Diagnostic features of the autoimmune retinopathies

Autoimmunity Reviews 13 (2014) 534–538

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Diagnostic features of the autoimmune retinopathies T. Braithwaite a,⁎, G.E. Holder a,b, R.W.J. Lee a,b,c, G.T. Plant a,d,e, A. Tufail a a

Moorfields Eye Hospital NHS Foundation Trust, UK UCL Institute of Ophthalmology, UK c School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, UK d The National Hospital for Neurology and Neurosurgery, London, UK e St Thomas' Hospital, London, UK b

a r t i c l e

i n f o

a b s t r a c t

Article history: Accepted 13 November 2013 Available online 11 January 2014

The term autoimmune retinopathy encompasses a spectrum of rare autoimmune diseases that affect retinal function, often but not exclusively at the level of the photoreceptor. They typically present with painless visual loss, which may be accompanied by normal fundus examination. Some are progressive, often rapidly. They present a diagnostic challenge because there are no standardised clinical or laboratory based diagnostic criteria. Included within the spectrum are cancer-associated retinopathy, melanoma-associated retinopathy and presumed non-paraneoplastic autoimmune retinopathy. Differentiation from other retinopathies can be challenging, with overlap in symptoms, signs, and investigation findings, and an absence of pathognomonic features. However, technological developments in ophthalmic imaging and serological investigation over the past decade are adding novel dimensions to the investigation and classification of patients with these rare diseases. This review addresses the clinical, imaging, and serological features of the autoimmune retinopathies, and discusses the relative strengths and limitations of candidate diagnostic features. © 2014 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . 2. History and epidemiology . . . . 3. Presenting symptoms . . . . . . 4. Relevant medical history . . . . . 5. Fundus features . . . . . . . . . 6. Visual fields . . . . . . . . . . 7. Electrophysiology . . . . . . . . 8. Optical coherence tomography . . 9. Fundus autofluorescence imaging . 10. Fundus fluorescein angiography . 11. Serological investigation for AIR . 12. Conclusion . . . . . . . . . . . Acknowledgement . . . . . . . . . . References . . . . . . . . . . . . . .

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1. Introduction Autoimmune retinopathy, a term encompassing a spectrum of rare autoimmune diseases which predominantly affect outer retinal function, and cause painless visual loss, was first reported nearly four

⁎ Corresponding author. E-mail address: [email protected] (T. Braithwaite). 1568-9972/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2014.01.039

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decades ago. Hundreds of cases have since been reported in the medical literature, in variable detail. Considerable heterogeneity in clinical presentation, overlap in signs and symptoms with other retinopathies, and the lack of a standardised approach to investigation limit the potential for evidenced-based diagnostic criteria to be determined and tested. Whilst the identification of reliable diagnostic criteria with acceptable discriminant validity remains elusive, numerous characteristic features are apparent which together assist the clinician in making a diagnosis of autoimmune retinopathy.

T. Braithwaite et al. / Autoimmunity Reviews 13 (2014) 534–538

2. History and epidemiology Carcinoma associated retinopathy (CAR) was first described in 1976 in three patients with bronchial carcinoma, who presented with rapid visual loss, positive visual phenomena, and visual field defects due to a degenerative retinopathy [1]. Antibodies against retinal ganglion cells and photoreceptors were subsequently reported in CAR [2,3] which stained all retinal layers [4], and were later identified as anti-recoverin [5]. A related clinical phenotype, melanoma associated retinopathy (MAR), was described in 1988 in patients with cutaneous malignant melanoma who developed an acquired night blindness and shimmering photopsias [6], and who were found to have autoantibodies to an unknown antigen on bipolar cells [7]. Since the first descriptions of these paraneoplastic disorders, hundreds of cases have been reported [8,9]. Subsequently, a non-paraneoplastic autoimmune retinopathy (npAIR) was reported, of uncertain aetiology, similar in phenotype and electrophysiology to CAR [10]. Over the past three decades, many further autoantibodies to novel retinal antigens have been characterised in CAR, MAR and npAIR [11–13]. Such retinal autoantibodies may serve as molecular biomarkers for clinical phenotypes, [13,14] but many cases are seronegative [15], or show multiple autoantibodies of uncertain pathogenic significance. The term autoimmune retinopathy (AIR) has been proposed to encompass CAR, MAR and presumed npAIR [16]. There are no population-based epidemiological data on AIR, and it is rare, although other paraneoplastic syndromes occur in 10–15% of cancers, most frequently small cell lung, breast and ovarian carcinoma [17]. The largest case series of CAR (n = 175), MAR (n = 62) and npAIR (n = 141) suggested women to be affected twice as frequently as men by CAR and npAIR, whilst MAR occurs more frequently in men [8,9,18]. In those series the mean age of onset was 65 years (CAR; range 24 to 85) [9]; 57.5 years (MAR; range 30–78) [8]; and 55 years (npAIR) [18]. 3. Presenting symptoms CAR usually presents with rapid, painless, progressive visual loss, which is usually bilateral but may be unilateral or asymmetric in onset and severity [19]. Predominant cone system dysfunction manifests with difficulty seeing in bright light, photosensitivity, reduced visual acuity and impaired colour vision. Rod system dysfunction results in night blindness, and positive phenomena such as photopsias (perceived flashes of light) or shimmering vision are common [19]. The symptoms are usually rapidly progressive but may stabilise. MAR usually presents with a sudden onset of acquired night blindness accompanied by shimmering photopsias [8,20]. There is no or slow progression. The presentation of npAIR is more variable, with acuity loss, field loss, positive phenomena or night blindness [13,21]. Similar symptoms occur in numerous other retinal disorders, for example acute zonal occult outer retinopathy (AZOOR) [22], and diagnostic criteria based on symptoms alone would have poor discriminant (external) validity. 4. Relevant medical history Vision loss in CAR precedes diagnosis of an underlying malignancy in half of cases [19]. CAR is most frequently associated with small-cell lung carcinoma, followed by gynaecological (cervical, endometrial and ovarian) and breast malignancies [23]. Less frequently, CAR is associated with solid tumours including non-small cell lung, prostate, thymus, thyroid, pancreatic, colon and bladder cancers, and haematological malignancies (including leukaemia, lymphoma, myeloma) [9,19,23]. The latency between cancer diagnosis and CAR ranges from weeks to many years [9,24]. A shorter latency to onset of retinopathy is associated with more rapidly progressive visual loss [9]. CAR may be associated with autoimmune disease [25]. MAR is associated with cutaneous malignant melanoma in a majority of patients, although uveal and rarely mucosal melanoma are described [23]. It develops at a mean

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latency of 3.6 years (range 2 months to 19 years) from diagnosis, and may indicate the presence of metastasis [8]. MAR precedes diagnosis in approximately 7% patients (in 3 of 43) [8,20]. Vitiligo-like symptoms [26], and autoimmune disease are sometimes associated with MAR [20]. NpAIR is associated with autoimmune disease in approximately 50% patients [21,25]. Presumed npAIR should only be diagnosed following comprehensive systemic investigation to exclude occult malignancy. 5. Fundus features In CAR the fundus may be normal at presentation, later developing retinal pigment epithelium (RPE) atrophy and mottling, and vessel attenuation [9,23,27]. In MAR the fundus may remain normal (in 44%, 19 of 43), or may develop vessel attenuation (30%) and optic disc pallor (23%) [8], and vitreous cells may be present (30%) [8]. Diffuse RPE atrophy has been reported in one case series (in 8 of 11) [20]. Patients with npAIR may retain normal fundus appearance or develop subtle, granular pigment changes at the fovea [13,21]. Retinal dysfunction with a normal fundus appearance may also be found in hereditary cone dystrophies [28], AZOOR and the idiopathic big blind spot syndrome (IBBSS) [22,29], and vitamin A deficiency [30,31]. 6. Visual fields Field loss occurs in the majority of patients with AIR and the pattern of field loss is variable. CAR is associated with central scotoma in 61% (11 of 18), paracentral scotoma in 50% (9 of 18), and generalised sensitivity loss in 11% (2 of 18) [32]. MAR is associated with peripheral constriction in 62% (in 23 of 38), paracentral scotoma in 44% (in 17 of 38), central scotoma in 33% (in 13 of 38) and generalised sensitivity loss 13% (in 5 of 38) [8,20]. NpAIR is associated with generalised sensitivity loss or peripheral constriction in 82% (9 of 11) with relative sparing of the central or paracentral area in 55% (6 of 11) [21]. α-Enolase npAIR is associated with a higher frequency of central or paracentral scotoma, in 64% (7 of 11) [33]. Visual field investigation is less reliable for patients with poor central fixation, and who report positive visual phenomena, such as the shimmering lights (particularly in MAR) as these may prevent the patient from discerning the target [21]. The visual field loss seen in AZOOR is typically limited to distinct zones or blind spot enlargement in IBBSS [22]. 7. Electrophysiology The electroretinogram is a vital component in the diagnosis of AIR, providing objective evaluation of abnormal retinal or macular function in the vast majority of patients. It is beyond the scope of this article to give a full account of electrophysiological techniques, for which the reader is referred elsewhere [34,35]. In brief, the massed electrical response to a full-field flash stimulus of 3.0 cd·s·m−2 under scotopic conditions (dark-adapted; DA 3.0), consists of 2 main components, a negative going a-wave largely arising in the photoreceptors, and a larger positive going b-wave largely arising in the bipolar cells of the inner nuclear layer [35]. Photoreceptor disease affects both a- and b-waves, whilst diseases affecting the post-receptoral pathways give a so-called “negative” ERG, where a largely normal a-wave is followed by a bwave of lower amplitude. Cone function is recorded under photopic adaptation (suppressing rod function) both to a 30 Hz flicker stimulus (LA 30 Hz), and using a single flash (LA 3.0) [35]. CAR predominantly affects the photoreceptors [36], and thus gives a-wave reduction in the DA 10.0 response. It can be severe even shortly after presentation, with extinguished responses [11,27,37,38]. There is usually 30 Hz flicker ERG peak-time delay and amplitude reduction [36], which in some patients is more severe than that in the rod system. Pattern ERG and multifocal ERG abnormalities in CAR are common, reflecting macular involvement. When there is a rod N cone abnormality pattern, early macular involvement in CAR may assist the

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differentiation from an inherited rod–cone dystrophy, but visual acuity reduction in CAR can also relate to cystoid changes [39]. The antirecoverin CAR phenotype has been associated with severe loss of rod and cone function [36], whereas anti-enolase retinopathy typically presents with only cone dysfunction [11]. Inner retinal dysfunction, evidenced by a negative ERG, can also occur in CAR in the absence of photoreceptor involvement but this is uncommon [40]. The findings in MAR are far more consistent, with loss of On-bipolar cell (BPC) function but preserved Off-BPC function in rods and all 3 cone types. This results in electronegative waveforms that are indistinguishable from those of “complete” congenital stationary night blindness (cCSNB), with a negative waveform DA 10.0 ERG and a distinctive appearance in the LA 3.0 response [41]. The vast majority shows the findings described above (93%, 62 of 67) with an extinguished ERG in only 6% (4 of 67) patients, suggesting photoreceptor dysfunction is uncommon [8,20]. Electronegative ERGs are found in numerous other diseases including central retinal artery occlusion, photoreceptor dystrophy, ocular siderosis, quinine toxicity, vincristine-induced retinotoxicity, and juvenile x-linked retinoschisis, and occasionally in CAR [41]. The findings in patients with npAIR are highly variable. In one series (n = 16), electrophysiology indicated predominant cone-system dysfunction, either macular or generalised, with postphototransduction involvement in 56% (9 of 16) [21]. Anti-transducinα associated npAIR is reported to show reduced scotopic and photopic responses, with increased peak times [13]. Anti-enolase retinopathy is associated with cone dysfunction [33]. One report of two patients with npAIR described full-field ERG extinction in one patient, but selective b-wave loss (a negative ERG waveform) in the other [10]. 8. Optical coherence tomography Optical coherence tomography (OCT) is a non-invasive structural imaging modality which emerged in the mid 1990s, that utilises low coherence interferometry to obtain high-resolution cross-sectional images of the retina and optic nerve head [42]. Recent case series using spectral domain (sd) OCT in selected patients report outer retinal abnormalities in a majority with CAR (8 of 8) [27,37,38] and npAIR (10 of 11) [27,37,38,43] but not MAR (0 of 1) [37]. Identified abnormalities in these series include loss of the photoreceptor layer, disruption of the photoreceptor inner segment/outer segment junction, loss of the external limiting membrane and thinning of the outer nuclear layer. General reduction in central macular thickness is also reported [37]. OCT aids the differentiation of patients with AIR from those with CSNB, who have reduced retinal thickness but qualitatively normal retinal structure [44]. Given the spectrum of immune reactivity seen histopathologically in AIR, it is likely that there will be diverse findings with OCT as more cases are imaged in the future. 9. Fundus autofluorescence imaging Fundus autofluorescence (FAF) occurs when light of an appropriate wavelength stimulates naturally occurring fluorophores in the eye to absorb electromagnetic energy, become excited to a higher energy state, and emit light of a longer wavelength. Recent, small case series have reported early FAF abnormalities (both hypo and hyper) in CAR (in 87%, 13 of 15 CAR) [27,38,39], and less frequently in npAIR (in 21%, 4 of 19) [21,27,37,38], including a hyperautofluorescent ring in the parafoveal region in CAR (3 of 6) [27] and npAIR (3 of 19) [21,27,37,38]. This hyperautofluorescent ring corresponds to OCT abnormalities in the outer retina, which begin in the transition zone of the ring and extend peripherally, and suggest compromised RPE function due to increased metabolic demand, which may be a precursor to apoptosis [27,38]. Abnormal hyperFAF has also been observed in patients with retinitis pigmentosa [37]. FAF is a non-invasive imaging modality which may help differentiate AIR from CSNB [44] and AZOOR [45]. Whether it is also useful in MAR is unknown.

10. Fundus fluorescein angiography In contrast to numerous other retinal disorders, the FFA is usually unremarkable in the early stages of AIR, although subtle window defects have been reported in association with pigment mottling at the fovea in patients with npAIR [21].

11. Serological investigation for AIR Various techniques are available to investigate the presence of serum autoantibodies to components of retina including immunohistochemistry, Western Blotting, ELISA, cytotoxicity assays and multiplex assays; details have been reviewed elsewhere [46]. The frequency of anti-retinal seropositivity amongst patients referred for serological investigation ranges from about 65% in CAR and MAR (of 209 patients) [9] to 41% (58 of 141) in npAIR [18,33]. CAR-associated antibody targets include recoverin (23 kDa) in 10%, α-enolase (46 kDa) in 30%, and rod transducin-α (40 kDa) in 17% [9]. Numerous other antiretinal antibodies have been characterized in CAR, targeting antigens on photoreceptors, retinal ganglion cells, Müller cells, cones and rods [47], and on malignant cells, and these are reviewed elsewhere [46]. MAR-associated antibody targets include enolase [9], transducin-β [12], rhodopsin [48], arrestin (48 kDa) [49], a 35 kDa protein in Muller glial cells, a 22 kDa neuronal antigen, mitofilin, titin, COX [50], and the TRPM1 transduction channel in On-BPCs [51]. Melanoma cells have been found to express these and other phototransduction proteins [48]. The loss of On-BPC function associated with the electronegative ERG in MAR is thought to relate to the effect of autoantibodies to TRPM1 [51]; mutations in the gene encoding TRPM1 have been associated with recessively inherited cCSNB in humans [52]. NpAIR associated antibody targets overlap with CAR, with the exception of recoverin, which has not been reported in npAIR [18,21]. It remains unclear whether all of the autoantibodies identified in association with AIR play a direct pathogenic role, or are epiphenomenal [50]. Antibody-specific clinical phenotypes have been proposed for anti-recoverin associated CAR [32,53,54], anti-enolase associated CAR, MAR and npAIR [33], and anti-rod transducin-α associated CAR and npAIR [13], but the validity and reproducibility of observations from these small, uncontrolled case series have yet to be determined. The discriminant validity of anti-retinal antibodies in AIR will need to be determined, as anti-recoverin antibodies have been reported in 1.9% (10 of 521) patients with retinitis pigmentosa [55], anti-CAII and anti-enolase antibodies have been found in patients with cystoid macular oedema resulting from other disease processes [56], and antibodies to the outer segments of photoreceptors and Müller cells have been identified in some patients with Vogt–Koyanagi–Harada, Behçet's, sympathetic ophthalmia, toxoplasma retinochoroiditis and onchocerciasis [57–60]. Numerous anti-retinal antibodies have also been identified in association with dry and exudative age-related macular degeneration [61–63], diabetic retinopathy [64], idiopathic retinal vasculitis [65], and idiopathic uveitis [66]. Anti-retinal antibodies have also been reported in 62% (57 of 92) samples of laboratory ‘normal control’ human sera [15], and anti-enolase antibodies have been reported in 10% of healthy subjects [11] and in patients with systemic autoimmune disease and no AIR [67]. However, these antibodies may target different epitopes that do not induce apoptosis, in comparison to those found in the sera of patients with AIR, which are frequently cytotoxic [68]. The absence of internationally validated, reproducible, standardised methodological approaches to serological investigation has been highlighted and reviewed elsewhere [69–71], and significant discrepancies have been found between laboratories [72]. The sensitivity, specificity, positive and negative predictive values of assays for antiretinal antibodies will need to be determined before these can contribute to reliable diagnostic criteria [69]. How antibodies cross an intact blood retina barrier is also an evolving area.

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12. Conclusion This review has examined available empiric data from case reports and case series to explore numerous diagnostic features of the spectrum of AIR. Further work is required to ascertain whether these features, in some combination, have the potential to yield reliable diagnostic criteria with good discriminant validity and useful predictive value. Accurate, early diagnosis of AIR would facilitate timely treatment attempts and would minimise inappropriate investigation and treatment of non-autoimmune mimics. Numerous interventions of potential value require further investigation through randomised controlled clinical trials with well-defined cases. Non-invasive FAF and OCT imaging may provide additional diagnostic criteria, with indication already from small case series of their value in facilitating early differentiation from other diseases. Table summarising some diagnostic features of AIR. Most frequent diagnostic features Mean age at presentation: 5th decade [8,9,18] Presenting symptoms: Rapid onset painless vision loss or disturbance, usually bilateral Presenting medical history • CAR: Malignancy 50%[19] • MAR: Melanoma (cutaneous, uveal and rarely mucosal) 93% (40 of 43) [8,20] • npAIR: autoimmune disease in 41% (11 of 27) [21,27,37,38] Normal fundus at presentation OCT evidence of outer retinal abnormality and reduction in central macular thickness • CAR 100% (8 of 8) [27,37,38], limited data • MAR: inadequate data • npAIR: 91% (10 of 11) [27,37,38,43], limited data Visual field abnormality at presentation in majority • CAR: central scotoma 61% (11 of 18) [32] • MAR: peripheral constriction 62% (in 23 of 38) [8,20] • npAIR: more variable patterns [21,33] ERG abnormality at presentation in majority • CAR: photoreceptor dysfunction or extinguished ERG, occasionally electronegative [11,27,37,38] • MAR: electronegative ERG 93% (62 of 67) [8,20] • npAIR: more variable ERG abnormalities [13,21,33,37] Fundus fluorescein angiography: normal at presentation, or subtle window defects at fovea [21] Abnormal fundus autofluorescence • CAR 87% (13 of 15) [27,38,39], limited data • MAR: no data • npAIR: 21% (4 of 19) [21,27,37,38], limited data Seropositive for anti-retinal antibodies associated with AIR • CAR 65% (n = 175) [9] • MAR 65% (n = 34) [9] • npAIR 41% (58 of 141) [18]

Acknowledgement This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. References [1] Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 1976;81(5):606–13 [Epub 1976/05/01]. [2] Kornguth SE, Klein R, Appen R, Choate J. Occurrence of anti-retinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 1982;50(7):1289–93 [Epub 1982/10/01]. [3] Keltner JL, Roth AM, Chang RS. Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol 1983;101(4):564–9 [Epub 1983/04/01]. [4] Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol 1987;105(3):372–5 [Epub 1987/03/01].

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