Blindness and ophthalmoplegia from metastatic breast carcinoma.

SUMMARY: We report a very rare complication from metastatic breast cancer of right-sided blindness and ophthalmoplegia in a 70-year-old female. Cavernous sinus syndrome, superior orbital fissure syndrome and complicated sinusitis were considered in the differential diagnosis but involvement of cranial nerves II, III, IV, VI and the ophthalmic division of V were consistent with an orbital apex syndrome. She had been diagnosed with breast carcinoma 10 years previously. This report highlights the correct clinical and diagnostic pathway with computed tomography (CT) scan of the brain and paranasal sinuses to evaluate for the presence and extent of pathology and biopsy route for any causative mass. In this patient, the mass in the right parasellar region and orbital apex with extension into the sphenoid sinus was amenable to transsphenoidal biopsy which showed features suggestive of metastatic breast carcinoma. She was treated with palliative whole brain radiotherapy without resolution of symptoms.

Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration.

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.

Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations.

Leber's congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.

Para-neoplastic optic neuritis presenting in a child with fusion positive localised para-testicular alveolar rhabdomyosarcoma.

We present the case of a 13 year old boy, with sudden onset painful unilateral visual loss, prior to commencing chemotherapy for alveolar rhabdomyosarcoma. Cases of para-neoplastic optic neuritis have been reported in adult cancer patients, however there are no published reports of this phenomenon occurring in children. Our patient had full recovery of his vision, following 6 weeks treatment with steroids, immunoglobulins and standard chemotherapy as per high risk arm of European pediatric soft tissue sarcoma group (EpSSG) Rhabdomyosarcoma (RMS) 2005 guidelines. Our case highlights that para-neoplastic optic neuritis can occur in children. In pediatric patients presenting with optic neuritis and normal auto-antibody screen, an occult or underlying tumor should be considered.

Ultrasonographic Halo Score in giant cell arteritis: association with intimal hyperplasia and ischaemic sight loss.

OBJECTIVES: We investigated the relationship between the ultrasonographic Halo Score and temporal artery biopsy (TAB) findings in GCA. METHODS: This is a prospective study including 90 patients suspected of having GCA. Ultrasonography of temporal/axillary arteries and a TAB were obtained in all patients at baseline. An experienced pathologist evaluated whether TAB findings were consistent with GCA, and whether transmural inflammation, giant cells and intimal hyperplasia were present. Ultrasonographic Halo Scores were determined. Receiver operating characteristic analysis was performed. RESULTS: Twenty-seven patients had a positive TAB, while 32 patients with a negative TAB received a clinical diagnosis of GCA after 6 months of follow-up. Patients with a positive TAB showed higher Halo Scores than patients with a negative TAB. The presence of intimal hyperplasia in the biopsy, rather than the presence of transmural inflammation or giant cells, was associated with elevated Halo Scores in patients with GCA. The Halo Score discriminated well between TAB-positive patients with and without intimal hyperplasia, as indicated by an area under the curve of 0.82 in the receiver operating characteristic analysis. Patients with a positive TAB and intimal hyperplasia more frequently presented with ocular ischaemia (40%) than the other patients with GCA (13-14%). CONCLUSION: The ultrasonographic Halo Score may help to identify a subset of GCA patients with intimal hyperplasia, a TAB feature associated with ischaemic sight loss.

Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome.

Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders.This article has an associated First Person interview with the first author of the paper.

Loss of CLN3, the gene mutated in juvenile neuronal ceroid lipofuscinosis, leads to metabolic impairment and autophagy induction in retinal pigment epithelium.

Juvenile neuronal ceroid lipofuscinosis (JNCL, aka. juvenile Batten disease or CLN3 disease) is a lysosomal storage disease characterized by progressive blindness, seizures, cognitive and motor failures, and premature death. JNCL is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene, whose function is unclear. Although traditionally considered a neurodegenerative disease, CLN3 disease displays eye-specific effects: Vision loss not only is often one of the earliest symptoms of JNCL, but also has been reported in non-syndromic CLN3 disease. Here we described the roles of CLN3 protein in maintaining healthy retinal pigment epithelium (RPE) and normal vision. Using electroretinogram, fundoscopy and microscopy, we showed impaired visual function, retinal autofluorescent lesions, and RPE disintegration and metaplasia/hyperplasia in a Cln3 ~ 1 kb-deletion mouse model [1] on C57BL/6J background. Utilizing a combination of biochemical analyses, RNA-Seq, Seahorse XF bioenergetic analysis, and Stable Isotope Resolved Metabolomics (SIRM), we further demonstrated that loss of CLN3 increased autophagic flux, suppressed mTORC1 and Akt activities, enhanced AMPK activity, and up-regulated gene expression of the autophagy-lysosomal system in RPE-1 cells, suggesting autophagy induction. This CLN3 deficiency induced autophagy induction coincided with decreased mitochondrial oxygen consumption, glycolysis, the tricarboxylic acid (TCA) cycle, and ATP production. We also reported for the first time that loss of CLN3 led to glycogen accumulation despite of impaired glycogen synthesis. Our comprehensive analyses shed light on how loss of CLN3 affect autophagy and metabolism. This work suggests possible links among metabolic impairment, autophagy induction and lysosomal storage, as well as between RPE atrophy/degeneration and vision loss in JNCL.

A novel c.287G>T NDP missense mutation in a Chinese family with Norrie disease.

BACKGROUND: Norrie disease is a rare X-linked recessive disorder in affected males. The typical features are congenital blindness, progressive hearing impairment, and, in some cases, some degree of mental retardation, microphthalmia, microcornea, growth failure, and seizures. Norrie disease is caused by mutations in the Norrie disease pseudoglioma gene (NDP), which encodes the Norrin protein that plays a crucial role in vascular development, neural cell differentiation, and proliferation in the retina and cerebellum. The aim of the present study was to identify the genetic cause of the disease and the phenotypic characteristics of the patients in an affected Chinese family. MATERIALS AND METHODS: A Chinese family with Norrie disease was studied, and clinical phenotypes of the proband were observed. With informed consent from the patients' family, blood samples from family members were collected, genomic DNA was extracted, and Sanger sequencing was performed to identify the disease-causing mutation. RE: sults: The c.287 G > T mutation of NDP was identified by Sanger sequencing and resulted in p.Cys96Phe. The pathogenicity prediction was performed by MutationTaster, Polyphen-2, SIFT, and PROVEAN, all of which suggested that the mutation is disease-causing and may be responsible for the phenotypes of Norrie disease. CONCLUSION: The c.287 G > T of NDP is a novel mutation responsible for Norrie disease in a Chinese family.

Macular Perfusion Changes and Ganglion Cell Complex Loss in Patients with Silicone Oil-related Visual Loss.

OBJECTIVE: The aim of this study was to investigate macular perfusion changes and ganglion cell complex (GCC) loss in patients with unexplained visual loss following vitrectomy and silicone oil (SO) tamponade, and to evaluate the correlation between retinal blood flow and GCC loss using optical coherence tomography angiography (OCTA) and optical coherence tomography (OCT). METHODS: This retrospective study included seven eyes (seven patients) with unexpected visual loss after vitrectomy and SO tamponade. OCTA was used to evaluate the alterations in retinal vessel density (VD) in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and radial peripapillary capillary plexus (RPCP). OCT was used to measure the thickness of GCC and retinal nerve fiber layer (RNFL). Medical records of patients were reviewed. RESULTS: Quantitative analysis of OCTA images revealed a significant reduction in SCP VD in the affected eyes compared with the controls (all sections P < 0.05). No difference was found in GCC thickness, but FLV (focal loss volume) and GLV (global loss volume) were significantly higher in the affected eyes (both P < 0.001). SCP VD was inversely correlated with FLV and GLV. CONCLUSIONS: Silicone oil-related severe visual loss was associated with superficial retinal microvasculature damage and ganglion cell apoptosis.

Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness.

Pathogenic variants of the KCNJ13 gene are known to cause Leber congenital amaurosis (LCA16), an inherited pediatric blindness. KCNJ13 encodes the Kir7.1 subunit that acts as a tetrameric, inwardly rectifying potassium ion channel in the retinal pigment epithelium (RPE) to maintain ionic homeostasis and allow photoreceptors to encode visual information. We sought to determine whether genetic approaches might be effective in treating blindness arising from pathogenic variants in KCNJ13. We derived human induced pluripotent stem cell (hiPSC)-RPE cells from an individual carrying a homozygous c.158G>A (p.Trp53∗) pathogenic variant of KCNJ13. We performed biochemical and electrophysiology assays to confirm Kir7.1 function. We tested both small-molecule readthrough drug and gene-therapy approaches for this "disease-in-a-dish" approach. We found that the LCA16 hiPSC-RPE cells had normal morphology but did not express a functional Kir7.1 channel and were unable to demonstrate normal physiology. After readthrough drug treatment, the LCA16 hiPSC cells were hyperpolarized by 30 mV, and the Kir7.1 current was restored. Similarly, we rescued Kir7.1 channel function after lentiviral gene delivery to the hiPSC-RPE cells. In both approaches, Kir7.1 was expressed normally, and there was restoration of membrane potential and the Kir7.1 current. Loss-of-function variants of Kir7.1 are one cause of LCA. Using either readthrough therapy or gene augmentation, we rescued Kir7.1 channel function in iPSC-RPE cells derived from an affected individual. This supports the development of precision-medicine approaches for the treatment of clinical LCA16.

Atypical location of unusual supratentorial neurenteric cyst: a case report.

We report a case of a right anterior clinoid process (ACP) neurenteric cyst which presented with gradual impairment of vision in the right eye. Imaging suggested an infective cystic lesion. In view of rapid visual loss urgent surgery was conducted. Erosion of the ACP was found from where white mucus like material was aspirated. The cyst wall was completely excised. Immunohistochemistry indicated an endodermal origin of the cyst.

Eye injury from electrical weapon probes: Mechanisms and treatment.

PURPOSE: While generally reducing morbidity and mortality, TASER® electrical weapons have risks associated with their usage, including burn injuries and head and cervical trauma associated with uncontrolled falls. The primary non-fatal complications appear to be significant eye injury but no analysis of the mechanisms or suggested treatments has been published. METHODS: We used a biomechanical model to predict the risk of eye injury as a function of distance from the weapon muzzle to the eye. We compared our model results to recently published epidemiological findings. We also describe the typical presentation and suggest treatment options. RESULTS: The globe rupture model predicted that a globe rupture can be expected (50% risk) when the eye is within 6 m of the muzzle and decreases rapidly beyond that. This critical distance is 9 m for lens and retinal damage which is approximately the range of the most common probe cartridges. Beyond 9 m, hyphema is expected along with a perforation by the dart portion of the probe. Our prediction of globe rupture out to 6 m (out of a typical range of 9 m) is consistent with the published risk of enucleation or unilateral blindness being 69 ±â€¯18%, with an eye penetration. CONCLUSIONS: Significant eye injury is expected from a penetration by an electrical weapon probe at close range. The risk decreases rapidly at extended distances from the muzzle. Not all penetrating globe injuries from electrical weapon probes will result in blindness.

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes.

Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. Our results suggest that deficiency of a ciliopathy protein could be mitigated by small-molecule compounds that target other ciliary components that interact with the ciliopathy protein.

Transplanted Donor- or Stem Cell-Derived Cone Photoreceptors Can Both Integrate and Undergo Material Transfer in an Environment-Dependent Manner.

Human vision relies heavily upon cone photoreceptors, and their loss results in permanent visual impairment. Transplantation of healthy photoreceptors can restore visual function in models of inherited blindness, a process previously understood to arise by donor cell integration within the host retina. However, we and others recently demonstrated that donor rod photoreceptors engage in material transfer with host photoreceptors, leading to the host cells acquiring proteins otherwise expressed only by donor cells. We sought to determine whether stem cell- and donor-derived cones undergo integration and/or material transfer. We find that material transfer accounts for a significant proportion of rescued cells following cone transplantation into non-degenerative hosts. Strikingly, however, substantial numbers of cones integrated into the Nrl-/- and Prph2rd2/rd2, but not Nrl-/-;RPE65R91W/R91W, murine models of retinal degeneration. This confirms the occurrence of photoreceptor integration in certain models of retinal degeneration and demonstrates the importance of the host environment in determining transplantation outcome.

Transient and localized optogenetic activation of somatostatin-interneurons in mouse visual cortex abolishes long-term cortical plasticity due to vision loss.

Unilateral vision loss through monocular enucleation (ME) results in partial reallocation of visual cortical territory to another sense in adult mice. The functional recovery of the visual cortex occurs through a combination of spared-eye potentiation and cross-modal reactivation driven by whisker-related, somatosensory inputs. Brain region-specific intracortical inhibition was recently recognized as a crucial regulator of the cross-modal component, yet the contribution of specific inhibitory neuron subpopulations remains poorly understood. Somatostatin (SST)-interneurons are ideally located within the cortical circuit to modulate sensory integration. Here we demonstrate that optogenetic stimulation of visual cortex SST-interneurons prior to eye removal decreases ME-induced cross-modal recovery at the stimulation site. Our results suggest that SST-interneurons act as local hubs, which are able to control the influx and extent of cortical cross-modal inputs into the deprived cortex. These insights critically expand our understanding of SST-interneuron-specific regulation of cortical plasticity induced by sensory loss.

Disseminated Cryptococcosis With Severe Increased Intracranial Pressure Complicated With Cranial Nerve Palsy in a Child.

Cryptococcosis is less common in children than in adults but remains an important cause of pneumonia and meningoencephalitis in both immunocompromised and immunocompetent patients. Intracranial hypertension commonly complicates cryptococcal meningitis and may cause significant visual and neurologic morbidity and mortality. Early and aggressive management of intracranial hypertension in accordance with established guidelines reduces the risk of long-term complications and death. In this case report, we present a 12-year-old girl with cryptococcal meningitis, pneumonitis and dermatitis complicated with cranial nerve palsy and loss of vision. She was successfully treated with serial cerebrospinal fluid drainage, antifungal and interferon gamma therapy.