**2. AZOOR**

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 [6–8], 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%).

*Retinal Dysfunction Caused by Autoimmune Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.109263*

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.

#### **3. Autoimmune retinopathy**

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 *Retinal Dysfunction Caused by Autoimmune Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.109263*

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 electrooculogram (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.

#### **4. Acute inner retinal dysfunction**

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 autoimmunerelated 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].

#### **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 acuteonset 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**).

#### **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 [76–78]. 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 rodcone 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−<sup>2</sup> ) 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**).

#### **4.6 Pathophysiology**

The patient was elderly at the time of onset and was aware of the sudden photophobia at the time of onset [76–78]. No obvious genetic mutations have been




*Bold type indicates the affected eye.*

**Table 1.**

*Patient chracteristics of unilateral acute inner retinal dysfunction.*

*Retinal Dysfunction Caused by Autoimmune Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.109263*

#### **Figure 1.**

*Multimodal imaging. (A) Fundus photographs and (B) fundus autofluorescence (FAF) images of a 66-yearold 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].*

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 antiretinal 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,

#### **Figure 2.**

*Electroretinograms of unilateral inner retinal dysfunction. (A) Full-field electroretinograms (ERGs) of a 66-yearold 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].*

(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.
