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 to 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 (SD-OCT), and AOSLO imaging. Cone spacing was measured in 4 eyes and compared with 27 age-similar normal eyes. Additional functional testing in 1 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 1 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 ∼45 kd 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.
Acute zonal occult outer retinopathy (AZOOR) is a syndrome characterized by acute loss of 1 or more zones of visual function, usually accompanied by photopsia, reduced outer retinal function measured by electroretinography in 1 or both eyes, and, in some cases, death of retinal photoreceptor cells without biomicroscopic or fluorescein angiographic abnormalities. AZOOR occurs more frequently in young myopic women, and recovery of visual function occurs infrequently.
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. However, no abnormal anti-retinal antibodies have previously been identified in patients with AZOOR. 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.
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 and inner nuclear and outer nuclear layers in regions with visual field defects imaged using time-domain and spectral-domain optical coherence tomography (SD-OCT) in patients with AZOOR.
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. Several reports have demonstrated the utility of using adaptive optics to characterize patients with retinal disease. In the present article, adaptive optics scanning laser ophthalmoscopy (AOSLO) combined with SD-OCT 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 SD-OCT (Spectralis HRA + OCT Laser Scanning Camera System; Heidelberg Engineering, Vista, California, USA). Goldmann kinetic perimetry was performed with II3̄c, V3̄c, 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 200 ms; patients were tested using either the 30-2, 24-2, or 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, California, USA). 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, Iowa, USA), as described previously. Eyes were tested simultaneously and measured individually, according to standards specified by the International Society for Clinical Electrophysiology and Vision (ISCEV). Multifocal ERG (mfERG) testing was performed in a light-adapted state (VERIS 5.1.10C, Electrodiagnostic Imaging, Inc, Redwood City, California, USA) with Burian-Allen contact lens electrodes, also according to ISCEV standards and as described previously. Fundus-guided microperimetry (MP-1; Nidek Technologies America Inc, Greensboro, North Carolina, USA) used a Goldmann size III stimulus of 200 ms duration with a 4-2 threshold strategy as described previously. Serum from all patients was analyzed for anti-retinal antibody activity using Western blots of porcine retina (PelFreez, Rogers, Arkansas, USA) at the Ocular Immunology Laboratory, UC Davis, California. 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, 2-color dark-adapted Goldmann perimetry and fundus-guided 2-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. In order to ensure that the parameters were correct for measuring rods, fields were measured and sensitivity was compared for 2 different wavelengths. Visual fields were measured for the Goldmann II3̄c and V3̄c target sizes, each with a long-wavelength and a short-wavelength filter, as described previously. 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 used were Wratten 25 and 47B, respectively. The stimuli were 2 log units lower in luminance (II3̄c and V3̄c) 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. 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 blackout cloth to prevent any light leakage. To monitor the patient’s fixation, monovision night goggles (Zenit NV, Famous Trails, San Diego, California, USA) 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, New Jersey, USA) filters were introduced into the stimulus light path with the background set to red, such that the background illumination was effectively 0 cd/m 2 (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) 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 using 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. Given our testing parameters, sensitivity at retinal locations with at least 8 dB 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.
High-Resolution Imaging
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. Cone spacing was measured at locations in which unambiguous cones were visualized, and compared to normative data from 27 age-similar individuals. Cone spacing greater than 2 standard deviations above the normal mean at that location was considered abnormal.
Results
The Table provides a summary of clinical results for all 4 patients.
| Best-Corrected Visual Acuity | ffERG | mfERG | Microperimetry | HVF | SD-OCT | AOSLO | Antibody Against ∼45 kd Antigen | |
|---|---|---|---|---|---|---|---|---|
| Case 1 |
| 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, 38 dB OS) | Disrupted IS/OS junction OU in regions of reduced cone reflectivity | Reduced cone reflectivity in the region of scotoma OD | Not detected |
| Case 2 |
| 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 (40 dB) 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 |
| Reduced photopic b-wave amplitude by 33% OD relative to OS and reduced 30 Hz flicker implicit time (30 ms OD vs 27.5 ms 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 compared with OS | Normal cone mosaic in the region of reduced foveal sensitivity OD | Not detected |
| Case 4 |
| 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 (18 dB OD, 26 dB OS) | Loss of IS/OS junction in the central macula with thinning of outer nuclear layer OU | Abnormal cone coverage and spacing within macula OD | Detected |
Case 1
An 18-year-old healthy emmetropic woman 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). Multifocal ERG revealed localized macular outer retinal dysfunction.
AOSLO images within the foveal center showed normal cone spacing and density. 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 SD-OCT studies showed no significant changes over 14 months.
Case 2
A 42-year-old myopic woman 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 coverage to a region beginning 4 degrees temporal to the fovea corresponding to a discrete scotoma where cones were less contiguous and showed increased spacing ( Figure 2 ) . Beyond 4 degrees, regularly arranged cells were observed, but with higher density than has been reported for cones, and these were suspected to be rods. The region of the relative scotoma also showed some structure consistent with retinal pigment epithelial (RPE) cells, which have been shown to be directly visible in instances where photoreceptor cells have been lost ( Figure 2 ).
Two-color dark-adapted modified Goldmann kinetic perimetry 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 2 stimuli indicated that the test was rod-mediated ( Figure 3 ) . Two-color dark-adapted modified microperimetry, as described previously, also indicated rod-mediated function ( Figure 3 ).
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