Nonparaneoplastic Autoimmune Retinopathy Research Articles

Diagnostic yield of an inherited retinal disease gene panel in retinopathy of unknown origin

Purpose: Evaluating the presence of class 3, 4 and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). Methods: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmological history, complete ophthalmological examination, anti-retinal antibodies and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: non-paraneoplastic autoimmune retinopathy (npAIR), unilateral pigmentary retinopathy (UPR), asymmetrical pigmentary retinopathy (APR) and acute zonal occult outer retinopathy (AZOOR). Results: We included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20 – 68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, 2 also demonstrated class 5 variants in other IRD genes. The remaining 5 patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) npAIR patient in our RUO cohort. When considering the npAIR subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. Conclusions: Every suspected npAIR patient should benefit from gene panel testing in order not to overlook undiagnosed IRDs. In contrast, UPR, APR and AZOOR subpopulations did not benefit from genetic analysis in this study.

TOWARD AN IMAGING-CENTRIC DEFINITION OF NONPARANEOPLASTIC AUTOIMMUNE RETINOPATHY.

To explore characteristic imaging features of nonparaneoplastic autoimmune retinopathy (npAIR) to augment diagnostic criteria. This is a retrospective cohort study of patients with npAIR evaluated at the Emory Eye Center between 2013 and 2019. Multimodal fundus images were evaluated to characterize the evolution of the disease. Twenty-one eyes of 12 patients were classified as having npAIR. Five patients (42%) were female, with median (range) age of 59 years (45-85 years). Median baseline visual acuity was 20/30 (20/20 to hand motions). Disease was asymmetric in 11 patients (92%). Common imaging findings included absence of bone spicules (86% of affected eyes), presence of attenuated vessels (86%), and speckled hypoautofluorescence in perimacular and perivenular regions. Three eyes were noted to present early with subtle splotchy fundus autofluorescence abnormality, ultimately developing characteristic speckled perimacular hypoautofluorescence. On optical coherence tomography, 18 eyes (86%) had loss of outer retinal bands with relative foveal sparing and a tapered transition zone. Many eyes with npAIR exhibit a subacute, asymmetric, generalized photoreceptor degeneration featuring outer retinal atrophy with relative foveal sparing, retinal vascular attenuation, absence of bone spicules, and speckled hypoautofluorescence often in a perimacular and perivenular distribution. Findings of this study augment diagnostic criteria to improve specificity and accessibility of testing for npAIR.

Circular Perivascular Autofluorescence Pattern in Patients With Autoimmune Retinopathy.

Purpose: To report the characteristics and prevalence of a previously undescribed circular perivascular fundus autofluorescence (FAF) pattern in paraneoplastic and nonparaneoplastic autoimmune retinopathy. Methods: This retrospective case series used clinical and imaging data extracted from charts of patients with autoimmune retinopathy in whom FAF imaging was performed from the initial presentation to the last visit. Results: Six of 25 patients with autoimmune retinopathy and FAF imaging developed circular perivascular FAF changes. Three patients had paraneoplastic autoimmune retinopathy, and 3 had nonparaneoplastic autoimmune retinopathy. The lesions appeared a mean of 25 months after symptom onset; however, the timing varied from months to years and did not correlate with the overall disease course. The lesions were initially typically hyperautofluorescent and varied in progression, distribution, and quality. Optical coherence tomography showed hyperreflective subretinal deposits in the corresponding areas in most patients. Conclusions: To our knowledge, these are the first reported cases with this circular perivascular FAF pattern in nonparaneoplastic autoimmune retinopathy. This finding could also be a useful diagnostic imaging marker in some patients with autoimmune retinopathy.

Structural and Functional Changes in Non-Paraneoplastic Autoimmune Retinopathy.

To describe longitudinal changes in patients with non-paraneoplastic autoimmune retinopathy (npAIR) by utilizing different diagnostic modalities/tests. The index study is a retrospective longitudinal review of sixteen eyes of eight patients from a tertiary care eye hospital diagnosed with npAIR. Multiple diagnostic modalities such as wide-angle fundus photography (WAFP), WA fundus autofluorescence (WAFAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann visual field (GVF) perimetry, microperimetry (MP), electrophysiologic testing, and adaptive optics scanning laser ophthalmoscopy (AOSLO) were reviewed and analyzed. At the baseline visits, anomalies were detected by multimodal diagnostic tests on all patients. Subjects were followed up for a median duration of 11.5 [3.0-18.7] months. Structural changes at the baseline were detected in 14 of 16 (87.5%) eyes on WAFP and WAFAF and 13 of 16 (81.2%) eyes on SD-OCT. Eight of the ten (80%) eyes that underwent AOSLO imaging depicted structural changes. Functional changes were detected in 14 of 16 (87.5%) eyes on GVF, 15 of 16 (93.7%) eyes on MP, and 11 of 16 (68.7%) eyes on full-field electroretinogram (ff-ERG). Multifocal electroretinogram (mf-ERG) and visual evoked potential (VEP) tests were performed in 14 eyes, of which 12 (85.7%) and 14 (100%) of the eyes demonstrated functional abnormalities, respectively, at baseline. Compared to all the other structural diagnostic tools, AOSLO had a better ability to demonstrate deterioration in retinal microstructures occurring at follow-ups. Functional deterioration at follow-up was detected on GVF in 8 of 10 (80%) eyes, mf-ERG in 4 of 8 (50%) eyes, and MP in 7 of 16 (43.7%) eyes. The ff-ERG and VEP were stable in the majority of cases at follow-up. The utilization of multimodal imaging/tests in the diagnosing and monitoring of npAIR patients can aid in identifying anomalous changes over time. Analysis of both the anatomical and functional aspects by these devices can be supportive of detecting the changes early in such patients. AOSLO shows promise as it enables the capture of high-resolution images demonstrating quantifiable changes to retinal microstructure.

Post-infectious Non-paraneoplastic Autoimmune Retinopathy in Paediatric age group: A high index of suspicion, Multimodal Imaging and Early treatment can restore vision.

To report a case of non-paraneoplastic Auto-immune retinopathy (npAIR) in a paediatric patient who showed excellent visual recovery with early diagnosis and prompt treatment. Retrospective Case report. A five year old girl presented to us with bilateral profound vision loss of sub-acute onset following an episode of high fever, without any previous visual abnormality. A diagnosis of npAIR was made based on history, clinical findings and multimodal imaging. Intravenous methylprednisolone was started urgently followed by oral steroid. Visual acuity showed good improvement along with gradual restoration of anatomy of retinal layers in Optical Coherence Tomography (OCT) over a period of three months. Our case highlights the importance of suspecting npAIR in paediatric patients presenting with sudden bilateral painless progressive loss of vision without prior visual difficulties and the role of multimodal imaging to aid in diagnosis. The recovery of vision with restoration of photoreceptor layer also shows the nature of the disease to recover with early intervention despite a negative anti-retinal antibody test but with features highly suggestive of npAIR.

Non-paraneoplastic autoimmune retinopathy versus Pericentral Retinal Degeneration phenotype: which came first? A case report.

To report a case of non-paraneoplastic autoimmune retinopathy (npAIR) with phenotypical features of pericentral retinal degeneration (PRD) who responded to intravenous immunoglobulin therapy. A case report. A 27-year-old male presented with a recent subacute progressive nyctalopia and photopsia. Dilated fundoscopy demonstrated confluent yellow-white patches along the main temporal vascular arcades with sparing of the central island in the posterior pole. Color vision, fundus autofluorescence, fluorescein angiography, static visual field, and electroretinographic studies were inconclusive for retinal degeneration. Subsequent genetic testing for known mutations were negative. Work-up for paraneoplastic autoimmune retinopathy was negative. Anti-retinal antibodies were positive. The patient was diagnosed with non-paraneoplastic autoimmune retinopathy and was treated with intravenous immunoglobulin, which resulted in objective and subjective improvement on electroretinography, visual field, and optical coherence tomography of retina. and importance: Non-paraneoplastic autoimmune retinopathy may present in a patient with the clinical phenotype of PRD. It is essential to rule out non-paraneoplastic autoimmune retinopathy in patients with subacute changes in the natural course of pericentral retinal degeneration, as treatment with intravenous immunoglobulin may be helpful.

A MIDDLE-AGED PATIENT WITH BILATERAL VISION LOSS AND NYCTALOPIA.

Purpose: To report a case of nonparaneoplastic autoimmune retinopathy in a patient with diagnosis of Lambert Eaton Myasthenic Syndrome. Case report. Main outcome measures included findings on retinal examination and analysis of fundus autofluorescence, spectral domain optical coherence tomography, and full field electroretinogram. Vitamin A levels and results of antiretinal antibody testing and paraneoplastic work up are also presented. A 47-year-old male presented with a 1-year history of bilateral vision loss and nyctalopia. Past medical history was significant for Lambert-Eaton myasthenic syndrome (LEMS), confirmed by positive voltage-gated calcium channel (VGCC) antibodies, and thymectomy reported as thymic follicular hyperplasia. OCT showed bilateral diffuse outer retinal atrophy and ellipsoid zone loss. Fundus autofluorescence displayed a bull's pattern of hyperautofluorescence around each fovea. Full field ERG showed an extinguished rod response and a severely depressed cone response in each eye. We describe a case of nonparaneoplastic autoimmune retinopathy in a patient with Lambert Eaton Myasthenic Syndrome. Multimodal retinal imaging and ERG confirmed the presence of autoimmune retinopathy with severe rod-cone degeneration. The association of this myasthenic syndrome with AIR is novel.

Serum antiretinal antibodies and cytokine profiling in autoimmune retinopathy and their association with clinical outcomes.

Autoimmune retinopathy (AIR) is a group of autoimmune retinal diseases that can cause blindness. The purpose of this study is to investigate the profiles of serum antiretinal antibodies (ARAs) and cytokines and their association with disease diagnosis as well as clinical features in AIR. The patients with presumed para (p) and non-paraneoplastic (np) AIR diagnosis, the patients with retinitis pigmentosa and bilateral uveitis as disease controls, and healthy subjects were prospectively enrolled. Western blotting and Luminex multiple cytokine assay/enzyme linked immunosorbent assay were used to determine the presence of serum ARAs and the concentration of cytokines, respectively. Kruskal-Wallis or chi square test was applied to compare the profiles of ARA and cytokines among various groups. The multilevel mixed-effect regression was used to investigate the association of ARA or cytokines with clinical features. No significant difference in the band number and subtypes of serum ARAs was found between AIR patients and their controls. AIR patients had higher concentration of serum IFN-ɤ, CXCL9, or CXCL10 than non-AIR controls. A positive correlation was found between increased number of ARAs and elevated TNF-α in np-AIR patients. Elevated pro-inflammatory cytokines or ARA subtypes (antibody against recoverin and α-enolase) were associated with worse retinal functions or anatomy, including visual acuity, visual field, ERG parameters, and central retinal thickness. The data of our study demonstrate that detection of serum ARAs has limited value in the diagnosis of AIR. Th1-type cytokines/chemokines or specific ARA subtypes are associated with pathogenesis and disease severity of the AIR.

Comparison of Clinical and Immunological Features of Para- and Non-Paraneoplastic Autoimmune Retinopathy in Chinese - A Series of 48 Cases

ABSTRACT Purpose To characterize and compare clinical and immunological features of para(p)-autoimmune retinopathy (AIR) and non-para(np)-AIR and to assess the clinical significance of the presence of serum anti-retinal antibodies (ARAs). Methods We retrospectively reviewed 48 Chinese patients with p-AIR or np-AIR who took comprehensive ophthalmic examinations and lab tests of the presence of serum ARAs. Results p-AIR patients differed from np-AIR patients in terms of disease progression, ocular inflammation, findings of OCT, FFA, and presence of ARAs. No significant difference was found in the band number of serum ARAs between AIR patients and healthy controls. The prevalence of antibodies to recoverin and ɑ-enolase in the sera of p-AIR was significantly higher than that of the healthy individuals. Conclusion While having many similar clinical signs, patients with p-AIR or np-AIR nevertheless displayed unique characteristics. Detection of ARAs subtypes, rather than their quantity, may be helpful in evaluating the conditions in the verified instances.

Rituximab Monotherapy versus Rituximab and Bortezomib Combination Therapy for Treatment of Non-paraneoplastic Autoimmune Retinopathy.

To study whether rituximab and bortezomib combination therapy is more effective than rituximab monotherapy in the treatment of non-paraneoplastic autoimmune retinopathy (npAIR). Retrospective case series involving six patients with npAIR, taking either rituximab and bortezomib combination therapy (three cases) or rituximab monotherapy (one case and two historical patients). Patients on both treatment regimens showed stability in most of the visual function parameters during the one year of follow-up. Combination therapy resulted in improvement of scotopic combined rod and cone a-wave and b-wave amplitudes in all eyes where they were available (four eyes); however, rituximab monotherapy resulted in only two eyes with stable scotopic combined rod and cone a-wave and b-wave amplitudes, while four eyes showed a decrease in both a- and b-wave amplitudes. The average improvement in b-wave amplitude (50.7% 29.4% [range, 25-90%]) was higher than the average improvement in a-wave amplitude (35.7% 9.74 [range, 25-63%]). No severe adverse effects were reported. Rituximab and bortezomib combination therapy may not be more effective than rituximab monotherapy in npAIR patients for most of the visual function parameters; however, this combination therapy may be more effective in improving scotopic combined rod and cone a- and b-wave amplitudes. This may indicate the higher efficacy of combination therapy when there is involvement of the inner retina.

Non-neoplastic autoimmune retinopathy - A rare disorder in unusual age group

<br>Nonparaneoplastic autoimmune retinopathy (npAIR) is a subtype in the spectrum of autoimmune retinopathy (AIR) disorders. Diagnosis is a challenging task due to its rare incidence, lack of epidemiological data, no accepted standardized diagnostic criteria, nonavailability of testing facilities, and economic factors. As per available data, npAIR is more common (60%) in females above 50 years, but in our case, it presented in a relatively young lady of 32 years. We report a rare disorder with diagnostic challenges presenting in an unusual age group.<br>

Atypical non-paraneoplastic autoimmune retinopathy with anti-recoverin antibodies: a case report

Autoimmune retinopathy (AIR) is caused by antiretinal antibodies damaging the retinal tissue, classified as paraneoplastic or non-paraneoplastic. Non-paraneoplastic AIR usually presents as a rapidly progressive and often asymmetrical visual loss with an unfavorable visual prognosis. Only a few cases of non-paraneoplastic AIR associated with anti-recoverin antibodies have been described in literature.

Anti–Interleukin-6 Antibodies for Autoimmune Retinopathy with Macular Edema

In this cohort of patients with non-paraneoplastic autoimmune retinopathy and cystoid macular edema (CME), treatment with anti-interleukin-6 antibodies was associated with reduced CME, partial restoration of the ellipsoid zone on optical coherence tomography, and a trend towards improved visual acuity.

Diagnosis and treatment of autoimmune retinopathy

: Autoimmune retinopathy (AIR) refers to both paraneoplastic and non-paraneoplastic forms of a rare, acquired retinal degeneration thought to be mediated by the production of antiretinal antibodies. However, the mechanisms underlying AIR pathogenesis are incompletely understood, and it remains a diagnosis of exclusion given the lack of definitive testing as well as its protean clinical presentation. This review summarizes the current literature on the epidemiology, diagnosis, and management of AIR, with a focus on non-paraneoplastic disease and the potential role of immunomodulatory therapy. A recent expert consensus statement on diagnosis and management of non-paraneoplastic AIR served as a framework for interpreting the limited data available, a process that was complicated by the small sample sizes, heterogeneity, and retrospective nature of these studies. Additional work is needed to characterize AIR patients on the basis of cytokine and immunogenetic profiling; to establish the pathogenicity of antiretinal antibodies; and to standardize treatment regimens as well as assessment of clinical outcomes.

Rituximab for autoimmune retinopathy: Results of a Phase I/II clinical trial.

PURPOSE:This prospective study evaluates whether rituximab is a safe and potentially effective treatment for nonparaneoplastic autoimmune retinopathy (npAIR).MATERIALS AND METHODS:Five npAIR patients were enrolled in a Phase I/II, prospective, nonrandomized, open-label, single-center study. All patients received a cycle of 1000 mg intravenous rituximab at weeks 0 and 2, with a second cycle of rituximab 6 to 9 months later. Clinical evaluation was performed at baseline, 6 and 12 weeks after each rituximab cycle, and then every 3 months for a total duration of 18 months. The primary outcome for this study was treatment success based on visual field and full-field electroretinography at 6 months. The secondary outcomes included treatment success at months 12 and 18, drug-related adverse events, changes in visual symptoms, and changes in quality of life.RESULTS:Two patients met criteria for treatment success: one based solely on electroretinography and the other based solely on visual field area, but treatment success was not sustained. Clinical response over the course of the 18-month study showed disease stabilization in three patients and treatment failure in two patients. There were no severe drug-related adverse events.CONCLUSION:This is the first clinical trial prospectively evaluating the effect of rituximab in npAIR and, although rituximab was well tolerated, there was no clear-cut clinical improvement conferred by B cell depletion with rituximab.

Non-paraneoplastic autoimmune retinopathy that developed in fellow eye 10\u2009years after onset in first eye: a case report

BackgroundEvidence-based criteria for the treatment of autoimmune retinopathy (AIR) have not been established. The pathology and clinical features of each antibody causing AIR, and its long-term course are still undetermined. We report our findings in a case of non-paraneoplastic AIR (npAIR) that developed in the fellow eye 10 years after the onset in the first eye.Case presentationOur patient had photophobia in both eyes and a rapidly progressing visual field defect in his right eye at the initial examination. He was diagnosed with non-paraneoplastic AIR based on the clinical findings and immunoblot analyses for anti-retinal antibodies, and he was treated with steroids. Ten years later, a visual field defect developed in the fellow eye, and a diagnosis of npAIR was made. Immunoblot analyses were positive for anti-α-enolase antibodies. He was treated with steroids, immunosuppressants, and plasma exchange. However, the response to the treatment was poor and both eyes eventually became blind.ConclusionsAs best we know, this is the first case report of npAIR that developed in the fellow eye over 10 years after the development in the first eye. Long-term follow-up and a search for tumor lesions are necessary in cases of npAIR. Further understanding of the long-term course of AIR can contribute to an understanding of the pathology and treatment of npAIR.

RECONSTITUTION OF THE ELLIPSOID ZONE WITH TOCILIZUMAB IN AUTOIMMUNE RETINOPATHY

To demonstrate improvement and stabilization of retinal findings, including recalcitrant cystoid macular edema, in a patient with nonparaneoplastic autoimmune retinopathy after treatment with tocilizumab, a humanized monoclonal antibody against soluble and membrane-bound IL-6 receptor. Observational case report. A 46-year-old woman was diagnosed with nonparaneoplastic autoimmune retinopathy and followed over 4 years on various immunosuppressive medications with worsening disease and recalcitrant cystoid macular edema. This report describes the rapid improvement and stabilization of her ocular disease once tocilizumab was initiated. Tocilizumab, a monoclonal antibody against the IL-6 receptor, was initiated at a dose of 8 mg/kg every 4 weeks. Cystoid macular edema was significantly decreased after just two infusions and nearly resolved after five infusions. Ellipsoid zone and outer retinal integrity also improved on optical coherence tomography. The patient tolerated the medication with limited side effects. Long-term immunosuppression is the cornerstone of treatment for nonparaneoplastic autoimmune retinopathy, although success is highly variable. We report a case treated with tocilizumab with dramatic improvement in refractory macular edema and reconstitution of the ellipsoid zone on optical coherence tomography in a patient with nonparaneoplastic autoimmune retinopathy. This case highlights the potential role of treatment with an IL-6 inhibitor in autoimmune retinopathy though further studies are needed.

Autoimmune retinopathy with positive anti-recoverin antibodies not associated with neoplasms: Case report

Abstract The case is presented of a non-paraneoplastic autoimmune retinopathy (AIR) with positive anti-recoverin autoantibodies. A 28-year-old woman presented with a rapidly progressive bilateral visual loss of 8 months onset. Funduscopic examination revealed diffuse fine mottled atrophic changes in both eyes. Fluorescein angiographic studies showed a pattern of mottled areas of early hyperfluorescence without leakage of dye. In the ocular coherence tomography it was observed that was a loss of external layers. The electroretinogram showed absence of rod and cone responses in the right eye, and diminished cone response associated to absence of rod response in the left eye. AIR was suspected, and empirical corticosteroid treatment was started while waiting for Western blot results, which was finally positive for recoverin, GAPDH, anti-alpha-enolase, and aldolase. The patient was able to be treated, and her visual acuity remained stable, but as soon as it was suspended, vision was completely lost in the right eye and reduced to hand movement in the left eye.

Retinopatía autoinmune con anticuerpos antirecoverina no asociado a neoplasia: a propósito de un caso

The case is presented of a non-paraneoplastic autoimmune retinopathy (AIR) with positive anti-recoverin autoantibodies.A 28-year-old woman presented with a rapidly progressive bilateral visual loss of 8 months onset. Funduscopic examination revealed diffuse fine mottled atrophic changes in both eyes. Fluorescein angiographic studies showed a pattern of mottled areas of early hyperfluorescence without leakage of dye. In the ocular coherence tomography it was observed that was a loss of external layers. The electroretinogram showed absence of rod and cone responses in the right eye, and diminished cone response associated to absence of rod response in the left eye. AIR was suspected, and empirical corticosteroid treatment was started while waiting for Western-blot results, which was finally positive for recoverin, GAPDH, anti-alpha-enolase, and aldolase. The patient was able to be treated, and her visual acuity remained stable, but as soon as it was suspended, vision was completely lost in the right eye and reduced to hand movement in the left eye.

Combination Treatment with Rituximab and Bortezomib in a Patient with Non-Paraneoplastic Autoimmune Retinopathy

ABSTRACT Purpose To describe outcomes of combined rituximab and bortezomib treatment for non-paraneoplastic autoimmune retinopathy. Case A 37-year-old female developed photopsias and reduced vision. Electroretinography, optical coherence tomography, and positive serum anti-retinal antibodies were consistent with autoimmune retinopathy. A negative malignancy work-up specified her non-paraneoplastic presentation. Given absence of response to periocular steroids, azathioprine, and methotrexate, a combination of rituximab and bortezomib was initiated as fifth-line therapy. Results There was no significant improvement in the patient’s symptoms or visual function following treatment. The full field electroretinogram amplitudes were reduced with progressive outer retinal degeneration evident on optical coherence tomography. Post-treatment anti-retinal antibody testing demonstrated the persistence of antibodies and revealed additional antibodies not previously detected. Conclusion Combined rituximab and bortezomib treatment did not result in significant clinical improvement and there was evidence of disease progression. Further prospective studies are required to assess the efficacy of immunotherapy in patients with autoimmune retinopathy.