Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

BACKGROUND: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. RESULTS: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 µm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.

Visual Dysfunction in Multiple Sclerosis and its Animal Model, Experimental Autoimmune Encephalomyelitis: a Review.

Visual disabilities in central nervous system autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are important symptoms. Past studies have focused on neuro-inflammatory changes and demyelination in the white matter of the brain and spinal cord. In MS, neuro-inflammatory lesions have been diagnosed in the visual pathway; the lesions may perturb visual function. Similarly, neuropathological changes in the retina and optic nerves have been found in animals with chronic EAE. Although the retina and optic nerves are immunologically privileged sites via the blood-retina barrier and blood-brain barrier, respectively, inflammation can occur via other routes, such as the uvea (e.g., iris and choroid) and cerebrospinal fluid in the meninges. This review primarily addresses the direct involvement of the blood-retina barrier and the blood-brain barrier in the development of retinitis and optic neuritis in EAE models. Additional routes, including pro-inflammatory mediator-filled choroidal and subarachnoid spaces, are also discussed with respect to their roles in EAE-induced visual disability and as analogues of MS in humans.

The role of lymphocytes and phagocytes in age-related macular degeneration (AMD).

Age-related macular degeneration (AMD) is a leading cause of visual impairment of the elderly population. Since AMD is a multifactorial age-related disease with various genetic risk factors, the understanding of its complex pathophysiology is still limited. However, animal experiments, genome-wide association data and the molecular profiling of AMD patient samples have highlighted a key role of systemic and local immune processes that contribute to this chronic eye disease. In this overview article, we concentrate on the role of lymphocytes and mononuclear phagocytes and their interplay in triggering a persistent immune response in the AMD retina. We preferentially review findings from human immune cell analyses and complement these with related findings in experimental models. We conclude that both immune cell types as their signaling network may be a rich source to identify novel molecular targets for immunomodulation in AMD.

Clinical Heterogeneity in Patients with Glutamate Decarboxylase Antibody.

OBJECTIVE: To explore the diversity and clinical features of anti-glutamate decarboxylase (GAD) antibody-associated neurological diseases. METHODS: Clinical data of a series of 5 patients positive for anti-GAD antibodies were retrospectively analyzed. RESULTS: All 5 patients were female, with a median age of 41.5 years (range 19-60 years). Their neurological symptoms included stiff-person syndrome (SPS), encephalitis, myelitis, cramp, visual loss, and paresthesia. Three patients (60%) were diagnosed with tumors, 2 cases of thymic tumor and 1 of breast cancer. On immunohistochemistry for tumor pathology, expression of GAD65 was found only in 1 patient. Four patients (80%) had abnormal brain MRI findings. All patients received immunotherapy and improved significantly after treatment, but 4 (80%) then experienced a relapse. CONCLUSIONS: Neurological manifestations in anti-GAD-positive patients are diverse and include SPS, encephalitis, myelitis, cramp, visual loss, and paresthesia.

Headache and vision changes in an elderly man with rheumatoid arthritis.

We present a case of an elderly, immunosuppressed patient with rheumatoid arthritis who was not appropriately vaccinated, and subsequently developed herpes zoster ophthalmicus, which initially presented similar to giant cell arteritis. Evidence-based vaccinations are integral in decreasing the incidence of preventable diseases and promoting optimal health at the individual and population level. Although the patient ultimately did not suffer any long-term adverse sequelae, this case highlights the importance of vaccination in the rheumatology setting, and to consider both inflammatory and infectious causes of headache and vision changes in the elderly.

Involvement of Innate Immune System in Late Stages of Inherited Photoreceptor Degeneration.

Retinitis pigmentosa (RP) is a group of inherited retinal degenerations that lead to progressive vision loss. Over 200 mutations in 60 different genes have been shown to cause RP. Given the diversity of genes and mutations that cause RP, corrective gene therapy approaches currently in development may prove both time-consuming and cost-prohibitive for treatment of all forms of RP. An alternative approach is to find common biological pathways that cause retinal degeneration in various forms of RP, and identify new molecular targets. With this goal, we analyzed the retinal transcriptome of two non-allelic forms of RP in dogs, rcd1 and xlpra2, at clinically relevant advanced stages of the two diseases. Both diseases showed very similar trends in changes in gene expression compared to control normal dogs. Pathway analysis revealed upregulation of various components of the innate immune system in both diseases, including inflammasome and complement pathways. Our results show that the retinal transcriptome at advanced stages of RP is very similar to that of other retinal degenerative diseases such as age-related macular degeneration and diabetic retinopathy. Thus, drugs and therapeutics already in development for targeting these retinopathies may also prove useful for the treatment of many forms of RP.

Lutein and Zeaxanthin Isomers in Eye Health and Disease.

Current evidence suggests lutein and its isomers play important roles in ocular development in utero and throughout the life span, in vision performance in young and later adulthood, and in lowering risk for the development of common age-related eye diseases in older age. These xanthophyll (oxygen-containing) carotenoids are found in a wide variety of vegetables and fruits, and they are present in especially high concentrations in leafy green vegetables. Additionally, egg yolks and human milk appear to be bioavailable sources. The prevalence of lutein, zeaxanthin, and meso-zeaxanthin in supplements is increasing. Setting optimal and safe ranges of intake requires additional research, particularly in pregnant and lactating women. Accumulating evidence about variable interindividual response to dietary intake of these carotenoids, based on genetic or metabolic influences, suggests that there may be subgroups that benefit from higher levels of intake and/or alternate strategies to improve lutein and zeaxanthin status.

Autoimmunity in visual loss.

There are a number of autoimmune disorders which can affect visual function. There are a very large number of mechanisms in the visual pathway which could potentially be the targets of autoimmune attack. In practice it is the retina and the anterior visual pathway (optic nerve and chiasm) that are recognised as being affected in autoimmune disorders. Multiple Sclerosis is one of the commonest causes of visual loss in young adults because of the frequency of attacks of optic neuritis in that condition, however the basis of the inflammation in Multiple Sclerosis and the confirmation of autoimmunity is lacking. The immune process is known to be highly unusual in that it is not systemic and confined to the CNS compartment. Previously an enigmatic partner to Multiple Sclerosis, Neuromyelitis Optica is now established to be autoimmune and two antibodies - to Aquaporin4 and to Myelin Oligodendrocyte Glycoprotein - have been implicated in the pathogenesis. The term Chronic Relapsing Inflammatory Optic Neuropathy is applied to those cases of optic neuritis which require long term immunosuppression and hence are presumed to be autoimmune but where no autoimmune pathogenesis has been confirmed. Optic neuritis occurring post-infection and post vaccination and conditions such as Systemic Lupus Erythematosus and various vasculitides may cause direct autoimmune attack to visual structures or indirect damage through occlusive vasculopathy. Chronic granulomatous disorders such as Sarcoidosis affect vision commonly by a variety of mechanisms, whether and how these are placed in the autoimmune panoply is unknown. As far as the retina is concerned Cancer Associated Retinopathy and Melanoma Associated Retinopathy are well characterised clinically but a candidate autoantibody (recoverin) is only described in the former disorder. Other, usually monophasic, focal retinal inflammatory disorders (Idiopathic Big Blind Spot Syndrome, Acute Zonal Occult Outer Retinopathy and Acute Macular Neuroretinitis) are of obscure pathogenesis but an autoimmune disorder of the post-infectious type is plausible. Visual loss in autoimmunity is an expanding field: the most significant advances in research have resulted from taking a well characterised phenotype and making educated guesses at the possible molecular targets of autoimmune attack.

Clinicopathological features in anterior visual pathway in neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin-4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia-neuron interaction in NMOsd. METHODS: Thirty Japanese patients with serologically verified NMOsd were assessed with a neuro-ophthalmological study. Using 27 tissue blocks from 13 other cases of NMOsd, we performed neuropathological analysis of glial and neuroaxonal involvement in the AVP. RESULTS: The AVP involvement in NMOsd was characterized by the following, compared to multiple sclerosis: (1) longitudinally extensive optic neuritis (ON); (2) more severe visual impairment and worse prognosis for ON; (3) unique AQP4 dynamics, including loss of AQP4 immunoreactivity on astrocytes with complement activation in ON lesions, loss of AQP4 immunoreactivity on Müller cells with no deposition of complement in the retinas, and densely packed AQP4 immunoreactivity on astrocytes in gliosis of secondary anterograde/retrograde degeneration in the optic nerves and retinal nerve fiber layer (RNFL); and (4) more severe neurodegeneration, including axonal accumulation of degenerative mitochondria and transient receptor potential melastatin 4 channel with complement-dependent astrocyte pathology in ON lesions, mild loss of horizontal cells, and RNFL thinning and loss of ganglion cells with abundance of AQP4(+) astrocytes, indicating secondary retrograde degeneration after ON. INTERPRETATION: Severe and widespread neuroaxonal damage and unique dynamics of astrocytes/Müller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd.

Acute macular neuroretinopathy associated with systemic lupus erythematosus.

Acute macular neuroretinopathy (AMN) is a rare disorder that presents with abrupt visual change with wedge-shaped or flower-like lesions pointing towards the fovea. Ischemic insults to the retinal capillary plexus may be important for development of this disease. While many case reports have been published on AMN, none have described AMN in association with systemic lupus erythematosus (SLE). Here, we report a case of AMN associated with newly-diagnosed SLE. We speculate that in patients with lupus flares, immune complex-mediated vascular injury and microvascular thrombosis may disrupt the deep retinal capillary network, causing ischemic damages to the outer retina and leading to the development of AMN. AMN can develop in patients with lupus flares, and must be considered as an SLE-associated ophthalmologic complication. To the best of our knowledge, this is the first case report of AMN associated with SLE.

Latest updates on antiretinal autoantibodies associated with vision loss and breast cancer.

Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic disorder of the retina that is frequently associated with breast cancer in pre- and postmenopausal women older than 50 years. In this review, we will give an update on the current knowledge regarding the association of antiretinal autoantibodies with the breast-CAR syndrome. Women with breast cancer and visual indications of CAR have a significantly increased incidence of autoantibodies (AAbs) against retinal proteins when compared to healthy women. The onset of visual loss in association with antiretinal AAbs peaks 2 to 3 years after the clinical diagnosis of breast cancer. Differences in severity of symptoms between women with or without antiretinal AAbs are evident, revealing more unfavorable presentation in seropositive women. The incidence of CAR in breast cancer is likely to rise as the survival time of patients with breast cancer increases; consequently, a prediction of breast-CAR based on autoimmunity to individual retinal antigens, or to panels of antigens (signatures), is clinically important.

Clinical features of IgG4-related dacryoadenitis.

BACKGROUND: To elucidate the clinical characteristics of IgG4-related dacryoadenitis. METHODS: Clinical features, laboratory findings, radiological findings, associated diseases, treatment, and prognosis were prospectively examined in 12 patients (seven men, five women; mean age, 60.9 ± 15.1 years) with IgG4-related dacryoadenitis. RESULTS: In addition to eyelid swelling, other ophthalmologic symptoms were observed in seven patients, including diplopia (n = 4), ptosis (n = 2), visual field disturbance (n = 2), eye pain (n = 2), decrease of visual acuity (n = 2), eye-movement disturbance (n = 1), dry eye (n = 1), corneal ulcer (n = 1), and epiphora (n = 1). Swelling of the lacrimal glands was bilateral in half of the patients. Other IgG4-related diseases were present in nine patients, including sialadenitis (n = 5), autoimmune pancreatitis (n = 4), retroperitoneal fibrosis (n = 2), and lymphadenopathy (n = 8). Serum IgG4 levels were significantly higher in patients with other IgG4-related disease (1070 ± 813 mg/dl) than in those without (197 ± 59 mg/dl, p = 0.017). Allergic histories and elevated serum IgE levels were each detected in six patients. Eight patients showed inflammatory extension beyond the lacrimal gland, such as thickened rectus muscle (n = 6), inflammation of the optic nerve (n = 2), and retrobulbar inflammation (n = 3). Steroid therapy was effective in seven patients, but dacryoadenitis relapsed in two patients with markedly higher serum IgG4 levels and autoimmune pancreatitis. CONCLUSIONS: IgG4-related dacryoadenitis showed various ophthalmologic symptoms due to extensive inflammation beyond the lacrimal gland, frequent association with other IgG4-related disease or allergic phenomena, and steroid responsiveness.

[Biological adaptation and immune status of preschool children with visual function disorders in conditions of preschool educational institutions of compensating type].

For implementation of a comprehensive approach in the elaboration of preventive and corrective measures in children with impaired visual function in conditions of preschool educational institutions of compensating type there were studied adaptation reserves of their organism, as well as indices of immune status. Biological adaptation was studied with the help ofcardiointervalography in 111 children aged 6-7years. With the use of ELISA 88 children were examined in terms of IgA, IgM, IgG, slgA in saliva.

HLA associations in chronic vision threatening uveitis.

Chronic uveitides can lead to serious sequlae over time including blindness. Human Leukocyte antigen (HLA) plays an important role in immunological response of the eyes. Some of these uveitides are associated with certain Human Leukocyte antigen (HLA) types. This article reviews these relationships and their significance.

Visual loss from scleritis in C-ANCA-positive microscopic polyangiitis.

Scleritis is an inflammation of the outer eye coating that manifests with redness and ocular pain, and tends to be more severe when associated with a systemic collagen disease. Antineutrophil cytoplasmic antibody (ANCA)-positive microscopic polyangiitis is an autoimmune, multisystem, chronic disease characterised by damage to the endothelial lining of small vessels, and can be associated with severe scleritis that necessitates early aggressive therapy to prevent severe ocular complications.

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.