Diagnostic and Therapeutic Challenges
Edited by H. Richard McDonald
Drs. Xiaoyan Peng, Yongpeng Zhang, Li Yibin, and Richard H. Roe
T
evoked potential showed the P-visual evoked potential of the left eye and the P1 latent period of the right eye to be normal. The amplitude of N1 and N2 at the middle and high SF was lower in the right eye than in the left eye. The amplitude of F-visual evoked potential was similar in both eyes. The electro-oculogram (EOG) showed the Arden ratio of both eyes decreased sharply (,1.5) with the photopeak latent period of the left eye prolonged (Figure 11). The patient is presented for discussion of diagnosis and treatment.
his case is submitted by Drs. Xiaoyan Peng, Yongpeng Zhang, and Li Yibin of the Beijing Ophthalmology and Visual Science Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China; commented by Dr. Richard H. Roe, Los Angeles, California. Case Report
A 33-year-old female patient complained of blurred vision and metamorphopsia in the right eye for 1 month and was seen on December 9, 2010. She had thyroid surgery 1 year before presentation for thyroid adenoma, but otherwise had no medical or family history of disease. On ocular examination, the best-corrected visual acuity was 20/60 in the right eye and 20/20 in the left eye. Intraocular pressure in both eyes was normal. The anterior segment of both eyes was normal. There were multiple yellow-white spots in the posterior pole but no visible lesions in the peripheral retina (Figures 1 and 2). The fluorescein and indocyanine green angiogram showed mottled fluorescence in the posterior pole and peripheral retina of both eyes, and late phase cystoid macular edema (CME) in the right eye. A dark choroid was suspected (Figures 3–6). The optical coherence tomography (OCT) showed CME in the right eye with a central foveal thickness of 654 mm (Figure 7). The focal electroretinogram (ERG) was normal (Figures 8 and 9). A periocular injection of triamcinolone (40 mg) was given to the right eye for treatment of the CME. The patient came back for re-examination after 3 months. The best-corrected visual acuity was 20/400 in the right eye and 20/20 in the left eye. The yellow-white spots in the posterior pole seemed reduced and the CME in the right eye decreased. The FFA and ICGA showed mottled fluorescence in the macula and the peripheral retina of both eyes with leakage in the macula of the right eye. The OCT showed CME of the right eye with decreased thickness in the central fovea to 269 mm. The patient returned after 5 months. She complained of continued decreased vision and metamorphopsia. The best-corrected visual acuity was 20/200 in the right eye and 20/20 in the left eye. A multitude of yellow-white granules were concentrated in the macula (Figure 10). The OCT showed an increased thickness of central fovea to 335 mm. The visual field showed a central scotoma in the right eye. The ERG was roughly normal with the amplitude of the right photopic ERG slightly lower than in the left eye. A visual
Dr. Richard H. Roe (Los Angeles, California): Dr. Peng et al present an interesting case of a 33-year-old healthy woman complaining of blurred vision and metamorphopsia in the right eye for 1 month. The authors state that the patient had a history of “maculopathy” diagnosed 5 years before initial presentation. She denied nyctalopia, drug abuse or toxicity, and hereditary disease. Posterior segment examination revealed multiple yellow-white spots confined to the posterior pole in both eyes. Fluorescein angiography showed bilateral mottled hyperfluorescence of the macula with suggestion of “dark choroid.” Cystoid macular edema in the right eye was observed in the late phase of the angiogram, which was confirmed by OCT. The patient was given a periocular injection of triamcinolone that reduced the edema but did not improve the vision. Follow-up of the patient after 8 months showed a significant decline in vision in the right eye with increased deposition and confluence of the yellow-white spots in the macula. Full-field ERG was essentially normal, whereas visual evoked potential of the right eye was abnormally decreased. Electro-oculogram was also reduced in both eyes with an Arden ratio less than 1.5. The case presented most likely represents a macular dystrophy, and therefore the differential diagnosis should reflect as such. Over the past 20 years, a number of genes have been identified in the pathogenesis of various macular dystrophies, including ABCA4, RDS/ 1041
1042 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 5
Fig. 1. Many yellow-white spots were noted in the posterior pole.
peripherin, EFEMP1, MCDR, ELOVL4, TIMP-3, and VMD2. Mutations or alterations in these genes have resulted in a wide array of phenotypes including Stargardt’s disease, pattern dystrophy, familial drusen, Sorsby’s fundus dystrophy, North Carolina macular dystrophy, adult vitelliform macular dystrophy, and Best disease. Mutations in the ABCA4 gene have been identified to cause a number of macular dystrophies, including the autosomal recessive form of Stargardt’s disease, fundus flavimaculatus, and cone–rod dystrophy.1 In the case presented, if we interpret the yellow-white spots in the macula of both eyes to be flecks, then Stargardt’s disease could certainly be a possibility. In addition, fluorescein angiogram of the patient showed mottled hyperfluorescence centrally in both eyes along with suggestion of “dark choroid,” both common find-
Fig. 2. Many yellow-white spots were noted in the posterior pole.
Fig. 3. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
ings in Stargardt’s disease. However, the absence of “beaten bronze” foveal atrophy in the patient makes Stargardt’s disease less likely. Other phenotypes of the ABCA4 gene such as fundus flavimaculatus and cone–rod dystrophy are also likely ruled out given the absence of flecks in the periphery and a normal ERG. An autosomal dominant form of Stargardt’s disease
Fig. 4. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 5. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
has been linked to a mutation in the ELOVL4 gene on chromosome 6 but the dark choroid effect on fluorescein angiography is characteristically absent in these patients.2 Macular dystrophies associated with the RDS/peripherin gene should also be considered. Located on the short arm of chromosome 6, the RDS/peripherin gene has been linked to a number of different retinal
Fig. 6. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
1043
dystrophies, including autosomal dominant retinitis pigmentosa, retinitis punctata albescens, central areolar choroidal dystrophy, pattern dystrophy, adult vitelliform dystrophy, and fundus flavimaculatus. The precise function of the gene product is unknown though it has been hypothesized to act as an adhesion molecule in rod and cone photoreceptors.3 In this case, the normal ERG essentially rules out autosomal dominant retinitis pigmentosa and its variants such as retinitis punctata albescens. Multifocal pattern dystrophy, however, is a strong possibility. This variant of pattern dystrophy is an autosomal dominant disorder characterized by yellow, gray, or white deposits in the macula. Boon et al described that 10 patients with multifocal pattern dystrophy confirmed to have a mutation in the RDS/peripherin gene with confluent yellow material similar in appearance to Stargardt’s disease in the macula and nasal to the optic nerve.4 Several of the patients had significant vision loss secondary to central chorioretinal atrophy, whereas the majority of the patients had significantly abnormal EOG testing. Interestingly, 39 other family members were examined as well and found to have incomplete penetrance with variable expressivity of the disease. Mutations in the EFEMP1 gene causing familial drusen, known also as Doyne honeycomb retinal dystrophy or Malattia Leventinese, could also be considered in this case. First described by R. W. Doyne in 1899 and then later in 1932 by Klainguti in patients living in the Leventine valley in Switzerland, this autosomal dominant disease typically starts with the deposition of hard drusen in the macula in the third decade of life.5 Patients can then go on to develop extensive confluent radial drusen in the macula and nasal to the optic disc. In the most severe forms, patients may experience significant retinal and retinal pigment epithelial atrophy of the fovea with decreased vision and central scotoma. Electrophysiological testing is usually normal. VMD2 gene abnormalities causing adult vitelliform dystrophy and Best dystrophy should also be considered. The significantly decreased Arden ratio would certainly support the diagnosis of Best disease, but the accumulation and confluence of the yellow-white material centrally over time would go against supporting the diagnosis. Adult vitelliform dystrophy could also be considered in this case given its association with basal laminar drusen.6 However, no vitelliform or pseudovitelliform lesions were seen on clinical examination or on OCT testing, and the EOG would be expected to be normal. Other possibilities in this case include the MCDR gene causing North Carolina macular dystrophy and the TIMP-3 gene causing Sorsby’s fundus dystrophy.
1044 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 5
Fig. 7. OCT showed CME of the right eye with the thickness of the central fovea 654 mm.
Both of these entities can present in the early stages with macular drusen, though not completely similar in appearance to this patient. About one-third of patients with North Carolina macular dystrophy will go on to develop a macular coloboma, whereas patients with Sorsby’s fundus dystrophy may develop choroidal neovascularization. Both ERG and EOG are typically normal. The occurrence of CME in this case is unusual. Though CME in retinitis pigmentosa is relatively common, CME associated with macular dystrophies is rare. The mechanism of CME in retinitis pigmentosa is hypothesized to be secondary to widespread loss of polarization in the retinal pigment epithelium leading to inability of the retinal pigment epithelium to pump ions and fluid from the outer retina.7 Other hypotheses include loss of Muller cell integrity or inflammation secondary to circulating antiretinal antibodies with subsequent compromise of the blood–retinal barrier.8 Treatment for CME in patients with retinal and macular dystrophies has included carbonic anhydrase inhibitors, glucocorticoids, and anti-vascular endothelial growth factor agents. Interestingly, unilateral CME similar to that seen in this patient has been reported in one case of pattern dystrophy confirmed to have an
RDS/peripherin mutation and in one case of Stargardt’s disease.9 In both cases, the CME and vision improved with oral acetazolamide therapy. Given the above differential, genetic testing for the ABCA4 and RDS/peripherin gene should be obtained to help narrow the diagnosis. Testing for mutations in the TIMP-3 and VMD2 genes could also be considered. Examination of family members could also help establish the inheritance pattern and differentiate between various genotypes. Autofluorescence imaging would also help further elucidate the morphology of the yellow accumulated material in the macula and reveal any fluorescence patterns specific for certain phenotypes. For instance, patients with ABCA4 mutations have been observed to have a characteristic ring of normal autofluorescence around the optic nerve.10 As for treatment of the CME, a trial of oral or topical acetazolamide in the patient should be considered.
Editor’s Note: Drs. Peng, Yongpeng, and Yibin present a 33-yearold woman with blurred vision and metamorphopsia for 1 month. The patient had CME and received
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 8. F-ERG was normal.
1045
1046 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 5
Fig. 9. F-ERG was normal.
a periocular injection, but the vision continued to decline, though the edema was improved. There was a suggestion of a dark choroid, though there was no history of nyctalopia. The ERG was normal, but the EOG was bilaterally reduced. Dr. Rick Roe has consulted on this case and feels that the patient has a macular dystrophy. He lists the
genes identified in the pathogenesis of a number of macular dystrophies. Genes associated with macular dystrophies: 1. 2. 3. 4. 5. 6. 7.
ABCA4 RDS/peripherin EFEMP1 MCDR ELOVL4 TIMP-3 VMD2.
Mutations or alterations in these genes have been associated with a number of phenotypes: 1. 2. 3. 4. 5. 6.
Fig. 10. Yellow-white granular deposits were concentrated in the macula.
Stargardt’s disease Pattern macular dystrophies Familial drusen Sorsby’s fundus dystrophy North Carolina macular dystrophy Adult vitelliform macular dystrophy.
Dr. Roe considers all of these diagnostic entities, but concentrates his comments on mutations in the ABCA4 gene and the RDS/peripherin gene. He suggests that if one considers the yellow macular spots to be flecks, then Stargardt’s disease (ABCA4
1047
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 11. EOG showed the Arden ratio of both eyes decreased sharply (,1.5) with the photopeak latent period of the left eye prolonged.
mutation) would be the diagnosis. This is made more probable by the finding on fluorescein angiography of a “dark choroid.” But, he is disturbed by the absence of a “beaten bronze” foveal atrophy. The RDS/peripherin gene has been linked to a number of different retinal dystrophies: 1. 2. 3. 4. 5. 6.
AD retinitis pigmentosa Retinitis punctata albescens Central areolar choroidal dystrophy Pattern dystrophy Adult vitelliform dystrophy Fundus flavimaculatus.
Dr. Roe feels that a multifocal pattern dystrophy is a strong diagnostic possibility and references the study by Boon in patients with RDS/peripherin mutations who had confluent yellow material similar in appearance to Stargardt’s disease, with central chorioretinal atrophy and abnormal EOGs. He notes the appearance of CME and the rarity with which it is seen in macular dystrophies.
Genetic testing, especially for ABCA4 and RDS/ peripherin, is recommended along with TIMP-3 ad VMD2 genes. Examination of family members and fundus autofluorescence might provide valuable information. Dr. Roe concludes by suggesting a trial of acetazolamide. We thank our presenters for their case, and Dr. Roe for his discussion. References 1. Westerfeld C, Mukai S. Stargardt’s disease and the ABCR gene. Semin Ophthalmol 2008;23:59–65. 2. Donoso LA, Edwards AO, Frost A, et al. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol 2001;46: 149–163. 3. Wells J, Wroblewski J, Keen J, et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet 1993;3:213–218. 4. Boon CJ, van Schooneveld MJ, den Hollander AI, et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol 2007;91:1504–1511.
1048 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 5. Stone EM, Lotery AJ, Munier FL, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999;22:199–202. 6. Lima LH, Laud K, Freund KB, et al. Acquired vitelliform lesion associated with large drusen. Retina 2012;32:647–651. 7. Cox SN, Hay E, Bird AC. Treatment of chronic macular edema with acetazolamide. Arch Ophthalmol 1988;106:1190–1195. 8. Heckenlively JR, Jordan BL, Aptsiauri N. Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 1999;127:565–573. 9. Abouzeid H, Wolfensberger TJ, Schorderet DF, et al. Unilateral macular oedema in Zermatt and Stargardt macular dystrophies. Br J Ophthalmol 2009;93:1376–1377, 1407–1408. 10. Cideciyan AV, Swider M, Aleman TS, et al. ABCA4-associated retinal degenerations spare structure and function of the human
2015 VOLUME 35 NUMBER 5
parapapillary retina. Invest Ophthalmol Vis Sci 2005;46: 4739–4746.
RETINAÒ, The Journal of Retinal and Vitreous Diseases, encourages readers to submit Diagnostic and Therapeutic Challenges to retina@ retinajournal.com. Cases for the Diagnostic and Therapeutic Challenges section should include a detailed history of the patient, the diagnosis, the workup, the management, and finally, the question or questions that the submitter wishes to have answered by the consultants.
Edited by H. Richard McDonald
Drs. Xiaoyan Peng, Yongpeng Zhang, Li Yibin, and Richard H. Roe
T
evoked potential showed the P-visual evoked potential of the left eye and the P1 latent period of the right eye to be normal. The amplitude of N1 and N2 at the middle and high SF was lower in the right eye than in the left eye. The amplitude of F-visual evoked potential was similar in both eyes. The electro-oculogram (EOG) showed the Arden ratio of both eyes decreased sharply (,1.5) with the photopeak latent period of the left eye prolonged (Figure 11). The patient is presented for discussion of diagnosis and treatment.
his case is submitted by Drs. Xiaoyan Peng, Yongpeng Zhang, and Li Yibin of the Beijing Ophthalmology and Visual Science Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China; commented by Dr. Richard H. Roe, Los Angeles, California. Case Report
A 33-year-old female patient complained of blurred vision and metamorphopsia in the right eye for 1 month and was seen on December 9, 2010. She had thyroid surgery 1 year before presentation for thyroid adenoma, but otherwise had no medical or family history of disease. On ocular examination, the best-corrected visual acuity was 20/60 in the right eye and 20/20 in the left eye. Intraocular pressure in both eyes was normal. The anterior segment of both eyes was normal. There were multiple yellow-white spots in the posterior pole but no visible lesions in the peripheral retina (Figures 1 and 2). The fluorescein and indocyanine green angiogram showed mottled fluorescence in the posterior pole and peripheral retina of both eyes, and late phase cystoid macular edema (CME) in the right eye. A dark choroid was suspected (Figures 3–6). The optical coherence tomography (OCT) showed CME in the right eye with a central foveal thickness of 654 mm (Figure 7). The focal electroretinogram (ERG) was normal (Figures 8 and 9). A periocular injection of triamcinolone (40 mg) was given to the right eye for treatment of the CME. The patient came back for re-examination after 3 months. The best-corrected visual acuity was 20/400 in the right eye and 20/20 in the left eye. The yellow-white spots in the posterior pole seemed reduced and the CME in the right eye decreased. The FFA and ICGA showed mottled fluorescence in the macula and the peripheral retina of both eyes with leakage in the macula of the right eye. The OCT showed CME of the right eye with decreased thickness in the central fovea to 269 mm. The patient returned after 5 months. She complained of continued decreased vision and metamorphopsia. The best-corrected visual acuity was 20/200 in the right eye and 20/20 in the left eye. A multitude of yellow-white granules were concentrated in the macula (Figure 10). The OCT showed an increased thickness of central fovea to 335 mm. The visual field showed a central scotoma in the right eye. The ERG was roughly normal with the amplitude of the right photopic ERG slightly lower than in the left eye. A visual
Dr. Richard H. Roe (Los Angeles, California): Dr. Peng et al present an interesting case of a 33-year-old healthy woman complaining of blurred vision and metamorphopsia in the right eye for 1 month. The authors state that the patient had a history of “maculopathy” diagnosed 5 years before initial presentation. She denied nyctalopia, drug abuse or toxicity, and hereditary disease. Posterior segment examination revealed multiple yellow-white spots confined to the posterior pole in both eyes. Fluorescein angiography showed bilateral mottled hyperfluorescence of the macula with suggestion of “dark choroid.” Cystoid macular edema in the right eye was observed in the late phase of the angiogram, which was confirmed by OCT. The patient was given a periocular injection of triamcinolone that reduced the edema but did not improve the vision. Follow-up of the patient after 8 months showed a significant decline in vision in the right eye with increased deposition and confluence of the yellow-white spots in the macula. Full-field ERG was essentially normal, whereas visual evoked potential of the right eye was abnormally decreased. Electro-oculogram was also reduced in both eyes with an Arden ratio less than 1.5. The case presented most likely represents a macular dystrophy, and therefore the differential diagnosis should reflect as such. Over the past 20 years, a number of genes have been identified in the pathogenesis of various macular dystrophies, including ABCA4, RDS/ 1041
1042 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 5
Fig. 1. Many yellow-white spots were noted in the posterior pole.
peripherin, EFEMP1, MCDR, ELOVL4, TIMP-3, and VMD2. Mutations or alterations in these genes have resulted in a wide array of phenotypes including Stargardt’s disease, pattern dystrophy, familial drusen, Sorsby’s fundus dystrophy, North Carolina macular dystrophy, adult vitelliform macular dystrophy, and Best disease. Mutations in the ABCA4 gene have been identified to cause a number of macular dystrophies, including the autosomal recessive form of Stargardt’s disease, fundus flavimaculatus, and cone–rod dystrophy.1 In the case presented, if we interpret the yellow-white spots in the macula of both eyes to be flecks, then Stargardt’s disease could certainly be a possibility. In addition, fluorescein angiogram of the patient showed mottled hyperfluorescence centrally in both eyes along with suggestion of “dark choroid,” both common find-
Fig. 2. Many yellow-white spots were noted in the posterior pole.
Fig. 3. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
ings in Stargardt’s disease. However, the absence of “beaten bronze” foveal atrophy in the patient makes Stargardt’s disease less likely. Other phenotypes of the ABCA4 gene such as fundus flavimaculatus and cone–rod dystrophy are also likely ruled out given the absence of flecks in the periphery and a normal ERG. An autosomal dominant form of Stargardt’s disease
Fig. 4. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 5. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
has been linked to a mutation in the ELOVL4 gene on chromosome 6 but the dark choroid effect on fluorescein angiography is characteristically absent in these patients.2 Macular dystrophies associated with the RDS/peripherin gene should also be considered. Located on the short arm of chromosome 6, the RDS/peripherin gene has been linked to a number of different retinal
Fig. 6. FFA and ICGA showed mottled fluorescence in the posterior pole and peripheral retina of both eyes. CME of the right eye was noted in the late phase. A dark choroid was suspected.
1043
dystrophies, including autosomal dominant retinitis pigmentosa, retinitis punctata albescens, central areolar choroidal dystrophy, pattern dystrophy, adult vitelliform dystrophy, and fundus flavimaculatus. The precise function of the gene product is unknown though it has been hypothesized to act as an adhesion molecule in rod and cone photoreceptors.3 In this case, the normal ERG essentially rules out autosomal dominant retinitis pigmentosa and its variants such as retinitis punctata albescens. Multifocal pattern dystrophy, however, is a strong possibility. This variant of pattern dystrophy is an autosomal dominant disorder characterized by yellow, gray, or white deposits in the macula. Boon et al described that 10 patients with multifocal pattern dystrophy confirmed to have a mutation in the RDS/peripherin gene with confluent yellow material similar in appearance to Stargardt’s disease in the macula and nasal to the optic nerve.4 Several of the patients had significant vision loss secondary to central chorioretinal atrophy, whereas the majority of the patients had significantly abnormal EOG testing. Interestingly, 39 other family members were examined as well and found to have incomplete penetrance with variable expressivity of the disease. Mutations in the EFEMP1 gene causing familial drusen, known also as Doyne honeycomb retinal dystrophy or Malattia Leventinese, could also be considered in this case. First described by R. W. Doyne in 1899 and then later in 1932 by Klainguti in patients living in the Leventine valley in Switzerland, this autosomal dominant disease typically starts with the deposition of hard drusen in the macula in the third decade of life.5 Patients can then go on to develop extensive confluent radial drusen in the macula and nasal to the optic disc. In the most severe forms, patients may experience significant retinal and retinal pigment epithelial atrophy of the fovea with decreased vision and central scotoma. Electrophysiological testing is usually normal. VMD2 gene abnormalities causing adult vitelliform dystrophy and Best dystrophy should also be considered. The significantly decreased Arden ratio would certainly support the diagnosis of Best disease, but the accumulation and confluence of the yellow-white material centrally over time would go against supporting the diagnosis. Adult vitelliform dystrophy could also be considered in this case given its association with basal laminar drusen.6 However, no vitelliform or pseudovitelliform lesions were seen on clinical examination or on OCT testing, and the EOG would be expected to be normal. Other possibilities in this case include the MCDR gene causing North Carolina macular dystrophy and the TIMP-3 gene causing Sorsby’s fundus dystrophy.
1044 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 5
Fig. 7. OCT showed CME of the right eye with the thickness of the central fovea 654 mm.
Both of these entities can present in the early stages with macular drusen, though not completely similar in appearance to this patient. About one-third of patients with North Carolina macular dystrophy will go on to develop a macular coloboma, whereas patients with Sorsby’s fundus dystrophy may develop choroidal neovascularization. Both ERG and EOG are typically normal. The occurrence of CME in this case is unusual. Though CME in retinitis pigmentosa is relatively common, CME associated with macular dystrophies is rare. The mechanism of CME in retinitis pigmentosa is hypothesized to be secondary to widespread loss of polarization in the retinal pigment epithelium leading to inability of the retinal pigment epithelium to pump ions and fluid from the outer retina.7 Other hypotheses include loss of Muller cell integrity or inflammation secondary to circulating antiretinal antibodies with subsequent compromise of the blood–retinal barrier.8 Treatment for CME in patients with retinal and macular dystrophies has included carbonic anhydrase inhibitors, glucocorticoids, and anti-vascular endothelial growth factor agents. Interestingly, unilateral CME similar to that seen in this patient has been reported in one case of pattern dystrophy confirmed to have an
RDS/peripherin mutation and in one case of Stargardt’s disease.9 In both cases, the CME and vision improved with oral acetazolamide therapy. Given the above differential, genetic testing for the ABCA4 and RDS/peripherin gene should be obtained to help narrow the diagnosis. Testing for mutations in the TIMP-3 and VMD2 genes could also be considered. Examination of family members could also help establish the inheritance pattern and differentiate between various genotypes. Autofluorescence imaging would also help further elucidate the morphology of the yellow accumulated material in the macula and reveal any fluorescence patterns specific for certain phenotypes. For instance, patients with ABCA4 mutations have been observed to have a characteristic ring of normal autofluorescence around the optic nerve.10 As for treatment of the CME, a trial of oral or topical acetazolamide in the patient should be considered.
Editor’s Note: Drs. Peng, Yongpeng, and Yibin present a 33-yearold woman with blurred vision and metamorphopsia for 1 month. The patient had CME and received
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 8. F-ERG was normal.
1045
1046 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2015 VOLUME 35 NUMBER 5
Fig. 9. F-ERG was normal.
a periocular injection, but the vision continued to decline, though the edema was improved. There was a suggestion of a dark choroid, though there was no history of nyctalopia. The ERG was normal, but the EOG was bilaterally reduced. Dr. Rick Roe has consulted on this case and feels that the patient has a macular dystrophy. He lists the
genes identified in the pathogenesis of a number of macular dystrophies. Genes associated with macular dystrophies: 1. 2. 3. 4. 5. 6. 7.
ABCA4 RDS/peripherin EFEMP1 MCDR ELOVL4 TIMP-3 VMD2.
Mutations or alterations in these genes have been associated with a number of phenotypes: 1. 2. 3. 4. 5. 6.
Fig. 10. Yellow-white granular deposits were concentrated in the macula.
Stargardt’s disease Pattern macular dystrophies Familial drusen Sorsby’s fundus dystrophy North Carolina macular dystrophy Adult vitelliform macular dystrophy.
Dr. Roe considers all of these diagnostic entities, but concentrates his comments on mutations in the ABCA4 gene and the RDS/peripherin gene. He suggests that if one considers the yellow macular spots to be flecks, then Stargardt’s disease (ABCA4
1047
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
Fig. 11. EOG showed the Arden ratio of both eyes decreased sharply (,1.5) with the photopeak latent period of the left eye prolonged.
mutation) would be the diagnosis. This is made more probable by the finding on fluorescein angiography of a “dark choroid.” But, he is disturbed by the absence of a “beaten bronze” foveal atrophy. The RDS/peripherin gene has been linked to a number of different retinal dystrophies: 1. 2. 3. 4. 5. 6.
AD retinitis pigmentosa Retinitis punctata albescens Central areolar choroidal dystrophy Pattern dystrophy Adult vitelliform dystrophy Fundus flavimaculatus.
Dr. Roe feels that a multifocal pattern dystrophy is a strong diagnostic possibility and references the study by Boon in patients with RDS/peripherin mutations who had confluent yellow material similar in appearance to Stargardt’s disease, with central chorioretinal atrophy and abnormal EOGs. He notes the appearance of CME and the rarity with which it is seen in macular dystrophies.
Genetic testing, especially for ABCA4 and RDS/ peripherin, is recommended along with TIMP-3 ad VMD2 genes. Examination of family members and fundus autofluorescence might provide valuable information. Dr. Roe concludes by suggesting a trial of acetazolamide. We thank our presenters for their case, and Dr. Roe for his discussion. References 1. Westerfeld C, Mukai S. Stargardt’s disease and the ABCR gene. Semin Ophthalmol 2008;23:59–65. 2. Donoso LA, Edwards AO, Frost A, et al. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol 2001;46: 149–163. 3. Wells J, Wroblewski J, Keen J, et al. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet 1993;3:213–218. 4. Boon CJ, van Schooneveld MJ, den Hollander AI, et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol 2007;91:1504–1511.
1048 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 5. Stone EM, Lotery AJ, Munier FL, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999;22:199–202. 6. Lima LH, Laud K, Freund KB, et al. Acquired vitelliform lesion associated with large drusen. Retina 2012;32:647–651. 7. Cox SN, Hay E, Bird AC. Treatment of chronic macular edema with acetazolamide. Arch Ophthalmol 1988;106:1190–1195. 8. Heckenlively JR, Jordan BL, Aptsiauri N. Association of antiretinal antibodies and cystoid macular edema in patients with retinitis pigmentosa. Am J Ophthalmol 1999;127:565–573. 9. Abouzeid H, Wolfensberger TJ, Schorderet DF, et al. Unilateral macular oedema in Zermatt and Stargardt macular dystrophies. Br J Ophthalmol 2009;93:1376–1377, 1407–1408. 10. Cideciyan AV, Swider M, Aleman TS, et al. ABCA4-associated retinal degenerations spare structure and function of the human
2015 VOLUME 35 NUMBER 5
parapapillary retina. Invest Ophthalmol Vis Sci 2005;46: 4739–4746.
RETINAÒ, The Journal of Retinal and Vitreous Diseases, encourages readers to submit Diagnostic and Therapeutic Challenges to retina@ retinajournal.com. Cases for the Diagnostic and Therapeutic Challenges section should include a detailed history of the patient, the diagnosis, the workup, the management, and finally, the question or questions that the submitter wishes to have answered by the consultants.
