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Autoimmune retinal disorders have been identified, including acute zonal occult outer retinopathy (AZOOR), AZOOR complex, autoimmune retinopathy (AIR) comprising paraneoplastic AIR (pAIR), cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and non-paraneoplastic AIR (npAIR). Patients with autoimmune retinal disorders typically present with sudden or acute onset of photopsia, photophobia, night blindness, rapid visual loss, and visual field abnormalities. The combination of multimodal imaging and electrophysiology is crucial because these diseases are challenging to diagnose. In particular, electroretinograms (ERGs) are essential for diagnosis. However, no treatment has been established to date. Additionally, a case of inner retinal dysfunction, thought to be a type of AIR, was recently reported. The diagnosis is difficult because most cases occur in one eye, and although the patient complains of severe photophobia, retinal imaging is almost normal, vision is preserved and there is almost no progression. The ERG is very characteristic, with cone-rod dysfunction and negative ERG. This chapter describes in detail the characteristics of AZOOR, AIR, and acute inner retinal dysfunction as new phenotypes of AIR.
Faculty of Medicine, Department of Ophthalmology, Juntendo University, Tokyo, Japan
*Address all correspondence to: t-hirakata@juntendo.ac.jp
1. Introduction
Retinal diseases related to autoimmunity include acute zonal occult outer retinopathy (AZOOR), AZOOR-associated diseases, and autoimmune retinopathy (AIR). These disease conditions are often difficult to diagnose even with the recent retinal imaging tests that have been developed, and it is crucial to combine retinal electrophysiological tests and systemic examinations in treating these diseases. The pathogenesis of these diseases remains unclear and they have no established treatment; however, it has been suggested that often-identified anti-retinal antibodies may play a key role.
Although previous reports have shown that autoimmune-mediated retinopathies often involve the outer retinal layers, current studies have revealed a rare type of retinopathy involving the inner retinal layers. Since it is difficult to diagnose this type of retinopathy using retinal imaging examinations, the use of electroretinograms (ERGs) is important. In this chapter, AZOOR and AIR are reviewed, and this unusual disease type is discussed.
AZOOR was first described by J.D. Gass in 1993 [1], and he described it as a disease characterized by the sudden onset of subjective scotomas and photopsia due to loss of areas of the outer retina with a normal fundus aspect [2]. The aggregated data on AZOOR show that it affects young to middle-aged patients, is largely predominant in women, and starts with an acute onset of visual field defects in one or both eyes combined with photopsia, decreased contrast sensitivity, and photophobia [3, 4].
The diagnosis of AZOOR is challenging, and the differential diagnosis includes AIR, syphilitic outer retinopathy, retinal dystrophy, uveitis, and optic nerve disease. Therefore, comprehensive retinal imaging examinations, especially optical coherence tomography (OCT), electroretinograms (ERGs), and systemic examinations, are vital for correct diagnosis.
2.1 Patient demographics
According to studies, the majority of patients with AZOOR are women. Monson et al. reported that 76% of patients with AZOOR were women (n = 99) and 24% were men (n = 31) in 130 published cases [4]. Similarly, Gass et al. demonstrated that women (37 cases, 73%) were more often affected than men (14 cases, 27%) [2]. Saito et al. also reported that among Japanese patients, the population of females (n = 31, 81.6%) with AZOOR was higher than the male (n = 7, 18.4%) [5].
Additionally, most patients with AZOOR are young to middle-aged individuals. The average age at presentation of 103 published AZOOR cases was 36.7 years, with an age range of 13 to 79 years [4]. The median age of 51 patients with AZOOR was 33 years (mean, 36 years; range 13–63 years), and the mean presumed age of AZOOR onset was 33.2 ± 8.7 years (range, 15–47 years), including in Caucasian (39 cases, 91%), Hispanic (3 cases, 7%), and Asian (1 case, 2%) [2]. In 38 Japanese patients with AZOOR, the mean presumed age of AZOOR onset was 33.2 ± 8.7 years (range, 15–47 years) [5].
2.2 Symptoms
Patients presented with acute vision loss affecting one or more zones of the visual field in one or both eyes usually experience photopsia [2, 4, 5]. Moreover, patients occasionally suffer from photophobia and night blindness. Scotomas are often described as dark blind spots or zones involving one or several aspects of the visual field. Interestingly, most patients reported worsening visual function under brightly illuminated conditions, and the temporal relationship between photopsia and visual field defects varied.
2.3 Visual acuity and visual field
Although most patients retained visual acuity of 20/20, the course and severity of AZOOR may vary by race. Saito et al. reported that the final best-corrected visual acuity (BCVA) (logMAR; logarithm of the minimum angle of resolution) was 0.0 or less in 85% of Japanese patients [5]. In contrast, Gass et al. reported that final visual acuity of 39%, 29%, and 10% of the eyes was between 20/10 and 20/20, 20/25 and 20/40, and worse than 4/200, respectively [2].
Moreover, blind spot enlargement and central scotoma can sometimes be observed using visual field tests [2]. Visual field defects remain stable when the disease stabilizes within 4–6 months; however, it can progress in some patients [4].
2.4 Findings in slit lamp test and ophthalmoscopy
A relative afferent pupillary defect was found in 21% of 131 patients with AZOOR [4], and 23.5% of 51 eyes of Japanese patients with AZOOR [5]. Specific abnormalities of the anterior segment are rarely observed in AZOOR, whereas vitreous cells are sometimes observed [2, 4, 5]. Gass et al. suggested that patients without cellular infiltration of the vitreous were more likely to recover vision and less likely to develop clinically apparent retinal pathology [2].
2.5 Multimodal imaging
In most cases, the fundus is normal at initial presentation; however, retinal pigment epithelial (RPE) changes are occasionally observed [2, 4, 5]. Notably, after long-term follow-up, fundus changes, including diffuse retinal, choroidal atrophy resembling retinitis pigmentosa (RP), regional retinal, choroidal atrophy, follicular macular edema, and leukocoria of the retinal vessels are increasingly observed.
OCT is one of the essential ophthalmic examinations for AZOOR diagnosis [6, 7, 8], and it shows irregularities of the outer retinal line, including missing or obscured ellipsoid zone (EZ) and the absence of interdigitation zones (IZ). Spaide et al. reported that OCT images showed loss of the EZ, loss of the outer nuclear layer, and thinning of the inner nuclear layer, which could be correlated with the area of visual field loss [9]. Notably, it is crucial to observe the outer retinal layers at the highest possible resolution in OCT.
Adaptive optics scanning laser ophthalmoscopy (AOSLO) revealed focal abnormal cone reflectivity and cone loss regions in patients with AZOOR, corresponding to visual field defects and reduced multifocal electroretinogram (mfERG) responses [10].
Fluorescein angiography (FA) and indocyanine green angiography (ICGA) show abnormalities [5, 11]. FA sometimes shows optic disc and retinal vascular wall staining with leakage in the late phase and hyperfluorescent punctate lesions, while ICGA occasionally indicates diffuse choroidal hyperfluorescence from the posterior pole to the mid-peripheral region during the middle phase. ICGA revealed punctate patchy hypofluorescence at the posterior pole to the mid-peripheral region and hyperfluorescence along the choroidal middle or large vessels.
2.6 ERG change
Electroretinograms (ERGs) are essential for the diagnosis of AZOOR. AZOORs frequently have a strong cone response reduction when comparing rod and cone responses in full-field ERGs; hence, detailed observation of cone and 30-Hz flicker responses is helpful for diagnosis [12]. The severity of the ERG abnormalities varied and generally correlated with the degree of visual field loss. Patients with bilateral AZOOR frequently demonstrated asymmetry in the affected parameters [2].
Moreover, mfERG may be essential for AZOOR diagnosis. Full-field ERG sometimes shows normal results, which may be due to a narrow AZOOR lesion area or mild severity of AZOOR. However, mfERG shows a decrease in the near fixation point or diffuse reduction [13]. Saito et al. showed a normal amplitude in more than half of the patients with single-flash full-field ERG, and there were noticeably reduced mfERG responses corresponding to visual field loss in all eyes examined [5]. Since mfERG reflects retinal function, it is useful for differentiating AZOOR from optic nerve disease near the central visual field.
2.7 Pathophysiology
The etiology of AZOOR is speculative, including the hypothesis of the involvement of an unknown infective viral agent with subsequent autoimmune alteration of photoreceptors. Indeed, some patients reported flu-like symptoms before the onset of AZOOR [5], and the development of AZOOR after hepatitis B vaccination, a Mantoux skin test, and a tick bite has been reported [4].
Patients with AZOOR often have a history of autoimmune disease. Gass et al. reported that 28% of 51 patients with AZOOR with long-term follow-up had a history of experiencing autoimmune diseases, including Hashimoto’s disease, multiple sclerosis, transverse myelopathy, Addison’s disease, myasthenia gravis, Graves’ disease, diabetes, CREST syndrome, and Sjogren syndrome [2].
Based on previous reports, there are two possible hypotheses regarding the mechanism of AZOOR [14]. The first hypothesis is that choroidal circulatory impairment is involved in the pathogenesis of AZOOR [15]. Notably, ICGA has revealed hypofluorescence in areas related or unrelated to AZOOR lesions [5, 11, 15]. Subfoveal choroidal thickness in the AZOOR-affected area decreased significantly as the AZOOR condition improved, suggesting that this anatomic change is correlated with functional recovery [16]. Moreover, in AZOOR-affected eyes, the choroid flow velocity in the affected area significantly increased along with improved visual functions [15]. The choriocapillaris supplies oxygen and nutrition to the outer retinal layers, and OCT images in AZOOR clearly show abnormalities in the outer retinal layers [9]. However, whether the pathogenesis begins with a choroidal circulation disorder remains unclear. The second hypothesis was that anti-retinal antibodies trigger AZOOR onset. Several anti-retinal antibodies are detected in patients with AZOOR [14, 17]. However, the relationship between AZOOR and disease pathology and severity has not yet been clearly proven. The relationship between AZOOR and anti-retinal antibodies is discussed in more detail in the next section.
2.8 AZOOR and anti-retinal antibody
The detection of retinal autoantibodies has been reported in the sera of patients with AZOOR. However, it is unclear how retinal autoantibodies are involved in AZOOR pathogenesis. A previous report showed anti-retinal antibody activity against a 45 kDa antigen in one patient with AZOOR [10]. In 18 Chinese patients with AZOOR, all (100%) were detected with anti-retinal antibodies from serum samples by western blot assay, including recoverin, α-enolase, carbonic anhydrase II, and collapsin response-mediated protein 5 [17]. In contrast, the report detected anti-retinal antibodies in presumed AIR (78.2%), patients with RP (35.0%), bilateral uveitis (63.3%), and healthy donors (33.3%).
Hashimoto et al. assessed the clinical characteristics of patients with AZOOR according to the presence or absence of anti-retinal antibodies [14]. They detected autoantibodies for recoverin, carbonic anhydrase II, and α-enolase in the serum of 33 patients with AZOOR using immunoblot analysis, and at least one serum anti-retinal antibody was detected in 42% of these patients. Interestingly, there were no significant differences in clinical factors between patients with AZOOR who exhibited anti-retinal antibodies and those who did not, including BCVA and mean deviation, a-wave amplitude on single-flash electroretinography, and frequencies of improvement of the macular ellipsoid zone and AZOOR recurrence.
2.9 Treatment
Currently, there is no established treatment for AZOOR. Owing to the presumed involvement of autoimmunity and inflammation in the pathogenesis of AZOOR, systemic corticosteroids are often administered intravenously or orally, especially in severe cases of AZOOR. Some reports have shown successful cases of the treatment of AZOOR using systemic steroids and/or immunosuppressive agents [18, 19]. A study reported the efficacy of intravitreal injection of Ozurdex (corticosteroid) in a patient with AZOOR whose vision did not improve after initial treatment with systemic corticosteroids and calcium channel blockers, which was consistent with the recovered ellipsoid zone disruption [20].
Chiba et al. reported that infliximab was effective in treating retinitis similar to AZOOR in a patient with ulcerative colitis [21]. Takeuchi et al. reported a case of disruption of the external limiting membrane (ELM), EZ, and IZ shown on the spectral domain (SD)-OCT, such as AZOOR in Behcet’s disease-associated uveitis reconstituted by continuous infliximab treatment, which led to the improvement of visual acuity [22]. These findings reveal the importance of carefully examining background factors and drug administration.
However, Gass et al. found no difference in final visual function between patients treated and those not treated with corticosteroids [2]. It is unclear whether the recovery was spontaneous or due to the effects of steroids. Further clarification of the pathogenesis of AZOOR and the establishment of treatment for AZOOR are required in the future.
AIR is an acquired retinal dysfunction caused by anti-retinal antibodies. It was first described in 1976 by Sawyer et al. when degenerative retinopathies were diagnosed in three elderly females with bronchial carcinoma following the onset of symptoms, including transitory visual obscuration and visual field loss [23]. AIR is usually characterized by bilateral, sudden progressive, painless visual deterioration, scotomas, visual field defects, and retinal (photoreceptor) dysfunction. Despite several years of studies, the underdiagnosis of AIR, a rare inflammatory condition that can lead to blindness, persists. The diagnosis of AIR is challenging and often delayed owing to its rarity and variety of clinical manifestations, including an unrevealing examination in many early stages [24].
AIR can be divided into two main forms: presumed non-paraneoplastic AIR (npAIR) and paraneoplastic AIR. The first category is probably the most prevalent and unrelated to cancer, while the second includes cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR).
3.1 Patient demographic
However, there is a lack of population-based epidemiological studies on AIR. CAR and npAIR occur predominantly in females (63–66%), whereas MAR occurs more frequently in men [24, 25]. Additionally, histories of autoimmune disease are common among patients with npAIR [24, 26]. The combined AIR group (CAR and npAIR with or without cystoid macular edema) had a median age of 51 years (range, 11–85 years) [27]. One large case series of 141 patients with npAIR reported a younger mean age at presentation (55.9 years) than that of another report for patients with paraneoplastic AIR, including CAR and MAR [28].
Essential elements for the diagnosis of npAIR include no evidence of malignancy after a thorough work-up, absence of degenerative eye diseases such as RP, a positive screen for serum anti-retinal antibodies, and an abnormality in ERG findings with or without visual field abnormalities [26]. Additionally, supportive criteria included the presence of symptoms, including photopsia, scotomas, nyctalopia or photo aversion, and dyschromatopsia.
3.2 Symptoms
AIR is usually characterized by bilateral, sudden progressive, painless visual deterioration, scotomas, visual field defects, and retinal (photoreceptor) dysfunction. Patients are typically presented with subacute vision loss, scotomas, photopsia, photophobia, night blindness, and dyschromatopsia [26]. Notably, the disease is usually bilateral but can be asymmetric.
3.3 Visual acuity and visual field
Visual acuity can be quite good in the early stages of the disease [26, 29], and visual field tests reveal constriction and central or paracentral scotomas. However, severe cases can lead to blindness and rapid disease progression. The course of vision condition depends on whether npAIR, CAR or MAR, and the type of retinal autoantibody.
3.4 Multimodal imaging
Fundus ophthalmoscopy shows normal or minimal changes in the early stages of AIR, and the fundus may appear unremarkable or demonstrate retinal vascular attenuation, diffuse retinal atrophy, RPE changes, and waxy disc pallor [26]. OCT can reveal cystoid macular edema, typically in the form of cystic spaces. Moreover, fundus autofluorescence (FAF) shows an abnormal autofluorescence pattern, primarily in the form of a hyperautofluorescent ring in the parafoveal region [30], in which OCT shows loss of ISE and thinning of the outer nuclear layer [31]. FA is performed to exclude other potential causes of vision loss [32]. Because AIR often shows the retinal artery attenuation, retinal ischemic diseases such as retinal artery occlusion should be ruled out by FA.
3.5 Electroretinogram
ERGs are essential ophthalmic examinations used for the diagnosis of AIR, and the full-field ERG, conducted under various conditions, provides information about activity in the rod and cone systems and other neural elements. The mfERG indicates the topographical location of the disease within the retina, while the electro-oculogram (EOG) provides a measurement of the integrity of the RPE layer [31, 33]. In particular, in early cases, more severe ERG changes in the presence of relatively normal retinas or larger visual field sizes contribute to AIR diagnosis [29].
Full-field ERG can show abnormalities in the dark- or light-adapted responses, bipolar cell responses, or a combination of these responses [27], and negative waveforms were often observed [29]. Moreover, different electroretinographic patterns help differentiate between diseases affecting different retinal layers and cell types [31].
3.6 Cancer-associated retinopathy
CAR was first described in three elderly females with bronchial carcinoma in 1976 [23], and it is characterized by sudden and progressive loss of vision associated with photosensitivity, reduced visual acuity, defects in color vision, constriction of visual fields, ring scotoma, and attenuated retinal arterioles [34]. It affects the photoreceptors, cones, and rods. A review of 209 patients with CAR and MAR reported a mean age of 65 years (range, 24–85 years) at diagnosis, with twice as many women affected as men [34]. Major cancer was associated with included breast (16%), lung (16%), melanoma (16%), hematological (15%; such as lymphomas, leukemias, and myelomas), gynecological (9%), prostate (7%), and colon (6%) cancers. Importantly, some patients were diagnosed with cancer during a systemic examination after AIR was presented. A systemic search is crucial when AIR is suspected, notwithstanding the rarity. Although most CAR is bilateral, some are unilateral [35].
3.7 Melanoma-associated retinopathy
MAR is a rare paraneoplastic autoimmune manifestation of malignant melanomas, and the first MAR case was reported in 1988 by Berson and Lessell [36]. MAR is typically defined as the following triad: (i) symptoms of night blindness (nyctalopia), positive visual phenomena, or visual field defects; (ii) ERG findings of a reduction in b-wave amplitude; and (iii) presence of serum autoantibodies that are reactive with retinal bipolar cells [37].
Melanomas express rhodopsin, transducin, recoverin, arrestin, and other phototransduction proteins [38]. Furthermore, when sera and IgG fractions are tested using indirect immunofluorescence, autoantibodies against a melanoma antigen are observed, which cross-react with bipolar cells of the retina [39]. Transient receptor potential cation channel subfamily M member 1 (TRPM1), also known as melastatin, is a member of the melastatin-related transient receptor channel family. Notably, TRPM1 was originally identified as a candidate gene for melanoma metastasis suppression [40].
Previous studies have revealed a relationship between MAR, anti-TRPM1 antibody, and ON bipolar cells. Staining of mouse and primate retinas with MAR sera revealed immunoreactivity in all types of ON bipolar cells, while MAR serum did not stain ON bipolar cells in Trpm1−/− mice [41]. Ueno et al. injected serum including anti-TRPM1 antibodies from a patient intravitreally into mice, and then ERGs of the mice were altered acutely, and the shape of the ERGs, including rod response disappearance, negative ERG, and severely affected cone response resembled that of the patient [42].
Immunohistochemical analysis of the eyes injected with serum showed immunoreactivity against bipolar cells only in wild-type animals and not in TRPM1 knockout mice, which was consistent with the serum containing anti-TRPM1 antibodies [42]. Histology also showed that some of the bipolar cells were apoptotic 5 h after the injection in wild-type mice; however, no bipolar cell death was found in TRPM1 knockout mice. At 3 months, the inner nuclear layer was thinner, and the amplitudes of the ERGs remained reduced. These results indicated that the serum of a patient with MAR contained an antibody against TRPM1, which caused acute death of retinal ON bipolar cells in mice.
Patients with MAR suffer from night blindness, photophobia, and bilateral photopsia, and unilateral cases have also been reported though it is rare [43]. Visual acuity and color vision are relatively preserved [44]; however, decreased color discrimination has been reported.
Fundal examination results are usually normal at the onset. Nevertheless, studies have reported some abnormal findings, including white or atrophic retinal spots or diffuse retinal pigment epithelium loss [37, 45, 46]. Moreover, MAR is associated with different patterns of visual field loss, including central and paracentral scotomas, generalized depression or constriction of the peripheral field, and arcuate defects [37, 47].
ERGs are among the most vital ophthalmic examinations that reflect ON bipolar cell dysfunction. The typical ERG pattern is a normal photopic response and markedly reduced scotopic response [48], the rod responses of the ERGs are absent, and the bright-flash ERGs are electronegative. Additionally, ON responses of focal macular ERGs and full-field long-flash ERGs are absent.
3.8 Anti-retinal antibody
The demonstration of anti-retinal antibodies is crucial for the diagnosis of AIR [27]. They can be detected using western blotting, immunohistochemistry, or enzyme-linked immunosorbent assay (ELISA). Possible causes for the generation of autoantibodies that react with retinal antigens include antimicrobial responses (infection) against similar antigens released after infection, antitumor responses (tumor) against upregulated similar proteins, or anti-retinal responses to released sequestered proteins (retinal injury) from dying retinal cells [49].
Notably, autoantibodies may trigger retinal degeneration, exacerbate the degenerative process in response to the release of sequestered antigens, and influence disease progression.
Numerous retinal autoantibodies have been reported to be involved in both npAIR and pAIR. Antibodies against recoverin [50], the inner plexiform layer [51], the inner retinal layer (35-kDa antibody against retinal Müller cell–associated antigen) [52], α-enolase [28, 53], carbonic anhydrase II [54], and rod transducin-α [55, 56] have been described in npAIR. Moreover, antibodies against recoverin [57, 58], enolase [59, 60], tubby-like protein 1 (TULP1) [61], heat shock cognate protein 70 (HSC 70) [62], carbonic anhydrase II [63] have been described in CAR. Autoantibodies against bestrophin [64], Transient receptor potential cation channel, subfamily M, member 1 (TRPM1, also known as melastatin 1 or MLSN1) [41, 65, 66], aldolase A and C [46], and interphotoreceptor retinoid-binding protein [67] have been found in MAR.
Considering the great diversity of anti-retinal antibodies, it is likely that some antibodies have a greater pathogenic potential than others. Anti-recoverin-associated CAR progresses to severe vision loss, often to no light perception [68, 69]. Andoh et al. reported that logMAR BCVA at the final visit was 0.0 or less in 18 eyes (37%), and compared with baseline, the final LogMAR BCVA of 37 eyes (76%) stably maintained vision [53]. They classified α-enolase-positive patients with AIR into three groups as follows: multiple drusen (48%), retinal degeneration (36%), and normal fundus (16%). Their study showed no significant differences in the initial or final BCVA between the drusen and degeneration groups.
3.9 Treatment
AIR can progress rapidly and cause diffuse retinal degeneration; therefore, its early diagnosis and treatment are critical to lowering the risk of irreversible immunological damage to retinal cells [24]. Many clinicians aim to modulate the immune system and reduce autoimmune attacks on the retina before irreversible damage occurs [70]. Various immunomodulatory approaches have been tried because of the presumed autoimmune nature of AIR; however, the evidence base for therapeutic intervention comprises only a small number of retrospective case series and case reports, and there is no established treatment protocol for CAR, MAR, or presumed npAIR.
Generally, AIR is suggested, to begin with, steroids (local or systemic) and/or with antimetabolites/T-cell inhibitors as the first or second-line treatment, respectively [24, 27, 71]. In a cohort of 24 patients with npAIR who received therapy of various combinations of prednisone, cyclosporine, azathioprine, mycophenolate mofetil, and periocular or intravitreal steroid injections, 15 of the 24 (62.5%) patients showed varying degrees of improvement in visual acuity or visual field, and cystoid macular edema improved in approximately half of them [27].
The best approach for pAIR is to reduce the tumor burden through surgery, chemotherapy, or radiation, as applicable [26]. However, the removal of cancer alone may not be sufficient to affect the course of CAR [72]. Intravenous methylprednisolone has been frequently used as a more effective treatment than oral steroids for the initiation of treatment [73, 74]. Contrastly, Mizobuchi et al. reported the effectiveness of oral prednisolone therapy in patients with CAR who exhibited progressive retinal degeneration [75]. Despite the aggressive immunomodulatory therapy, some patients still progress to experience significant vision loss [68].
Notably, it is important to make an early diagnosis based on ophthalmologic and systemic examinations and early treatment intervention. Further clarification of the pathogenesis of AIR will lead to the development of more effective treatment methods.
AIR often affects the outer retinal layers; however, recently, a rare type of AIR has been reported, which damages the inner retinal layers is suspected. Moreover, Hirakata et al. reported eight cases of unilateral retinopathy [76], Kido et al. reported four cases [77], and Ueno et al. reported three cases of bilateral retinopathy [78]. All these cases have been reported in Japan. ERGs are essential for AIR diagnosis because vision is preserved, and there are virtually no changes in fundus photographs or OCT. Although the cause of the disease remains known, retinal autoantibodies have been detected in several cases, indicating it is acquired, acute at onset, and autoimmune-related to its pathogenesis. Interestingly, the affected eyes have been observed to be unprogressive over a long observation period.
4.1 Patients’ demographic
AIR is characterized by an older age of onset. In unilateral cases, five males and three females, seven Japanese, and one Caucasian were reported by Hirakata et al. [76], and two males and two females, four Japanese, were reported by Kido et al. [77]. Patients’ demographic of unilateral retinopathy is shown in Table 1. Additionally, the mean age at the onset of symptoms was 62.2 ± 7.9 years (range 48–76), and three patients had a history of systemic autoimmune diseases, including asthma, palmoplantar pustulosis, and polymyalgia rheumatic [76, 77].
Patient chracteristics of unilateral acute inner retinal dysfunction.
A, abnormal; CSC, central serous chorioretinopathy; h.m., hand motion; HL, hyperlipidemia; HT, hypertension; L, left; N, normal; R, right; TIA, transient ischemic attack; VA, visual acuity; and VF, visual field.
Bold type indicates the affected eye.
4.2 Symptoms
The majority of the patients experienced sudden and severe photophobia in one eye [76, 77], and some patients required dark glasses to walk under light-adapted conditions. Additionally, some patients developed visual field loss in the affected eye, which was especially severe under light-adapted conditions. Interestingly, photopsia was not observed in any of the patients, and bilateral cases also experienced acute-onset photophobia in both eyes [78].
4.3 Visual acuity and visual field
Although patients suffered from photophobia, visual acuity was relatively well preserved in most patients [76, 77]. Additionally, visual field patterns of Goldmann perimetry (GP) varied in the affected eyes, from almost normal to narrow isopters and scotomas compared with the fellow eye. Humphrey field analyzer (HFA) was also identified in affected patients with atypical abnormalities, possibly due to photophobia.
4.4 Multimodal imaging
Ophthalmoscopy and FAF showed a normal fundus appearance, except for attenuation of the retinal arteries (Figure 1A and B) [76]. Therefore, performing FA is crucial to rule out ischemic signs, such as the presence of broad non-perfused areas and delayed arm-to-retina time. The OCT images showed three patterns in the affected eye as follows: normal appearance, outer retinal degeneration, and reduced inner nuclear layer (INL) thickness (Figure 1C and D).
Figure 1.
Multimodal imaging. (A) Fundus photographs and (B) fundus autofluorescence (FAF) images of a 66-year-old caucasian man (Case 1) were shown. (C) OCT images show almost normal in both eyes. (D) Reduced inner nuclear layer (INL) thickness was observed in the affected left eye compared to the fellow right eye. Yellow arrows show INL thickness. R, right; L, left. These data were previously reported by Hirakata et al [76].
4.5 Electroretinogram
The full-field ERGs of the affected eyes were characterized as having severe cone-rod system dysfunction with negative ERGs in all patients [76, 77, 78]. The ERGs of the fellow eyes were either normal or mildly abnormal, and the rod ERGs (DA 0.01), cone, and 30 Hz flicker ERGs were severely reduced or undetectable. The mixed rod-cone ERG (DA 10.0 or 30.0) had slightly to moderately reduced a-waves and severely reduced b-waves, resulting in a negative-type ERG. Additionally, the a-, b-, and d-waves elicited by long-duration stimuli (300.0 cd m−2) were also either severely reduced or undetectable in all affected eyes (Figure 2A), and mfERG responses were almost absent in the periphery and relatively preserved in the central retinas of the affected eyes (Figure 2B).
Figure 2.
Electroretinograms of unilateral inner retinal dysfunction. (A) Full-field electroretinograms (ERGs) of a 66-year-old Caucasian man (Case 1) were shown in the upper side. ERGs in the lower side were shown as a normal control. The full-field ERGs of the affected left eye were classified as severe cone-rod system dysfunction with negative ERGs. On the other hand, the ERGs of the fellow eye were normal. (B) Multifocal ERGs (mfERGs) of a 54-year-old Japanese man (Case 3) showed almost absent in the periphery and relatively preserved responses in the central retina of the affected left eye, while mfERG of the right eye was normal. Upper panel shows the mfERG responses and lower panel shows the mfERG 3D map. These data were previously reported by Hirakata et al [76].
4.6 Pathophysiology
The patient was elderly at the time of onset and was aware of the sudden photophobia at the time of onset [76, 77, 78]. No obvious genetic mutations have been revealed as far as we could examine [76]. Anti-retinal antibodies from some patients were detected using western blot analysis in the sera as follows: 63 and 66 kDa anti-retinal specific antibodies, 64 and 47 kDa nonspecific antibodies, 29 kDa anti-retinal specific antibody (anti-CAII antibody), and 46 kDa anti-retinal specific antibody (an anti-α enolase antibody) [76, 77]. Notably, there is a gap between retinal multimodal imaging and ERGs. Despite the almost normal findings of retinal imaging studies, the following ERG changes were significant: severe cone-rod dysfunction with negative ERG configuration and bipolar cell response dysfunction. Moreover, OCT images showed thinning of the INL in the affected eyes of some patients. There were no obvious systemic diseases, such as malignancy, associated with retinal dysfunction. Therefore, these findings suggested AIR and bipolar cell dysfunction. Moreover, retinopathy is not progressive in most patients; thus, there are no reports of treatment yet. Although the syndrome has progressed without progression during follow-up, there has been a report of one case of npAIR with the development of bilateral eyes after more than 10 years [79]; therefore, follow-up should be performed with caution.
4.7 Diagnosis
These patients share some common features as follows: (1) sudden onset of (almost unilateral) photophobia at an older age, (2) preserved visual acuity, (3) negative ERG with well-preserved a-wave, (4) severe cone and rod dysfunction (particularly cone) on ERG, (5) minimal abnormality on multimodal imaging, and (6) no progression after a relatively long-term observation period. Additionally, detection of retinal autoantibodies is helpful for AIR diagnosis, and systemic scrutiny is necessary to rule out pAIR. Since unilateral negative ERG is sometimes caused by retinal ischemia, evidence of the absence of retinal ischemia with FA is also a diagnostic aid.
Autoimmune retinal disorders have been described previously, and a combination of multimodal imaging and electrophysiology is crucial because its diagnosis is challenging. Therefore, systemic scrutiny is important. Further clarification of the pathogenesis of this disease is required as there is no established treatment yet in this field.
1.Gass JD. Acute zonal occult outer retinopathy. Donders Lecture: The Netherlands Ophthalmological Society, Maastricht, Holland, June 19, 1992. Journal of Clinical Neuro-Ophthalmology. 1993;13(2):79-97
2.Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: A long-term follow-up study. American Journal of Ophthalmology. 2002;134(3):329-339
3.Herbort CP Jr, Arapi I, Papasavvas I, Mantovani A, Jeannin B. Acute Zonal Occult Outer Retinopathy (AZOOR) results from a clinicopathological mechanism different from choriocapillaritis diseases: A multimodal imaging analysis. Diagnostics (Basel). 2021;11(7):1184
4.Monson DM, Smith JR. Acute zonal occult outer retinopathy. Survey of Ophthalmology. 2011;56(1):23-35
5.Saito S, Saito W, Saito M, Hashimoto Y, Mori S, Noda K, et al. Acute zonal occult outer retinopathy in Japanese patients: Clinical features, visual function, and factors affecting visual function. PLoS One. 2015;10(4):e0125133
6.Tsunoda K, Fujinami K, Miyake Y. Selective abnormality of cone outer segment tip line in acute zonal occult outer retinopathy as observed by spectral-domain optical coherence tomography. Archives of Ophthalmology. 2011;129(8):1099-1101
7.Matsui Y, Matsubara H, Ueno S, Ito Y, Terasaki H, Kondo M. Changes in outer retinal microstructures during six month period in eyes with acute zonal occult outer retinopathy-complex. PLoS One. 2014;9(10):e110592
8.Li D, Kishi S. Loss of photoreceptor outer segment in acute zonal occult outer retinopathy. Archives of Ophthalmology. 2007;125(9):1194-1200
9.Spaide RF, Koizumi H, Freund KB. Photoreceptor outer segment abnormalities as a cause of blind spot enlargement in acute zonal occult outer retinopathy-complex diseases. American Journal of Ophthalmology. 2008;146(1):111-120
10.Mkrtchyan M, Lujan BJ, Merino D, Thirkill CE, Roorda A, Duncan JL. Outer retinal structure in patients with acute zonal occult outer retinopathy. American Journal of Ophthalmology. 2012;153(4):757-768
11.Saito A, Saito W, Furudate N, Ohno S. Indocyanine green angiography in a case of punctate inner choroidopathy associated with acute zonal occult outer retinopathy. Japanese Journal of Ophthalmology. 2007;51(4):295-300
12.Francis PJ, Marinescu A, Fitzke FW, Bird AC, Holder GE. Acute zonal occult outer retinopathy: Towards a set of diagnostic criteria. The British Journal of Ophthalmology. 2005;89(1):70-73
13.Takai Y, Ishiko S, Kagokawa H, Fukui K, Takahashi A, Yoshida A. Morphological study of acute zonal occult outer retinopathy (AZOOR) by multiplanar optical coherence tomography. Acta Ophthalmologica. 2009;87(4):408-418
14.Hashimoto Y, Saito W, Kanaizumi S, Saito M, Noda K, Kanda A, et al. Comparison of clinical characteristics in patients with acute zonal occult outer retinopathy according to anti-retinal antibody status. Graefe's Archive for Clinical and Experimental Ophthalmology. 2021;259(10):2967-2976
15.Saito M, Saito W, Hashimoto Y, Yoshizawa C, Shinmei Y, Noda K, et al. Correlation between decreased choroidal blood flow velocity and the pathogenesis of acute zonal occult outer retinopathy. Clinical & Experimental Ophthalmology. 2014;42(2):139-150
16.Hashimoto Y, Saito W, Saito M, Hasegawa Y, Takita A, Mori S, et al. Relationship between choroidal thickness and visual field impairment in acute zonal occult outer retinopathy. Journal of Ophthalmology. 2017;2017:2371032
17.Zeng HY, Liu Q , Peng XY, Cao K, Jin SS, Xu K. Detection of serum anti-retinal antibodies in the Chinese patients with presumed autoimmune retinopathy. Graefe's Archive for Clinical and Experimental Ophthalmology. 2019;257(8):1759-1764
18.Neri P, Ricci F, Giovannini A, Arapi I, De Felici C, Cusumano A, et al. Successful treatment of an overlapping choriocapillaritis between multifocal choroiditis and acute zonal occult outer retinopathy (AZOOR) with adalimumab (Humira). International Ophthalmology. 2014;34(2):359-364
19.Kitakawa T, Hayashi T, Takashina H, Mitooka K, Gekka T, Tsuneoka H. Improvement of central visual function following steroid pulse therapy in acute zonal occult outer retinopathy. Documenta Ophthalmologica. 2012;124(3):249-254
20.Kuo YC, Chen N, Tsai RK. Acute Zonal Occult Outer Retinopathy (AZOOR): A case report of vision improvement after intravitreal injection of Ozurdex. BMC Ophthalmology. 2017;17(1):236
21.Chiba-Mayumi M, Hirakata T, Yamaguchi M, Murakami A. Infliximab recovers central cone dysfunction with normal fundus in a patient with ulcerative colitis. American Journal of Ophthalmological Case Report. 2022;25:101244
22.Takeuchi M, Harimoto K, Taguchi M, Sakurai Y. Reconstitution of disrupted photoreceptor layer in uveitis associated with Behcet's disease by infliximab treatment. BMC Ophthalmology. 2015;15:177
23.Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. American Journal of Ophthalmology. 1976;81(5):606-613
24.Dutta Majumder P, Marchese A, Pichi F, Garg I, Agarwal A. An update on autoimmune retinopathy. Indian Journal of Ophthalmology. 2020;68(9):1829-1837
25.Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: Eleven new cases and a review of 51 previously published cases. Journal of Neuro-Ophthalmology. 2001;21(3):173-187
26.Grange L, Dalal M, Nussenblatt RB, Sen HN. Autoimmune retinopathy. American Journal of Ophthalmology. 2014;157(2):266-272
27.Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Archives of Ophthalmology. 2009;127(4):390-397
28.Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmology. 2004;4:5
29.Heckenlively JR, Ferreyra HA. Autoimmune retinopathy: A review and summary. Seminars in Immunopathology. 2008;30(2):127-134
30.Canamary AM Jr, Takahashi WY, Sallum JMF. Autoimmune retinopathy: A review. International Journal of Retina Vitreous. 2018;4:1
31.Braithwaite T, Vugler A, Tufail A. Autoimmune retinopathy. Ophthalmologica. 2012;228(3):131-142
32.Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management. Survey of Ophthalmology. 2013;58(5):430-458
33.Holopigian K, Hood DC. Electrophysiology. Ophthalmology Clinics of North America. 2003;16(2):237-251
34.Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmunity Reviews. 2009;8(5):410-414
35.Javaid Z, Rehan SM, Al-Bermani A, Payne G. Unilateral cancer-associated retinopathy: A case report. Scottish Medical Journal. 2016;61(3):155-159
36.Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. American Journal of Ophthalmology. 1988;106(3):307-311
38.Hartmann TB, Bazhin AV, Schadendorf D, Eichmuller SB. SEREX identification of new tumor antigens linked to melanoma-associated retinopathy. International Journal of Cancer. 2005;114(1):88-93
39.Milam AH, Saari JC, Jacobson SG, Lubinski WP, Feun LG, Alexander KR. Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Investigative Ophthalmology & Visual Science. 1993;34(1):91-100
40.Duncan LM, Deeds J, Hunter J, Shao J, Holmgren LM, Woolf EA, et al. Down-regulation of the novel gene melastatin correlates with potential for melanoma metastasis. Cancer Research. 1998;58(7):1515-1520
41.Dhingra A, Fina ME, Neinstein A, Ramsey DJ, Xu Y, Fishman GA, et al. Autoantibodies in melanoma-associated retinopathy target TRPM1 cation channels of retinal ON bipolar cells. The Journal of Neuroscience. 2011;31(11):3962-3967
42.Ueno S, Nishiguchi KM, Tanioka H, Enomoto A, Yamanouchi T, Kondo M, et al. Degeneration of retinal on bipolar cells induced by serum including autoantibody against TRPM1 in mouse model of paraneoplastic retinopathy. PLoS One. 2013;8(11):e81507
43.Janaky M, Palffy A, Kolozsvari L, Benedek G. Unilateral manifestation of melanoma-associated retinopathy. Archives of Ophthalmology. 2002;120(6):866-867
44.Chan C, O’Day J. Melanoma-associated retinopathy: Does autoimmunity prolong survival? Clinical & Experimental Ophthalmology. 2001;29(4):235-238
45.Singh AD, Milam AH, Shields CL, De Potter P, Shields JA. Melanoma-associated retinopathy. American Journal of Ophthalmology. 1995;119(3):369-370
46.Lu Y, Jia L, He S, Hurley MC, Leys MJ, Jayasundera T, et al. Melanoma-associated retinopathy: A paraneoplastic autoimmune complication. Archives of Ophthalmology. 2009;127(12):1572-1580
47.Shinohara Y, Mukai R, Ueno S, Akiyama H. Clinical findings of melanoma-associated retinopathy with anti-TRPM1 antibody. Case Report in Ophthalmological Medicine. 2021;2021:6607441
48.Potter MJ, Thirkill CE, Dam OM, Lee AS, Milam AH. Clinical and immunocytochemical findings in a case of melanoma-associated retinopathy. Ophthalmology. 1999;106(11):2121-2125
49.Adamus G. Are anti-retinal autoantibodies a cause or a consequence of retinal degeneration in autoimmune retinopathies? Frontiers in Immunology. 2018;9:765
50.Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I. Recoverin-associated retinopathy: A clinically and immunologically distinctive disease. American Journal of Ophthalmology. 1998;126(2):230-237
51.Mizener JB, Kimura AE, Adamus G, Thirkill CE, Goeken JA, Kardon RH. Autoimmune retinopathy in the absence of cancer. American Journal of Ophthalmology. 1997;123(5):607-618
52.Peek R, Verbraak F, Coevoet HM, Kijlstra A. Muller cell-specific autoantibodies in a patient with progressive loss of vision. Investigative Ophthalmology & Visual Science. 1998;39(10):1976-1979
53.Ando R, Saito W, Kanda A, Kase S, Fujinami K, Sugahara M, et al. Clinical features of Japanese patients with anti-alpha-enolase antibody-positive autoimmune retinopathy: Novel Subtype of Multiple Drusen. American Journal of Ophthalmology. 2018;196:181-196
54.Adamus G, Karren L. Autoimmunity against carbonic anhydrase II affects retinal cell functions in autoimmune retinopathy. Journal of Autoimmunity. 2009;32(2):133-139
55.Lerea CL, Somers DE, Hurley JB, Klock IB, Bunt-Milam AH. Identification of specific transducin alpha subunits in retinal rod and cone photoreceptors. Science. 1986;234(4772):77-80
56.Grewal DS, Fishman GA, Jampol LM. Autoimmune retinopathy and antiretinal antibodies: A review. Retina. 2014;34(5):827-845
57.Shiraga S, Adamus G. Mechanism of CAR syndrome: Anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway. Journal of Neuroimmunology. 2002;132(1-2):72-82
58.Ohguro H, Nakazawa M. Pathological roles of recoverin in cancer-associated retinopathy. Advances in Experimental Medicine and Biology. 2002;514:109-124
59.Dot C, Guigay J, Adamus G. Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell carcinoma of the lung. American Journal of Ophthalmology. 2005;139(4):746-747
60.Adamus G, Aptsiauri N, Guy J, Heckenlively J, Flannery J, Hargrave PA. The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clinical Immunology and Immunopathology. 1996;78(2):120-129
61.Kikuchi T, Arai J, Shibuki H, Kawashima H, Yoshimura N. Tubby-like protein 1 as an autoantigen in cancer-associated retinopathy. Journal of Neuroimmunology. 2000;103(1):26-33
62.Ohguro H, Ogawa K, Nakagawa T. Recoverin and Hsc 70 are found as autoantigens in patients with cancer-associated retinopathy. Investigative Ophthalmology & Visual Science. 1999;40(1):82-89
63.Adamus G, Yang S, Weleber RG. Unique epitopes for carbonic anhydrase II autoantibodies related to autoimmune retinopathy and cancer-associated retinopathy. Experimental Eye Research. 2016;147:161-168
64.Eksandh L, Adamus G, Mosgrove L, Andreasson S. Autoantibodies against bestrophin in a patient with vitelliform paraneoplastic retinopathy and a metastatic choroidal malignant melanoma. Archives of Ophthalmology. 2008;126(3):432-435
65.Varin J, Reynolds MM, Bouzidi N, Tick S, Wohlschlegel J, Becquart O, et al. Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy. PLoS One. 2020;15(4):e0231750
66.Kondo M, Sanuki R, Ueno S, Nishizawa Y, Hashimoto N, Ohguro H, et al. Identification of autoantibodies against TRPM1 in patients with paraneoplastic retinopathy associated with ON bipolar cell dysfunction. PLoS One. 2011;6(5):e19911
67.Bianciotto C, Shields CL, Thirkill CE, Materin MA, Shields JA. Paraneoplastic retinopathy with multiple detachments of the neurosensory retina and autoantibodies against interphotoreceptor retinoid binding protein (IRBP) in cutaneous melanoma. The British Journal of Ophthalmology. 2010;94(12):1684-1685
68.Shildkrot Y, Sobrin L, Gragoudas ES. Cancer-associated retinopathy: Update on pathogenesis and therapy. Seminars in Ophthalmology. 2011;26(4-5):321-328
69.Adamus G, Guy J, Schmied JL, Arendt A, Hargrave PA. Role of anti-recoverin autoantibodies in cancer-associated retinopathy. Investigative Ophthalmology & Visual Science. 1993;34(9):2626-2633
70.Braithwaite T, Holder GE, Lee RW, Plant GT, Tufail A. Diagnostic features of the autoimmune retinopathies. Autoimmunity Reviews. 2014;13(4-5):534-538
72.Chan JW. Paraneoplastic retinopathies and optic neuropathies. Survey of Ophthalmology. 2003;48(1):12-38
73.Katsuta H, Okada M, Nakauchi T, Takahashi Y, Yamao S, Uchida S. Cancer-associated retinopathy associated with invasive thymoma. American Journal of Ophthalmology. 2002;134(3):383-389
74.Jacobzone C, Cochard-Marianowski C, Kupfer I, Bettembourg S, Dordain Y, Misery L, et al. Corticosteroid treatment for melanoma-associated retinopathy: Effect on visual acuity and electrophysiologic findings. Archives of Dermatology. 2004;140(10):1258-1261
75.Mizobuchi K, Katagiri S, Hayashi T, Ninomiya W, Okude S, Asano Y, et al. Unique and progressive retinal degeneration in a patient with cancer associated retinopathy. American Journal of Ophthalmology Case Reports. 2020;20:100908
76.Hirakata T, Fujinami K, Saito W, Kanda A, Hirakata A, Ishida S, et al. Acute unilateral inner retinal dysfunction with photophobia: Importance of electrodiagnosis. Japanese Journal of Ophthalmology. 2021;65(1):42-53
77.Kido A, Ogino K, Miyake Y, Yanagida K, Kikuchi T, Yoshimura N. Unilateral negative electroretinogram presenting as photophobia. Documenta Ophthalmologica. 2016;133(1):71-79
78.Ueno S, Inooka D, Meinert M, Ito Y, Tsunoda K, Fujinami K, et al. Three cases of acute-onset bilateral photophobia. Japanese Journal of Ophthalmology. 2019;63(2):172-180
79.Miura G, Baba T, Iwase T, Ohde H, Kanda A, Saito W, et al. Non-paraneoplastic autoimmune retinopathy that developed in fellow eye 10 years after onset in first eye: A case report. BMC Ophthalmology. 2020;20(1):132
Written By
Toshiaki Hirakata
Submitted: 03 October 2022Reviewed: 30 November 2022Published: 23 December 2022
Open access peer-reviewed chapter
