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Clinical and Experimental Ophthalmology 2014; 42: 103–104 doi: 10.1111/ceo.12295
Editorial A new insight into an old mystery In the present issue, Saito et al. present their findings of choroidal blood flow estimates in patients with acute zonal occult outer retinopathy (AZOOR).1 The paper raises an old debate and provides a new insight. Firstly, owing to its rarity and lack of ophthalmoscopic findings, the pathogenesis and treatment of AZOOR has long eluded consensus. Secondly, the proliferation of imaging modalities has provided us with an abundance of nascent information to digest. Even the nomenclature of this condition can be of considerable contention. Gass coined AZOOR to encompass numerous inflammatory fundus conditions, such as acute macular neuro-retinopathy (AMN), multifocal choroiditis (MFC)* and multiple evanescent white-dot syndrome.2 This and every subsequent attempt at proposing a collective noun for such a group has been fraught with difficulty. The oft-used and rudimentary appellation ‘white-dot syndromes’ reveals much about our knowledge deficiencies. It is particularly inappropriate for AZOOR given the absence of white dots! In contemporary parlance, AZOOR has become synonymous with Gass’ subcategory of ‘AZOOR without focal fundus lesions’. In a 2003 edition of the American Journal of Ophthalmology, the debate is borne out in Gass’ editorial3 on the Jampol and Becker article in the same issue.4 The commonly accepted elements for a diagnosis of AZOOR include the sudden onset of photophsias and scotomas in a fundoscopically normal eye. Confirmation is required with formal perimetry and electrophysiology. Up to 23% of patients may have vitritis,5 and in chronic cases, a pigmentary retinopathy may develop in the affected area. Of utmost importance in the diagnostic algorithm of an AZOOR like malady is the exclusion of a para-neoplastic retinopathy. The search for a potential primary malignancy can be distressing for patient and physician alike. Saito et al. performed extensive serum tests but did not mention any radiological investigations. In Gass’ original 13 patients, most had magnetic resonance imaging or computed topography.1
Neoplastic retinopathy and AZOOR are clinically similar. It is prudent for the ophthalmologist to undertake or refer for a targeted primary neoplasm search. New imaging modalities can provide insight into pathology. A study has shown that AZOOR affected fundi display segmental hypo-autofluorescence and thinned photoreceptor layers on optical coherence tomography (OCT) but normal choroidal thickness.6 This seems to support hypotheses that inflammation directed at outer retinal elements is the primary disease focus. Saito et al. employ the non-invasive modality of laser speckle flowgraphy, the principles of which were first elucidated by Briers and Fercher in 1982.7 Technological advances have allowed Saito et al. to objectively analyse choroidal blood flow and repeatedly re-image temporal changes in a defined area. They demonstrate reduced choroidal blood flow in an area of AZOOR with improvement over time. Based on their results, they postulate that the choroid, rather than the outer retina, may be the primary inflammatory target. They propose that this accounts for the paucity of early retinal findings. Although this may well be correct, an alternative hypothesis could equally be proffered: primary inflammation of the outer retina leads to destruction of photoreceptor outer segments that diminishes metabolic demand and choroidal blood flow. As the authors mention, primary choroidal inflammation should produce at least a temporary increase in choroidal blood flow, but this was not observed. Furthermore, the retinal pigment epithelium (RPE) is also dependent on choroidal blood flow. If reduced choroidal blood flow is the primary event in AZOOR, then the RPE would be metabolically compromised. One would expect this to manifest in hypo-reflective lines on OCT or earlier pigmentary retinopathy. More vexing than a cohesive definition or mechanism is the issue of treatment. Saito et al. administered systemic corticosteroid therapy to five patients with progressive, central acuity loss and elected to observe six cases with non-progressive, non-centre
Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. *Gass originally used the term ‘pseudo-presumed ocular histoplas mosis syndrome’ to describe what is now referred to as multifocal choroiditis and punctate inner choroidopathy. © 2014 Royal Australian and New Zealand College of Ophthalmologists
104
Editorial
involving disease. AZOOR is a condition without an accepted or predictable natural history. Gass’ series showed disease activity for 6 months followed by relative quiescence in most patients.8 It is therefore challenging to implement a treatment paradigm. Therapies that have been previously attempted include corticosteroid,8 non-steroidal immunosuppression9 and anti-microbials.8 Saito et al. propose a prospective, randomized controlled trial to validate their results conclusively. Such a trial in this exceptionally rare disease is unfeasible. Consequently, we must accept uncertainty to make calculated decisions about individual patient circumstances and the judicious use of potentially toxic pharmacotherapies. Formal electrophysiology remains the gold standard for monitoring but parameters from less onerous tests, such as LFSG, may have particular clinical utility. The advent of cheaper, smaller and faster microprocessors has provided us with a wealth of tests. All patients in the present paper were concomitantly studied with fluorescein angiography, indocynanine green angiography, multifocal electroretinography and spectral domain OCT. Other modalities such as swept-source OCT, enhanced depth imaging OCT, en-face OCT, multiple wavelength autofluoresence and adaptive optics are also possible in the modern armamentarium of imaging modalities. The problem is no longer test scarcity but choosing which to request. One marvels anew at Gass’ original description in an era of far less advanced imaging. These new imaging capabilities are drawing both similarities and distinctions between the conditions originally grouped in the AZOOR spectrum. Punctate inner choroidopathy and MFC both have a high propensity for choroidal neovascularization but have traditionally been separated by clinical features such as vitritis. On the basis of multimodal imaging, Spaide et al. have made a compelling argument to abandon this differentiation.10 Adaptive optics has provided information through highresolution visualization of disrupted cone photoreceptors in AZOOR11 and similar changes have been shown in AMN.12 In contrast, features characteristic of AMN have been shown on infrared reflectance13 and OCT studies have suggested abnormalities of the deep or superficial retinal capillary plexus may produce subsets of this condition.14 Presently, it is unclear whether such findings reflect disparate clinical entities or the limited capacity of the fundus to display pathology. Much remains to be discovered and hypothesized about this condition. We are witness to an unprecedented bloom of investigative devices. Synthesis of the information provided by these devices will hopefully foster further insight into retinal function,
disease and treatment that we can employ to benefit our patients. Xavier J Fagan FRANZCO1,2,3 Medical Retina and Ocular Inflammation Clinics, Royal Victorian Eye And Ear Hospital, 2Centre for Eye Research Australia, University of Melbourne, Melbourne, and 3 Ophthalmology Unit, Austin Hospital, Heidelberg, Victoria, Australia 1
REFERENCES 1. Saito M, Saito W, Hashimoto Y et al. Correlation between decreased choroidal blood flow velocity and the pathogenesis of acute zonal occult outer retinopathy. Clin Experiment Ophthalmol 2014; 42: 139–50. 2. Gass JDM. Acute zonal occult outer retinopathy. J Clin Neuroophthal 1993; 13: 79–97. 3. Gass JDM. Editorial: are acute zonal occult outer retinopathy and the white spot syndromes (AZOOR Complex) specific autoimmune diseases? Am J Ophthlamol 2003; 125: 380–1. 4. Jampol LM, Becker KG. Perspective: white spot syndromes of the retina: a hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. Am J Ophthalmol 2003; 135: 376–9. 5. Monson DM, Smith JR. Acute zonal occult outer retinopathy. Surv Ophthalmol 2011; 56: 23–35. 6. Fujiwara T, Imamura Y, Giovinazzo VJ, Spaide RF. Fundus autofluorescence and optical coherence tomographic findings in acute zonal occult outer retinopathy. Retina 2010; 30: 1206–16. 7. Briers JD, Fercher AF. Retinal blood flow visualization by means of laser speckle. Invest Ophthalmol Vis Sci 1982; 22: 255–9. 8. Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: a long-term follow-ip study. Am J Ophthalmol 2002; 134: 329–39. 9. Spaide RF, Koizumi H, Freund KB. Photoreceptor outer segment abnomrlaities as a cause of blind spot enlargement in acute zonal occult outer retinopathycomplex diseases. Am J Ophthalmol 2008; 146: 111– 20. 10. Spaide RF, Goldberg N, Freund B. Redefining multifocal choroiditis and panuveitis and punctate inner choroidopathy through multimodal imaging. Retina 2013; 33: 1315–24. 11. Mkrtchyan M, Lujan BJ, Merino D. Outer retinal structure in patients with acute zonal occult outer retinopathy. Am J Opthalmol 2012; 153: 757–68. 12. Hansen SO, Cooper RF, Dubra A. Selective cone photoreceptor injury in acute macular neuroretinopathy. Retina 2013; 33: 1650–8. 13. Fawzi AA, Pappuru RR, Sarraf D et al. Acute macular neuroretinopathy. Long-term insights revealed by multimodal imaging. Retina 2012; 32: 1500–13. 14. Sarraf D, Rahimy E, Fawzi AA et al. Paracentral acute middle maculopathy. JAMA Ophthalmol 2013; 131: 1275–87.
© 2014 Royal Australian and New Zealand College of Ophthalmologists
Clinical and Experimental Ophthalmology 2014; 42: 103–104 doi: 10.1111/ceo.12295
Editorial A new insight into an old mystery In the present issue, Saito et al. present their findings of choroidal blood flow estimates in patients with acute zonal occult outer retinopathy (AZOOR).1 The paper raises an old debate and provides a new insight. Firstly, owing to its rarity and lack of ophthalmoscopic findings, the pathogenesis and treatment of AZOOR has long eluded consensus. Secondly, the proliferation of imaging modalities has provided us with an abundance of nascent information to digest. Even the nomenclature of this condition can be of considerable contention. Gass coined AZOOR to encompass numerous inflammatory fundus conditions, such as acute macular neuro-retinopathy (AMN), multifocal choroiditis (MFC)* and multiple evanescent white-dot syndrome.2 This and every subsequent attempt at proposing a collective noun for such a group has been fraught with difficulty. The oft-used and rudimentary appellation ‘white-dot syndromes’ reveals much about our knowledge deficiencies. It is particularly inappropriate for AZOOR given the absence of white dots! In contemporary parlance, AZOOR has become synonymous with Gass’ subcategory of ‘AZOOR without focal fundus lesions’. In a 2003 edition of the American Journal of Ophthalmology, the debate is borne out in Gass’ editorial3 on the Jampol and Becker article in the same issue.4 The commonly accepted elements for a diagnosis of AZOOR include the sudden onset of photophsias and scotomas in a fundoscopically normal eye. Confirmation is required with formal perimetry and electrophysiology. Up to 23% of patients may have vitritis,5 and in chronic cases, a pigmentary retinopathy may develop in the affected area. Of utmost importance in the diagnostic algorithm of an AZOOR like malady is the exclusion of a para-neoplastic retinopathy. The search for a potential primary malignancy can be distressing for patient and physician alike. Saito et al. performed extensive serum tests but did not mention any radiological investigations. In Gass’ original 13 patients, most had magnetic resonance imaging or computed topography.1
Neoplastic retinopathy and AZOOR are clinically similar. It is prudent for the ophthalmologist to undertake or refer for a targeted primary neoplasm search. New imaging modalities can provide insight into pathology. A study has shown that AZOOR affected fundi display segmental hypo-autofluorescence and thinned photoreceptor layers on optical coherence tomography (OCT) but normal choroidal thickness.6 This seems to support hypotheses that inflammation directed at outer retinal elements is the primary disease focus. Saito et al. employ the non-invasive modality of laser speckle flowgraphy, the principles of which were first elucidated by Briers and Fercher in 1982.7 Technological advances have allowed Saito et al. to objectively analyse choroidal blood flow and repeatedly re-image temporal changes in a defined area. They demonstrate reduced choroidal blood flow in an area of AZOOR with improvement over time. Based on their results, they postulate that the choroid, rather than the outer retina, may be the primary inflammatory target. They propose that this accounts for the paucity of early retinal findings. Although this may well be correct, an alternative hypothesis could equally be proffered: primary inflammation of the outer retina leads to destruction of photoreceptor outer segments that diminishes metabolic demand and choroidal blood flow. As the authors mention, primary choroidal inflammation should produce at least a temporary increase in choroidal blood flow, but this was not observed. Furthermore, the retinal pigment epithelium (RPE) is also dependent on choroidal blood flow. If reduced choroidal blood flow is the primary event in AZOOR, then the RPE would be metabolically compromised. One would expect this to manifest in hypo-reflective lines on OCT or earlier pigmentary retinopathy. More vexing than a cohesive definition or mechanism is the issue of treatment. Saito et al. administered systemic corticosteroid therapy to five patients with progressive, central acuity loss and elected to observe six cases with non-progressive, non-centre
Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. *Gass originally used the term ‘pseudo-presumed ocular histoplas mosis syndrome’ to describe what is now referred to as multifocal choroiditis and punctate inner choroidopathy. © 2014 Royal Australian and New Zealand College of Ophthalmologists
104
Editorial
involving disease. AZOOR is a condition without an accepted or predictable natural history. Gass’ series showed disease activity for 6 months followed by relative quiescence in most patients.8 It is therefore challenging to implement a treatment paradigm. Therapies that have been previously attempted include corticosteroid,8 non-steroidal immunosuppression9 and anti-microbials.8 Saito et al. propose a prospective, randomized controlled trial to validate their results conclusively. Such a trial in this exceptionally rare disease is unfeasible. Consequently, we must accept uncertainty to make calculated decisions about individual patient circumstances and the judicious use of potentially toxic pharmacotherapies. Formal electrophysiology remains the gold standard for monitoring but parameters from less onerous tests, such as LFSG, may have particular clinical utility. The advent of cheaper, smaller and faster microprocessors has provided us with a wealth of tests. All patients in the present paper were concomitantly studied with fluorescein angiography, indocynanine green angiography, multifocal electroretinography and spectral domain OCT. Other modalities such as swept-source OCT, enhanced depth imaging OCT, en-face OCT, multiple wavelength autofluoresence and adaptive optics are also possible in the modern armamentarium of imaging modalities. The problem is no longer test scarcity but choosing which to request. One marvels anew at Gass’ original description in an era of far less advanced imaging. These new imaging capabilities are drawing both similarities and distinctions between the conditions originally grouped in the AZOOR spectrum. Punctate inner choroidopathy and MFC both have a high propensity for choroidal neovascularization but have traditionally been separated by clinical features such as vitritis. On the basis of multimodal imaging, Spaide et al. have made a compelling argument to abandon this differentiation.10 Adaptive optics has provided information through highresolution visualization of disrupted cone photoreceptors in AZOOR11 and similar changes have been shown in AMN.12 In contrast, features characteristic of AMN have been shown on infrared reflectance13 and OCT studies have suggested abnormalities of the deep or superficial retinal capillary plexus may produce subsets of this condition.14 Presently, it is unclear whether such findings reflect disparate clinical entities or the limited capacity of the fundus to display pathology. Much remains to be discovered and hypothesized about this condition. We are witness to an unprecedented bloom of investigative devices. Synthesis of the information provided by these devices will hopefully foster further insight into retinal function,
disease and treatment that we can employ to benefit our patients. Xavier J Fagan FRANZCO1,2,3 Medical Retina and Ocular Inflammation Clinics, Royal Victorian Eye And Ear Hospital, 2Centre for Eye Research Australia, University of Melbourne, Melbourne, and 3 Ophthalmology Unit, Austin Hospital, Heidelberg, Victoria, Australia 1
REFERENCES 1. Saito M, Saito W, Hashimoto Y et al. Correlation between decreased choroidal blood flow velocity and the pathogenesis of acute zonal occult outer retinopathy. Clin Experiment Ophthalmol 2014; 42: 139–50. 2. Gass JDM. Acute zonal occult outer retinopathy. J Clin Neuroophthal 1993; 13: 79–97. 3. Gass JDM. Editorial: are acute zonal occult outer retinopathy and the white spot syndromes (AZOOR Complex) specific autoimmune diseases? Am J Ophthlamol 2003; 125: 380–1. 4. Jampol LM, Becker KG. Perspective: white spot syndromes of the retina: a hypothesis based on the common genetic hypothesis of autoimmune/inflammatory disease. Am J Ophthalmol 2003; 135: 376–9. 5. Monson DM, Smith JR. Acute zonal occult outer retinopathy. Surv Ophthalmol 2011; 56: 23–35. 6. Fujiwara T, Imamura Y, Giovinazzo VJ, Spaide RF. Fundus autofluorescence and optical coherence tomographic findings in acute zonal occult outer retinopathy. Retina 2010; 30: 1206–16. 7. Briers JD, Fercher AF. Retinal blood flow visualization by means of laser speckle. Invest Ophthalmol Vis Sci 1982; 22: 255–9. 8. Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: a long-term follow-ip study. Am J Ophthalmol 2002; 134: 329–39. 9. Spaide RF, Koizumi H, Freund KB. Photoreceptor outer segment abnomrlaities as a cause of blind spot enlargement in acute zonal occult outer retinopathycomplex diseases. Am J Ophthalmol 2008; 146: 111– 20. 10. Spaide RF, Goldberg N, Freund B. Redefining multifocal choroiditis and panuveitis and punctate inner choroidopathy through multimodal imaging. Retina 2013; 33: 1315–24. 11. Mkrtchyan M, Lujan BJ, Merino D. Outer retinal structure in patients with acute zonal occult outer retinopathy. Am J Opthalmol 2012; 153: 757–68. 12. Hansen SO, Cooper RF, Dubra A. Selective cone photoreceptor injury in acute macular neuroretinopathy. Retina 2013; 33: 1650–8. 13. Fawzi AA, Pappuru RR, Sarraf D et al. Acute macular neuroretinopathy. Long-term insights revealed by multimodal imaging. Retina 2012; 32: 1500–13. 14. Sarraf D, Rahimy E, Fawzi AA et al. Paracentral acute middle maculopathy. JAMA Ophthalmol 2013; 131: 1275–87.
© 2014 Royal Australian and New Zealand College of Ophthalmologists
