Journal of Neuro-Ophthalmology, September 1996, Volume 16, Issue 3

Acute Zonal Occult Outer Retinopathy and Central Nervous System Inflammation

This case report describes a patient who developed the characteristic features of acute zonal occult outer retinopathy (AZOOR), but whose case was unusual because of macular involvement, recurrences, and association with an inflammatory CNS disorder. The patient was followed for > 7 years; clinical examinations, electroretinography, electro-oculography, cerebrospinal fluid evaluations, and magnetic resonance imaging (MRI) were used to document the recurrent AZOOR and CNS disorder. The patient first presented with entoptic symptoms and a scotoma referable to dysfunction of her peripapillary and peripheral right retina. At that time, she also had asymptomatic involvement of her peripheral left retina, cerebrospinal fluid pleocytosis, and multiple brain MRI signal abnormalities. During the next several years, she developed recurrences of AZOOR, which first affected her right macula and later involved her peripheral left retina. Visual electrophysiological studies confirmed impairment of outer retinal function. The patient developed her first neurological symptom, acute relapsing-remitting cervical myelitis, > 6 years after her visual presentation. Her clinical course, laboratory studies, and neurodiagnostic evaluations were consistent with CNS inflammation, but they were not typical of multiple sclerosis. Since AZOOR is a newly recognized disorder, its full clinical spectrum may not yet be established and could include CNS involvement.

journal of Neuro- Ophthalmology 16( 3): 172- 177, 1996. © 1996 Lippincott- Raven Publishers, Philadelphia Acute Zonal Occult Outer Retinopathy and Central Nervous System Inflammation Daniel M. Jacobson, M. D. This case report describes a patient who developed the characteristic features of acute zonal occult outer reti­nopathy ( AZOOR), but whose case was unusual be­cause of macular involvement, recurrences, and associ­ation with an inflammatory CNS disorder. The patient was followed for > 7 years; clinical examinations, elec-troretinography, electro- oculography, cerebrospinal fluid evaluations, and magnetic resonance imaging ( MRI) were used to document the recurrent AZOOR and CNS disorder. The patient first presented with entoptic symptoms and a scotoma referable to dysfunction of her peripapillary and peripheral right retina. At that time, she also had asymptomatic involvement of her periph­eral left retina, cerebrospinal fluid pleocytosis, and mul­tiple brain MRI signal abnormalities. During the next several years, she developed recurrences of AZOOR, which first affected her right macula and later involved her peripheral left retina. Visual electrophysiological studies confirmed impairment of outer retinal funciion. The patient developed her first neurological symptom, acute relapsing- remitting cervical myelitis, > 6 years af­ter her visual presentation. Her clinical course, labora­tory studies, and neurodiagnostic evaluations were con­sistent with CNS inflammation, but they were not typ­ical of multiple sclerosis. Since AZOOR is a newly recognized disorder, its full clinical spectrum may not yet be established and could include CNS involvement. Key Words: Retinopathy- Scotoma- Photopsia- Multiple sclerosis- Electroretinography. Manuscript received April 24, 1995; accepted August 10, 1995. From the Departments of Neurology and Ophthalmology, Marshfield Clinic, Marshfield, Wisconsin, U. S. A. Address correspondence and reprint requests to Dr. Daniel M. Jacobson, Neuro- Ophthalmology ( 4F), Marshfield Clinic, 1000 N. Oak Avenue, Marshfield, WI 54449, U. S. A. Gass ( 1) recently described 13 young adults who developed sudden photopsias and scotomas refer­able to localized regions of outer retinal impair­ment. Gass named the condition acute zonal occult outer retinopathy ( AZOOR) to emphasize its abrupt onset, sectorial retinal involvement, absence of ophthalmoscopic findings in the acute stage, and outer retina localization of dysfunction. Bilateral involvement was common. Significant impairment of visual acuity, macular involvement, and symp­tomatic recurrences were rare. Since Gass's origi­nal report ( 1), descriptions of affected patients with additional retinal findings ( 2) and associa­tions ( 3) have shown that the full clinical spectrum of AZOOR has yet to be defined. No reported pa­tient thus far has had clinical, neuroimaging, or cerebrospinal fluid ( CSF) evidence of CNS involve­ment ( 1). The patient described here developed the characteristic features of AZOOR described by Gass ( 1), but her case was unusual because of mac-ulopathy, recurrences, and association with para-clinical and clinical evidence of an undefined in­flammatory CNS disorder. CASE REPORT A 28- year- old woman complained of sudden continuous flashes of uncolored lights and a swirl­ing illusion of imagery in the temporal field of her right eye in November of 1987. These symptoms were more apparent in bright ambient light. Fog-giness involving the central visual field of her right eye was noted 2 weeks later. There was no preced­ing viral prodrome, and the patient denied any concurrent neurologic or systemic symptoms or past symptoms of multiple sclerosis. A retina con­sultant found a visual acuity of 20/ 80, a small af­ferent pupillary defect, 1 + vitreous cells, slight optic disc hyperemia, and fine perivascular infil- 272 OUTER RETINOPATHY 173 trates in the inferior retina periphery of the right eye. Examination of the left eye was unremark­able. Fluorescein angiography of the right poste­rior pole was felt to be unrevealing. Optic neuritis was diagnosed, and the patient was treated with prednisone, 80 mg daily, for 2 weeks; this treat­ment had no effect on her symptoms. She was then referred for a neuro- ophthalmologic opinion. When first evaluated 3 weeks after the onset of her symptoms, the patient's visual acuity was 20/ 40 in the right eye. She had a temporal wedge scotoma in that eye and an asymptomatic visual field defect in the nasal field of the left eye ( Fig. 1). Her optic discs, maculas, peripheral retina, and retinal vessels appeared normal in both eyes. The previously performed fluorescein angiogram was reviewed; it showed a large zone of hyperfluores-cence temporal to the fovea of the left eye ( Fig. 2), which corresponded to the asymptomatic nasal scotoma found during visual field testing of that eye ( Fig. 1). The patient's medical evaluations included the following normal studies: chest radiograph, rou­tine blood cell counts and serum chemistries, erythrocyte sedimentation rate, serum protein electrophoresis, Lyme titer, antinuclear antibody assay, and venereal disease research laboratory test. Magnetic resonance imaging ( MRI) of the brain showed multiple areas of increased signal intensity scattered throughout the brain, including the periventricular white matter, deeper struc­tures, and brain stem ( Fig. 3). The CSF contained 13 white cells/ ml3 ( 94% lymphocytes, 6% mono­cytes), protein at 56 mg/ dl ( normal, < 45 mg/ dl), no oligoclonal bands, and an elevated IgG index of 2.2 ( normal, < 0.6). Glucose concentration, cytology, and complete microbiological strains and cultures were all normal; myelin basic protein was not as­sayed. A neurological examination was normal, as were results from visual, brain stem- auditory, and somatosensory evoked responses. The patient was followed during the next year; she had persistent, although less frequent, pho-topsias, stable visual sensory findings, and no ophthalmoscopic abnormalities. She returned in February of 1991, at the age of 31 years; she said that the central vision of her right eye had been declining for an unclear period of time since her last visit. She denied intercurrent neurologic symptoms. She had a visual acuity of 20/ 200, a new central scotoma ( Fig. 1), and new mottling of the macula pigment epithelium in the right eye. A window defect of the central macula was demon­strated during fluorescein angiography ( Fig. 4). Vi­sual electrophysiological testing, performed using December 1987 VA 20/ 20' 3 20/ 40 Color 10/ 14 10/ 14 RAPD 0.9 log unit February 1991 - fa '-'- Ssf - Tir^-• SB-LEFT RIGHT VA 20/ 20 20/ 200 Color 13/ 14 6/ 14 RAPD 0.9 log unit September 1993 VA 20/ 152 20/ 200 Color 12/ 14 7/ 14 RAPD 0.6 log unit FIG. 1. Shown are serial results from Goldmann pe­rimetry and visual sensory testing, including Snellen visual acuity ( VA), assessment of correctly identified pseudoisochromatic plates ( Color) from the American Optical 14 Plate Test Book ( Richmond Products, Boca Raton, Florida), and quantification of the relative af­ferent pupillary defect ( RAPD) using neutral density filters. standards recommended by the International So­ciety for Clinical Electrophysiology of Vision ( 4,5), demonstrated that the amplitude of the scotopic A- wave recorded from the right eye was reduced and that the Arden ratio recorded from the right ] Neuro- Ophtlmlmol, Vol. 16, No. 3, 1996 174 D. M. JACOBSON FIG. 2. Fluorescein angiogram of the left eye during the late phase reveals a zone of hyperfluorescence temporal to the fovea, consistent with retinal pigment epithelial atrophy. eye was reduced relative to that recorded from the left eye ( Table 1). The patient was followed for the next year; her visual sensory deficits remained stable. During this period, however, increased mottling and thin­ning of the retina pigment epithelium of the right macula were observed ( Fig. 5). In addition, a new FIG. 3. T2- weighted ( TR, 2,500 ms; TE, 60 ms) mag­netic resonance image reveals multiple hyperintensity signal lesions distributed around the rostral portion of the lateral ventricles. ( TR, repitition time; TE, echo time.) / Newo- Oplitlmlmol, Vol. 16, No. 3, 1996 FIG. 4. Fluorescein angiogram of the right eye during the late phase shows patchy, bull's- eye- like hyperflu­orescence of the central macula, consistent with atro­phy of the retinal pigment epithelium. zone of subtle retinal pigment epithelial thinning was noted in the right eye, involving the inferior-nasal peripapillary retina and corresponding to the superior- temporal wedge scotoma in that eye ( Fig. 1). Fluorescein angiography confirmed the pres­ence of a new zone of hyperfluorescence in this area ( Fig. 6). Retinal pigment epithelial atrophy and pigment migration within the zone of previ­ously noted hyperfluorescence temporal to the fovea of the left eye were also seen ( Fig. 7). Focal segments of perivenous sheathing were seen along peripheral vessels in the retina of both eyes ( Fig. 8). The patient had no further problems until Sep­tember of 1993 when, at the age of 34 years, she experienced abrupt, bright, bubble- like, continu­ous, positive visual obscurations slowly drifting upward in the temporal field of her left eye, fol­lowed a few weeks later by a gray, swirling, fog-giness of the temporal field of that eye. Physical examination identified a new scotoma involving the temporal field of the left eye ( Fig. 1), but no ophthalmoscopic abnormalities of the retina corre­sponded to this scotoma. Visual electrophysiology studies were repeated and showed reduced sco-topic amplitudes and Arden ratio recorded from her left eye compared with results from 1991, and a reduced amplitude of the photopic B- wave in the right eye relative to that recorded in 1991 ( Table 1). Neurological examination remained normal. Nor­mal studies included a chest radiograph, angioten-sin- converting enzyme assay, and fluorescent treponemal antibody absorption test. MRI of the brain was repeated and revealed no new lesions, a decrease in size of some of the previously seen OUTER RETINOPATHY 175 TABLE 1. Results of electroretinography and electro- oculography Parameter Scotopic B, dim white light Scotopic B, dim white light Scotopic A, bright white light Scotopic A, bright white light Scotopic B, bright white light Scotopic B, bright white light Photopic A, bright white light Photopic A, bright white light Photopic B, bright white light Photopic B, bright white light Arden ratio0 Arden ratio Eye OD OS OD OS OD OS OD OS OD OS OD OS 1991a 277 272 272 323 511 572 47 43 179 216 2.2 2.5 1993a 287 223 266 250 472 440 44 68 100 224 2.2 2.2 Normal'' > 204 > 204 > 276 > 276 > 451 > 451 > 28 > 28 > 114 > 114 > 1.6 > 1.6 B, electroretinogram B- wave; A, electroretinogram A- wave; OD, right; OS, left. a Electroretinogram results are reported as the largest amplitudes ( mV) re­corded from two trials. bThe 95th percentile cut- off was established by testing both eyes from 14 healthy women, 20- 34 years of age. c Electro- oculogram, light peak/ dark trough. lesions, and no enhancement of any lesion follow­ing administration of gadolinium. The entoptic symptoms in the left eye persisted for the next several months. In March of 1994, the patient developed an acute cervical myelopathy characterized by ascending paresthesias, pathologically brisk muscle stretch reflexes, and increased- signal- intensity lesions of the cervical spinal cord on MRI. CSF contained 25 white cells/ ml3 ( 96% lymphocytes, 4% monocytes), protein at 68 mg/ dl, IgG index at 2.5, and only one oligoclonal band; myelin basic protein was not as­sayed. She was treated with pulse i. v. methylpred-nisolone and experienced gradual resolution of her deficits during the next several weeks. Human leu­kocyte antigen class I subtyping was positive for A- ll, A- 32, B- 14, and B- 18. She has not experi­enced any further neurological or visual symptoms during 18 months of follow- up. DISCUSSION Similar to the patients with AZOOR reported by Gass ( 1), the patient described here was a young woman who developed abrupt photopsias and scotomas. Her initial fundus appearance was un-revealing. Zones of retinal pigment epithelial atro­phy later developed in regions corresponding to the location of the visual field defects. Visual elec­trophysiological studies confirmed the outer reti­nal localization of dysfunction. This patient also had MRI and CSF inflammatory abnormalities that were consistent with, but not diagnostic of, CNS demyelination or vasculitis ( 6,7). Similar paraclinical abnormalities can be seen FIG. 5. Macula of the right eye shows atrophic changes of the retinal pigment epithelium. FIG. 6. Fluorescein angiogram of the right eye during the delayed phase shows a zone of hyperfluorescence involving the inferior- nasal peripapillary retina, con­sistent with retinal pigment epithelial atrophy. / Nciiw- Ophtlmlmol, Vol. 16, No. 3, 1996 176 D. M. JACOBSON FIG. 7. Temporal retina of the left eye shows patchy depigmentation and pigmentary migration; the retinal arterioles appear thin. in other systemic inflammatory disorders associ­ated with CNS involvement, such as sarcoidosis ( 8,9) and systemic lupus erythematosus ( 10,11). However, this patient had no clinical or laboratory evidence to suggest that she had an underlying systemic inflammatory condition. The paraclinical abnormalities in this patient were documented at the time she first presented with visual symptoms, > 6 years before her first CNS symptom. Because she has experienced only one clinical attack of neurological dysfunction dur­ing her > 7- year follow- up thus far, she does not fulfill the generally accepted clinical criteria for a diagnosis of definite, or even probable, multiple sclerosis ( 12,13). If one considers her paraclinical abnormalities, however, then her neurological disorder could be categorized as laboratory- sup­ported multiple sclerosis ( 14). Unlike most individuals with multiple sclerosis, FIG. 8. Peripheral retina of the right eye shows multi­ple focal segments of perivenous sheathing ( arrows). this patient did not demonstrate new, enlarging, or enhancing lesions on serial MRI evaluations of her brain ( 15- 17). Also unlike most patients with multiple sclerosis, even those with stable disease, she did not have multiple oligoclonal bands de­tected in her CSF when she first presented or 6 years later when she experienced her first neuro­logical relapse ( 18). The degree of her CSF pleocy-tosis and protein content were also somewhat un­usual for multiple sclerosis. According to Tourtel-lotte and Walsh ( 19), the white cell count is < 5/ ml3 in two thirds of patients with multiple sclerosis in remission or exacerbation, < 20/ ml3 in > 99% of all patients with multiple sclerosis, and an average of 5.6/ ml3 in large populations of patients with mul­tiple sclerosis. CSF protein is < 55 mg/ dl in 77% of patients with multiple sclerosis ( 19). The patient's human leukocyte antigen subtyping did not con­firm the class I associations of multiple sclerosis, A- 3 and B- 7; however, it should be emphasized that such associations are thought to represent susceptibility factors currently useful only for in­vestigational purposes ( 20). Because of the atypical aspects of this case, it seems reasonable to consider the possibility that the outer retinopathy and CNS disorder are related in some noncasual manner. Acute posterior mul­tifocal placoid pigment epitheliopathy is an exam­ple of another outer retinopathy initially consid­ered to be restricted to the retina when originally described ( 21); later reports documenting associ­ated CNS vasculitis led to an appreciation for its expanded clinical spectrum ( 22- 25). The patient re­ported by Kersten and colleagues ( 26) is especially pertinent because she developed a chronic neuro­logical disorder characterized by partially cortico-steroid- responsive CNS deficits and CSF pleocyto-sis > 5 years following bilateral acute posterior multifocal placoid pigment epitheliopathy, a tem­poral relationship similar to the long delay be­tween onset of outer retinopathy and first neuro­logical symptoms in the patient discussed here. Another way to account for the two involved organs in this patient would be to assume that the outer retinal lesions represent an unusual ocular manifestation of CNS demyelination, similar to the infrequent occurrence of retinal periphlebitis ( 27), uveitis ( 28), or pars planitis ( 29) in patients with multiple sclerosis. This association is unlikely in this patient, however, since slowly progressive zones of retinal depigmentation and atrophy have not been described in large populations of system­atically evaluated patients with multiple sclerosis ( 27,30,31). Finally, it remains possible that this patient's ret- / Neuro- Ophthalmol, Vol. 16, No. 3, 1996 OUTER RETINOPATHY 177 ina and CNS disorder are completely unrelated and simply represent the chance occurrence of AZOOR and an atypical presentation of multiple sclerosis in the same individual. Further experi­ence with this newly recognized disorder will help to determine whether its clinical spectrum should be expanded to include CNS involvement. REFERENCES 1. Gass JDM. Acute zonal occult outer retinopathy. Donders lecture: the Netherlands Ophthalmology Society, Maas­tricht, Holland, June 19, 1992. / Clin Neuro Ophthalmol 1993; 13: 79- 97. 2. Gass JDM, Stern C. Acute annular outer retinopathy as a variant of acute zonal occult outer retinopathy. 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