Chronic relapsing inflammatory optic neuropathy (CRION): a manifestation of myelin oligodendrocyte glycoprotein antibodies.

BACKGROUND: Key clinical features of chronic relapsing inflammatory optic neuropathy (CRION) include relapsing inflammatory optic neuritis (ON) and steroid dependency, both of which have been reported among patients with myelin oligodendrocyte glycoprotein antibodies (MOG-Abs). We investigated the relevance of the presence of serum MOG-IgG with the current diagnostic criteria for CRION among patients with idiopathic inflammatory optic neuritis (iON). METHODS: Retrospective reviews of a database prospectively collated between 2011 and 2017 from the tertiary referral center for multiple sclerosis and neuromyelitis optica were performed. Sixty-four patients with iON, who did not meet the diagnostic criteria for multiple sclerosis, neuromyelitis optica (NMO) spectrum disorder with/without NMO-IgG, or acute disseminated encephalomyelitis and who had no symptomatic central nervous system (CNS) lesions other than on the optic nerve, were included from a cohort of 615 patients with inflammatory demyelinating diseases of the CNS. Fulfillment of the current diagnostic criteria for CRION, assay results for the serum IgG1 MOG-Ab, and characteristics of CRION patients with MOG-IgG were compared to those of non-CRION patients with MOG-IgG. RESULTS: Twelve iON patients fulfilled the current diagnostic criteria for CRION, 11 patients were positive for MOG-IgG, and one patient was borderline. Among the other 52 iON patients not meeting the criteria for CRION, 14 had relapsing disease courses and 38 had monophasic courses, of which MOG-IgG positivity were 0% and 29%, respectively. CRION patients with MOG-IgG had more relapsing disease courses (first steroid-dependent worsening/relapse in 2.3 months, range 0.4-7.0) and poorer optical coherence tomography outcomes at follow-up than non-CRION patients with MOG-IgG. However, patients in the two groups did not differ in terms of age of onset, sex, or steroid treatment duration after initial attack. CONCLUSIONS: CRION, according to the current diagnostic criteria, is a relapsing optic neuritis associated with MOG-IgG. Among iON patients with MOG-IgG, the absence of steroid-dependent attacks in the early stages of the disease may predict a long-term non-relapsing disease course and a more favorable outcome.

A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and α-enolase.

BACKGROUND: Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies. CASE PRESENTATION: A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient's optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient's serum detected autoantibodies against recoverin, CRMP-5, and α-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma. CONCLUSIONS: The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.

The 2023 revised diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a clinical entity characterized by elevated serum IgG4 concentrations and infiltration of IgG4-immunopositive plasmacytes in various organs, including ophthalmic lesions. Diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD) were established in 2014 and describe the most affected ocular adnexal tissues such as lacrimal glands, trigeminal nerves and extraocular muscles, but do not mention optic neuropathy, the most severe indication of ophthalmic lesions. We reviewed published case reports of optic neuropathy in IgG4-related disease (n = 44), and in many cases, decreased visual acuities recovered well following treatment such as systemic corticosteroids, rituximab, and orbital surgery. However, some patients did not recover, especially when pretreatment visual acuities were as low as light perception or less. Herein, we propose a 2023 revised diagnostic criteria for IgG4-ROD, which include a reminder not to overlook optic neuropathy. The 2014 diagnostic criteria specify mucosa-associated lymphoid tissue (MALT) lymphoma as an important differential diagnosis for the relationship between IgG4-ROD and orbital lymphoma. The 2023 revision directs physicians' attention toward lymphomas other than MALT lymphoma, considering that the 2014 criteria might have placed too much emphasis on MALT lymphoma.

Pancreatic neuroendocrine paraneoplastic optic neuropathy: confirmation with antibody to optic nerve and hepatic metastasis.

A 68-year-old woman presented with bilateral visual loss as the only clinical manifestation of an occult pancreatic nonsecretory neuroendocrine tumor (NET). The suspected diagnosis of paraneoplastic optic neuropathy was confirmed using immunofluorescence assays to demonstrate the presence of antibodies in the patient's serum that reacted with antigen(s) in the optic nerve and in the pancreatic NET hepatic metastasis. Treatment of the underlying cancer was followed by marked improvement in visual function.

Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss.

We report a 77-year-old Caucasian man with a 1-year complaint of unexplained visual loss and a 4-year history of prostate cancer. A complete ophthalmologic exam, Goldmann visual fields (GVFs), intravenous fluorescein angiography (IVFA), macular and disc optical coherence tomography (OCT), pattern-reversal visual evoked potentials (PVEPs), and flash electroretinograms (ERGs) were performed. On examination, visual acuity was reduced bilaterally. Fundus exam showed juxtapapillary changes (OS > OD) and, in OS, disc pallor, peripheral RPE dropout and whitish retinal discoloration along the arcades. OCTs were normal OU. Cancer-associated retinopathy (CAR) was suspected. A flash ERG was normal OD and markedly reduced and electronegative OS. An IVFA showed bilateral juxtapapillary staining and changes highly suggestive of sequelae of central retinal artery occlusion (CRAO) OS , in which a cilioretinal artery existed along the papillomacular bundle. GVFs showed bilateral blind spot enlargement and centrocecal scotomas, and PVEPs were delayed. These findings suggested cancer-associated optic neuropathy (CAON), confirmed by presence of anti-optic nerve autoantibodies (auto-Abs). No anti-retinal auto-Abs were found. CAON is a less common paraneoplastic manifestation than CAR and it is rarely observed in association with prostate cancer. A combination of visual function testing methods permitted the recognition, in this highly unusual case, of the concurrent presence of unilateral ERG changes most likely attributable to CRAO complications in OS, in all likelihood unrelated to CAON, and not to be confused with unilateral CAR. Auto-Ab testing in combination with visual function tests helps achieve a better understanding of the pathophysiology of vision loss in paraneoplastic visual syndromes.

[The current conception about the pathogenic mechanisms of the diabetic optical neuropathy development].

Diabetic Optical Neuropathy (DON) is the optical nerve damage induced by the Diabetes Mellitus. Optical nerve sufferings in Diabetes Mellitus were studied much less compare to the retinal changes. But according to the literature data, the DON has been detected in 7 to 24.3% of Diabetes Mellitus patients. That's why the investigators great interest refers to the optical nerve pathological changes pathways in Diabetes Mellitus studying. This article was focused to the up-to-date scientific views of the DON pathogenesis summarizing. Two basic ways of the DON pathogenesis were demonstrated: metabolic and vascular. The metabolic pathway was connected with the neural tissue damage induced by the diabetic changed metabolism. The vascular pathway was connected with the ischemia and endoneural blood flow malfunction.

The immune response in glaucoma: a perspective on the roles of oxidative stress.

Neurodegenerative insults and glial activation during glaucomatous neurodegeneration initiate an immune response to restore tissue homeostasis and facilitate tissue cleaning and healing. However, increasing risk factors over a chronic and cumulative period may lead to a failure in the regulation of innate and adaptive immune response pathways and represent a route for conversion of the beneficial immunity into a neuroinflammatory degenerative process contributing to disease progression. Oxidative stress developing through the pathogenic cellular processes of glaucoma, along with the aging-related component of oxidative stress, likely plays a critical role in shifting the physiological equilibrium. This review aims to provide a perspective on the complex interplay of cellular events during glaucomatous neurodegeneration by proposing a unifying scheme that integrates oxidative stress-related risk factors with the altered regulation of immune response in glaucoma.

Relationship between retinal nerve fiber layer thickness and driving ability in patients with human immunodeficiency virus infection.

BACKGROUND: The aim of this work is to study the possible association between retinal nerve fiber layer (NFL) thickness and driving ability. METHODS: Thirty-eight drivers including 22 HIV-positive (HIV+) and 16 age-matched HIV-negative controls participants underwent a full ophthalmologic evaluation, including assessment of retinal NFL thickness. In the undilated state with standard optical correction and under standard illumination they also completed a computer-based, wide field-of-view driving simulation in which they were to obey traffic laws, engage in crash avoidance, and pass slower automobiles. Crashes, speeding and traffic light tickets, and off-road excursions contributed to a weighted score of driving errors. RESULTS: HIV-seropositive participants had a significantly higher weighted error score than control participants (18.4 [9.2] vs. 11.1 [4.5], p = 0.006). NFL thickness was significantly correlated with driving errors (r = -0.51, p = 0.025); there was a trend for participants with a CD4 nadir <100 to have more errors than those with a nadir >100 (29.7 [13.2] vs. 19.3 [8.4], p = 0.056). The highest number of driving errors occurred in individuals with both CD4 <100 and NFL thickness <80. CONCLUSIONS: Driving ability may be impacted by reductions in retinal nerve fiber layer thickness. Physicians should consider the potential impact that more complex ophthalmologic conditions in HIV-infected patients may have on driving performance.

Combination Model of Thyrotrophin Receptor Antibody and Volumetric Orbital Apex Crowding Index as an Indicator of Dysthyroid Optic Neuropathy.

BACKGROUND: Dysthyroid optic neuropathy (DON) is one of the most serious vision-threatening complications of thyroid eye disease (TED); however, accurate and established diagnostic tools for DON are yet lacking. The present study was aimed at identifying new diagnostic factors for the accurate diagnosis of DON. METHODS: This retrospective cross-sectional study included 25 TED patients (50 eyes) with enlarged extraocular muscles, no previous anti-inflammatory therapy, and the absence of other vision-affecting diseases between May 2017 and August 2019. Baseline data, such as gender, age, ophthalmological history, thyroid disease and management, TED history including clinical features, management, and long-term results, ophthalmological examinations, serology examinations, and single-photon emission computed tomography/computed tomography (SPECT/CT) results, were extracted. The diagnostic criteria were as follows: (1) best-corrected visual acuity (BCVA) loss coexisting with either of the following-increased latency or reduction of amplitude on visual evoked potential (VEP), impaired color vision, visual field defects, contrast sensitivity impairment, and optic disk swelling-and (2) Barrett's index ≥ 60% in CT. Univariate and multivariate logistic regression analyses assessed the differences in age, gender, eyes, medical history, clinical activity, thyroid hormone and antibodies, uptake ratio (UR) of extraocular muscles in SPECT/CT, and volumetric orbital apex crowding index (VACI) using the generalized estimation equation. Consequently, the receiver operating characteristic curve (ROC) of the significant factors was constructed. RESULTS: Univariate analysis revealed significant differences in the clinical activity, free triiodothyronine (FT3), free thyroxine (FT4), thyrotrophin receptor antibody (TRAb) levels, the UR of superior and medial rectus, and VACI between DON and TED (without DON) groups. Multivariate regression analysis revealed that TRAb and VACI were significantly different. ROC analysis showed that the univariate models of TRAb or VACI and the multivariate model were effective indicators of DON, while the multivariate model had the highest area under the ROC curve. CONCLUSION: A combination of TRAb and VACI is an effective indicator for DON.

Anti-Neutrophil Cytoplasmic Antibody-Associated Ocular Manifestations in Japan: A Review of 18 Patients.

ABSTARCTPurpose: To investigate ocular manifestations in patients positive for serum anti-neutrophil cytoplasmic antibodies (ANCAs) in Japan.Methods: The clinical records of patients who had ocular manifestations and who were serum ANCA positive between 2011-2017 at Tokyo Medical and Dental University Hospital were retrospectively reviewed.Results: Eighteen patients were identified to be positive for serum ANCA and had ocular manifestations, including optic nerve involvement (50%), scleritis (27.8%), iritis (27.8%), retinal vasculitis (16.7%), oculomotor disorder (16.7%), and peripheral ulcerative keratitis (11.1%). Six patients had ANCA-associated vasculitis (AAV), including 5 patients with granulomatosis with polyangiitis and 1 patient with microscopic polyangiitis. Most patients with optic nerve involvement were myeloperoxidase-ANCA positive. Contrastingly, most patients with anterior segment involvement were proteinase-3-ANCA positive.Conclusion: Ocular manifestations were observed in some patients positive for serum ANCAs. Serum ANCA evaluation is useful for identifying the etiology of ocular inflammation and for diagnosing AAV, a life-threatening disease.

Optic, trigeminal, and facial neuropathy related to anti-neurofascin 155 antibody.

OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

A case of autoimmune-related retinopathy and optic neuropathy syndrome treated by autologous nonmyeloablative hematopoietic stem cell transplantation.

Autoimmune-related retinopathy and optic neuropathy (ARRON) syndrome is characterized by visual loss and often the presence of antibodies against retinal or optic nerve antigens in the absence of cancer. Limited success has been reported in treatment of ARRON syndrome with medications that suppress the immune system. In many patients, current strategies are insufficient to control the disease. A 47-year-old woman with progressive visual and hearing loss attributed to ARRON syndrome that was resistant to conventional therapies underwent autologous hematopoietic stem cell transplantation (HSCT). Clinical manifestations appeared to stabilize. This report suggests that autologous HSCT may have a therapeutic role in ARRON syndrome.

Distinct clinical characteristics of paraneoplastic optic neuropathy.

OBJECTIVE: Paraneoplastic optic neuropathy (PON) is relatively uncommon, and the visual outcomes and prognosis of this disease have not been well documented. The aim of this study was to investigate the clinical features and prognosis of antibody-mediated PON. METHODS: Clinical data were retrospectively collected from hospitalised patients diagnosed with PON at the Neuro-Ophthalmology Department at the Chinese People's Liberation Army General Hospital from January 2015 to June 2017. RESULTS: A total of seven patients (four females and three males, 13 involved eyes) were included with a mean age of 56.28±11.32 years (36-70 years). Simultaneous or early sequential bilateral eye involvement (5/7, 71.4%) was common in the patients with PON. Severe vision loss (≤0.1) was seen in 76.9% (10/13) of the eyes. There were 13 eyes in the acute phase of the disease, and six eyes presented with optic disc oedema. All patients had definite evidence of paraneoplastic-associated antibodies (three with serum positive for antiamphilphysin, one for anti-PNMA2 (Ma2/Ta), one for anti-Yo, one for anti-Ma2 and one for anti-CV2). All of the serum samples were negative for myelin oligodendrocyte glycoprotein antibody and two patients companied with seropositive for the aquaporin-4 antibody. Five patients had history of primary malignancy, including thyroid cancer, type B thymoma, testicular seminoma, cervical cancer and lung carcinoma. Two patients had positive paraneoplastic syndrome antibodies (anti-Yo and antiamphiphysin), but the solid tumour had not been found through a PET scan. Visual acuity in 9/13 (69.2%) eyes was below 0.1, and all of the patients survived to the follow-up with no metastatic lesions. CONCLUSIONS: PON is relative rare, with a predominance of bilateral involvement and more with a poor visual prognosis. Paraneoplastic antibody testing can contribute to the diagnosis of PON, distinct from other types of optic neuropathies, which can help doctors to find the primary cancer earlier to guide further treatment.

High-titer collapsin response-mediating protein-associated (CRMP-5) paraneoplastic optic neuropathy and Vitritis as the only clinical manifestations in a patient with small cell lung carcinoma.

Paraneoplastic optic neuropathy (PON) is a rare syndrome usually associated with small cell lung carcinoma. In the 27 rigorously reported cases, neurologic manifestations other than visual loss have been present in all but 2. In the single case in which vision improved in response to treatment of the cancer, the collapsin response-mediating protein (CRMP)-5 titer did not change, and the ophthalmic examination was not detailed. We describe a patient with optic neuropathy and vitritis as the only clinical manifestations of PON marked by an extremely high titer of CRMP-5 antibody. Treatment of the underlying small cell lung cancer coincided with resolution of the visual abnormalities and a dramatic decrease in the CRMP-5 titer.

Mechanisms of immune system activation in glaucoma: oxidative stress-stimulated antigen presentation by the retina and optic nerve head glia.

PURPOSE: Evidence supports the immune system activity accompanying glaucomatous neurodegeneration. This study aimed to determine the in vitro effects of reactive oxygen species (ROS) on the phenotype and antigen-presenting function of the retina and optic nerve head glia. METHODS: Cultures of rat retina and optic nerve head glia were treated with a mixture of ROS-generating compounds for 24 and 48 hours. Pretreated glial cells were then coincubated with syngeneic CD4(+) T cells for 48 hours. ROS generation and cell viability were assessed with the use of dihydroethidium and calcein assays, respectively. Flow cytometry and immunocytochemistry were used to determine major histocompatibility complex (MHC) class II molecules. In addition, functional experiments were performed to determine the proliferation and cytokine secretion of T cells using [(3)H]-thymidine incorporation and TNF-alpha assays, respectively. RESULTS: MHC class II molecules were upregulated on glial cells exposed to ROS. Compared with the control glia, glial cells in ROS-generating systems were found to be more potent inducers of T-cell activation in a cell density- and time-dependent manner, as assessed by increased T-cell proliferation (approximately threefold) and TNF-alpha secretion (approximately sixfold; P < 0.01). When an ROS scavenging treatment was applied, MHC class II upregulation on glial cells persisted, but antigen-mediated T-cell activation was significantly decreased (P < 0.01), indicating an additional costimulatory function of ROS during antigen presentation. CONCLUSIONS: These in vitro findings support that ROS regulate the immune response by stimulating the antigen-presenting ability of glial cells and functioning as costimulatory molecules for antigen presentation.