Abstract
Purpose
To correlate visual function with high-resolution images of retinal structure using adaptive optics scanning laser ophthalmoscopy (AOSLO) in 4 patients with acute zonal occult outer retinopathy (AZOOR).
Design
Observational case series.
Methods
Four women, aged 18–51, with acute focal loss of visual field or visual acuity, photopsia, and minimal funduscopic changes were studied with best-corrected visual acuity (BCVA), Goldmann kinetic and automated perimetry and fundus-guided microperimetry, full-field and multifocal electroretinography (ffERG and mfERG), spectral domain optical coherence tomography (SDOCT) and AOSLO imaging. Cone spacing was measured in four eyes and compared with 27 age-similar normal eyes. Additional functional testing in one patient suggested that cones were absent but rods remained. Serum from all patients was analyzed for anti-retinal antibody activity.
Results
In all patients vision loss was initially progressive, then stable. Symptoms were unilateral in 2 and bilateral but asymmetric in 2 patients. In each patient, loss of retinal function correlated with structural changes in the outer retina. AOSLO showed focal cone loss in most patients, although in one patient with central vision loss such change was absent. In another patient, structural and functional analyses suggested that cones had degenerated but rods remained. Anti-retinal antibody activity against a ~45kd antigen was detected in 1 of the patients; the other 3 patients showed no evidence of abnormal anti-retinal antibodies.
Conclusions
Focal abnormalities of retinal structure correlated with vision loss in patients with AZOOR. High-resolution imaging can localize and demonstrate the extent of outer retinal abnormality in AZOOR patients.
Introduction
Acute zonal occult outer retinopathy (AZOOR) is a syndrome characterized by acute loss of one or more zones of visual function, usually accompanied by photopsia, reduced outer retinal function measured by electroretinography in one or both eyes, and in some cases, death of retinal photoreceptor cells without biomicroscopic or fluorescein angiographic abnormalities.1–3 AZOOR occurs more frequently in young myopic women, and recovery of visual function occurs infrequently.1
The etiology of AZOOR is unknown, but infectious and autoimmune mechanisms have been proposed. Viral or other infectious agents may enter the eye at the optic nerve head or ora serrata and trigger an immune response to viral antigens that are similar to antigens expressed by photoreceptor cells, producing zones of acute photoreceptor cell dysfunction or loss.1 However, no abnormal anti-retinal antibodies have previously been identified in patients with AZOOR.2 Alternatively, genetic factors may predispose some individuals to autoimmune or inflammatory responses against retinal cells, and visual symptoms may develop upon exposure to specific environmental triggers.4
Photoreceptor dysfunction is responsible for vision loss in AZOOR, and interocular asymmetry in electroretinographic responses is common. Photoreceptor outer segment dysfunction and degeneration has been correlated with loss or attenuation of the photoreceptor inner segment/outer segment (IS/OS) junction, inner nuclear and outer nuclear layers in regions with visual field defects imaged using time-domain5 and spectral-domain optical coherence tomography (SDOCT) in patients with AZOOR.6–8
Adaptive optics is a set of techniques to reduce blur caused by imperfections in the eye’s optics and, when used in an ophthalmoscope, allows for direct imaging of the cone photoreceptor mosaic in vivo.9,10 Several reports have demonstrated the utility of using adaptive optics to characterize patients with retinal disease.11–18 In the present manuscript, adaptive optics scanning laser ophthalmoscopy (AOSLO) combined with spectral-domain optical coherence tomography (SDOCT) demonstrated changes in retinal structure that correlated with reduced visual function in 4 AZOOR patients in whom retinal changes sufficient to explain the visual abnormalities were not visible using standard clinical techniques.
Methods
Common tests for all patients
All subjects underwent a complete eye examination including best-corrected visual acuity measured according to the Early Treatment of Diabetic Retinopathy Study protocol, slit lamp biomicroscopy, color fundus photography and infrared fundus photography with spectral domain optical coherence tomography (SDOCT) (Spectralis HRA + OCT Laser Scanning Camera System; Heidelberg Engineering, Vista CA). Goldmann kinetic perimetry was performed with II3c, V3c and I4e targets, and automated perimetry was completed with measurement of foveal thresholds using a Goldmann III stimulus on a white background (31.5 asb) and exposure duration of 200ms; patients were tested using either the 30-2, 24-2, and 10-2 protocol depending on the extent and location of the scotoma (SITA Standard, Humphrey Visual Field Analyzer; HFA II 750-6116-12.6; Carl Zeiss Meditec, Inc., Dublin, CA). Pupils were dilated with 1% tropicamide and 2.5% phenylephrine before bilateral full-field electroretinography (ffERG) was performed after 45 minutes of dark adaptation using Burian-Allen contact lens electrodes (Hansen Ophthalmic Development Laboratory, Iowa City, IA), as described previously.16 Eyes were tested simultaneously and measured individually, according to standards specified by the International Society for Clinical Electrophysiology and Vision (ISCEV).19 Multifocal ERG (mfERG) testing was performed in a light-adapted state (VERIS 5.1.10C, Electrodiagnostic Imaging, Inc., Redwood City, CA) with Burian-Allen contact lens electrodes, also according to ISCEV standards20 and as described previously.16 Fundus guided microperimetry (MP-1; Nidek Technologies America Inc., Greensboro, NC) used a Goldmann size III stimulus of 200-ms duration with a 4–2 threshold strategy as described previously.16 Serum from all patients was analyzed for anti-retinal antibody activity using Western blots of porcine retina (PelFreez, Arkansas) at the Ocular Immunology Laboratory, UC Davis, CA. Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast was performed in patients 2 and 3 to exclude central nervous system or orbital disease.
Assessment of rod- and cone-mediated sensitivity
In patient 2, two-color dark-adapted Goldmann perimetry and fundus-guided two-color dark-adapted microperimetry were used to investigate localized rod and cone function. Chromatic dark-adapted 2-color kinetic perimetry was performed to measure the rod contribution to the dark-adapted kinetic visual field.21 In order to ensure that the parameters were correct for measuring rods, fields were measured and sensitivity was compared for two different wavelengths.21 Visual fields were measured for the Goldmann II3c and V3c target sizes, each with a long-wavelength and a short-wavelength filter, as described previously.21 The long-wavelength filter had a cut-on at 600 nm, while the short wavelength filter had a cutoff at 510 nm. Long-wavelength and short-wavelength filters utilized were Wratten 25 and 47B, respectively. The stimuli were 2 log units lower in luminance (II c and V c) for the short-wavelength stimulus, based on the spectral emittance of the Goldmann perimeter bulb, the scotopic luminance efficiency function and spectral transmittance of the chromatic filters.21 A fixation target was provided with a dim red light presented in the Ganzfeld dome. The background light in the bowl was occluded by moving the sliding diaphragm up to its maximal height, in addition to covering it with several layers of black-out cloth to prevent any light leakage. To monitor the patient’s fixation, monovision night goggles (Zenit NV, Famous Trails, San Diego) were employed. Two healthy normal subjects were also tested to verify that the stimuli were matched scotopically.
Two-color dark-adapted microperimetry was also performed to investigate retinal sensitivity with higher resolution using a custom test pattern with a 40-degree testing array using a Goldmann size V stimulus of 200-ms duration spaced in 0.5 degree increments, extending 10 degrees from the fovea in the nasal and temporal directions. Blue (NT30-635, 500 nm short pass) and red (NT30-34, 600 nm long pass, Edmund Industrial Optics, Inc., Barrington, NJ) filters were introduced into the stimulus light path with the background set to red, such that the background illumination was effectively 0 cd/m2 (Crossland MD, et al. IOVS 2010;51:ARVO E-Abstract 3640). Neutral density (ND) filters attenuated the red stimulus by 1.0 log unit (NT48-095, Edmund Industrial Optics, Inc., Barrington, NJ) and the blue stimulus by 2.0 log units (NT48-097). After 30 minutes of dark adaptation, rod function was tested using the blue and 2.0 ND filters, then with the red and 1.0 ND filters. Stray light was shielded by placing a black curtain between the patient and the monitor. The patient’s fixation was monitored and the chin position was adjusted to maintain good fundus tracking. The sensitivity values for each location using blue dark adapted (Blue DA) and red dark adapted (Red DA) stimuli were compared with the expectation that, if the eye was normal, it would show at least 18 dB greater sensitivity to short wavelength compared to long wavelength stimuli in the dark-adapted state.22 Given our testing parameters, sensitivity at retinal locations with at least 8dB greater sensitivity to Blue DA than to Red DA stimuli indicates rod-mediated function, while sensitivities with differences of less than 8 dB indicate cone-mediated function (Crossland MD, et al. IOVS 2010;51:ARVO E-Abstract 3640).
High resolution imaging
Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO) was used to generate high-resolution en-face images of the central retina of the affected eye of each patient, or the better eye in bilateral cases, as described previously.16 Cone spacing was measured23 at locations in which unambiguous cones were visualized, and compared to normative data from 27 age-similar individuals.16 Cone spacing greater than 2 standard deviations above the normal mean at that location was considered abnormal.13,14,16
Results
Please see the Table for a summary of clinical results for all 4 patients.
Table.
Best- Corrected Visual Acuity | ffERGa | mfERGb | Micro- perimetry | HVFc | SDOCTd | AOSLOe | Antibody against ~45kd antigen | |
---|---|---|---|---|---|---|---|---|
Case 1 | OD: 20/20 OS: 20/20 |
Normal amplitude and timing OU, no significant interocular asymmetry | Reduced response densities and delayed timing in the region of scotoma OU | Not performed | Paracentral scotoma OU with normal foveal sensitivities (37 dB OD, 38dB OS) | Disrupted IS/OSf junction OD in the region of reduced cone reflectivity | Reduced cone reflectivity in the region of scotoma OD | Not detected |
Case 2 | OD: 20/20 OS: 20/20−1 |
20% decrease in photopic and scotopic amplitudes OS compared to OD | Reduced response densities and delayed timing in the region of scotoma OS | Cone-mediated scotoma with rod- mediated sensitivity in the region of scotoma OS | Paracentral scotoma with normal foveal sensitivity (40dB) OS | Reduced reflectance of IS/OS junction within scotoma region OS | Absence of cones in the region of scotoma OS with higher density cells suspected to be rods | Not detected |
Case 3 | OD: 20/200+1 OS: 20/20 |
Reduced photopic b- wave amplitude by 33% OD relative to OS and reduced 30Hz flicker implicit time (30ms OD vs 27.5ms OS ) | Reduced response densities and delayed timing centrally OD | Severe loss of foveal sensitivity by 3.5 log units OD | Temporal scotoma extending into fixation OD | Relative thinning of outer nuclear layer and ganglion cell layer, intact ELM- OS/RPE in the region of scotoma OD | Normal cone mosaic in the region of reduced foveal sensitivity OD | Not detected |
Case 4 | OD: 20/200 OS: 20/200 |
Normal amplitude and timing OU, 20–25% lower response to all stimuli OD compared to OS | Reduced response densities and delayed timing centrally OU | Reduced sensitivity in the fovea OU | Central scotoma OU with reduced foveal sensitivities (18dB OD, 26dB OS) | Loss of IS/OS junction in the central macula with thinning of outer nuclear layer OD | Abnormal cone coverage and spacing within macula OD | Detected |
full-field electroretinography
multifocal electroretinography
Humphrey visual field
spectral-domain optical coherence tomography
adaptive optics scanning laser ophthalmoscopy
inner segment/outer segment
Case 1
An 18-year-old healthy emmetropic female presented 5 weeks after the acute onset of scotomas and photopsias in both eyes. Past medical history included migraines and seasonal allergies, with no history of autoimmune disease. There were no fundus abnormalities in either eye (Figure 1, right eye shown). MfERG revealed localized macular outer retinal dysfunction.
AOSLO images within foveal center showed normal cone spacing and density.16 Beyond 1.5 degrees, cone reflectivity was reduced, but cone spacing was normal and contiguous except in a region adjacent to a patch of weakly reflecting retina (Figure 1). The patient experienced no improvement or progression of visual loss, and repeated perimetry, mfERG, AOSLO and SDOCT studies showed no significant changes over 14 months.
Case 2
A 42-year-old myopic female presented with acute onset of a blind spot in her left eye associated with transient flashing lights that occurred only in total darkness. The patient had a history of complex partial seizures, hypertension, panic disorder, psychogenic amnesia and short term memory loss. MRI of the head with and without contrast was normal.
AOSLO imaged the transition from normal cone spacing and coverage16 to a region beginning 4 degrees temporal to the fovea corresponding to a discrete scotoma where cones were less contiguous and showed increased spacing13,14,16 (Figure 2). Beyond 4 degrees, regularly arranged cells were observed, but with higher density than has been reported for cones13,14,16, and these were suspected to be rods24. The region of the relative scotoma also showed some structure consistent with RPE cells, which have been shown to be directly visible in instances where photoreceptor cells have been lost14 (Figure 2).
Two-color dark-adapted modified Goldmann kinetic perimetry21 and fundus-guided microperimetry were performed to assess whether the remaining visual function was rod-mediated in the region of relative scotoma. The superimposed isopters from the two stimuli indicated that sensitivity in this region was rod-mediated (Figure 3). Two-color dark-adapted modified microperimetry, as described previously (Crossland MD, et al. IOVS 2010;51:ARVO E-Abstract 3640), also indicated rod-mediated function (Crossland MD, et al. IOVS 2010;51:ARVO E-Abstract 3640),22 (Figure 3).
AOSLO images were taken at four time points over a period of 48 months. Although the image quality of the imaging sessions differed, the cone mosaic appeared stable, and there was no evidence of progressive cone loss. SDOCT images taken 10 months apart also indicated no change in the decreased reflectance of the IS/OS junction within the region of lesion.
Case 3
A 27-year-old myopic female presented with acute vision loss and photopsias in the right eye, initially starting in the mid-periphery and moving to involve fixation. The peripheral visual field abnormalities improved over the next 3 months but she retained a central scotoma with discrete borders. Past medical history included autoimmune hepatitis diagnosed at age 16 and autoimmune thyroiditis. MRI of the head was normal. There were no fundus abnormalities in either eye.
Although the highest density cones in the foveal center were not resolved, which is typical for eyes with normal cone packing,16 the remainder of the foveal image showed a normal cone mosaic, despite severely reduced foveal sensitivity (Figure 4).
AOSLO images taken 24 months later revealed no change in the appearance of the cones; SDOCT was also unchanged with stable relative thinning of the inner retinal layers including the ONL but normal reflectance of the IS/OS, OS and RPE layers in the affected eye.
Case 4
A 51-year-old myopic female patient presented with 4 months of reduced central vision in each eye, worse in bright light and associated with photosensitivity, and difficulty adapting from dark into light conditions.
AOSLO images of the right eye showed abnormal cone structure within the central 4 degrees from the fovea.13,14,16 (Figure 5, right eye shown). SDOCT images obtained 12 months later showed loss of the external limiting membrane at the fovea. Anti-retinal antibody activity involving a ~45 kd antigen was identified in a Western blot of porcine retina.25,26,27,28
Discussion
The mechanism of vision loss in AZOOR patients remains uncertain, although photoreceptor, inner retinal and RPE dysfunction has been documented.1,2,3 To our knowledge, no histological studies exist describing the effect of AZOOR on cone structure, but several recent reports have shown attenuation of the IS/OS junction and outer retinal loss in cross-section using both time- and spectral-domain OCT.5–8,29 We observed similar findings in 3 of our 4 patients, and extended our studies to include direct en-face visualization of cone photoreceptor cells using AOSLO.
The AOSLO image in the first patient showed focal areas of reduced cone reflectivity indicated by dark patches, interspersed with regions of contiguous and normal cone spacing (Figure 1). The reduced cone reflectivity could indicate morphological alterations that interfere with the wave-guiding properties of the cones.30
Despite the loss of visible cones in the AOSLO image in patient 2, the IS/OS junction was continuous, although reflectance of this layer was reduced (Figure 2), representing a significant change in actual reflectance in the region of the relative scotoma since OCT images are displayed on a logarithmic scale. Whereas loss of cone reflectance is generally observed as disruption of the IS/OS layer (Figure 1), the presence of a visible IS/OS junction in the scotomatous area where unambiguous cones were not visible suggests cones may have been absent or very sparse in the areas of the scotoma, but that rods remained. We did not see a shift in the outer termination of the photoreceptor outer segments across the transition to the rod-only region as we might have expected based on some recent high resolution SD-OCT studies.31 We suspect this is due to the poorer resolution of our commercial SD-OCT system.
In patients with dense scotomas and areas in which unambiguous cones were not visualized, mosaics of polygonal RPE cells were imaged (Figures 2 and 5), Although these images provide no information on the health of the RPE cells, they suggest that in some AZOOR patients, RPE cells persist in the absence of overlying cones. In patient 3 cone reflectivity, contiguity and spacing were no different from normal, despite central visual loss (Figure 4). Photoreceptors may be initially dysfunctional but preserved in early stages of AZOOR, and lost only in later stages5, but serial AOSLO images over 24 months showed no evidence of progressive photoreceptor loss in this patient.Inner retinal dysfunction as measured by delayed 30 Hz flicker implicit time has been reported in AZOOR patients,3 and was present in patient 3. The present manuscript provides images of an intact cone mosaic and outer retinal layers in a region with central vision loss and evidence of inner retinal dysfunction measured by delayed 30 Hz flicker timing, as well as thinning of the inner retinal layers, providing support for the observation that vision loss in AZOOR can be caused by inner retinal dysfunction in the presence of normal cone structure.
In patient 4 repeated SDOCT imaging revealed reduced outer retinal thickness over 1 year (Figure 5), consistent with reports that AZOOR may progress in 4% of patients.1 The patient with a history of autoimmune disease (patient 3) showed no abnormal anti-retinal antibody activity. The 45 kd reaction in the fourth patient represents the first report of potentially clinically significant anti-retinal antibody activity in a patient with AZOOR, and may support the hypothesis that autoimmune reactions against retinal cells may, in some cases, contribute to or occur in response to the development of AZOOR.
In conclusion, we have used AOSLO to image AZOOR patients providing high-resolution montages of the central retina. Adaptive optics provide a sensitive measure of macular cone structure in normal subjects,16 and in AZOOR patients AOSLO was used to demonstrate photoreceptor structure in regions of vision loss that were manifest as a normal mosaic of cones, regions of cone loss as well as alteration in cone structure. This study is the first to measure in vivo cone spacing and to image rods in AZOOR patients. We report retinal heterogeneity in subjects diagnosed with AZOOR based on direct visualization of photoreceptors in living retina.
Acknowledgments
Funding/Support: This study was supported by Foundation Fighting Blindness, Research to Prevent Blindness, Hope for Vision, That Man May See, NIH EY014375, EY002162, 1 P30 EY12576-6, NIH K12 EY017269, NIH T35 EY007139-16.
The authors thank David Birch, PhD, Retina Foundation of the Southwest, Dallas, TX for guidance on dark- and light-adapted two-color microperimetry protocol development. The authors also thank Carl Jacobsen, OD FAAO, UC Berkeley School of Optometry, Berkeley, CA for sharing his clinical findings on patient 3.
Biography
Marianna Mkrtchyan, OD practices at Kagan Institute in Los Angeles, California. She received a BS with departmental honors in molecular, cell, and developmental biology from University of California, Los Angeles in 2004, OD from University of California, Berkeley with clinic and research honors in 2011. Before entering graduate school, she worked at UCLA studying stem cells in Drosophila and co-authored article publications in Nature and in Developmental Genes Evolution. Her interests are in clinical research.
Footnotes
Financial Disclosures: Austin Roorda holds a patent (US Patent # 7118216) for adaptive optics scanning laser ophthalmoscopy technology. Brandon Lujan is a consultant for Carl Zeiss Meditec, AG and Genentech, Inc. The other authors have no financial disclosures to report.
Contributions of Authors: Design and conduct of the study (AR, BL, JLD); Collection, management, analysis and interpretation of the data (MM, BJL, DM, CET, AR, JLD); Preparation, review and approval of the manuscript (MM, BLJ, CET, AR, JLD);
Statement about Conformity with Human: Subjects Protections Policies: Research procedures adhered to the tenets of the Declaration of Helsinki. The study protocol was approved prospectively by the institutional review boards of the University of California, San Francisco, the University of California, Berkeley and the University of California, Davis. All subjects gave written informed consent before participation in the studies, and the work was HIPAA-compliant. The trial was registered on www.clinicaltrials.gov as NCT00254605.
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