, and poor oscillatory potentials. Asymmetric ERG responses between eyes in these five patients also were seen and correlated with the amount of chorioretinal involvement. In eyes with severe involvement, rod and cone dysfunctions were evident with poor oscillatory potentials. On clinical follow-up, as noted above, the majority had recurrent inflammation. Average follow-up visual acuity for this group was better than the average initial visual acuity with 55% retaining 20/40 or better visual acuity. However, 8 of 45 (18%) eyes had visual acuity of 20/200 or worse, with 3 patients having poor vision bilaterally. Visual field testing was repeated in 14 patients who had field defects in 18 eyes. Four (22%) eyes had resolution of their enlarged blind spots; three improved spontaneously, whereas one patient was treated with oral prednisone. The other 14 (78%) eyes had no appreciable improvement in the field defect with (4 eyes) or without (10 eyes) immunosuppression.
Punctate Inner Choroidopathy Sixteen patients had PIC involving 30 eyes (Table 2). Bilateral involvement was seen in all except two patients. All except one patient were women. Initial visual complaints were similar to those of patients with MCP. Initial visual acuity in approximately 75% of patients was 20/40 or better. Patients with poor initial visual acuity had clustering of lesions around the fovea or neurosensory detachment of the retina caused by active lesions in the macula. Visual field evaluation was done on 22 of 30 (73%) affected eyes. Enlarged blind spots were the most frequently seen field defect (Table 2). Many of the enlarged
Reddy et al . Chorioretinal Inflammatory Disorders
Figure 1. A 51-year-old woman with multifocal choroiditis and panuveitis (Mep). A, fundus photograph shows acute swelling of lesions in the superonasal midperiphery as well as juxtapapillary choroidal neovascularization. B, fundus fluorescein angiogram shows many small and subtle lesions between the more obvious scars. Many of the smaller lesions were not seen clinically. C, angiogram shows late leakage from lesions and the choroidal neovascularization. D, shows an inferotemporal field defect corresponding to the area of chorioretinal involvement. The field defect did not improve after the inflammation resolved.
blind spots extended toward the macula rather than the temporal periphery, as seen in the patients with MCP. Central and paracentral defects were seen in three of the involved eyes. Most of the fundus lesions in this group were seen in the macula, in contrast to patients with MCP who had relatively fewer lesions in the macula compared with other areas of the fundus. Five eyes had nasal clustering as seen in patients with MCP. Also, in this group of patients, the amount of peripapillary scarring or disc edema seen on fluorescein angiography did not appear to sufficiently account for the the enlarged blind spot. The ERG testing showed findings within the normal range in all seven patients who were tested. Three of the seven patients who were tested had mild asymmetry in B-wave amplitudes between the two involved eyes. This correlated with differences in the number of lesions in each eye. With follow-up, only one patient had recurrent episodes of swelling around previous lesions without any signs of anterior chamber or vitreous cells. Average follow-up visual acuity was better than average initial acuity even though 69% of patients were not treated with steroids.
Five (17%) eyes developed neovascular membranes. Two of the patients underwent surgery for removal of subfoveal membranes with improvement of visual acuity to 20/40 or better. Follow-up visual fields on seven involved eyes showed improvement in all patients. Three patients were treated with prednisone, whereas the other four improved without treatment. Review of the photographic files showed nine patients with a minimum of 6 months' photographic follow-up, with a mean of 44 months and a median of 33 months. The PIC lesions, which started as indistinct, yellow lesions, with time became more discrete and pigmented (Fig 3). The amount of pigmentation was typically less than that in MCP lesions, which also were bigger than the PIC lesions. Detailed examination showed no new lesions in eyes with follow-up photographs.
Diffuse Subretinal Fibrosis Syndrome Six patients were identified with the diffuse subretinal fibrosis syndrome (Table 3). They all had bilateral involvement, although in three patients, only one eye was initially involved. This group of patients had the worst initial visual
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Figure 2. A 2S-year-old woman with multifocal choroiditis and panuveitis and a I-year history of temporal field loss and counting fingers vision. A and B, show clustering of lesions nasally and swelling of the lesions in the posterior pole. C and D, fluorescein angiograms show leakage from the lesions and optic nerve head. E, fluorescein angiogram shows less swelling around lesions after oral and depot corticosteroids. F and G, show the visual field defect before and after treatment. The temporal field defect improved and the visual acuity improved from counting fingers at 2 ft to 20/40, despite visual loss for more than 1 year.
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Reddy et al . Chorioretinal Inflammatory Disorders Table 2. Punctate Inner Choroidopathy N = 16 patients, 30 eyes Age at onset Average: 30.3 yrs Range 20-41 yrs Sex: 15 females (94%) Race: 16 white Bilateral involvement: 14 (88%) Presenting symptom Blurred vision/ scotomata: 12 patients Photopsias: 6 patients Floaters: 1patient Visual acuity" Initial average: 20/41 Range: 20/15 to 20/500 Final average: 20/ 33 Range: 20/ 15 to counting fingers Refractive error (spherical equivalent) Average: -3.67 diopters Range: -8.25 to + 1.00 diopters Recurrent infiammation:t 1 patient (6%) Choroidal neovascularization: 5 eyes (17%) Disc edema/hyperemia: 4 e yes (13%) Visual field defectsT Enlarged blind spot: 9 eyes (41%) Central/paracentral: 3 eyes (14%) Cecocentral: 0 eyes Peripheral: 0 eyes Full: 10 eyes (45%) Distribution of lesions§ Macular: 18 eyes Nasal: 5 eyes Temporal: 2 eyes Superior: 0 eyes Inferior: 0 eyes Diffuse: 2 eyes ERG findings II Normal full-field ERG Asymmetry between eyes in 3 patients ERG
=
Table 3. Diffuse Subretinal Fibrosis Syndrome N = 6 patients, 12 eyes Age at onset Average: 27.3 yrs Range: 7-58 yrs Sex: 5 females (83%) Race: 5 white, 1 black Bilateral involvement: 6 (100%) Presenting symptom Blurred ViSion/scotoma: 5 patients Photopsias: 2 patients Floaters: 1patient Visual acuity" Initial average: 20/ 291 Range: 20/ 15 to counting fingers Final average: 20/163 Range: 20/20 to hand motions Refractive error (spherical equivalent) Average: -1.25 diopter Range: -7.00 to plano diopters Recurrent infiammation:t 100% Anterior chamber cells: 4 eyes (33%) Vitreous cells: 10 eyes (83%) Choroidal neovascularization: 2 eyes (17%) Disc edema/ hyperemia: 8 eyes (66%) Visual field defectsT Enlarged blind spot: 2 eyes (20%) Central/paracentral: 2 eyes (20%) Cecocentral: 3 eyes (30%) Peripheral/diffuse: 2 eyes (20%) Full: 1eye (10%) Distribution of lesions§ Macular: 9 eyes Nasal: 5 eyes Temporal: 0 eyes Superior: 1eye Inferior: 0 eyes Diffuse: 2 eyes ERG findings II Normal full-field ERG Cone implicit prolonged Abnormal focal ERG in 1 patient
electroretinogram.
"In patients with a minimum of 6 months' follow-up (N 41.5 months; range, 6-154 months).
t
In patients with a minimum of 12 months' follow-up (N recurrent and not persistent inflammation.
t
involvement of the peripheral fundus. Acute lesions typically were small, yellow, and indistinct. Over a few days, they coalesced into dirty, yellow mounds beneath the retinal pigment epithelium or neurosensory retina. These mounds consisted of turbid pockets of severe inflammation. This was followed by the development of subretinal
= =
14; average, 12) to ensure
Twenty-two (73%) of 30 involved eyes had visual fields.
§ Eyes with a minimum of 10 lesions in each of the involved areas.
II ERG testing done on 7 (44%) patients.
acuity with all involved eyes having 20/200 visual acuity or worse. The uninvolved fellow eye had better vision. Visual field defects in patients with diffuse subretinal fibrosis involved fixation at some time during the course of the disease in most patients. Enlarged blind spots were less frequent. With treatment, the size of the field defect frequently improved but typically worsened with recurrence of inflammation. The lesions in patients with diffuse subretinal fibrosis were seen predominantly in the macula, with much less
ERG
=
electroretinogram.
• Patients with a minimum of 6 months' follow-up (N months; range, 22-120 months).
t Patients with a minimum of 1 year follow-up (N and not persistent inflammation. t
=
=
6; average, 63.8
6) to ensure recurrent
Ten (83%) of the 12 affected eyes underwent visual field testing.
§ Eyes with a minimum of 10 lesions in each of the involved areas. I Two patients tested.
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Figure 3. A, a 36-year-old woman with punctate inner choroidopathy. B, 7 years later, there appeared to be a new lesion adjacent to the inferior arcade. However, scrutiny of the fundus fluorescein angiogram taken the same day as Figure 3A shows that a subtle lesion was already present (C). Therefore, no new scars developed on follow-up in this patient.
fibrous bands, which appeared over a few weeks. On follow-up, recurrent bouts of inflammation were characterized by leakage around pre-existing lesions. No new lesions were seen with extended follow-up (mean, 64 months), but frequently there was increased fibrosis around individual lesions in the macula and the midperiphery (Fig 4). Aggressive and prolonged treatment with corticosteroids was required in all patients. Two patients who developed side effects from corticosteroids and had intractable disease benefited from cyclosporine or azathioprine or both. The ERG studies in two patients with diffuse subretinal fibrosis and severe involvement of the macula showed normal full-field ERG responses. One of the two patients had detectable asymmetry in the focal ERG between the two eyes, although the eyes appeared to be similarly affected ophthalmoscopically.
Multiple Evanescent White Dot Syndrome Sixteen patients had MEWDS (Table 4). Bilateral involvement was seen in four patients. The complaint of photopsia was fairly prominent as with patients with MCP and PIC. Eight (50%) patients with MEWDS presented with this complaint. Initial visual acuity was 20/40 or better in all except two eyes. Vitreous or anterior chamber cells or both were a common feature on presentation.
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Visual field testing showed enlarged blind spots in two thirds of involved eyes along with or without central defects. Follow-up visual fields in seven patients with nine involved eyes showed resolution of all defects without any treatment. Examination of the fundus photographs and angiograms of patients with MEWDS showed no evidence of clustering oflesions in any particular quadrant and, notably, not in a peripapillary or nasal distribution. Five patients with MEWDS had inactive chorioretinal scars noted on peripheral fundus examination or with photography. Three of these patients had only two to four nonspecific chorioretinal scars. The other two patients with MEWDS had more numerous chorioretinal scars. They were both men. One of them had findings highly suggestive of ocular histoplasmosis and had undergone laser photocoagulation for neovascular membranes in both eyes 10 years earlier. He had no intervening episodes of inflammation during that time. The other man also appeared to have ocular histoplasmosis lesions in both eyes, but had vitreous inflammation in only the eye with the MEWDS lesions. In all five of these patients with old chorioretinal lesions and MEWDS, the former preceded the development of the acute lesions. There were no subsequent episodes of inflammation.
Reddy et al . Chorioretinal Inflammatory Disorders
Figure 4. A 31-year-old patient with diffuse subretinal fibrosis syndrome. A, left eye shows coalescing of lesions into yellow deposits. B, this was followed by scarring and severe visual loss. C, right eye shows quiescent scars. D, oral prednisone was tapered, and the patient returned 2 months later with new symptoms and swelling around old lesions. E, oral prednisone was increased, the symptoms improved, and less swelling of lesions was noted 3 months later. Notice, however, mild subretinal scarring inferior to the fovea.
The ERG testing done on three patients with acute MEWDS showed one patient with dysfunction of both rods and cones along with poorly developed oscillatory potentials; the other two patients had normal ERG responses. The same patient had poor amplitudes in the fovea and papillomacular bundle with focal ERG testing. Follow-up ERGs done on four patients showed normal ERG responses. These patients were tested between 5 and 32 months after their initial inflammation subsided.
On follow-up, all patients with MEWDS had resoiution of symptoms. None of the patients in this series had recurrent inflammation.
Discussion As described above, most patients with MCP, PIC, MEWDS, and diffuse subretinal fibrosis syndrome are young and otherwise healthy women (Table 5). Some of
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4. Multiple Evanescent White Dot Syndrome
N = 16 patients, 20 eyes Age at onset Average: 28.1 yrs Range: 11-49 yrs Sex: 8 females (50%) Race: 14 white, 1 black, 1 Asian Bilateral involvement: 4 (25%) Presenting symptom Blurred vision/scotomata: 10 patients Photopsias: 8 patients Floaters: 1 patient Visual acuity· Initial average: 20/26 Range: 20/15 to 20/200 Final average: 20/20 Range: 20/15 to 20/40 Refractive error (spherical equivalent) Average: -1.25 diopter Range: -7.00 to plano Recurrent infiammation:t 0% Anterior chamber cells: 7 eyes (35%) Vitreous cells: 11 eyes (55%) Choroidal neovascularization: 2 eyes (10%)'1' Disc edemajhyperemia: 9 eyes (45%) Visual field defects§ Enlarged blind spot: 12 eyes (67%) Central/paracentral: 1 eye (6%) Cecocentral: 1 eye (6%) Peripheral: 0 (0%) Full: 5 eyes (28%) Distribution of lesions II Macular: 4 eyes Nasal: 3 eyes Temporal: 7 eyes Superior: 6 eyes Inferior: 6 eyes Diffuse: 4 eyes ERG findings~ Acutely: 1 eye had abnormal focal and full ERG With prolonged follow-up: all ERGs normal ERG
=
electroretinogram.
• Patients with a minimum of 6 months' follow-up (N months; range, 6-47 months).
t Patients with a minimum of 1 year follow-up (N was recurrent and not persistent inflammation.
=
=
8; average, 21.8
6) to ensure there
t One patient had bilateral extrafoveal neovascular membranes secondary to histoplasmosis treated 10 years earlier. §Eighteen (90%) of the 20 affected eyes underwent visual field testing.
II Eyes with a minimum of 10 lesions in each of the involved areas. 11 Three patients tested acutely; 4 patients tested 2 months after active lesions disappeared.
these patients describe an antecedent flu-like illness. Other features that are similar in these patients include the prominent complaint of photopsia, level of involvement
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in the retina and choroid, as well as certain overlapping features described by others. 8,9 This study showed that visual field abnormalities are a common feature of these disorders, particularly enlarged blind spots (Table 5). Gass has suggested that these diseases may represent a spectrum of disease and may be closely related. One of the purposes of the present study was to determine whether these diseases are different, with emphasis on MEWDS, compared with the other three disorders. The largest group of patients in this series had MCP. These patients had recurrent bouts of inflammation consisting of vitreous or anterior chamber cells or both and swelling around previously noted lesions. It was interesting that none of the patients developed new lesions but had recurrent inflammation around old lesions, causing swelling and leakage on fluorescein angiography. With time, these lesions increased in size and pigmentation. Morgan and Schatz 17 described a group of 11 patients with multifocal choroiditis and recurrent bouts of inflammation. They noted "new sites developing adjacent to old ones." Figure 3 illustrates a case with increasing size and pigmentation over an 8-year period. Although a fluorescein angiogram at initial presentation was not available for comparison, it appears that there were not any new lesions, but that the older lesions became larger and more pigmented after recurrent bouts of inflammation. If an infectious etiology is invoked for MCP, 18 it would appear that the primary insult was a one-time occurrence with recurrent inflammation occurring as in patients with reactivated histoplasmosis lesions. 19,20 Areas of minimally involved retina-choroid between more obvious scars were common but more subtle and often best seen with fluorescein angiography. Also of note was the strong nasal preponderance of lesions in these patients. One plausible explanation for this finding is that the peripapillary choroid extending nasally to the equator (the area where most of the MCP lesions were seen) is supplied by the medial posterior ciliary arteryY If MCP is caused by a bloodborne agent, perhaps these agents are shed through the medial ciliary artery more readily for unclear reasons. The location of lesions around the nerve and in the nasal periphery directly corresponded to the enlarged blind spots and temporal field defects seen in patients with MCP. Some patients with recurrent inflammation also experienced visual field defects. Occasionally, patients with MCP with longstanding (longer than 6 months) visual loss and visual field defects improved with immunosuppression. Patients with PIC are the most difficult to distinguish from patients with MCP. Their clinical differences include the absence of anterior chamber and vitreous cells and the rare recurrent swelling around old lesions. Similar to patients with MCP, patients with PIC did not develop new lesions on prolonged follow-up. Also, the smaller and typically fewer PIC lesions were seen more often in the macula than were MCP lesions. The visual field defects in these patients also could be directly traced back to fundus lesions. The ERG testing showed patients with PIC had essentially normal ERG responses, in contrast to patients with moderate and severe MCP who typically had abnormal-to-extinguished-ERG responses. This also
Reddy et al . Chorioretinal Inflammatory Disorders Table 5. Comparison of Clinical Features of Multiple Evanescent White Dot Syndrome, Multifocal Choroiditis with Panuveitis, Punctate Inner Choroidopathy, and Diffuse Subretinal Fibrosis Syndrome Features
MEWDS
MCP
Age (mean) (yrs) Vitreous inflammation Recurrences Subretinal scarring Yellow subretinal mounds Location of lesions
20 55% of eyes Extremely rare None No Posterior pole, midperiphery 67% of eyes Rod and cone dysfunction acutely
36 76% of eyes Common Minimal No Posterior pole, midperiphery 47% of eyes Rod dysfunction, poor oscillatory potentials Fair
Blind spot enlargement Electroretinography
Prognosis
Excellent
PIC
nSF
30 None Rare Minimal No Posterior pole
27 83% of eyes Always Severe Yes Posterior pole
41% of eyes Normal
20% of eyes Normal
Good unless CNV
Poor
MEWDS = multiple evanescent white dot syndrome; MCP = multifocal choroiditis with panuveitis; PIC = punctate inner choroidopathy; DSF = diffuse subretinal fibrosis syndrome; CNV = choroidal neovascularization.
points out that in MCP, there appears to be more widespread disease than is apparent on clinical examination alone. On follow-up, the visual field defects in most patients with PIC generally improved without treatment, whereas most patients with MCP did not have any improvement, even with treatment. Patients with MCP who responded to treatment required prolonged (months) immunosuppression. The above differences are minor yet definite. It is possible that MCP and PIC represent a continuum of clinical responses to similar etiologic agents. Diffuse subretinal fibrosis syndrome may be a variant of MCP with more exuberant reaction to the inflammation. However, most lesions were limited to the posterior pole and provide an explanation for normal full-field ERG responses seen in these patients. Visual field defects corresponded to active lesions or old scarring. On follow-up, recurrent bouts of inflammation characterized by swelling around old lesions were the rule. These patients required aggressive treatment to limit the scarring and prevent severe visual loss. Patients with MEWDS were the most dissimilar from the other three groups. They were least likely to have bilateral involvement, any permanent chorioretinal scars, and had the best visual prognosis. The explanation for enlarged blind spots in these patients was less apparent. Although many had disc edema on angiography, the patients' amount of swelling did not sufficiently account for the enlarged blind spots. Moreover, lesions were scattered throughout the posterior pole and midperiphery, and there was no clustering of lesions clinically or angiographically around the optic nerve head. This is consistent with Dodwell and colleagues, 3 who did not find any peripapillary clustering. The ERG findings in one patient with acute MEWDS suggested widespread retinal photoreceptor dysfunction. The complaint of photopsia by many of these patients would support photoreceptor involvement. In their series of patients with MEWDS, Sieving et al 22 showed detailed ERG findings. Both rods and cones are
involved, with perhaps the former being more involved. Curcio et al 23 have described the regional variations in photoreceptors in the human retina. Rod photoreceptors were found to be of the highest density in a horizontal ellipse centered in the macula but extending nasally to the optic nerve. The center of the macula itself had fewer rods. When they examined the relative density of rods to cones, Curcio et al found one of the highest ratios anywhere within the retina in a peripapillary distribution extending nasally (i.e., more than 10 from the nerve). If the chorioretinal inflammation affects rods severely, it may explain the enlarged blind spots. The enlarged blind spots in patients with MEWDS improved without treatment as the inflammation subsided. The patients reviewed in the present series were carefully evaluated for overlapping features. Only two men were found with more than five old chorioretinallesions along with acute MEWDS lesions. The chorioretinal lesions in these two patients likely represented ocular histoplasmosis. Conversely, patients with MCP or PIC did not develop any new lesions, particularly none resembling MEWDS lesions. Although enlarged blind spots were a feature of these different clinical entities, they appear to be a common pathophysiologic response to different types of insults. A patient with birdshot chorioretinopathy (the diagnosis was supported with the finding of human leukocyte antigen-A29) also had an enlarged blind spot in one eye with temporal field defects close to the blind spot in the other eye. In MCP and PIC, the enlargement is partially because of peripapillary clustering of lesions, whereas this does not appear to be the case with MEWDS. Diffuse subretinal fibrosis appears to be more like MCP and PIC. The present study points out several clinical features that distinguish these entities (Table 5). Conversely, MEWDS appears to be quite different from MCP in terms of frequency of bilaterality, recurrences of inflammation, propensity for choroidal neovascu-
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larization, scarring, and the reversibility of visual field loss. It is possible that they may have similar bloodborne etiologic agents, and the response to this agent is determined by hormonal or immunologic influences or both, such as the human leukocyte antigens. Further work needs to be done to elucidate the causes and pathogenesis of these different clinical entities.
References 1. Hamed LM, Glaser JS, Gass JDM, Schatz NJ. Protracted enlargement of the blind spot in multiple evanescent white dot syndrome. Arch Ophthalmol 1989;107:194-8. 2. Kimmel AS, Folk JC, Thompson HS, Strnad LS. The multiple evanescent white-dot syndrome with acute blind spot enlargement [letter]. Am J Ophthalmol 1989;107:425-6. 3. Dodwell DG, Jampol LM, Rosenberg M, et al. Optic nerve involvement associated with the multiple evanescent whitedot syndrome. Ophthalmology 1990;97:862-8. 4. Fletcher WA, Imes RK, Goodman D, Hoyt WF. Acute idiopathic blind spot enlargement. A big blind spot syndrome without optic disc edema. Arch Ophthalmol 1988;106:449. 5. Hamed LA, Schatz NJ, Glaser JS, Gass JDM. Acute idiopathic blind spot enlargement without optic disc edema [letter]. Arch Ophthalmol 1988;106:1030-1. 6. Khorram KD, Jampol LM, Rosenberg MA. Blind spot enlargement as a manifestation of multifocal choroiditis. Arch Ophthalmol 1991; 109: 1403-7. 7. Singh K, de Frank MP, Shults WT, Watzke RC. Acute idiopathic blind spot enlargement. A spectrum of disease. Ophthalmology 1991 ;98:497-502. 8. Gass JDM. Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992. J Clin Neuro Ophthalmol 1993;13:79-97. 9. Callanan D, Gass JDM. Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99: 1678-85.
10. Watzke RC, Packer AJ, Folk JC, et al. Punctate inner choroidopathy. Am J Ophthalmol 1984;98:572-84. 11. Reddy CV, Folk Je. Multifocal choroiditis with panuveitis, diffuse subretinal fibrosis, and punctate inner choroidopathy. In: Schachat AP, Murphy RB, eds. Medical Retina. Vol. 2 of: Ryan SJ, ed. Retina, 2nd ed. St. Louis: Mosby, 1994; chap. 105. 12. Dreyer RF, Gass JDM. Multifocal choroiditis and panuveitis: a syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984; 102: 1776-84. 13. Cantrill HL, Folk Je. Multifocal choroiditis associated with progressive subretinal fibrosis. Am J Ophthalmol 1986; 10 1: 170-80. 14. Palestine AG, Nussenblatt RB, Parver LM, Knox DL. Progressive subretinal fibrosis and uveitis. Br J Ophthalmol 1984;68:667-73. 15. International Standardization Committee. Standard for clinical electroretinography. Arch Ophthalmol 1989; 107: 816-19. 16. Westheimer G. Scaling of visual acuity measurements. Arch Ophthalmol 1979;97:327-30. 17. Morgan CM, Schatz H. Recurrent multifocal choroiditis. Ophthalmology 1986;93:1138-47. 18. Tiedeman JS. Epstein-Barr viral antibodies in multifocal choroiditis and panuveitis. Am J Ophthalmol1987; 103:65963. 19. Schlaegel TF Jr, Cofield DD, Clark G, Weber Je. Photocoagulation and other therapy for histoplasmic choroiditis. Trans Am Acad Ophthalmol Otolaryngol 1968;72:355-63. 20. Smith RE, Knox DL, Jensen AD. Ocular histoplasmosis. Significance of asymptomatic macular scars. Arch Ophthalmol 1973;89:296-300. 21. Hayreh SS. Segmental nature of the choroidal vasculature. Br J Ophthalmol 1975;59:631-48. 22. Sieving PA, Fishman GA, Jampol LM, Pugh D. Multiple evanescent white dot syndrome. II. Electrophysiology of the photoreceptors during retinal pigment epithelial disease. Arch Ophthalmol 1984; 102:675-79. 23. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol 1990;292:497523.
Discussion by Lee M. Jampol, MD As clinicians, we are faced with a bewildering array of multifocal, idiopathic inflammatory retinal and choroidal diseases in young and middle-aged patients. These patients are free of obvious systemic disease and have no known immunologic abnormalities. These entities include acute macular neuroretinopathy, multifocal choroiditis, punctate inner choroidopathy, diffuse subretinal fibrosis, and the multiple evanescent white dot syndrome (MEWDS). In some of these patients, an infectious cause is suspected, particularly a virus, but evidence to support this is scant or absent. We probe for abnormalities ofthe immunologic system that may account for an autoimmune attack. Again, evidence for this is scant. We may treat with anti-inflammatory or immunosuppressive compounds, such as corticosteroids or cyclosporine, with apparently beneficial results in some patients. In
From the Department of Ophthalmology, Northwestern University Medical School, Chicago.
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some patients who are desperate, we try antiviral agents, such as acyclovir. We search for reason in this chaotic area. Gass and co-workers l - 3 noted some similarity in the symptoms and clinical findings in patients with acute macular neuroretinopathy, multifocal choroiditis, and MEWDS. All may present with photopsias and enlarged physiologic blind spots. There is a clustering of these cases in young women. In addition, Gass and Hamed2 reported the occurrence of acute macular neuroretinopathy in two patients, who, at other times, also showed characteristics of MEWDS. They hypothesized that these diseases are related and may represent a spectrum of responses to one etiology. In our original description ofMEWDS, enlargement of the blind spot was described in one of the patients. 4 It was not until subsequent publications that the high incidence of enlargement of the physiologic blind spot was appreciated. 5 ,6 Subsequent studies showed that this may persist beyond the period of the evanescent white dots,6-S When Fletcher and coworkers9 described acute idiopathic blind spot enlargement in young women, Hamed and co-workers7,s and Aaberg6 were quick
Reddy et al . Chorioretinal Inflammatory Disorders to point out that these patients might have MEWDS with either the absence or disappearance of the white dots. Subsequently, our group described a similar enlargement of the physiologic blind spot in patients with multifocal choroiditis. 1O Studies of patients with MEWDS showed that the blind spot enlargement is absolute and has steep margins.4-1O These measurements and eIectrophysiologic studies suggest that the enlargement is because of peripapillary retinal dysfunction rather than optic nerve dysfunction . Gass and Hamed 2 hypothesized that the peripapillary retinal dysfunction seen with MEWDS and multifocal choroiditis is etiologically related to the more widespread, progressive outer retinal dysfunction seen in patients with acute zonal occult outer retinopathy. This remains unproved. Reddy and co-workers attempt to differentiate, using clinical observations, electroretinography measurements and perimetry, MEWDS, multifocal choroiditis, punctate inner choroidopathy, and diffuse subretinal fibrosis. They reviewed 79 patients. There were not enough patients studied to attempt to differentiate multifocal choroiditis from punctate inner choroidopathy and diffuse subretinal fibrosis. There were similarities between these entities, and many of the differences were the features used to define the syndrome, such as the presence or absence of vitreous inflammation and the location of the lesions. Most ofthe authors' efforts are directed to separate multifocal choroiditis from MEWDS. The authors report that multifocal choroiditis was usually bilateral, whereas MEWDS was unilateral, but there were exceptions to these rules. In patients with multifocal choroiditis, there was a clustering of visible discrete lesions around the optic nerve (with additional abnormalities of the retinal pigment epithelium around the optic nerve) that corresponded to the area of the enlarged blind spot. However, some patients with peripapillary scars did not have blind spot enlargement, and the photopsias did not correspond to any definite change in the scars. The authors report that the enlarged blind spots in this disease often did not improve. They note that in patients with MEWDS, the visible white dots were generally symmetric and did not correspond to the area of the enlarged blind spot. Pigmentary changes were rare in patients with MEWDS and were believed to be secondary to presumed ocular histoplasmosis in two patients. The authors note the good visual acuity outcome in these patients, with universal improvement in the enlarged blind spot without treatment. They conclude that the clinical findings and the course of the enlarged blind spot are different in MEWDS and multifocal choroiditis and, therefore, these clinical syndromes are distinct diseases. Although I do not believe that MEWDS, multifocal choroiditis, and acute macular neuroretinopathy are the same disease, I am not convinced from reviewing the present manuscript that the authors have enough evidence to support their definitive conclusions. Some of the patients did not have visual field testing, and most did not have sequential field measurements. Thus, episodes of worsening or improvement in the blind spot may well have been missed. After reviewing the manuscript, I still conclude that the mechanisms of enlargement of the blind spot and the photopsias in these patients remain uncertain. The authors point out that the visible spots in MEWDS do not cluster around the optic nerve. However, recent indocyanine green angiography has shown that more lesions are present than are visible clinically. II Perhaps these hypofluorescent lesions cluster more often around the optic nerve. This might explain the enlarged blind spot seen with this entity. The long-term natural history
of patients with enlarged blind spots due to multifocal choroiditis and MEWDS has previously been uncertain. The present article suggests that patients with MEWDS show invariable spontaneous improvement in the peripapillary retinal dysfunction, whereas those with multifocal choroiditis usually do not. But we have reported dramatic improvement in blind spot enlargement in patients with multifocal choroiditis,IO and the authors report similar cases. The long-term natural course of the enlarged blind spot in patients with multifocal choroiditis, thus, remains certain. Most patients with MEWDS have a single episode with a favorable outcome, but there are exceptions to this rule. We have recently reported several patients with multiple recurrences of MEWDS.12 In these patients, there was a waxing and waning of the size of the peripapillary scotomata. During periods of disease activity, the blind spots enlarged and photopsias often were present. We need to have careful prospective follow-up of the peripapillary retinal function in patients with these various entities to determine the mechanisms of blind spot enlargement and whether there are differences in the natural history of these diseases. These data may provide us with additional evidence as to whether these various entities are related. References I. Callanan D, Gass JDM. Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot syndrome and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99: 1678-85. 2. Gass JDM, Hamed LM. Acute macular neuroretinopathy and multiple evanescent white dot syndrome occurring in the same patients. Arch Ophthalmol 1989;107:189-93. 3. Gass JDM. Acute zonal occult outer retinopathy. J. Clin Neuro-ophthalmol 1993; 13:79-97. 4. Jampol LM, Sieving PA, Pugh D, Fishman GA, Gilbert H. Multiple evanescent white dot syndrome I. Clinical findings. Arch Ophthalmol 1984; I 02:671-4. 5. Dodwell DG, Jampol LM, Rosenberg M, Berman A, Zaret CR. Optic nerve involvement associated with the multiple evanescent white dot syndrome. Ophthalmology 1990;97: 862-8. 6. Aaberg TM. Multiple evanescent white dot syndrome. Arch Ophthalmol 1988; 106: 1162-3. 7. Hamed LM, Schatz NJ, Glaser JS, Gass JDM. Acute idiopathic blind spot enlargement without optic disc edema. Arch Ophthalmol 1988; 106: 1030-31 . 8. Hamed LM, Glaser JS, Gass JDM, Schatz NJ. Protracted enlargement of the blind spot in multiple evanescent white dot syndrome. Arch Ophthalmol 1989; 107: 194-8. 9. Retcher WA, Imes RK, Goodman D, Hoyt WF. Acute idiopathic blind spot enlargement: a big blind spot syndrome without optic disc edema. Arch Ophthalmol 1988;106:449. 10. Khorram KD, Jampol LM, Rosenberg MA. Blind spot enlargement as a manifestation ofmultifocal choroiditis. Arch OphthalmoI1991 ;109:1403-7. II. Ie D, Glaser BM, Murphy RP, Gordon LW, Sjaarda RN, Thompson JT. Indocyanine green angiography in multiple evanescent white dot syndrome. Am J Ophthalmol 1994;117:7-12. 12. Tsai L, Jampol LM, Pollock SC, Olk J. Chronic recurrent multiple evanescent white dot syndrome. Retina 1994;14: 160-3.
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Enlarged blind spots are a well-recognized occurrence in patients with multiple evanescent white dot syndrome (MEWDS).1-3 In fact, patients initially described with the acute idiopathic enlarged blind spot syndrome likely represent those patients with MEWDS in whom the white fundus lesions have faded. 4 ,5 More recently, Khorram et Originally received: October 30, 1994. Revision accepted: January 3, 1996. From the Department of Ophthalmology, The University oflowa Hospitals and Clinics, Iowa City. Presented at the American Academy of Ophthalmology Annual Meeting, San Francisco, November 1994. Correspondence to Chittaranjan V. Reddy, MD, Retina Consultants of Central Illinois, 5016 N. University St, Peoria, IL 616144763.
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al 6 described three patients with multifocal choroiditis and Singh et al? described one patient with presumed ocular histoplasmosis and one with acute macular neuroretinopathy having associated enlarged blind spots. It has been proposed that many of these disorders are closely related and may, in fact, have the same etiologic basis. 8 The rationale for this has been that these disorders, namely multifocal choroiditis and panuveitis (MCP), MEWDS, acute macular neuroretinopathy, as well as acute idiopathic enlarged blind spot syndrome, typically occur in young women in their 30s and 40s and have overlapping features. 8 ,9 The present study describes the clinical, visual field, and electroretinographic findings in a series of patients with MEWDS, MCP, punctate inner choroidopathy (PIC), 10,11 and the diffuse subretinal fibrosis syndrome.
Reddy et al . Chorioretinal Inflammatory Disorders The findings in these disorders were compared to determine whether they are separate entities or different manifestations along a spectrum of a single disorder.
Methods and Patients Patients for the study were recruited prospectively beginning in July 1980 with the remainder of the patients being found through review of the photographic files at The University of Iowa Hospitals and Clinics. These patients had the diagnosis of nonspecific multifocal choroiditis. Patients with MCp I2 were included only if there were any sign of active vitritis, anterior chamber inflammation, or active chorioretinallesions at any time during the clinical course. In particular, any patient who could not be clearly differentiated from the presumed ocular histoplasmosis syndrome was excluded. Patients with sarcoidosis, inflammatory bowel disease, lymphoma, tuberculosis, or any other identifiable cause for the choroiditis were excluded as well. Patients with PIC were seen by either of two observers (JCF or CVR). Patients were considered to have PIC if they had symptoms attributable to the typical small chorioretinal lesions, which evolved into scars on follow-up. These patients also had no sign of vitreous or anterior chamber cells during the clinical course or any new fundus lesions on follow-up. 10,1 1 Patients with MEWDS were included only if white dots could be seen at the time of examination or if photographs clearly showing the white fundus lesions were available from the referring physicians. Most of these latter patients had the characteristic orange granularity around the fovea. Patients with enlarged blind spots and no fundus lesions were not included. Patients with the diffuse subretinal fibrosis syndrome presented with numerous small, yellow lesions in the posterior pole along with variable vitreous inflammation. Often, the lesions coalesced into subretinal pigment epithelial or subretinal lumps followed by rapid subretinal scarring. 11,13, 14 All patients in the study had best corrected visual acuity measurements, slit-lamp examinations of the anterior segment and vitreous, and detailed fundus examinations. Patients were evaluated with either the Goldmann perimeter or Humphrey 30-2 or both. An enlarged blind spot was defined as being at least 15 0 to 20 0 in diameter with features of an absolute scotoma and steep margins. Electroretinography (ERG) was performed using a protocol established by the International Standardization Committee l5 on aUT AS E2000 instrument (LKC Technologies, Gaithersburg, MD). Responses were recorded with a bipolar Burian-Allen contact lens (Hansen Ophthalmic Development Lab, Iowa City, IA). Dark adaptometry was performed with a Goldmann-Weekers dark adaptometer (Haag Streit, Bern, Switzerland). Focal ERG was performed using a MaculoScope (Doran Instruments, Littleton, MA). Fluorescein angiography was obtained on all consenting patients. Many of the patients in the study were brought back for the different clinical evaluations.
All photographic files were reviewed. The number of lesions within the temporal arcades, in the nasal, temporal, superior, and inferior periphery were quantitated for each eye. The severity of disease in each eye was graded as follows: mild involvement (1 to 20 lesions), moderate involvement (21 to 50 lesions), and severe involvement (more than 50 lesions). Additionally, each area with 10 or more lesions was noted. The pigmentation of the lesions, the presence of swelling around the lesions, disc edema, peripapillary scarring or fibrosis, choroidal neovascularization, and cystoid macular edema were noted as well. All serial photographs, including the angiograms, were scrutinized for the presence of new chorioretinal lesions. Initial and final visual acuity data for each of the different groups were analyzed. The average was determined using the 10gMAR scale. 16
Results A total of 182 patients were reviewed and 79 were found to meet the entry criteria of the study. Of these, 41 patients had MCP, 16 had PIC, 6 had diffuse subretinal fibrosis syndrome, and 16 had MEWDS. Multifocal Choroiditis Sixty-eight eyes of 41 patients with MCP were involved. The patients' average age at onset, gender, and race are listed in Table 1. Presenting complaints included decreased vision, scotomata, photopsia, and floaters. Of note, many patients complained of temporal photopsia and scotomata, which persisted for several weeks to months. Few patients complained of pain or photophobia. Initial vision was relatively good with most patients having visual acuity of20/50 or better. All patients had varying amounts of either anterior chamber or vitreous cells or both. Fifty-one of the 68 (75%) affected eyes underwent visual field testing during the clinical course of the disease. As listed in Table 1, enlarged blind spots and full fields were the two most frequent findings. The enlarged blind spot was seen as a manifestation of the initial episode of inflammation in approximately 40% of eyes with this visual field defect, whereas the other eyes developed enlarged blind spots as a consequence of recurrent inflammation. The enlarged blind spots ranged from 25 0 in size to those extending to the far temporal periphery. All patients had discrete chorioretinallesions in the areas of involvement. Smaller lesions and diffuse intervening areas of involvement were more apparent with fluorescein angiography (Fig 1). Twenty three (34%) eyes had disc edema or staining with fluorescein angiography. However, this did not appear to be sufficient to account for the visual field defect. Additionally, most central and paracentral scotomata were directly related to chorioretinal lesions, choroidal neovascular membranes, or cystoid macular edema. A review of fundus photographic files of patients with multifocal choroiditis showed a large preponderance of lesions clustered around the optic nerve and in the nasal midperiphery and periphery (Fig 2). This was seen not
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Table 1. Multifocal Choroiditis N = 41 patients, 68 eyes Age at onset Average: 35.5 yrs Range: 13-63 yrs Sex: 32 females (78%) Race: 40 white, 1 black Bilateral involvement: 27 (66%) Presenting symptom Blurred vision/scotomata: 27 patients Photopsias: 15 patients Floaters: 9 patients Visual acuity· Initial average: 20/45 Range: 20/15 to counting fingers Final average: 20/33 Range: 20/15 to counting fingers Refractive error (spherical equivalent) Average: -2.19 diopter Range: -9.00 to +2.50 diopters Recurrent infiammation:t 86% Anterior chamber cells: 22 eyes (32%) Vitreous cells: 52 eyes (76%) Choroidal neovascularization: 17 eyes (25%) Disc edema/hyperemia: 23 eyes (34%) Visual field defectst Enlarged blind spot: 24 eyes (47%) Central/paracentral: 13 eyes (25%) Cecocentral: 2 eyes (4%) Peripheral: 4 eyes (8%) Full: 22 eyes (43%) Distribution of lesions§ Macular: 23 eyes Nasal: 28 eyes Temporal: 2 eyes Superior: 3 eyes Inferior: 3 eyes Diffuse: 4 eyes ERG findings II Mild: normal ERG Moderate: rod dysfunction and poor OPs Severe: rod and cone dysfunction; poor OPs ERG
= electroretinogram; OP = oscillatory potential.
• Patients with a minimum of 6 months' follow-up (N months; range, 6-234 months).
=
25; average, 64.9
t Patients with a minimum of 1 year follow-up (N = 21) to ensure recurrent and not persistent inflammation. t
Fifty-one (75%) of the 68 affected eyes underwent visual field testing.
§ Eyes with a minimum of 10 lesions in each of the involved areas.
II Ten (27%) patients tested; severity of fundus lesions compared with ERG findings.
only in the patients with enlarged blind spots but also in those with full visual fields. Identifying 10 or more lesions in the other peripheral areas (outside the temporal arcades) was relatively less common. The review of photographic files probably underestimated the frequency of nasal clustering compared with macular lesions, because there were
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frequently better photographs of the latter. Nineteen photographic files with fundus photographs or angiograms or both and a minimum follow-up of 6 months were available for review. The mean period of follow-up for these photographic files was 64 months, with a median of 50 months. In all involved eyes, no new inflammatory chorioretinallesions were noted. Although the lesions became larger and more pigmented with time, they could be directly traced to previous lesions seen on color photographs or fluorescein angiograms. These findings were made independently by two observers (JCF and CVR). This was surprising because 86% of eyes (n = 21) observed clinically for 1 year or longer had recurrent inflammation characterized by new symptoms, along with either anterior chamber or vitreous cells. These patients had swelling around old lesions on ophthalmoscopy, and fluorescein angiography showed leakage around pre-existing scars. Some patients had new symptoms without any visible change ophthalmoscopically or angiographically. Electroretinography was performed on 10 patients during the course of their disease. Two patients with mild disease (20 lesions or fewer/eye) had essentially normal ERG responses. Five patients had moderate disease (21 to 50 lesions) and 3 had severe disease (>50 lesions). The patients with moderate disease had abnormal ERG responses characterized by rod dysfunction, prolonged cone B-wave-implicit times, and poor oscillatory potentials. Asymmetric ERG responses between eyes in these five patients also were seen and correlated with the amount of chorioretinal involvement. In eyes with severe involvement, rod and cone dysfunctions were evident with poor oscillatory potentials. On clinical follow-up, as noted above, the majority had recurrent inflammation. Average follow-up visual acuity for this group was better than the average initial visual acuity with 55% retaining 20/40 or better visual acuity. However, 8 of 45 (18%) eyes had visual acuity of 20/200 or worse, with 3 patients having poor vision bilaterally. Visual field testing was repeated in 14 patients who had field defects in 18 eyes. Four (22%) eyes had resolution of their enlarged blind spots; three improved spontaneously, whereas one patient was treated with oral prednisone. The other 14 (78%) eyes had no appreciable improvement in the field defect with (4 eyes) or without (10 eyes) immunosuppression.
Punctate Inner Choroidopathy Sixteen patients had PIC involving 30 eyes (Table 2). Bilateral involvement was seen in all except two patients. All except one patient were women. Initial visual complaints were similar to those of patients with MCP. Initial visual acuity in approximately 75% of patients was 20/40 or better. Patients with poor initial visual acuity had clustering of lesions around the fovea or neurosensory detachment of the retina caused by active lesions in the macula. Visual field evaluation was done on 22 of 30 (73%) affected eyes. Enlarged blind spots were the most frequently seen field defect (Table 2). Many of the enlarged
Reddy et al . Chorioretinal Inflammatory Disorders
Figure 1. A 51-year-old woman with multifocal choroiditis and panuveitis (Mep). A, fundus photograph shows acute swelling of lesions in the superonasal midperiphery as well as juxtapapillary choroidal neovascularization. B, fundus fluorescein angiogram shows many small and subtle lesions between the more obvious scars. Many of the smaller lesions were not seen clinically. C, angiogram shows late leakage from lesions and the choroidal neovascularization. D, shows an inferotemporal field defect corresponding to the area of chorioretinal involvement. The field defect did not improve after the inflammation resolved.
blind spots extended toward the macula rather than the temporal periphery, as seen in the patients with MCP. Central and paracentral defects were seen in three of the involved eyes. Most of the fundus lesions in this group were seen in the macula, in contrast to patients with MCP who had relatively fewer lesions in the macula compared with other areas of the fundus. Five eyes had nasal clustering as seen in patients with MCP. Also, in this group of patients, the amount of peripapillary scarring or disc edema seen on fluorescein angiography did not appear to sufficiently account for the the enlarged blind spot. The ERG testing showed findings within the normal range in all seven patients who were tested. Three of the seven patients who were tested had mild asymmetry in B-wave amplitudes between the two involved eyes. This correlated with differences in the number of lesions in each eye. With follow-up, only one patient had recurrent episodes of swelling around previous lesions without any signs of anterior chamber or vitreous cells. Average follow-up visual acuity was better than average initial acuity even though 69% of patients were not treated with steroids.
Five (17%) eyes developed neovascular membranes. Two of the patients underwent surgery for removal of subfoveal membranes with improvement of visual acuity to 20/40 or better. Follow-up visual fields on seven involved eyes showed improvement in all patients. Three patients were treated with prednisone, whereas the other four improved without treatment. Review of the photographic files showed nine patients with a minimum of 6 months' photographic follow-up, with a mean of 44 months and a median of 33 months. The PIC lesions, which started as indistinct, yellow lesions, with time became more discrete and pigmented (Fig 3). The amount of pigmentation was typically less than that in MCP lesions, which also were bigger than the PIC lesions. Detailed examination showed no new lesions in eyes with follow-up photographs.
Diffuse Subretinal Fibrosis Syndrome Six patients were identified with the diffuse subretinal fibrosis syndrome (Table 3). They all had bilateral involvement, although in three patients, only one eye was initially involved. This group of patients had the worst initial visual
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Figure 2. A 2S-year-old woman with multifocal choroiditis and panuveitis and a I-year history of temporal field loss and counting fingers vision. A and B, show clustering of lesions nasally and swelling of the lesions in the posterior pole. C and D, fluorescein angiograms show leakage from the lesions and optic nerve head. E, fluorescein angiogram shows less swelling around lesions after oral and depot corticosteroids. F and G, show the visual field defect before and after treatment. The temporal field defect improved and the visual acuity improved from counting fingers at 2 ft to 20/40, despite visual loss for more than 1 year.
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Reddy et al . Chorioretinal Inflammatory Disorders Table 2. Punctate Inner Choroidopathy N = 16 patients, 30 eyes Age at onset Average: 30.3 yrs Range 20-41 yrs Sex: 15 females (94%) Race: 16 white Bilateral involvement: 14 (88%) Presenting symptom Blurred vision/ scotomata: 12 patients Photopsias: 6 patients Floaters: 1patient Visual acuity" Initial average: 20/41 Range: 20/15 to 20/500 Final average: 20/ 33 Range: 20/ 15 to counting fingers Refractive error (spherical equivalent) Average: -3.67 diopters Range: -8.25 to + 1.00 diopters Recurrent infiammation:t 1 patient (6%) Choroidal neovascularization: 5 eyes (17%) Disc edema/hyperemia: 4 e yes (13%) Visual field defectsT Enlarged blind spot: 9 eyes (41%) Central/paracentral: 3 eyes (14%) Cecocentral: 0 eyes Peripheral: 0 eyes Full: 10 eyes (45%) Distribution of lesions§ Macular: 18 eyes Nasal: 5 eyes Temporal: 2 eyes Superior: 0 eyes Inferior: 0 eyes Diffuse: 2 eyes ERG findings II Normal full-field ERG Asymmetry between eyes in 3 patients ERG
=
Table 3. Diffuse Subretinal Fibrosis Syndrome N = 6 patients, 12 eyes Age at onset Average: 27.3 yrs Range: 7-58 yrs Sex: 5 females (83%) Race: 5 white, 1 black Bilateral involvement: 6 (100%) Presenting symptom Blurred ViSion/scotoma: 5 patients Photopsias: 2 patients Floaters: 1patient Visual acuity" Initial average: 20/ 291 Range: 20/ 15 to counting fingers Final average: 20/163 Range: 20/20 to hand motions Refractive error (spherical equivalent) Average: -1.25 diopter Range: -7.00 to plano diopters Recurrent infiammation:t 100% Anterior chamber cells: 4 eyes (33%) Vitreous cells: 10 eyes (83%) Choroidal neovascularization: 2 eyes (17%) Disc edema/ hyperemia: 8 eyes (66%) Visual field defectsT Enlarged blind spot: 2 eyes (20%) Central/paracentral: 2 eyes (20%) Cecocentral: 3 eyes (30%) Peripheral/diffuse: 2 eyes (20%) Full: 1eye (10%) Distribution of lesions§ Macular: 9 eyes Nasal: 5 eyes Temporal: 0 eyes Superior: 1eye Inferior: 0 eyes Diffuse: 2 eyes ERG findings II Normal full-field ERG Cone implicit prolonged Abnormal focal ERG in 1 patient
electroretinogram.
"In patients with a minimum of 6 months' follow-up (N 41.5 months; range, 6-154 months).
t
In patients with a minimum of 12 months' follow-up (N recurrent and not persistent inflammation.
t
involvement of the peripheral fundus. Acute lesions typically were small, yellow, and indistinct. Over a few days, they coalesced into dirty, yellow mounds beneath the retinal pigment epithelium or neurosensory retina. These mounds consisted of turbid pockets of severe inflammation. This was followed by the development of subretinal
= =
14; average, 12) to ensure
Twenty-two (73%) of 30 involved eyes had visual fields.
§ Eyes with a minimum of 10 lesions in each of the involved areas.
II ERG testing done on 7 (44%) patients.
acuity with all involved eyes having 20/200 visual acuity or worse. The uninvolved fellow eye had better vision. Visual field defects in patients with diffuse subretinal fibrosis involved fixation at some time during the course of the disease in most patients. Enlarged blind spots were less frequent. With treatment, the size of the field defect frequently improved but typically worsened with recurrence of inflammation. The lesions in patients with diffuse subretinal fibrosis were seen predominantly in the macula, with much less
ERG
=
electroretinogram.
• Patients with a minimum of 6 months' follow-up (N months; range, 22-120 months).
t Patients with a minimum of 1 year follow-up (N and not persistent inflammation. t
=
=
6; average, 63.8
6) to ensure recurrent
Ten (83%) of the 12 affected eyes underwent visual field testing.
§ Eyes with a minimum of 10 lesions in each of the involved areas. I Two patients tested.
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Figure 3. A, a 36-year-old woman with punctate inner choroidopathy. B, 7 years later, there appeared to be a new lesion adjacent to the inferior arcade. However, scrutiny of the fundus fluorescein angiogram taken the same day as Figure 3A shows that a subtle lesion was already present (C). Therefore, no new scars developed on follow-up in this patient.
fibrous bands, which appeared over a few weeks. On follow-up, recurrent bouts of inflammation were characterized by leakage around pre-existing lesions. No new lesions were seen with extended follow-up (mean, 64 months), but frequently there was increased fibrosis around individual lesions in the macula and the midperiphery (Fig 4). Aggressive and prolonged treatment with corticosteroids was required in all patients. Two patients who developed side effects from corticosteroids and had intractable disease benefited from cyclosporine or azathioprine or both. The ERG studies in two patients with diffuse subretinal fibrosis and severe involvement of the macula showed normal full-field ERG responses. One of the two patients had detectable asymmetry in the focal ERG between the two eyes, although the eyes appeared to be similarly affected ophthalmoscopically.
Multiple Evanescent White Dot Syndrome Sixteen patients had MEWDS (Table 4). Bilateral involvement was seen in four patients. The complaint of photopsia was fairly prominent as with patients with MCP and PIC. Eight (50%) patients with MEWDS presented with this complaint. Initial visual acuity was 20/40 or better in all except two eyes. Vitreous or anterior chamber cells or both were a common feature on presentation.
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Visual field testing showed enlarged blind spots in two thirds of involved eyes along with or without central defects. Follow-up visual fields in seven patients with nine involved eyes showed resolution of all defects without any treatment. Examination of the fundus photographs and angiograms of patients with MEWDS showed no evidence of clustering oflesions in any particular quadrant and, notably, not in a peripapillary or nasal distribution. Five patients with MEWDS had inactive chorioretinal scars noted on peripheral fundus examination or with photography. Three of these patients had only two to four nonspecific chorioretinal scars. The other two patients with MEWDS had more numerous chorioretinal scars. They were both men. One of them had findings highly suggestive of ocular histoplasmosis and had undergone laser photocoagulation for neovascular membranes in both eyes 10 years earlier. He had no intervening episodes of inflammation during that time. The other man also appeared to have ocular histoplasmosis lesions in both eyes, but had vitreous inflammation in only the eye with the MEWDS lesions. In all five of these patients with old chorioretinal lesions and MEWDS, the former preceded the development of the acute lesions. There were no subsequent episodes of inflammation.
Reddy et al . Chorioretinal Inflammatory Disorders
Figure 4. A 31-year-old patient with diffuse subretinal fibrosis syndrome. A, left eye shows coalescing of lesions into yellow deposits. B, this was followed by scarring and severe visual loss. C, right eye shows quiescent scars. D, oral prednisone was tapered, and the patient returned 2 months later with new symptoms and swelling around old lesions. E, oral prednisone was increased, the symptoms improved, and less swelling of lesions was noted 3 months later. Notice, however, mild subretinal scarring inferior to the fovea.
The ERG testing done on three patients with acute MEWDS showed one patient with dysfunction of both rods and cones along with poorly developed oscillatory potentials; the other two patients had normal ERG responses. The same patient had poor amplitudes in the fovea and papillomacular bundle with focal ERG testing. Follow-up ERGs done on four patients showed normal ERG responses. These patients were tested between 5 and 32 months after their initial inflammation subsided.
On follow-up, all patients with MEWDS had resoiution of symptoms. None of the patients in this series had recurrent inflammation.
Discussion As described above, most patients with MCP, PIC, MEWDS, and diffuse subretinal fibrosis syndrome are young and otherwise healthy women (Table 5). Some of
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4. Multiple Evanescent White Dot Syndrome
N = 16 patients, 20 eyes Age at onset Average: 28.1 yrs Range: 11-49 yrs Sex: 8 females (50%) Race: 14 white, 1 black, 1 Asian Bilateral involvement: 4 (25%) Presenting symptom Blurred vision/scotomata: 10 patients Photopsias: 8 patients Floaters: 1 patient Visual acuity· Initial average: 20/26 Range: 20/15 to 20/200 Final average: 20/20 Range: 20/15 to 20/40 Refractive error (spherical equivalent) Average: -1.25 diopter Range: -7.00 to plano Recurrent infiammation:t 0% Anterior chamber cells: 7 eyes (35%) Vitreous cells: 11 eyes (55%) Choroidal neovascularization: 2 eyes (10%)'1' Disc edemajhyperemia: 9 eyes (45%) Visual field defects§ Enlarged blind spot: 12 eyes (67%) Central/paracentral: 1 eye (6%) Cecocentral: 1 eye (6%) Peripheral: 0 (0%) Full: 5 eyes (28%) Distribution of lesions II Macular: 4 eyes Nasal: 3 eyes Temporal: 7 eyes Superior: 6 eyes Inferior: 6 eyes Diffuse: 4 eyes ERG findings~ Acutely: 1 eye had abnormal focal and full ERG With prolonged follow-up: all ERGs normal ERG
=
electroretinogram.
• Patients with a minimum of 6 months' follow-up (N months; range, 6-47 months).
t Patients with a minimum of 1 year follow-up (N was recurrent and not persistent inflammation.
=
=
8; average, 21.8
6) to ensure there
t One patient had bilateral extrafoveal neovascular membranes secondary to histoplasmosis treated 10 years earlier. §Eighteen (90%) of the 20 affected eyes underwent visual field testing.
II Eyes with a minimum of 10 lesions in each of the involved areas. 11 Three patients tested acutely; 4 patients tested 2 months after active lesions disappeared.
these patients describe an antecedent flu-like illness. Other features that are similar in these patients include the prominent complaint of photopsia, level of involvement
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in the retina and choroid, as well as certain overlapping features described by others. 8,9 This study showed that visual field abnormalities are a common feature of these disorders, particularly enlarged blind spots (Table 5). Gass has suggested that these diseases may represent a spectrum of disease and may be closely related. One of the purposes of the present study was to determine whether these diseases are different, with emphasis on MEWDS, compared with the other three disorders. The largest group of patients in this series had MCP. These patients had recurrent bouts of inflammation consisting of vitreous or anterior chamber cells or both and swelling around previously noted lesions. It was interesting that none of the patients developed new lesions but had recurrent inflammation around old lesions, causing swelling and leakage on fluorescein angiography. With time, these lesions increased in size and pigmentation. Morgan and Schatz 17 described a group of 11 patients with multifocal choroiditis and recurrent bouts of inflammation. They noted "new sites developing adjacent to old ones." Figure 3 illustrates a case with increasing size and pigmentation over an 8-year period. Although a fluorescein angiogram at initial presentation was not available for comparison, it appears that there were not any new lesions, but that the older lesions became larger and more pigmented after recurrent bouts of inflammation. If an infectious etiology is invoked for MCP, 18 it would appear that the primary insult was a one-time occurrence with recurrent inflammation occurring as in patients with reactivated histoplasmosis lesions. 19,20 Areas of minimally involved retina-choroid between more obvious scars were common but more subtle and often best seen with fluorescein angiography. Also of note was the strong nasal preponderance of lesions in these patients. One plausible explanation for this finding is that the peripapillary choroid extending nasally to the equator (the area where most of the MCP lesions were seen) is supplied by the medial posterior ciliary arteryY If MCP is caused by a bloodborne agent, perhaps these agents are shed through the medial ciliary artery more readily for unclear reasons. The location of lesions around the nerve and in the nasal periphery directly corresponded to the enlarged blind spots and temporal field defects seen in patients with MCP. Some patients with recurrent inflammation also experienced visual field defects. Occasionally, patients with MCP with longstanding (longer than 6 months) visual loss and visual field defects improved with immunosuppression. Patients with PIC are the most difficult to distinguish from patients with MCP. Their clinical differences include the absence of anterior chamber and vitreous cells and the rare recurrent swelling around old lesions. Similar to patients with MCP, patients with PIC did not develop new lesions on prolonged follow-up. Also, the smaller and typically fewer PIC lesions were seen more often in the macula than were MCP lesions. The visual field defects in these patients also could be directly traced back to fundus lesions. The ERG testing showed patients with PIC had essentially normal ERG responses, in contrast to patients with moderate and severe MCP who typically had abnormal-to-extinguished-ERG responses. This also
Reddy et al . Chorioretinal Inflammatory Disorders Table 5. Comparison of Clinical Features of Multiple Evanescent White Dot Syndrome, Multifocal Choroiditis with Panuveitis, Punctate Inner Choroidopathy, and Diffuse Subretinal Fibrosis Syndrome Features
MEWDS
MCP
Age (mean) (yrs) Vitreous inflammation Recurrences Subretinal scarring Yellow subretinal mounds Location of lesions
20 55% of eyes Extremely rare None No Posterior pole, midperiphery 67% of eyes Rod and cone dysfunction acutely
36 76% of eyes Common Minimal No Posterior pole, midperiphery 47% of eyes Rod dysfunction, poor oscillatory potentials Fair
Blind spot enlargement Electroretinography
Prognosis
Excellent
PIC
nSF
30 None Rare Minimal No Posterior pole
27 83% of eyes Always Severe Yes Posterior pole
41% of eyes Normal
20% of eyes Normal
Good unless CNV
Poor
MEWDS = multiple evanescent white dot syndrome; MCP = multifocal choroiditis with panuveitis; PIC = punctate inner choroidopathy; DSF = diffuse subretinal fibrosis syndrome; CNV = choroidal neovascularization.
points out that in MCP, there appears to be more widespread disease than is apparent on clinical examination alone. On follow-up, the visual field defects in most patients with PIC generally improved without treatment, whereas most patients with MCP did not have any improvement, even with treatment. Patients with MCP who responded to treatment required prolonged (months) immunosuppression. The above differences are minor yet definite. It is possible that MCP and PIC represent a continuum of clinical responses to similar etiologic agents. Diffuse subretinal fibrosis syndrome may be a variant of MCP with more exuberant reaction to the inflammation. However, most lesions were limited to the posterior pole and provide an explanation for normal full-field ERG responses seen in these patients. Visual field defects corresponded to active lesions or old scarring. On follow-up, recurrent bouts of inflammation characterized by swelling around old lesions were the rule. These patients required aggressive treatment to limit the scarring and prevent severe visual loss. Patients with MEWDS were the most dissimilar from the other three groups. They were least likely to have bilateral involvement, any permanent chorioretinal scars, and had the best visual prognosis. The explanation for enlarged blind spots in these patients was less apparent. Although many had disc edema on angiography, the patients' amount of swelling did not sufficiently account for the enlarged blind spots. Moreover, lesions were scattered throughout the posterior pole and midperiphery, and there was no clustering of lesions clinically or angiographically around the optic nerve head. This is consistent with Dodwell and colleagues, 3 who did not find any peripapillary clustering. The ERG findings in one patient with acute MEWDS suggested widespread retinal photoreceptor dysfunction. The complaint of photopsia by many of these patients would support photoreceptor involvement. In their series of patients with MEWDS, Sieving et al 22 showed detailed ERG findings. Both rods and cones are
involved, with perhaps the former being more involved. Curcio et al 23 have described the regional variations in photoreceptors in the human retina. Rod photoreceptors were found to be of the highest density in a horizontal ellipse centered in the macula but extending nasally to the optic nerve. The center of the macula itself had fewer rods. When they examined the relative density of rods to cones, Curcio et al found one of the highest ratios anywhere within the retina in a peripapillary distribution extending nasally (i.e., more than 10 from the nerve). If the chorioretinal inflammation affects rods severely, it may explain the enlarged blind spots. The enlarged blind spots in patients with MEWDS improved without treatment as the inflammation subsided. The patients reviewed in the present series were carefully evaluated for overlapping features. Only two men were found with more than five old chorioretinallesions along with acute MEWDS lesions. The chorioretinal lesions in these two patients likely represented ocular histoplasmosis. Conversely, patients with MCP or PIC did not develop any new lesions, particularly none resembling MEWDS lesions. Although enlarged blind spots were a feature of these different clinical entities, they appear to be a common pathophysiologic response to different types of insults. A patient with birdshot chorioretinopathy (the diagnosis was supported with the finding of human leukocyte antigen-A29) also had an enlarged blind spot in one eye with temporal field defects close to the blind spot in the other eye. In MCP and PIC, the enlargement is partially because of peripapillary clustering of lesions, whereas this does not appear to be the case with MEWDS. Diffuse subretinal fibrosis appears to be more like MCP and PIC. The present study points out several clinical features that distinguish these entities (Table 5). Conversely, MEWDS appears to be quite different from MCP in terms of frequency of bilaterality, recurrences of inflammation, propensity for choroidal neovascu-
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larization, scarring, and the reversibility of visual field loss. It is possible that they may have similar bloodborne etiologic agents, and the response to this agent is determined by hormonal or immunologic influences or both, such as the human leukocyte antigens. Further work needs to be done to elucidate the causes and pathogenesis of these different clinical entities.
References 1. Hamed LM, Glaser JS, Gass JDM, Schatz NJ. Protracted enlargement of the blind spot in multiple evanescent white dot syndrome. Arch Ophthalmol 1989;107:194-8. 2. Kimmel AS, Folk JC, Thompson HS, Strnad LS. The multiple evanescent white-dot syndrome with acute blind spot enlargement [letter]. Am J Ophthalmol 1989;107:425-6. 3. Dodwell DG, Jampol LM, Rosenberg M, et al. Optic nerve involvement associated with the multiple evanescent whitedot syndrome. Ophthalmology 1990;97:862-8. 4. Fletcher WA, Imes RK, Goodman D, Hoyt WF. Acute idiopathic blind spot enlargement. A big blind spot syndrome without optic disc edema. Arch Ophthalmol 1988;106:449. 5. Hamed LA, Schatz NJ, Glaser JS, Gass JDM. Acute idiopathic blind spot enlargement without optic disc edema [letter]. Arch Ophthalmol 1988;106:1030-1. 6. Khorram KD, Jampol LM, Rosenberg MA. Blind spot enlargement as a manifestation of multifocal choroiditis. Arch Ophthalmol 1991; 109: 1403-7. 7. Singh K, de Frank MP, Shults WT, Watzke RC. Acute idiopathic blind spot enlargement. A spectrum of disease. Ophthalmology 1991 ;98:497-502. 8. Gass JDM. Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992. J Clin Neuro Ophthalmol 1993;13:79-97. 9. Callanan D, Gass JDM. Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99: 1678-85.
10. Watzke RC, Packer AJ, Folk JC, et al. Punctate inner choroidopathy. Am J Ophthalmol 1984;98:572-84. 11. Reddy CV, Folk Je. Multifocal choroiditis with panuveitis, diffuse subretinal fibrosis, and punctate inner choroidopathy. In: Schachat AP, Murphy RB, eds. Medical Retina. Vol. 2 of: Ryan SJ, ed. Retina, 2nd ed. St. Louis: Mosby, 1994; chap. 105. 12. Dreyer RF, Gass JDM. Multifocal choroiditis and panuveitis: a syndrome that mimics ocular histoplasmosis. Arch Ophthalmol 1984; 102: 1776-84. 13. Cantrill HL, Folk Je. Multifocal choroiditis associated with progressive subretinal fibrosis. Am J Ophthalmol 1986; 10 1: 170-80. 14. Palestine AG, Nussenblatt RB, Parver LM, Knox DL. Progressive subretinal fibrosis and uveitis. Br J Ophthalmol 1984;68:667-73. 15. International Standardization Committee. Standard for clinical electroretinography. Arch Ophthalmol 1989; 107: 816-19. 16. Westheimer G. Scaling of visual acuity measurements. Arch Ophthalmol 1979;97:327-30. 17. Morgan CM, Schatz H. Recurrent multifocal choroiditis. Ophthalmology 1986;93:1138-47. 18. Tiedeman JS. Epstein-Barr viral antibodies in multifocal choroiditis and panuveitis. Am J Ophthalmol1987; 103:65963. 19. Schlaegel TF Jr, Cofield DD, Clark G, Weber Je. Photocoagulation and other therapy for histoplasmic choroiditis. Trans Am Acad Ophthalmol Otolaryngol 1968;72:355-63. 20. Smith RE, Knox DL, Jensen AD. Ocular histoplasmosis. Significance of asymptomatic macular scars. Arch Ophthalmol 1973;89:296-300. 21. Hayreh SS. Segmental nature of the choroidal vasculature. Br J Ophthalmol 1975;59:631-48. 22. Sieving PA, Fishman GA, Jampol LM, Pugh D. Multiple evanescent white dot syndrome. II. Electrophysiology of the photoreceptors during retinal pigment epithelial disease. Arch Ophthalmol 1984; 102:675-79. 23. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol 1990;292:497523.
Discussion by Lee M. Jampol, MD As clinicians, we are faced with a bewildering array of multifocal, idiopathic inflammatory retinal and choroidal diseases in young and middle-aged patients. These patients are free of obvious systemic disease and have no known immunologic abnormalities. These entities include acute macular neuroretinopathy, multifocal choroiditis, punctate inner choroidopathy, diffuse subretinal fibrosis, and the multiple evanescent white dot syndrome (MEWDS). In some of these patients, an infectious cause is suspected, particularly a virus, but evidence to support this is scant or absent. We probe for abnormalities ofthe immunologic system that may account for an autoimmune attack. Again, evidence for this is scant. We may treat with anti-inflammatory or immunosuppressive compounds, such as corticosteroids or cyclosporine, with apparently beneficial results in some patients. In
From the Department of Ophthalmology, Northwestern University Medical School, Chicago.
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some patients who are desperate, we try antiviral agents, such as acyclovir. We search for reason in this chaotic area. Gass and co-workers l - 3 noted some similarity in the symptoms and clinical findings in patients with acute macular neuroretinopathy, multifocal choroiditis, and MEWDS. All may present with photopsias and enlarged physiologic blind spots. There is a clustering of these cases in young women. In addition, Gass and Hamed2 reported the occurrence of acute macular neuroretinopathy in two patients, who, at other times, also showed characteristics of MEWDS. They hypothesized that these diseases are related and may represent a spectrum of responses to one etiology. In our original description ofMEWDS, enlargement of the blind spot was described in one of the patients. 4 It was not until subsequent publications that the high incidence of enlargement of the physiologic blind spot was appreciated. 5 ,6 Subsequent studies showed that this may persist beyond the period of the evanescent white dots,6-S When Fletcher and coworkers9 described acute idiopathic blind spot enlargement in young women, Hamed and co-workers7,s and Aaberg6 were quick
Reddy et al . Chorioretinal Inflammatory Disorders to point out that these patients might have MEWDS with either the absence or disappearance of the white dots. Subsequently, our group described a similar enlargement of the physiologic blind spot in patients with multifocal choroiditis. 1O Studies of patients with MEWDS showed that the blind spot enlargement is absolute and has steep margins.4-1O These measurements and eIectrophysiologic studies suggest that the enlargement is because of peripapillary retinal dysfunction rather than optic nerve dysfunction . Gass and Hamed 2 hypothesized that the peripapillary retinal dysfunction seen with MEWDS and multifocal choroiditis is etiologically related to the more widespread, progressive outer retinal dysfunction seen in patients with acute zonal occult outer retinopathy. This remains unproved. Reddy and co-workers attempt to differentiate, using clinical observations, electroretinography measurements and perimetry, MEWDS, multifocal choroiditis, punctate inner choroidopathy, and diffuse subretinal fibrosis. They reviewed 79 patients. There were not enough patients studied to attempt to differentiate multifocal choroiditis from punctate inner choroidopathy and diffuse subretinal fibrosis. There were similarities between these entities, and many of the differences were the features used to define the syndrome, such as the presence or absence of vitreous inflammation and the location of the lesions. Most ofthe authors' efforts are directed to separate multifocal choroiditis from MEWDS. The authors report that multifocal choroiditis was usually bilateral, whereas MEWDS was unilateral, but there were exceptions to these rules. In patients with multifocal choroiditis, there was a clustering of visible discrete lesions around the optic nerve (with additional abnormalities of the retinal pigment epithelium around the optic nerve) that corresponded to the area of the enlarged blind spot. However, some patients with peripapillary scars did not have blind spot enlargement, and the photopsias did not correspond to any definite change in the scars. The authors report that the enlarged blind spots in this disease often did not improve. They note that in patients with MEWDS, the visible white dots were generally symmetric and did not correspond to the area of the enlarged blind spot. Pigmentary changes were rare in patients with MEWDS and were believed to be secondary to presumed ocular histoplasmosis in two patients. The authors note the good visual acuity outcome in these patients, with universal improvement in the enlarged blind spot without treatment. They conclude that the clinical findings and the course of the enlarged blind spot are different in MEWDS and multifocal choroiditis and, therefore, these clinical syndromes are distinct diseases. Although I do not believe that MEWDS, multifocal choroiditis, and acute macular neuroretinopathy are the same disease, I am not convinced from reviewing the present manuscript that the authors have enough evidence to support their definitive conclusions. Some of the patients did not have visual field testing, and most did not have sequential field measurements. Thus, episodes of worsening or improvement in the blind spot may well have been missed. After reviewing the manuscript, I still conclude that the mechanisms of enlargement of the blind spot and the photopsias in these patients remain uncertain. The authors point out that the visible spots in MEWDS do not cluster around the optic nerve. However, recent indocyanine green angiography has shown that more lesions are present than are visible clinically. II Perhaps these hypofluorescent lesions cluster more often around the optic nerve. This might explain the enlarged blind spot seen with this entity. The long-term natural history
of patients with enlarged blind spots due to multifocal choroiditis and MEWDS has previously been uncertain. The present article suggests that patients with MEWDS show invariable spontaneous improvement in the peripapillary retinal dysfunction, whereas those with multifocal choroiditis usually do not. But we have reported dramatic improvement in blind spot enlargement in patients with multifocal choroiditis,IO and the authors report similar cases. The long-term natural course of the enlarged blind spot in patients with multifocal choroiditis, thus, remains certain. Most patients with MEWDS have a single episode with a favorable outcome, but there are exceptions to this rule. We have recently reported several patients with multiple recurrences of MEWDS.12 In these patients, there was a waxing and waning of the size of the peripapillary scotomata. During periods of disease activity, the blind spots enlarged and photopsias often were present. We need to have careful prospective follow-up of the peripapillary retinal function in patients with these various entities to determine the mechanisms of blind spot enlargement and whether there are differences in the natural history of these diseases. These data may provide us with additional evidence as to whether these various entities are related. References I. Callanan D, Gass JDM. Multifocal choroiditis and choroidal neovascularization associated with the multiple evanescent white dot syndrome and acute idiopathic blind spot enlargement syndrome. Ophthalmology 1992;99: 1678-85. 2. Gass JDM, Hamed LM. Acute macular neuroretinopathy and multiple evanescent white dot syndrome occurring in the same patients. Arch Ophthalmol 1989;107:189-93. 3. Gass JDM. Acute zonal occult outer retinopathy. J. Clin Neuro-ophthalmol 1993; 13:79-97. 4. Jampol LM, Sieving PA, Pugh D, Fishman GA, Gilbert H. Multiple evanescent white dot syndrome I. Clinical findings. Arch Ophthalmol 1984; I 02:671-4. 5. Dodwell DG, Jampol LM, Rosenberg M, Berman A, Zaret CR. Optic nerve involvement associated with the multiple evanescent white dot syndrome. Ophthalmology 1990;97: 862-8. 6. Aaberg TM. Multiple evanescent white dot syndrome. Arch Ophthalmol 1988; 106: 1162-3. 7. Hamed LM, Schatz NJ, Glaser JS, Gass JDM. Acute idiopathic blind spot enlargement without optic disc edema. Arch Ophthalmol 1988; 106: 1030-31 . 8. Hamed LM, Glaser JS, Gass JDM, Schatz NJ. Protracted enlargement of the blind spot in multiple evanescent white dot syndrome. Arch Ophthalmol 1989; 107: 194-8. 9. Retcher WA, Imes RK, Goodman D, Hoyt WF. Acute idiopathic blind spot enlargement: a big blind spot syndrome without optic disc edema. Arch Ophthalmol 1988;106:449. 10. Khorram KD, Jampol LM, Rosenberg MA. Blind spot enlargement as a manifestation ofmultifocal choroiditis. Arch OphthalmoI1991 ;109:1403-7. II. Ie D, Glaser BM, Murphy RP, Gordon LW, Sjaarda RN, Thompson JT. Indocyanine green angiography in multiple evanescent white dot syndrome. Am J Ophthalmol 1994;117:7-12. 12. Tsai L, Jampol LM, Pollock SC, Olk J. Chronic recurrent multiple evanescent white dot syndrome. Retina 1994;14: 160-3.
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